Clinical trial NCT04057573
Conditions: Non-segmental Vitiligo
Keywords: Vitiligo non-segmental JAK inhibitor
Sponsor: Incyte Corporation
Start date: 2019-10-03; Completion date: 2021-10-01
Enrollment: 344 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
The purpose of this study is to evaluate the efficacy and safety of ruxolitinib cream in adolescent and adult participants with non-segmental vitiligo for whom total body involved vitiligo area (facial and nonfacial) does not exceed 10% body surface area (BSA).

Detailed description:

Arms: arm 1: Participants applied ruxolitinib 1.5% cream twice daily (BID) for 24 weeks. arm 2: Participants applied matching vehicle cream BID for 24 weeks. arm 3: Participants who completed the Week 24 assessments with no safety concerns could continue into the 28-week Treatment-Extension Period. Participants who applied ruxolitinib cream 1.5% BID during the Double-Blind Period continued to apply ruxolitinib cream 1.5% BID for an additional 28 weeks in the Treatment-Extension Period. arm 4: Participants who completed the Week 24 assessments with no safety concerns could continue into the 28-week Treatment-Extension Period. Participants who applied vehicle cream BID during the Double-Blind Period applied ruxolitinib cream 1.5%m BID for 28 weeks in the Treatment-Extension Period.
Interventions: intervention 1: Ruxolitinib cream intervention 2: Vehicle
Intervention descriptions: intervention 1: Ruxolitinib cream is a topical formulation applied as a thin film to affected areas. intervention 2: Vehicle cream is a topical formulation applied as a thin film to affected areas.

Protocol documents:
Prot_000.pdf: 
Official Title: 
Topical Ruxolitinib Evaluation in Vitiligo Study 2 (TRuE-V2): A Phase 3, Double-Blind, 
Randomized, Vehicle-Controlled, Efficacy and Safety Study of Ruxolitinib Cream 
NCT Number: 
NCT04057573 
Document Date: 
Clinical Study Protocol Version 1: 23 June 2019
Followed by an Extension Period in Participants With Vitiligo


Clinical Study Protocol 
INCB 18424-307 
Topical Ruxolitinib Evaluation in Vitiligo Study 2 
(TRuE-V2) 
A Phase 3, Double-Blind, Randomized, Vehicle-Controlled, Efficacy 
and Safety Study of Ruxolitinib Cream Followed by an Extension Period 
in Participants With Vitiligo 
Product: 
Ruxolitinib Cream 
IND Number: 
77,101 
EudraCT Number: 
2019-000847-28 
Phase of Study: 
3 
Sponsor: 
Incyte Corporation 
1801 Augustine Cut-Off 
Wilmington, DE 19803 
Original Protocol: 
23 JUN 2019 
This study will be performed in accordance with ethical principles that have their origin in the Declaration of 
Helsinki and conducted in adherence to the study Protocol, applicable Good Clinical Practices, and applicable laws 
and country-specific regulations in which the study is being conducted. 
The 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 18424-307 Protocol (dated 23 JUN 2019) and agree to conduct the study as 
outlined.  I agree to maintain the confidentiality of all information received or developed in 
connection with this Protocol. 
(Printed Name of Investigator) 
(Signature of Investigator) 
(Date) 
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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ..........................................................................................................8 
1. 
PROTOCOL SUMMARY ..........................................................................................10 
2. 
INTRODUCTION ......................................................................................................18 
2.1. 
Epidemiology of Vitiligo ............................................................................................18 
2.2. 
Current Treatment and Unmet Need in Vitiligo .........................................................19 
2.3. 
Role of Janus Kinases in Vitiligo ...............................................................................20 
2.4. 
Ruxolitinib Cream ......................................................................................................21 
 
21 
2.4.2. 
Clinical Experience .....................................................................................................22 
 
22 
2.4.2.2. 
Efficacy of Ruxolitinib Cream ....................................................................................24 
 
28 
 
28 
 
28 
 
29 
3. 
OBJECTIVES AND ENDPOINTS ............................................................................30 
4. 
STUDY DESIGN .......................................................................................................33 
4.1. 
Overall Design ............................................................................................................33 
4.2. 
Overall Study Duration ...............................................................................................33 
4.3. 
Study Termination ......................................................................................................34 
5. 
STUDY POPULATION .............................................................................................34 
5.1. 
Inclusion Criteria ........................................................................................................34 
5.2. 
Exclusion Criteria .......................................................................................................35 
5.3. 
Lifestyle Considerations .............................................................................................37 
5.4. 
Screen Failures ............................................................................................................37 
5.5. 
Replacement of Participants .......................................................................................37 
6. 
STUDY TREATMENT ..............................................................................................38 
6.1. 
Study Treatment Application ......................................................................................38 
6.1.1. 
Application During the Double-Blind Vehicle-Controlled Treatment Period ...........39 
6.1.2. 
Application During the Treatment Extension Period .................................................39 
6.2. 
Preparation, Handling, and Accountability ................................................................39 
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6.3. 
Measures to Minimize Bias:  Randomization and Blinding .......................................40 
6.4. 
Study Treatment Compliance .....................................................................................40 
6.5. 
Dose Modifications .....................................................................................................41 
6.5.1. 
Criteria and Procedures for Application Interruptions of Study Drug .......................41 
6.5.2. 
Criteria for Permanent Discontinuation of Study Drug Due to an Adverse 
Event ...........................................................................................................................42 
6.6. 
Concomitant Medications and Procedures .................................................................42 
 
43 
 
43 
 
44 
6.8. 
Treatment After the End of the Study .........................................................................44 
7. 
DISCONTINUATION OF STUDY TREATMENT AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ..................................................................45 
7.1. 
Discontinuation of Study Treatment ...........................................................................45 
7.1.1. 
Reasons for Discontinuation .......................................................................................45 
7.1.2. 
Discontinuation Procedures ........................................................................................45 
7.2. 
Participant Withdrawal From the Study .....................................................................46 
7.3. 
Lost to Follow-Up.......................................................................................................46 
8. 
STUDY ASSESSMENTS AND PROCEDURES ......................................................47 
8.1. 
Administrative and General Procedures .....................................................................47 
8.1.1. 
Informed Consent Process ..........................................................................................47 
8.1.2. 
Screening Procedures ..................................................................................................48 
8.1.3. 
Interactive Response Technology Procedure ..............................................................48 
8.1.4. 
Distribution of Study Reminder Cards and Diaries ....................................................48 
8.1.5. 
Demography and Medical History ..............................................................................49 
8.1.5.1. 
Demographics and General Medical History .............................................................49 
8.1.5.2. 
Disease Characteristics and Treatment History ..........................................................49 
8.2. 
Efficacy Assessments .................................................................................................49 
8.2.1. 
Body Surface Area ......................................................................................................49 
8.2.2. 
Vitiligo Area Scoring Index ........................................................................................49 
8.2.3. 
Physician’s Global Vitiligo Assessment (Facial) .......................................................50 
8.2.4. 
Physician’s Global Vitiligo Assessment (Total Body) ...............................................50 
8.2.5. 
Photography ................................................................................................................51 
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8.2.6. 
Patient-Reported Outcomes ........................................................................................51 
8.2.6.1. 
Vitiligo Noticeability Scale ........................................................................................52 
8.2.6.2. 
Color-Matching Question ...........................................................................................52 
8.2.6.3. 
Patient Global Impression of Change-Vitiligo (Facial) ..............................................52 
8.2.6.4. 
Patient Global Impression of Change-Vitiligo (Total Body) .....................................52 
8.2.6.5. 
Dermatology Life Quality Index ................................................................................53 
8.2.6.6. 
WHO-5 .......................................................................................................................53 
8.2.6.7. 
Treatment Satisfaction Questionnaire for Medication ................................................54 
8.2.6.8. 
VitiQoL .......................................................................................................................54 
8.2.6.9. 
Hospital Anxiety and Depression Scale .....................................................................54 
8.3. 
Safety Assessments .....................................................................................................54 
8.3.1. 
Adverse Events ...........................................................................................................54 
8.3.2. 
Physical Examinations ................................................................................................55 
8.3.3. 
Vital Signs ..................................................................................................................55 
8.3.4. 
Electrocardiograms .....................................................................................................55 
8.3.5. 
Laboratory Assessments .............................................................................................56 
8.3.5.1. 
Pregnancy Testing ......................................................................................................57 
8.3.5.2. 
Serology ......................................................................................................................58 
8.4. 
Pharmacokinetic Assessments ....................................................................................58 
8.5. 
Pharmacodynamic and Translational Assessments ....................................................58 
8.6. 
Unscheduled Visits .....................................................................................................58 
8.7. 
End of Treatment and/or Early Termination ..............................................................58 
8.8. 
Safety Follow-Up ........................................................................................................59 
9. 
ADVERSE EVENTS:  DEFINITIONS AND PROCEDURES FOR 
RECORDING, EVALUATING, FOLLOW-UP, AND REPORTING ......................59 
9.1. 
Definition of Adverse Event .......................................................................................59 
9.2. 
Definition of Serious Adverse Event ..........................................................................60 
9.3. 
Recording and Follow-Up of Adverse Events and/or Serious Adverse Events .........61 
9.4. 
Reporting of Serious Adverse Events .........................................................................63 
9.5. 
Emergency Unblinding of Treatment Assignment .....................................................64 
9.6. 
Pregnancy ...................................................................................................................65 
9.7. 
Warnings and Precautions ..........................................................................................65 
9.8. 
Product Complaints ....................................................................................................65 
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9.9. 
Treatment of Overdose ...............................................................................................66 
10. 
STATISTICS ..............................................................................................................66 
10.1. 
Sample Size Determination ........................................................................................66 
10.2. 
Populations for Analysis .............................................................................................66 
10.3. 
Statistical Analyses .....................................................................................................67 
10.3.1. 
Efficacy Analyses .......................................................................................................68 
10.3.1.1. 
Primary Analysis ........................................................................................................68 
10.3.1.2. 
Key Secondary Analysis .............................................................................................69 
10.3.1.3. 
Secondary Analysis ....................................................................................................69 
10.3.2. 
Safety Analyses ..........................................................................................................69 
10.4. 
Analysis Plan ..............................................................................................................70 
11. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS ..................................................................................................70 
11.1. 
Investigator Responsibilities .......................................................................................70 
11.2. 
Data Management .......................................................................................................71 
11.3. 
Data Privacy and Confidentiality of Study Records ...................................................73 
11.4. 
Financial Disclosure ...................................................................................................73 
11.5. 
Publication Policy .......................................................................................................73 
11.6. 
Study and Site Closure................................................................................................74 
12. 
REFERENCES ...........................................................................................................75 
APPENDIX A. INFORMATION REGARDING EFFECTIVENESS OF 
CONTRACEPTIVE METHODS ...............................................................................78 
APPENDIX B. PROTOCOL AMENDMENT SUMMARY OF CHANGES ............................79 
 
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LIST OF TABLES 
Table 1: 
Primary and Secondary Objectives and Endpoints .....................................................10 
Table 2: 
Key Study Design Elements .......................................................................................11 
Table 3: 
Schedule of Activities:  Double-Blind, Vehicle-Controlled Treatment Period 
(Day 1-Week 24) ........................................................................................................13 
Table 4: 
Schedule of Activities:  Treatment Extension Period (Week 28-Week 52) ...............16 
 
23 
 
24 
 
27 
Table 8: 
Objectives and Endpoints ...........................................................................................30 
Table 9: 
Study Treatment Information .....................................................................................38 
Table 10: Guidelines for Interruption and Restarting of Study Drug .........................................42 
Table 11: Facial Physician's Global Vitiligo Assessment Scale .................................................50 
Table 12: Total Body Physician's Global Vitiligo Assessment Scale ........................................51 
Table 13: Required Laboratory Analytes ....................................................................................57 
Table 14: Powering for Primary and Key Secondary Endpoints ................................................66 
Table 15: Populations for Analysis .............................................................................................67 
 
LIST OF FIGURES 
Figure 1: 
Study Design Schema .................................................................................................12 
 
23 
Figure 3: 
INCB 18424-211 Study Schema ................................................................................25 
 
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LIST OF ABBREVIATIONS  
The following abbreviations and special terms are used in this clinical study Protocol. 
Abbreviations and 
Special Terms 
Definition 
2D 
2-dimensional 
3D 
3-dimensional 
AA 
alopecia areata 
AD 
atopic dermatitis 
AE 
adverse event 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
BID 
twice daily 
BSA 
body surface area 
CDLQI 
Children’s Dermatology Life Quality Index 
CFR 
Code of Federal Regulations 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
cytochrome P450 
DLQI 
Dermatology Life Quality Index 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EDC 
electronic data capture 
EOS 
end of study 
EOT 
end of treatment 
F-BSA 
facial body surface area 
F-PaGIC-V 
facial assessment of Patient Global Impression of Change-Vitiligo 
F-PaGVA 
facial assessment of Patient's Global Vitiligo Assessment 
F-PhGVA 
facial assessment of Physician Global Vitiligo Assessment 
FSH 
follicle-stimulating hormone 
F-VASI 
Face Vitiligo Area Scoring Index 
F-VASI25/50/75/90 
≥ 25%/ 50%/ 75%/ 90% improvement from baseline in Face Vitiligo Area 
Scoring Index score 
GCP 
Good Clinical Practice 
HADS 
Hospital Anxiety and Depression Scale 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
human immunodeficiency virus 
IB 
Investigator's Brochure 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
ID 
identification 
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Abbreviations and 
Special Terms 
Definition 
IEC 
independent ethics committee 
IRB 
institutional review board 
IRT 
interactive response technology 
ITT 
intent to treat 
JAK 
Janus kinase 
LOCF 
last observation carry forward 
MI 
multiple imputation 
MMRM 
mixed-effect model repeat measurement 
NB-UVB 
narrow-band ultraviolet B 
Pa-GIC-V 
Patient Global Impression of Change-Vitiligo 
PhGVA 
Physician Global Vitiligo Assessment 
PK 
pharmacokinetic 
PP 
per protocol 
PUVA 
psoralen and ultraviolet A 
QD 
once daily 
SAE 
serious adverse event 
SD 
standard deviation 
SoA 
schedule of assessments 
SOP 
standard operating procedure 
STAT 
signal transducer and activator of transcription  
SUSAR 
suspected unexpected adverse reaction 
T-BSA 
total body surface area 
TCS 
topical corticosteroid 
TEAE 
treatment-emergent adverse event 
T-PaGIC-V 
total body assessment of Patient Global Impression of Change-Vitiligo 
T-PaGVA 
total body assessment of Patient's Global Vitiligo Assessment 
T-PhGVA 
total body assessment of Physician Global Vitiligo Assessment 
TSH 
thyroid-stimulating hormone 
TSQM 
Treatment Satisfaction Questionnaire for Medication 
T-VASI 
total body Vitiligo Area Scoring Index 
T-VASI25/50/75/90 
≥ 25%/ 50%/ 75%/ 90% improvement in total body Vitiligo Area Scoring Index 
TYK 
tyrosine kinase 
ULN 
upper limit of normal 
UV 
ultraviolet 
VASI 
Vitiligo Area Scoring Index 
VitiQoL 
Vitiligo-specific quality of life 
VNS 
Vitiligo Noticeability Scale 
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1.
PROTOCOL SUMMARY
Protocol Title:  A Phase 3, Double-Blind, Randomized, Vehicle-Controlled, Efficacy and Safety 
Study of Ruxolitinib Cream Followed by an Extension Period in Participants With Vitiligo 
Protocol Number:  INCB 18424-307
Objectives and Endpoints: 
Table 1 presents the primary, key secondary, and selected secondary objectives and endpoints. 
Table 1: 
Primary and Secondary Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
To evaluate the efficacy of ruxolitinib cream in 
participants with vitiligo. 
• Proportion of participants achieving F-VASI75 at
Week 24.
Key Secondary 
To further assess the efficacy of ruxolitinib 
cream. 
• Percentage change from baseline in F-BSA at
Week 24.
• Proportion of participants achieving F-VASI50 at
Week 24.
• Proportion of participants achieving F-VASI75 at
Week 52.
• Proportion of participants achieving F-VASI90 at
Week 24.
• Proportion of participants achieving F-VASI90 at
Week 52.
• Proportion of participants achieving T-VASI50 at
Week 24.
• Proportion of participants achieving T-VASI50 at
Week 52.
• Proportion of participants achieving T-VASI75 at
Week 52.
• Proportion of participants achieving a VNS of
“4 – A lot less noticeable” or “5 – No longer
noticeable” at Week 24.
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Table 1: 
Primary and Secondary Objectives and Endpoints (Continued) 
Objectives 
Endpoints 
Selected Secondary 
To evaluate the safety and tolerability of 
ruxolitinib cream. 
• The frequency, duration, and severity of AEs; 
physical examinations; vital signs; and laboratory 
data for hematology, serum chemistry, and 
urinalysis. 
To further assess the efficacy of ruxolitinib 
cream. 
• Proportion of participants achieving 
F-VASI25/50/75/90 during the treatment period 
(double-blind and treatment extension periods).  
• Proportion of participants achieving 
T-VASI25/50/75/90 during the treatment period 
(double-blind and treatment extension periods).  
• Proportion of participants in each category of VNS 
during the treatment period (double-blind and 
treatment extension periods). 
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 3 
Clinical Indication 
Vitiligo 
Population 
Males and females, aged ≥ 12 years, who have vitiligo with ≥ 0.5% BSA on the 
face, ≥ 0.5 F-VASI, ≥ 3% BSA on nonfacial areas, and ≥ 3 T-VASI.  Total 
body vitiligo area (facial and nonfacial) should not exceed 10% BSA. 
Number of 
Participants 
Approximately 300 participants will be randomized 2:1 (ruxolitinib cream 1.5% 
BID:vehicle). 
Study Design 
Randomized, double-blind, vehicle-controlled, with a treatment extension 
period. 
Estimated 
Duration of Study 
Participation 
Screening:  Up to 32 days 
Double-blind period:  24 weeks 
Treatment extension period:  28 weeks 
Safety follow-up:  30 days after last application of study medication or last 
study visit 
Total:  Up to approximately 60 weeks 
The study design is shown in Figure 1.  The SoA is detailed in Table 3 (for the double-blind 
period) and Table 4 (for the treatment extension period).  Adherence to the study design 
requirements, including those specified in the SoA, is essential and required for study conduct. 
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Figure 1: 
Study Design Schema 
This is a randomized, vehicle-controlled study in adolescent and adult participants (age 
≥ 12 years) with non-segmental vitiligo who have depigmented area including ≥ 0.5% BSA on 
the face, ≥ 0.5 F-VASI, ≥ 3% BSA on nonfacial areas, and ≥ 3 T-VASI.  Total body involved 
vitiligo area (facial and nonfacial) should not exceed 10% BSA.  Approximately 300 participants 
will be randomized 2:1 to receive initial study treatment (ruxolitinib cream 1.5% BID:vehicle; 
applied to depigmented vitiligo areas on the face and body up to 10% total BSA) for 24 weeks 
(see Figure 1).  Participants will be stratified by age (≤ 40 or > 40 years) and skin type 
(Fitzpatrick scale Type I and II vs Type III, IV, V, and VI).  Adolescents (≥ 12 to < 18 years) 
will make up at least 10% of the study population, and no more than 50% of participants will be 
> 40 years old. 
After completion of the Week 24 assessments, participants will be offered the opportunity to 
receive an additional 28 weeks of treatment extension with ruxolitinib cream 1.5% BID.  To be 
eligible for the treatment extension, participants must have completed the baseline and Week 24 
visit assessments, be compliant with study procedures, and not have any safety issues.  The total 
treated area should not exceed 10% BSA (facial and nonfacial). 
See Section 4.1 for full details of the study design. 
Participants who successfully complete the 52-week treatment in this study may be eligible to 
participate in a separate extension study to evaluate durability of effect and maintenance 
regimens. 
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Table 3: 
Schedule of Activities:  Double-Blind, Vehicle-Controlled Treatment Period (Day 1-Week 24) 
Procedure 
Screening 
Double-Blind, Vehicle Controlled Treatment 
Notes 
Days 
-32 to -1 
Day 1 
 
Wk 4 
± 3 d 
Wk 8 
± 3 d 
Wk 12 
± 3 d 
Wk 18 
± 7 d 
Wk 24* 
(EOT1) 
± 7 d 
*Week 24 is considered the first visit of the treatment 
extension period. 
Administrative procedures 
 
Informed consent 
X 
 
 
 
 
 
 
 
Contact IRT 
X 
X 
X 
X 
X 
X 
X 
 
Inclusion and exclusion criteria 
X 
X 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
General and disease medical 
history 
X 
 
 
 
 
 
 
 
Prior/concomitant medications  
X 
X 
X 
X 
X 
X 
X 
 
Apply study drug 
 
X 
X 
X 
X 
X 
X* 
At each study visit starting at Day 1, the participant should 
apply the study drug under direct supervision of the site staff.  
*Not applicable to the EOT1 visit. 
Dispense (D) and return (R) 
study drug and diary cards 
 
D 
R/D 
R/D 
R/D 
R/D 
R/D* 
All tubes of study drug will be weighed before being 
dispensed.  All returned tubes of study drug will be weighed, 
and those that are unused may be re-dispensed. 
Re-dispension is not allowed at Week 24. 
*Dispension is not applicable to the EOT1 visit.  At the 
Week 24 visit, study drug and diary cards are only dispensed 
to participants continuing in the treatment extension period. 
Collect study drug and collect/ 
review study drug diary cards 
 
 
X 
X 
X 
X 
X 
 
Assess compliance 
 
 
X 
X 
X 
X 
X 
 
Safety assessments 
 
AE assessment  
X 
X 
X 
X 
X 
X 
X 
Ad hoc photography of skin-related AEs may also occur as 
applicable.  
Targeted physical examinations 
 
X 
X 
X 
X 
X 
 
 
Comprehensive physical 
examination 
X 
 
 
 
 
 
X 
 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
 
12-lead ECG 
X 
 
 
 
 
 
 
12-lead ECG performed within 2 months before baseline is 
acceptable. 
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Table 3: 
Schedule of Activities:  Double-Blind, Vehicle-Controlled Treatment Period (Day 1-Week 24) (Continued) 
Procedure 
Screening 
Double-Blind, Vehicle Controlled Treatment 
Notes 
Days 
-32 to -1 
Day 1 
 
Wk 4 
± 3 d 
Wk 8 
± 3 d 
Wk 12 
± 3 d 
Wk 18 
± 7 d 
Wk 24* 
(EOT1) 
± 7 d 
*Week 24 is considered the first visit of the treatment 
extension period. 
Efficacy assessments 
 
F-BSA 
X 
X 
X 
X 
X 
X 
X 
 
T-BSA 
X 
X 
X 
X 
X 
X 
X 
Includes facial and nonfacial areas. 
F-VASI 
X 
X 
X 
X 
X 
X 
X 
 
T-VASI 
X 
X 
X 
X 
X 
X 
X 
Includes facial and nonfacial areas. 
F-PhGVA 
 
X 
 
 
X 
 
X 
 
T-PhGVA 
 
X 
 
 
X 
 
X 
 
Photography of face 
X 
X* 
 
 
X 
 
X 
2D photography at all sites; 3D photography at selected sites. 
*If photo quality at screening is not adequate, the 
photography may be repeated at Day 1. The baseline photos 
are defined as the adequate ones either taken at screening or 
Day 1. 
Photography of nonfacial target 
area 
X 
X* 
 
 
X 
 
X 
2D photography at all sites. The genitalia area should not be 
photographed. 
*If photo quality at screening is not adequate, the 
photography may be repeated at Day 1. The baseline photos 
are defined as the adequate ones either taken at screening or 
Day 1.  
Patient-reported outcomes 
To be evaluated prior to any other study 
procedures/assessments. 
VNS 
 
 
 
 
X 
 
X 
The participant will be provided their baseline photo and a 
mirror to perform this assessment. 
Color-matching question 
 
 
 
 
X 
 
X 
The participant will be provided their baseline photo and a 
mirror to perform this assessment. 
F-PaGIC-V 
 
 
 
 
X 
 
X 
 
T-PaGIC-V 
 
 
 
 
X 
 
X 
 
DLQI 
 
X 
 
 
X 
 
X 
For participants who are age ≥ 12 years to < 16 years at 
baseline, the CDLQI will be completed instead. 
WHO-5 
 
X 
 
 
X 
 
X 
 
TSQM 
 
 
 
 
X 
 
X 
 
VitiQoL 
 
X 
 
 
X 
 
X 
 
HADS 
 
X 
 
 
 
 
X 
 
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Table 3: 
Schedule of Activities:  Double-Blind, Vehicle-Controlled Treatment Period (Day 1-Week 24) (Continued) 
Procedure 
Screening 
Double-Blind, Vehicle Controlled Treatment 
Notes 
Days 
-32 to -1 
Day 1 
 
Wk 4 
± 3 d 
Wk 8 
± 3 d 
Wk 12 
± 3 d 
Wk 18 
± 7 d 
Wk 24* 
(EOT1) 
± 7 d 
*Week 24 is considered the first visit of the treatment 
extension period. 
Laboratory assessments  
 
Hematology and chemistry 
assessments 
X 
X 
X 
X* 
X 
X* 
X 
*The blood draw at Week 8 and Week 18 is optional for 
participants who are age < 18 years 
Serology and thyroid testing 
X 
 
 
 
 
 
 
Serology includes HIV antibody. 
Urinalysis 
X 
 
 
 
 
 
 
 
FSH 
X 
 
 
 
 
 
 
For confirmation of nonchildbearing status of women who 
are postmenopausal defined as having amenorrhea for at least 
12 months before screening.  
Pregnancy testing 
X* 
X 
X 
X 
X 
X 
X 
*Female participants of childbearing potential will have a 
serum test at screening and safety follow-up visits.  A urine 
test will be conducted at all other visits.  A positive urine test 
must be confirmed by a serum test. 
PK and translational assessments 
 
Population-based PK plasma 
sampling (trough) 
 
 
X 
 
 
 
X 
Time of last study drug application to be recorded in eCRF.  
Blood samples must not be drawn from the area that has been 
treated with study drug. 
Samples will be drawn at predose. 
Serum sampling for biomarker 
analysis 
 
X 
 
 
X 
 
X 
 
Note:  Unscheduled visits may occur at any time at the investigator's discretion, and appropriate clinical and laboratory tests may be performed, as clinically indicated. 
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Table 4: 
Schedule of Activities:  Treatment Extension Period (Week 28-Week 52) 
Procedure 
Treatment Extension 
Safety Follow-Up 
Notes 
Wk 28 
± 7 d 
Wk 34 
± 7 d 
Wk 40 
± 7 d 
Wk 46 
± 7 d 
Wk 52 
(EOT2*) 
± 7 d 
30 days 
+ 7 d After 
EOT1/EOT2** 
(EOS) 
*EOT2 assessments should be performed in the 
event a participant’s treatment is stopped before 
Week 52 at any relevant study visit before that time. 
**After last application of study drug or last visit. 
Administrative procedures 
 
Contact IRT 
X 
X 
X 
X 
X 
X 
 
Prior/concomitant medications  
X 
X 
X 
X 
X 
X 
 
Apply study drug 
X 
X 
X 
X 
 
 
At each study visit, the participant should apply the 
study drug under direct supervision of the site staff. 
Dispense (D) and return (R) study 
drug and diary cards 
R/D 
R/D 
R/D 
R/D 
R 
 
All tubes of study drug will be weighed before 
being dispensed.  All returned tubes of study drug 
will be weighed, and those that are unused may be 
re-dispensed.  
Collect study drug and collect/ 
review study drug diary cards 
X 
X 
X 
X 
X 
 
 
Safety assessments 
 
AE assessment 
X 
X 
X 
X 
X 
X 
 
Targeted physical examinations 
X 
X 
X 
X 
 
X 
 
Comprehensive physical 
examination 
 
 
 
 
X 
 
 
Vital signs 
X 
X 
X 
X 
X 
X 
 
Efficacy assessments 
 
F-BSA 
X 
X 
X 
X 
X 
X 
 
T-BSA 
X 
X 
X 
X 
X 
X 
Includes facial and nonfacial areas. 
F-VASI 
X 
X 
X 
X 
X 
X 
 
T-VASI 
X 
X 
X 
X 
X 
X 
Includes facial and nonfacial areas. 
F-PhGVA 
 
 
X 
 
X 
 
 
T-PhGVA 
 
 
X 
 
X 
 
 
Photography of face 
 
 
X 
 
X 
 
2D photograph at all sites; 3D photography at 
selected sites. 
Photography of nonfacial target 
area 
 
 
X 
 
X 
 
2D photography at all sites. The genitalia area 
should not be photographed. 
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Table 4: 
Schedule of Activities:  Treatment Extension Period (Week 28-Week 52) (Continued) 
Procedure 
Treatment Extension 
Safety Follow-Up 
Notes 
Wk 28 
± 7 d 
Wk 34 
± 7 d 
Wk 40 
± 7 d 
Wk 46 
± 7 d 
Wk 52 
(EOT2*) 
± 7 d 
30 days 
+ 7 d After 
EOT1/EOT2** 
(EOS) 
*EOT2 assessments should be performed in the 
event a participant’s treatment is stopped before 
Week 52 at any relevant study visit before that time. 
**After last application of study drug or last visit. 
Patient-reported outcomes 
To be evaluated prior to any other study 
procedures/assessments. 
VNS 
 
 
X 
 
X 
 
The participant will be provided their baseline photo 
and a mirror to perform this assessment. 
Color-matching question 
 
 
X 
 
X 
 
The participant will be provided their baseline photo 
and a mirror to perform this assessment. 
F-PaGIC-V 
 
 
X 
 
X 
 
 
T-PaGIC-V 
 
 
X 
 
X 
 
 
DLQI 
 
 
X 
 
X 
 
For participants who are age ≥ 12 years to 
< 16 years at baseline, the CDLQI will be 
completed instead. 
WHO-5 
 
 
X 
 
X 
 
 
TSQM 
 
 
X 
 
X 
 
 
VitiQoL 
 
 
X 
 
X 
 
 
HADS 
 
 
 
 
X 
 
 
Laboratory assessments 
 
Hematology and chemistry 
assessments 
X 
X 
X 
X* 
X 
X 
*The blood draw at Week 46 is optional for 
participants who are age < 18 years 
Urinalysis 
 
 
 
 
 
 
 
Pregnancy testing 
X 
X 
X 
X 
X 
X* 
*Female participants of childbearing potential will 
have a serum test at screening and safety follow-up 
visits.  A urine test will be conducted at all other 
visits.  A positive urine test must be confirmed by a 
serum test. 
PK and Translational assessments 
Population-based PK plasma 
sampling (trough) 
 
 
X 
 
 
 
Time of last study drug application to be recorded in 
eCRF.  Blood samples must not be drawn from the 
area that has been treated with study drug. 
Samples will be drawn at predose. 
Serum sampling for biomarker 
analysis 
 
 
X 
 
X 
 
 
Note:  Unscheduled visits may occur at any time at the investigator's discretion, and appropriate clinical and laboratory tests may be performed, as clinically indicated. 
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2. 
INTRODUCTION 
Ruxolitinib cream is a topical formulation of ruxolitinib phosphate under development for the 
treatment of participants with AD, AA, plaque psoriasis, and vitiligo.  Ruxolitinib phosphate is 
an inhibitor of the JAK family of protein TYKs.  Inflammatory cytokines are strongly implicated 
in the pathogenesis of several dermatologic diseases.  Because JAKs serve to translate 
extracellular signals from a number of relevant cytokines and growth factors upregulated in 
inflammatory diseases such as AD, AA, plaque psoriasis, and vitiligo, JAK inhibitors represent 
potential therapeutic agents for these disease states. 
2.1. 
Epidemiology of Vitiligo 
Vitiligo is an autoimmune pigmentary disease characterized by depigmented patches of skin with 
a selective loss of melanocytes.  It is estimated to affect 0.5% to 2% of the population worldwide 
(Krüger and Schallreuter 2012).  The prevalence is similar between men and women, and there is 
no known difference in presentation according to skin type or race.  Almost 50% of patients 
present before 20 years of age, and many of them present before 10 years of age (Rodrigues et al 
2017).  Generalized (non-segmental) vitiligo is the most common type, accounting for up to 
90% of cases (Taieb et al 2009).  Vitiligo is associated with autoimmune diseases such as Sutton 
nevus, thyroid disorders, juvenile diabetes mellitus, pernicious anemia, and Addison's disease.  
The natural course of the disease is generally unpredictable, but it is often progressive.  Some 
degree of spontaneous repigmentation may occur in 10% to 20% of patients; however, it is 
typically not cosmetically acceptable (Castanet and Ortonne 1997). 
Vitiligo is a serious disease owing to its substantial psychological impact on patients’ day-to-day 
functioning, and its progressive course if left untreated.  Studies have shown that the effect 
vitiligo has on quality of life, particularly psychological impairment, is similar to other skin 
diseases, such as psoriasis and AD (Linthorst et al 2009).  Involvement of exposed skin, such as 
the face and hands, can have a major impact on self-esteem and eventually link to the 
psychological burden and quality of life (Silverberg and Silverberg 2013).  In some societies, 
there is poor acceptance and understanding of the disease, to the extent of discrimination against 
affected individuals (Yazdani Abyaneh et al 2014).  Approximately 75% of vitiligo sufferers feel 
their appearance is moderately to severely intolerable, and 41% of patients feel that there is little 
they can do to improve their condition, and feelings of hopelessness increase with time (Salzer 
and Schallreuter 1995).  Not surprisingly, 66% of patients report being distressed by their 
disease, and 92% have experienced stigmatization (Krüger et al 2014).  Feelings of 
embarrassment and fear of rejection can cause vitiligo patients to withdraw and lead to social 
isolation in both personal and professional relationships.  A majority of patients with vitiligo 
have reported feelings of anxiety and embarrassment when meeting strangers or beginning a new 
sexual relationship (Porter et al 1990). Additionally, clinical depression or depressive symptoms 
are associated with vitiligo.  Based on various meta-analyses, patients with vitiligo were 
approximately 5 times more likely to suffer from depression than healthy controls (Lai et al 
2017, Osinubi et al 2018).  A recent results of the analysis indicated that the pooled prevalence 
of depression across 17 unique populations (n = 1711) was 29% (Wang et al 2017). 
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Studies also suggest that the onset of vitiligo beginning in childhood can be associated with 
significant psychological trauma that may have long lasting effects on self-esteem.  The extent of 
vitiligo is associated with QOL impairment in children and adolescents, especially 
self-consciousness, but also bullying and teasing.  Teenagers ages 15 to 17 years seem to 
experience the most self-consciousness of all pediatric age groups (Silverberg and Silverberg 
2013).  In a study comparing social development and the health-related quality of life of young 
adult patients with childhood vitiligo with healthy controls, vitiligo patients reporting negative 
childhood experiences reported significantly more problems in social development than those not 
reporting negative experiences.  Furthermore, negative childhood experiences were significantly 
associated with more health-related quality of life impairment in early adulthood (Linthorst 
Homan et al 2008).  Thus, vitiligo is considered to be one of the most psychologically 
devastating diseases in dermatology. 
2.2. 
Current Treatment and Unmet Need in Vitiligo 
Currently, there is no approved drug treatment for vitiligo.  The conclusions of the most recent 
updated Cochrane systematic review were hampered by the heterogeneity of the performed 
clinical studies (Whitton et al 2016).  A systemic review on outcomes in a vitiligo study also 
showed that the 25 different outcomes had been measured in 54 randomized clinical studies.  
Although repigmentation was measured in 94% of studies, 48 different scales were used to 
measure it, making comparison among studies impossible (Eleftheriadou et al 2012).  Therefore, 
a definitive clinical recommendation for treatment of vitiligo could not be proposed, and the 
management of vitiligo is empirical and based on the most recent consensus guidelines 
(American Academy of Dermatology, Gawkrodger et al 2008, Taieb et al 2013, Vitiligo 
Research Foundation).  In general, first-line treatments consist of topical steroids and calcineurin 
inhibitors, which are most useful for treating disease that is localized.  Second-line treatments 
consist of phototherapy (NB-UVB and PUVA) and systemic steroid treatment.  Third-line 
treatments consist of surgical grafting techniques and depigmenting treatments.   However, 
response to current treatment varies, can be time-intensive, can be slow to respond to treatment, 
and often produces disappointing results if repigmentation is cosmetically unacceptable. 
There has been a limited number of randomized controlled clinical studies conducted to 
adequately support the efficacy of drug treatments in vitiligo.  Factors that further limit the 
evidence for efficacy are variations in study design and outcome measures, small study size (the 
majority of which included fewer than 50 participants), and deficiencies in methodological 
quality based on a systematic review of randomized clinical studies evaluating interventions for 
vitiligo (Whitton et al 2016).  Apart from inconclusive (or insufficient) evidence for the efficacy 
of current off-label drug treatments in vitiligo, their safety profiles may also carry specific 
restrictions for their topical use.  For example, TCS may be associated with local adverse effects, 
including irreversible ones such as skin atrophy and striae distensae, and an increased 
susceptibility to skin infections (Coondoo et al 2014).  More potent TCS, through their 
percutaneous absorption and depot-like accumulation in the epidermis, may also produce 
well-known systemic AEs typical for corticosteroids.  Additionally, there are restrictions on the 
use of such TCS on sensitive skin areas, particularly on the face, and for the overall treatment 
duration (ie, not to exceed 4 weeks).  Therefore, judicious use of high potency preparations of 
TCS is critical.  Topical calcineurin inhibitors are known for the induction of skin burning 
sensation immediately after their application, which makes their use on the face problematic.  
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Topical calcineurin inhibitors have been implied in their possible contribution to cutaneous 
malignancy when used long-term. 
Available phototherapy treatments include NB-UVB and PUVA.  Phototherapy regimens 
typically require 2 to 3 treatments per week and long-term duration of treatment.  For both 
NB-UVB and PUVA, 12 to 24 months of continuous phototherapy may be necessary to acquire 
maximal repigmentation (Taieb et al 2013).  A minimum of 6 months of continuous 
phototherapy is recommended before being considered nonresponsive (Taieb et al 2013, Bae 
et al 2017).  Relapses are common; approximately 60% to 70% of patients resume 
depigmentation in areas repigmented by treatment within 1 year with PUVA or NB-UVB 
therapy (Boniface et al 2018).  There are also important safety limitations with phototherapy.  
PUVA carries a risk of phototoxic effects, nausea, and the potential risk for skin cancer.  
Moreover, PUVA phototherapy is not recommended for children or pregnant women due to risks 
associated with systemic exposure of psoralen.  NB-UVB phototherapy is considered to have 
safety advantages over PUVA but is also associated with AEs such as erythema, itching, and 
mild burning or pain (Bae et al 2017).  Excimer laser or monochromatic excimer lamp (both at 
308 nm) that may reach deeper targets such as amelanotic melanocytes of the hair follicle, and 
also avoid irradiation of uninvolved skin, may improve clinical outcomes; however, they are 
limited to localized treatment (Boniface et al 2018). 
Lastly, surgical treatments in vitiligo may be considered after failure to respond to drug and light 
therapies and only for cosmetically sensitive sites where there have been no new vitiligo areas, 
no Koebner phenomenon, and no extension of the vitiligo area in the previous 12 months.  
Unsatisfactory cosmetic results and a high incidence of AEs have been reported with certain 
surgical procedures (Gawkrodger et al 2008, Taieb et al 2013).  Surgery is best indicated for 
stable and localized forms of vitiligo, and only a small number of patients with vitiligo are 
considered suitable candidates. 
Given the lack of approved therapies and safety concerns and modest effectiveness of current 
off-label drug treatments, there is a need to identify a safe and effective new treatment for 
vitiligo. 
2.3. 
Role of Janus Kinases in Vitiligo 
Vitiligo pathogenesis involves intrinsic defects within melanocytes and autoimmunity that 
targets these cells.  Studies have shown that melanocytes from vitiligo patients are more 
vulnerable than those from healthy individuals (Rodrigues et al 2017, Speeckaert and van Geel 
2017).  Once melanocytes become stressed, they release inflammatory signals that activate innate 
immunity, which may represent the initiation event in vitiligo.  The oxidative stress, cell damage, 
and cytokines secreted from innate immune cells then trigger CXCL10 release by skin cells, and 
that recruits CD8+ T cells to the site.  Activated CD8+ T cells produce IFN-γ and other 
inflammatory mediators to target and destroy melanocytes (Frisoli and Harris 2017).  Because 
IFN-γ signaling utilizes the JAK-STAT pathway, inhibition of JAK signaling may be an 
effective strategy for vitiligo treatment development. 
There are several case reports and case series suggesting that modulation of the immune response 
through JAK inhibition may be effective in treating vitiligo.  A patient with both AA and vitiligo 
was treated with oral ruxolitinib 20 mg BID for 20 weeks and subsequently had hair regrowth as 
well as significant repigmentation of areas affected with vitiligo (Harris et al 2016).  In another 
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report, a patient with widespread and progressive vitiligo who did not have a response to topical 
steroids, tacrolimus ointment, and NB-UVB phototherapy treated with oral tofacitinib at 5 mg 
QD and resulted in near complete repigmentation after 5 months of treatment (Craiglow and 
King 2015). 
There was a 20-week open-label study using topical ruxolitinib cream (INCB018424) in 
12 participants with vitiligo who had a minimum of 1% BSA affected.  The results showed a 
76% improvement in F-VASI and 26% improvement in T-VASI within 7 of 9 participants who 
completed the study (Rothstein et al 2017).  The same group conducted an additional 32-week 
extension study with optional NB-UVB treatment (Joshipura et al 2018).  Five participants 
completed the study, and 3 of them received NB-UVB.  At Week 52 (Week 20 + Week 32), 
results showed 92% improvement in F-VASI and 37% in T-VASI.  The results also indicated 
that 2 participants who had failed prior phototherapy and topical INCB18424 cream 
monotherapy on truncal vitiligo areas responded after combined therapies.  Additionally, 
participants were followed up with at 6 months after treatment discontinuation, and all 5 
participants maintained response with maximum duration of more than 40 weeks. 
2.4. 
Ruxolitinib Cream 
 
 
 
 
 
  
An oral formulation of ruxolitinib has been clinically evaluated for the treatment of patients with 
inflammatory disease, myeloproliferative diseases, hematologic malignancies, and solid tumors 
and is currently approved for the treatment of myelofibrosis and polycythemia vera in multiple 
countries.  In addition to the safety pharmacology and toxicology studies that were completed to 
support development of ruxolitinib cream, the toxicologic and toxicokinetic profiles of 
ruxolitinib have also been characterized following oral administration.  
 
 
 
 
 
Please refer to the ruxolitinib cream IB. 
 
 
 
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2.4.2. 
Clinical Experience 
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2.4.2.2. 
Efficacy of Ruxolitinib Cream 
2.4.2.2.1. Psoriasis 
Ruxolitinib cream has been evaluated in over 200 adults with plaque psoriasis in 3 clinical 
studies with application of 4 to 12 weeks duration.  Overall, ruxolitinib cream (0.5%, 1.0%, or 
1.5%) was effective in decreasing disease severity.  Observed AEs were mild to moderate in 
intensity and most were judged unrelated to study medication, with no treatment-related SAEs or 
withdrawals.  Ruxolitinib cream demonstrated to be safe and well-tolerated when applied QD for 
12 weeks to plaque psoriasis affecting 2% to 20% of the BSA. 
2.4.2.2.2. Atopic Dermatitis 
There were 307 adult participants with mild to moderate AD affecting total 3% to 20% BSA 
enrolled in a Phase 2, randomized, vehicle- and active (triamcinolone 0.1% cream)-controlled 
dose-ranging study.  The mean percentage change from baseline at Week 4 in EASI score 
demonstrated a significant improvement (1.5% BID [-71.6%0 vs vehicle [-15.5%]).  At the 
highest exposure (1.5% BID), ruxolitinib cream was noninferior to triamcinolone.  In addition, 
significant reductions in itch were noted as early as within a day from the initiation of therapy 
with ruxolitinib cream.  The most frequently reported TEAE was nasopharyngitis, which 
occurred in 2.0% to 7.8% of participants across dose strengths in the double-blind period and in 
5.2% of participants in the open-label period.  No fatal or serious TEAEs occurred in participants 
who received ruxolitinib cream.  Phase 3 studies (INCB 18424-303 and -304) in adults and 
adolescents are ongoing. 
More details are included in the ruxolitinib cream IB. 
2.4.2.2.3. Vitiligo 
INCB 18424-211 (see Figure 3) is a Phase 2, randomized, double-blind, vehicle-controlled study 
in adults with vitiligo who have depigmented areas including at least 0.5% BSA on the face and 
at least 3% BSA on nonfacial areas.  A total of 157 participants were equally randomized to 
receive ruxolitinib cream 1.5% BID, 1.5% QD, 0.5% QD, 0.15% QD, or vehicle BID for 
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24 weeks.  In the second part of the study, all participants initially randomized to vehicle BID 
and participants initially randomized to 0.15% QD who did not achieve ≥ 25% improvement 
from baseline in F-VASI were rerandomized to 1 of the 3 higher dosing groups for an additional 
28 weeks.  All other participants maintained the same treatment until Week 52.  After Week 52, 
participants could receive open-label 1.5% BID for an additional 52 weeks.  The primary 
endpoint was the proportion of participants who achieved a ≥ 50% improvement from baseline in 
F-VASI50 at Week 24. 
Figure 3: 
INCB 18424-211 Study Schema 
 
All ruxolitinib treatment arms demonstrated clinically meaningful efficacy and superiority over 
vehicle.  The proportion of participants who achieved an F-VASI50 at Week 24 was statistically 
significantly greater for ruxolitinib cream versus vehicle with response rates of 32.3%, 25.8%, 
50.0%, and 45.5% for ruxolitinib cream 0.15% QD, 0.5% QD, 1.5% QD, and 1.5% BID, 
respectively, and 3.1% for vehicle.  The proportion of participants who achieved an F-VASI75 at 
Week 24 was also statistically significantly greater for ruxolitinib cream versus vehicle with 
response rates of 9.7%, 16.1%, 16.7%, and 30.3% for ruxolitinib cream 0.15% QD, 0.5% QD, 
1.5% QD, and 1.5% BID, respectively, and 0% for vehicle.  Participants who were initially 
randomized to ruxolitinib cream 0.5% QD, 1.5% QD, and 1.5% BID continued on these 
treatments until Week 52.  Continued improvement in F-VASI response in these treatment was 
observed with the proportion of participants who achieved an F-VASI75 at Week 52 
demonstrating response rates of 29.0%, 30.0%, and 51.5% for ruxolitinib cream 0.5% QD, 
1.5% QD, and 1.5% BID. 
Improvements in T-VASI were observed for both Week 24 and Week 52.  The proportion of 
participants who achieved a T-VASI50 at Week 24 was also statistically significantly greater for 
ruxolitinib cream 0.15% QD, 0.5% QD, 1.5% QD, and 1.5% BID compared with vehicle with 
response rates of 16.1%, 6.5%%, 23.3%, and 12.1%, respectively, compared with 0% in 
vehicle-treated participants.  Continued improvement in participants treated with 0.5% QD, 
1.5% QD, and 1.5% BID through Week 52 was observed with response rates in T-VASI50 of 
25.8%, 30.0%, and 36.4%, respectively. 
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Compared with F-VASI, improvement in T-VASI was slower.  This observation is not 
unexpected given that repigmentation on the body and acral areas progresses at a slower rate 
than facial repigmentation.  Despite that, response rates for the F-VASI50, F-VASI75, and 
T-VASI50 favored the higher strength treatment regimens (both 1.5% QD and 1.5% BID) versus 
vehicle at Week 24 and 1.5% BID regimen at Week 52 across the endpoints.  Given that many 
participants may not achieve peak response by Week 24 and that there are constraints to the 
length of the vehicle period, the 1.5% BID regimen appears to have given a higher response over 
time.  Key secondary endpoints including percentage change in F-BSA, F-PhGVA, and PaGIC 
also followed a similar pattern, with separation from vehicle at Week 24 and continued 
improvement through Week 52.  
All ruxolitinib treatment arms were generally safe and well-tolerated with no significant TEAEs 
or application site events and no clinically relevant hematological changes.  TEAE rate overall is 
low and similar between active treatment and vehicle treatment.  There were 4 SAEs through 
52 weeks and all of them were not treatment-related.  Discontinuations from treatment through 
52 weeks was low.  Safety and tolerability were similar between the Week 24 and Week 52 
period.  
 
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3. 
OBJECTIVES AND ENDPOINTS 
Table 8 presents the objectives and endpoints. 
Table 8: 
Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
To evaluate the efficacy of ruxolitinib cream in 
participants with vitiligo. 
• Proportion of participants achieving F-VASI75 
at Week 24. 
Key Secondary 
To further assess the efficacy of ruxolitinib cream. • Percentage change from baseline in F-BSA at 
Week 24. 
• Proportion of participants achieving F-VASI50 
at Week 24. 
• Proportion of participants achieving F-VASI75 
at Week 52. 
• Proportion of participants achieving F-VASI90 
at Week 24. 
• Proportion of participants achieving F-VASI90 
at Week 52. 
• Proportion of participants achieving T-VASI50 
at Week 24. 
• Proportion of participants achieving T-VASI50 
at Week 52. 
• Proportion of participants achieving T-VASI75 
at Week 52. 
• Proportion of participants achieving a VNS of 
“4 – A lot less noticeable” or “5 – No longer 
noticeable” at Week 24. 
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Table 8: 
Objectives and Endpoints (Continued) 
Objectives 
Endpoints 
Secondary 
To evaluate the safety and tolerability of 
ruxolitinib cream. 
• The frequency, duration, and severity of AEs; 
physical examinations; vital signs; and 
laboratory data for hematology, serum 
chemistry, and urinalysis. 
To further assess the efficacy of ruxolitinib cream. • Proportion of participants achieving 
F-VASI25/50/75/90 during the treatment period 
(double-blind and treatment extension periods).  
• Percentage change from baseline in F-VASI 
during the treatment period (double-blind and 
treatment extension periods). 
• Percentage change from baseline in F-BSA 
during the treatment period (double-blind and 
treatment extension periods). 
• Percentage change from baseline in T-VASI 
during the treatment period (double-blind and 
treatment extension periods). 
• Percentage change from baseline in T-BSA 
during the treatment period (double-blind and 
treatment extension periods). 
• Proportion of participants achieving 
T-VASI25/50/75/90 during the treatment period 
(double-blind and treatment extension periods).  
• Proportion of participants in each category of 
VNS during the treatment period (double-blind 
and treatment extension periods). 
To evaluate the ruxolitinib PK in plasma after 
treatment of ruxolitinib cream. 
• Population-based (trough) plasma 
concentrations of ruxolitinib at Weeks 4, 24 and 
40. 
Exploratory 
To determine the participants’ quality of life. 
• Proportion of participants achieving an 
F-PhGVA of clear (0) or almost clear (1) during 
the treatment period (double-blind and 
treatment extension periods). 
• Proportion of participants achieving an 
T-PhGVA of clear (0) or almost clear (1) during 
the treatment period (double-blind and 
treatment extension periods). 
• Proportion of participants in each F-PhGVA 
category during the treatment period 
(double-blind and treatment extension periods). 
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Table 8: 
Objectives and Endpoints (Continued) 
Objectives 
Endpoints 
Exploratory (continued) 
To determine the participants’ quality of life. 
(continued) 
• Proportion of participants in each T-PhGVA 
category during the treatment period 
(double-blind and treatment extension periods). 
• Proportion of participants who report 
F-PaGIC-V of very much improved or much 
improved during the treatment period 
(double-blind and treatment extension periods). 
• Proportion of participants in each F-PaGIC-V 
category during the treatment period 
(double-blind and treatment extension periods). 
• Proportion of participants who report 
T-PaGIC-V of very much improved or much 
improved during the treatment period 
(double-blind and treatment extension periods). 
• Proportion of participants in each T-PaGIC-V 
category during the treatment period 
(double-blind and treatment extension periods). 
• Proportion of participant in each category for 
the color-matching question during the 
treatment period (double-blind and treatment 
extension periods). 
• Change from baseline in DLQI (or CDLQI) 
during the treatment period (double-blind and 
treatment extension periods). 
• Change from baseline in WHO-5 during the 
treatment period (double-blind and treatment 
extension periods). 
• Change from baseline in TSQM during the 
treatment period (double-blind and treatment 
extension periods). 
• Change from baseline in VitiQoL during the 
treatment period (double-blind and treatment 
extension periods). 
• Change from baseline in HADS during the 
treatment period (double-blind and treatment 
extension periods). 
To evaluate translational biomarkers in the blood 
of participants treated with ruxolitinib cream. 
• Change from baseline in the expression of select 
biomarkers in peripheral blood at Weeks 12, 24, 
40, and 52. 
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4. 
STUDY DESIGN 
4.1. 
Overall Design 
This is a randomized, vehicle-controlled study in adolescent and adult participants (age 
≥ 12 years) with non-segmental vitiligo who have depigmented area including ≥ 0.5% BSA on 
the face, ≥ 0.5 F-VASI, ≥ 3% BSA on nonfacial areas, ≥ 3 T-VASI, and for whom total body 
involved vitiligo area (facial and nonfacial) does not exceed 10% BSA.  Approximately 
300 participants will be randomized 2:1 to receive initial study treatment (ruxolitinib cream 1.5% 
BID:vehicle) for 24 weeks (see Figure 1).  Participants will be stratified by age (≤ 40 or 
> 40 years) and skin type (Fitzpatrick scale Type I and II vs Type III, IV, V, and VI).  
Adolescents (≥ 12 to < 18 years) will make up at least 10% of the study population, and no more 
than 50% of participants will be > 40 years old. 
During the double-blind, vehicle-controlled period, participants will receive ruxolitinib cream 
1.5% BID or vehicle for 24 weeks to be applied to depigmented areas only on the face and body 
up to 10% total BSA.  Participants should continue to treat depigmented areas identified for 
treatment at baseline even if the area begins to improve or fully repigment. 
After completion of the Week 24 assessments, participants will be offered the opportunity to 
continue in the treatment extension period.  Participants initially randomized to vehicle will be 
crossed over to active drug, and participants treated with ruxolitinib cream will receive an 
additional 28 weeks of treatment with ruxolitinib cream 1.5% BID.  To be eligible for the 
treatment extension, participants must have completed the baseline and Week 24 visit 
assessments, be compliant with study procedures, and not have any safety issues.  During the 
treatment extension, participants should continue to treat depigmented areas identified for 
treatment at baseline even if the area begins to improve or fully repigment.  Total treated areas 
(facial and nonfacial areas) should not exceed to 10% BSA.   
Safety endpoints, such as nature of AEs (type, frequency, and severity), vital signs, targeted 
physical examination, and routine laboratory investigations, will be monitored and recorded 
throughout the course of this study. 
Following the last application of ruxolitinib cream at Week 52, there will be a 30-day safety 
follow-up period to evaluate safety and duration of response.   
Participants who successfully complete the 52-week treatment in this study may be eligible to 
participate in a separate extension study to evaluate durability of effect and maintenance 
regimens.  
See Section 6.5 for detailed information of study drug modification and application guidance. 
4.2. 
Overall Study Duration 
Screening is up to 32 days (~4 weeks); the double-blind, vehicle-controlled treatment period is 
24 weeks; the treatment extension period is 28 weeks; and safety follow-up is 30 days.  Total 
duration is up to approximately 60 weeks (see Figure 1). 
The study will begin when the first participant (or parent or guardian) signs the ICF.  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 discontinued study drug and completed applicable safety follow-up 
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assessments or is lost to follow-up.  A participant is considered to have completed the study if 
he/she has completed all study visits, including the safety follow-up visit. 
4.3. 
Study Termination 
The investigator retains the right to terminate study participation at any time, according to the 
terms specified in the study contract.  The investigator is to notify the IRB/IEC in writing of the 
study's completion or early termination, send a copy of the notification to the sponsor or 
sponsor's designee, and retain 1 copy for the site study regulatory file. 
The sponsor may terminate the study electively or if required by regulatory agency.  In the event 
of significant safety findings, the study will be terminated.  If the study is terminated 
prematurely, the sponsor or designee will notify the investigators, the IRBs/IECs, and regulatory 
bodies of the decision and reason for termination of the study.   
5. 
STUDY POPULATION 
Deviations from eligibility criteria are prohibited because they can potentially jeopardize the 
scientific integrity of the study, regulatory acceptability, and/or participant safety.  Therefore, 
adherence to the criteria as specified in the Protocol is essential.  Prospective approval of 
Protocol deviations to recruitment and enrollment criteria, also known as Protocol waivers or 
exemptions, are not permitted. 
5.1. 
Inclusion Criteria 
Participants are eligible to be included in the study only if all of the following criteria apply: 
1. Adolescents and adults aged ≥ 12 years. 
2. Participants with a clinical diagnosis of non-segmental vitiligo with depigmented area 
including ≥ 0.5% BSA on the face, ≥ 0.5 F-VASI, ≥ 3% BSA on nonfacial areas, 
≥ 3 T-VASI, and total body vitiligo area (facial and nonfacial) not exceeding 10% BSA. 
3. Participants who agree to discontinue all agents used to treat vitiligo from screening 
through the final safety follow-up visit.  Over-the-counter preparations deemed 
acceptable by the investigator and camouflage makeups are permitted. 
4. Male and female participants must be willing to take appropriate contraceptive measures 
to avoid pregnancy or fathering a child for the duration of study participation with the 
exception of the following: 
a. Females of non-childbearing potential (ie, or surgically sterile with a hysterectomy 
and/or bilateral oophorectomy OR ≥ 12 months of amenorrhea). 
b. Prepubescent adolescents. 
Note:  Information about specific types of acceptable contraceptive measures and 
duration of contraceptive use are provided in Appendix A. 
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5. Ability to comprehend and willingness to sign an ICF or written informed consent of the 
parent(s) or legal guardian and written assent from the participant when possible. 
Note:  Adolescents, who during the course of the study become legal adults, will be asked 
for their consent to continue the study, and in the event of lack thereof, will be 
discontinued from further participation. 
5.2. 
Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply: 
1. Participants who have no pigmented hair within any of the vitiligo areas on the face. 
2. Other forms of vitiligo (eg, segmental) or other differential diagnosis of vitiligo or other 
skin depigmentation disorders (eg, piebaldism, pityriasis alba, leprosy, postinflammatory 
hypopigmentation, progressive macule hypomelanosis, nevus anemicus, chemical 
leukoderma, and tinea versicolor). 
3. Participants who have used depigmentation treatments (eg, monobenzone) for past 
treatment of vitiligo or other pigmented areas. 
Note:  Prior use of hydroquinone is not prohibited (as it is a bleaching agent, not a 
depigmentation treatment). 
4. Participants with concurrent conditions and history of other diseases: 
a. Any other skin disease that, in the opinion of the investigator, would interfere with 
the study medication application or study assessments. 
b. Active acute bacterial, fungal, or viral skin infection (eg, herpes simplex, herpes 
zoster, chicken pox) within 1 week before baseline. 
c. Conditions at baseline that would interfere with evaluation of vitiligo. 
d. 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.  
Examples include but are not limited to the following: 
− Clinically significant or uncontrolled cardiac disease, including unstable angina, 
acute myocardial infarction within 6 months from Day 1 of study drug 
administration, New York Heart Association Class III or IV congestive heart 
failure, and arrhythmia requiring therapy or uncontrolled hypertension (blood 
pressure > 150/90 mmHg) unless approved by the medical monitor/sponsor.  
− History of thrombosis, including deep venous thrombosis and pulmonary 
embolism. 
− Participants with concurrent malignant disease or a history of that in the 5 years 
preceding the baseline visit except for adequately treated nonmetastatic 
malignancies. 
− Current and/or history of liver disease, including known hepatitis B or C, with 
hepatic or biliary abnormalities.  
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− 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. 
− Participants who are committed to an institution by virtue of an order issued either 
by the judicial or the administrative authorities. 
5. Participants using any of the following treatments within the indicated washout period 
before baseline: 
a. 1 week:  Topical drugs when used on the vitiligo areas, for example, corticosteroids, 
calcineurin, and phosphodiesterase type 4 inhibitors or retinoids. 
b. 4 weeks: 
− Melanocyte-stimulating agents (eg, afamelanotide). 
− Immunomodulating systemic medications (eg, corticosteroids, methotrexate, 
cyclosporine). 
− Any other systemic therapies that could increase the skin sensitivity to UV/visible 
light or impact skin pigmentation, for example, tetracyclines, metoxypsoralens. 
− Received live vaccine. 
Note:  Live vaccine is prohibited during the course of the study and within 
4 weeks after the EOT visit. 
c. 8 weeks:  Laser or any kind of phototherapy, including tanning bed or intentional UV 
exposure. 
d. 5 half-lives or 12 weeks, whichever is longer:  Biologic agents, investigational or 
experimental therapy or procedures for vitiligo.  Investigational biologics should be 
discussed with the sponsor to determine whether a longer period of discontinuation is 
required. 
6. Participants who have previously received JAK inhibitors, systemic or topical. 
7. Participants with clinically significant abnormal laboratory values at screening:  
a. Hemoglobin (< 10 g/dL).  
b. Liver function tests:  
− AST or ALT ≥ 2 × ULN. 
− Alkaline phosphatase and/or bilirubin > 1.5 × ULN (isolated bilirubin 
> 1.5 × ULN is acceptable if bilirubin is fractionated and direct bilirubin < 35%). 
c. Severe renal disease (with creatinine clearance < 30 ml/min) or renal disease 
requiring dialysis. 
d. Clinically significant abnormal TSH or free T4 at screening as determined by the 
investigator. 
e. Positive serology test results at screening for HIV antibody. 
8. Body mass index < 17 or > 40 kg/m2. 
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9. Pregnant or lactating participants, or those considering pregnancy during the period of 
their study participation. 
10. Participants who, in the opinion of the investigator, are unable or unlikely to comply with 
the administration schedule and study evaluations.  
11. Employees of the sponsor or investigator or are otherwise dependents of them.  
5.3. 
Lifestyle Considerations 
Participants should be cautioned to avoid excessive exposure to artificial sunlight (including 
tanning booths, sun lamps, etc). 
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). 
It is recommended that swimming should not take place within 2 hours before and after the 
planned study drug application. 
5.4. 
Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently assigned to study treatment.  Tests with results that fail eligibility requirements 
may be repeated once during screening if the investigator believes that the participant would be 
eligible if retested.  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 or any 
laboratory abnormality is inconsistent with the participant’s medical history.  Participants who 
rescreen must be assigned a new screening number.  
5.5. 
Replacement of Participants 
Participants will not be replaced during the study. 
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6. 
STUDY TREATMENT 
6.1. 
Study Treatment Application 
Table 9 presents the study treatment information. 
Table 9: Study Treatment Information 
Study treatment name: 
Ruxolitinib 
Vehicle 
Dosage formulation: 
Cream 
Unit dose strength(s)/dosage 
level(s): 
1.5% 
Not applicable 
Route of administration: 
Topical 
Administration 
instructions: 
Double-blind and treatment 
extension periods:  BID.  A thin 
film is applied to depigmented 
vitiligo areas. 
Double-blind period:  BID.  A 
thin film is applied to the 
depigmented vitiligo areas. 
Treatment extension period:  Not 
applicable. 
Packaging and labeling: 
Ruxolitinib cream and vehicle cream will be provided in 60 g tube.  
Each tube will be labeled as required per country requirement. 
Storage: 
Ambient (15°C-30°C/59°F-86°F) 
Status of treatment in 
participating countries: 
Investigational 
Not applicable 
On visit days, study drug will be applied in the clinic during the visit.  Participants should 
remove study drug from the tube in fingertip units until all of the areas to be treated are covered 
by a thin film; the tube will be weighed before and after application to determine the 
participant’s dosage.  On the day of a visit, the participant should not apply the study drug at 
home and will apply study drug from the new kit in the clinic.  Participants will be instructed to 
document treated areas and advised to limit use to no more than one 60 g tube per week.  
Application instructions will be provided by the site study staff, and the participants will record 
their daily applications via a diary card given to the participants during each study visit.  Refer to 
the Study Pharmacy Manual for participant instructions for handling study of drug. 
At any time, if vitiligo areas become significantly more extensive than from the previous visit, 
the participant should contact the study site to discuss with the investigator whether additional 
evaluation at the clinic is required.  If any other skin products that are permitted under the study 
Protocol are used, participants should continue these unchanged during the study.  
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6.1.1. 
Application During the Double-Blind Vehicle-Controlled Treatment Period 
During the double-blind vehicle-controlled period (up to Week 24), participants should follow 
the below study drug application guidance: 
• Participants should apply study drug only to depigmented vitiligo areas up to a 
T-BSA (facial and nonfacial) of ≤ 10% BSA. 
• Participants should continue to treat all depigmented vitiligo areas identified for 
treatment at baseline even if the area begins to improve or fully repigment. 
6.1.2. 
Application During the Treatment Extension Period  
During treatment extension period (Week 24 to Week 52), participants should follow the below 
study drug application guidance: 
• Participants should apply study drug to depigmented vitiligo areas up to a T-BSA 
(facial and nonfacial) of ≤ 10% BSA. 
• Participants should continue to treat all depigmented vitiligo areas identified for 
treatment at baseline even if the area begins to improve or fully repigment. 
• Participants who have an expansion of existing areas of vitiligo during the course of 
the treatment extension period may treat these areas after a visit to document the 
VASI score and other measures of vitiligo (may be unscheduled visit), as long as the 
new treated T-BSA (facial and nonfacial) does not exceed 10% BSA. 
6.2. 
Preparation, Handling, and Accountability 
The investigator or designee must confirm appropriate temperature conditions (both ruxolitinib 
cream and vehicle cream are to be stored between 15°C and 30°C [59°F-86°F]) have been 
maintained during transit for all study treatments received and any discrepancies are reported and 
resolved before use of the study treatment. 
Only participants enrolled in the study may receive study treatment, and only authorized site 
staff may supply study treatment.  Immediately after application of ruxolitinib cream, 
participants are to wash their hands thoroughly with soap and warm water.  Refer to the Study 
Pharmacy Manual for participant instructions for handling of study drug. 
All study treatment must be stored in a secure, environmentally controlled, and monitored 
(manual or automated) area in accordance with the labeled storage conditions with access limited 
to the investigator and authorized site staff.  Participants should store study treatment at ambient 
temperature conditions. 
The investigator (or designee) is responsible for study treatment accountability, reconciliation, 
and record maintenance (ie, receipt, reconciliation, and final disposition records).  Inventory and 
accountability records must be maintained and readily available for inspection by the study 
monitor and are open to inspection at any time by any applicable regulatory authorities.  The 
investigator or designee must maintain records that document: 
• Delivery of study drug(s) to the study site. 
• Inventory of study drug(s) at the site. 
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• Participant use of the study drug(s) including tube counts from each supply 
dispensed. 
• Return of study drug(s) to the investigator or designee by participants. 
The investigational product must be used only in accordance with the Protocol.  The investigator 
will also maintain records adequately documenting that the participants were provided the 
specified study drug.  These records should include dates, quantities, and any available batch or 
serial numbers or unique code numbers assigned to the investigational product and study 
participants. 
Completed accountability records will be archived by the site.  The investigator or designee will 
be expected to collect and retain all used, unused, and partially used containers of study drug 
until verified by the study monitor (unless otherwise agreed to by the sponsor).  At the 
conclusion of the study, the investigator or designee will oversee shipment of any remaining 
study drug back to the sponsor or its designee for destruction according to institutional SOPs.  If 
local procedures mandate on-site destruction of investigational supply, the site should (where 
local procedures allow) maintain the investigational supply until the study monitor inspects the 
accountability records in order to evaluate compliance and accuracy of accountability by the 
investigative site.  At sites where the study drug is destroyed before monitor inspection, the 
monitors rely on documentation of destruction per the site SOP. 
Further guidance and information for the final disposition of unused study treatments are 
provided in the study materials provided to sites. 
6.3. 
Measures to Minimize Bias:  Randomization and Blinding 
All participants will be centrally assigned to study treatment using an IRT system.  The system 
will assign in a 2:1 ratio (ruxolitinib cream 1.5% BID:vehicle), stratified by age (≤ 40 or 
> 40 years old) and skin type (Fitzpatrick scale Type I and II vs Type III, IV, V, and VI).  
Adolescents will make up at least 10% or participants, and no more than 50% of participants will 
be aged greater than 40 years.  The IRT will assign participant ID numbers, track participant 
visits, randomize participants according to the defined parameters, maintain the blinding, and 
manage study drug inventory.  Full details will be provided in the IRT Manual.  Study treatment 
will be dispensed at the study visits summarized in the Schedule of Activities (see Table 3 and 
Table 4). 
After the database lock for the primary analysis, the sponsor will be unblinded, but investigators 
and participants will still be blinded to individual treatment assignments.  This is implemented to 
minimize bias for the Week 52 analyses.   After Week 52, investigators and participants will be 
unblinded. 
6.4. 
Study Treatment Compliance 
Compliance with all study-related treatments must be emphasized to the participant by the site 
personnel, and appropriate steps should be taken to optimize compliance during the study.  
Compliance with ruxolitinib cream will be evaluated by participants' adherence to the application 
regimen and drug accountability documented by the site staff and monitored by the 
sponsor/designee (tube counts).  
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In general, the application compliance will be determined by the number of actual versus 
anticipated number of applications, which should be within 70% to 130% of the prescribed 
number of applications.  Participants will be instructed to bring all study drugs with them to the 
study visits in order for site personnel to conduct tube counts to assess study drug accountability.  
The drug accountability documentation will be used by the sponsor to calculate treatment 
compliance. 
6.5. 
Dose Modifications 
6.5.1. 
Criteria and Procedures for Application Interruptions of Study Drug 
Safety concerns should be discussed with the sponsor immediately upon occurrence or awareness 
to determine whether the participant should continue or discontinue study treatment. 
In some circumstances, it may be necessary to temporarily interrupt treatment with ruxolitinib 
cream.  Except in cases of emergency, it is recommended that any findings of concern (eg, AE) 
be confirmed and that the investigator consult with the sponsor medical monitor (or other 
representative of the sponsor) before interrupting study drug.  Additionally, the investigator must 
obtain approval from the sponsor before restarting study drug.  Participants who experience a 
recurrence of the initial AEs upon restarting the study drug may need the study drug to be 
permanently discontinued.  
Instructions for application interruptions for ruxolitinib cream are outlined in Table 10.  
Individual decisions regarding interruptions should be made using clinical judgment in 
consultation with the medical monitor (whenever possible), taking into account relatedness of the 
AE to the study treatment and the participant's underlying condition. 
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Table 10: 
Guidelines for Interruption and Restarting of Study Drug 
Adverse Event 
Action Taken 
Chemistry 
ALT (> 3 × ULN) or AST (> 3 × ULN)  
• Laboratory abnormalities should be confirmed with 
repeat testing within 48 hours whenever possible 
and immediate delivery of the laboratory results 
requested. 
• Study drug applications must be interrupted.  At the 
discretion of the investigator, after consultation with 
the sponsor, study drug application may be restored 
once these have resolved. 
Other laboratory abnormalities 
Any other Grade 3 or higher laboratory 
abnormality, with the exception of 
asymptomatic elevations in triglyceride, 
cholesterol, or amylase 
• Laboratory abnormalities should be confirmed with 
repeat testing within 48 hours whenever possible 
and immediate delivery of the laboratory results 
requested. 
• Study drug applications must be interrupted.  At the 
discretion of the investigator, after consultation with 
the sponsor, study drug application may be restored 
once these have resolved.  
Any Grade 4 laboratory abnormality or AST 
or ALT (> 5 × ULN)  
• Laboratory abnormalities should be confirmed with 
repeat testing within 48 hours whenever possible 
and immediate delivery of the laboratory results 
requested.  
• Discontinue study drug if lab abnormalities are 
confirmed.  
6.5.2. 
Criteria for Permanent Discontinuation of Study Drug Due to an Adverse Event 
The occurrence of unacceptable severity of an AE not caused by the underlying disease will be 
presumed to be related to study drug treatment and will require that the study drug be 
permanently discontinued.  Unacceptable severity is defined as follows: 
• Occurrence of an AE that is related to treatment with the study drug that, in the 
judgment of the investigator or the sponsor's medical monitor, compromises the 
participant's ability to continue study-specific procedures or continuing treatment is 
considered to not be in the participant's best interest. 
• Worsening of vitiligo that requires treatment with a prohibited concomitant 
medication. 
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 32 days before the first dose of study treatment through 30 days 
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after the last dose of study treatment will be recorded in the eCRF.  Any addition, deletion, or 
change in the dose of these medications will also be recorded.  Concomitant 
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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6.8. 
Treatment After the End of the Study 
Participants who successfully complete the 52-week treatment in this study may be eligible to 
participate in a separate extension study to evaluate durability of effect and maintenance 
regimens.  
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7. 
DISCONTINUATION OF STUDY TREATMENT AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL 
7.1. 
Discontinuation of Study Treatment 
7.1.1. 
Reasons for Discontinuation 
Participants must be discontinued from study treatment for the following reasons: 
• The participant becomes pregnant. 
• Consent is withdrawn. 
Note:  Consent withdrawn means that the participant has explicitly indicated that they 
do not want to be followed any longer; in this case no further data, except data in 
public domain, may be solicited from or collected on the participant.  Participants 
may choose to discontinue study treatment and remain in the study for safety 
monitoring. 
• Further participation would be injurious to the participant's health or well-being, in 
the investigator's medical judgment. 
• Any AE of unacceptable severity as noted in Section 6.5.2. 
• The study is terminated by the sponsor. 
• The study is terminated by the local health authority, IRB, or IEC. 
A participant may be discontinued from study treatment as follows: 
• If, at 2 consecutive study visits, a participant's drug usage exceeds one 60 g tube per 
week.   
• If, during the course of the study, a participant is found not to have met eligibility 
criteria, the medical monitor, in collaboration with the investigator, will determine 
whether the participant should be withdrawn from study treatment. 
• If a participant is noncompliant with study procedures or study drug administration in 
the investigator's opinion, the medical monitor should be consulted for instruction on 
handling the participant. 
7.1.2. 
Discontinuation Procedures 
In the event that the decision is made to permanently discontinue the study treatment, the EOT 
visit should be conducted (EOT1 or EOT2 depending on the period during with the participant 
discontinues treatment).  Reasonable efforts should be made to have the participant return for a 
safety follow-up visit.  The last date of the last dose of study drug(s)/treatment and the reason for 
discontinuation of study treatment will be recorded in the eCRF. 
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If a participant is discontinued from study treatment: 
• The study monitor or sponsor must be notified. 
• The reason(s) for withdrawal must be documented in the participant's medical record 
and the primary reason for withdrawal must be included in the eCRF. 
• The EOT visit should be performed. 
• The date of the EOT visit should be recorded in the eCRF. 
• Participants must be followed for safety until the time of the safety follow-up visit or 
until study drug/treatment–related AEs resolve, return to baseline, or are deemed 
irreversible, whichever is longest. 
If the participant discontinues study treatment and actively withdraws consent for collection of 
follow-up data (safety follow-up or disease assessment), then no additional data collection 
should occur; however, participants will have the option of withdrawing consent for study 
treatment but continuing in the safety follow-up period of the study for safety/efficacy 
assessments. 
7.2. 
Participant Withdrawal From the Study 
A participant may withdraw from the study at any time at his/her own request, or may be 
withdrawn at any time at the discretion of the investigator for safety, behavioral, compliance, or 
administrative reasons. 
If the participant withdraws consent for disclosure of future information, the sponsor may retain 
and continue to use any data collected before such a withdrawal of consent. 
If a participant withdraws from the study, he/she may request destruction of any samples taken 
and not tested, and the investigator must document this in the site study records. 
See Table 3 and Table 4 for data to be collected at the time of study discontinuation and 
follow-up and for any further evaluations that need to be completed. 
7.3. 
Lost to Follow-Up 
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit: 
• The site must attempt to contact the participant and reschedule the missed visit as 
soon as possible.  The participant will be counseled regarding 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 (where possible, 3 telephone 
calls and, if necessary, a certified letter to the participant's last known mailing address 
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or local equivalent methods).  These contact attempts should be documented in the 
participant's medical record. 
• Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up. 
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 the study, and in the event of lack 
thereof, will be discontinued from further participation. 
− Informed consent/assent must be obtained using the IRB/IEC-approved version in 
a language that is native and understandable to the participant.  A template will be 
provided by the sponsor or its designee.  The sponsor or its designee must review 
and acknowledge the site-specific changes to the ICF/assent template.  The 
ICF/assent must include a statement that the sponsor or its designee and 
regulatory authorities have direct access to participant records. 
− The ICF/assent must contain all required elements and describe the nature, scope, 
and possible consequences of the study in a form understandable to the study 
participant. 
• Participants must be informed that their participation is voluntary.  Participants or 
their legally authorized representative will be required to sign a statement of informed 
consent 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. 
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• The medical record must include a statement that written informed consent was 
obtained before the participant was enrolled in the study and the date the written 
consent was obtained.  The authorized person obtaining the informed consent must 
also sign the ICF. 
• Participants must provide consent to the most current version of the ICF(s) during 
their participation in the study. 
• A copy of the ICF(s) must be provided to the participant or the participant's legally 
authorized representative. 
• Participants who are rescreened are required to sign a new ICF. 
8.1.2. 
Screening Procedures 
Screening is the interval between signing the ICF and the day that the participant is assigned to 
the study drug (Day 1).  Screening assessments for determination of eligibility may be performed 
over a period lasting up to 32 days. 
Procedures conducted as part of the participant's routine clinical management (eg, clinical 
laboratory tests) and collected before informed consent is obtained may be used for screening or 
baseline purposes, provided the procedure meets the Protocol-defined criteria and has been 
performed within 32 days before Day 1.  All information associated with eligibility 
requirements, including demography and medical history, must be entered into the appropriate 
eCRF pages. 
Results from the screening assessments will be reviewed by the investigators to confirm 
eligibility before Day 1 and administration of study drug.  Tests results that fail eligibility 
requirements may be repeated once during screening if the investigator believes that the 
participant would be eligible if retested.  For screening assessments that are repeated, the most 
recent available result before administration of study drug will be used to determine eligibility.  
See Section 5.4 regarding screen failures. 
8.1.3. 
Interactive Response Technology Procedure 
Each participant will be identified in the study by a participant ID number, which is a 
combination of the site ID and participant number.  Site personnel should contact the IRT system 
to obtain the participant ID number during screening.  Upon determining that the participant is 
eligible for study entry, the IRT system will be contacted to obtain the study medication kit 
assignment.  Additionally, the IRT system will be contacted at each regular study visit to update 
the study drug supply.  Additional details are provided in the IRT Manual. 
8.1.4. 
Distribution of Study Reminder Cards and Diaries 
Starting at the Day 1 visit and each visit thereafter, a study drug–specific diary will be given to 
each participant in order to record use of the study drug.  The completed diary will be collected 
during each of the participant's visits. 
Qualified clinical site staff will review the participants' entries for compliance.  Participants who 
are noncompliant with their study drug schedule (defined as < 70% or > 130% of the expected 
number of applications between study visits) will have their administration instructions 
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reinforced by the investigator or a qualified designee.  Participants will be considered compliant 
with the treatment regimen if they apply at least 70% but no more than 130% of the expected 
applications during participation in the treatment period of the study.  
Participants will be provided with a reminder card starting on Day 1 and at all visits (through 
Week 52).  The reminder card will indicate the date/time of the next visit and will also remind 
the participant that they should have their application at the clinic during the visit under site 
supervision after their blood draws for PK and safety evaluations have been completed. 
8.1.5. 
Demography and Medical History 
8.1.5.1. 
Demographics and General Medical History 
Demographic data and general medical history will be collected at screening by the investigator 
or qualified designee and will include year of birth/age, race, ethnicity, medical and surgical 
history, and current illnesses.  Medical history will include relevant medical or surgical treatment 
within the last 2 years that are considered to be clinically significant by the investigator. 
8.1.5.2. 
Disease Characteristics and Treatment History 
A vitiligo medical and treatment history, including date of diagnosis, relevant disease 
characteristics, and prior treatments, including systemic treatments, phototherapy, and surgical 
procedures, will be recorded.  A medical history of other conditions related to vitiligo will also 
be collected at screening. 
8.2. 
Efficacy Assessments 
8.2.1. 
Body Surface Area 
Total % BSA (includes facial and nonfacial areas) depigmented by vitiligo will be estimated at 
each visit.  Body surface area assessment will be performed by the Palmar Method.  BSA should 
be estimated to the nearest 0.1%.  The approximate size of the participant’s entire palmar surface 
(ie, the palm plus 5 digits) should be considered as 1% BSA, and the approximate size of the 
participant’s thumb should be considered as 0.1% BSA. 
8.2.2. 
Vitiligo Area Scoring Index 
Areas affected by depigmentation due to vitiligo will be assessed using the VASI.  It is based on 
a composite estimate of the overall area of vitiligo patches at baseline and the degree of macular 
repigmentation within these patches over time. 
Facial VASI is measured by percentage of vitiligo involvement (% of BSA) and the degree of 
depigmentation.  The percentage of BSA (hand unit) vitiligo involvement is estimated by the 
investigator using the Palmar Method (see Section 8.2.1).  Hand unit is based on participant’s 
hand size.  Investigator uses his/her hand to mimic the participant’s hand size to evaluate 
percentage of BSA vitiligo involvement.  The degree of depigmentation for each vitiligo 
involvement site is determined and estimated to the nearest of the following percentages:  0, 
10%, 25%, 50%, 75%, 90%, or 100%.  At 100% depigmentation, no pigment is present; at 90%, 
specks of pigment are present; at 75%, the depigmented area exceeds the pigmented area; at 
50%, the depigmented and pigmented area are equal; at 25%, the pigmented area exceeds the 
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depigmented area; at 10%, only specks of depigmentation are present.  The F-VASI is then 
derived by multiplying the values assessed for the vitiligo involvement by the percentage of 
affected skin for each site on the face and summing the values of all sites together (possible 
range 0-3). 
 
 
Total body VASI is calculated using a formula that includes contributions from all body regions 
(possible range, 0-100). 
𝑉𝑉𝑉𝑉𝑉𝑉𝑉𝑉 = Σ [ℎ𝑎𝑎𝑎𝑎𝑎𝑎 𝑢𝑢𝑢𝑢𝑢𝑢𝑢𝑢𝑢𝑢] 𝑥𝑥 [𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅 𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷] 𝑎𝑎𝑎𝑎𝑎𝑎 𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏 𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠 
The body is divided into the following 6 separate and mutually exclusive sites:   (1) head/neck, 
(2) hands, (3) upper extremities (excluding hands), (4) trunk, (5) lower extremities (excluding 
feet), and (6) feet.  The percentage of vitiligo involvement is estimated in hand units (% of BSA) 
by the same investigator during the entire course of the study.  Hand unit is based on 
participant’s hand size.  The investigator uses his/her hand to mimic the participant’s hand size to 
evaluate % BSA vitiligo involvement.  The degree of depigmentation for each body site is 
determined and estimated to the nearest of the following percentages:  0, 10%, 25%, 50%, 75%, 
90%, or 100%.  The T-VASI is then derived by multiplying the values assessed for the vitiligo 
involvement by the percentage of affected skin for each body site and summing the values of all 
body sites together (Hamzavi et al 2004).  Full details will be provided in the Study Manual. 
8.2.3. 
Physician’s Global Vitiligo Assessment (Facial) 
The severity of vitiligo will be assessed by the physician using the PhGVA, which has a 5-point 
scale (Table 11).  Response will be reported for face (F-PhGVA). 
Table 11: 
Facial Physician's Global Vitiligo Assessment Scale 
Score 
Severity 
Description 
0 
Clear 
No signs of vitiligo or complete/near complete repigmentation 
1 
Almost Clear 
Mostly pigmented areas with small depigmented or difficult to 
repigment areas (eg, philtrum, nares, corners of eyes, perioral skin) 
2 
Mild Disease 
Modest areas of depigmentation (not more than half of facial skin) with 
approximately 50% pigmentation within vitiligo areas or significant 
perifollicular pattern present 
3 
Moderate Disease 
Large areas of depigmented vitiligo areas (more than half of facial skin); 
significant depigmentation within vitiligo areas 
4 
Severe Disease 
Extensive areas of vitiligo to complete depigmentation on face 
8.2.4. 
Physician’s Global Vitiligo Assessment (Total Body) 
The severity of total body vitiligo will be assessed by the physician using the PhGVA, which has 
a 5-point scale (Table 12).  Response will be reported for total body (T-PhGVA). 
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Table 12: 
Total Body Physician's Global Vitiligo Assessment Scale 
Score 
Severity 
Description 
0 
Clear 
No signs of vitiligo or complete/near complete repigmentation 
1 
Almost Clear 
Mostly pigmented areas with small depigmented or difficult to repigment 
areas (eg, hands, feet, philtrum, nares, corners of eyes, perioral skin) 
2 
Mild Disease 
Modest areas of depigmentation with approximately 50% pigmentation 
within vitiligo areas or significant perifollicular pattern present 
3 
Moderate Disease 
Large areas of depigmented vitiligo areas; significant depigmentation 
within vitiligo areas 
4 
Severe Disease 
Extensive areas of vitiligo with complete depigmentation 
8.2.5. 
Photography 
Photography of the face and/or body areas affected with vitiligo will be obtained at visits listed 
in Table 3 and Table 4. 
All sites will use 2D photography, and selected sites will also use 3D photography, to 
photograph areas of the participant’s face affected with vitiligo.  2D photography will be used at 
all sites for the target nonfacial depigmented area. 
Target nonfacial vitiligo depigmented area definition:  At the baseline visit, depigmented 
nonfacial areas that are representative of the participant's overall disease and that are to be 
treated with study drug will be selected as targeted nonfacial vitiligo depigmented areas.  These 
areas will be assessed, measured, and documented in the participant's medical record at each 
subsequent visit during the study (see Table 3 and Table 4).  A note should be made in their 
medical record, and the baseline photographs can be marked with the location of the target 
depigmented area.  The genitalia area should not be photographed. 
Ad hoc photography of skin-related AEs is recommended. 
Photographic procedures will be standardized, and a full description of the methodology will be 
provided in a photography manual to be provided to the sites. 
8.2.6. 
Patient-Reported Outcomes 
Quality of life will be assessed (see Table 3 and Table 4) using the following tools: 
• VNS (Section 8.2.6.1) 
• Color-matching question (Section 8.2.6.2) 
• F-PaGIC-V (Section 8.2.6.3) 
• T-PaGIC-V (Section 8.2.6.4) 
• DLQI or CDLQI (Section 8.2.6.5) 
• WHO-5 (Section 8.2.6.6) 
• TSQM (Section 8.2.6.7) 
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• VitiQoL (Section 8.2.6.8) 
• HADS (Section 8.2.6.9) 
In order to avoid bias in the participants' responses to the questionnaires, all these assessments 
should be completed before any other evaluations or study procedures on the day of the study 
visit and prior to discussions with the investigator or study site staff. 
At the baseline visit, all patient-reported outcomes must be completed before the participant's 
first study drug application. 
8.2.6.1. 
Vitiligo Noticeability Scale 
The VNS is a patient‐reported measure of vitiligo treatment success, which has a 5-point scale 
(Batchelor et al 2016).  The baseline facial photograph will be shown to the participants for 
reference and a mirror will be provided for the participants to assess the vitiligo on their face. 
The participant will be asked to respond to the following query: 
Compared with before treatment, how noticeable is the vitiligo now?  Responses:  (1) More 
noticeable, (2) As noticeable, (3) Slightly less noticeable, (4) A lot less noticeable, and 
(5) No longer noticeable.  
VNS scores of 4 or 5 can be interpreted as representing treatment success. 
8.2.6.2. 
Color-Matching Question 
The baseline photograph and current participants’ facial image (participants will be provided a 
mirror) will be shown to the participant for reference, and the participant will be asked to 
respond to the following query: 
At this point of your treatment, how well does your skin color match between your face 
treated vitiligo skin and face normal skin?  Responses:  (1) Excellent, (2) Very good, 
(3) Good, (4) Poor, and (5) Very poor. 
8.2.6.3. 
Patient Global Impression of Change-Vitiligo (Facial) 
The F-PaGIC-V is an assessment of improvement by the participant.  It is a 7-point scale 
comparing the vitiligo areas at baseline with the participant's treated areas of facial vitiligo at the 
study visit.  Response will be reported for face (F-PaGIC-V).  The participant will be asked to 
respond to the following query: 
Since the start of the treatment you've received in this study, your vitiligo on your face 
treated with the study drug is:  (1) Very much improved, (2) Much improved, (3) Minimally 
improved, (4) No change, (5) Minimally worse, (6) Much worse, and (7) Very much worse. 
F-PaGIC-V scores of 1 or 2 can be interpreted as representing treatment success. 
8.2.6.4. 
Patient Global Impression of Change-Vitiligo (Total Body) 
The T-PaGIC-V is an assessment of improvement by the participant.  It is a 7-point scale 
comparing the vitiligo areas at baseline with the participant's treated areas of total body vitiligo 
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at the study visit.  Response will be reported for total body (T-PaGIC-V).  The participant will be 
asked to respond to the following query: 
Since the start of the treatment you've received in this study, your vitiligo on your total body 
treated with the study drug is:  (1) Very much improved, (2) Much improved, (3) Minimally 
improved, (4) No change, (5) Minimally worse, (6) Much worse, and (7) Very much worse. 
T-PaGIC-V scores of 1 or 2 can be interpreted as representing treatment success. 
8.2.6.5. 
Dermatology Life Quality Index 
The DLQI is a simple, 10-question validated questionnaire to measure how much the skin 
problem has affected the participant over the previous 7 days (Finlay and Khan 1994).  
Participants age ≥ 16 years will answer the questionnaire with (1) very much, (2) a lot, (3) a 
little, or (4) not at all. 
The questionnaire is analyzed under 6 headings as follows: 
• Symptoms and feelings (Questions 1 and 2)  
• Daily activities (Questions 3 and 4)  
• Leisure (Questions 5 and 6)  
• Work and school (Question 7)  
• Personal relations (Questions 8 and 9)  
• Treatment (Question 10)  
CDLQI is the youth/children’s version of the DLQI.  For participants who are age ≥ 12 years to 
< 16 years at baseline, the CDLQI will be completed instead of the CDLQI throughout their 
participation in the study.  This questionnaire is self-explanatory and can be simply given to the 
participant who is asked to fill it in and who may ask the help of the parent or guardian.  The 
questionnaire is analyzed under 6 headings as follows:  
• Symptoms and feelings (Questions 1 and 2)  
• Leisure (Questions 4, 5, and 6)  
• School or holidays (Question 7)  
• Personal relationships (Questions 3 and 8)  
• Sleep (Question 9)  
• Treatment (Question 10)  
Full details will be provided in the Study Manual. 
8.2.6.6. 
WHO-5 
The WHO-5 is a validated, self-administered, 5-item questionnaire designed to assess mental 
well-being over the past 2 weeks, which can be used as an outcome measure for the wanted and 
unwanted effects of treatments (WHO Collaborating Center for Mental Health, Topp et al 2015).  
The questionnaire consists of 5 statements, which respondents rate according to the following 
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scale:  0 = At no time; 1 = Some of the time; 2 = Less than half of the time; 3 = More than half of 
the time; 4 = Most of the time; 5 = All of the time. 
The raw score is calculated by totaling the figures of the 5 answers for a range of 0 to 25, with 
0 representing the worst possible and 25 representing the best possible quality of life.  A score 
below 13 indicates poor well-being. 
Full details will be provided in the Study Manual. 
8.2.6.7. 
Treatment Satisfaction Questionnaire for Medication 
TSQM is a validated 9-item questionnaire that measures a participant’s satisfaction with 
medication taken in a clinical study using a recall period of the past 2 to 3 weeks or since the 
medication was last used.  The questionnaire uses a 7-point scale for each question (Bharmal 
et al 2009).  Full details will be provided in the Study Manual. 
8.2.6.8. 
VitiQoL 
VitiQoL is a 15-item quality-of-life assessment that asks participants to rate various aspects of 
their condition during the past month using a 7-point scale (“Not at all” to “All of the time”) 
(Lilly et al 2013).  Full details will be provided in the Study Manual. 
8.2.6.9. 
Hospital Anxiety and Depression Scale 
HADS is 14-item questionnaire that assesses the levels of anxiety and depression that a person is 
currently experiencing (Zigmond and Snaith 1983).  There are 7 questions each for measuring 
anxiety and for measuring depression, with 4 possible responses to each question (responses are 
scored as 0, 1, 2, or 3).  Separate scores are calculated for anxiety and depression.  Full details 
will be provided in the Study Manual. 
8.3. 
Safety Assessments 
Planned timepoints for all safety assessments are provided in the Table 3 and Table 4. 
See Section 6.5 for guidelines regarding the management of relevant laboratory or other safety 
assessment abnormalities. 
8.3.1. 
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 treatment.  Adverse events that begin or worsen after 
informed consent should be recorded on the Adverse Event 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 treatment, or that caused the participant to discontinue the study 
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treatment.  Care will be taken not to introduce bias when detecting AEs and/or SAEs.  
Open-ended and nonleading verbal questioning of the participant, such as "How are you 
feeling?" is the preferred method to inquire about AE occurrences.  Adverse events may also be 
detected when they are volunteered by the participant during the screening process or between 
visits, or through physical examinations, laboratory tests, or other assessments.  The definition, 
reporting, and recording requirements for AEs are described in Section 9. 
All SAEs will be recorded and reported to the sponsor or designee within 24 hours.  The 
investigator will submit any updated SAE data to the sponsor within 24 hours of it being 
available. 
After the initial AE/SAE report, the investigator is required to proactively follow each participant 
at subsequent visits/contacts.  All SAEs will be followed until resolution, stabilization, the event 
is otherwise explained, or the participant is lost to follow-up (as defined in Section 7.3). 
8.3.2. 
Physical Examinations 
Physical examinations will be conducted at the timepoints listed in Table 3 and Table 4. 
A comprehensive physical examination will include height and body weight and assessment of 
the following organ or body systems:  skin; head, eyes, ears, nose, and throat; thyroid; lungs; 
cardiovascular system; abdomen (liver, spleen); extremities; and lymph nodes.  A brief 
neurological examination will also be performed. 
A targeted physical examination should be conducted as indicated by symptoms reported by the 
participant, AEs, or other findings.  Abnormalities that are considered clinically significant in the 
judgment of the investigator are to be reported as AEs. 
Physical examinations must be performed by a medically qualified individual such as a licensed 
physician, physician's assistant, or an advanced registered nurse practitioner, as local law 
permits. 
8.3.3. 
Vital Signs 
Vital sign measurements include blood pressure, pulse, respiratory rate, and body temperature.  
Blood pressure and pulse will be taken with the participant in the recumbent, semi-recumbent, or 
sitting position after 5 minutes of rest.  Any abnormalities that are considered clinically 
significant in the judgment of the investigator are to be reported as AEs. 
8.3.4. 
Electrocardiograms 
All 12-lead ECGs will be performed with the participant in a recumbent or semi-recumbent 
position after 5 minutes of rest.  Electrocardiograms should be performed as indicated in Table 3.  
Additional 12-lead ECGs may be performed at other visits as deemed clinically necessary.  
Twelve-lead ECG performed within 2 months before baseline is acceptable for using as a 
screening value.  
Electrocardiograms will be interpreted by the investigator at the site or designee, and the results 
will be used for immediate management of the participant's care.  There is no central reader of 
ECGs for this study. The decision to include or exclude a participant or withdraw a participant 
from the study based on an ECG flagged as "Abnormal, Clinically Significant" is the 
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responsibility of the investigator, in consultation with the sponsor's medical monitor, as 
appropriate.  Any abnormalities that are considered clinically significant in the judgment of the 
investigator are to be reported as AEs. 
8.3.5. 
Laboratory Assessments 
Required laboratory tests are listed in Table 13, which include hematology, chemistry, urinalysis, 
serology, free T4, TSH, FSH, and pregnancy test (see Table 3 and Table 4).  Clinical laboratory 
tests will be performed at a central laboratory (refer to the Laboratory Manual for sample 
handling and shipping instructions). 
Clinically significant abnormal laboratory findings are those that are not associated with the 
underlying disease, unless judged by the investigator to be more severe than expected for the 
participant's condition.  All laboratory tests with values considered clinically significantly 
abnormal during participation in the study, or within 30 days after the last dose of study 
treatment, should be repeated until the values return to normal or baseline or are no longer 
considered clinically significant by the investigator or medical monitor. 
See Section 9.1 for information regarding laboratory abnormalities that should be recorded as an 
AE in the eCRF. 
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Table 13: 
Required Laboratory Analytes 
Serum Chemistriesa 
Hematology 
Urinalysis With 
Microscopic 
Examination 
Serology 
Other 
Albumin 
Alkaline phosphatase 
ALT 
AST 
Bicarbonate or CO2 
Blood urea nitrogen or 
urea 
Calcium 
Chloride 
Creatinine 
Glucose 
Lactate dehydrogenase 
Phosphate 
Potassium 
Sodium 
Total bilirubin 
Direct bilirubin (if total 
bilirubin is elevated 
above ULN) 
Total protein 
Complete blood 
count, including: 
• Hemoglobin 
• Hematocrit 
• Mean 
corpuscular 
volume (MCV) 
• Platelet count 
• Mean platelet 
volume 
• Red blood cell 
count 
• Reticulocyte 
count 
• White blood cell 
count 
 
Differential count, 
including: 
• Basophils 
• Eosinophils 
• Lymphocytes 
• Monocytes 
• Neutrophils 
Color and 
appearance 
pH and specific 
gravity 
Bilirubin 
Glucose 
Ketones 
Leukocytes 
Nitrite 
Occult blood 
Protein 
HIV antibody 
FSH 
Free T4  
TSH 
Pregnancy Testing 
Female participants of childbearing potential have a serum test 
at screening and safety follow-up visits.  A urine test will be 
conducted at all other visits.  A positive urine test will be 
confirmed by a serum test. 
a All serum chemistries will be performed on samples collected without respect to food intake (ie, non-fasting). 
Note:  Additional tests may be required, as agreed by investigator and sponsor, based on emerging safety data. 
8.3.5.1. 
Pregnancy Testing 
A serum pregnancy test will be required for all women of childbearing potential during screening 
and at the safety follow-up visit (30 [+ 7] days after EOT; EOT1 or EOT2 as applicable).  Urine 
pregnancy tests will be conducted as outlined in Table 3 and Table 4, as medically indicated, or 
per country-specific requirement.  Urine pregnancy tests will be performed locally.  If a urine 
pregnancy test is positive, the results should be confirmed with a serum pregnancy test, which 
may be performed locally. 
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 9.6 for reporting 
requirements. 
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8.3.5.2. 
Serology 
An HIV antibody assessment will be performed at the screening visit to rule out infection (see 
Table 3).  Serology 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. 
8.4. 
Pharmacokinetic Assessments 
Venous blood samples will be collected to assess the PK of ruxolitinib cream in this study 
population at each study visit indicated in Table 3. 
The exact date and time of the PK blood draws and the date and time of the last application of 
study drug preceding the blood draw (if applicable) will be recorded in the eCRF.  
Instructions for sample preparation and shipping will be provided in the Laboratory Manual.  
Participants will receive reminder cards in advance of the study visit providing instruction to 
hold the application of study drug on the day of the visit and a place to record the time of the 
prior dose of study drug.  
Pharmacokinetic blood samples can be collected at any time during study visits noted in the 
Table 3.  Blood samples must not be drawn from the area that has been treated with study drug.  
If it is not possible to access an area that is not treated with study drug, the site must adequately 
document this in the eCRF and not take the PK blood sample for that visit.  After the PK sample 
is drawn, participants will apply ruxolitinib cream 1.5% or vehicle cream at the site.  
All analyses will be conducted by Incyte Corporation (Wilmington, DE) or Incyte's designee. 
8.5. 
Pharmacodynamic and Translational Assessments 
Serum will be collected from all participants at all sites for proteomic analysis at timepoints 
outlined in Table 3 and Table 4.  The purpose of this analysis will be to retrospectively evaluate 
correlative and pharmacodynamic biomarkers of response. 
All analyses will be conducted by Incyte Corporation (Wilmington, DE) or Incyte's designee.  
Refer to the Study Manual for detailed instructions. 
8.6. 
Unscheduled Visits 
Unscheduled visits may occur at any time at the investigator's discretion, and appropriate clinical 
and laboratory tests may be performed, as clinically indicated. 
8.7. 
End of Treatment and/or Early Termination 
If a decision is made that the participant will permanently discontinue study drug, then the EOT 
visit should be conducted (EOT1 or EOT2 depending on the study period when the participant 
discontinues).  If the EOT visit coincides with a regular study visit, then the EOT evaluations 
will supersede those of that scheduled visit, and the data should be entered in the EOT page in 
the eCRF.  If this decision does not coincide with a regular visit, reasonable efforts should be 
made to have the participant return to the site to have the EOT procedures completed. 
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8.8. 
Safety Follow-Up 
For participants who do not participate in a separate extension study, the safety follow-up period 
is the interval between the EOT visit (EOT1 or EOT2 depending on the study period when the 
participant discontinues) and the scheduled safety follow-up visit, which should occur 
30 (+ 7) days after the EOT visit (or after the last dose of study drug/treatment if an EOT visit 
was not performed).  
Adverse events and SAEs must be reported up until at least 30 days after the last dose of study 
drug/treatment, the date of the safety follow-up visit, or until toxicities resolve, return to 
baseline, or are deemed irreversible, whichever is longer.  Reasonable efforts should be made to 
have the participant return for the safety follow-up visit and report any AEs that may occur 
during this period. 
9. 
ADVERSE EVENTS:  DEFINITIONS AND PROCEDURES FOR 
RECORDING, EVALUATING, FOLLOW-UP, AND REPORTING 
9.1. 
Definition of Adverse Event 
Adverse Event Definition 
• An AE is any untoward medical occurrence associated with the use of a drug in humans, whether or 
not considered drug-related. 
• An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease (new or exacerbated) temporally associated with the use of study 
treatment. 
Events Meeting the Adverse Event Definition 
• Any safety assessments (eg, ECG, vital signs measurements), including those that worsen from 
baseline, considered clinically significant in the medical and scientific judgment of the investigator 
(ie, not related to progression of underlying disease). 
• Abnormal laboratory test results constitute an AE if they are considered clinically meaningful, 
induce clinical signs or symptoms, require concomitant therapy, or require changes in study drug.  
Whenever possible, a diagnosis (eg, anemia, thrombocytopenia) should be recorded in the eCRF 
rather than the abnormal lab result (eg, low hemoglobin, platelet count decreased). 
• Exacerbation of a chronic or intermittent pre-existing condition including either an increase in 
frequency and/or intensity of the condition. 
• New conditions detected or diagnosed after study treatment administration even though it may have 
been present before the start of the study. 
• Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
• Signs, symptoms, or the clinical sequelae of a suspected overdose of either study treatment or a 
concomitant medication.  Overdose per se will not be reported as an AE/SAE unless it is an 
intentional overdose taken with possible suicidal/self-harming intent.  Such overdoses should be 
reported regardless of sequelae. 
• "Lack of efficacy" or "failure of expected pharmacological action" per se will not be reported as an 
AE or SAE.  Such instances will be captured in the efficacy assessments.  However, the signs, 
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symptoms, and/or clinical sequelae resulting from lack of efficacy will be reported as AE or SAE if 
they fulfill the definition of an AE or SAE.   
Events NOT Meeting the Adverse Event Definition 
• Any clinically significant abnormal laboratory findings or other abnormal safety assessments that are 
associated with the underlying disease, unless judged by the investigator to be more severe than 
expected for the participant's condition. 
• The disease/disorder being studied or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the participant's condition or 
considered to be treatment-related by the investigator. 
• Medical or surgical procedure (eg, endoscopy, appendectomy):  the condition that leads to the 
procedure is the AE if it occurred after signing the ICF.  If present before entering the study, the 
condition should be captured as medical history. 
• Situations in which an untoward medical occurrence did not occur (social and/or convenience 
admission to a hospital). 
• Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or detected at 
the start of the study that do not worsen. 
9.2. 
Definition of Serious Adverse Event 
If an event is not an AE per 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 occurred.  This does not include an adverse drug experience that, had it occurred in a 
more severe form, might have caused death. 
c. Requires inpatient hospitalization or prolongation of existing hospitalization 
In general, hospitalization signifies that the participant has been detained (usually involving at least an 
overnight stay) at the hospital or emergency ward for observation and/or treatment that would not have 
been appropriate in the physician's office or outpatient setting.  Complications that occur during 
hospitalization are AEs.  If a complication prolongs hospitalization or fulfills any other serious criteria, 
the event is serious.  When in doubt as to whether "hospitalization" occurred or was necessary, the AE 
should be considered serious. 
Hospitalization for elective treatment of a pre-existing condition that did not worsen from baseline is 
not considered an AE. 
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 
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(eg, sprained ankle), that may interfere with or prevent everyday life functions but do not constitute a 
substantial disruption. 
e. Is a congenital anomaly/birth defect 
f. Other situations (Important Medical Event) 
An event that may not result in death, be immediately life-threatening, or require hospitalization, but 
may be considered serious when, based on appropriate medical judgment, the event may jeopardize the 
participant and may require medical or surgical intervention to prevent one of the outcomes listed in 
the above definition.  Examples of such events include invasive or malignant cancers (excluding the 
disease[s] under study in oncology protocols), intensive treatment in an emergency department or at 
home for allergic bronchospasm, blood dyscrasias, or convulsions that do not result in hospitalization, 
or development of drug dependency or drug abuse. 
9.3. 
Recording and Follow-Up of Adverse Events and/or Serious Adverse 
Events 
Adverse Event and Serious Adverse Event Recording 
• An AE/SAE that begins or worsens after informed consent is signed should be recorded on the 
Adverse Event Form in the eCRF.  Conditions that were present at the time informed consent was 
given should be recorded on the Medical History Form in the eCRF. 
• When an AE/SAE occurs, it is the responsibility of the investigator to review all documentation 
(eg, hospital progress notes, laboratory reports, and diagnostics reports) related to the event. 
• The investigator (or delegate) will then record all relevant AE/SAE information in the eCRF. 
• It is not acceptable for the investigator to send photocopies of the participant's medical records to 
sponsor or designee in lieu of completing the AE eCRF page. 
• There may be instances when copies of medical records for certain cases are requested.  In this case, 
all participant identifiers, with the exception of the participant number, will be redacted on the copies 
of the medical records before submission. 
• The investigator will attempt to establish a diagnosis of the event based on signs, symptoms, and/or 
other clinical information.  Whenever possible, the diagnosis (not the individual signs/symptoms) 
will be documented as the AE/SAE.  When a clear diagnosis cannot be identified, each sign or 
symptom should be reported as a separate AE/SAE. 
To the extent possible, each AE/SAE should be evaluated to determine: 
• The severity grade (CTCAE 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 final safety follow-up. 
• The action taken with regard to study drug as a result of the AE/SAE(s). 
• The event outcome (eg, not recovered/not resolved, recovered/resolved, recovering/resolving, 
recovered/resolved with sequelae, fatal, unknown). 
• 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 
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should be specified on the appropriate eCRF (eg, Prior/Concomitant Medications, Procedures and 
Non-Drug Therapy). 
Assessment of Intensity 
The severity of AEs will be assessed using CTCAE 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; 
intervention not indicated. 
• Grade 2:  Moderate; minimal, local, or noninvasive intervention 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 intervention indicated. 
• Grade 5:  Fatal. 
Assessment of Causality 
• The investigator is obligated to assess the relationship between study treatment and each occurrence 
of each AE/SAE. 
• A "reasonable possibility" of a relationship conveys that there are facts, evidence, and/or arguments 
to suggest a causal relationship, rather than that a relationship cannot be ruled out. 
• The investigator will use clinical judgment to determine the relationship. 
• The investigator will also consult the RSI in the IB and/or Product Information, for marketed 
products, in his/her assessment. 
• Alternative causes, such as underlying disease(s), concomitant therapy, and other risk factors, as well 
as the temporal relationship of the event to study treatment administration, will be considered and 
investigated. 
• For each AE/SAE, the investigator must document in the medical notes that he/she has reviewed the 
AE/SAE and has provided an assessment of causality. 
• With regard to assessing causality of SAEs: 
− There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to the sponsor or designee.  However, it is very 
important that the investigator always make an assessment of causality for every event 
before the initial transmission of the SAE data to the sponsor or designee. 
− The investigator may change his/her opinion of causality in light of follow-up information and 
send a SAE follow-up report with the updated causality assessment. 
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 or designee to elucidate the 
nature and/or causality of the AE/SAE as fully as possible.  This may include additional laboratory 
tests or investigations, histopathological examinations, or consultation with other healthcare 
professionals. 
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• If a participant dies during participation in the study or during a recognized safety follow-up period, 
the investigator will provide the sponsor or designee with a copy of any postmortem findings, 
including histopathology. 
• New or updated information will be recorded in the originally completed eCRF. 
• Any updated SAE data will be submitted to the sponsor or designee within 24 hours of receipt of the 
information. 
• Once an AE is detected, it should be followed until it has resolved or until it is judged to be 
permanent; assessment should be made at each visit (or more frequently if necessary) of any changes 
in severity, the suspected relationship to the study drug, the interventions required to treat the event, 
and the outcome. 
• When the severity of an AE changes over time for a reporting period (eg, between visits), each 
change in severity will be reported as a separate AE until the event resolves. 
9.4. 
Reporting of Serious Adverse Events 
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 study visit (or 30 days after the 
last dose of study treatment, whichever occurs later) must be reported to the sponsor (or 
designee) within 24 hours of learning of its occurrence, unless otherwise specified by the 
Protocol.  The investigator will submit any updated SAE data to the sponsor (or designee) within 
24 hours of it being available. 
Investigators are not obligated to actively seek AE or SAE information after conclusion of the 
study participation.  However, if the investigator learns of any SAE, including a death, at any 
time after a participant has been discharged from the study, and he/she considers the event to be 
reasonably related to the study treatment or study participation, the investigator must notify the 
sponsor (or designee) within 24 hours of becoming aware of the event. 
After the initial AE/SAE report, the investigator is required to proactively follow each participant 
at subsequent visits/contacts.  All SAEs will be followed until resolution, stabilization, the event 
is otherwise explained, or the participant is lost to follow-up (as defined in Section 7.3). 
Prompt notification by the investigator to the sponsor of a SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of a study 
treatment under clinical investigation are met. 
If the SAE is not documented in the IB for the study drug (new occurrence) and is thought to be 
related to the sponsor's study drug, the sponsor or its designee may urgently require further 
information from the investigator for reporting to health authorities.  The sponsor or its designee 
may need to issue an Investigator Notification to inform all investigators involved in any study 
with the same drug that this SAE has been reported.  Suspected Unexpected Serious Adverse 
Reactions will be collected and reported to the competent authorities and relevant ethics 
committees in accordance with Directive 2001/20/EC, or as per national regulatory requirements 
in participating countries. 
The sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study treatment under clinical investigation.  The 
sponsor will comply with country-specific regulatory requirements relating to safety reporting to 
the regulatory authority, IRB/IEC, and investigators. 
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Investigator safety reports must be prepared for SUSARs according to local regulatory 
requirements and sponsor policy and forwarded to investigators as necessary. 
An investigator who receives an investigator safety report describing a SAE or other specific 
safety information (eg, summary or listing of SAEs) from the sponsor will review and then file it 
along with the 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 also complete the Incyte Serious Adverse Event Report Form, in English.  
Refer to the Incyte Reference Guide for Completing the Serious Adverse Event Report Form. 
• Facsimile or email transmission of the Serious Adverse Event Report Form is the preferred method 
to transmit this information to the PhV/designee.  The contact information of the sponsor's 
study-specific representatives is listed in the Study Manual provided to each site.  The original copy 
of the Serious Adverse Event Report Form and the confirmation sheet must be kept at the study site. 
• Follow-up information is recorded on an amended or new Serious Adverse Event Report Form, with 
an indication that it is follow-up to the previously reported SAE and the date of the original report.  
The follow-up report should include information that was not provided on the previous Serious 
Adverse Event Report Form, such as the outcome of the event (eg, resolved or ongoing), treatment 
provided, action taken with study drug because of the SAE (eg, dose reduced, interrupted, or 
discontinued), or participant disposition (eg, continued or withdrew from study participation).  Each 
recurrence, complication, or progression of the original event should be reported as follow-up to that 
event, regardless of when it occurs. 
• In rare circumstances and in the absence of facsimile or computer equipment, notification by 
telephone is acceptable with a copy of the Incyte Serious Adverse Event Report Form sent by 
overnight mail or courier service.  Initial notification via telephone does not replace the need for the 
investigator to complete and sign the Serious Adverse Event Report Form within the designated 
reporting time frames. 
• Contacts for SAE reporting can be found in the Study Manual. 
9.5. 
Emergency Unblinding of Treatment Assignment 
In a medical emergency during the double-blind, vehicle-controlled period, if the investigator 
deems it necessary to determine optimal medical management of the participant, emergency 
unblinding will be performed exclusively by the Principal Investigator and subinvestigator as 
described in the IRT Study Manual.  The IRT system has an option to select for "Emergency 
Code Break" action for a given participant.  After entering the 6-digit study drug tube number 
and verification of the unmasking information, the investigator/subinvestigator will proceed to 
either final confirmation or cancellation of the code break procedure. 
If a participant's treatment assignment is unblinded, the sponsor or its designee must be notified 
immediately by telephone followed-up with an email.  
If an investigator, site personnel performing assessments, or participant is unblinded, the 
participant must be withdrawn from the study treatment, unless there are ethical reasons to have 
the participant remain on the study treatment.  In these cases, the investigator must obtain 
specific approval from the sponsor's (or its designee's) medical monitor for the participant to 
continue in the study 
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9.6. 
Pregnancy 
Pregnancy, in and of itself, is not regarded as an AE unless there is suspicion that study drug may 
have interfered with the effectiveness of a contraceptive medication or method.  When a 
pregnancy has been confirmed in a participant during maternal or paternal exposure to study 
drug, the following procedures should be followed in order to ensure safety: 
• The study drug must be discontinued immediately. 
• The investigator must complete and submit the Incyte Clinical Trial Pregnancy Form 
to the sponsor or its designee within 24 hours of learning of the pregnancy. 
Data on fetal outcome are collected for regulatory reporting and drug safety evaluation.  
Follow-up should be conducted for each pregnancy to determine outcome, including spontaneous 
or voluntary termination, details of the birth, and the presence or absence of any birth defects, 
congenital abnormalities, or maternal and/or newborn complications, by following until the first 
well-baby visit.  Pregnancy should be recorded on a Clinical Trial Pregnancy Form and reported 
by the investigator to the sponsor or its designee.  Pregnancy follow-up information should be 
recorded on the same form and should include an assessment of the possible causal relationship 
to the sponsor's study drug to any pregnancy outcome, as well as follow-up to the first well-baby 
visit or the duration specified in local regulations, whichever is later.  Refer to the Incyte 
Reference Guide for Completing the Clinical Trial Pregnancy Form. 
Any SAE occurring during pregnancy of a study participant must be recorded on the 
Serious Adverse Event Report Form and submitted to the sponsor or designee. 
Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, or ectopic pregnancy) are considered SAEs (if occurring in the study participant) and 
must be reported as described in Section 9.4.  If an abnormal pregnancy outcome is reported in a 
study participant's partner, the event should be reported to the sponsor on the Clinical Trial 
Pregnancy Form. 
9.7. 
Warnings and Precautions 
Special warnings or precautions for the study drug, derived from safety information collected by 
the sponsor or its designee, are presented in the IB.  Additional safety information collected 
between IB updates will be communicated in the form of Investigator Notifications.  Any 
important new safety information should be discussed with the participant during the study, as 
necessary.  If new significant risks are identified, they will be added to the ICF. 
9.8. 
Product Complaints 
The sponsor collects product complaints on study drugs and drug delivery systems used in 
clinical studies in order to ensure the safety of study participants, monitor quality, and facilitate 
process and product improvements. 
All product complaints associated with material packaged, labeled, and released by the sponsor 
or its designee will be reported to the sponsor.  All product complaints associated with other 
study material will be reported directly to the respective manufacturer. 
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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. 
9.9. 
Treatment of Overdose 
There has been no clinical experience with overdose of ruxolitinib cream.  Treatment of 
overdose should consist of general supportive measures. 
10. 
STATISTICS 
10.1. 
Sample Size Determination 
Approximately 300 participants will be randomized 2:1 to ruxolitinib cream 1.5% BID or vehicle 
and stratified by baseline skin type (Fitzpatrick scale Type I and II vs Type III, IV, V, and VI) 
and age (≤ 40 vs > 40 years).  The sample size is calculated to provide sufficient power (> 85%) 
to detect a difference between the 1.5% BID with the vehicle in primary and key secondary 
endpoints.  The powers for different endpoints are provided in Table 14.  The Fisher’s exact test 
with a 2-sided alpha of 0.05 is used to provide a conservative evaluation of statistical power, and 
it is accurate when there is a small expected number of responders in the vehicle group. 
Table 14: 
Powering for Primary and Key Secondary Endpoints 
Endpoints 
Response Rates in 
Ruxolitinib 1.5% BIDa 
Response Rates 
in Vehiclea 
Powerb 
F-VASI75 at Week 24 
20% 
5% 
95% 
F-VASI50 at Week 24 
30% 
10% 
 
 95% 
F-VASI75 at Week 52 
30% 
10% 
95% 
F-VASI90 at Week 24 
10% 
1% 
88% 
F-VASI90 at Week 52 
20% 
5% 
95% 
T-VASI50 at Week 24 
10% 
1% 
88% 
T-VASI50 at Week 52 
20% 
5% 
95% 
T-VASI75 at Week 52 
10% 
1% 
88% 
Vitiligo - VNS 
Response at Week 24 
10% 
1% 
88% 
a Based on the results from a Phase 2, randomized, dose-ranging study (INCB18424-211). 
b Based on the Fisher’s exact test with a 2-sided alpha of 0.05. 
10.2. 
Populations for Analysis 
The populations for analysis are presented in Table 15. 
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Table 15: 
Populations for Analysis 
Population 
Description 
ITT 
The ITT population includes all randomized participants.  Treatment groups for 
this population will be defined according to the treatment assignment at 
randomization. 
PP 
The PP population includes randomized participants who are considered to be 
sufficiently compliant with the Protocol. 
Safety 
The safety population includes all participants who applied at least 1 dose of 
study drug.  Treatment groups for this population will be determined according to 
the actual treatment the participant received on Day 1. 
PK/ 
pharmacodynamic 
evaluable 
The PK/pharmacodynamic evaluable population includes participants who 
applied at least 1 dose of ruxolitinib cream and provided at least 1 postdose blood 
sample for PK.  The study pharmacokineticist will review data listings of 
participant administration and sample records to identify participants to be 
excluded from the analysis. 
10.3. 
Statistical Analyses 
The Statistical Analysis Plan will be developed and finalized before database lock and will 
describe the details of the statistical analyses and procedures for accounting for missing data.  
This section is a summary of the planned statistical analyses of the primary and secondary 
endpoints. 
The gatekeeping testing strategy for the primary and key secondary analyses will be 
implemented to control the overall Type I error rate, 2-sided α = 0.05.  These endpoints will be 
tested in a fixed sequence at 2-sided α = 0.05 level in the following order: 
• Proportion of participants achieving F-VASI75 at Week 24 
• Percentage change from baseline in F-BSA at Week 24 
• Proportion of participants achieving F-VASI50 at Week 24 
• Proportion of participants achieving F-VASI75 at Week 52 
• Proportion of participants achieving F-VASI90 at Week 24 
• Proportion of participants achieving F-VASI90 at Week 52 
• Proportion of participants achieving T-VASI50 at Week 24 
• Proportion of participants achieving T-VASI50 at Week 52 
• Proportion of participants achieving T-VASI75 at Week 52 
• Vitiligo - VNS Response at Week 24 
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10.3.1. 
Efficacy Analyses 
10.3.1.1. Primary Analysis 
The primary analysis will be based on the intent-to-treat population.  The primary alternative 
hypothesis (superiority of ruxolitinib cream 1.5% BID compared with vehicle) will be tested 
using logistic regression.  This model will include the treatment group (1.5% BID and vehicle) 
and stratification factors.  The p-value for between-treatment group testing will be calculated 
based on the Wald test, which will be compared with 0.05.  Exact logistic regression (Mehta and 
Patel 1995) will be used for all of the comparisons if 1.5% BID or vehicle group has an expected 
cell count less than 5. 
The difference in F-VASI75 rates (ruxolitinib cream 1.5% BID vs vehicle) at Week 24 will also 
be computed.  The 95% confidence interval for the difference will be computed based on a 
large-sample normal approximation with continuity correction.  All nonresponders in the 
double-blind treatment period, as well as all participants who discontinue study treatment at any 
time before the timepoint of interest, or discontinue from the study for any reason, will be 
defined as nonresponders for the nonresponder imputation analysis. 
Analysis will also be performed in the PP population for the primary endpoint.  The following 
deviations are considered major:  
• Lack of informed consent; 
• Missing primary endpoints on F-VASI; 
• Compliance less than 60% based on the application numbers. 
Participants with 1 or more such deviations will be excluded from the PP population.  In 
addition, Protocol deviations related to inclusion/exclusion criteria, discontinuation criteria, and 
use of excluded concomitant medications will be evaluated and decided whether they should be 
excluded. 
In addition, sensitivity analyses, including MI and LOCF, may be performed.  For MI, a fully 
conditional specification method (van Buuren et al 2007) that assumes the existence of a joint 
distribution for all variables will be used to impute F-VASI scores. After the missing values are 
imputed, the binary variables will be derived based on the definition. The imputation will be 
repeated  a number of times to generate corresponding complete data sets, in order to reflect the 
uncertainty around the true value. Logistic regression will be applied to each imputed dataset, 
and then the results will be combined for the inference.  For LOCF, for the subjects who 
discontinue study treatment at any time before the timepoint of interest or discontinue from the 
study for any reason, the last observed nonmissing value will be used to fill in missing values at 
the timepoint of interest.  A tipping point analysis will be conducted to examine the potential 
effects of missing data.  The missing binary response on F-VASI75 at Week 24 in each treatment 
group will be replaced by a range of values and to see how far we must change them for the 
results of the study to tip from significant to not.  Between-treatment comparisons will be 
performed using a chi-square test. 
Subgroup analysis by baseline character, for example, skin type, age, and region, will be 
performed.  Details will be provided in the Statistical Analysis Plan. 
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10.3.1.2. Key Secondary Analysis 
If the primary objective is achieved, the statistical hypotheses for key secondary endpoints will 
be tested in the frequency specified in Section 10.3. 
Key secondary efficacy analyses at Week 24 will be conducted in the ITT population.  The 
statistical comparisons for binary outcomes (VASI50/90 and VNS response) will be analyzed 
using the similar method as specified in the primary analysis.  For F-BSA, an MMRM will be 
fitted for the comparisons between INCB018424 1.5% BID and vehicle cream based on 
percentage change in F-BSA from baseline to Week 24.  The MMRM will include the fixed 
effect of treatment, the randomization stratification factors, the visit, and treatment by visit 
interaction.  The variance-covariance matrix of the within-subject errors in MMRM will be 
modeled as unstructured.  A test for superiority between INCB018424 1.5% BID and vehicle 
cream will be performed using the least squares mean estimate of the percentage change from 
baseline in F-BSA at Week 24 from the MMRM specified above.  Superiority will be established 
if the p-value of the difference (INCB018424 1.5% BID minus vehicle) is less than 0.05. 
ANCOVA (LCOF) models will be fit as sensitivity analysis. 
Key secondary endpoints analyses at Week 52 (F-VASI75/90 and T-VASI50/75) will be 
performed in the ITT population with the following method: 
• Patients who discontinue the study drug before Week 24, due to any reason, will be 
defined as nonresponders for subsequent visits until Week 52. 
• For patients who completed Week 24 in Vehicle and 1.5% BID group, missing values 
of VASI in treatment extension period (including Week 52) will be imputed using 
linear extrapolation method.  The binary outcomes on responses, VASI50/75/90, will 
be derived based on the imputed values.  The statistical comparisons for these 
endpoints will be analyzed using the similar method as specified in the primary 
analysis.  
• LOCF will also be applied to impute missing data as a sensitivity analysis.  
10.3.1.3. Secondary Analysis 
All other secondary and exploratory efficacy variables will be summarized using descriptive 
statistics.  For categorical measurements, summary statistics will include sample size, frequency, 
and percentages.  Similar logistic regression models as specified in the primary and key 
secondary analysis will be used if applicable.  For continuous measurements, summary statistics 
will include sample size, mean, median, SD, 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 repeated measurement. 
10.3.2. 
Safety Analyses 
A TEAE is any AE either reported for the first time or worsening of a pre-existing event after 
first dose of study drug.  Analysis of AEs will be limited to TEAEs, but data listings will include 
all AEs regardless of their timing to study drug administration.  Adverse events will be tabulated 
by the MedDRA preferred term and system organ class.  Severity of AEs will be based on the 
National Cancer Institute CTCAE v5.0 using Grades 1 through 5. 
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The subset of AEs considered by the investigator to have a relationship to study drug will be 
considered to be treatment-related AEs.  If the investigator does not specify the relationship of 
the AE to study drug, then the AE will be considered treatment-related.  The incidence of AEs 
and treatment-related AEs will be tabulated. 
The clinical laboratory data will be analyzed using summary statistics; no formal treatment group 
comparisons are planned.  Laboratory test values outside the normal range will be assessed for 
severity based on the normal ranges for the clinical reference laboratory.  The incidence of 
abnormal laboratory values and shift tables relative to baseline will be tabulated. 
Descriptive statistics and mean change from baseline will be determined for vital signs (blood 
pressure, pulse, respiratory rate, and body temperature) at each assessment time. 
10.4. 
Analysis Plan 
No formal interim analysis is planned in this study.  The primary analysis will occur after the 
primary database lock, when all participants have completed the vehicle-controlled, double-blind 
treatment period.  Sponsors will all be unblinded, while investigators and participants will still be 
blinded, to the study treatment after the primary database lock.  After Week 52, investigators and 
participants will be unblinded.   
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 IRB/IEC approval before 
implementation of changes made to the study design, except for changes necessary to 
eliminate an immediate hazard to study participants. 
• The investigator will be responsible for the following: 
− Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC. 
− Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures. 
− Providing oversight of the conduct of the study at the site and adherence to GCP, 
IRB/IEC requirements, institutional requirements, and applicable laws and 
country-specific regulations. 
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• Adhering to the Protocol as described in this document and agreeing that changes to 
the Protocol procedures, with the exception of medical emergencies, must be 
discussed and approved, first, by the sponsor or its designee and, second, by the 
IRB/IEC.  Each investigator is responsible for enrolling participants who have met 
the specified eligibility criteria. 
• Retaining records in accordance with all local, national, and regulatory laws, but for a 
minimum period of at least 2 years after the last marketing application approval in an 
ICH region and until there are no pending or contemplated marketing applications in 
an ICH region, or if not approved, 2 years after the termination of the test article for 
investigation to ensure the availability of study documentation should it become 
necessary for the sponsor or a regulatory authority to review. 
− The investigator must not destroy any records associated with the study without 
receiving approval from the sponsor.  The investigator must notify the sponsor or 
its designee in the event of accidental loss or destruction of any study records.  If 
the investigator leaves the institution where the study was conducted, the sponsor 
or its designee must be contacted to arrange alternative record storage options. 
− 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, or study charters, or biomarker plans, as applicable. 
The sponsor (or designee) will be responsible for: 
• 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. 
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The investigator will be responsible for: 
• 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.   
• 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, or 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 at the 
investigator's site. 
− 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.  Also, current applicable medical records must be 
available. 
• May have responsibility for 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. 
• Permitting study-related monitoring, sponsor audits, IRB/IEC review, and regulatory 
inspections by providing direct access to source data and other relevant clinical study 
documents. 
− Monitoring:  Qualified representatives of the sponsor or its designee, study 
monitors, will monitor the study according to a predetermined plan.  The 
investigator must allow the study monitors to review any study materials and 
participant records at each monitoring visit. 
− Auditing:  Qualified representatives of the sponsor or its designee may audit the 
clinical study site and study data to evaluate compliance with the Protocol, 
applicable local clinical study regulations, and overall study conduct.  The 
investigator must allow the auditors to review original source records and study 
documentation for all participants. 
− Regulatory inspection:  Regulatory authorities may conduct an inspection of the 
study and the site at any time during the development of an investigational 
product.  The investigator and staff are expected to cooperate with the inspectors 
and allow access to all source documents supporting the eCRFs and other 
study-related documents.  The investigator must immediately notify the sponsor 
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when contacted by any regulatory authority for the purposes of conducting an 
inspection. 
11.3. 
Data Privacy and Confidentiality of Study Records 
The investigator and the sponsor or its designee must adhere to applicable data privacy laws and 
regulations.  The investigator and the sponsor or its designee are responsible for ensuring that 
sensitive information is handled in accordance with local requirements (eg, HIPAA).  
Appropriate consent and authorizations for use and disclosure and/or transfer (if applicable) of 
protected information must be obtained. 
Participant names will not be supplied to the sponsor or its designee.  Only the participant 
number and the participant's initials (participant's initials will only be recorded if allowable by 
local regulations) will be recorded in the eCRF, where permitted; 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 local data protection laws. 
11.4. 
Financial Disclosure 
Before study initiation, all clinical investigators participating in clinical studies subject to 
21 CFR Part 54 – Financial Disclosure by Clinical Investigators (ie, "covered studies") are 
required to submit a completed Clinical Investigator Financial Disclosure Form that sufficiently 
details any financial interests and arrangements that apply.  For the purpose of this regulation, 
"clinical investigator" is defined as any investigator or subinvestigator who is directly involved 
in the treatment or evaluation of research participants, including the spouse and each dependent 
child of the clinical investigator or subinvestigator.  These requirements apply to both US and 
foreign clinical investigators conducting covered clinical studies. 
Any new clinical investigators added to the covered clinical study during its conduct must also 
submit a completed Investigator Financial Disclosure Form.  During a covered clinical study, 
any changes to the financial information previously reported by a clinical investigator must be 
reported to the sponsor or its designee.  At the conclusion of the covered clinical study, the 
clinical investigators will be reminded of their obligations.  In the event that the clinical 
investigator is not reminded, they nevertheless will remain obligated to report to the sponsor or 
its designee any changes to the financial information previously reported, as well as any changes 
in their financial information for a period of 1 year after completion of the covered clinical study. 
11.5. 
Publication Policy 
By signing the study Protocol, the investigator and his or 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. 
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The results of this study may be published or presented at scientific meetings.  If this is foreseen, 
the investigator agrees to submit all manuscripts or abstracts to the sponsor before submission.  
This allows the sponsor to protect proprietary information and to provide comments. 
The sponsor will comply with the requirements for publication of study results.  In accordance 
with standard editorial and ethical practice, the sponsor will generally support publication of 
multicenter studies only in their entirety and not as individual site data.  In this case, a 
coordinating investigator will be designated by mutual agreement. 
Authorship will be determined in line with International Committee of Medical Journal Editors 
authorship requirements. 
11.6. 
Study and Site Closure 
The sponsor designee reserves the right to close the study site or terminate the study at any time 
for any reason at the sole discretion of the sponsor.  Study sites will be closed upon study 
completion.  A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed. 
The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to: 
• Failure of the investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the sponsor's procedures, or GCP guidelines. 
• Inadequate recruitment of participants by the investigator. 
• Discontinuation of further study treatment development. 
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12. 
REFERENCES 
American Academy of Dermatology. Vitiligo: Treatment. https://www.aad.org/public/diseases/ 
color-problems/vitiligo#treatment. Accessed February 12, 2019. 
Bae JM, Jung HM, Hong BY, Lee JH, Choi WJ, Lee JH, Kim GM. Phototherapy for vitiligo: a 
systematic review and meta-analysis. JAMA Dermatol 2017;153:666-674. 
Bharmal M, Payne K, Atkinson MJ, Desrosiers MP, Morisky DE, Gemmen E. Validation of an 
abbreviated Treatment Satisfaction Questionnaire for Medication (TSQM-9) among patients on 
antihypertensive medications. Health Qual Life Outcomes 2009;7:36. 
Batchelor JM, Tan W, Tour S, Yong A, Montgomery AA, Thomas KS. Validation of the Vitiligo 
Noticeability Scale: a patient-reported outcome measure of vitiligo treatment success. Br J 
Dermatol 2016;174:386-394. 
Boniface K, Seneschal J, Picardo M, Taïeb A. Vitiligo: focus on clinical aspects, 
immunopathogenesis, and therapy. Clin Rev Allergy Immunol 2018;54:52-67. 
Castanet J, Ortonne JP. Pathophysiology of vitiligo. Clin Dermatol 1997:15:845-851. 
Clinical Trial Facilitation Group. Recommendations related to contraception and pregnancy 
testing in clinical trials. September 15, 2014. http://www.hma.eu/ctfg.html. Accessed November 
23, 2106. 
Coondoo A, Phiske M, Verma S, Lahiri K. Side-effects of topical steroids: a long overdue 
revisit. Indian Dermatol Online J 2014;5:416-425. 
Craiglow BG, King BA. Tofacitinib citrate for the treatment of vitiligo: a pathogenesis-directed 
Therapy. JAMA Dermatol 2015;151:1110-1112. 
Eleftheriadou V, Thomas KS, Whitton ME, Batchelor JM, Ravenscroft JC. Which outcomes 
should we measure in vitiligo? Results of a systematic review and a survey among patients and 
clinicians on outcomes in vitiligo trials. Br J Dermatol 2012;167:804-814. 
Finlay AY, Khan GK. Dermatology Life Quality Index (DLQI)--a simple practical measure for 
routine clinical use. Clin Exp Dermatol 1994;19:210-216. 
Frisoli ML, Harris JE. Vitiligo: mechanistic insights lead to novel treatments. J Allergy Clin 
Immunol 2017;140:654-662. 
Gawkrodger DJ, Ormerod AD, Shaw L, et al. Guideline for the diagnosis and management of 
vitiligo. Br J Dermatol 2008;159:1051-1076. 
González U, Whitton M, Eleftheriadou V, Pinart M, Batchelor J, Leonardi-Bee J. Guidelines for 
designing and reporting clinical trials in vitiligo. ArchDermatol 2011;147:1428-1436. 
Hamzavi I, Jain H, McLean D, Shapiro J, Zeng H, Lui H. Parametric modeling of narrowband 
UV-B phototherapy for vitiligo using a novel quantitative tool: the Vitiligo Area Scoring Index. 
Arch Dermatol 2004;140:677-683. 
Harris JE, Rashighi M, Nguyen N, et al. Rapid skin repigmentation on oral ruxolitinib in a 
patient with coexistent vitiligo and alopecia areata (AA). J Am Acad Dermatol 2016;74:370-371. 
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Joshipura D, Alomran A, Zancanaro P, Rosmarin D. Treatment of vitiligo with the topical Janus 
kinase inhibitor ruxolitinib: a 32-week open-label extension study with optional narrow-band 
ultraviolet B. J Am Acad Dermatol 2018;78:1205-1207. 
Krüger C, Panske A, Schallreuter KU. Disease-related behavioral patterns and experiences affect 
quality of life in children and adolescents with vitiligo. Int J Dermatol 2014;53:43-50. 
Krüger C, Schallreuter KU. A review of the worldwide prevalence of vitiligo in 
children/adolescents and adults. Int J Dermatol 2012;51:1206-1212. 
Lai YC, Yew YW, Kennedy C, Schwartz RA. Vitiligo and depression: a systematic review and 
meta-analysis of observational studies. Br J Dermatol 2017;177:708-718. 
Lilly E, Lu PD, Borovicka JH, et al. Development and validation of a vitiligo-specific 
quality-of-life instrument (VitiQoL). J Am Acad Dermatol 2013;69:e11-18. 
Linthorst Homan MW, de Korte J, Grootenhuis MA, Bos JD, Sprangers MA, van der Veen JP. 
Impact of childhood vitiligo on adult life. Br J Dermatol 2008;159:915-920. 
Linthorst Homan MW, Spuls PI, de Korte J, Bos JD, Sprangers MA, van der Veen JP. The 
burden of vitiligo: patient characteristics associated with quality of life. J Am Acad Dermatol 
2009;61:411-420. 
Mehta CR, Patel NR. Exact logistic regression: theory and examples. Stat Med 
1995;14:2143-2160. 
Osinubi O, Grainge MJ, Hong L, et al. The prevalence of psychological comorbidity in people 
with vitiligo: a systematic review and meta-analysis. Br J Dermatol 2018;178:863-878. 
Porter JR, Beuf AH, Lerner AB, Nordlund JJ, et al. The effect of vitiligo on sexual relationships. 
J Am Acad Dermatol 1990;22:221-222. 
Rodrigues M, Ezzedine K, Hamzavi I, Pandya AG, Harris JE, Vitiligo Working Group. New 
discoveries in the pathogenesis and classification of vitiligo. J Am Acad Dermatol 2017;77:1-13. 
Rothstein B, Joshipura D, Saraiya A, et al. Treatment of vitiligo with the topical Janus kinase 
inhibitor ruxolitinib. J Am Acad Dermatol 2017;76:1054-1060. 
Ruxolitinib Cream Investigator's Brochure. Wilmington, DE: Incyte Corporation. 
Salzer BA, Schallreuter KU. Investigation of the personality structure in patients with vitiligo 
and a possible association with impaired catecholamine metabolism. Dermatology 
1995;190:109-115. 
Silverberg JI, Silverberg NB. Association between vitiligo extent and distribution and 
quality-of-life impairment. JAMA Dermatol 2013;149:159-164. 
Speeckaert R, van Geel N. Vitiligo: an update on pathophysiology and treatment options. Am J 
Clin Dermatol 2017;18:733-744. 
Taieb A, Alomar A, Böhm M, et al. Guidelines for the management of vitiligo: the European 
Dermatology Forum consensus. Br J Dermatol 2013;168:5-19. 
Taieb A, Picardo M. Clinical practice. Vitiligo. N Engl J Med 2009;360:160-169. 
Topp CW, Østergaard SD, Søndergaard S, Bech P. The WHO-5 Well-Being Index: a systematic 
review of the literature. Psychother Psychosom 2015;84:167-176. 
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van Buuren S. Multiple imputation of discrete and continuous data by fully conditional 
specification. Stat Methods Med Res 2007;16:219-242. 
Vitiligo Research Foundation. Treatment Guidelines. 
https://vrfoundation.org/treatment_guidelines. Accessed February 12, 2019. 
Wang G, Qiu D, Yang H, Liu W. The prevalence and odds of depression in patients with vitiligo: 
a meta-analysis [published online ahead of print December 9, 2017]. J Eur Acad Dermatol 
Venereol. doi: 10.1111/jdv.14739. 
Whitton M, Pinart M, Batchelor JM, et al. Evidence-based management of vitiligo: summary of a 
Cochrane systematic review. Br J Dermatol 2016;174:962-969. 
WHO Collaborating Center for Mental Health, Psychiatric Research Unit. WHO-5. 
https://www.psykiatri-regionh.dk/who-5/Pages/default.aspx. Accessed June 6, 2019. 
Yazdani Abyaneh MA, Griffith R, Falto-Aizpurua L, Nouri K. The dark history of white spots. 
JAMA Dermatol 2014;150:936. 
Zigmond AS, Snaith RP. The hospital anxiety and depression scale. Acta Psychiatr Scand 
1983;67:361-370. 
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APPENDIX A. INFORMATION REGARDING EFFECTIVENESS OF 
CONTRACEPTIVE METHODS 
For male participants in the study: 
Male participants should use a condom during treatment through 90 days after the end of systemic 
exposure.  If the male participant has a partner that is of child-bearing potential, the partner should also 
use contraception through 90 days after the end of relevant systemic exposure.  In addition, male 
participants must refrain from donating sperm during the study through 90 days after the end of 
relevant systemic exposure.  Males who have had a vasectomy qualify as having met the requirement 
for a highly effective birth control method. 
For female participants in the study: 
The following methods that can achieve a failure rate of less than 1% per year when used consistently 
and correctly are considered as highly effective birth control methods: 
• 
Combined (estrogen and progestogen containing) hormonal contraception associated with 
inhibition of ovulationa 
− 
oral 
− 
intravaginal 
− 
transdermal 
• 
Progestogen-only hormonal contraception associated with inhibition of ovulationa 
− 
oral 
− 
injectable 
− 
implantableb 
• 
Intrauterine deviceb 
• 
Intrauterine hormone-releasing systemb 
• 
Bilateral tubal occlusionb 
• 
Vasectomized partnerbc 
• 
Sexual abstinenced 
Acceptable birth control methods that result in a failure rate of more than 1% per year include: 
• 
Progestogen-only oral hormonal contraception, where inhibition of ovulation is not the primary 
mode of action 
• 
Male or female condom with or without spermicidee 
• 
Cap, diaphragm, or sponge with spermicidee 
• 
Tubal ligation 
a Hormonal contraception may be susceptible to interaction with the investigational medicinal product, which may 
reduce the efficacy of the contraception method. 
b Contraception methods that in the context of this guidance are considered to have low user dependency. 
c Vasectomized partner is a highly effective method of avoiding pregnancy provided that partner is the sole sexual 
partner of the woman of childbearing potential study participant and that the vasectomized partner has received 
medical assessment of the surgical success. 
d In the context of this guidance, sexual abstinence is considered a highly effective method only if defined as 
refraining from heterosexual intercourse during the entire period of risk associated with the study treatments.  The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical study and the 
preferred and usual lifestyle of the participant. 
e A combination of male condom with either cap, diaphragm, or sponge with spermicide (double barrier methods) 
are also considered acceptable, but not highly effective, birth control methods. 
Source:  Clinical Trial Facilitation Group 2014. 
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APPENDIX B. PROTOCOL AMENDMENT SUMMARY OF CHANGES 
Not applicable. 
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Official Title: 
Topical Ruxolitinib Evaluation in Vitiligo Study 2 (TRuE-V2): A Phase 3, Double-Blind, 
Randomized, Vehicle-Controlled, Efficacy and Safety Study of Ruxolitinib Cream 
NCT Number: 
NCT04057573 
Document Date: 
 Clinical Study Protocol Version 4: 13 March 2020
Followed by an Extension Period in Participants With Vitiligo


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Protocol INCB 18424-307 Am 3-US-CA 
Version 4-US-CA 
13 MAR 2020 
CONFIDENTIAL 
 
Clinical Study Protocol 
 
INCB 18424-307 
Topical Ruxolitinib Evaluation in Vitiligo Study 2 
(TRuE-V2) 
A Phase 3, Double-Blind, Randomized, Vehicle-Controlled, Efficacy 
and Safety Study of Ruxolitinib Cream Followed by an Extension Period 
in Participants With Vitiligo 
 
Product: 
Ruxolitinib Cream 
IND Number: 
77,101 
EudraCT Number: 
2019-000847-28 
Phase of Study: 
3 
Sponsor: 
Incyte Corporation 
1801 Augustine Cut-Off 
Wilmington, DE 19803 
Original Protocol: 
23 JUN 2019 
Amendment 1: 
31 OCT 2019 
Amendment 2:  
12 DEC 2019 
Amendment 3: 
21 FEB 2020 
Amendment 3-US-CA: 
13 MAR 2020 
 
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 18424-307 Protocol Amendment 3-US-CA (dated 13 MAR 2020) and 
agree to conduct the study as outlined.  I agree to maintain the confidentiality of all information 
received or developed in connection with this Protocol. 
 
 
 
 
 
(Printed Name of Investigator) 
 
 
 
 
 
 
 
 
(Signature of Investigator) 
 
(Date) 
 


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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ..........................................................................................................8 
1. 
PROTOCOL SUMMARY ..........................................................................................11 
2. 
INTRODUCTION ......................................................................................................20 
2.1. 
Epidemiology of Vitiligo ............................................................................................20 
2.2. 
Current Treatment and Unmet Need in Vitiligo .........................................................21 
2.3. 
Role of Janus Kinases in Vitiligo ...............................................................................22 
2.4. 
Ruxolitinib Cream ......................................................................................................23 
 
23 
2.4.2. 
Clinical Experience .....................................................................................................24 
 
24 
2.4.2.2. 
Efficacy of Ruxolitinib Cream ....................................................................................26 
 
30 
 
30 
 
31 
 
31 
3. 
OBJECTIVES AND ENDPOINTS ............................................................................33 
4. 
STUDY DESIGN .......................................................................................................36 
4.1. 
Overall Design ............................................................................................................36 
4.2. 
Overall Study Duration ...............................................................................................36 
4.3. 
Study Termination ......................................................................................................37 
5. 
STUDY POPULATION .............................................................................................37 
5.1. 
Inclusion Criteria ........................................................................................................37 
5.2. 
Exclusion Criteria .......................................................................................................38 
5.3. 
Lifestyle Considerations .............................................................................................40 
5.4. 
Screen Failures ............................................................................................................40 
5.5. 
Replacement of Participants .......................................................................................40 
6. 
STUDY TREATMENT ..............................................................................................41 
6.1. 
Study Treatment Application ......................................................................................41 
6.1.1. 
Application During the Double-Blind Vehicle-Controlled Treatment Period ...........42 
6.1.2. 
Application During the Treatment Extension Period .................................................42 
6.2. 
Preparation, Handling, and Accountability ................................................................42 


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6.3. 
Measures to Minimize Bias:  Randomization and Blinding .......................................43 
6.4. 
Study Treatment Compliance .....................................................................................44 
6.5. 
Dose Modifications .....................................................................................................44 
6.5.1. 
Criteria and Procedures for Application Interruptions of Study Drug .......................44 
6.5.2. 
Criteria for Permanent Discontinuation of Study Drug Due to an Adverse 
Event ...........................................................................................................................45 
6.6. 
Concomitant Medications and Procedures .................................................................45 
 
46 
 
46 
 
47 
6.8. 
Treatment After the End of the Study .........................................................................47 
7. 
DISCONTINUATION OF STUDY TREATMENT AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ..................................................................48 
7.1. 
Discontinuation of Study Treatment ...........................................................................48 
7.1.1. 
Reasons for Discontinuation .......................................................................................48 
7.1.2. 
Discontinuation Procedures ........................................................................................48 
7.2. 
Participant Withdrawal From the Study .....................................................................49 
7.3. 
Lost to Follow-Up .......................................................................................................49 
8. 
STUDY ASSESSMENTS AND PROCEDURES ......................................................50 
8.1. 
Administrative and General Procedures .....................................................................50 
8.1.1. 
Informed Consent Process ..........................................................................................50 
8.1.2. 
Screening Procedures ..................................................................................................51 
8.1.3. 
Interactive Response Technology Procedure ..............................................................51 
8.1.4. 
Distribution of Study Reminder Cards and Diaries ....................................................51 
8.1.5. 
Demography and Medical History ..............................................................................52 
8.1.5.1. 
Demographics and General Medical History .............................................................52 
8.1.5.2. 
Disease Characteristics and Treatment History ..........................................................52 
 
52 
8.2. 
Efficacy Assessments .................................................................................................53 
8.2.1. 
Body Surface Area ......................................................................................................53 
8.2.2. 
Vitiligo Area Scoring Index ........................................................................................53 
8.2.3. 
Physician’s Global Vitiligo Assessment (Facial) .......................................................54 
8.2.4. 
Physician’s Global Vitiligo Assessment (Total Body) ...............................................54 


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8.2.5. 
Photography ................................................................................................................55 
8.2.6. 
Patient-Reported Outcomes ........................................................................................55 
8.2.6.1. 
Vitiligo Noticeability Scale ........................................................................................56 
8.2.6.2. 
Color-Matching Question ...........................................................................................56 
8.2.6.3. 
Patient Global Impression of Change-Vitiligo (Facial) ..............................................56 
8.2.6.4. 
Patient Global Impression of Change-Vitiligo (Total Body) .....................................57 
8.2.6.5. 
Dermatology Life Quality Index ................................................................................57 
8.2.6.6. 
WHO-5 .......................................................................................................................58 
8.2.6.7. 
Treatment Satisfaction Questionnaire for Medication ................................................58 
8.2.6.8. 
VitiQoL .......................................................................................................................58 
8.2.6.9. 
Hospital Anxiety and Depression Scale .....................................................................58 
8.3. 
Safety Assessments .....................................................................................................58 
8.3.1. 
Adverse Events ...........................................................................................................58 
8.3.2. 
Physical Examinations ................................................................................................59 
8.3.3. 
Vital Signs ..................................................................................................................59 
8.3.4. 
Electrocardiograms .....................................................................................................59 
8.3.5. 
Laboratory Assessments .............................................................................................60 
8.3.5.1. 
Pregnancy Testing ......................................................................................................61 
8.3.5.2. 
Serology ......................................................................................................................62 
8.4. 
Pharmacokinetic Assessments ....................................................................................62 
8.5. 
Pharmacodynamic and Translational Assessments ....................................................62 
8.6. 
Unscheduled Visits .....................................................................................................62 
8.7. 
End of Treatment and/or Early Termination ..............................................................62 
8.8. 
Safety Follow-Up ........................................................................................................63 
9. 
ADVERSE EVENTS:  DEFINITIONS AND PROCEDURES FOR 
RECORDING, EVALUATING, FOLLOW-UP, AND REPORTING ......................63 
9.1. 
Definition of Adverse Event .......................................................................................63 
9.2. 
Definition of Serious Adverse Event ..........................................................................64 
9.3. 
Recording and Follow-Up of Adverse Events and/or Serious Adverse Events .........65 
9.4. 
Reporting of Serious Adverse Events .........................................................................67 
9.5. 
Emergency Unblinding of Treatment Assignment .....................................................68 
9.6. 
Pregnancy ...................................................................................................................69 
9.7. 
Warnings and Precautions ..........................................................................................69 


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9.8. 
Product Complaints ....................................................................................................69 
9.9. 
Treatment of Overdose ...............................................................................................70 
10. 
STATISTICS ..............................................................................................................70 
10.1. 
Sample Size Determination ........................................................................................70 
10.2. 
Populations for Analysis .............................................................................................71 
10.3. 
Statistical Analyses .....................................................................................................71 
10.3.1. 
Efficacy Analyses .......................................................................................................71 
10.3.1.1. 
Primary Analysis ........................................................................................................71 
10.3.1.2. 
Key Secondary Analysis .............................................................................................72 
10.3.1.3. 
Secondary Analysis ....................................................................................................73 
10.3.2. 
Safety Analyses ..........................................................................................................73 
10.4. 
Analysis Plan ..............................................................................................................74 
11. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS ..................................................................................................74 
11.1. 
Investigator Responsibilities .......................................................................................74 
11.2. 
Data Management .......................................................................................................75 
11.3. 
Data Privacy and Confidentiality of Study Records ...................................................77 
11.4. 
Financial Disclosure ...................................................................................................77 
11.5. 
Publication Policy .......................................................................................................77 
11.6. 
Study and Site Closure ................................................................................................78 
12. 
REFERENCES ...........................................................................................................79 
APPENDIX A. INFORMATION REGARDING EFFECTIVENESS OF 
CONTRACEPTIVE METHODS ...............................................................................82 
APPENDIX B. WHO CLASSIFICATION OF TOPICAL CORTICOSTEROIDS ...................83 
APPENDIX C. PROTOCOL AMENDMENT SUMMARY OF CHANGES ............................84 
 


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LIST OF TABLES 
Table 1: 
Primary and Secondary Objectives and Endpoints .....................................................11 
Table 2: 
Key Study Design Elements .......................................................................................12 
Table 3: 
Schedule of Activities:  Double-Blind, Vehicle-Controlled Treatment Period 
(Day 1-Week 24) ........................................................................................................14 
Table 4: 
Schedule of Activities:  Treatment Extension Period (Week 28-Week 52) ...............17 
 
25 
 
 
26 
 
29 
Table 8: 
Objectives and Endpoints ...........................................................................................33 
Table 9: 
Study Treatment Information .....................................................................................41 
Table 10: Guidelines for Interruption and Restarting of Study Drug .........................................45 
Table 11: Facial Physician's Global Vitiligo Assessment Scale .................................................54 
Table 12: Total Body Physician's Global Vitiligo Assessment Scale ........................................55 
Table 13: Required Laboratory Analytes ....................................................................................61 
Table 14: Powering for Primary and Key Secondary Endpoints ................................................70 
Table 15: Populations for Analysis .............................................................................................71 
 
LIST OF FIGURES 
Figure 1: 
Study Design Schema .................................................................................................13 
 
 
25 
Figure 3: 
INCB 18424-211 Study Schema ................................................................................27 
 


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LIST OF ABBREVIATIONS  
The following abbreviations and special terms are used in this clinical study Protocol. 
Abbreviations and 
Special Terms 
Definition 
2D 
2-dimensional 
3D 
3-dimensional 
AA 
alopecia areata 
AD 
atopic dermatitis 
AE 
adverse event 
ALT 
alanine aminotransferase 
ANCOVA 
analysis of covariance 
AST 
aspartate aminotransferase 
BID 
twice daily 
BSA 
body surface area 
CDLQI 
Children’s Dermatology Life Quality Index 
CFR 
Code of Federal Regulations 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
cytochrome P450 
DLQI 
Dermatology Life Quality Index 
DSMB 
Data Safety Monitoring Board 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EDC 
electronic data capture 
EOS 
end of study 
EOT 
end of treatment 
F-BSA 
facial body surface area 
F-PaGIC-V 
facial assessment of Patient Global Impression of Change-Vitiligo 
F-PaGVA 
facial assessment of Patient's Global Vitiligo Assessment 
F-PhGVA 
facial assessment of Physician Global Vitiligo Assessment 
FSH 
follicle-stimulating hormone 
F-VASI 
Face Vitiligo Area Scoring Index 
F-VASI25/50/75/90 
≥ 25%/ 50%/ 75%/ 90% improvement from baseline in Face Vitiligo Area 
Scoring Index score 
GCP 
Good Clinical Practice 
HADS 
Hospital Anxiety and Depression Scale 
hCG 
human chorionic gonadotrophin 


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Abbreviations and 
Special Terms 
Definition 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
human immunodeficiency virus 
IB 
Investigator's Brochure 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
ID 
identification 
IEC 
independent ethics committee 
INFO 
International Initiative for Outcomes 
IRB 
institutional review board 
IRT 
interactive response technology 
ITT 
intent to treat 
JAK 
Janus kinase 
LOCF 
last observation carry forward 
MI 
multiple imputation 
MMRM 
mixed-effect model repeat measurement 
NB-UVB 
narrow-band ultraviolet B 
Pa-GIC-V 
Patient Global Impression of Change-Vitiligo 
PhGVA 
Physician Global Vitiligo Assessment 
PK 
pharmacokinetic 
PP 
per protocol 
PUVA 
psoralen and ultraviolet A 
QD 
once daily 
SAE 
serious adverse event 
SD 
standard deviation 
SoA 
schedule of assessments 
SOP 
standard operating procedure 
STAT 
signal transducer and activator of transcription  
SUSAR 
suspected unexpected adverse reaction 
T-BSA 
total body surface area 
TCS 
topical corticosteroid 
TEAE 
treatment-emergent adverse event 
T-PaGIC-V 
total body assessment of Patient Global Impression of Change-Vitiligo 
T-PaGVA 
total body assessment of Patient's Global Vitiligo Assessment 
T-PhGVA 
total body assessment of Physician Global Vitiligo Assessment 
TSH 
thyroid-stimulating hormone 
TSQM 
Treatment Satisfaction Questionnaire for Medication 


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Abbreviations and 
Special Terms 
Definition 
T-VASI 
total body Vitiligo Area Scoring Index 
T-VASI25/50/75/90 
≥ 25%/ 50%/ 75%/ 90% improvement in total body Vitiligo Area Scoring Index 
TYK 
tyrosine kinase 
ULN 
upper limit of normal 
UV 
ultraviolet 
VASI 
Vitiligo Area Scoring Index 
VitiQoL 
Vitiligo-specific quality of life 
VNS 
Vitiligo Noticeability Scale 
WHO-5 
World Health Organization-Five Well-Being Index 


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1. 
PROTOCOL SUMMARY 
Protocol Title:  A Phase 3, Double-Blind, Randomized, Vehicle-Controlled, Efficacy and Safety 
Study of Ruxolitinib Cream Followed by an Extension Period in Participants With Vitiligo 
Protocol Number:  INCB 18424-307 
Objectives and Endpoints: 
Table 1 presents the primary, key secondary, and selected secondary objectives and endpoints. 
Table 1: 
Primary and Secondary Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
To evaluate the efficacy of ruxolitinib cream in 
participants with vitiligo. 
• Proportion of participants achieving F-VASI75 at 
Week 24. 
Key Secondary 
To further assess the efficacy of ruxolitinib 
cream. 
• Proportion of participants achieving F-VASI50 at 
Week 24. 
• Proportion of participants achieving F-VASI90 at 
Week 24. 
• Proportion of participants achieving T-VASI50 at 
Week 24. 
• Proportion of participants achieving a VNS of  
“4 – A lot less noticeable” or “5 – No longer 
noticeable” at Week 24. 
• Percentage change from baseline in F-BSA at 
Week 24. 
Selected Secondary 
To evaluate the safety and tolerability of 
ruxolitinib cream. 
• The frequency, duration, and severity of AEs; 
physical examinations; vital signs; and laboratory 
data for hematology and serum chemistry. 
To further assess the efficacy of ruxolitinib 
cream. 
• Proportion of participants achieving 
F-VASI25/50/75/90 during the treatment period 
(double-blind and treatment extension periods).  
• Proportion of participants achieving 
T-VASI25/50/75/90 during the treatment period 
(double-blind and treatment extension periods).  
• Proportion of participants in each category of VNS 
during the treatment period (double-blind and 
treatment extension periods). 


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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 3 
Clinical Indication 
Vitiligo 
Population 
Males and females, aged ≥ 12 years, who have vitiligo with ≥ 0.5% BSA on the 
face, ≥ 0.5 F-VASI, ≥ 3% BSA on nonfacial areas, and ≥ 3 T-VASI.  Total body 
vitiligo area (facial and nonfacial) should not exceed 10% BSA. 
Participants must have a clinical diagnosis of non-segmental vitiligo.  Other forms 
of vitiligo (eg, segmental) or other differential diagnosis of vitiligo or other skin 
depigmentation disorders will be excluded. 
See Section 5 for all inclusion and exclusion criteria.  
Number of 
Participants 
Approximately 300 participants will be randomized 2:1 (ruxolitinib cream 1.5% 
BID:vehicle). 
Study Design 
Randomized, double-blind, vehicle-controlled, with a treatment extension period. 
Exit interviews will be conducted with participants at selected sites to better 
understand their perception of repigmentation improvement and quality of life 
(see Section 8.1.6). 
Estimated Duration 
of Study 
Participation 
Screening:  Up to 32 days 
Double-blind period:  24 weeks 
Treatment extension period:  28 weeks 
Safety follow-up:  30 days after last application of study medication or last study 
visit 
Total:  Up to approximately 60 weeks 
DSMB 
The study is not evaluating an endpoint with serious morbidity/mortality.  Thus, a 
DSMB is not required. 
The study design is shown in Figure 1.  The SoA is detailed in Table 3 (for the double-blind 
period) and Table 4 (for the treatment extension period).  Adherence to the study design 
requirements, including those specified in the SoA, is essential and required for study conduct. 


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Figure 1: 
Study Design Schema 
 
This is a randomized, vehicle-controlled study in adolescent and adult participants (age 
≥ 12 years) with non-segmental vitiligo who have depigmented area including ≥ 0.5% BSA on 
the face, ≥ 0.5 F-VASI, ≥ 3% BSA on nonfacial areas, and ≥ 3 T-VASI.  Total body involved 
vitiligo area (facial and nonfacial) should not exceed 10% BSA.  Approximately 300 participants 
will be randomized 2:1 to receive initial study treatment (ruxolitinib cream 1.5% BID:vehicle; 
applied to depigmented vitiligo areas on the face and body up to 10% total BSA) for 24 weeks 
(see Figure 1).  Participants will be stratified by region (North America or Europe) and skin type 
(Fitzpatrick scale Type I and II vs Type III, IV, V, and VI).  Adolescents (≥ 12 to < 18 years) 
will make up at least 10% of the study population, and no more than 50% of participants will be 
> 40 years old. 
After completion of the Week 24 assessments, participants will be offered the opportunity to 
receive an additional 28 weeks of treatment extension with ruxolitinib cream 1.5% BID.  To be 
eligible for the treatment extension, participants must have completed the baseline and Week 24 
visit assessments, be compliant with study procedures, and not have any safety issues.  The total 
treated area should not exceed 10% BSA (facial and nonfacial). 
See Section 4.1 for full details of the study design. 
Participants who successfully complete the 52-week treatment in this study may be eligible to 
participate in a separate extension study to evaluate durability of effect and maintenance 
regimens. 


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Table 3: 
Schedule of Activities:  Double-Blind, Vehicle-Controlled Treatment Period (Day 1-Week 24) 
Procedure 
Screening 
Double-Blind, Vehicle Controlled Treatment 
Notes 
Days 
-32 to -1 
Day 1 
 
Wk 4 
± 3 d 
Wk 8 
± 3 d 
Wk 12 
± 3 d 
Wk 18 
± 7 d 
Wk 24* 
(EOT1) 
± 7 d 
*Week 24 is considered the first visit of the treatment 
extension period. 
Administrative procedures 
 
Informed consent 
X 
 
 
 
 
 
 
 
Informed consent for optional 
qualitative exit interviews 
X* 
 
 
 
 
 
 
A subgroup of participants at sponsor-selected sites will be 
included in a substudy involving exit interviews. 
*If consent to provide exit interviews was not obtained at 
screening, it can be obtained at the participant’s next study 
visit. 
Contact IRT 
X* 
X 
X 
X 
X 
X 
X 
*Entry of age and skin type information into the IRT will be 
required at screening. 
Inclusion and exclusion criteria 
X 
X 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
General and disease medical 
history 
X 
 
 
 
 
 
 
 
Prior/concomitant medications  
X 
X 
X 
X 
X 
X 
X 
 
Apply study drug 
 
X 
X 
X 
X 
X 
X* 
At each study visit starting at Day 1, the participant should 
apply the study drug under direct supervision of the site staff.  
*Not applicable to the EOT1 visit. 
Dispense (D) and return (R) 
study drug and diary cards 
 
D 
R/D 
R/D 
R/D 
R/D 
R/D* 
All tubes of study drug will be weighed before being 
dispensed.  All returned tubes of study drug will be weighed. 
*Dispension is not applicable to the EOT1 visit.  At the Week 
24 visit, study drug and diary cards are only dispensed to 
participants continuing in the treatment extension period. 
Collect study drug and collect/ 
review study drug diary cards 
 
 
X 
X 
X 
X 
X 
 
Assess compliance 
 
 
X 
X 
X 
X 
X 
 
Qualitative exit interview 
 
 
 
 
 
 
X* 
*The qualitative exit interview is conducted only for the 
subgroup of participants who consented to participate. 


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Table 3: 
Schedule of Activities:  Double-Blind, Vehicle-Controlled Treatment Period (Day 1-Week 24) (Continued) 
Procedure 
Screening 
Double-Blind, Vehicle Controlled Treatment 
Notes 
Days 
-32 to -1 
Day 1 
 
Wk 4 
± 3 d 
Wk 8 
± 3 d 
Wk 12 
± 3 d 
Wk 18 
± 7 d 
Wk 24* 
(EOT1) 
± 7 d 
*Week 24 is considered the first visit of the treatment 
extension period. 
Safety assessments 
 
AE assessment  
X 
X 
X 
X 
X 
X 
X 
Ad hoc photography of skin-related AEs may also occur as 
applicable.  
Targeted physical examinations 
 
X 
X 
X 
X 
X 
 
A targeted physical examination should be conducted as 
indicated by symptoms reported by the participant, AEs, or 
other findings.  Abnormalities that are considered clinically 
significant in the judgment of the investigator are to be 
reported as AEs.  See Section 8.3.2. 
Comprehensive physical 
examination 
X 
 
 
 
 
 
X 
 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
 
12-lead ECG 
X 
 
 
 
 
 
 
12-lead ECG performed within 2 months before baseline is 
acceptable. 
Efficacy assessments 
 
F-BSA 
X 
X 
X 
X 
X 
X 
X 
 
T-BSA 
X 
X 
X 
X 
X 
X 
X 
Includes facial and nonfacial areas. 
F-VASI 
X 
X 
X 
X 
X 
X 
X 
 
T-VASI 
X 
X 
X 
X 
X 
X 
X 
Includes facial and nonfacial areas. 
F-PhGVA 
 
X 
 
 
X 
 
X 
 
T-PhGVA 
 
X 
 
 
X 
 
X 
 
Photography of face 
X 
X* 
 
 
X 
 
X 
2D photography at all sites; 3D photography at selected sites. 
*If photo quality at screening is not adequate, the photography 
may be repeated at Day 1. The baseline photos are defined as 
the adequate ones either taken at screening or Day 1. 
Photography of nonfacial target 
area 
X 
X* 
 
 
X 
 
X 
2D photography at all sites. The genitalia area should not be 
photographed. 
*If photo quality at screening is not adequate, the photography 
may be repeated at Day 1. The baseline photos are defined as 
the adequate ones either taken at screening or Day 1.  


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Table 3: 
Schedule of Activities:  Double-Blind, Vehicle-Controlled Treatment Period (Day 1-Week 24) (Continued) 
Procedure 
Screening 
Double-Blind, Vehicle Controlled Treatment 
Notes 
Days 
-32 to -1 
Day 1 
 
Wk 4 
± 3 d 
Wk 8 
± 3 d 
Wk 12 
± 3 d 
Wk 18 
± 7 d 
Wk 24* 
(EOT1) 
± 7 d 
*Week 24 is considered the first visit of the treatment extension 
period. 
Patient-reported outcomes 
To be evaluated prior to any other study procedures/assessments. 
VNS 
 
 
 
 
X 
 
X 
The participant will be provided their baseline photo and a mirror 
to perform this assessment. 
Color-matching question 
 
 
 
 
X 
 
X 
The participant will be provided their baseline photo and a mirror 
to perform this assessment. 
F-PaGIC-V 
 
 
 
 
X 
 
X 
 
T-PaGIC-V 
 
 
 
 
X 
 
X 
 
DLQI 
 
X 
 
 
X 
 
X 
For participants who are age ≥ 12 years to < 16 years at baseline, 
the CDLQI will be completed instead. 
WHO-5 
 
X 
 
 
X 
 
X 
 
TSQM 
 
 
 
 
X 
 
X 
 
VitiQoL 
 
X 
 
 
X 
 
X 
 
HADS 
 
X 
 
 
 
 
X 
 
Laboratory assessments  
 
Hematology and chemistry 
assessments 
X 
X 
X 
X* 
X 
X* 
X 
*The blood draw at Week 8 and Week 18 is optional for 
participants who are age < 18 years 
Serology and thyroid testing 
X 
 
 
 
 
 
 
Serology includes HIV antibody. 
Urinalysis 
X 
 
 
 
 
 
 
 
FSH 
X 
 
 
 
 
 
 
For confirmation of nonchildbearing status of women who are 
postmenopausal defined as having amenorrhea for at least 
12 months without an alternative medical cause before screening.  
Pregnancy testing 
X* 
X 
X 
X 
X 
X 
X 
*Female participants of childbearing potential will have a serum 
test at screening and safety follow-up visits.  A urine test will be 
conducted at all other visits.  A positive urine test must be 
confirmed by a serum test. 
PK and translational assessments 
 
Population-based PK plasma 
sampling (trough) 
 
 
X 
 
 
 
X 
Time of last study drug application to be recorded in eCRF.  
Blood samples must not be drawn from the area that has been 
treated with study drug. 
Samples will be drawn at predose. 
Serum sampling for biomarker 
analysis 
 
X 
 
 
X 
 
X 
 
Note:  Unscheduled visits may occur at any time at the investigator's discretion, and appropriate clinical and laboratory tests may be performed, as clinically indicated. 


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Table 4: 
Schedule of Activities:  Treatment Extension Period (Week 28-Week 52) 
Procedure 
Treatment Extension 
Safety Follow-Up 
Notes 
Wk 28 
± 7 d 
Wk 34 
± 7 d 
Wk 40 
± 7 d 
Wk 46 
± 7 d 
Wk 52 
(EOT2*) 
± 7 d 
30 days 
+ 7 d After 
EOT1/EOT2** 
(EOS) 
*EOT2 assessments should be performed in the 
event a participant’s treatment is stopped before 
Week 52 at any relevant study visit before that time. 
**After last application of study drug or last visit. 
Administrative procedures 
 
Contact IRT 
X 
X 
X 
X 
X 
X 
 
Prior/concomitant medications  
X 
X 
X 
X 
X 
X 
 
Apply study drug 
X 
X 
X 
X 
 
 
At each study visit, the participant should apply the 
study drug under direct supervision of the site staff. 
Dispense (D) and return (R) study 
drug and diary cards 
R/D 
R/D 
R/D 
R/D 
R 
 
All tubes of study drug will be weighed before being 
dispensed.  All returned tubes of study drug will be 
weighed. 
Collect study drug and collect/ 
review study drug diary cards 
X 
X 
X 
X 
X 
 
 
Assess compliance 
X 
X 
X 
X 
X 
 
 
Qualitative exit interview 
 
 
 
 
X* 
 
*The qualitative exit interview is conducted only for 
the subgroup of participants who consented to 
participate. 
Safety assessments 
 
AE assessment 
X 
X 
X 
X 
X 
X 
A targeted physical examination should be 
conducted as indicated by symptoms reported by the 
participant, AEs, or other findings.  Abnormalities 
that are considered clinically significant in the 
judgment of the investigator are to be reported as 
AEs.  See Section 8.3.2. 
Targeted physical examinations 
X 
X 
X 
X 
 
X 
 
Comprehensive physical 
examination 
 
 
 
 
X 
 
 
Vital signs 
X 
X 
X 
X 
X 
X 
 
Efficacy assessments 
 
F-BSA 
X 
X 
X 
X 
X 
X 
 
T-BSA 
X 
X 
X 
X 
X 
X 
Includes facial and nonfacial areas. 
F-VASI 
X 
X 
X 
X 
X 
X 
 
T-VASI 
X 
X 
X 
X 
X 
X 
Includes facial and nonfacial areas. 
F-PhGVA 
 
 
X 
 
X 
 
 


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Table 4: 
Schedule of Activities:  Treatment Extension Period (Week 28-Week 52) (Continued) 
Procedure 
Treatment Extension 
Safety Follow-Up 
Notes 
Wk 28 
± 7 d 
Wk 34 
± 7 d 
Wk 40 
± 7 d 
Wk 46 
± 7 d 
Wk 52 
(EOT2*) 
± 7 d 
30 days 
+ 7 d After 
EOT1/EOT2** 
(EOS) 
*EOT2 assessments should be performed in the 
event a participant’s treatment is stopped before 
Week 52 at any relevant study visit before that time. 
**After last application of study drug or last visit. 
T-PhGVA 
 
 
X 
 
X 
 
 
Photography of face 
 
 
X 
 
X 
 
2D photograph at all sites; 3D photography at 
selected sites. 
Photography of nonfacial target 
area 
 
 
X 
 
X 
 
2D photography at all sites. The genitalia area should 
not be photographed. 
Patient-reported outcomes 
To be evaluated prior to any other study 
procedures/assessments. 
VNS 
 
 
X 
 
X 
 
The participant will be provided their baseline photo 
and a mirror to perform this assessment. 
Color-matching question 
 
 
X 
 
X 
 
The participant will be provided their baseline photo 
and a mirror to perform this assessment. 
F-PaGIC-V 
 
 
X 
 
X 
 
 
T-PaGIC-V 
 
 
X 
 
X 
 
 
DLQI 
 
 
X 
 
X 
 
For participants who are age ≥ 12 years to < 16 years 
at baseline, the CDLQI will be completed instead. 
WHO-5 
 
 
X 
 
X 
 
 
TSQM 
 
 
X 
 
X 
 
 
VitiQoL 
 
 
X 
 
X 
 
 
HADS 
 
 
 
 
X 
 
 
Laboratory assessments 
 
Hematology and chemistry 
assessments 
X 
X 
X 
X* 
X 
X 
*The blood draw at Week 46 is optional for 
participants who are age < 18 years 
Pregnancy testing 
X 
X 
X 
X 
X 
X* 
*Female participants of childbearing potential will 
have a serum test at screening and safety follow-up 
visits.  A urine test will be conducted at all other 
visits.  A positive urine test must be confirmed by a 
serum test. 


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Table 4: 
Schedule of Activities:  Treatment Extension Period (Week 28-Week 52) (Continued) 
Procedure 
Treatment Extension 
Safety Follow-Up 
Notes 
Wk 28 
± 7 d 
Wk 34 
± 7 d 
Wk 40 
± 7 d 
Wk 46 
± 7 d 
Wk 52 
(EOT2*) 
± 7 d 
30 days 
+ 7 d After 
EOT1/EOT2** 
(EOS) 
*EOT2 assessments should be performed in the 
event a participant’s treatment is stopped before 
Week 52 at any relevant study visit before that time. 
**After last application of study drug or last visit. 
PK and Translational assessments 
Population-based PK plasma 
sampling (trough) 
 
 
X 
 
 
 
Time of last study drug application to be recorded in 
eCRF.  Blood samples must not be drawn from the 
area that has been treated with study drug. 
Samples will be drawn at predose. 
Serum sampling for biomarker 
analysis 
 
 
X 
 
X 
 
 
Note:  Unscheduled visits may occur at any time at the investigator's discretion, and appropriate clinical and laboratory tests may be performed, as clinically indicated. 


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2. 
INTRODUCTION 
Ruxolitinib cream is a topical formulation of ruxolitinib phosphate under development for the 
treatment of participants with AD, AA, plaque psoriasis, and vitiligo.  Ruxolitinib phosphate is 
an inhibitor of the JAK family of protein TYKs.  Inflammatory cytokines are strongly implicated 
in the pathogenesis of several dermatologic diseases.  Because JAKs serve to translate 
extracellular signals from a number of relevant cytokines and growth factors upregulated in 
inflammatory diseases such as AD, AA, plaque psoriasis, and vitiligo, JAK inhibitors represent 
potential therapeutic agents for these disease states. 
2.1. 
Epidemiology of Vitiligo 
Vitiligo is an autoimmune pigmentary disease characterized by depigmented patches of skin with 
a selective loss of melanocytes.  It is estimated to affect 0.5% to 2% of the population worldwide 
(Krüger and Schallreuter 2012).  The prevalence is similar between men and women, and there is 
no known difference in presentation according to skin type or race.  Almost 50% of patients 
present before 20 years of age, and many of them present before 10 years of age (Rodrigues et al 
2017).  Generalized (non-segmental) vitiligo is the most common type, accounting for up to 
90% of cases (Taieb et al 2009).  Vitiligo is associated with autoimmune diseases such as Sutton 
nevus, thyroid disorders, juvenile diabetes mellitus, pernicious anemia, and Addison's disease.  
The natural course of the disease is generally unpredictable, but it is often progressive.  Some 
degree of spontaneous repigmentation may occur in 10% to 20% of patients; however, it is 
typically not cosmetically acceptable (Castanet and Ortonne 1997). 
Vitiligo is a serious disease owing to its substantial psychological impact on patients’ day-to-day 
functioning, and its progressive course if left untreated.  Studies have shown that the effect 
vitiligo has on quality of life, particularly psychological impairment, is similar to other skin 
diseases, such as psoriasis and AD (Linthorst et al 2009).  Involvement of exposed skin, such as 
the face and hands, can have a major impact on self-esteem and eventually link to the 
psychological burden and quality of life (Silverberg and Silverberg 2013).  In some societies, 
there is poor acceptance and understanding of the disease, to the extent of discrimination against 
affected individuals (Yazdani Abyaneh et al 2014).  Approximately 75% of vitiligo sufferers feel 
their appearance is moderately to severely intolerable, and 41% of patients feel that there is little 
they can do to improve their condition, and feelings of hopelessness increase with time (Salzer 
and Schallreuter 1995).  Not surprisingly, 66% of patients report being distressed by their 
disease, and 92% have experienced stigmatization (Krüger et al 2014).  Feelings of 
embarrassment and fear of rejection can cause vitiligo patients to withdraw and lead to social 
isolation in both personal and professional relationships.  A majority of patients with vitiligo 
have reported feelings of anxiety and embarrassment when meeting strangers or beginning a new 
sexual relationship (Porter et al 1990). Additionally, clinical depression or depressive symptoms 
are associated with vitiligo.  Based on various meta-analyses, patients with vitiligo were 
approximately 5 times more likely to suffer from depression than healthy controls (Lai et al 
2017, Osinubi et al 2018).  A recent results of the analysis indicated that the pooled prevalence 
of depression across 17 unique populations (n = 1711) was 29% (Wang et al 2017). 


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Studies also suggest that the onset of vitiligo beginning in childhood can be associated with 
significant psychological trauma that may have long lasting effects on self-esteem.  The extent of 
vitiligo is associated with QOL impairment in children and adolescents, especially 
self-consciousness, but also bullying and teasing.  Teenagers ages 15 to 17 years seem to 
experience the most self-consciousness of all pediatric age groups (Silverberg and Silverberg 
2013).  In a study comparing social development and the health-related quality of life of young 
adult patients with childhood vitiligo with healthy controls, vitiligo patients reporting negative 
childhood experiences reported significantly more problems in social development than those not 
reporting negative experiences.  Furthermore, negative childhood experiences were significantly 
associated with more health-related quality of life impairment in early adulthood (Linthorst 
Homan et al 2008).  Thus, vitiligo is considered to be one of the most psychologically 
devastating diseases in dermatology. 
2.2. 
Current Treatment and Unmet Need in Vitiligo 
Currently, there is no approved drug treatment for vitiligo.  The conclusions of the most recent 
updated Cochrane systematic review were hampered by the heterogeneity of the performed 
clinical studies (Whitton et al 2016).  A systemic review on outcomes in a vitiligo study also 
showed that the 25 different outcomes had been measured in 54 randomized clinical studies.  
Although repigmentation was measured in 94% of studies, 48 different scales were used to 
measure it, making comparison among studies impossible (Eleftheriadou et al 2012).  Therefore, 
a definitive clinical recommendation for treatment of vitiligo could not be proposed, and the 
management of vitiligo is empirical and based on the most recent consensus guidelines 
(American Academy of Dermatology, Gawkrodger et al 2008, Taieb et al 2013, Vitiligo 
Research Foundation).  In general, first-line treatments consist of topical steroids and calcineurin 
inhibitors, which are most useful for treating disease that is localized.  Second-line treatments 
consist of phototherapy (NB-UVB and PUVA) and systemic steroid treatment.  Third-line 
treatments consist of surgical grafting techniques and depigmenting treatments.   However, 
response to current treatment varies, can be time-intensive, can be slow to respond to treatment, 
and often produces disappointing results if repigmentation is cosmetically unacceptable. 
There has been a limited number of randomized controlled clinical studies conducted to 
adequately support the efficacy of drug treatments in vitiligo.  Factors that further limit the 
evidence for efficacy are variations in study design and outcome measures, small study size (the 
majority of which included fewer than 50 participants), and deficiencies in methodological 
quality based on a systematic review of randomized clinical studies evaluating interventions for 
vitiligo (Whitton et al 2016).  Apart from inconclusive (or insufficient) evidence for the efficacy 
of current off-label drug treatments in vitiligo, their safety profiles may also carry specific 
restrictions for their topical use.  For example, TCS may be associated with local adverse effects, 
including irreversible ones such as skin atrophy and striae distensae, and an increased 
susceptibility to skin infections (Coondoo et al 2014).  More potent TCS, through their 
percutaneous absorption and depot-like accumulation in the epidermis, may also produce 
well-known systemic AEs typical for corticosteroids.  Additionally, there are restrictions on the 
use of such TCS on sensitive skin areas, particularly on the face, and for the overall treatment 
duration (ie, not to exceed 4 weeks).  Therefore, judicious use of high potency preparations of 
TCS is critical.  Topical calcineurin inhibitors are known for the induction of skin burning 
sensation immediately after their application, which makes their use on the face problematic.  


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Topical calcineurin inhibitors have been implied in their possible contribution to cutaneous 
malignancy when used long-term. 
Available phototherapy treatments include NB-UVB and PUVA.  Phototherapy regimens 
typically require 2 to 3 treatments per week and long-term duration of treatment.  For both 
NB-UVB and PUVA, 12 to 24 months of continuous phototherapy may be necessary to acquire 
maximal repigmentation (Taieb et al 2013).  A minimum of 6 months of continuous 
phototherapy is recommended before being considered nonresponsive (Taieb et al 2013, Bae 
et al 2017).  Relapses are common; approximately 60% to 70% of patients resume 
depigmentation in areas repigmented by treatment within 1 year with PUVA or NB-UVB 
therapy (Boniface et al 2018).  There are also important safety limitations with phototherapy.  
PUVA carries a risk of phototoxic effects, nausea, and the potential risk for skin cancer.  
Moreover, PUVA phototherapy is not recommended for children or pregnant women due to risks 
associated with systemic exposure of psoralen.  NB-UVB phototherapy is considered to have 
safety advantages over PUVA but is also associated with AEs such as erythema, itching, and 
mild burning or pain (Bae et al 2017).  Excimer laser or monochromatic excimer lamp (both at 
308 nm) that may reach deeper targets such as amelanotic melanocytes of the hair follicle, and 
also avoid irradiation of uninvolved skin, may improve clinical outcomes; however, they are 
limited to localized treatment (Boniface et al 2018). 
Lastly, surgical treatments in vitiligo may be considered after failure to respond to drug and light 
therapies and only for cosmetically sensitive sites where there have been no new vitiligo areas, 
no Koebner phenomenon, and no extension of the vitiligo area in the previous 12 months.  
Unsatisfactory cosmetic results and a high incidence of AEs have been reported with certain 
surgical procedures (Gawkrodger et al 2008, Taieb et al 2013).  Surgery is best indicated for 
stable and localized forms of vitiligo, and only a small number of patients with vitiligo are 
considered suitable candidates. 
Given the lack of approved therapies and safety concerns and modest effectiveness of current 
off-label drug treatments, there is a need to identify a safe and effective new treatment for 
vitiligo. 
2.3. 
Role of Janus Kinases in Vitiligo 
Vitiligo pathogenesis involves intrinsic defects within melanocytes and autoimmunity that 
targets these cells.  Studies have shown that melanocytes from vitiligo patients are more 
vulnerable than those from healthy individuals (Rodrigues et al 2017, Speeckaert and van Geel 
2017).  Once melanocytes become stressed, they release inflammatory signals that activate innate 
immunity, which may represent the initiation event in vitiligo.  The oxidative stress, cell damage, 
and cytokines secreted from innate immune cells then trigger CXCL10 release by skin cells, and 
that recruits CD8+ T cells to the site.  Activated CD8+ T cells produce IFN-γ and other 
inflammatory mediators to target and destroy melanocytes (Frisoli and Harris 2017).  Because 
IFN-γ signaling utilizes the JAK-STAT pathway, inhibition of JAK signaling may be an 
effective strategy for vitiligo treatment development. 
There are several case reports and case series suggesting that modulation of the immune response 
through JAK inhibition may be effective in treating vitiligo.  A patient with both AA and vitiligo 
was treated with oral ruxolitinib 20 mg BID for 20 weeks and subsequently had hair regrowth as 
well as significant repigmentation of areas affected with vitiligo (Harris et al 2016).  In another 


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report, a patient with widespread and progressive vitiligo who did not have a response to topical 
steroids, tacrolimus ointment, and NB-UVB phototherapy treated with oral tofacitinib at 5 mg 
QD and resulted in near complete repigmentation after 5 months of treatment (Craiglow and 
King 2015). 
There was a 20-week open-label study using topical ruxolitinib cream (INCB018424) in 
12 participants with vitiligo who had a minimum of 1% BSA affected.  The results showed a 
76% improvement in F-VASI and 26% improvement in T-VASI within 7 of 9 participants who 
completed the study (Rothstein et al 2017).  The same group conducted an additional 32-week 
extension study with optional NB-UVB treatment (Joshipura et al 2018).  Five participants 
completed the study, and 3 of them received NB-UVB.  At Week 52 (Week 20 + Week 32), 
results showed 92% improvement in F-VASI and 37% in T-VASI.  The results also indicated 
that 2 participants who had failed prior phototherapy and topical INCB18424 cream 
monotherapy on truncal vitiligo areas responded after combined therapies.  Additionally, 
participants were followed up with at 6 months after treatment discontinuation, and all 
5 participants maintained response with maximum duration of more than 40 weeks. 
2.4. 
Ruxolitinib Cream 
 
 
 
 
 
 
An oral formulation of ruxolitinib has been clinically evaluated for the treatment of patients with 
inflammatory disease, myeloproliferative diseases, hematologic malignancies, and solid tumors 
and is currently approved for the treatment of myelofibrosis and polycythemia vera in multiple 
countries.  In addition to the safety pharmacology and toxicology studies that were completed to 
support development of ruxolitinib cream, the toxicologic and toxicokinetic profiles of 
ruxolitinib have also been characterized following oral administration.  
 
 
 
 
 
Please refer to the ruxolitinib cream IB. 
 
 
 


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2.4.2. 
Clinical Experience 


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2.4.2.2. 
Efficacy of Ruxolitinib Cream 
2.4.2.2.1. Psoriasis 
Ruxolitinib cream has been evaluated in over 200 adults with plaque psoriasis in 3 clinical 
studies with application of 4 to 12 weeks duration.  Overall, ruxolitinib cream (0.5%, 1.0%, or 
1.5%) was effective in decreasing disease severity.  Observed AEs were mild to moderate in 
intensity and most were judged unrelated to study medication, with no treatment-related SAEs or 
withdrawals.  Ruxolitinib cream demonstrated to be safe and well-tolerated when applied QD for 
12 weeks to plaque psoriasis affecting 2% to 20% of the BSA. 
2.4.2.2.2. Atopic Dermatitis 
There were 307 adult participants with mild to moderate AD affecting total 3% to 20% BSA 
enrolled in a Phase 2, randomized, vehicle- and active (triamcinolone 0.1% cream)-controlled 
dose-ranging study.  The mean percentage change from baseline at Week 4 in EASI score 
demonstrated a significant improvement (1.5% BID [-71.6%0 vs vehicle [-15.5%]).  At the 
highest exposure (1.5% BID), ruxolitinib cream was noninferior to triamcinolone.  In addition, 
significant reductions in itch were noted as early as within a day from the initiation of therapy 
with ruxolitinib cream.  The most frequently reported TEAE was nasopharyngitis, which 
occurred in 2.0% to 7.8% of participants across dose strengths in the double-blind period and in 
5.2% of participants in the open-label period.  No fatal or serious TEAEs occurred in participants 
who received ruxolitinib cream.  Phase 3 studies (INCB 18424-303 and -304) in adults and 
adolescents are ongoing. 
More details are included in the ruxolitinib cream IB. 
2.4.2.2.3. Vitiligo 
INCB 18424-211 (see Figure 3) is a Phase 2, randomized, double-blind, vehicle-controlled study 
in adults with vitiligo who have depigmented areas including at least 0.5% BSA on the face and 
at least 3% BSA on nonfacial areas.  A total of 157 participants were equally randomized to 
receive ruxolitinib cream 1.5% BID, 1.5% QD, 0.5% QD, 0.15% QD, or vehicle BID for 


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24 weeks.  In the second part of the study, all participants initially randomized to vehicle BID 
and participants initially randomized to 0.15% QD who did not achieve ≥ 25% improvement 
from baseline in F-VASI were rerandomized to 1 of the 3 higher dosing groups for an additional 
28 weeks.  All other participants maintained the same treatment until Week 52.  After Week 52, 
participants could receive open-label 1.5% BID for an additional 52 weeks.  The primary 
endpoint was the proportion of participants who achieved a ≥ 50% improvement from baseline in 
F-VASI50 at Week 24. 
Figure 3: 
INCB 18424-211 Study Schema 
 
All ruxolitinib treatment arms demonstrated clinically meaningful efficacy and superiority over 
vehicle.  The proportion of participants who achieved an F-VASI50 at Week 24 was statistically 
significantly greater for ruxolitinib cream versus vehicle with response rates of 32.3%, 25.8%, 
50.0%, and 45.5% for ruxolitinib cream 0.15% QD, 0.5% QD, 1.5% QD, and 1.5% BID, 
respectively, and 3.1% for vehicle.  The proportion of participants who achieved an F-VASI75 at 
Week 24 was also statistically significantly greater for ruxolitinib cream versus vehicle with 
response rates of 9.7%, 16.1%, 16.7%, and 30.3% for ruxolitinib cream 0.15% QD, 0.5% QD, 
1.5% QD, and 1.5% BID, respectively, and 0% for vehicle.  Participants who were initially 
randomized to ruxolitinib cream 0.5% QD, 1.5% QD, and 1.5% BID continued on these 
treatments until Week 52.  Continued improvement in F-VASI response in these treatment was 
observed with the proportion of participants who achieved an F-VASI75 at Week 52 
demonstrating response rates of 29.0%, 30.0%, and 51.5% for ruxolitinib cream 0.5% QD, 
1.5% QD, and 1.5% BID.  Large effect size (Cohen’s D = 1.14) is observed based on percentage 
change from baseline between ruxolitinib cream 1.5%BID and vehicle.   
Improvements in T-VASI were observed for both Week 24 and Week 52.  The proportion of 
participants who achieved a T-VASI50 at Week 24 was also statistically significantly greater for 
ruxolitinib cream 0.15% QD, 0.5% QD, 1.5% QD, and 1.5% BID compared with vehicle with 
response rates of 16.1%, 6.5%%, 23.3%, and 12.1%, respectively, compared with 0% in 
vehicle-treated participants.  Continued improvement in participants treated with 0.5% QD, 
1.5% QD, and 1.5% BID through Week 52 was observed with response rates in T-VASI50 


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of 25.8%, 30.0%, and 36.4%, respectively.  Similar to F-VASI, large effect sizes 
(Cohen’s D = 1.24) is observed based on percentage change from baseline between ruxolitinib 
cream 1.5%BID and vehicle.   
Compared with F-VASI, improvement in T-VASI was slower.  This observation is not 
unexpected given that repigmentation on the body and acral areas progresses at a slower rate 
than facial repigmentation.  Despite that, response rates for the F-VASI50, F-VASI75, and 
T-VASI50 favored the higher strength treatment regimens (both 1.5% QD and 1.5% BID) versus 
vehicle at Week 24 and 1.5% BID regimen at Week 52 across the endpoints.  Given that many 
participants may not achieve peak response by Week 24 and that there are constraints to the 
length of the vehicle period, the 1.5% BID regimen appears to have given a higher response over 
time.  Key secondary endpoints including percentage change in F-BSA, F-PhGVA, and PaGIC 
also followed a similar pattern, with separation from vehicle at Week 24 and continued 
improvement through Week 52.  
All ruxolitinib treatment arms were generally safe and well-tolerated with no significant TEAEs 
or application site events and no clinically relevant hematological changes.  TEAE rate overall is 
low and similar between active treatment and vehicle treatment.  There were 4 SAEs through 
52 weeks and all of them were not treatment-related.  Discontinuations from treatment through 
52 weeks was low.  Safety and tolerability were similar between the Week 24 and Week 52 
period.  
 


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3. 
OBJECTIVES AND ENDPOINTS 
Table 8 presents the objectives and endpoints. 
Table 8: 
Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
To evaluate the efficacy of ruxolitinib cream in 
participants with vitiligo. 
• Proportion of participants achieving F-VASI75 at 
Week 24. 
Key Secondary 
To further assess the efficacy of ruxolitinib cream. 
• Proportion of participants achieving F-VASI50 at 
Week 24. 
• Proportion of participants achieving F-VASI90 at 
Week 24. 
• Proportion of participants achieving T-VASI50 at 
Week 24. 
• Proportion of participants achieving a VNS of 
“4 – A lot less noticeable” or “5 – No longer 
noticeable” at Week 24. 
• Percentage change from baseline in F-BSA at 
Week 24. 
Secondary 
To evaluate the safety and tolerability of ruxolitinib 
cream. 
• The frequency, duration, and severity of AEs; 
physical examinations; vital signs; and laboratory 
data for hematology and serum chemistry. 
To further assess the efficacy of ruxolitinib cream. 
• Proportion of participants achieving 
F-VASI25/50/75/90 during the treatment period 
(double-blind and treatment extension periods).  
• Percentage change from baseline in F-VASI 
during the treatment period (double-blind and 
treatment extension periods). 
• Percentage change from baseline in F-BSA 
during the treatment period (double-blind and 
treatment extension periods). 
• Percentage change from baseline in T-VASI 
during the treatment period (double-blind and 
treatment extension periods). 
• Percentage change from baseline in T-BSA 
during the treatment period (double-blind and 
treatment extension periods). 
• Proportion of participants achieving 
T-VASI25/50/75/90 during the treatment period 
(double-blind and treatment extension periods).  
• Proportion of participants in each category of 
VNS during the treatment period (double-blind 
and treatment extension periods). 


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Table 8: 
Objectives and Endpoints (Continued) 
Objectives 
Endpoints 
Secondary (continued) 
To evaluate the ruxolitinib PK in plasma after 
treatment of ruxolitinib cream. 
• Population-based (trough) plasma concentrations 
of ruxolitinib at Weeks 4, 24 and 40. 
Exploratory 
To further assess the efficacy of ruxolitinib cream. 
• Proportion of participants achieving an 
F-PhGVA of clear (0) or almost clear (1) during 
the treatment period (double-blind and treatment 
extension periods). 
• Proportion of participants achieving an 
T-PhGVA of clear (0) or almost clear (1) during 
the treatment period (double-blind and treatment 
extension periods). 
• Proportion of participants in each F-PhGVA 
category during the treatment period 
(double-blind and treatment extension periods). 
• Proportion of participants in each T-PhGVA 
category during the treatment period 
(double-blind and treatment extension periods). 
• Proportion of participants who report F-PaGIC-V 
of very much improved or much improved during 
the treatment period (double-blind and treatment 
extension periods). 
• Proportion of participants in each F-PaGIC-V 
category during the treatment period 
(double-blind and treatment extension periods). 
• Proportion of participants who report T-PaGIC-V 
of very much improved or much improved during 
the treatment period (double-blind and treatment 
extension periods). 
• Proportion of participants in each T-PaGIC-V 
category during the treatment period 
(double-blind and treatment extension periods). 
• Proportion of participant in each category for the 
color-matching question during the treatment 
period (double-blind and treatment extension 
periods). 
 


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Table 8: 
Objectives and Endpoints (Continued) 
Objectives 
Endpoints 
Exploratory (continued) 
To determine the participants’ quality of life. 
• Change from baseline in DLQI (or CDLQI) 
during the treatment period (double-blind and 
treatment extension periods). 
• Change from baseline in WHO-5 during the 
treatment period (double-blind and treatment 
extension periods). 
• Change from baseline in TSQM during the 
treatment period (double-blind and treatment 
extension periods). 
• Change from baseline in VitiQoL during the 
treatment period (double-blind and treatment 
extension periods). 
• Change from baseline in HADS during the 
treatment period (double-blind and treatment 
extension periods). 
To evaluate translational biomarkers in the blood of 
participants treated with ruxolitinib cream. 
• Change from baseline in the expression of select 
biomarkers in peripheral blood at Weeks 12, 24, 
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4. 
STUDY DESIGN 
4.1. 
Overall Design 
This is a randomized, vehicle-controlled study in adolescent and adult participants (age 
≥ 12 years) with non-segmental vitiligo who have depigmented area including ≥ 0.5% BSA on 
the face, ≥ 0.5 F-VASI, ≥ 3% BSA on nonfacial areas, ≥ 3 T-VASI, and for whom total body 
involved vitiligo area (facial and nonfacial) does not exceed 10% BSA.  Approximately 
300 participants will be randomized 2:1 to receive initial study treatment (ruxolitinib cream 1.5% 
BID:vehicle) for 24 weeks (see Figure 1).  Participants will be stratified by region (North 
America or Europe) and skin type (Fitzpatrick scale Type I and II vs Type III, IV, V, and VI).  
Adolescents (≥ 12 to < 18 years) will make up at least 10% of the study population, and no more 
than 50% of participants will be > 40 years old. 
During the double-blind, vehicle-controlled period, participants will receive ruxolitinib cream 
1.5% BID or vehicle for 24 weeks to be applied to depigmented areas only on the face and body 
up to 10% total BSA.  Participants should continue to treat depigmented areas identified for 
treatment at baseline even if the area begins to improve or fully repigment. 
After completion of the Week 24 assessments, participants will be offered the opportunity to 
continue in the treatment extension period.  Participants initially randomized to vehicle will be 
crossed over to active drug, and participants treated with ruxolitinib cream will receive an 
additional 28 weeks of treatment with ruxolitinib cream 1.5% BID.  To be eligible for the 
treatment extension, participants must have completed the baseline and Week 24 visit 
assessments, be compliant with study procedures, and not have any safety issues.  During the 
treatment extension, participants should continue to treat depigmented areas identified for 
treatment at baseline even if the area begins to improve or fully repigment.  Total treated areas 
(facial and nonfacial areas) should not exceed to 10% BSA.   
Safety endpoints, such as nature of AEs (type, frequency, and severity), vital signs, targeted 
physical examination, and routine laboratory investigations, will be monitored and recorded 
throughout the course of this study. 
Following the last application of ruxolitinib cream at Week 52, there will be a 30-day safety 
follow-up period to evaluate safety and duration of response.   
Participants who successfully complete the 52-week treatment in this study may be eligible to 
participate in a separate extension study to evaluate durability of effect and maintenance 
regimens.  
See Section 6.5 for detailed information of study drug modification and application guidance. 
4.2. 
Overall Study Duration 
Screening is up to 32 days (~4 weeks); the double-blind, vehicle-controlled treatment period is 
24 weeks; the treatment extension period is 28 weeks; and safety follow-up is 30 days.  Total 
duration is up to approximately 60 weeks (see Figure 1). 


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The study will begin when the first participant (or parent or guardian) signs the ICF.  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 discontinued study drug and completed applicable safety follow-up 
assessments or is lost to follow-up.  A participant is considered to have completed the study if 
he/she has completed all study visits, including the safety follow-up visit. 
4.3. 
Study Termination 
The investigator retains the right to terminate study participation at any time, according to the 
terms specified in the study contract.  The investigator is to notify the IRB/IEC in writing of the 
study's completion or early termination, send a copy of the notification to the sponsor or 
sponsor's designee, and retain 1 copy for the site study regulatory file. 
The sponsor may terminate the study electively or if required by regulatory agency.  In the event 
of significant safety findings, the study will be terminated.  If the study is terminated 
prematurely, the sponsor or designee will notify the investigators, the IRBs/IECs, and regulatory 
bodies of the decision and reason for termination of the study.   
5. 
STUDY POPULATION 
Deviations from eligibility criteria are prohibited because they can potentially jeopardize the 
scientific integrity of the study, regulatory acceptability, and/or participant safety.  Therefore, 
adherence to the criteria as specified in the Protocol is essential.  Prospective approval of 
Protocol deviations to recruitment and enrollment criteria, also known as Protocol waivers or 
exemptions, are not permitted. 
5.1. 
Inclusion Criteria 
Participants are eligible to be included in the study only if all of the following criteria apply: 
1. Adolescents and adults aged ≥ 12 years. 
2. Participants with a clinical diagnosis of non-segmental vitiligo with depigmented area 
including ≥ 0.5% BSA on the face, ≥ 0.5 F-VASI, ≥ 3% BSA on nonfacial areas, 
≥ 3 T-VASI, and total body vitiligo area (facial and nonfacial) not exceeding 10% BSA. 
3. Participants who agree to discontinue all agents used to treat vitiligo from screening 
through the final safety follow-up visit.  Over-the-counter preparations deemed 
acceptable by the investigator and camouflage makeups are permitted. 
4. Male and female participants must be willing to take appropriate contraceptive measures 
to avoid pregnancy or fathering a child for the duration of study participation with the 
exception of the following: 
a. Females of non-childbearing potential (ie, or surgically sterile with a hysterectomy 
and/or bilateral oophorectomy OR postmenopausal, ≥ 12 months of amenorrhea 
without an alternative medical cause). 
b. Prepubescent adolescents. 
Note:  Information about specific types of acceptable contraceptive measures and 
duration of contraceptive use are provided in Appendix A. 


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5. For adult participant, ability to comprehend and willingness to sign an ICF; for 
adolescent participant, written informed consent of the parent(s) or legal guardian and 
written assent from the adolescent participant. 
Note:  Adolescents, who during the course of the study become legal adults, will be asked 
for their consent to continue the study, and in the event of lack thereof, will be 
discontinued from further participation. 
5.2. 
Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply: 
1. Participants who have no pigmented hair within any of the vitiligo areas on the face. 
2. Other forms of vitiligo (eg, segmental) or other differential diagnosis of vitiligo or other 
skin depigmentation disorders (eg, piebaldism, pityriasis alba, leprosy, postinflammatory 
hypopigmentation, progressive macule hypomelanosis, nevus anemicus, chemical 
leukoderma, and tinea versicolor). 
3. Participants who have used depigmentation treatments (eg, monobenzone) for past 
treatment of vitiligo or other pigmented areas. 
Note:  Prior use of hydroquinone is not prohibited (as it is a bleaching agent, not a 
depigmentation treatment). 
4. Participants with concurrent conditions and history of other diseases: 
a. Any other skin disease that, in the opinion of the investigator, would interfere with 
the study medication application or study assessments. 
b. Active acute bacterial, fungal, or viral skin infection (eg, herpes simplex, herpes 
zoster, chicken pox) within 1 week before baseline. 
c. Conditions at baseline that would interfere with evaluation of vitiligo. 
d. 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.  
Examples include but are not limited to the following: 
− Clinically significant or uncontrolled cardiac disease, including unstable angina, 
acute myocardial infarction within 6 months from Day 1 of study drug 
administration, New York Heart Association Class III or IV congestive heart 
failure, and arrhythmia requiring therapy or uncontrolled hypertension (blood 
pressure > 150/90 mmHg) unless approved by the medical monitor/sponsor.  
− History of thrombosis, including deep venous thrombosis and pulmonary 
embolism. 
− Participants with concurrent malignant disease or a history of that in the 5 years 
preceding the baseline visit except for adequately treated nonmetastatic 
malignancies. 
− Current and/or history of liver disease, including known hepatitis B or C, with 
hepatic or biliary abnormalities.  


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− Current and/or history of tuberculosis.  
− 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. 
− Participants who are committed to an institution by virtue of an order issued either 
by the judicial or the administrative authorities. 
5. Participants using any of the following treatments within the indicated washout period 
before baseline: 
a. 1 week:  Topical drugs when used on the vitiligo areas, for example, corticosteroids, 
calcineurin, and phosphodiesterase type 4 inhibitors or retinoids. 
b. 4 weeks: 
− Melanocyte-stimulating agents (eg, afamelanotide). 
− Immunomodulating systemic medications (eg, corticosteroids, methotrexate, 
cyclosporine). 
− Any other systemic therapies that could increase the skin sensitivity to UV/visible 
light or impact skin pigmentation, for example, tetracyclines, metoxypsoralens. 
− Received live vaccine. 
Note:  Live vaccine is prohibited during the course of the study and within 
4 weeks after the EOT visit. 
c. 8 weeks:  Laser or any kind of phototherapy, including tanning bed or intentional UV 
exposure. 
d. 5 half-lives or 12 weeks, whichever is longer:  Biologic agents, investigational or 
experimental therapy or procedures for vitiligo.  Investigational biologics should be 
discussed with the sponsor to determine whether a longer period of discontinuation is 
required. 
6. Participants who have previously received JAK inhibitors, systemic or topical. 
7. Participants with clinically significant abnormal laboratory values at screening:  
a. Hemoglobin (< 10 g/dL).  
b. Liver function tests:  
− AST or ALT ≥ 2 × ULN. 
− Alkaline phosphatase and/or bilirubin > 1.5 × ULN (isolated bilirubin 
> 1.5 × ULN is acceptable if bilirubin is fractionated and direct bilirubin < 35%). 
c. Severe renal disease (with creatinine clearance < 30 ml/min) or renal disease 
requiring dialysis. 
d. Clinically significant abnormal TSH or free T4 at screening as determined by the 
investigator. 
e. Positive serology test results at screening for HIV antibody. 


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8. Body mass index < 17 or > 40 kg/m2 for adult participants (age ≥ 18 years).  BMI-for-age 
in the < 5th percentile or ≥ 85th percentile range for adolescent participants (age ≥ 12 to 
< 18 years) according to according to the CDC BMI Percentile Calculator for Child and 
Teen (2019). 
9. Pregnant or lactating participants, or those considering pregnancy during the period of 
their study participation. 
10. Participants who, in the opinion of the investigator, are unable or unlikely to comply with 
the administration schedule and study evaluations.  
11. Employees of the sponsor or investigator or are otherwise dependents of them. 
12. Participants with known allergy or reaction to any component of the study formulation. 
13. Participants who live with anyone participating in any current Incyte-sponsored 
ruxolitinib cream study.  
5.3. 
Lifestyle Considerations 
Participants should be cautioned to avoid excessive exposure to artificial sunlight (including 
tanning booths, sun lamps, etc). 
If sunscreen, makeup, or other cosmetics have been applied to the areas to be treated, participants 
should follow the application guidance (see Section 6.6.1). 
It is recommended that swimming should not take place within 2 hours before and after the 
planned study drug application. 
5.4. 
Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently assigned to study treatment.  Tests with results that fail eligibility requirements 
may be repeated once during screening if the investigator believes that the participant would be 
eligible if retested.  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 or any 
laboratory abnormality is inconsistent with the participant’s medical history.  Participants who 
rescreen must be assigned a new screening number.  
5.5. 
Replacement of Participants 
Participants will not be replaced during the study. 


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6. 
STUDY TREATMENT 
6.1. 
Study Treatment Application 
Table 9 presents the study treatment information. 
Table 9: Study Treatment Information 
Study treatment name: 
Ruxolitinib 
Vehicle 
Dosage formulation: 
Cream 
Unit dose strength(s)/dosage 
level(s): 
1.5% 
Not applicable 
Route of administration: 
Topical 
Administration instructions: 
Double-blind and treatment 
extension periods:  BID.  A thin 
film is applied to depigmented 
vitiligo areas. 
Double-blind period:  BID.  A thin 
film is applied to the depigmented 
vitiligo areas. 
Treatment extension period:  Not 
applicable. 
Packaging and labeling: 
Ruxolitinib cream and vehicle cream will be provided in 60 g tube.  
Each tube will be labeled as required per country requirement. 
Storage: 
Ambient (15°C-30°C/59°F-86°F) 
Status of treatment in 
participating countries: 
Investigational 
Not applicable 
On visit days, study drug will be applied in the clinic during the visit.  Participants should 
remove study drug from the tube in fingertip units until all of the areas to be treated are covered 
by a thin film; the tube will be weighed before and after application to determine the 
participant’s dosage.  On the day of a visit, the participant should not apply the study drug at 
home and will apply study drug from the new kit in the clinic.  Participants will be instructed to 
document treated areas and advised to limit use to no more than one 60 g tube per week.  
Application instructions will be provided by the site study staff, and the participants will record 
their daily applications via a diary card given to the participants during each study visit.  Refer to 
the Study Pharmacy Manual for participant instructions for handling study of drug. 
At any time, if vitiligo areas become significantly more extensive than from the previous visit, 
the participant should contact the study site to discuss with the investigator whether additional 
evaluation at the clinic is required.  If any other skin products that are permitted under the study 
Protocol are used, participants should continue these unchanged during the study.  


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6.1.1. 
Application During the Double-Blind Vehicle-Controlled Treatment Period 
During the double-blind vehicle-controlled period (up to Week 24), participants should follow 
the below study drug application guidance: 
• Participants should apply study drug only to depigmented vitiligo areas identified by 
the investigators up to a T-BSA (facial and nonfacial) of ≤ 10% BSA. 
• Participants should continue to treat all depigmented vitiligo areas identified for 
treatment at baseline even if the area begins to improve or fully repigment. 
6.1.2. 
Application During the Treatment Extension Period  
During treatment extension period (Week 24 to Week 52), participants should follow the below 
study drug application guidance: 
• Participants should apply study drug to depigmented vitiligo areas identified by the 
investigators up to a T-BSA (facial and nonfacial) of ≤ 10% BSA. 
• Participants should continue to treat all depigmented vitiligo areas identified by the 
investigators for treatment at baseline even if the area begins to improve or fully 
repigment. 
• Participants who have an expansion of existing areas of vitiligo during the course of 
the treatment extension period may treat these areas identified by the investigators 
after a visit to document the VASI score and other measures of vitiligo (may be 
unscheduled visit), as long as the new treated T-BSA (facial and nonfacial) does not 
exceed 10% BSA. 
6.2. 
Preparation, Handling, and Accountability 
The investigator or designee must confirm and document that appropriate temperature conditions 
(both ruxolitinib cream and vehicle cream are to be stored between 15°C and 30°C [59°F-86°F]) 
have been maintained during transit for all study treatments received and any discrepancies are 
reported and resolved before use of the study treatment. 
Only participants enrolled in the study may receive study treatment, and only authorized site 
staff may supply study treatment.  Immediately after application of ruxolitinib cream, 
participants are to wash their hands thoroughly with soap and warm water (unless the area to be 
treated includes the hands).  Refer to the Study Pharmacy Manual for participant instructions for 
handling of study drug. 
All study treatment must be stored in a secure, environmentally controlled, and monitored 
(manual or automated) area in accordance with the labeled storage conditions with access limited 
to the investigator and authorized site staff.  Participants should store study treatment at ambient 
temperature conditions. 


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The investigator (or designee) is responsible for study treatment accountability, reconciliation, 
and record maintenance (ie, receipt, reconciliation, and final disposition records).  Inventory and 
accountability records must be maintained and readily available for inspection by the study 
monitor and are open to inspection at any time by any applicable regulatory authorities.  The 
investigator or designee must maintain records that document: 
• Delivery of study drug(s) to the study site. 
• Inventory of study drug(s) at the site. 
• Participant use of the study drug(s) including tube counts from each supply 
dispensed. 
• Return of study drug(s) to the investigator or designee by participants. 
The investigational product must be used only in accordance with the Protocol.  The investigator 
will also maintain records adequately documenting that the participants were provided the 
specified study drug.  These records should include dates, quantities, and any available batch or 
serial numbers or unique code numbers assigned to the investigational product and study 
participants. 
Completed accountability records will be archived by the site.  The investigator or designee will 
be expected to collect and retain all used, unused, and partially used containers of study drug 
until verified by the study monitor (unless otherwise agreed to by the sponsor).  At the 
conclusion of the study, the investigator or designee will oversee shipment of any remaining 
study drug back to the sponsor or its designee for destruction according to institutional SOPs.  If 
local procedures mandate on-site destruction of investigational supply, the site should (where 
local procedures allow) maintain the investigational supply until the study monitor inspects the 
accountability records in order to evaluate compliance and accuracy of accountability by the 
investigative site.  At sites where the study drug is destroyed before monitor inspection, the 
monitors rely on documentation of destruction per the site SOP. 
Further guidance and information for the final disposition of unused study treatments are 
provided in the study materials provided to sites. 
6.3. 
Measures to Minimize Bias:  Randomization and Blinding 
All participants will be centrally assigned to study treatment using an IRT system.  The system 
will assign in a 2:1 ratio (ruxolitinib cream 1.5% BID:vehicle), stratified by region (North 
America or Europe) and skin type (Fitzpatrick scale Type I and II vs Type III, IV, V, and VI).  
Adolescents will make up at least 10% or participants, and no more than 50% of participants will 
be aged greater than 40 years.  The IRT will assign participant ID numbers, track participant 
visits, randomize participants according to the defined parameters, maintain the blinding, and 
manage study drug inventory.  Full details will be provided in the IRT Manual.  Study treatment 
will be dispensed at the study visits summarized in the Schedule of Activities (see Table 3 and 
Table 4). 
After the database lock for the primary analysis, the sponsor will be unblinded, but investigators 
and participants will still be blinded to individual treatment assignments.  This is implemented to 
minimize bias for the Week 52 analyses.   After Week 52, investigators and participants will be 
unblinded. 


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6.4. 
Study Treatment Compliance 
Compliance with all study-related treatments must be emphasized to the participant by the site 
personnel, and appropriate steps should be taken to optimize compliance during the study.  
Compliance with ruxolitinib cream will be evaluated by participants' adherence to the application 
regimen and drug accountability documented by the site staff and monitored by the 
sponsor/designee (tube counts).  
In general, the application compliance will be determined by the number of actual versus 
anticipated number of applications, which should be within 70% to 130% of the prescribed 
number of applications.  Participants will be instructed to bring all study drugs with them to the 
study visits in order for site personnel to conduct tube counts to assess study drug accountability.  
The drug accountability documentation will be used by the sponsor to calculate treatment 
compliance. 
6.5. 
Dose Modifications 
6.5.1. 
Criteria and Procedures for Application Interruptions of Study Drug 
Safety concerns should be discussed with the sponsor immediately upon occurrence or awareness 
to determine whether the participant should continue or discontinue study treatment. 
In some circumstances, it may be necessary to temporarily interrupt treatment with ruxolitinib 
cream.  Except in cases of emergency, it is recommended that any findings of concern (eg, AE) 
be confirmed and that the investigator consult with the sponsor medical monitor (or other 
representative of the sponsor) before interrupting study drug.  Additionally, the investigator must 
obtain approval from the sponsor before restarting study drug.  Participants who experience a 
recurrence of the initial AEs upon restarting the study drug may need the study drug to be 
permanently discontinued.  
Instructions for application interruptions for ruxolitinib cream are outlined in Table 10.  
Individual decisions regarding interruptions should be made using clinical judgment in 
consultation with the medical monitor (whenever possible), taking into account relatedness of the 
AE to the study treatment and the participant's underlying condition. 


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Table 10: 
Guidelines for Interruption and Restarting of Study Drug 
Adverse Event 
Action Taken 
Chemistry 
ALT (> 3 × ULN) or AST (> 3 × ULN)  
• Laboratory abnormalities should be confirmed with 
repeat testing within 48 hours whenever possible and 
immediate delivery of the laboratory results 
requested. 
• Study drug applications must be interrupted.  At the 
discretion of the investigator, after consultation with 
the sponsor, study drug application may be restored 
once these have resolved. 
Other laboratory abnormalities 
Any other Grade 3 or higher laboratory 
abnormality, with the exception of 
asymptomatic elevations in triglyceride, 
cholesterol, or amylase 
• Laboratory abnormalities should be confirmed with 
repeat testing within 48 hours whenever possible and 
immediate delivery of the laboratory results 
requested. 
• Study drug applications must be interrupted.  At the 
discretion of the investigator, after consultation with 
the sponsor, study drug application may be restored 
once these have resolved.  
Any Grade 4 laboratory abnormality or AST or 
ALT (> 5 × ULN)  
• Laboratory abnormalities should be confirmed with 
repeat testing within 48 hours whenever possible and 
immediate delivery of the laboratory results 
requested.  
• Discontinue study drug if lab abnormalities are 
confirmed.  
6.5.2. 
Criteria for Permanent Discontinuation of Study Drug Due to an Adverse Event 
The occurrence of unacceptable severity of an AE not caused by the underlying disease will be 
presumed to be related to study drug treatment and will require that the study drug be 
permanently discontinued.  Unacceptable severity is defined as follows: 
• Occurrence of an AE that is related to treatment with the study drug that, in the 
judgment of the investigator or the sponsor's medical monitor, compromises the 
participant's ability to continue study-specific procedures or continuing treatment is 
considered to not be in the participant's best interest. 
• Worsening of vitiligo that requires treatment with a prohibited concomitant 
medication. 
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 32 days before the first dose of study treatment through 30 days 


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after the last dose of study treatment will be recorded in the eCRF.  Any addition, deletion, or 
change in the dose of these medications will also be recorded.  Concomitant 
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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6.8. 
Treatment After the End of the Study 
Participants who successfully complete the 52-week treatment in this study may be eligible to 
participate in a separate extension study to evaluate durability of effect and maintenance 
regimens.  


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7. 
DISCONTINUATION OF STUDY TREATMENT AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL 
7.1. 
Discontinuation of Study Treatment 
7.1.1. 
Reasons for Discontinuation 
Participants must be discontinued from study treatment for the following reasons: 
• A participant is found not to have met eligibility criteria (any exclusion criterion or 
any inclusion criteria related to participant safety) or if legal requirements have been 
violated. 
• The participant becomes pregnant. 
• Consent is withdrawn. 
Note:  Consent withdrawn means that the participant has explicitly indicated that they 
do not want to be followed any longer; in this case no further data, except data in 
public domain, may be solicited from or collected on the participant.  Participants 
may choose to discontinue study treatment and remain in the study for safety 
monitoring. 
• Further participation would be injurious to the participant's health or well-being, in 
the investigator's medical judgment. 
• Any AE of unacceptable severity as noted in Section 6.5.2. 
• The study is terminated by the sponsor. 
• The study is terminated by the local health authority, IRB, or IEC. 
A participant may be discontinued from study treatment as follows: 
• If, at 2 consecutive study visits, a participant's drug usage exceeds one 60 g tube per 
week.   
• If a participant is noncompliant with study procedures or study drug administration in 
the investigator's opinion, the medical monitor should be consulted for instruction on 
handling the participant. 
7.1.2. 
Discontinuation Procedures 
In the event that the decision is made to permanently discontinue the study treatment, the EOT 
visit should be conducted (EOT1 or EOT2 depending on the period during with the participant 
discontinues treatment).  Reasonable efforts should be made to have the participant return for a 
safety follow-up visit.  The last date of the last dose of study drug(s)/treatment and the reason for 
discontinuation of study treatment will be recorded in the eCRF. 
If a participant is discontinued from study treatment: 
• The study monitor or sponsor must be notified. 
• The reason(s) for withdrawal must be documented in the participant's medical record 
and the primary reason for withdrawal must be included in the eCRF. 


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


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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 the study, and in the event of lack 
thereof, will be discontinued from further participation. 
− Informed consent/assent must be obtained using the IRB/IEC-approved version in 
a language that is native and understandable to the participant.  A template will be 
provided by the sponsor or its designee.  The sponsor or its designee must review 
and acknowledge the site-specific changes to the ICF/assent template.  The 
ICF/assent must include a statement that the sponsor or its designee and 
regulatory authorities have direct access to participant records. 
− The ICF/assent must contain all required elements and describe the nature, scope, 
and possible consequences of the study in a form understandable to the study 
participant. 
• Participants must be informed that their participation is voluntary.  Participants or 
their legally authorized representative will be required to sign a statement of informed 
consent 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 must include a statement that written informed consent was 
obtained before the participant was enrolled in the study and the date the written 
consent was obtained.  The authorized person obtaining the informed consent must 
also sign the ICF. 
• Participants must provide consent to the most current version of the ICF(s) during 
their participation in the study. 


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• A copy of the ICF(s) must be provided to the participant or the participant's legally 
authorized representative. 
• Participants who are rescreened are required to sign a new ICF. 
8.1.2. 
Screening Procedures 
Screening is the interval between signing the ICF and the day that the participant is assigned to 
the study drug (Day 1).  Screening assessments for determination of eligibility may be performed 
over a period lasting up to 32 days. 
Procedures conducted as part of the participant's routine clinical management (eg, clinical 
laboratory tests) and collected before informed consent is obtained may be used for screening or 
baseline purposes, provided the procedure meets the Protocol-defined criteria and has been 
performed within 32 days before Day 1.  All information associated with eligibility 
requirements, including demography and medical history, must be entered into the appropriate 
eCRF pages. 
Results from the screening assessments will be reviewed by the investigators to confirm 
eligibility before Day 1 and administration of study drug.  Tests results that fail eligibility 
requirements may be repeated once during screening if the investigator believes that the 
participant would be eligible if retested.  For screening assessments that are repeated, the most 
recent available result before administration of study drug will be used to determine eligibility.  
See Section 5.4 regarding screen failures. 
Participants aged ≥ 12 to < 18 years screened in Germany and found to have hemoglobin 
between 10 g/dL and 12 g/dL should be assessed for the cause of the abnormality per local 
practice guidelines/institutional standard of care before randomization.  This is a Germany-
specific requirement.  Specific cases may be reviewed with the medical monitor.  Participants 
with hemoglobin < 10 g/dL are not enrolled per the exclusion criteria. 
8.1.3. 
Interactive Response Technology Procedure 
Each participant will be identified in the study by a participant ID number, which is a 
combination of the site ID and participant number.  Site personnel should contact the IRT system 
to obtain the participant ID number during screening.  Upon determining that the participant is 
eligible for study entry, the IRT system will be contacted to obtain the study medication kit 
assignment.  Additionally, the IRT system will be contacted at each regular study visit to update 
the study drug supply.  Additional details are provided in the IRT Manual. 
8.1.4. 
Distribution of Study Reminder Cards and Diaries 
Starting at the Day 1 visit and each visit thereafter, a study drug–specific diary will be given to 
each participant in order to record use of the study drug.  The completed diary will be collected 
during each of the participant's visits. 
Qualified clinical site staff will review the participants' entries for compliance.  Participants who 
are noncompliant with their study drug schedule (defined as < 70% or > 130% of the expected 
number of applications between study visits) will have their administration instructions 
reinforced by the investigator or a qualified designee.  Participants will be considered compliant 


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with the treatment regimen if they apply at least 70% but no more than 130% of the expected 
applications during participation in the treatment period of the study.  
Participants will be provided with a reminder card starting on Day 1 and at all visits (through 
Week 52).  The reminder card will indicate the date/time of the next visit and will also remind 
the participant that they should have their application at the clinic during the visit under site 
supervision after their blood draws for PK and safety evaluations have been completed. 
8.1.5. 
Demography and Medical History 
8.1.5.1. 
Demographics and General Medical History 
Demographic data and general medical history will be collected at screening by the investigator 
or qualified designee and will include year of birth/age, race, ethnicity, medical and surgical 
history, and current illnesses.  Medical history will include relevant medical or surgical treatment 
within the last 2 years that are considered to be clinically significant by the investigator. 
8.1.5.2. 
Disease Characteristics and Treatment History 
A vitiligo medical and treatment history, including date of diagnosis, relevant disease 
characteristics, and prior treatments, including systemic treatments, phototherapy, and surgical 
procedures, will be recorded.  A medical history of other conditions related to vitiligo will also 
be collected at screening. 


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8.2. 
Efficacy Assessments 
8.2.1. 
Body Surface Area 
Total % BSA (includes facial and nonfacial areas) depigmented by vitiligo will be estimated at 
each visit.  Body surface area assessment will be performed by the Palmar Method.  BSA should 
be estimated to the nearest 0.1%.  The approximate size of the participant’s entire palmar surface 
(ie, the palm plus 5 digits) should be considered as 1% BSA, and the approximate size of the 
participant’s thumb should be considered as 0.1% BSA. 
8.2.2. 
Vitiligo Area Scoring Index 
Areas affected by depigmentation due to vitiligo will be assessed using the VASI.  It is based on 
a composite estimate of the overall area of vitiligo patches at baseline and the degree of macular 
repigmentation within these patches over time. 
Facial VASI is measured by percentage of vitiligo involvement (% of BSA) and the degree of 
depigmentation.  The percentage of BSA (hand unit) vitiligo involvement is estimated by the 
investigator using the Palmar Method (see Section 8.2.1).  Hand unit is based on participant’s 
hand size.  Investigator uses his/her hand to mimic the participant’s hand size to evaluate 
percentage of BSA vitiligo involvement.  The degree of depigmentation for each vitiligo 
involvement site is determined and estimated to the nearest of the following percentages:  0, 
10%, 25%, 50%, 75%, 90%, or 100%.  At 100% depigmentation, no pigment is present; at 90%, 
specks of pigment are present; at 75%, the depigmented area exceeds the pigmented area; at 
50%, the depigmented and pigmented area are equal; at 25%, the pigmented area exceeds the 
depigmented area; at 10%, only specks of depigmentation are present.  The F-VASI is then 
derived by multiplying the values assessed for the vitiligo involvement by the percentage of 
affected skin for each site on the face and summing the values of all sites together (possible 
range 0-3). 


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Total body VASI is calculated using a formula that includes contributions from all body regions 
(possible range, 0-100). 
VASI = Σ [hand units] × [Residual Depigmentation] all body sites 
The body is divided into the following 6 separate and mutually exclusive sites:   (1) head/neck, 
(2) hands, (3) upper extremities (excluding hands), (4) trunk, (5) lower extremities (excluding 
feet), and (6) feet.  The percentage of vitiligo involvement is estimated in hand units (% of BSA) 
by the same investigator during the entire course of the study.  Hand unit is based on 
participant’s hand size.  The investigator uses his/her hand to mimic the participant’s hand size to 
evaluate % BSA vitiligo involvement.  The degree of depigmentation for each body site is 
determined and estimated to the nearest of the following percentages:  0, 10%, 25%, 50%, 75%, 
90%, or 100%.  The T-VASI is then derived by multiplying the values assessed for the vitiligo 
involvement by the percentage of affected skin for each body site and summing the values of all 
body sites together (Hamzavi et al 2004).  Full details will be provided in the Study Manual. 
8.2.3. 
Physician’s Global Vitiligo Assessment (Facial) 
The severity of vitiligo will be assessed by the physician using the PhGVA, which has a 5-point 
scale (Table 11).  Response will be reported for face (F-PhGVA). 
Table 11: 
Facial Physician's Global Vitiligo Assessment Scale 
Score 
Severity 
Description 
0 
Clear 
No signs of vitiligo or complete/near complete repigmentation 
1 
Almost Clear 
Mostly pigmented areas with small depigmented or difficult to repigment 
areas (eg, philtrum, nares, corners of eyes, perioral skin) 
2 
Mild Disease 
Modest areas of depigmentation (not more than half of facial skin) with 
approximately 50% pigmentation within vitiligo areas or significant 
perifollicular pattern present 
3 
Moderate Disease 
Large areas of depigmented vitiligo areas (more than half of facial skin); 
significant depigmentation within vitiligo areas 
4 
Severe Disease 
Extensive areas of vitiligo to complete depigmentation on face 
8.2.4. 
Physician’s Global Vitiligo Assessment (Total Body) 
The severity of total body vitiligo will be assessed by the physician using the PhGVA, which has 
a 5-point scale (Table 12).  Response will be reported for total body (T-PhGVA). 


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Table 12: 
Total Body Physician's Global Vitiligo Assessment Scale 
Score 
Severity 
Description 
0 
Clear 
No signs of vitiligo or complete/near complete repigmentation 
1 
Almost Clear 
Mostly pigmented areas with small depigmented or difficult to repigment 
areas (eg, hands, feet, philtrum, nares, corners of eyes, perioral skin) 
2 
Mild Disease 
Modest areas of depigmentation with approximately 50% pigmentation 
within vitiligo areas or significant perifollicular pattern present 
3 
Moderate Disease 
Large areas of depigmented vitiligo areas; significant depigmentation 
within vitiligo areas 
4 
Severe Disease 
Extensive areas of vitiligo with complete depigmentation 
8.2.5. 
Photography 
Photography of the face and/or body areas affected with vitiligo will be obtained at visits listed 
in Table 3 and Table 4. 
All sites will use 2D photography, and selected sites will also use 3D photography, to 
photograph areas of the participant’s face affected with vitiligo.  2D photography will be used at 
all sites for the target nonfacial depigmented area. 
Target nonfacial vitiligo depigmented area definition:  At the baseline visit, depigmented 
nonfacial areas that are representative of the participant's overall disease and that are to be 
treated with study drug will be selected as targeted nonfacial vitiligo depigmented areas.  These 
areas will be assessed, measured, and documented in the participant's medical record at each 
subsequent visit during the study (see Table 3 and Table 4).  A note should be made in their 
medical record, and the baseline photographs can be marked with the location of the target 
depigmented area.  The genitalia area should not be photographed. 
Ad hoc photography of skin-related AEs is recommended. 
Photographic procedures will be standardized, and a full description of the methodology will be 
provided in a photography manual to be provided to the sites. 
8.2.6. 
Patient-Reported Outcomes 
Patient-reported outcomes and quality of life will be assessed (see Table 3 and Table 4) using the 
following tools: 
• VNS (Section 8.2.6.1) 
• Color-matching question (Section 8.2.6.2) 
• F-PaGIC-V (Section 8.2.6.3) 
• T-PaGIC-V (Section 8.2.6.4) 
• DLQI or CDLQI (Section 8.2.6.5) 
• WHO-5 (Section 8.2.6.6) 


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• TSQM (Section 8.2.6.7) 
• VitiQoL (Section 8.2.6.8) 
• HADS (Section 8.2.6.9) 
In order to avoid bias in the participants' responses to the questionnaires, all these assessments 
should be completed before any other evaluations or study procedures on the day of the study 
visit and prior to discussions with the investigator or study site staff. 
At the baseline visit, all patient-reported outcomes must be completed before the participant's 
first study drug application. 
8.2.6.1. 
Vitiligo Noticeability Scale 
The VNS is a patient‐reported measure of vitiligo treatment success, which has a 5-point scale 
(Batchelor et al 2016).  The baseline facial photograph will be shown to the participants for 
reference and a mirror will be provided for the participants to assess the vitiligo on their face. 
The participant will be asked to respond to the following query: 
Compared with before treatment, how noticeable is the vitiligo now?  Responses:  (1) More 
noticeable, (2) As noticeable, (3) Slightly less noticeable, (4) A lot less noticeable, and 
(5) No longer noticeable.  
VNS scores of 4 or 5 can be interpreted as representing treatment success. 
8.2.6.2. 
Color-Matching Question 
The baseline photograph and current participants’ facial image (participants will be provided a 
mirror) will be shown to the participant for reference, and the participant will be asked to 
respond to the following query: 
At this point of your treatment, how well does your skin color match between your face 
treated vitiligo skin and face normal skin?  Responses:  (1) Excellent, (2) Very good, 
(3) Good, (4) Poor, and (5) Very poor. 
8.2.6.3. 
Patient Global Impression of Change-Vitiligo (Facial) 
The F-PaGIC-V is an assessment of improvement by the participant.  It is a 7-point scale 
comparing the vitiligo areas at baseline with the participant's treated areas of facial vitiligo at the 
study visit.  Response will be reported for face (F-PaGIC-V).  The baseline photograph and 
current participants’ facial image (participants will be provided a mirror) will be shown to the 
participant for reference.  The participant will be asked to respond to the following query: 
Since the start of the treatment you've received in this study, your vitiligo on your face 
treated with the study drug is:  (1) Very much improved, (2) Much improved, (3) Minimally 
improved, (4) No change, (5) Minimally worse, (6) Much worse, and (7) Very much worse. 
F-PaGIC-V scores of 1 or 2 can be interpreted as representing treatment success. 


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8.2.6.4. 
Patient Global Impression of Change-Vitiligo (Total Body) 
The T-PaGIC-V is an assessment of improvement by the participant.  It is a 7-point scale 
comparing the vitiligo areas at baseline with the participant's treated areas of total body vitiligo 
at the study visit.  Response will be reported for total body (T-PaGIC-V).  The participant will be 
asked to respond to the following query: 
Since the start of the treatment you've received in this study, your vitiligo on your total body 
treated with the study drug is:  (1) Very much improved, (2) Much improved, (3) Minimally 
improved, (4) No change, (5) Minimally worse, (6) Much worse, and (7) Very much worse. 
T-PaGIC-V scores of 1 or 2 can be interpreted as representing treatment success. 
8.2.6.5. 
Dermatology Life Quality Index 
The DLQI is a simple, 10-question validated questionnaire to measure how much the skin 
problem has affected the participant over the previous 7 days (Finlay and Khan 1994).  
Participants age ≥ 16 years will answer the questionnaire with (1) very much, (2) a lot, (3) a 
little, or (4) not at all. 
The questionnaire is analyzed under 6 headings as follows: 
• Symptoms and feelings (Questions 1 and 2)  
• Daily activities (Questions 3 and 4)  
• Leisure (Questions 5 and 6)  
• Work and school (Question 7)  
• Personal relations (Questions 8 and 9)  
• Treatment (Question 10)  
CDLQI is the youth/children’s version of the DLQI.  For participants who are age ≥ 12 years to 
< 16 years at baseline, the CDLQI will be completed instead of the CDLQI throughout their 
participation in the study.  This questionnaire is self-explanatory and can be simply given to the 
participant who is asked to fill it in and who may ask the help of the parent or guardian.  The 
questionnaire is analyzed under 6 headings as follows:  
• Symptoms and feelings (Questions 1 and 2)  
• Leisure (Questions 4, 5, and 6)  
• School or holidays (Question 7)  
• Personal relationships (Questions 3 and 8)  
• Sleep (Question 9)  
• Treatment (Question 10)  
Full details will be provided in the Study Manual. 


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8.2.6.6. 
WHO-5 
The WHO-5 is a validated, self-administered, 5-item questionnaire designed to assess mental 
well-being over the past 2 weeks, which can be used as an outcome measure for the wanted and 
unwanted effects of treatments (WHO Collaborating Center for Mental Health, Topp et al 2015).  
The questionnaire consists of 5 statements, which respondents rate according to the following 
scale:  0 = At no time; 1 = Some of the time; 2 = Less than half of the time; 3 = More than half of 
the time; 4 = Most of the time; 5 = All of the time. 
The raw score is calculated by totaling the figures of the 5 answers for a range of 0 to 25, with 
0 representing the worst possible and 25 representing the best possible quality of life.  A score 
below 13 indicates poor well-being. 
Full details will be provided in the Study Manual. 
8.2.6.7. 
Treatment Satisfaction Questionnaire for Medication 
TSQM is a validated 9-item questionnaire that measures a participant’s satisfaction with 
medication taken in a clinical study using a recall period of the past 2 to 3 weeks or since the 
medication was last used.  The questionnaire uses a 7-point scale for each question (Bharmal 
et al 2009).  Full details will be provided in the Study Manual. 
8.2.6.8. 
VitiQoL 
VitiQoL is a 15-item quality-of-life assessment that asks participants to rate various aspects of 
their condition during the past month using a 7-point scale (“Not at all” to “All of the time”) 
(Lilly et al 2013).  Full details will be provided in the Study Manual. 
8.2.6.9. 
Hospital Anxiety and Depression Scale 
HADS is 14-item questionnaire that assesses the levels of anxiety and depression that a person is 
currently experiencing (Zigmond and Snaith 1983).  There are 7 questions each for measuring 
anxiety and for measuring depression, with 4 possible responses to each question (responses are 
scored as 0, 1, 2, or 3).  Separate scores are calculated for anxiety and depression.  Full details 
will be provided in the Study Manual. 
8.3. 
Safety Assessments 
Planned timepoints for all safety assessments are provided in the Table 3 and Table 4. 
See Section 6.5 for guidelines regarding the management of relevant laboratory or other safety 
assessment abnormalities. 
8.3.1. 
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 treatment.  Adverse events that begin or worsen after 
informed consent should be recorded on the Adverse Event 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. 


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Adverse events will be reported by the participant (or, when appropriate, by a caregiver, 
surrogate, or the participant's legally authorized representative).  The investigator and any 
qualified designees are responsible for detecting, documenting, and recording events that meet 
the definition of an AE or SAE and remain responsible for following-up on AEs that are serious, 
considered related to the study treatment, or that caused the participant to discontinue the study 
treatment.  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. 
The investigator will submit any updated SAE data to the sponsor immediately, without undue 
delay, under no circumstances later than 24 hours following knowledge 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). 
8.3.2. 
Physical Examinations 
Physical examinations will be conducted at the timepoints listed in Table 3 and Table 4. 
A comprehensive physical examination will include height and body weight and assessment of 
the following organ or body systems:  skin; head, eyes, ears, nose, and throat; thyroid; lungs; 
cardiovascular system; abdomen (liver, spleen); extremities; and lymph nodes.  A brief 
neurological examination will also be performed. 
A targeted physical examination should be conducted as indicated by symptoms reported by the 
participant, AEs, or other findings.  Abnormalities that are considered clinically significant in the 
judgment of the investigator are to be reported as AEs. 
Physical examinations must be performed by a medically qualified individual such as a licensed 
physician, physician's assistant, or an advanced registered nurse practitioner, as local law 
permits. 
8.3.3. 
Vital Signs 
Vital sign measurements include blood pressure, pulse, respiratory rate, and body temperature.  
Blood pressure and pulse will be taken with the participant in the recumbent, semi-recumbent, or 
sitting position after 5 minutes of rest.  Any abnormalities that are considered clinically 
significant in the judgment of the investigator are to be reported as AEs. 
8.3.4. 
Electrocardiograms 
All 12-lead ECGs will be performed with the participant in a recumbent or semi-recumbent 
position after 5 minutes of rest.  Electrocardiograms should be performed as indicated in Table 3.  
Additional 12-lead ECGs may be performed at other visits as deemed clinically necessary.  
Twelve-lead ECG performed within 2 months before baseline is acceptable for using as a 
screening value.  


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Electrocardiograms will be interpreted by the investigator at the site or designee, and the results 
will be used for immediate management of the participant's care.  There is no central reader of 
ECGs for this study. The decision to include or exclude a participant or withdraw a participant 
from the study based on an ECG flagged as "Abnormal, Clinically Significant" is the 
responsibility of the investigator, in consultation with the sponsor's medical monitor, as 
appropriate.  Any abnormalities that are considered clinically significant in the judgment of the 
investigator are to be reported as AEs. 
8.3.5. 
Laboratory Assessments 
Required laboratory tests are listed in Table 13, which include hematology, chemistry, urinalysis, 
serology, free T4, TSH, FSH, and pregnancy test (see Table 3 and Table 4).  Clinical laboratory 
tests will be performed at a central laboratory (refer to the Laboratory Manual for sample 
handling and shipping instructions). 
Clinically significant abnormal laboratory findings are those that are not associated with the 
underlying disease, unless judged by the investigator to be more severe than expected for the 
participant's condition.  All laboratory tests with values considered clinically significantly 
abnormal during participation in the study, or within 30 days after the last dose of study 
treatment, should be repeated until the values return to normal or baseline or are no longer 
considered clinically significant by the investigator or medical monitor. 
See Section 9.1 for information regarding laboratory abnormalities that should be recorded as an 
AE in the eCRF. 


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Table 13: 
Required Laboratory Analytes 
Serum Chemistriesa 
Hematology 
Urinalysis With 
Microscopic 
Examination 
Serology 
Other 
Albumin 
Alkaline phosphatase 
ALT 
AST 
Bicarbonate or CO2 
Blood urea nitrogen or 
urea 
Calcium 
Chloride 
Creatinine 
Glucose 
Lactate dehydrogenase 
Phosphate 
Potassium 
Sodium 
Total bilirubin 
Direct bilirubin (if total 
bilirubin is elevated 
above ULN) 
Total protein 
Complete blood 
count, including: 
• Hemoglobin 
• Hematocrit 
• Mean corpuscular 
volume (MCV) 
• Platelet count 
• Mean platelet 
volume 
• Red blood cell 
count 
• Reticulocyte 
count 
• White blood cell 
count 
 
Differential count, 
including: 
• Basophils 
• Eosinophils 
• Lymphocytes 
• Monocytes 
• Neutrophils 
Color and 
appearance 
pH and specific 
gravity 
Bilirubin 
Glucose 
Ketones 
Leukocytes 
Nitrite 
Occult blood 
Protein 
HIV antibody 
FSH 
Free T4  
TSH 
Pregnancy Testing 
Female participants of childbearing potential have a serum test at 
screening and safety follow-up visits.  A urine test will be 
conducted at all other visits.  A positive urine test will be 
confirmed by a serum test. 
a All serum chemistries will be performed on samples collected without respect to food intake (ie, non-fasting). 
Note:  Additional tests may be required, as agreed by investigator and sponsor, based on emerging safety data. 
8.3.5.1. 
Pregnancy Testing 
A serum pregnancy test will be required for all women of childbearing potential during screening 
and at the safety follow-up visit (30 [+ 7] days after EOT; EOT1 or EOT2 as applicable).  Urine 
pregnancy tests will be conducted as outlined in Table 3 and Table 4, as medically indicated, or 
per country-specific requirement.  Urine pregnancy tests will be performed locally.  If a urine 
pregnancy test is positive, the results should be confirmed with a serum pregnancy test, which 
may be performed locally. 
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 9.6 for reporting 
requirements. 


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8.3.5.2. 
Serology 
An HIV antibody assessment will be performed at the screening visit to rule out infection (see 
Table 3).  Serology 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. 
8.4. 
Pharmacokinetic Assessments 
Venous blood samples will be collected to assess the PK of ruxolitinib cream in this study 
population at each study visit indicated in Table 3. 
The exact date and time of the PK blood draws and the date and time of the last application of 
study drug preceding the blood draw (if applicable) will be recorded in the eCRF.  
Instructions for sample preparation and shipping will be provided in the Laboratory Manual.  
Participants will receive reminder cards in advance of the study visit providing instruction to 
hold the application of study drug on the day of the visit and a place to record the time of the 
prior dose of study drug.  
Pharmacokinetic blood samples can be collected at any time during study visits noted in the 
Table 3.  Blood samples must not be drawn from the area that has been treated with study drug.  
If it is not possible to access an area that is not treated with study drug, the site must adequately 
document this in the eCRF and not take the PK blood sample for that visit.  After the PK sample 
is drawn, participants will apply ruxolitinib cream 1.5% or vehicle cream at the site.  
All analyses will be conducted by Incyte Corporation (Wilmington, DE) or Incyte's designee. 
8.5. 
Pharmacodynamic and Translational Assessments 
Serum will be collected from all participants at all sites for proteomic analysis at timepoints 
outlined in Table 3 and Table 4.  The purpose of this analysis will be to retrospectively evaluate 
correlative and pharmacodynamic biomarkers of response. 
All analyses will be conducted by Incyte Corporation (Wilmington, DE) or Incyte's designee.  
Refer to the Study Manual for detailed instructions. 
8.6. 
Unscheduled Visits 
Unscheduled visits may occur at any time at the investigator's discretion, and appropriate clinical 
and laboratory tests may be performed, as clinically indicated. 
8.7. 
End of Treatment and/or Early Termination 
If a decision is made that the participant will permanently discontinue study drug, then the EOT 
visit should be conducted (EOT1 or EOT2 depending on the study period when the participant 
discontinues).  If the EOT visit coincides with a regular study visit, then the EOT evaluations 
will supersede those of that scheduled visit, and the data should be entered in the EOT page in 
the eCRF.  If this decision does not coincide with a regular visit, reasonable efforts should be 
made to have the participant return to the site to have the EOT procedures completed. 


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8.8. 
Safety Follow-Up 
For participants who do not participate in a separate extension study, the safety follow-up period 
is the interval between the EOT visit (EOT1 or EOT2 depending on the study period when the 
participant discontinues) and the scheduled safety follow-up visit, which should occur 
30 (+ 7) days after the EOT visit (or after the last dose of study drug/treatment if an EOT visit 
was not performed).  
Adverse events and SAEs must be reported up until at least 30 days after the last dose of study 
drug/treatment, the date of the safety follow-up visit, or until toxicities resolve, return to 
baseline, or are deemed irreversible, whichever is longer.  Reasonable efforts should be made to 
have the participant return for the safety follow-up visit and report any AEs that may occur 
during this period. 
9. 
ADVERSE EVENTS:  DEFINITIONS AND PROCEDURES FOR 
RECORDING, EVALUATING, FOLLOW-UP, AND REPORTING 
9.1. 
Definition of Adverse Event 
Adverse Event Definition 
• An AE is any untoward medical occurrence associated with the use of a drug in humans, whether or not 
considered drug-related. 
• An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease (new or exacerbated) temporally associated with the use of study 
treatment. 
Events Meeting the Adverse Event Definition 
• Any safety assessments (eg, ECG, vital signs measurements), including those that worsen from 
baseline, considered clinically significant in the medical and scientific judgment of the investigator (ie, 
not related to progression of underlying disease). 
• Abnormal laboratory test results constitute an AE if they are considered clinically meaningful, induce 
clinical signs or symptoms, require concomitant therapy, or require changes in study drug.  Whenever 
possible, a diagnosis (eg, anemia, thrombocytopenia) should be recorded in the eCRF rather than the 
abnormal lab result (eg, low hemoglobin, platelet count decreased). 
• Exacerbation of a chronic or intermittent pre-existing condition including either an increase in 
frequency and/or intensity of the condition. 
• New conditions detected or diagnosed after study treatment administration even though it may have 
been present before the start of the study. 
• Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
• Signs, symptoms, or the clinical sequelae of a suspected overdose of either study treatment or a 
concomitant medication.  Overdose per se will not be reported as an AE/SAE unless it is an intentional 
overdose taken with possible suicidal/self-harming intent.  Such overdoses should be reported 
regardless of sequelae. 
• "Lack of efficacy" or "failure of expected pharmacological action" per se will not be reported as an AE 
or SAE.  Such instances will be captured in the efficacy assessments.  However, the signs, symptoms, 
and/or clinical sequelae resulting from lack of efficacy will be reported as AE or SAE if they fulfill the 
definition of an AE or SAE.   


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Events NOT Meeting the Adverse Event Definition 
• Any clinically significant abnormal laboratory findings or other abnormal safety assessments that are 
associated with the underlying disease, unless judged by the investigator to be more severe than 
expected for the participant's condition. 
• The disease/disorder being studied or expected progression, signs, or symptoms of the disease/disorder 
being studied, unless more severe than expected for the participant's condition or considered to be 
treatment-related by the investigator. 
• Medical or surgical procedure (eg, endoscopy, appendectomy):  the condition that leads to the 
procedure is the AE if it occurred after signing the ICF.  If present before entering the study, the 
condition should be captured as medical history. 
• Situations in which an untoward medical occurrence did not occur (social and/or convenience 
admission to a hospital). 
• Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or detected at the 
start of the study that do not worsen. 
9.2. 
Definition of Serious Adverse Event 
If an event is not an AE per 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 occurred.  This does not include an adverse drug experience that, had it occurred in a 
more severe form, might have caused death. 
c. Requires inpatient hospitalization or prolongation of existing hospitalization 
In general, hospitalization signifies that the participant has been detained (usually involving at least an 
overnight stay) at the hospital or emergency ward for observation and/or treatment that would not have 
been appropriate in the physician's office or outpatient setting.  Complications that occur during 
hospitalization are AEs.  If a complication prolongs hospitalization or fulfills any other serious criteria, 
the event is serious.  When in doubt as to whether "hospitalization" occurred or was necessary, the AE 
should be considered serious. 
Hospitalization for elective treatment of a pre-existing condition that did not worsen from baseline is not 
considered an AE. 
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. 


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e. Is a congenital anomaly/birth defect 
f. Other situations (Important Medical Event) 
An event that may not result in death, be immediately life-threatening, or require hospitalization, but may 
be considered serious when, based on appropriate medical judgment, the event may jeopardize the 
participant and may require medical or surgical intervention to prevent one of the outcomes listed in the 
above definition.  Examples of such events include invasive or malignant cancers (excluding the 
disease[s] under study in oncology protocols), intensive treatment in an emergency department or at home 
for allergic bronchospasm, blood dyscrasias, or convulsions that do not result in hospitalization, or 
development of drug dependency or drug abuse. 
9.3. 
Recording and Follow-Up of Adverse Events and/or Serious Adverse 
Events 
Adverse Event and Serious Adverse Event Recording 
• An AE/SAE that begins or worsens after informed consent is signed should be recorded on the Adverse 
Event Form in the eCRF.  Conditions that were present at the time informed consent was given should 
be recorded on the Medical History Form in the eCRF. 
• When an AE/SAE occurs, it is the responsibility of the investigator to review all documentation 
(eg, hospital progress notes, laboratory reports, and diagnostics reports) related to the event. 
• The investigator (or delegate) will then record all relevant AE/SAE information in the eCRF. 
• It is not acceptable for the investigator to send photocopies of the participant's medical records to 
sponsor or designee in lieu of completing the AE eCRF page. 
• There may be instances when copies of medical records for certain cases are requested.  In this case, all 
participant identifiers, with the exception of the participant number, will be redacted on the copies of 
the medical records before submission. 
• The investigator will attempt to establish a diagnosis of the event based on signs, symptoms, and/or 
other clinical information.  Whenever possible, the diagnosis (not the individual signs/symptoms) will 
be documented as the AE/SAE.  When a clear diagnosis cannot be identified, each sign or symptom 
should be reported as a separate AE/SAE. 
To the extent possible, each AE/SAE should be evaluated to determine: 
• The severity grade (CTCAE 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 final safety follow-up. 
• The action taken with regard to study drug as a result of the AE/SAE(s). 
• The event outcome (eg, not recovered/not resolved, recovered/resolved, recovering/resolving, 
recovered/resolved with sequelae, fatal, unknown). 
• 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; intervention 
not indicated. 
• Grade 2:  Moderate; minimal, local, or noninvasive intervention 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 intervention indicated. 
• Grade 5:  Fatal. 
Assessment of Causality 
• The investigator is obligated to assess the relationship between study treatment and each occurrence of 
each AE/SAE. 
• A "reasonable possibility" of a relationship conveys a relationship cannot be ruled out. 
• The investigator will use clinical judgment to determine the relationship. 
• The investigator will also consult the RSI in the IB and/or Product Information, for marketed products, 
in his/her assessment. 
• Alternative causes, such as underlying disease(s), concomitant therapy, and other risk factors, as well as 
the temporal relationship of the event to study treatment administration, will be considered and 
investigated. 
• For each AE/SAE, the investigator must document in the medical notes that he/she has reviewed the 
AE/SAE and has provided an assessment of causality. 
• With regard to assessing causality of SAEs: 
− There may be situations in which an SAE has occurred and the investigator has minimal information 
to include in the initial report to the sponsor or designee.  However, it is very important that the 
investigator always make an assessment of causality for every event before the initial 
transmission of the SAE data to the sponsor or designee. 
− The investigator may change his/her opinion of causality in light of follow-up information and send a 
SAE follow-up report with the updated causality assessment. 
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 or designee to elucidate the 
nature and/or causality of the AE/SAE as fully as possible.  This may include additional laboratory tests 
or investigations, histopathological examinations, or consultation with other healthcare professionals. 
• If a participant dies during participation in the study or during a recognized safety follow-up period, the 
investigator will provide the sponsor or designee with a copy of any postmortem findings, including 
histopathology. 
• New or updated information will be recorded in the originally completed eCRF. 
• Any updated SAE data will be submitted to the sponsor or designee immediately, without undue delay, 
under no circumstances later than 24 hours following knowledge of the event. 


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• Once an AE is detected, it should be followed until it has resolved or until it is judged to be permanent; 
assessment should be made at each visit (or more frequently if necessary) of any changes in severity, 
the suspected relationship to the study drug, the interventions required to treat the event, and the 
outcome. 
• When the severity of an AE changes over time for a reporting period (eg, between visits), each change 
in severity will be reported as a separate AE until the event resolves. 
9.4. 
Reporting of Serious Adverse Events 
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 study visit (or 30 days after the 
last dose of study treatment, whichever occurs later) must be reported to the sponsor (or 
designee) immediately, without undue delay, under no circumstances later than 24 hours 
following knowledge of the event. 
Investigators are not obligated to actively seek AE or SAE information after conclusion of the 
study participation.  However, if the investigator learns of any SAE, including a death, at any 
time after a participant has been discharged from the study, and he/she considers it is at least 
reasonably possible that the event is related to the study treatment or study participation, then the 
investigator must notify the sponsor (or designee) immediately, without undue delay, under no 
circumstances later than 24 hours following knowledge of the event. 
After the initial AE/SAE report, the investigator is required to proactively follow each participant 
at subsequent visits/contacts.  All SAEs will be followed until resolution, stabilization, the event 
is otherwise explained, or the participant is lost to follow-up (as defined in Section 7.3). 
Prompt notification by the investigator to the sponsor of a SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of a study 
treatment under clinical investigation are met. 
If the SAE is not documented in the IB for the study drug (new occurrence) and is thought to be 
related to the sponsor's study drug, the sponsor or its designee may urgently require further 
information from the investigator for reporting to health authorities.  The sponsor or its designee 
may need to issue an Investigator Notification to inform all investigators involved in any study 
with the same drug that this SAE has been reported.  Suspected Unexpected Serious Adverse 
Reactions will be collected and reported to the competent authorities and relevant ethics 
committees in accordance with Directive 2001/20/EC, or as per national regulatory requirements 
in participating countries. 
The sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study treatment under clinical investigation.  The 
sponsor will comply with country-specific regulatory requirements relating to safety reporting to 
the regulatory authority, IRB/IEC, and investigators. 
Investigator safety reports must be prepared for SUSARs according to local regulatory 
requirements and sponsor policy and forwarded to investigators as necessary. 
An investigator who receives an investigator safety report describing a SAE or other specific 
safety information (eg, summary or listing of SAEs) from the sponsor will review and then file it 
along with the IB and will notify the IRB/IEC, if appropriate according to local requirements. 


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Serious Adverse Event Reporting 
• Information about all SAEs is collected and recorded on the Adverse Event Form in the eCRF. 
• The investigator must also complete the Incyte Serious Adverse Event Report Form, in English.  Refer 
to the Incyte Reference Guide for Completing the Serious Adverse Event Report Form. 
• Facsimile or email transmission of the Serious Adverse Event Report Form is the preferred method to 
transmit this information to the PhV/designee.  The contact information of the sponsor's study-specific 
representatives is listed in the Study Manual provided to each site.  The original copy of the Serious 
Adverse Event Report Form and the confirmation sheet must be kept at the study site. 
• Follow-up information is recorded on an amended or new Serious Adverse Event Report Form, with an 
indication that it is follow-up to the previously reported SAE and the date of the original report.  The 
follow-up report should include information that was not provided on the previous Serious Adverse 
Event Report Form, such as the outcome of the event (eg, resolved or ongoing), treatment provided, 
action taken with study drug because of the SAE (eg, dose reduced, interrupted, or discontinued), or 
participant disposition (eg, continued or withdrew from study participation).  Each recurrence, 
complication, or progression of the original event should be reported as follow-up to that event, 
regardless of when it occurs. 
• In rare circumstances and in the absence of facsimile or computer equipment, notification by telephone 
is acceptable with a copy of the Incyte Serious Adverse Event Report Form sent by overnight mail or 
courier service.  Initial notification via telephone does not replace the need for the investigator to 
complete and sign the Serious Adverse Event Report Form within the designated reporting time 
frames. 
• Contacts for SAE reporting can be found in the Study Manual. 
9.5. 
Emergency Unblinding of Treatment Assignment 
In a medical emergency during the double-blind, vehicle-controlled period, if the investigator 
deems it necessary to determine optimal medical management of the participant, emergency 
unblinding will be performed exclusively by the Principal Investigator and subinvestigator as 
described in the IRT Study Manual.  The IRT system has an option to select for "Emergency 
Code Break" action for a given participant.  After entering the 6-digit study drug tube number 
and verification of the unmasking information, the investigator/subinvestigator will proceed to 
either final confirmation or cancellation of the code break procedure. 
If a participant's treatment assignment is unblinded, the sponsor or its designee must be notified 
immediately by telephone followed-up with an email.  
If an investigator, site personnel performing assessments, or participant is unblinded, the 
participant must be withdrawn from the study treatment, unless there are ethical reasons to have 
the participant remain on the study treatment.  In these cases, the investigator must obtain 
specific approval from the sponsor's (or its designee's) medical monitor for the participant to 
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9.6. 
Pregnancy 
Pregnancy, in and of itself, is not regarded as an AE unless there is suspicion that study drug may 
have interfered with the effectiveness of a contraceptive medication or method.  When a 
pregnancy has been confirmed in a participant during maternal or paternal exposure to study 
drug, the following procedures should be followed in order to ensure safety: 
• The study drug must be discontinued immediately. 
• The investigator must complete and submit the Incyte Clinical Trial Pregnancy Form 
to the sponsor or its designee within 24 hours of learning of the pregnancy. 
Data on fetal outcome are collected for regulatory reporting and drug safety evaluation.  
Follow-up should be conducted for each pregnancy to determine outcome, including spontaneous 
or voluntary termination, details of the birth, and the presence or absence of any birth defects, 
congenital abnormalities, or maternal and/or newborn complications, by following until the first 
well-baby visit.  Pregnancy should be recorded on a Clinical Trial Pregnancy Form and reported 
by the investigator to the sponsor or its designee.  Pregnancy follow-up information should be 
recorded on the same form and should include an assessment of the possible causal relationship 
to the sponsor's study drug to any pregnancy outcome, as well as follow-up to the first well-baby 
visit or the duration specified in local regulations, whichever is later.  Refer to the Incyte 
Reference Guide for Completing the Clinical Trial Pregnancy Form. 
Any SAE occurring during pregnancy of a study participant must be recorded on the 
Serious Adverse Event Report Form and submitted to the sponsor or designee. 
Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, or ectopic pregnancy) are considered SAEs (if occurring in the study participant) and 
must be reported as described in Section 9.4.  If an abnormal pregnancy outcome is reported in a 
study participant's partner, the event should be reported to the sponsor on the Clinical Trial 
Pregnancy Form. 
9.7. 
Warnings and Precautions 
Special warnings or precautions for the study drug, derived from safety information collected by 
the sponsor or its designee, are presented in the IB.  Additional safety information collected 
between IB updates will be communicated in the form of Investigator Notifications.  Any 
important new safety information should be discussed with the participant during the study, as 
necessary.  If new significant risks are identified, they will be added to the ICF. 
9.8. 
Product Complaints 
The sponsor collects product complaints on study drugs and drug delivery systems used in 
clinical studies in order to ensure the safety of study participants, monitor quality, and facilitate 
process and product improvements. 
All product complaints associated with material packaged, labeled, and released by the sponsor 
or its designee will be reported to the sponsor.  All product complaints associated with other 
study material will be reported directly to the respective manufacturer. 


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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. 
9.9. 
Treatment of Overdose 
There has been no clinical experience with overdose of ruxolitinib cream.  Treatment of 
overdose should consist of general supportive measures. 
10. 
STATISTICS 
10.1. 
Sample Size Determination 
Approximately 300 participants will be randomized 2:1 to ruxolitinib cream 1.5% BID or vehicle 
and stratified by baseline skin type (Fitzpatrick scale Type I and II vs Type III, IV, V, and VI) 
and region (North America or Europe). The sample size is calculated to provide sufficient power 
(> 85%) to detect a difference between the 1.5% BID with the vehicle in primary and key 
secondary endpoints.  The powers for different endpoints are provided in Table 14.  The Fisher’s 
exact test with a 2-sided alpha of 0.05 is used to provide a conservative evaluation of statistical 
power, and it is accurate when there is a small expected number of responders in the vehicle 
group. 
Table 14: 
Powering for Primary and Key Secondary Endpoints 
Endpoints 
Response Rates in 
Ruxolitinib 1.5% BIDa 
Response Rates 
in Vehiclea 
Powerb 
F-VASI75 at Week 24 
20% 
5% 
95% 
F-VASI50 at Week 24 
30% 
10% 
 
 95% 
F-VASI90 at Week 24 
10% 
1% 
88% 
T-VASI50 at Week 24 
10% 
1% 
88% 
Vitiligo - VNS Response 
at Week 24 
10% 
1% 
88% 
a Based on the results from a Phase 2, randomized, dose-ranging study (INCB18424-211). 
b Based on the Fisher’s exact test with a 2-sided alpha of 0.05. 


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10.2. 
Populations for Analysis 
The populations for analysis are presented in Table 15. 
Table 15: 
Populations for Analysis 
Population 
Description 
ITT 
The ITT population includes all randomized participants.  Treatment groups for this 
population will be defined according to the treatment assignment at randomization. 
PP 
The PP population includes randomized participants who are considered to be 
sufficiently compliant with the Protocol. 
Safety 
The safety population includes all participants who applied at least 1 dose of study 
drug.  Treatment groups for this population will be determined according to the 
actual treatment the participant received on Day 1. 
PK/ 
pharmacodynamic 
evaluable 
The PK/pharmacodynamic evaluable population includes participants who applied 
at least 1 dose of ruxolitinib cream and provided at least 1 postdose blood sample 
for PK.  The study pharmacokineticist will review data listings of participant 
administration and sample records to identify participants to be excluded from the 
analysis. 
10.3. 
Statistical Analyses 
The Statistical Analysis Plan will be developed and finalized before database lock and will 
describe the details of the statistical analyses and procedures for accounting for missing data.  
This section is a summary of the planned statistical analyses of the primary and secondary 
endpoints. 
The gatekeeping testing strategy for the primary and key secondary analyses will be 
implemented to control the overall Type I error rate, 2-sided α = 0.05.  These endpoints will be 
tested in a fixed sequence at 2-sided α = 0.05 level in the following order: 
• Proportion of participants achieving F-VASI75 at Week 24 
• Proportion of participants achieving F-VASI50 at Week 24 
• Proportion of participants achieving F-VASI90 at Week 24 
• Proportion of participants achieving T-VASI50 at Week 24 
• Vitiligo - VNS Response at Week 24 
• Percentage change from baseline in F-BSA at Week 24 
10.3.1. 
Efficacy Analyses 
10.3.1.1. Primary Analysis 
The primary analysis will be based on the intent-to-treat population.  The primary alternative 
hypothesis (superiority of ruxolitinib cream 1.5% BID compared with vehicle) will be tested 
using exact logistic regression (Mehta and Patel 1995).  This model will include the treatment 
group (1.5% BID and vehicle) and stratification factors.  The p-value for between-treatment 


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group testing will be compared with 0.05.  Odds ratio and corresponding 95% confidence 
interval will be provided for comparing ruxolitinib cream and vehicle group at Week 24. 
All nonresponders in the double-blind treatment period, as well as all participants who 
discontinue study treatment at any time before the timepoint of interest, or discontinue from the 
study for any reason, will be defined as nonresponders for the nonresponder imputation analysis. 
Analysis will also be performed in the PP population for the primary endpoint.  The following 
deviations are considered major: 
• Missing primary endpoints on F-VASI; 
• Compliance less than 60% based on the application numbers. 
Participants with 1 or more such deviations will be excluded from the PP population.  In 
addition, Protocol deviations related to inclusion/exclusion criteria, discontinuation criteria, and 
use of excluded concomitant medications will be evaluated and decided whether they should be 
excluded.  Any exclusion from the PP population will be decided prior to breaking the blind. 
In addition, sensitivity analyses, including MI and LOCF, may be performed.  For MI, a fully 
conditional specification method (van Buuren et al 2007) that assumes the existence of a joint 
distribution for all variables will be used to impute F-VASI scores.  A regression model 
including treatment group, stratification factors, and baseline and postbaseline F-VASI scores up 
to Week 24 will be specified for the fully conditional specification method.  After the missing 
values are imputed, the binary variables will be derived based on the definition.  The 
randomization seed will set to be 18424307 and the imputation will be repeated 10 times to 
generate corresponding complete data sets, in order to reflect the uncertainty around the true 
value.  Exact logistic regression will be applied to each imputed dataset, and then the results will 
be combined for the inference.  For LOCF, for the participants who discontinue study treatment 
at any time before the timepoint of interest or discontinue from the study for any reason, the last 
observed nonmissing value will be used to fill in missing values at the timepoint of interest.  A 
tipping point analysis will be conducted to examine the potential effects of missing data.  The 
missing binary response on F-VASI75 at Week 24 in each treatment group will be replaced by a 
range of values from the most conservative case to the most aggressive case.  The most 
conservative case is that all the missing participants in active treatment groups are nonresponders 
and all the missing participants in the placebo group are responders, while the most aggressive 
case is the other way around.  For each scenario, between-treatment comparisons will be 
performed using a chi-square test. 
Subgroup analysis by baseline character, for example, skin type, age, and region, will be 
performed.  Details will be provided in the Statistical Analysis Plan. 
10.3.1.2. Key Secondary Analysis 
If the primary objective is achieved, the statistical hypotheses for key secondary endpoints will 
be tested in the frequency specified in Section 10.3. 
Key secondary efficacy analyses at Week 24 will be conducted in the ITT population.  The 
statistical comparisons for binary outcomes (VASI50/90 and VNS response) will be analyzed 
using the similar method as specified in the primary analysis.  For F-BSA, the missing values at 
Week 24 will be imputed using the similar multiple imputation method specified in the primary 


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analysis.  Then the derived percentage change from baseline in F-BSA at Week 24 will be 
analyzed using an ANCOVA model with treatment group, stratification factors, and baseline 
value as covariates.  A test for superiority between INCB018424 1.5% BID and vehicle cream 
will be performed using the least squares mean estimate of the percentage change from baseline 
in F-BSA at Week 24 from the ANCOVA model specified above.  Superiority will be 
established if the p-value of the difference (INCB018424 1.5% BID minus vehicle) is less than 
0.05. 
10.3.1.3. Secondary Analysis 
All other secondary and exploratory efficacy variables will be summarized using descriptive 
statistics.  For categorical measurements, summary statistics will include sample size, frequency, 
and percentages.  Similar exact logistic regression models as specified in the primary and key 
secondary analysis will be used if applicable.  For continuous measurements, summary statistics 
will include sample size, mean, median, SD, 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 repeated measurement. 
Secondary endpoint analyses at Week 52 on VASI (eg, F-VASI25/50/75/90 and 
T-VASI25/50/75/90) will be performed in the ITT population with the following methods: 
• Participants who discontinue the study drug before Week 24 due to any reason will be 
defined as nonresponders for subsequent visits until Week 52. 
• For participants who completed Week 24 in the vehicle and 1.5% BID group, missing 
values of VASI in treatment extension period (including Week 52) will be imputed 
using linear extrapolation method.  The binary outcomes on responses, 
VASI50/75/90, will be derived based on the imputed values.  The statistical 
comparisons for these endpoints will be analyzed using the similar method as 
specified in the primary analysis.  
10.3.2. 
Safety Analyses 
A TEAE is any AE either reported for the first time or worsening of a pre-existing event after 
first dose of study drug.  Analysis of AEs will be limited to TEAEs, but data listings will include 
all AEs regardless of their timing to study drug administration.  Adverse events will be tabulated 
by the MedDRA preferred term and system organ class.  Severity of AEs will be based on the 
National Cancer Institute CTCAE 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. 
The clinical laboratory data will be analyzed using summary statistics; no formal treatment group 
comparisons are planned.  Laboratory test values outside the normal range will be assessed for 
severity based on the normal ranges for the clinical reference laboratory.  The incidence of 
abnormal laboratory values and shift tables relative to baseline will be tabulated. 


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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. 
10.4. 
Analysis Plan 
No formal interim analysis is planned in this study.  The primary analysis will occur after the 
primary database lock, when all participants have completed the vehicle-controlled, double-blind 
treatment period.  Sponsors will all be unblinded, while investigators and participants will still be 
blinded, to the study treatment after the primary database lock.  After Week 52, investigators and 
participants will be unblinded.   
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 IRB/IEC approval before 
implementation of changes made to the study design, except for changes necessary to 
eliminate an immediate hazard to study participants. 
• The investigator will be responsible for the following: 
− Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC. 
− Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures. 
− Providing oversight of the conduct of the study at the site and adherence to GCP, 
IRB/IEC requirements, institutional requirements, and applicable laws and 
country-specific regulations. 
• Adhering to the Protocol as described in this document and agreeing that changes to 
the Protocol procedures, with the exception of medical emergencies, must be 
discussed and approved, first, by the sponsor or its designee and, second, by the 
IRB/IEC.  Each investigator is responsible for enrolling participants who have met 
the specified eligibility criteria. 


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• Retaining records in accordance with all local, national, and regulatory laws, but for a 
minimum period of at least 2 years after the last marketing application approval in an 
ICH region and until there are no pending or contemplated marketing applications in 
an ICH region, or if not approved, 2 years after the termination of the test article for 
investigation to ensure the availability of study documentation should it become 
necessary for the sponsor or a regulatory authority to review. 
− The investigator must not destroy any records associated with the study without 
receiving approval from the sponsor.  The investigator must notify the sponsor or 
its designee in the event of accidental loss or destruction of any study records.  If 
the investigator leaves the institution where the study was conducted, the sponsor 
or its designee must be contacted to arrange alternative record storage options. 
− 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, or study charters, or biomarker plans, as applicable. 
The sponsor (or designee) will be responsible for: 
• 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. 


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The investigator will be responsible for: 
• 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.   
• 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, or 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 at the 
investigator's site. 
− 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.  Also, current applicable medical records must be 
available. 
• May have responsibility for 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. 
• Permitting study-related monitoring, sponsor audits, IRB/IEC review, and regulatory 
inspections by providing direct access to source data and other relevant clinical study 
documents. 
− Monitoring:  Qualified representatives of the sponsor or its designee, study 
monitors, will monitor the study according to a predetermined plan.  The 
investigator must allow the study monitors to review any study materials and 
participant records at each monitoring visit. 
− Auditing:  Qualified representatives of the sponsor or its designee may audit the 
clinical study site and study data to evaluate compliance with the Protocol, 
applicable local clinical study regulations, and overall study conduct.  The 
investigator must allow the auditors to review original source records and study 
documentation for all participants. 
− Regulatory inspection:  Regulatory authorities may conduct an inspection of the 
study and the site at any time during the development of an investigational 
product.  The investigator and staff are expected to cooperate with the inspectors 
and allow access to all source documents supporting the eCRFs and other 
study-related documents.  The investigator must immediately notify the sponsor 
when contacted by any regulatory authority for the purposes of conducting an 
inspection. 


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11.3. 
Data Privacy and Confidentiality of Study Records 
The investigator and the sponsor or its designee must adhere to applicable data privacy laws and 
regulations.  The investigator and the sponsor or its designee are responsible for ensuring that 
sensitive information is handled in accordance with local requirements (eg, HIPAA).  
Appropriate consent and authorizations for use and disclosure and/or transfer (if applicable) of 
protected information must be obtained. 
Participant names will not be supplied to the sponsor or its designee.  Only the participant 
number and the participant's initials (participant's initials will only be recorded if allowable by 
local regulations) will be recorded in the eCRF, where permitted; 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 local data protection laws. 
11.4. 
Financial Disclosure 
Before study initiation, all clinical investigators participating in clinical studies subject to 
21 CFR Part 54 – Financial Disclosure by Clinical Investigators (ie, "covered studies") are 
required to submit a completed Clinical Investigator Financial Disclosure Form that sufficiently 
details any financial interests and arrangements that apply.  For the purpose of this regulation, 
"clinical investigator" is defined as any investigator or subinvestigator who is directly involved 
in the treatment or evaluation of research participants, including the spouse and each dependent 
child of the clinical investigator or subinvestigator.  These requirements apply to both US and 
foreign clinical investigators conducting covered clinical studies. 
Any new clinical investigators added to the covered clinical study during its conduct must also 
submit a completed Investigator Financial Disclosure Form.  During a covered clinical study, 
any changes to the financial information previously reported by a clinical investigator must be 
reported to the sponsor or its designee.  At the conclusion of the covered clinical study, the 
clinical investigators will be reminded of their obligations.  In the event that the clinical 
investigator is not reminded, they nevertheless will remain obligated to report to the sponsor or 
its designee any changes to the financial information previously reported, as well as any changes 
in their financial information for a period of 1 year after completion of the covered clinical study. 
11.5. 
Publication Policy 
By signing the study Protocol, the investigator and his or 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.  Sponsor commits to also adhere to supranational/international rules regarding 
publishing research results, as set by the Helsinki Declaration.  If necessary, the authorities will 
be notified of the investigator's name, address, qualifications, and extent of involvement.  The 
terms regarding the publication of study results are contained in the agreement signed with the 
sponsor or its designee.  A signed agreement will be retained by the sponsor or its designee. 


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The results of this study may be published or presented at scientific meetings.  If this is foreseen, 
the investigator agrees to submit all manuscripts or abstracts to the sponsor before submission.  
This allows the sponsor to protect proprietary information and to provide comments. 
The sponsor will comply with the requirements for publication of study results.  In accordance 
with standard editorial and ethical practice, the sponsor will generally support publication of 
multicenter studies only in their entirety and not as individual site data.  In this case, a 
coordinating investigator will be designated by mutual agreement. 
Authorship will be determined in line with International Committee of Medical Journal Editors 
authorship requirements. 
11.6. 
Study and Site Closure 
The sponsor designee reserves the right to close the study site or terminate the study at any time 
for any reason at the sole discretion of the sponsor.  Study sites will be closed upon study 
completion.  A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed. 
The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to: 
• Failure of the investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the sponsor's procedures, or GCP guidelines. 
• Inadequate recruitment of participants by the investigator. 
• Discontinuation of further study treatment development. 


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12. 
REFERENCES 
American Academy of Dermatology. Vitiligo: Diagnosis and Treatment. 2020. 
Bae JM, Jung HM, Hong BY, Lee JH, Choi WJ, Lee JH, Kim GM. Phototherapy for vitiligo: a 
systematic review and meta-analysis. JAMA Dermatol 2017;153:666-674. 
Bharmal M, Payne K, Atkinson MJ, Desrosiers MP, Morisky DE, Gemmen E. Validation of an 
abbreviated Treatment Satisfaction Questionnaire for Medication (TSQM-9) among patients on 
antihypertensive medications. Health Qual Life Outcomes 2009;7:36. 
Batchelor JM, Tan W, Tour S, Yong A, Montgomery AA, Thomas KS. Validation of the Vitiligo 
Noticeability Scale: a patient-reported outcome measure of vitiligo treatment success. Br J 
Dermatol 2016;174:386-394. 
Boniface K, Seneschal J, Picardo M, Taïeb A. Vitiligo: focus on clinical aspects, 
immunopathogenesis, and therapy. Clin Rev Allergy Immunol 2018;54:52-67. 
Castanet J, Ortonne JP. Pathophysiology of vitiligo. Clin Dermatol 1997:15:845-851. 
Centers for Disease Control and Prevention. BMI Percentile Calculator for Child and Teen. 
2019. 
Clinical Trials Facilitation and Coordination Group. Recommendations related to contraception 
and pregnancy testing in clinical trials. 2014. 
Coondoo A, Phiske M, Verma S, Lahiri K. Side-effects of topical steroids: a long overdue 
revisit. Indian Dermatol Online J 2014;5:416-425. 
Craiglow BG, King BA. Tofacitinib citrate for the treatment of vitiligo: a pathogenesis-directed 
Therapy. JAMA Dermatol 2015;151:1110-1112. 
Eleftheriadou V, Thomas KS, Whitton ME, Batchelor JM, Ravenscroft JC. Which outcomes 
should we measure in vitiligo? Results of a systematic review and a survey among patients and 
clinicians on outcomes in vitiligo trials. Br J Dermatol 2012;167:804-814. 
Finlay AY, Khan GK. Dermatology Life Quality Index (DLQI)--a simple practical measure for 
routine clinical use. Clin Exp Dermatol 1994;19:210-216. 
Frisoli ML, Harris JE. Vitiligo: mechanistic insights lead to novel treatments. J Allergy Clin 
Immunol 2017;140:654-662. 
Gawkrodger DJ, Ormerod AD, Shaw L, et al. Guideline for the diagnosis and management of 
vitiligo. Br J Dermatol 2008;159:1051-1076. 
González U, Whitton M, Eleftheriadou V, Pinart M, Batchelor J, Leonardi-Bee J. Guidelines for 
designing and reporting clinical trials in vitiligo. ArchDermatol 2011;147:1428-1436. 
Hamzavi I, Jain H, McLean D, Shapiro J, Zeng H, Lui H. Parametric modeling of narrowband 
UV-B phototherapy for vitiligo using a novel quantitative tool: the Vitiligo Area Scoring Index. 
Arch Dermatol 2004;140:677-683. 
Harris JE, Rashighi M, Nguyen N, et al. Rapid skin repigmentation on oral ruxolitinib in a 
patient with coexistent vitiligo and alopecia areata (AA). J Am Acad Dermatol 2016;74:370-371. 


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Joshipura D, Alomran A, Zancanaro P, Rosmarin D. Treatment of vitiligo with the topical Janus 
kinase inhibitor ruxolitinib: a 32-week open-label extension study with optional narrow-band 
ultraviolet B. J Am Acad Dermatol 2018;78:1205-1207. 
Krüger C, Panske A, Schallreuter KU. Disease-related behavioral patterns and experiences affect 
quality of life in children and adolescents with vitiligo. Int J Dermatol 2014;53:43-50. 
Krüger C, Schallreuter KU. A review of the worldwide prevalence of vitiligo in 
children/adolescents and adults. Int J Dermatol 2012;51:1206-1212. 
Lai YC, Yew YW, Kennedy C, Schwartz RA. Vitiligo and depression: a systematic review and 
meta-analysis of observational studies. Br J Dermatol 2017;177:708-718. 
Lilly E, Lu PD, Borovicka JH, et al. Development and validation of a vitiligo-specific 
quality-of-life instrument (VitiQoL). J Am Acad Dermatol 2013;69:e11-18. 
Linthorst Homan MW, de Korte J, Grootenhuis MA, Bos JD, Sprangers MA, van der Veen JP. 
Impact of childhood vitiligo on adult life. Br J Dermatol 2008;159:915-920. 
Linthorst Homan MW, Spuls PI, de Korte J, Bos JD, Sprangers MA, van der Veen JP. The 
burden of vitiligo: patient characteristics associated with quality of life. J Am Acad Dermatol 
2009;61:411-420. 
Mehta CR, Patel NR. Exact logistic regression: theory and examples. Stat Med 
1995;14:2143-2160. 
Osinubi O, Grainge MJ, Hong L, et al. The prevalence of psychological comorbidity in people 
with vitiligo: a systematic review and meta-analysis. Br J Dermatol 2018;178:863-878. 
Porter JR, Beuf AH, Lerner AB, Nordlund JJ, et al. The effect of vitiligo on sexual relationships. 
J Am Acad Dermatol 1990;22:221-222. 
Rodrigues M, Ezzedine K, Hamzavi I, Pandya AG, Harris JE, Vitiligo Working Group. New 
discoveries in the pathogenesis and classification of vitiligo. J Am Acad Dermatol 2017;77:1-13. 
Rothstein B, Joshipura D, Saraiya A, et al. Treatment of vitiligo with the topical Janus kinase 
inhibitor ruxolitinib. J Am Acad Dermatol 2017;76:1054-1060. 
Ruxolitinib Cream Investigator's Brochure. Wilmington, DE: Incyte Corporation. 
Salzer BA, Schallreuter KU. Investigation of the personality structure in patients with vitiligo 
and a possible association with impaired catecholamine metabolism. Dermatology 
1995;190:109-115. 
Silverberg JI, Silverberg NB. Association between vitiligo extent and distribution and 
quality-of-life impairment. JAMA Dermatol 2013;149:159-164. 
Speeckaert R, van Geel N. Vitiligo: an update on pathophysiology and treatment options. Am J 
Clin Dermatol 2017;18:733-744. 
Taieb A, Alomar A, Böhm M, et al. Guidelines for the management of vitiligo: the European 
Dermatology Forum consensus. Br J Dermatol 2013;168:5-19. 
Taieb A, Picardo M. Clinical practice. Vitiligo. N Engl J Med 2009;360:160-169. 
Topp CW, Østergaard SD, Søndergaard S, Bech P. The WHO-5 Well-Being Index: a systematic 
review of the literature. Psychother Psychosom 2015;84:167-176. 


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van Buuren S. Multiple imputation of discrete and continuous data by fully conditional 
specification. Stat Methods Med Res 2007;16:219-242. 
Vitiligo Research Foundation. Treatment Guidelines. 2020. 
Wang G, Qiu D, Yang H, Liu W. The prevalence and odds of depression in patients with vitiligo: 
a meta-analysis [published online ahead of print December 9, 2017]. J Eur Acad Dermatol 
Venereol. doi: 10.1111/jdv.14739. 
Whitton M, Pinart M, Batchelor JM, et al. Evidence-based management of vitiligo: summary of a 
Cochrane systematic review. Br J Dermatol 2016;174:962-969. 
World Health Organization. WHO Model Prescribing Information: Drugs Used in Skin Diseases. 
1997. 
WHO Collaborating Center for Mental Health, Psychiatric Research Unit. The WHO-5 website. 
Yazdani Abyaneh MA, Griffith R, Falto-Aizpurua L, Nouri K. The dark history of white spots. 
JAMA Dermatol 2014;150:936. 
Zigmond AS, Snaith RP. The hospital anxiety and depression scale. Acta Psychiatr Scand 
1983;67:361-370. 


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APPENDIX A. INFORMATION REGARDING EFFECTIVENESS OF 
CONTRACEPTIVE METHODS 
For male participants in the study: 
Male participants should use a condom during treatment through 90 days after the end of systemic 
exposure.  If the male participant has a partner that is of child-bearing potential, the partner should also 
use contraception through 90 days after the end of relevant systemic exposure.  In addition, male 
participants must refrain from donating sperm during the study through 90 days after the end of 
relevant systemic exposure.  Males who have had a vasectomy qualify as having met the requirement 
for a highly effective birth control method. 
For female participants in the study: 
The following methods that can achieve a failure rate of less than 1% per year when used consistently 
and correctly are considered as highly effective birth control methods: 
• Combined (estrogen and progestogen containing) hormonal contraception associated with 
inhibition of ovulation 
− oral 
− intravaginal 
− transdermal 
• Progestogen-only hormonal contraception associated with inhibition of ovulation 
− oral 
− injectable 
− implantablea 
• Intrauterine devicea 
• Intrauterine hormone-releasing systema 
• Bilateral tubal occlusiona 
• Vasectomized partnerab 
• Sexual abstinencec 
Acceptable birth control methods that result in a failure rate of more than 1% per year include:d 
• Progestogen-only oral hormonal contraception, where inhibition of ovulation is not the primary 
mode of action 
• Male or female condom with or without spermicidee 
• Cap, diaphragm, or sponge with spermicidee 
• Tubal ligation 
a Contraception methods that in the context of this guidance are considered to have low user dependency. 
b Vasectomized partner is a highly effective method of avoiding pregnancy provided that partner is the sole sexual 
partner of the woman of childbearing potential study participant and that the vasectomized partner has received 
medical assessment of the surgical success. 
c In the context of this guidance, sexual abstinence is considered a highly effective method only if defined as 
refraining from heterosexual intercourse during the entire period of risk associated with the study treatments.  The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical study and the 
preferred and usual lifestyle of the participant. 
d Choices are for US and Canada participants only and include above less than 1% failure rate methods. 
e A combination of male condom with either cap, diaphragm, or sponge with spermicide (double barrier methods) 
are also considered acceptable, but not highly effective, birth control methods. 
Source:  Clinical Trials Facilitation and Coordination Group 2014. 


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APPENDIX B. WHO CLASSIFICATION OF TOPICAL 
CORTICOSTEROIDS 
Hydrocortisone and betamethasone are examples of low- and high-potency topical 
corticosteroids.  Topical corticosteroids have been ranked in terms of potency into 4 groups 
consisting of 7 classes.  Class I topical corticosteroids are the most potent, and Class VII are the 
least potent.  Efficacy and side-effects are greatest with the Class I ultra-high–potency 
preparations, which should only be used for limited time periods (2-3 weeks).  Representative 
preparations by group are listed in the table below.  These groups may vary depending on the 
formulation and concentration and should be considered approximate.  In general, ointments are 
more potent than creams or lotions.  Potency is also increased when topical corticosteroids are 
used under occlusive dressings or in intertriginous areas. 
Potency 
Class 
Topical corticosteroid 
Formulation 
Ultra high 
I 
Clobetasol propionate 
Cream, 0.05% 
Diflorasone diacetate 
Ointment, 0.05% 
High 
II 
Amcinonide 
Ointment, 0.1% 
Betamethasone dipropionate 
Ointment, 0.05% 
Desoximetasone 
Cream or ointment, 0.025% 
Fluocinonide 
Cream, ointment or gel, 0.05% 
Halcinonide 
Cream, 0.1% 
III 
Betamethasone dipropionate 
Cream, 0.05% 
Betamethasone valerate 
Ointment, 0.1% 
Diflorasone diacetate 
Cream, 0.05% 
Triamcinolone acetonide 
Ointment, 0.1% 
Moderate 
IV 
Desoximetasone 
Cream, 0.05% 
Fluocinolone acetonide 
Ointment, 0.025% 
Fludroxycortide 
Ointment, 0.05% 
Hydrocortisone valerate 
Ointment, 0.2% 
Triamcinolone acetonide 
Cream, 0.1% 
V 
Betamethasone dipropionate 
Lotion, 0.02% 
Betamethasone valerate 
Cream, 0.1% 
Fluocinolone acetonide 
Cream, 0.025% 
Fludroxycortide 
Cream, 0.05% 
Hydrocortisone butyrate 
Cream, 0.1% 
Hydrocortisone valerate 
Cream, 0.2% 
Triamcinolone acetonide 
Lotion, 0.1% 
Low 
VI 
Betamethasone valerate 
Lotion, 0.05% 
Desonide 
Cream, 0.05% 
Fluocinolone acetonide 
Solution, 0.01% 
VII 
Dexamethasone sodium phosphate 
Cream, 0.1% 
Hydrocortisone acetate 
Cream, 1% 
Methylprednisolone acetate 
Cream, 0.25% 
Source:  WHO 1997. 


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APPENDIX C. PROTOCOL AMENDMENT SUMMARY OF CHANGES 
Document 
Date 
Amendment 1: 
31 OCT 2019 
Amendment 2: 
12 DEC 2019 
Amendment 3: 
21 FEB 2020 
Amendment 3-US-CA: 
13 MAR 2020 
Amendment 3-US-CA (13 MAR 2020) 
Overall Rationale for the Amendment:  To clarify BMI criteria for adult and adolescent 
participants. 
1. Section 5.2, Exclusion Criteria 
Description of changes:  Added BMI-for-age criterion for adolescent participants 
(≥ 12 to < 18 years) to exclusion criterion 8. 
Rationale for change:  Body mass index is interpreted differently for children and teens, 
even though it is calculated using the same formula as adult BMI.  For children and teens, 
BMI needs to be age- and sex-specific.  The normal or healthy weight category for BMI 
in children and teens per CDC is ≥ 5th to < 85th percentile range.  Therefore, for 
adolescent participants the BMI-for-age ≥ 5th to < 85th percentile ranking is considered 
eligible for this study. 
2. Incorporation of administrative changes.  Other minor, administrative changes have 
been incorporated throughout the Protocol and are noted in the redline version of the 
amendment. 
 


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Amendment 3 (21 FEB 2020) 
Overall Rationale for the Amendment:  The primary purpose of this amendment is to 
incorporate revisions requested by the German and French Ethics Committees (ECs) and FDA. 
1. Section 1, Protocol Summary (Table 1:  Primary and Secondary Objectives and 
Endpoints); Section 3, Objectives and Endpoints (Table 8: :Objectives and 
Endpoints); Section 10.1, Sample Size Determination (Table 14:  Powering for 
Primary and Key Secondary Endpoints); Section 10.3, Statistical Analyses, 
Section 10.3.1.1, Primary Analysis; Section 10.3.1.2, Key Secondary Analysis; 
Section 10.3.1.3, Secondary Analysis 
Description of changes:  Reordered and revised the key secondary endpoints and 
updated the analysis plan. 
Rationale for change:  To address FDA response. 
2. Section 1, Protocol Summary (Table 2: Key Study Design Elements) 
Description of changes:  Added 1 key exclusion criteria (exclude other forms of vitiligo) 
to the Population section, added information about the exit interview in the Study Design 
section, and added a DSMB section to indicate that a DSMB is not required in this study. 
Rationale for change:  To address French EC response. 
3. Section 1, Protocol Summary (Table 3:  Schedule of Activities:  Double-Blind, 
Vehicle-Controlled Treatment Period [Day 1-Week 24]; Table 4:  Schedule of 
Activities:  Treatment Extension Period [Week 28-Week 52]) 
Description of changes:  Added language that per protocol Section 8.3.2, targeted 
physical examination should be conducted as indicated by symptoms reported by the 
participant, AEs, or other findings.  Abnormalities that are considered clinically 
significant in the judgment of the investigator are to be reported as AEs. 
Rationale for change: To clarify that targeted physical examination is not required 
unless there are symptoms reported by the participant, AEs, or other findings. 
4. Section 8.1.2, Screening Procedures 
Description of changes:  Added language to instruct that adolescent participants 
screened in Germany whose hemoglobin is between 10 g/dL and 12 g/dL during the 
screening visit should be further evaluated per local guidelines before being enrolled into 
the study. 
Rationale for change:  To address German EC response. 
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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Amendment 2 (12 DEC 2019) 
Overall Rationale for the Amendment: 
The primary purpose of this amendment is to incorporate revisions requested by the Voluntary 
Harmonisation Procedure (VHP). 
1. Section 5.2, Exclusion Criteria 
Description of change:  Added language to exclude participant who has current and/or 
history of tuberculosis. 
Rationale for change:  To address VHP response. 
2. Section 5.2, Exclusion Criteria 
Description of changes:  Added language to exclude participants who live with anyone 
participating in any current Incyte-sponsored ruxolitinib cream study. 
Rationale for change:  To avoid study drug sharing and reinforce treatment compliance. 
3. Section 8.1.2, Screening Procedures 
Description of changes:  Added language to instruct that German participants whose 
hemoglobin is between 10 g/dL and 10.5 g/dL during the screening visit should be further 
evaluated per local guidelines before enrolling into the study.  
Rationale for change:  To address VHP response. 


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Amendment 1 (31 OCT 2019) 
Overall Rationale for the Amendment: 
This amendment is considered to be nonsubstantial based on the criteria set forth in Article 10(a) 
of Directive 2001/20/EC of the European Parliament and the Council of the European Union, 
because it does not have a significant impact on the safety or physical/mental integrity of the 
participants nor on the scientific value of the study. 
The primary purpose of this amendment is to incorporate revisions requested by the Voluntary 
Harmonisation Procedure (VHP) and to add the option for a subgroup of study participants to be 
included in a substudy involving exit interviews at Week 24 and Week 52.  
1. Section 1, Protocol Summary (Table 3:  Schedule of Activities:  Double-Blind, 
Vehicle-Controlled Treatment Period [Day 1-Week 24]; Table 4:  Schedule of 
Activities:  Treatment Extension Period [Week 28-Week 52]); Section 8.1.6, Exit 
Interviews 
Description of change:  Exit interviews and informed consent to participate in them 
were added to the Schedule of Activities, and a description of the exit interview was 
added.    
Rationale for change:  To provide details on the exit interviews and their timing, 
duration, and numbers of participants involved in the substudy. 
2. Section 2.5.1, Scientific Rationale for Study Design 
Description of changes:  Added the meaning and medical/clinical relevance of endpoints 
and their outcomes.  
Rationale for change:  To address VHP response. 
3. Section 2.4, Ruxolitinib Cream 
Description of changes:  Added language “no precautions are anticipated for [ruxolitinib 
cream’s] concomitant use with systemic drugs or for participants with hepatic 
impairment.” 
Rationale for change:  To address VHP response and add a statement regarding 
participants with hepatic function impairment. 
4. Appendix A, Information Regarding Effectiveness of Contraceptive Methods 
Description of change:  The following footnote was removed:  Hormonal contraception 
may be susceptible to interaction with the investigational medicinal product, which may 
reduce the efficacy of the contraception method. 
Rationale for change:  The statement is specific for oral ruxolitinib, as most of 
hormonal contraception is metabolized by the same enzyme (CYP3A4) for ruxolitinib.  
The systemic exposure for topical application of ruxolitinib cream is expected to be very 
limited.  Thus, this precaution is not warranted. 


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5. Appendix A, Information Regarding Effectiveness of Contraceptive Methods 
Description of change:  Added footnote and clarified that the acceptable birth control 
methods that result in a failure rate of more than 1% per year are for US and Canada 
participants only.  
Rationale:  To address VHP response. 
6. Section 1, Protocol Summary (Table 3:  Schedule of Activities:  Double-Blind, 
Vehicle-Controlled Treatment Period [Day1-Week 24]); Section 5.1, Inclusion 
Criteria 
Description of change:  Updated the definition of postmenopausal state to having 
amenorrhea for at least 12 months without an alternative medical cause. 
Rationale for change:  To address VHP request and provide completed definition of 
postmenopausal. 
7. Section 5.2, Exclusion Criteria (Exclusion Criterion 12) 
Description of change:  Added language in exclusion criteria to exclude participants 
with known allergy or reaction to any component of the study formulation. 
Rationale for change:  To address VHP request.  
8. Section 5.3, Lifestyle Considerations; Section 6.6.1, Permitted Medications and 
Procedures 
Description of changes:  Updated the study drug application guidance with respect to 
emollients, camouflage makeups, sunscreens, and after shaving. 
Rationale for change:  To remove unnecessary limitation of concomitant application of 
study drug and other cosmetic products. 
9. Section 6.2, Preparation, Handling, and Accountability 
Description of changes:  Added language of application guidance for participants with 
hand vitiligo. 
Rationale for change:  If patients have vitiligo on their hands, they do not need to wash 
the hand after study drug application. 
10. Section 6.6.2, Restricted Medications and Measures; Appendix B, WHO 
Classification of Topical Corticosteroids 
Description of changes:  Added WHO classification of topical corticosteroids.  
Rationale for change:  To address VHP response and provide topical corticosteroid 
classification that combines system for both the United States and most of the European 
VHP countries. 


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11. Section 8.2.6.3, Patient Global Impression of Change-Vitiligo (Facial) 
Description of changes:  Added that the baseline photograph and a mirror will be 
provided to the participant for reference. 
Rationale for change:  To allow participants to self-evaluate the before and after 
treatment facial repigmentation while they answer the F-PaGIC.  
12. Section 1, Protocol Summary (Table 4:  Schedule of Activities:  Treatment 
Extension Period (Week 28-Week 52)]) 
Description of changes:  Added “Assess compliance” up to Week 52 visits. 
Rationale for change: To further evaluate the compliance in the treatment extension 
period. 
13. Section 7.1.1, Reasons for Discontinuation 
Description of changes:   Language for participants found not to have met eligibility 
criteria was updated from “may be discontinued from study treatment” to “must be 
discontinued from study treatment.”  Also added definition of “not met eligibility 
criteria.” 
Rationale for change:  To address VHP response.  
14. Section 8.3.1, Adverse Events; Section 9.3, Recording and Follow-Up of Adverse 
Events and/or Serious Adverse Events; Section 9.4, Reporting of Serious Adverse 
Events 
Description of changes:  Updated SAE reporting timeframe from “within 24 hours” to 
“immediately, without undue delay, under no circumstances later than 24 hours following 
knowledge of the event.” 
Rationale for change:  To address VHP response. 
15. Section 9.3, Recording and Follow-Up of Adverse Events and/or Serious Adverse 
Events 
Description of changes:  Revised the language on “Assessment of Causality.” 
Rationale for change:  To address VHP response. 
16. Section 11.5, Publication Policy 
Description of changes:  Added language of “Sponsor commits to also adhere to 
supranational/international rules regarding publishing research results, as set by the 
Helsinki Declaration.” 
Rationale for change:  To address VHP response.  


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17. Section 1, Protocol Summary; Section 4.1, Overall Design; Section 6.3, Measures to 
Minimize Bias:  Randomization and Blinding; Section 10.1, Sample Size 
Determination 
Description of changes:  Removed the stratification criterion by age and added in 
stratification by region (North America or Europe).  
Rationale for change:  To address VHP response and include region as one of 
stratification factors. 
18. Section 10.3.1.1, Primary Analysis 
Description of changes:  Revised the definition of per protocol (PP) population and 
clarified the language of primary analysis. 
Rationale for change:  To address VHP response.  
19. Section 2.4.2.2.3, Vitiligo 
Description of changes:  Added language to address the observed effect size/efficacy 
rate of ruxolitinib cream (Cohen’s D), and the expected effect size/efficacy rate of 1.5% 
BID. 
Rationale for change:  To address VHP request. 
20. Section 5.1, Inclusion Criteria (Inclusion Criterion 5) 
Description of change:  Revised language in the inclusion criterion to clarify that for 
adolescent participants, the written informed consent of the parents or legal guardian and 
written assent from the adolescent participant are required.  Adult participants must 
possess the ability to comprehend and willingness to sign an ICF. 
Rationale for change:  To address VHP request. 
21. Section 10.3.1.1, Primary Analysis; Section 10.3.1.3, Secondary Analysis 
Description of changes:  The exact logistic regression will be used for primary and key 
secondary analysis. 
Rationale of change: To address VHP response. 
22. Section 3, Objectives and Endpoints (Table 8:  Objectives and Endpoints); 
Section 8.2.6, Patient-Reported Outcomes 
Description of changes:  Moved F-PhGVA, T-PhGVA, F-PaGIC-V, T-PaGIC-V, and 
color-matching endpoints from quality-of-life objective to efficacy objective. 
Rationale for change:  These are efficacy assessments not intended to evaluate patient 
quality of life. 


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23. Section 1, Protocol Summary (Table 3:  Schedule of Activities:  Double-Blind, 
Vehicle-Controlled Treatment Period [Day1-Week 24]; Table 4:  Schedule of 
Activities:  Treatment Extension Period [Week 28-Week 52]) 
Description of changes:  Removed re-dispended study drug language. 
Rationale for changes:  Unused study drugs and tubes will not be re-dispensed in this 
study. 
24. Incorporation of administrative changes.  Other minor, administrative changes have 
been incorporated throughout the Protocol and are noted in the redline version of the 
amendment. 

SAP_001.pdf: 
Official Title: 
Topical Ruxolitinib Evaluation in Vitiligo Study 2 (TRuE-V2): A Phase 3, Double-Blind, 
Randomized, Vehicle-Controlled, Efficacy and Safety Study of Ruxolitinib Cream 
NCT Number: 
NCT04057573 
Document Date: 
Statistical Analysis Plan Version 1: 09 March 2021
Followed by an Extension Period in Participants With Vitiligo


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Statistical Analysis Plan 
TITLE PAGE 
 
 
INCB 18424-306/307 
Topical Ruxolitinib Evaluation in Vitiligo Study 1/2 
(TRuE-V1/2) 
A Phase 3, Double-Blind, Randomized, Vehicle-Controlled, Efficacy 
and Safety Study of Ruxolitinib Cream Followed by an Extension Period 
in Participants With Vitiligo 
 
IND Number: 
77,101 
EudraCT Number: 
2019-000846-37/2019-000847-28 
Sponsor: 
Incyte Corporation 
1801 Augustine Cut-Off 
Wilmington, DE 19803 
United States 
Protocol Version: 
Protocol Amendment 3-US-CA dated 13 MAR 2020 
CRF Approval Date: 
04 JUN 2020/05 JUN 2020 
SAP Version: 
Original 
SAP Author: 
 
 Biostatistics 
Date of Plan: 
09 MAR 2021 
 
 
This study is being conducted in compliance with good clinical practice, 
including the archiving of essential documents. 
 


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TABLE OF CONTENTS 
TITLE PAGE ...................................................................................................................................1 
TABLE OF CONTENTS .................................................................................................................2 
LIST OF ABBREVIATIONS ..........................................................................................................6 
1. 
INTRODUCTION ........................................................................................................8 
2. 
STUDY INFORMATION, OBJECTIVES, AND ENDPOINTS.................................8 
2.1. 
Protocol and Case Report Form Version ......................................................................8 
2.2. 
Objectives and Endpoints .............................................................................................8 
3. 
STUDY DESIGN .......................................................................................................11 
3.1. 
Randomization ............................................................................................................11 
3.2. 
Control of Type I Error ...............................................................................................12 
3.3. 
Sample Size Considerations .......................................................................................12 
3.4. 
Schedule of Assessments ............................................................................................12 
4. 
DATA HANDLING DEFINITIONS AND CONVENTIONS ..................................13 
4.1. 
Scheduled Study Evaluations and Study Periods .......................................................13 
4.1.1. 
Day 1 ...........................................................................................................................13 
4.1.2. 
Study Day ...................................................................................................................13 
4.1.3. 
Baseline Value ............................................................................................................13 
4.1.4. 
Handling of Missing and Incomplete Data .................................................................14 
4.2. 
Variable Definitions ....................................................................................................14 
4.2.1. 
Body Mass Index ........................................................................................................14 
4.2.2. 
Prior and Concomitant Medication .............................................................................14 
5. 
STATISTICAL METHODOLOGY ...........................................................................15 
5.1. 
General Methodology .................................................................................................15 
5.2. 
Treatment Groups .......................................................................................................15 
5.3. 
Analysis Populations ..................................................................................................15 
5.3.1. 
Full Analysis Set .........................................................................................................15 
5.3.2. 
Per Protocol Population ..............................................................................................15 
5.3.3. 
Safety Population ........................................................................................................15 
5.3.4. 
Treatment-Extension Evaluable Population ...............................................................16 
5.3.5. 
Pharmacokinetic/Pharmacodynamic Evaluable Population .......................................16 
6. 
BASELINE, EXPOSURE, AND DISPOSITION VARIABLES AND 
ANALYSES ...............................................................................................................16 


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6.1. 
Baseline and Demographics, Physical Characteristics, and Disease History .............16 
6.1.1. 
Demographics .............................................................................................................16 
6.1.2. 
Baseline Disease Characteristics ................................................................................16 
6.1.3. 
Prior Therapy for Vitiligo ...........................................................................................17 
6.1.4. 
Medical History ..........................................................................................................17 
6.2. 
Disposition of Participants ..........................................................................................17 
6.3. 
Protocol Deviations ....................................................................................................17 
6.4. 
Exposure .....................................................................................................................17 
6.5. 
Study Drug Compliance .............................................................................................18 
6.6. 
Prior and Concomitant Medication .............................................................................18 
7. 
EFFICACY .................................................................................................................18 
7.1. 
General Considerations ...............................................................................................18 
7.2. 
Efficacy Measures ......................................................................................................18 
7.2.1. 
Body Surface Area ......................................................................................................18 
7.2.2. 
Vitiligo Area Scoring Index ........................................................................................19 
7.2.3. 
Physician’s Global Vitiligo Assessment (Facial) .......................................................19 
7.2.4. 
Physician’s Global Vitiligo Assessment (Total Body) ...............................................20 
7.2.5. 
Patient-Reported Outcomes ........................................................................................20 
7.2.5.1. 
Vitiligo Noticeability Scale ........................................................................................21 
7.2.5.2. 
Color-Matching Question ...........................................................................................21 
7.2.5.3. 
Patient Global Impression of Change-Vitiligo (Facial) ..............................................21 
7.2.5.4. 
Patient Global Impression of Change-Vitiligo (Total Body) .....................................21 
7.2.5.5. 
Dermatology Life Quality Index ................................................................................22 
7.2.5.6. 
WHO-5 .......................................................................................................................23 
7.2.5.7. 
Treatment Satisfaction Questionnaire for Medication ................................................24 
7.2.5.8. 
Vitiligo-Specific Health-Related Quality-of-Life Instrument ....................................24 
7.2.5.9. 
Hospital Anxiety and Depression Scale .....................................................................25 
7.3. 
Analysis of the Primary Efficacy Parameter ..............................................................25 
7.3.1. 
Primary Efficacy Analyses .........................................................................................25 
7.3.2. 
Subgroup Analyses for Primary Efficacy Endpoint ...................................................26 
7.3.3. 
Sensitivity and Supportive Analyses for Primary Endpoint .......................................26 
7.3.3.1. 
Nonresponder Imputation ...........................................................................................26 
7.3.3.2. 
Last Observation Carried Forward .............................................................................26 


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7.3.3.3. 
Tipping Point Analysis ...............................................................................................26 
7.4. 
Analysis of the Key Secondary Efficacy Parameters .................................................27 
7.5. 
Analysis of Other Secondary Efficacy Parameters .....................................................27 
7.5.1. 
Other Secondary Efficacy Analysis ............................................................................27 
7.5.1.1. 
Continuous Efficacy Endpoints ..................................................................................27 
7.5.1.2. 
Categorical Efficacy Endpoints ..................................................................................28 
7.6. 
Analysis of Exploratory Efficacy Parameters .............................................................28 
7.6.1. 
Exploratory Efficacy Analysis ....................................................................................28 
7.7. 
Pharmacokinetic Analyses ..........................................................................................29 
7.8. 
Pharmacodynamic Analyses .......................................................................................29 
7.9. 
Pharmacokinetic/Pharmacodynamic Analyses ...........................................................29 
8. 
SAFETY AND TOLERABILITY ..............................................................................29 
8.1. 
General Considerations ...............................................................................................29 
8.2. 
Adverse Events ...........................................................................................................29 
8.2.1. 
Adverse Event Definitions ..........................................................................................29 
8.2.2. 
Adverse Event Summaries ..........................................................................................30 
8.3. 
Clinical Laboratory Tests ...........................................................................................31 
8.3.1. 
Laboratory Value Definitions .....................................................................................31 
8.3.2. 
Laboratory Value Summaries .....................................................................................31 
8.4. 
Vital Signs ..................................................................................................................32 
9. 
PLANNED ANALYSES ............................................................................................33 
10. 
CHANGES AND MODIFICATIONS TO THE ANALYSIS PLAN ........................34 
10.1. 
Changes to Protocol-Defined Analyses ......................................................................34 
10.2. 
Changes to the Statistical Analysis Plan .....................................................................34 
11. 
REFERENCES ...........................................................................................................35 
APPENDIX A. PLANNED TABLES AND FIGURES .............................................................37 
 


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LIST OF TABLES 
Table 1: 
Objectives and Endpoints .............................................................................................9 
Table 2: 
Powering for Primary and Key Secondary Endpoints ................................................12 
Table 3: 
Facial Physician's Global Vitiligo Assessment Scale .................................................20 
Table 4: 
Total Body Physician's Global Vitiligo Assessment Scale ........................................20 
Table 5: 
Criteria for Clinically Notable Vital Sign Abnormalities for 12 to 15 Years 
Old ..............................................................................................................................32 
Table 6: 
Criteria for Clinically Notable Vital Sign Abnormalities for 16 to 17 Years 
Old ..............................................................................................................................32 
Table 7: 
Criteria for Clinically Notable Vital Sign Abnormalities for ≥ 18 Years Old ............33 
Table 8: 
Statistical Analysis Plan Versions ..............................................................................34 
 
LIST OF FIGURES 
Figure 1: 
Study Design Schema .................................................................................................11 
 


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LIST OF ABBREVIATIONS 
Abbreviations 
Definition 
AE 
adverse event 
ANCOVA 
analysis of covariance 
ASR 
application site reaction 
BID 
twice daily 
BMI 
Body Mass Index 
BSA 
body surface area 
CDLQI 
Children’s Dermatology Life Quality Index 
CI 
confidence interval 
CRF 
case report form 
CTCAE 
Common Terminology Criteria for Adverse Events 
DBP 
diastolic blood pressure 
DLQI 
Dermatology Life Quality Index 
eCRF 
electronic case report form 
FAS 
Full Analysis Set 
F-BSA 
facial body surface area 
F-PaGIC-V 
facial assessment of Patient Global Impression of Change-Vitiligo 
F-PhGVA 
facial assessment of Physician Global Vitiligo Assessment 
F-VASI 
Face Vitiligo Area Scoring Index 
F-VASI25/50/75/90 
≥ 25%/50%/ 75%/ 90% improvement from baseline in Face Vitiligo Area Scoring 
Index score 
HADS 
Hospital Anxiety and Depression Scale 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
multiple imputation 
MMRM 
mixed-effect model repeat measurement 
NCI 
National Cancer Institute 
NRI 
nonresponder imputation 
Pa-GIC-V 
Patient Global Impression of Change-Vitiligo 
PD 
pharmacodynamic  
PhGVA 
Physician Global Vitiligo Assessment 
PK 
pharmacokinetics 
PP 
per protocol 


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Abbreviations 
Definition 
PT 
preferred term 
SAP 
Statistical Analysis Plan 
SBP 
systolic blood pressure 
SOC 
system organ class 
T-BSA 
total body surface area 
TE 
treatment-extension 
TEAE 
treatment-emergent adverse event 
T-PaGIC-V 
total body assessment of Patient Global Impression of Change-Vitiligo 
T-PhGVA 
total body assessment of Physician Global Vitiligo Assessment 
TSQM 
Treatment Satisfaction Questionnaire for Medication 
T-VASI 
total body Vitiligo Area Scoring Index 
T-VASI25/50/75/90 
≥ 25%/50%/ 75%/ 90% improvement in total body Vitiligo Area Scoring Index 
VASI 
Vitiligo Area Scoring Index 
VitiQoL 
Vitiligo-specific quality of life 
VNS 
Vitiligo Noticeability Scale 
WHO-5 
World Health Organization-Five Well-Being Index 
 


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1. 
INTRODUCTION 
INCB 18424-306 is a randomized, vehicle-controlled study in adolescent and adult participants 
(age ≥ 12 years) with nonsegmental vitiligo who have depigmented area including ≥ 0.5% BSA 
on the face, ≥ 0.5 F-VASI, ≥ 3% BSA on nonfacial areas, ≥ 3 T-VASI, and for whom total body 
involved vitiligo area (facial and nonfacial) does not exceed 10% BSA.  Approximately 
300 participants will be randomized 2:1 to receive initial study treatment (ruxolitinib cream 1.5% 
BID:vehicle; applied to depigmented vitiligo areas on the face and body up to 10% total BSA) 
for 24 weeks.  Participants will be stratified by region (North America or Europe) and skin type 
(Fitzpatrick scale Type I and II vs Type III, IV, V, and VI).  Adolescents (≥ 12 to < 18 years) 
will make up at least 10% of the study population, and no more than 50% of participants will be 
> 40 years old. 
After completion of the Week 24 assessments, participants will be offered the opportunity to 
receive an additional 28 weeks of treatment extension with ruxolitinib cream 1.5% BID.  To be 
eligible for the treatment extension, participants must have completed the baseline and Week 24 
visit assessments, be compliant with study procedures, and not have any safety issues.  The total 
treated area should not exceed 10% BSA (facial and nonfacial). 
Participants who successfully complete the 52-week treatment in this study may be eligible to 
participate in a separate extension study to evaluate durability of effect and maintenance 
regimens. 
The purpose of this SAP is to provide details of the statistical analyses that have been outlined in 
the study Protocol.  The scope of this plan will be executed by the Department of Biostatistics or 
designee, and the analyses of PK will be executed by the Department of Clinical 
Pharmacokinetics or designee. 
Another Phase 3 study, INCB 18424-307, has the identical study design as INCB 18424-306.  
This SAP applies to both INCB 18424-306 and INCB 18424-307 studies. 
2. 
STUDY INFORMATION, OBJECTIVES, AND ENDPOINTS 
2.1. 
Protocol and Case Report Form Version 
This SAP is based on INCB 18424-306 and -307 Protocol Amendment 3-US-CA dated 
13 MAR 2020, INCB 18424-306 CRF approved 04 JUN 2020, and INCB 18424-307 CRF 
approved 05 JUN 2020.  Unless superseded by an amendment, this SAP will be effective for all 
subsequent Protocol amendments and CRF versions. 
2.2. 
Objectives and Endpoints 
Table 1 presents the objectives and endpoints. 


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Table 1: 
Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
To evaluate the efficacy of ruxolitinib cream in 
participants with vitiligo. 
• Proportion of participants achieving F-VASI75 at 
Week 24. 
Key Secondary 
To further assess the efficacy of ruxolitinib cream. 
• Proportion of participants achieving F-VASI50 at 
Week 24. 
• Proportion of participants achieving F-VASI90 at 
Week 24. 
• Proportion of participants achieving T-VASI50 at 
Week 24. 
• Proportion of participants achieving a VNS of “4 – A 
lot less noticeable” or “5 – No longer noticeable” at 
Week 24. 
• Percentage change from baseline in F-BSA at 
Week 24. 
Secondary 
To evaluate the safety and tolerability of ruxolitinib 
cream. 
• The frequency and severity of AEs; physical 
examinations; vital signs; and laboratory data for 
hematology and serum chemistry. 
To further assess the efficacy of ruxolitinib cream. 
• Proportion of participants achieving 
F-VASI25/50/75/90 during the treatment period 
(double-blind and treatment extension periods).  
• Percentage change from baseline in F-VASI during 
the treatment period (double-blind and treatment 
extension periods). 
• Percentage change from baseline in F-BSA during 
the treatment period (double-blind and treatment 
extension periods). 
• Percentage change from baseline in T-VASI during 
the treatment period (double-blind and treatment 
extension periods). 
• Percentage change from baseline in T-BSA during 
the treatment period (double-blind and treatment 
extension periods). 
• Proportion of participants achieving 
T-VASI25/50/75/90 during the treatment period 
(double-blind and treatment extension periods).  
• Proportion of participants in each category of VNS 
during the treatment period (double-blind and 
treatment extension periods). 
• Change from baseline in DLQI (or CDLQI) during 
the treatment period (double-blind and treatment 
extension periods). 
To evaluate the ruxolitinib PK in plasma after 
treatment of ruxolitinib cream. 
• Population-based (trough) plasma concentrations of 
ruxolitinib at Weeks 4, 24, and 40. 


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Table 1: 
Objectives and Endpoints (Continued) 
Objectives 
Endpoints 
Exploratory 
To further assess the efficacy of ruxolitinib cream. 
• Proportion of participants achieving an F-PhGVA of 
clear (0) or almost clear (1) during the treatment 
period (double-blind and treatment extension 
periods). 
• Proportion of participants achieving a T-PhGVA of 
clear (0) or almost clear (1) during the treatment 
period (double-blind and treatment extension 
periods). 
• Proportion of participants in each F-PhGVA category 
during the treatment period (double-blind and 
treatment extension periods). 
• Proportion of participants in each T-PhGVA 
category during the treatment period (double-blind 
and treatment extension periods). 
• Proportion of participants who report F-PaGIC-V of 
very much improved or much improved during the 
treatment period (double-blind and treatment 
extension periods). 
• Proportion of participants in each F-PaGIC-V 
category during the treatment period (double-blind 
and treatment extension periods). 
• Proportion of participants who report T-PaGIC-V of 
very much improved or much improved during the 
treatment period (double-blind and treatment 
extension periods). 
• Proportion of participants in each T-PaGIC-V 
category during the treatment period (double-blind 
and treatment extension periods). 
• Proportion of participant in each category for the 
color-matching question during the treatment period 
(double-blind and treatment extension periods). 
To determine the participants’ quality of life. 
• Change from baseline in WHO-5 during the 
treatment period (double-blind and treatment 
extension periods). 
• Actual measurements in TSQM during the treatment 
period (double-blind and treatment extension 
periods). 
• Change from baseline in VitiQoL during the 
treatment period (double-blind and treatment 
extension periods). 
• Change from baseline in HADS during the treatment 
period (double-blind and treatment extension 
periods). 
To evaluate translational biomarkers in the blood of 
participants treated with ruxolitinib cream. 
• Change from baseline in the expression of select 
biomarkers in peripheral blood at Weeks 12, 24, 40, 
and 52. 


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3. 
STUDY DESIGN 
INCB 18424-306 and -307 are randomized, vehicle-controlled studies in adolescent and adult 
participants (age ≥ 12 years) with nonsegmental vitiligo who have depigmented area including 
≥ 0.5% BSA on the face, ≥ 0.5 F-VASI, ≥ 3% BSA on nonfacial areas, ≥ 3 T-VASI, and for 
whom total body involved vitiligo area (facial and nonfacial) does not exceed 10% BSA.  
Approximately 300 participants will be randomized 2:1 to receive initial study treatment 
(ruxolitinib cream 1.5% BID:vehicle) for 24 weeks.  Participants will be stratified by region 
(North America or Europe) and skin type (Fitzpatrick scale Type I and II vs Type III, IV, V, and 
VI).  Adolescents (≥ 12 to < 18 years) will make up at least 10% of the study population, and no 
more than 50% of participants will be > 40 years old. 
After completion of the Week 24 assessments, participants will be offered the opportunity to 
receive an additional 28 weeks of treatment extension with ruxolitinib cream 1.5% BID.  To be 
eligible for the treatment extension, participants must have completed the baseline and Week 24 
visit assessments, be compliant with study procedures, and not have any safety issues.  The total 
treated area should not exceed 10% BSA (facial and nonfacial). 
Participants who successfully complete the 52-week treatment in this study may be eligible to 
participate in a separate extension study to evaluate durability of effect and maintenance 
regimens. 
The study schema is shown below in Figure 1.  All participants will have follow-up assessments 
30 (+ 7) days after the last application of study drug. 
Figure 1: 
Study Design Schema 
 
3.1. 
Randomization 
Approximately 300 participants will be randomized 2:1 to receive initial study treatment 
(ruxolitinib cream 1.5% BID:vehicle) for 24 weeks.  Participants will be stratified by skin type 
(Fitzpatrick scale Type I and II vs Type III, IV, V, and VI) and region (North America or 
Europe). 


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3.2. 
Control of Type I Error 
The gatekeeping testing strategy for the primary and key secondary analyses will be 
implemented to control the overall Type I error rate, 2-sided α = 0.05.  These endpoints will be 
tested in a fixed sequence at 2-sided α = 0.05 level in the following order: 
• Proportion of participants achieving F-VASI75 at Week 24 
• Proportion of participants achieving F-VASI50 at Week 24 
• Proportion of participants achieving F-VASI90 at Week 24 
• Proportion of participants achieving T-VASI50 at Week 24 
• Vitiligo – VNS Response at Week 24 
• Percentage change from baseline in F-BSA at Week 24 
The endpoint will be tested only if the primary endpoint (and the secondary endpoints in 
previous steps) are rejected. 
3.3. 
Sample Size Considerations 
Approximately 300 participants will be randomized 2:1 to ruxolitinib cream 1.5% BID or vehicle 
and stratified by baseline skin type (Fitzpatrick scale Type I and II vs Type III, IV, V, and VI) 
and region (North America or Europe).  The sample size is calculated to provide sufficient power 
(> 85%) to detect a difference between the 1.5% BID with the vehicle in primary and key 
secondary endpoints.  The powers for different endpoints are provided in Table 2.  The Fisher’s 
exact test with a 2-sided alpha of 0.05 is used to provide a conservative evaluation of statistical 
power, and it is accurate when there is a small expected number of responders in the vehicle 
group. 
Table 2: 
Powering for Primary and Key Secondary Endpoints 
Endpoints 
Response Rates in 
Ruxolitinib 1.5% BIDa 
Response Rates 
in Vehiclea 
Powerb 
F-VASI75 at Week 24 
20% 
5% 
95% 
F-VASI50 at Week 24 
30% 
10% 
 
 
95% 
F-VASI90 at Week 24 
10% 
1% 
88% 
T-VASI50 at Week 24 
10% 
1% 
88% 
Vitiligo - VNS Response at 
Week 24 
10% 
1% 
88% 
a Based on the results from a Phase 2, randomized, dose-ranging study (INCB18424-211). 
b Based on the Fisher’s exact test with a 2-sided alpha of 0.05. 
3.4. 
Schedule of Assessments 
Refer to Protocol Amendment 3-US-CA dated 13 MAR 2020 for a full description of all study 
procedures and assessment schedules (Protocol Tables 3 and 4) for this study. 


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4. 
DATA HANDLING DEFINITIONS AND CONVENTIONS 
4.1. 
Scheduled Study Evaluations and Study Periods 
4.1.1. 
Day 1 
Day 1 is the date that the first application of ruxolitinib cream or vehicle cream is administered 
to the participants in the specific period. 
For randomized participants not treated with any study drug, Day 1 is defined as the day of 
randomization. 
4.1.2. 
Study Day 
If a visit/reporting date is on or after Day 1, then the study day at the visit/reporting date will be 
calculated as 
Day # = (visit/reporting date – Day 1 date + 1). 
If the visit/reporting date is before Day 1, then the study day at the visit/reporting date will be 
calculated as 
Day # = (visit/reporting date – Day 1 date). 
A study day of −1 indicates 1 day before Day 1. 
4.1.3. 
Baseline Value 
Baseline is the last nonmissing measurement obtained before or on the day of first application of 
ruxolitinib cream or vehicle cream for double-blind period. 
For randomized participants not treated with any study drug, baseline is defined as the last 
nonmissing assessment before or on the day of randomization for all parameters. 
For participants who continue in the treatment extension period, baseline is defined as follows: 
• For efficacy evaluation, baseline is the last nonmissing measurement obtained before 
or on the day of first application of study treatment in double-blind period; 
• For safety evaluation, for participants who cross over from vehicle group to 
ruxolitinib cream, the baseline is the last nonmissing measurement obtained before or 
on the day of first application of ruxolitinib cream in the extension period; for 
participants who applies ruxolitinib cream in both periods, baseline is the last 
nonmissing measurement obtained before or on the day of first application of study 
treatment in double-blind period. 


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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, including F-VASI75, F-VASI50, F-VASI90, T-VASI50, and VNS 4 or 
5 as listed in the primary and key secondary endpoints, all participants who are missing 
postbaseline values, will be handled using MI under the missing-at-random assumption. 
For continuous endpoints, any participant who is missing postbaseline values may have missing 
data handled using MMRM or MI under the missing-at-random assumption.  MMRM model 
implicitly adjusts for missing data through a variance-covariance structure. 
For other endpoints, missing observations will be handled as detailed in the specific sections 
addressing each analysis. 
4.2. 
Variable Definitions 
4.2.1. 
Body Mass Index 
Body mass index (BMI) will be calculated as follows: 
BMI (kg/m2) = [weight (kg)] / [height (m)]2. 
4.2.2. 
Prior and Concomitant Medication 
Prior medication is defined as any nonstudy medication started before the first application of study 
treatment. 
Concomitant medication is defined as any nonstudy medication that is started accordingly: 
• Before the date of first application of study treatment and is ongoing throughout the 
study or ends on/after the date of first application of study treatment. 
• On/after the date of first application of study treatment and is ongoing or ends during 
the course of study treatment. 
A prior medication could also be classified as "both prior and concomitant medication" if the end 
date is on or after the first application of study treatment.  In the listing, it will be indicated whether 
a medication is prior-only, concomitant-only, or both prior and concomitant. 
For the purposes of analysis, all medications will be considered concomitant medications unless 
the medications can unequivocally be defined as not concomitant. 


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


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5.3.4. 
Treatment-Extension Evaluable Population 
Participants who applied at least 1 application of ruxolitinib cream in treatment extension period 
will constitute the TE evaluable population. 
5.3.5. 
Pharmacokinetic/Pharmacodynamic Evaluable Population 
The PK/PD evaluable population will include all participants who applied ruxolitinib cream at 
least once and provided at least 1 postdose plasma sample (1 PK/PD measurement) that complies 
with the instruction in the Protocol.  Participants in whom it is not possible to obtain a blood 
sample for PK/PD from an area of the body that was not treated with (exposed to) study drug 
(eg, due to difficulties of technical/ procedural nature) will not be included in the PK/PD 
evaluable population because of the material risk of the contamination of such a sample with 
study drug from the skin through which a needle is passed.  The study pharmacokineticist will 
review data listings of study drug application and sample records to identify participants to be 
excluded from PK data analyses.  The study research investigator will review data listings of PD 
data and sample records to identify participants to be excluded from analyses of PD data. 
6. 
BASELINE, EXPOSURE, AND DISPOSITION VARIABLES AND 
ANALYSES 
Appendix A provides a list of planned tables, figures, and listings.  Sample data displays are 
included in a separate document. 
6.1. 
Baseline and Demographics, Physical Characteristics, and Disease 
History 
6.1.1. 
Demographics 
The following demographics will be summarized for the FAS and Safety population during the 
DB period and the TE evaluable population in the TE period:  age, age group, sex, race, 
ethnicity, region, weight, height, and BMI. 
6.1.2. 
Baseline Disease Characteristics 
Baseline disease characteristics summarized for the FAS and Safety population include but are 
not limited to the following: 
• Time since initial diagnosis of vitiligo 
• Vitiligo diagnosed in childhood (No/Yes [age]:  0-5 years, 6-11 years, 12-17 years) 
• Disease status (stable/progressive) 
• Skin type (type I/II/III/IV/V/VI) 
• Other autoimmune disorders  
• Prior therapy given for vitiligo (predefined systemic treatments, phototherapy, and 
surgical procedures)  
• History of acne vulgaris (No/Yes) 


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• Currently have acne vulgaris on the face (No/Yes) 
• Vitiligo in genital area (No/Yes) 
• Baseline F-VASI  
• Baseline T-VASI  
• Baseline F-BSA involvement (% of the total body) 
• Baseline T-BSA involvement (% of the total body) 
6.1.3. 
Prior Therapy for Vitiligo 
Prior medication information for vitiligo will be used to identify other non-predefined 
medication received by participants before enrollment into the study.  Prior medications for 
vitiligo will be summarized by treatment group. 
6.1.4. 
Medical History 
For participants in the safety population during the DB period, medical history will be 
summarized by assigned treatment group.  This summary will include the number and percentage 
of participants with medical history for each body SOC/PT as documented in the eCRF. 
6.2. 
Disposition of Participants 
The number and percentage of participants who were randomized, treated, and completed the DB 
period and of participants who discontinued the treatment or withdrew from the study during the 
DB period with a primary reason for discontinuation will be summarized for both the FAS and 
safety population during the DB period. 
The number and percentage of participants who completed the TE period and discontinued 
treatment or withdrew from the study during the TE period with a primary reason for 
discontinuation will be summarized for the TE evaluable population in the TE period. 
6.3. 
Protocol Deviations 
In general, the following are important protocol deviations that may significantly affect the 
primary and gated secondary analyses: 
• Missing primary endpoint on F-VASI; 
• Compliance < 60% based on the application numbers. 
Participants with 1 or more such deviations will be excluded from the PP population.  In 
addition, protocol deviations related to inclusion/exclusion criteria, discontinuation criteria, and 
use of excluded concomitant medications will be reviewed.  Decisions as to whether any of these 
deviations warrant exclusion from the PP population will be made before breaking the blind. 
6.4. 
Exposure 
For participants in the safety population during the DB period and participants in the TE 
evaluable population during the TE period, descriptive statistics will be provided by treatment 
group for duration of treatment, average daily dose, and total dose.  Summary for overall 


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exposure including DB and TE periods will be provided for participants continually using 
1.5% BID.   Duration of treatment with ruxolitinib cream or vehicle cream is defined as the 
number of days from Day 1 to the last record of ruxolitinib cream or vehicle cream application in 
the specific period. 
6.5. 
Study Drug Compliance 
Overall compliance (%) for the application of ruxolitinib cream or vehicle cream during the DB 
and treatment extension periods will be calculated for all participants in the safety population as 
follows: 
Overall application compliance (%) = 100  [total number of nonmissing applications] / 
[total number of intended applications] 
where the total number of nonmissing applications is the total number of applications that the 
participant actually applied in each period during the study.  The total number of intended 
applications is the number of planned applications minus the number of interrupted applications.  
6.6. 
Prior and Concomitant Medication 
For participants in the safety population during the DB period, prior medications and 
concomitant medications will be coded using the WHO Drug Dictionary and summarized as 
number and percentage of participants with prior and concomitant medications by WHO drug 
class and WHO drug term.  For participants in the treatment extension period (ie, the TE 
evaluable population), only concomitant medications will be summarized. 
Prior and concomitant medications will be summarized by treatment group as well as listed. 
7. 
EFFICACY 
Appendix A provides a list of planned tables, figures, and listings.  Sample data displays are 
included in a separate document.  
7.1. 
General Considerations 
For all continuous variables, both the actual value and change and/or percentage from baseline 
(if available) will be analyzed. 
All by-visit analyses will include the follow-up period if the data are available. 
7.2. 
Efficacy Measures  
7.2.1. 
Body Surface Area 
Total % BSA (includes facial and nonfacial areas) depigmented by vitiligo will be estimated at 
each visit.  Body surface area assessment will be performed by the Palmar Method.  Body 
surface area should be estimated to the nearest 0.1%.  The approximate size of the participant’s 
entire palmar surface (ie, the palm plus 5 digits) should be considered as 1% BSA, and the 
approximate size of the participant’s thumb should be considered as 0.1% BSA. 


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7.2.2. 
Vitiligo Area Scoring Index  
Areas affected by depigmentation due to vitiligo will be assessed using the VASI.  It is based on 
a composite estimate of the overall area of vitiligo patches at baseline and the degree of macular 
repigmentation within these patches over time. 
Facial VASI (F-VASI) is measured by percentage of vitiligo involvement (% of BSA) and the 
degree of depigmentation.  The percentage of BSA (hand unit) vitiligo involvement is estimated 
by the investigator using the Palmar Method.  Hand unit is based on participant’s hand size.  
Investigator uses his/her hand to mimic the participant’s hand size to evaluate percentage of BSA 
vitiligo involvement.  The degree of depigmentation for each vitiligo involvement site is 
determined and estimated to the nearest of the following percentages:  0, 10%, 25%, 50%, 75%, 
90%, or 100%.  At 100% depigmentation, no pigment is present; at 90%, specks of pigment are 
present; at 75%, the depigmented area exceeds the pigmented area; at 50%, the depigmented and 
pigmented area are equal; at 25%, the pigmented area exceeds the depigmented area; at 10%, 
only specks of depigmentation are present.  The F-VASI is then derived by multiplying the 
values assessed for the vitiligo involvement by the percentage of affected skin for each site on 
the face and summing the values of all sites together (possible range 0-3). 
 
 
 
 
Total body VASI (T-VASI) is calculated using a formula that includes contributions from all 
body regions (possible range, 0-100). 
𝑉𝐴𝑆𝐼=
∑
[ℎ𝑎𝑛𝑑 𝑢𝑛𝑖𝑡𝑠] 𝑥 [𝑅𝑒𝑠𝑖𝑑𝑢𝑎𝑙 𝐷𝑒𝑝𝑖𝑔𝑚𝑒𝑛𝑡𝑎𝑡𝑖𝑜𝑛]
𝑎𝑙𝑙 𝑏𝑜𝑑𝑦 𝑠𝑖𝑡𝑒𝑠
 
The body is divided into the following 6 separate and mutually exclusive sites:  1) head/neck, 
2) hands, 3) upper extremities (excluding hands), 4) trunk, 5) lower extremities (excluding feet), 
and 6) feet.  The percentage of vitiligo involvement is estimated in hand units (% of BSA) by the 
same investigator during the entire course of the study.  Hand unit is based on participant’s hand 
size.  The investigator uses his/her hand to mimic the participant’s hand size to evaluate % BSA 
vitiligo involvement.  The degree of depigmentation for each body site is determined and 
estimated to the nearest of the following percentages:  0%, 10%, 25%, 50%, 75%, 90%, or 
100%.  The T-VASI is then derived by multiplying the values assessed for the vitiligo 
involvement by the percentage of affected skin for each body site and summing the values of all 
body sites together (Hamzavi et al 2004).   
The categorical variable F-VASI25 will be equal to 1 for percentage improvement from baseline 
in F-VASI of ≥ 25% and will be equal to 0 for percentage improvement of < 25%.  
F-VASI50/75/90 and T-VASI25/50/75/90 are defined with the same pattern. 
7.2.3. 
Physician’s Global Vitiligo Assessment (Facial)  
The severity of vitiligo will be assessed by the physician using the PhGVA, which has a 5-point 
scale (Table 3).  Response will be reported for face (F-PhGVA). 


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Table 3: 
Facial Physician's Global Vitiligo Assessment Scale 
Score 
Severity 
Description 
0 
Clear 
No signs of vitiligo or complete/near complete repigmentation 
1 
Almost Clear 
Mostly pigmented areas with small depigmented or difficult to repigment areas 
(eg, philtrum, nares, corners of eyes, perioral skin) 
2 
Mild Disease 
Modest areas of depigmentation (not more than half of facial skin) with 
approximately 50% pigmentation within vitiligo areas or significant 
perifollicular pattern present 
3 
Moderate Disease 
Large areas of depigmented vitiligo areas (more than half of facial skin); 
significant depigmentation within vitiligo areas 
4 
Severe Disease 
Extensive areas of vitiligo to complete depigmentation on face 
An F-PhGVA of clear (0) or almost clear (1) can be interpreted as F-PhGVA response. 
7.2.4. 
Physician’s Global Vitiligo Assessment (Total Body)  
The severity of total body vitiligo will be assessed by the physician using the PhGVA, which has 
a 5-point scale (Table 4).  Response will be reported for total body (T-PhGVA). 
Table 4: 
Total Body Physician's Global Vitiligo Assessment Scale 
Score 
Severity 
Description 
0 
Clear 
No signs of vitiligo or complete/near complete repigmentation 
1 
Almost Clear 
Mostly pigmented areas with small depigmented or difficult to repigment areas 
(eg, hands, feet, philtrum, nares, corners of eyes, perioral skin) 
2 
Mild Disease 
Modest areas of depigmentation with approximately 50% pigmentation within 
vitiligo areas or significant perifollicular pattern present 
3 
Moderate Disease 
Large areas of depigmented vitiligo areas; significant depigmentation within 
vitiligo areas 
4 
Severe Disease 
Extensive areas of vitiligo with complete depigmentation 
An T-PhGVA of clear (0) or almost clear (1) can be interpreted as T-PhGVA response. 
7.2.5. 
Patient-Reported Outcomes  
Patient-reported outcomes and quality of life will be assessed using the following tools: 
• VNS (Section 7.2.5.1) 
• Color-matching question (Section 7.2.5.2) 
• F-PaGIC-V (Section 7.2.5.3) 
• T-PaGIC-V (Section 7.2.5.4) 
• DLQI or CDLQI (Section 7.2.5.5) 
• WHO-5 (Section 7.2.5.6) 
• TSQM (Section 7.2.5.7) 


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• VitiQoL (Section 7.2.5.8) 
• HADS (Section 7.2.5.9) 
7.2.5.1. 
Vitiligo Noticeability Scale  
The VNS is a patient‐reported measure of vitiligo treatment success, which has a 5-point scale 
(Batchelor et al 2016).  The baseline facial photograph will be shown to the participants for 
reference, and a mirror will be provided for the participants to assess the vitiligo on their face.  
The participant will be asked to respond to the following query: 
Compared with before treatment, how noticeable is the vitiligo now?  Responses:  (1) More 
noticeable, (2) As noticeable, (3) Slightly less noticeable, (4) A lot less noticeable, and 
(5) No longer noticeable. 
VNS scores of 4 or 5 can be interpreted as representing treatment success. 
7.2.5.2. 
Color-Matching Question  
The baseline photograph and current participants’ facial image (participants will be provided a 
mirror) will be shown to the participant for reference, and the participant will be asked to 
respond to the following query: 
At this point of your treatment, how well does your skin color match between your face 
treated vitiligo skin and face normal skin? Responses:  (1) Excellent, (2) Very good, 
(3) Good, (4) Poor, and (5) Very poor. 
7.2.5.3. 
Patient Global Impression of Change-Vitiligo (Facial) 
The F-PaGIC-V is an assessment of improvement by the participant.  It is a 7-point scale 
comparing the vitiligo areas at baseline with the participant's treated areas of facial vitiligo at the 
study visit.  Response will be reported for face (F-PaGIC-V).  The baseline photograph and 
current participants’ facial image (participants will be provided a mirror) will be shown to the 
participant for reference.  The participant will be asked to respond to the following query: 
Since the start of the treatment you've received in this study, your vitiligo on your face 
treated with the study drug is:  (1) Very much improved, (2) Much improved, (3) Minimally 
improved, (4) No change, (5) Minimally worse, (6) Much worse, and (7) Very much worse. 
F-PaGIC-V scores of 1 or 2 can be interpreted as representing treatment success. 
7.2.5.4. 
Patient Global Impression of Change-Vitiligo (Total Body) 
The T-PaGIC-V is an assessment of improvement by the participant.  It is a 7-point scale 
comparing the vitiligo areas at baseline with the participant's treated areas of total body vitiligo 
at the study visit.  Response will be reported for total body (T-PaGIC-V).  The participant will be 
asked to respond to the following query: 
Since the start of the treatment you've received in this study, your vitiligo on your total body 
treated with the study drug is:  (1) Very much improved, (2) Much improved, (3) Minimally 
improved, (4) No change, (5) Minimally worse, (6) Much worse, and (7) Very much worse. 
T-PaGIC-V scores of 1 or 2 can be interpreted as representing treatment success. 


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7.2.5.5. 
Dermatology Life Quality Index 
The DLQI (Finlay and Khan 1994) is a simple 10-question validated questionnaire for use in 
participants aged 16 years and over to measure how much the skin problem has affected the 
participant over the previous 7 days. 
The scoring of each question is as follows:  Very much = 3; A lot = 2; A little = 1; Not at all = 0; 
Not relevant = 0; Question 7, “Prevented work or studying” = 3. 
The following imputation will be applied for incorrectly completed questionnaires: 
• If 1 question is left unanswered, this is scored 0 and the scores are summed and 
expressed as usual out of a maximum of 30. 
• If 2 or more questions are left unanswered, the questionnaire is not scored. 
• If Question 7 is answered “yes,” this is scored 3.  If Question 7 is answered “no,” but 
then either “a lot” or “a little” is ticked, this is then scored 2 or 1.  If “Not relevant” is 
ticked, the score for Question 7 is 0.  If it is answered “no,” but the second half is left 
incomplete, the score will remain 0. 
• If 2 or more response options are ticked, the response option with the highest score 
should be recorded. 
• If there is a response between 2 tick boxes, the lower of the 2 score options should be 
recorded. 
• For DLQI 6 subscales, if the answer to 1 question in a subscale is missing, that 
subscale should not be scored. 
The DLQI is calculated by summing the score of each question resulting in a maximum of 
30 and a minimum of 0.  The higher the score, the more quality of life is impaired. 
The meaning of total DLQI scores can be categorized as follows: 
• 0 to 1 = No effect 
• 2 to 5 = Small effect 
• 6 to 10 = Moderate effect 
• 11 to 20 = Very large effect 
• 21 to 30 = Extremely large effect 
A change from baseline in DLQI and CDLQI score of at least 4 points is considered clinically 
important (Basra et al 2015, Waters et al 2010). 
The questionnaire is also analyzed under 6 subscales as follows: 
• Symptoms and feelings (Questions 1 and 2) 
• Daily activities (Questions 3 and 4) 
• Leisure (Questions 5 and 6) 
• Work and school (Question 7) 


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• Personal relations (Questions 8 and 9) 
• Treatment (Question 10) 
CDLQI (Lewis‐Jones and Finlay 1995) is the youth/children’s version of the DLQI and will be 
completed by adolescents aged ≥ 12 years to < 16 years.  The scoring of each question is Very 
much = 3; Quite a lot = 2; Only a little  = 1; Not at all = 0; Question unanswered = 0; 
Question 7:  “Prevented school” = 3.  The CDLQI is calculated by summing the score of each 
question resulting in a maximum of 30 and a minimum of 0.  The higher the score, the more 
quality of life is impaired. 
The questionnaire is also analyzed under 6 subscales as follows: 
• Symptoms and feelings (Questions 1 and 2) 
• Leisure (Questions 4, 5, and 6) 
• School or holidays (Question 7) 
• Personal relationships (Questions 3 and 8) 
• Sleep (Question 9) 
• Treatment (Question 10) 
The severity banding for CDLQI scores is as follows: 
• 0 to 1 = No effect on child’s life 
• 2 to 6 = Small effect 
• 7 to 12 = Moderate effect 
• 13 to 18 = Very large effect 
• 19 to 30 = Extremely large effect 
The following imputation will be applied for incorrectly completed questionnaires for CDLQI: 
1. If 1 question is left unanswered, this is scored 0, and the scores are summed and 
expressed as usual out of a maximum of 30. 
2. If 2 or more questions are left unanswered, the questionnaire is not scored. 
3. If both parts of Question 7 are completed, the higher of the 2 scores should be counted. 
7.2.5.6. 
WHO-5 
The WHO-5 is a validated, self-administered, 5-item questionnaire designed to assess mental 
well-being over the past 2 weeks, which can be used as an outcome measure for the wanted and 
unwanted effects of treatments (WHO Collaborating Center for Mental Health, Topp et al 2015).  
The questionnaire consists of 5 statements, which respondents rate according to the following 
scale:  0 = At no time; 1 = Some of the time; 2 = Less than half of the time; 3 = More than half of 
the time; 4 = Most of the time; 5 = All of the time. 


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The raw score is calculated by totaling the figures of the 5 answers for a range of 0 to 25, with 
0 representing the worst possible and 25 representing the best possible quality of life.  A score 
below 13 indicates poor well-being.  No imputation will be performed for missing values. 
7.2.5.7. 
Treatment Satisfaction Questionnaire for Medication 
TSQM (Bharmal et al 2009) is a validated 9-item questionnaire that measures a participant’s 
satisfaction with medication taken in a clinical study using a recall period of the past 2 to 
3 weeks or since the medication was last used.  The TSQM comprises 3 subscales that assess the 
patient’s perception of medication effectiveness, convenience, and global satisfaction.  The 
effectiveness subscale assesses the patient’s satisfaction with the ability of the medication to treat 
the condition and relieve symptoms and the length of time it takes for the medication to start 
working.  The convenience subscale addresses the convenience of administration and ease of 
planning and following a schedule.  The global satisfaction subscale gauges a patient’s 
confidence that the medication is a good thing and that the advantages of taking it outweigh the 
disadvantages.  Each TSQM subscale consists of 3 items, with responses measured on a Likert 
scale ranging from 1 (low) to 7 (high).  Subscale scores were transformed to a range from 0 to 
100, with higher scores indicating greater satisfaction. 
Scale scoring algorithm (Atkinson et al 2005) is as follows: 
• Effectiveness:  [Item 1 + Item 2 +Item 3 − 3] /18 ×100. 
• Convenience:  [Item 4 + Item 5 + Item 6 − 3] /18× 100. 
• If one item in Effectiveness or convenience is missing, the algorithm will be 
[(Sum of nonmissing items) – 2] / 12 × 100. 
• Global satisfaction: 
− First recode Item 9_recode = (Item 9 − 1) × 4 / 6 + 1. 
− Then:  [Item 7 + Item 8 + Item 9_recode − 3] / 12 × 100. 
• If 1 item in overall satisfaction is missing, the algorithm will be 
[(Sum of nonmissing items) – 2] /8 × 100. 
No imputation will be performed for any subscale with missing items ≥ 2. 
7.2.5.8. 
Vitiligo-Specific Health-Related Quality-of-Life Instrument 
VitiQoL is a 15-item quality-of-life assessment that asks participants to rate various aspects of 
their condition during the past month.  Each item is scored on a 0 ("not at all") to 6 ("all of the 
time") continuous bipolar scale (Lilly et al 2013). 
Scores are pooled and reported for each of the following 3 domains: 
• Participation limitation (Item 3, 4, 6, 9, 10, 11, and 14); 
• Stigma (Item 1, 2, 5, 7, and 15); 
• Behaviors (Item 8, 12, and 13). 
A total score ranging from 0 (better) to 90 (worse) will be also provided. 


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No imputation will be performed for missing values. 
7.2.5.9. 
Hospital Anxiety and Depression Scale 
HADS is a 14-item questionnaire that assesses the levels of anxiety and depression that a person 
is currently experiencing (Zigmond and Snaith 1983).  There are 7 questions each for measuring 
anxiety and for measuring depression, with 4 possible responses to each question (responses are 
scored as 0, 1, 2, or 3).  Separate total scores are calculated for anxiety and depression, each total 
score being the sum of the 7 questions.  If 4 or more scores are missing (out of the 7) for anxiety 
or depression, the total score will be set to missing; otherwise, the total score will be the average 
score of the nonmissing items multiplied by 7. 
7.3. 
Analysis of the Primary Efficacy Parameter  
The primary efficacy endpoint is F-VASI75 at Week 24.  
7.3.1. 
Primary Efficacy Analyses 
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 exact logistic 
regression (Mehta and Patel 1995).  This model will include the treatment group (1.5% BID and 
vehicle) and stratification factors (skin type and region).  The unadjusted p-values between each 
treatment group versus vehicle will be compared with the procedure defined in Section 3.2. 
Odds ratio in response rates (ruxolitinib cream vs vehicle) at Week 24 will also be computed.  
All participants who are missing the F-VASI assessment at a given visit in the DB period will be 
handled using MI under the missing-at-random assumption. Rescue therapy is not allowed in the 
studies.  Any participant who received rescue therapy will be considered as a protocol violation 
and will be imputed as a nonresponder.  The numerical values for F-VASI will not be included in 
the MI model or other sensitivity analyses. 
For MI, a fully conditional specification method (van Buuren 2007) that assumes the existence of 
a joint distribution for all variables will be used to impute F-VASI score.  A regression model 
including treatment group, stratification factors, and baseline and postbaseline F-VASI scores up 
to Week 24 will be specified for the fully conditional specification method.  The randomization 
seed will set to be 18424306 for Study INCB 18424-306 and 18424307 for Study 
INCB 18424-307.  The imputation will be repeated 10 times to generate corresponding complete 
datasets, in order to reflect the uncertainty around the true value.  After the missing values have 
been imputed, the binary variable F-VASI75 response will be derived.  The exact logistic 
regression will be applied to each imputed dataset, and then the results will be combined for the 
inference. 
The following is example SAS code for MI: 
proc mi data=mi_wide seed=18424306 nimpute=10 out=impute_fvasi; 
    class trt01p strat1 strat2; 
var trt01p strat1 strat2 avalBASELINE avalWEEK4 avalWEEK8     
avalWEEK12 avalWEEK18 avalWEEK24; 
fcs; 
run; 


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The following is example SAS code for exact logistic regression: 
proc logistic data=fvasi75_mi exactonly; 
    class trt01p (ref='VEHICLE CREAM') strat1 strat2/param=ref; 
    model resp (event='Y') = trt01p strat1 strat2/covb; 
    exact trt01p/estimate=both; 
    by _Imputation_; 
run; 
The primary endpoint will also be examined for the PP population using the same model as the 
primary analysis. 
7.3.2. 
Subgroup Analyses for Primary Efficacy Endpoint 
Subgroup analysis will be performed based on the following participant characteristics and 
baseline variables for those participants whose data are available: 
• Skin type (Fitzpatrick scale Type I and II vs Type III, IV, V, VI) 
• Age (12 to 17, ≥ 18 to 64, ≥ 65 years; ≤ 40, > 40 years ) 
• Region (North America, Europe) 
• Sex (Male, Female) 
• Race  
• F-BSA (<1.5, ≥1.5) 
7.3.3. 
Sensitivity and Supportive Analyses for Primary Endpoint 
7.3.3.1. 
Nonresponder Imputation 
Nonresponder imputation will be used as an alternative method to handle missing data.  All 
participants who do not respond, as well as all participants who are missing postbaseline values, 
will be defined as nonresponders for the NRI analysis. 
7.3.3.2. 
Last Observation Carried Forward 
For the participants who are missing postbaseline values, the last observed nonmissing 
postbaseline value will be used to fill in missing values at Week 24.  Then the proposed exact 
logistic regression described in Section 7.3.1 will also applied to the imputed dataset. 
7.3.3.3. 
Tipping Point Analysis 
A tipping point sensitivity analysis will be conducted to examine the potential effects of missing 
data.  The missing F-VASI75 response at Week 24 in each treatment group will be replaced by a 
range of values from the most conservative case to the most aggressive case.  The most 
conservative case is that all the missing participants in 1.5% BID group are nonresponders and 
all the missing participants in vehicle group are responders, while the most aggressive case is the 
other way around.  For each scenario, between-treatment comparisons will be performed using a 
Fisher's exact test. 


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7.4. 
Analysis of the Key Secondary Efficacy Parameters 
If the primary objective is achieved, the statistical hypotheses for the following key secondary 
endpoints will be tested in a fixed sequence in the following order: 
• F-VASI50 at Week 24 
• F-VASI90 at Week 24 
• T-VASI50 at Week 24 
• Vitiligo – VNS Response at Week 24 
• Percentage change from baseline in F-BSA at Week 24. 
Key secondary efficacy analyses at Week 24 will be conducted in the FAS population.  The 
statistical comparisons for binary outcomes (F-VASI50/90, T-VASI50, and VNS response) will 
be analyzed using the similar method as specified in the primary analysis.   
For F-BSA, the missing values at Week 24 will be imputed using the MI method specified in the 
primary analysis.  Then the derived percentage change from baseline in F-BSA at Week 24 will 
be analyzed using an ANCOVA model with treatment group, stratification factors, and baseline 
value as covariates.  A test for superiority between ruxolitinib cream 1.5% BID and vehicle 
cream will be performed using the least squares mean estimate of the percentage change from 
baseline in F-BSA at Week 24 from the ANCOVA model.  Superiority will be established if the 
p-value of the difference (ruxolitinib cream 1.5% BID minus vehicle) is < 0.05.  
7.5. 
Analysis of Other Secondary Efficacy Parameters 
7.5.1. 
Other Secondary Efficacy Analysis 
All other secondary efficacy analyses will be conducted based on the FAS population during the 
treatment period (double-blind and treatment extension periods).  
7.5.1.1. 
Continuous Efficacy Endpoints 
By-visit summary statistics for the following continuous measurements, including actual 
measurement, change from baseline, and percentage change from baseline, will be presented: 
• F-VASI/T-VASI 
• F-BSA/T-BSA 
• DLQI (or CDLQI) Total score and Subscores 
Summary statistics, including sample size, mean, median, standard deviation, minimum, 
maximum, first quartile, third quartile, and 95% CI, will be presented by visits.  A mixed-effect 
model with repeated measurements may be fit for the comparisons between 1.5% BID cream 
group and vehicle cream group. 


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7.5.1.2. 
Categorical Efficacy Endpoints 
For the following categorical parameters, summary statistics, including sample size, frequency, 
and percentages, will be presented by visit.  Similar exact logistic regression models as specified 
in the primary and key secondary analysis will be used if applicable. 
• Proportion of participants achieving F-VASI25/50/75/90  
• Proportion of participants achieving T-VASI25/50/75/90  
• Proportion of participants in each category of VNS 
Secondary endpoint analyses at Week 52 on VASI (eg, F-VASI25/50/75/90 and 
T-VASI25/50/75/90) will be performed in the FAS population with the following methods:  
• For participants randomized in the vehicle group, VASI score at Week 52 in 
treatment extension period will be imputed using linear extrapolation method based 
on their data up to Week 24.  For participants who discontinue the study drug before 
Week 24 due to any reason, all missing values of VASI will be imputed using the MI 
until Week 24 before the extrapolation. 
• For participants randomized in the 1.5% BID group, VASI scores at Week 52 will be 
used for comparison.  If the VASI score at Week 52 is missing, the value will be 
imputed using the MI method based on the data from Day 1 to Week 52. 
In each scenario of missing value imputation, the binary outcomes on responses, 
VASI25/50/75/90, will be derived based on the imputed values.  The statistical comparisons for 
these endpoints will be analyzed using the similar method as specified in the primary analysis. 
7.6. 
Analysis of Exploratory Efficacy Parameters 
7.6.1. 
Exploratory Efficacy Analysis 
Similar to the secondary efficacy endpoints, all exploratory efficacy analyses will be conducted 
based on the FAS population during the treatment period (double-blind and treatment extension 
periods.  
Mean, change (if applicable) from baseline, and percentage change (if applicable) from baseline 
will be summarized by treatment and visit using descriptive statistics for the following: 
• WHO-5 Total Score 
• TSQM Subscales (Effectiveness, Convenience, Overall satisfaction) 
• VitiQoL Total scales and Subscales 
• HADS Anxiety and Depression scores 
Categorical endpoints at postbaseline visits will be summarized by treatment and visit using 
descriptive statistics, including the following: 
• F-PhGVA and T-PhGVA 
• F-PaGIC-V and T-PaGIC-V 
• Color-matching question 


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• Proportion of participants achieving T-PhGVA response 
• Proportion of participants achieving F-PhGVA response 
• Proportion of participants achieving F-PaGIC-V response 
• Proportion of participants achieving T-PaGIC-V response 
7.7. 
Pharmacokinetic Analyses 
Trough plasma concentrations of ruxolitinib at all study visits will be summarized using 
descriptive statistics by treatment group. 
7.8. 
Pharmacodynamic Analyses 
Biomarkers from serum samples will be summarized by descriptive statistics by treatment group.  
The purpose of these analyses will be to retrospectively evaluate changes in disease related 
biomarkers (eg, CXCL9, CXCL10, IL-15, IFN-gamma) at baseline before drug administration 
and at Weeks 12, 24, 40, and 52. 
7.9. 
Pharmacokinetic/Pharmacodynamic Analyses 
A basic linear or Emax model may be evaluated to characterize changes in disease related 
biomarkers (eg, CXCL9, CXCL10, IL-15, IFN-gamma) from baseline and as a function of 
plasma ruxolitinib steady-state exposures (Cmin).   
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 safety population in the DB period and the 
TE evaluable population in TE period.  Cumulative TEAEs across the treatment periods (DB and 
TE period) will be summarized.  In addition, summaries of exposure-adjusted TEAEs will be 
provided based on the actual treatment received. 
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. 
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 study drug and within 30 days of the last dose of study drug.  For participants 
who cross over treatments, the first application date is period-specific, and the end date is 
30 days after the last application date in this period, or the first application date in the next 
period, whichever comes first.  Analysis of AEs (as discussed below) will be limited to TEAEs, 


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but data listings will include all AEs regardless of their timing in relation to study drug 
application. 
Adverse events will be tabulated by MedDRA PT and SOC.  Severity of AEs will be graded 
using the NCI CTCAE.  The CTCAE v5.0 is used for this study.  The CTCAE reporting 
guidelines and grading details are available on the Cancer Therapy Evaluation Program website. 
The subset of AEs considered by the investigator to be related to study drug will be considered to 
be treatment-related AEs.  If the investigator does not specify the relationship of the AE to study 
drug, the AE will be considered to be treatment-related.  The incidence of AEs and 
treatment-related AEs will be tabulated.  Serious AEs will also be tabulated. 
Any missing onset date, causality, or severity must be queried for resolution.  Unresolved 
missing causality and severity will be handled according to the following rules: 
• An unresolved missing causality will be considered treatment-related. 
• An unresolved missing severity will be identified as an unknown severity. 
For purposes of analysis, all AEs will be considered TEAEs unless the AE can unequivocally be 
defined as not treatment-emergent. 
Application site reactions are AEs that occur at the site of drug application.  A summary of ASRs 
will be provided.  Exposure-adjusted summaries will be provided for the safety population 
including cumulative TEAEs. 
8.2.2. 
Adverse Event Summaries 
An overall summary of AEs by treatment group will include: 
• Number (%) of participants reporting any TEAEs 
• Number (%) of participants reporting any 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 TEAEs ≥ 1% in any treatment group by PT in decreasing order of 
frequency  


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• Summary of ASRs by PT in decreasing order of frequency 
• Summary of exposure-adjusted incidence rates of TEAEs by PT in decreasing order 
of frequency 
• Summary of Grade 3 or higher AEs by SOC and PT 
• Summary of Grade 3 or higher AEs by PT in decreasing order of frequency 
• Summary of serious TEAEs by SOC and PT 
• Summary of serious TEAEs by PT in decreasing order of frequency 
• Summary of treatment-related TEAEs by SOC and PT 
• Summary of treatment-related TEAEs by PT in decreasing order of frequency 
• 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 
8.3. 
Clinical Laboratory Tests 
8.3.1. 
Laboratory Value Definitions 
All laboratory assessments will be performed using a central laboratory except for urine 
pregnancy tests (as applicable).  Laboratory values and change from baseline values will be 
summarized descriptively by visit, and non-numeric test values will be tabulated when necessary. 
The baseline value will be determined using the last nonmissing value collected before the first 
application, prioritizing scheduled assessments for baseline identification over unscheduled 
visits.  The last record before application in the highest priority will be considered the baseline 
record.  For baseline laboratory candidates with the same date and time in the same priority 
category, additional rules may be provided after consultation with the medical monitor to 
delineate which value will be defined as baseline. 
8.3.2. 
Laboratory Value Summaries 
Clinical laboratory tests, including hematology and serum chemistry, will be performed at the 
Protocol-specified visits.  If specific safety issues arise, additional unscheduled laboratory 
tests/analyses may be performed at the discretion of the investigator. 
All test results and associated normal ranges from central laboratories will be reported in 
SI units.  All tests with numeric values will have a unique unit per test.  Any laboratory test 
results and associated normal ranges from local laboratories will be converted to SI units. 
When there are multiple laboratory nonmissing values for a participant's particular test within a 
visit window, the laboratory value with the smallest laboratory sequence number will be used in 
by-visit summaries. 


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For test results that will be summarized with available normal ranges, the number and percentage 
of participants with the laboratory values being low (but never high), normal, high (but never 
low), and both low and high will be calculated for each test.  This shift summary will be 
produced for each test for the safety population in DB and TE periods.  Shift tables will also be 
presented showing change in CTCAE grade from baseline to worst grade postbaseline.  The 
denominator for the percentage calculation will use the number of participants in the baseline 
category. 
8.4. 
Vital Signs 
Values at each scheduled visit, change, and percentage change from baseline for vital signs, 
including SBP, DBP, pulse, respiratory rate, and body temperature will be summarized 
descriptively. 
Criteria for clinically notable vital sign abnormalities are defined in Table 5, Table 6, and 
Table 7.  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 5: 
Criteria for Clinically Notable Vital Sign Abnormalities for 12 to 15 Years 
Old 
Parameter 
High Threshold 
Low Threshold 
Systolic blood pressure 
> 131 mmHg 
< 110 mmHg 
Diastolic blood pressure 
> 83 mmHg 
< 64 mmHg 
Pulse 
> 100 bpm 
< 60 bpm 
Temperature 
> 38.0ºC 
< 35.5ºC 
Respiratory rate 
> 20 breaths/min 
< 8 breaths/min 
Table 6: 
Criteria for Clinically Notable Vital Sign Abnormalities for 16 to 17 Years 
Old 
Parameter 
High Threshold 
Low Threshold 
Systolic blood pressure 
> 120 mmHg 
< 90 mmHg 
Diastolic blood pressure 
> 85 mmHg 
< 50 mmHg 
Pulse 
> 100 bpm 
< 45 bpm 
Temperature 
> 38.0ºC 
< 35.5ºC 
Respiratory rate 
> 20 breaths/min 
< 8 breaths/min 


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Table 7: 
Criteria for Clinically Notable Vital Sign Abnormalities for ≥ 18 Years Old 
Parameter 
High Threshold 
Low Threshold 
Systolic blood pressure 
> 155 mmHg 
< 85 mmHg 
Diastolic blood pressure 
> 100 mmHg 
< 40 mmHg 
Pulse 
> 100 bpm 
< 45 bpm 
Temperature 
> 38ºC 
< 35.5ºC 
Respiratory rate 
> 20 breaths/min 
< 8 breaths/min 
9. 
PLANNED ANALYSES 
No formal interim analysis is planned in this study.  
The primary analysis will occur after the primary database lock, when all participants have 
completed the vehicle-controlled, double-blind treatment period.  Sponsors will be unblinded, 
while investigators and participants will still be blinded to the study treatment after the primary 
database lock. 


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10. 
CHANGES AND MODIFICATIONS TO THE ANALYSIS PLAN 
All versions of the SAP are listed in Table 8. 
Table 8: 
Statistical Analysis Plan Versions 
SAP Version 
Date 
Original 
09 MAR 2020 
10.1. 
Changes to Protocol-Defined Analyses 
• The FAS will be used to replace ITT in evaluation of the efficacy during DB period.  
The participants with only baseline but not any postbaseline assessments are excluded 
from the FAS.  Those participants are not considered to be able to contribute to the 
efficacy analysis because of missing data in postbaseline visits. 
• Multiple imputation will be used to replace the NRI to handle missing values in the 
analysis for primary and key secondary endpoints.  Multiple imputation is able to 
provide unbiased estimates of the parameters under MAR.  
• DLQI/CDLQI have been moved from exploratory endpoints to secondary endpoints.  
10.2. 
Changes to the Statistical Analysis Plan 
Not applicable. 


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11. 
REFERENCES 
Atkinson MJ, Kumar R, Cappelleri JC, Hass SL. Hierarchical construct validity of the Treatment 
Satisfaction Questionnaire for Medication (TSQM Version II) among outpatient pharmacy 
consumers. Value Health 2005;8:S9-S24. 
Basra MK, Salek MS, Camilleri L, Sturkey R, Finlay AY. Determining the minimal clinically 
important difference and responsiveness of the Dermatology Life Quality Index (DLQI): further 
data. Dermatology 2015;230:27-33. 
Batchelor JM, Tan W, Tour S, Yong A, Montgomery AA, Thomas KS. Validation of the Vitiligo 
Noticeability Scale: a patient-reported outcome measure of vitiligo treatment success. Br J Dermatol 
2016;174:386-394. 
Bharmal M, Payne K, Atkinson MJ, Desrosiers MP, Morisky DE, Gemmen E. Validation of an 
abbreviated Treatment Satisfaction Questionnaire for Medication (TSQM-9) among patients on 
antihypertensive medications. Health Qual Life Outcomes 2009;7:36. 
Bretz F, Maurer W, Brannath W, Posch M. A graphical approach to sequentially rejective 
multiple test procedures. Stat Med 2009;28:586-604. 
Brookmeyer R, Crowley J. A confidence interval for the median survival time. Biometrics 
1982;38:29-41. 
Finlay AY, Khan GK. Dermatology Life Quality Index (DLQI)--a simple practical measure for 
routine clinical use. Clin Exp Dermatol 1994;19:210-216. 
Hamzavi I, Jain H, McLean D, Shapiro J, Zeng H, Lui H. Parametric modeling of narrowband 
UV-B phototherapy for vitiligo using a novel quantitative tool: the Vitiligo Area Scoring Index. 
Arch Dermatol 2004;140:677-683. 
Lewis‐Jones MS, Finlay AY. The Children's Dermatology Life Quality Index (CDLQI): initial 
validation and practical use. Br J Dermatol 1995;132:942-949. 
Lilly E, Lu PD, Borovicka JH, et al. Development and validation of a vitiligo-specific quality-of-life 
instrument (VitiQoL). J Am Acad Dermatol 2013;69:e11-18. 
Mehta CR, Patel NR. Exact logistic regression: theory and examples. Stat Med 
1995;14:2143-2160. 
Reilly MC, Zbrozek AS, Dukes EM. The validity and reproducibility of a work productivity and 
activity impairment instrument. PharmacoEconomics 1993;4:353-365. 
Rubin DB. Multiple Imputation for Nonresponse in Surveys. New York, NY: John Wiley & 
Sons;1987. 
Topp CW, Østergaard SD, Søndergaard S, Bech P. The WHO-5 Well-Being Index: a systematic 
review of the literature. Psychother Psychosom 2015;84:167-176. 
University of Nottingham. Harmonising Outcome Measures for Eczema (HOME). 
van Buuren S. Multiple imputation of discrete and continuous data by fully conditional 
specification. Stat Methods Med Res 2007;16:219-242. 


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Waters A, Sandhu D, Beattie P, Ezughah F, Lewis-Jones S. Severity stratification of Children's 
Dermatology Life Quality Index (CDLQI) scores. Br J Dermatol 2010;163(suppl 1):121. 
WHO Collaborating Center for Mental Health, Psychiatric Research Unit. The WHO-5 website. 
Zigmond AS, Snaith RP. The hospital anxiety and depression scale. Acta Psychiatr Scand 
1983;67:361-370. 


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APPENDIX A. PLANNED TABLES AND FIGURES 
This appendix provides a list of the planned tables, figures, and listings for the clinical study 
report.  Standard tables will follow the conventions in the Standard Safety Tables current 
version.  Shells are provided for nonstandard tables.  In-text tables are identical in structure and 
content as appendix tables, but follow a Rich Text Format. 
The list of tables, figures, listings, and the shells are to be used as guideline.  Modifications of 
the list or shells that do not otherwise affect the nature of the analysis will not warrant an 
amendment to the SAP. 
Tables 
Table No. 
Title 
Population 
Demographics and Disposition 
1.1.1 
Analysis Populations 
All 
1.1.2.1 
Summary of Participant Disposition in Double-Blind Period 
Safety/FAS 
1.1.2.2 
Summary of Participant Disposition in Treatment Extension Period 
TE 
1.1.3 
Summary of Number of Participants Enrolled by Country and Site 
Safety 
1.1.4.1 
Summary of Protocol Deviations in Double-Blind Period 
Safety 
1.1.4.2 
Summary of Protocol Deviations in Treatment Extension Period 
TE 
1.2.1 
Summary of Demographics and Baseline Characteristics 
Safety/FAS 
1.2.2 
Summary of Demographics and Baseline Characteristics 
TE 
1.3 
Summary of Baseline Disease Characteristics 
Safety/FAS 
1.4.1 
 Summary of Prior Therapy for Vitiligo 
Safety 
1.4.2 
Summary of Prior Medications 
Safety 
1.4.3.1 
Summary of Concomitant Medications in Double-Blind Period 
Safety 
1.4.3.2 
Summary of Concomitant Medications in Treatment Extension Period 
TE 
1.5 
Summary of General Medical History 
Safety 
1.6 
Summary of Participants With Assessments Not Done Due to COVID-19 Pandemic 
Safety 
Efficacy 
F-VASI / T-VASI 
2.1.1 
Summary and Analysis of Participants Achieving F-VASI75 During the Treatment 
Period 
FAS 
2.1.1.2 
Summary and Analysis of Participants Achieving F-VASI75 During the Treatment 
Period 
PP 
2.1.1.3 
Summary and Analysis of Participants Achieving F-VASI75 by Skin Type During 
the Treatment Period 
FAS 
2.1.1.4 
Summary and Analysis of Participants Achieving F-VASI75 by Age Group During 
the Treatment Period 
FAS 
2.1.1.5 
Summary and Analysis of Participants Achieving F-VASI75 by Region During the 
Treatment Period 
FAS 
2.1.1.6 
Summary and Analysis of Participants Achieving F-VASI75 by Sex During the 
Treatment Period 
FAS 
2.1.1.7 
Summary and Analysis of Participants Achieving F-VASI75 by Race During the 
Treatment Period 
FAS 
2.1.1.8 
Summary and Analysis of Participants Achieving F-VASI75 at Week 24 by F-BSA 
FAS 


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Table No. 
Title 
Population 
2.1.1.9 
Summary and Analysis of Participants Achieving F-VASI75 at Week 24 by Tipping 
Point Analysis 
FAS 
2.1.2 
Summary and Analysis of Participants Achieving F-VASI25 During the Treatment 
Period 
FAS 
2.1.3 
Summary and Analysis of Participants Achieving F-VASI50 During the Treatment 
Period 
FAS 
2.1.4 
Summary and Analysis of Participants Achieving F-VASI90 During the Treatment 
Period 
FAS 
2.1.5 
Summary and Analysis of  F-VASI During the Treatment Period 
FAS 
2.2.1 
Summary and Analysis of Participants Achieving T-VASI25 During the Treatment 
Period 
FAS 
2.2.2 
Summary and Analysis of Participants Achieving T-VASI50 During the Treatment 
Period 
FAS 
2.2.3 
Summary and Analysis of Participants Achieving T-VASI75 During the Treatment 
Period 
FAS 
2.2.4 
Summary and Analysis of Participants Achieving T-VASI90 During the Treatment 
Period 
FAS 
2.2.5 
Summary and Analysis of  T-VASI During the Treatment Period 
FAS 
F-BSA/T-BSA 
2.3.1 
Summary and Analysis of F-BSA During the Treatment Period 
FAS 
2.3.2 
Summary and Analysis of T-BSA During the Treatment Period 
FAS 
VNS 
2.4.1 
Summary and Analysis of Participants Achieving VNS Scores of 4 or 5 During the 
Treatment Period 
FAS 
2.4.2 
Summary of Participants in Each Category of VNS Scores During the Treatment 
Period 
FAS 
F-PhGVA/T-PhGVA 
2.5.1 
Summary and Analysis of Participants Achieving an F-PhGVA of Clear or Almost 
Clear During Treatment Period 
FAS 
2.5.2 
Summary of Participants in Each Category of F-PhGVA Scores During Treatment 
Period 
FAS 
2.6.1 
Summary and Analysis of Participants Achieving an T-PhGVA of Clear or Almost 
Clear During Treatment Period 
FAS 
2.6.2 
Summary of Participants in Each Category of  T-PhGVA Scores During Treatment 
Period 
FAS 
F-PaGIC-V/T-PaGIC-V 
2.7.1 
Summary and Analysis of Participants Who Report F-PaGIC-V of Very Much 
Improved or Much Improved During Treatment Period 
FAS 
2.7.2 
Summary of Participants in Each Category of  F-PaGIC-V Scores During Treatment 
Period 
FAS 
2.8.1 
Summary and Analysis of Participants Who Report T-PaGIC-V of Very Much 
Improved or Much Improved During Treatment Period 
FAS 
2.8.2 
Summary of Participants in Each Category of  T-PaGIC-V Scores During Treatment 
Period 
FAS 
All Other Efficacy Parameters 
2.9.1 
Summary of Participants in Each Category of Color-Matching Question During the 
Treatment Period 
FAS 
2.9.2 
Summary of DLQI During Treatment Period 
FAS 


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Table No. 
Title 
Population 
2.9.3 
Summary of CDLQI During Treatment Period 
FAS 
2.9.4 
Summary of WHO-5 During Treatment Period 
FAS 
2.9.5 
Summary of TSQM During Treatment Period 
FAS 
2.9.6 
Summary of VitiQoL During Treatment Period 
FAS 
2.9.7 
Summary of HADS During Treatment Period 
FAS 
Exposure & Compliance 
3.1.1.1 
Summary of Exposure in Double-Blind Period 
Safety 
3.1.1.2 
Summary of Exposure in Treatment Extension Period 
TE 
3.1.1.3 
Summary of Exposure in During Treatment Period 
Safety 
3.1.2.1 
Summary of Study Drug Compliance in Double-Blind Period 
Safety 
3.1.2.2 
Summary of Study Drug Compliance in Treatment Extension Period 
TE 
3.1.2.3 
Summary of Study Drug Compliance in During Treatment Period 
Safety 
Adverse Events 
3.2.1.1.X 
Overall Summary of Treatment-Emergent Adverse Events 
Safety 
3.2.1.1.Y 
Overall Summary of  Exposure-Adjusted Treatment-Emergent Adverse Events 
Safety 
3.2.2.1.X 
Summary of Treatment-Emergent Adverse Events by MedDRA System Organ Class 
and Preferred Term 
Safety 
3.2.3.1.X 
Summary of Treatment-Emergent Adverse Events by MedDRA Preferred Term in 
Decreasing Order of Frequency 
Safety 
3.2.3.1.1.X 
Summary of Treatment-Emergent Adverse Events ≥ 1% in Any Treatment Group by 
MedDRA Preferred Term in Decreasing Order of Frequency 
Safety 
3.2.3.1.2.X 
Summary of Application Site Reactions by MedDRA Preferred Term in Decreasing 
Order of Frequency 
Safety 
3.2.3.1.Y 
Summary of Treatment-Emergent Adverse Events With Vehicle Group by MedDRA 
Preferred Term in Decreasing Order of Frequency During the Treatment Period  
Safety 
3.2.3.1.1.Y 
Summary of Treatment-Emergent Adverse Events ≥ 1% in any Treatment Group 
With Vehicle Group by MedDRA Preferred Term in Decreasing Order of Frequency 
During the Treatment Period 
Safety 
3.2.3.1.2.Y 
Summary of Application Site Reactions With Vehicle Group by MedDRA Preferred 
Term in Decreasing Order of Frequency During the Treatment Period 
Safety 
3.2.3.1.3.Y 
Summary of Exposure-Adjusted Incidence Rates of Treatment-Emergent Adverse 
Events With Vehicle Group by MedDRA Preferred Terms in Decreasing Order of 
Frequency During the Treatment Period 
Safety 
3.2.3.1.4.Y 
Summary of Exposure-Adjusted Incidence Rates of Treatment-Emergent Adverse 
Events ≥ 1% in Any Treatment Group With Vehicle Group by MedDRA Preferred 
Term in Decreasing Order of Frequency During the Treatment Period 
Safety 
3.2.3.1.5.Y 
Summary of Exposure-Adjusted Incidence Rates of Application Site Reactions With 
Vehicle Group by MedDRA Preferred Term in Decreasing Order of Frequency 
During the Treatment Period 
Safety 
3.2.4.1.X 
Summary of Grade 3 or Higher Treatment-Emergent Adverse Events by MedDRA 
System Organ Class and Preferred Term  
Safety 
3.2.4.2.X 
Summary of Grade 3 or Higher Treatment-Emergent Adverse Events by MedDRA 
Preferred Term in Decreasing Order of Frequency  
Safety 
3.2.5.1.X 
Summary of Serious Treatment-Emergent Adverse Events by MedDRA System 
Organ Class and Preferred Term  
Safety 
3.2.5.2.X 
Summary of Serious Treatment-Emergent Adverse Events by MedDRA Preferred 
Term in Decreasing Order of Frequency  
Safety 


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Table No. 
Title 
Population 
3.2.6.1.X 
Summary of Treatment-Related Treatment-Emergent Adverse Events by MedDRA 
System Organ Class and Preferred Term  
Safety 
3.2.6.2.X 
Summary of Treatment-Related Treatment-Emergent Adverse Events by MedDRA 
Preferred Term in Decreasing Order of Frequency  
Safety 
3.2.7.1.X 
Summary of Grade 3 or Higher Treatment-Related Treatment-Emergent Adverse 
Events by MedDRA System Organ Class and Preferred Term  
Safety 
3.2.8.1.X 
Summary of Treatment-Related Serious Treatment-Emergent Adverse Events by 
MedDRA System Organ Class and Preferred Term  
Safety 
3.2.9.1.X 
Summary of Treatment-Emergent Adverse Events With a Fatal Outcome by 
MedDRA System Organ Class and Preferred Term  
Safety 
3.2.10.1.X 
Summary of Treatment-Emergent Adverse Events Leading to Dose Interruption by 
MedDRA System Organ Class and Preferred Term  
Safety 
3.2.11.1.X 
Summary of Treatment-Emergent Adverse Events Leading to Discontinuation of 
Study Drug by MedDRA System Organ Class and Preferred Term  
Safety 
Laboratory Values and Vital Signs 
3.3.1.X 
Summary of Laboratory Values – Hematology 
Safety 
3.3.3.X 
Shift Summary of Hematology Laboratory Values in CTC Grade – To the Worst 
Abnormal Value 
Safety 
3.3.4.X 
Summary of Laboratory Values – Chemistry 
Safety 
3.3.6.X 
Shift Summary of  Chemistry Laboratory Values in CTC Grade – To the Worst 
Abnormal Value  
Safety 
3.4.1.X 
Summary of Systolic Blood Pressure 
Safety 
3.4.2.X 
Summary of Diastolic Blood Pressure 
Safety 
3.4.3.X 
Summary of Pulse 
Safety 
3.4.4.X 
Summary of Respiration Rate 
Safety 
3.4.5.X 
Summary of Body Temperature 
Safety 
Note:  For AE tables ending with “X”, separate tables will be provided for the double-blind period, treatment extension period, 
and the treatment period (double-blind and treatment extension periods). 
Note:  For AE tables ending with “Y”, tables will be provided for the treatment period (double-blind and treatment extension 
periods).  For participants who cross over, he/she should be included in both treatment groups. 
Note:  For Laboratory Values/Vital Sign tables ending with “X”, separate tables will be provided for the double-blind period and 
treatment extension period. 
Figure 
Figure No. 
Title 
Population 
4.1.1 
Proportion of Participants Achieving F-VASI75  During Treatment Period 
FAS 
4.1.2 
Proportion of Participants Achieving F-VASI25  During Treatment Period 
FAS 
4.1.3 
Proportion of Participants Achieving F-VASI50  During Treatment Period 
FAS 
4.1.4 
Proportion of Participants Achieving F-VASI90  During Treatment Period 
FAS 
4.1.6 
Mean and Standard Error Plot of F-VASI During Treatment Period 
FAS 
4.1.7 
Mean and Standard Error Plot of Change From Baseline in F-VASI During 
Treatment Period 
FAS 
4.1.8 
Mean and Standard Error Plot of Percent Change From Baseline in F-VASI During 
Treatment Period 
FAS 
4.1.9 
Forest Plot of Response Rate Difference in Achieving F-VASI75 at Week 24 
FAS 
4.2.1 
Proportion of Participants Achieving T-VASI75  During Treatment Period 
FAS 
4.2.2 
Proportion of Participants Achieving T-VASI25  During Treatment Period 
FAS 


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INCB 18424-306/307 Statistical Analysis Plan 
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VV-CLIN-013789 
CONFIDENTIAL 
Figure No. 
Title 
Population 
4.2.3 
Proportion of Participants Achieving T-VASI50  During Treatment Period 
FAS 
4.2.4 
Proportion of Participants Achieving T-VASI90  During Treatment Period 
FAS 
4.2.6 
Mean and Standard Error Plot of T-VASI During Treatment Period 
FAS 
4.2.7 
Mean and Standard Error Plot of Change From Baseline in T-VASI During 
Treatment Period 
FAS 
4.2.8 
Mean and Standard Error Plot of Percent Change From Baseline in T-VASI 
During Treatment Period 
FAS 
4.3.1 
Mean and Standard Error Plot of F-BSA  During Treatment Period 
FAS 
4.3.2 
Mean and Standard Error Plot of Change From Baseline in F-BSA  During 
Treatment Period 
FAS 
4.3.3 
Mean and Standard Error Plot of Percent Change From Baseline in F-BSA  During 
Treatment Period 
FAS 
4.4.1 
Mean and Standard Error Plot of T-BSA  During Treatment Period 
FAS 
4.4.2 
Mean and Standard Error Plot of Change From Baseline in T-BSA  During 
Treatment Period 
FAS 
4.4.3 
Mean and Standard Error Plot of Percent Change From Baseline in T-BSA  During 
Treatment Period 
FAS 
4.5 
Proportion of Participants Achieving VNS scores of 4 or 5 During the Treatment 
Period 
FAS 
4.6 
Proportion of Participants Achieving an F PhGVA of Clear or Almost Clear 
During Treatment Period 
FAS 
4.7 
Proportion of Participants Achieving an T-PhGVA of Clear or Almost Clear 
During  Treatment Period 
FAS 
4.8 
Proportion of Participants who Report F PaGIC V of Very Much Improved or 
Much Improved During  Treatment Period 
FAS 
4.9 
Proportion of Participants who Report T-PaGIC-V of Very Much Improved or 
Much Improved During  Treatment Period 
FAS 
4.10.1 
Mean and Standard Error Plot of  DLQI During Treatment Period 
FAS 
4.10.2 
Mean and Standard Error Plot of Change From Baseline in DLQI During 
Treatment Period 
FAS 
4.10.3 
Mean and Standard Error Plot of Percent Change From Baseline in DLQI During 
Treatment Period 
FAS 
4.11.1 
Mean and Standard Error Plot of  CDLQI During Treatment Period 
FAS 
4.11.2 
Mean and Standard Error Plot of Change From Baseline in CDLQI During 
Treatment Period 
FAS 
4.11.3 
Mean and Standard Error Plot of Percent Change From Baseline in CDLQI During 
Treatment Period 
FAS 
4.12.1 
Mean and Standard Error Plot of WHO-5  During Treatment Period 
FAS 
4.12.2 
Mean and Standard Error Plot of Change From Baseline in WHO-5 During 
Treatment Period 
FAS 
4.12.3 
Mean and Standard Error Plot of Percent Change From Baseline in WHO-5 During 
Treatment Period 
FAS 
4.13.1 
Mean and Standard Error Plot of TSQM During Treatment Period 
FAS 
4.14.1 
Mean and Standard Error Plot of VitiQoL During Treatment Period 
FAS 
4.14.2 
Mean and Standard Error Plot of Change From Baseline in VitiQoL During 
Treatment Period 
FAS 
4.14.3 
Mean and Standard Error Plot of Percent Change From Baseline in VitiQoL 
During Treatment Period 
FAS 


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INCB 18424-306/307 Statistical Analysis Plan 
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VV-CLIN-013789 
CONFIDENTIAL 
Figure No. 
Title 
Population 
4.15.1 
Mean and Standard Error Plot of  HADS During Treatment Period 
FAS 
4.15.2 
Mean and Standard Error Plot of Change From Baseline in HADS During 
Treatment Period 
FAS 
4.15.3 
Mean and Standard Error Plot of Percent Change From Baseline in HADS During 
Treatment Period 
FAS 
Listings 
Listing No. 
Title 
Demographic and Baseline Characteristics 
2.1.1 
Participant Enrollment and Disposition Status 
2.1.2 
Participant Inclusion and Exclusion Criteria Violations 
2.1.3 
Participants Who Discontinued Treatment or Discontinued From Study Due to COVID-19 
2.1.4 
Participants With Assessments Not Done Due to COVID-19 Pandemic 
2.2.1 
Protocol Deviations and Violations 
2.3 
Analysis Populations 
2.4.1 
Demographic Characteristics 
2.4.2 
Baseline Disease Characteristics 
2.4.3 
Medical History 
2.4.4 
Prior and Concomitant Medications 
2.4.5 
Prior Medications for Vitiligo 
2.5.1 
Study Drug Exposure and Compliance 
Efficacy 
2.6.1 
F-VASI Score 
2.6.2 
T-VASI Score 
2.6.3 
F-BSA 
2.6.4 
T-BSA 
2.6.5 
VNS Score 
2.6.6 
F-PhGVA Score 
2.6.7 
T-PhGVA Score 
2.6.8 
F-PaGIC-V Score 
2.6.9 
T-PaGIC-V Score 
2.6.10 
Color-matching Questions 
2.6.11 
DLQI Score 
2.6.12 
CDLQI Score 
2.6.13 
TSQM Score 
2.6.14 
HADS 
2.6.15 
WHO-5 
2.6.16 
VitiQoL Score 
2.6.17 
Participants With F-VASI Assessments Not Done Due to COVID-19 Pandemic 
Adverse Events  
2.7.1 
Adverse Events 
2.7.2 
Adverse Events Leading to Study Drug Discontinuation 
2.7.3 
Serious Adverse Events 
2.7.4 
Treatment-Related Adverse Events 


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Listing No. 
Title 
2.7.5 
Adverse Events With a Fatal Outcome 
2.7.6 
Adverse Events Leading to Interruption of Study Drug 
2.7.8 
Grade 3 or Higher Adverse Events 
2.7.9 
Application Site Reactions 
Laboratory Data 
2.8.1.1 
Clinical Laboratory Values – Hematology 
2.8.1.2 
Clinical Laboratory Values – Chemistry 
2.8.1.3 
Abnormal Clinical Laboratory Values – Hematology 
2.8.1.4 
Abnormal Clinical Laboratory Values – Chemistry 
Vital Signs 
2.8.2.1 
Vital Signs 
2.8.2.2 
Abnormal Vital Sign Values 
2.8.2.3 
Alert Vital Sign Values