A Randomized, Double-Blind, Dose-Ranging Study of INCB018424 Phosphate Cream in Subjects With Vitiligo
Phase: PHASE2
Conditions: Vitiligo
Sponsor: Incyte Corporation

Official Title: 
A Randomized, Double-Blind, Dose-Ranging Study of INCB018424 
Phosphate Cream in Subjects With Vitiligo 
NCT Number: 
NCT03099304 
Document Date: 
Clinical Study Protocol Version 3: 01 August 2019 

Incyte Corporation 
Page 1 of 80 
Protocol INCB 18424-211 Am 3 
Version 3 
01 AUG 2019 
Clinical Study Protocol 
INCB 18424-211 
A Randomized, Double-Blind, Dose-Ranging Study of INCB018424 
Phosphate Cream in Subjects With Vitiligo 
Product: 
INCB018424 Phosphate Cream 
IND Number: 
77,101 
Phase of Study: 
2 
Sponsor: 
Incyte Corporation 
1801 Augustine Cut-Off 
Wilmington, DE 19803 
Original Protocol (Version 0): 
20 JAN 2017 
Amendment (Version) 1: 
17 MAY 2017 
Amendment (Version) 2: 
08 JAN 2018 
Amendment (Version) 3: 
01 AUG 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, Good Clinical Practices as defined in Title 21 of the 
US Code of Federal Regulations Parts 11, 50, 54, 56, and 312, as well as ICH GCP consolidated guidelines (E6) and 
applicable regulatory requirements. 
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 the prior 
written consent of Incyte Corporation. 
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Protocol INCB 18424-211 Am 3 
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INVESTIGATOR'S AGREEMENT 
I have read the INCB 18424-211 Protocol Amendment 3 (Version 3 dated 01 AUG 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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Protocol INCB 18424-211 Am 3 
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SYNOPSIS 
Name of Investigational Product:  INCB018424 Phosphate Cream (hereafter referred to as 
INCB018424 cream) 
Title of Study:  A Randomized, Double-Blind Dose-Ranging Study of INCB018424 Phosphate Cream in 
Subjects With Vitiligo  
Protocol Number:  INCB 18424-211 
Study Phase:  2 
Indication:  Vitiligo 
Primary Objective: 
• To establish the efficacy of 24 weeks of treatment with INCB018424 cream in subjects with vitiligo. 
Secondary Objectives: 
• To estimate the dose-response relationship of INCB018424 cream at Weeks 24 and 52. 
• To evaluate the safety and tolerability of INCB018424 cream in subjects with vitiligo. 
Primary Endpoint: 
• Proportion of subjects treated with INCB018424 cream who achieve a ≥ 50% improvement from 
baseline in Face Vitiligo Area Severity Index score (F-VASI50) at Week 24 compared with subjects 
treated with vehicle. 
Key Secondary Endpoints: 
• Proportion of subjects who achieve a Physician Global Vitiligo Assessment (PhGVA) on the face 
(F-PhGVA) of clear or almost clear at Week 24. 
• Proportion of subjects who achieve a ≥ 50% improvement from baseline in Total Vitiligo Area Severity 
Index score (T-VASI50) at Week 52. 
Overall Study Design: 
This is a 3-part, randomized, double-blind, and vehicle-controlled study in subjects with vitiligo who have 
depigmented areas including at least 0.5% of the total BSA on the face and at least 3% of the total BSA 
on nonfacial areas as determined by the palmar or handprint (palm plus 5 digits) method.  Approximately 
150 subjects, aged 18 to 75 years, will be randomized to 1 of 4 dose strengths of INCB018424 cream 
(1.5% BID, 1.5% QD, 0.5% QD, 0.15% QD) or vehicle in a 1:1:1:1:1 ratio and stratified by age (≤ 30 or 
> 30 years).  
The 3 parts of the study include a 24-week, double-blind, vehicle-controlled treatment period; a 28-week, 
continued, double-blind treatment period; and a 104-week, open-label extension period.  After completion 
of the Week 24 assessments, subjects randomized to vehicle will be randomized to 1 of the 3 higher 
active treatment groups in a 1:1:1 ratio while maintaining the blind.  Subjects in the 0.15% QD dose 
group who do not achieve a ≥ 25% improvement from baseline on F-VASI will be re-randomized to 1 of 
the 3 higher active treatment groups while maintaining the blind.  Subjects randomized to 
INCB018424 0.15% QD who achieve a ≥ 25% improvement from baseline on F-VASI will remain on the 
same dose until Week 52.  Subjects randomized to INCB018424 1.5% BID, 1.5% QD, and 0.5% QD will 
remain on the same dose until Week 52. 
After completion of the Week 52 assessments, subjects who continue to be eligible for the study will be 
offered the opportunity to receive an additional 104 weeks of open-label treatment with 
INCB018424 1.5% cream BID.  In the open-label extension, subjects may be offered low-dose narrow 
band-UVB phototherapy in addition to INCB018424 cream in consultation with the investigator and 
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sponsor.  Subjects who are eligible for the open-label extension who have complete facial repigmentation 
(F-PhGVA score of 0) may stop applying study drug to the face, decrease the application rate to QD, or 
continue BID based on investigator judgement at Weeks 52 and 80 (after Week 80, subjects may also be 
permitted to modify their treatment regimen after the investigator has consulted with the sponsor). 
Study Population: 
Male or female subjects, aged 18 to 75 years, who have been diagnosed with vitiligo with depigmented 
areas including at least 0.5% of the total BSA on the face and at least 3% of the total BSA on nonfacial 
areas will be eligible for the study. 
Key Inclusion Criteria:  
A subject who meets all of the following criteria may be included in the study: 
• Male or female subjects aged 18 to 75 years, inclusive. 
• Subjects with a clinical diagnosis of vitiligo. 
• Subjects with vitiligo with depigmented areas including: 
− at least 0.5% of the total BSA on the face (0.5% BSA is approximately equal to the area of the 
subject's palm [without digits]) AND 
− at least 3% of the total BSA on nonfacial areas (3% BSA is approximately equal to the area of 3 of 
the subject's handprints [palm plus 5 digits]). 
• Subjects who agree to discontinue all agents used to treat vitiligo from screening through the final 
follow-up visit.  Over-the-counter preparations deemed acceptable by the investigator and camouflage 
makeups are permitted. 
Key Exclusion Criteria:   
A subject who meets any of the following criteria will be excluded from the study: 
• Conditions at baseline that would interfere with evaluation of vitiligo. 
• Subjects who are receiving any kind of phototherapy, including tanning beds. 
• Subjects with other dermatologic disease besides vitiligo whose presence or treatments could 
complicate the assessment of repigmentation. 
• Subjects who have used skin bleaching treatments for past treatment of vitiligo or other pigmented 
areas. 
• Subjects who have received any of the following treatments within the minimum specified timeframes. 
− Use of any biologic, investigational, or experimental therapy or procedure for vitiligo within 
12 weeks or 5 half-lives (whichever is longer) of screening.  Investigational biologics should be 
discussed with the sponsor to determine if a longer period of discontinuation is required. 
− Use of laser or light-based vitiligo treatments, including tanning beds, within 8 weeks of screening. 
− Use of immunomodulating oral or systemic medications (eg, corticosteroids, methotrexate, 
cyclosporine) or topical treatments that may affect vitiligo (eg, corticosteroids, 
tacrolimus/pimecrolimus, retinoids) within 4 weeks of screening. 
• Use of any prior and concomitant therapy not listed above that may interfere with the objective of the 
study as per discretion of the investigator, including drugs that cause photosensitivity or skin 
pigmentation (eg, antibiotics such as tetracyclines, antifungals) within 8 weeks of screening. 
• Subjects with a clinically significant abnormal TSH or free T4 at screening as determined by the 
investigator. 
• Subjects with cytopenias at screening, defined as follows: 
− Leukocytes < 3.0 × 109/L (< 2.5 × 109/L for subjects who are African-American). 
− Neutrophils < lower limit of normal. 
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− Lymphocytes < 0.8 × 109/L. 
− Hemoglobin < 10 g/dL. 
− Platelets < 100 × 109/L. 
• Subjects with severely impaired liver function (Child-Pugh Class C) or alanine aminotransferase or 
aspartate aminotransferase ≥ 1.5 × upper limit of normal on repeated assessment. 
• Subjects with impaired renal function with estimated creatinine clearance less than 60 mL/min. 
• Positive serology test results for HIV, for hepatitis B surface antigen or core antibody, or for hepatitis C 
virus antibody with detectable RNA at screening. 
• Subjects taking potent systemic cytochrome P450 3A4 inhibitors or fluconazole within 2 weeks or 
5 half-lives, whichever is longer, before the baseline visit. 
• Subjects who have previously received JAK inhibitor therapy, systemic or topical. 
Study Drug, Dosage, and Mode of Administration:  INCB018424 cream is supplied in 3 dose strengths 
(1.5%, 0.5%, and 0.15%) and packaged as 15 g per tube. 
On Day 1, the application regimen is to be determined by weighing a tube before and after the subject 
applies a thin film of study drug to the affected areas.  For the determination of dosage, subjects should 
remove study drug from the tube in fingertip units until all of the areas to be treated are covered by a thin 
film.  Subjects will be advised to limit use to no more than 1 tube per application. 
Study drug will be applied topically as a thin film to the affected areas in the morning and in the evening 
at least 1 hour before bedtime. 
If a subject has vitiligo present on more than 20% of BSA, the application of study drug will be limited to 
≤ 20% of the subject's total BSA and areas treated at baseline should continue to receive treatment until 
the end of the double-blind period (Week 52) unless the subject meets criteria for stopping study drug 
because of an AE. 
Reference Therapy, Dosage, and Mode of Administration:  Vehicle cream is matching in appearance 
to INCB018424 cream and is to be applied in the same manner as INCB018424 cream. 
Study Schedule/Procedures: 
Study visits are as follows: 
Screening:  Up to 28 days before enrollment.  Screening will begin at the time that the subject signs the 
informed consent and will continue until the date the subject is enrolled in the study (Day 1). 
Vehicle-controlled, double-blind treatment:  Subjects will have study visits on Day 1 and at Weeks 4, 8, 
12, 18, and 24 for assessment of safety and efficacy. 
Continued double-blind treatment:  Subjects will have study visits at Weeks 28, 34, 40, 46, and 52 for 
assessment of safety and efficacy. 
Open-label extension:  Subjects will have visits at Weeks 56, 68, 80, 92, 104, 116, 128, 140, and 156 for 
assessment of safety and efficacy. 
On the day of a visit, subjects should not apply the study drug at home and will apply the next dose of 
study drug from the new kit in the clinic.  Subjects will be given a daily diary to record application times.  
Subjects will also be instructed to bring all study drug tubes with them to each visit so that compliance 
can be assessed. 
Safety follow-up:  Subjects will have follow-up assessments approximately 1, 3, and 6 months after the 
last dose of study drug to assess safety and efficacy.  If prohibited treatment for vitiligo is started, then an 
earlier follow-up visit will be performed as a final, and thus end-of-study, visit. 
Safety assessments: 
At each scheduled study visit at the clinical site, targeted physical examinations, vital sign collection, 
laboratory assessments, collection of concomitant medications, and AE assessments will be performed.  
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TABLE OF CONTENTS 
SYNOPSIS ......................................................................................................................................3 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ..................................................13 
1.
INTRODUCTION ......................................................................................................16 
1.1. 
Vitiligo ........................................................................................................................16 
1.2. 
Autoimmunity and Vitiligo.........................................................................................16 
1.3. 
Role of JAKs in Vitiligo .............................................................................................18 
 
18 
 
19 
1.6. 
Clinical Experience .....................................................................................................19 
1.6.1. 
Clinical Efficacy With Topical INCB018424 Cream in Vitiligo ...............................19 
1.6.2. 
Clinical Efficacy With Topical INCB018424 Cream in Psoriasis .............................20 
 
20 
 
20 
 
21 
 
22 
1.6.5. 
Oral INCB018424 (Ruxolitinib) Safety......................................................................24 
 
25 
 
26 
2.
STUDY OBJECTIVES AND ENDPOINTS ..............................................................27 
2.1. 
Study Objectives .........................................................................................................27 
2.1.1. 
Primary Objective .......................................................................................................27 
2.1.2. 
Secondary Objectives .................................................................................................27 
 
27 
2.2. 
Study Endpoints ..........................................................................................................27 
2.2.1. 
Primary Endpoint ........................................................................................................27 
2.2.2. 
Secondary Endpoints ..................................................................................................27 
2.2.2.1. 
Key Secondary Endpoints ...........................................................................................27 
2.2.2.2. 
Other Secondary Endpoints ........................................................................................27 
 
28 
3.
SUBJECT ELIGIBILITY ...........................................................................................29 
3.1. 
Subject Inclusion Criteria ...........................................................................................29 
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3.2. 
Subject Exclusion Criteria ..........................................................................................30 
4. 
INVESTIGATIONAL PLAN .....................................................................................32 
4.1. 
Overall Study Design ..................................................................................................32 
4.2. 
Measures Taken To Avoid Bias .................................................................................33 
4.3. 
Number of Subjects ....................................................................................................34 
4.4. 
Duration of Treatment and Subject Participation .......................................................34 
4.5. 
Overall Study Duration ...............................................................................................34 
4.6. 
Study Termination ......................................................................................................34 
5. 
TREATMENT ............................................................................................................34 
5.1. 
Treatment Assignment ................................................................................................34 
5.1.1. 
Subject Numbering and Treatment Assignment .........................................................34 
5.1.2. 
Randomization and Blinding ......................................................................................34 
5.2. 
INCB018424 Cream or Matching Vehicle .................................................................35 
5.2.1. 
Description and Administration ..................................................................................35 
5.2.2. 
Supply, Packaging, and Labeling ...............................................................................35 
5.2.3. 
Storage ........................................................................................................................35 
 
36 
5.3. 
Treatment Compliance ................................................................................................36 
5.4. 
Treatment Interruptions and Adjustments ..................................................................37 
5.4.1. 
Dose Modifications .....................................................................................................37 
5.4.2. 
Criteria and Procedures for Dose Interruptions and Adjustments of Study 
Drug ............................................................................................................................37 
5.4.3. 
Criteria for Permanent Discontinuation of Study Drug ..............................................38 
5.4.4. 
Criteria and Procedures for Dose Increases of Study Drug ........................................38 
5.5. 
Withdrawal of Subjects From Study Treatment .........................................................38 
5.5.1. 
Withdrawal Criteria ....................................................................................................38 
5.5.2. 
Withdrawal Procedures ...............................................................................................39 
5.6. 
Concomitant Medications ...........................................................................................39 
 
39 
 
39 
 
40 
6. 
STUDY ASSESSMENTS ..........................................................................................40 
6.1. 
Screening ....................................................................................................................45 
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6.2. 
Baseline .......................................................................................................................46 
6.3. 
Treatment ....................................................................................................................46 
6.4. 
Follow-Up ...................................................................................................................46 
6.5. 
Unscheduled Visits .....................................................................................................47 
6.6. 
Early Termination .......................................................................................................47 
7. 
CONDUCT OF STUDY ASSESSMENTS AND PROCEDURES ...........................47 
7.1. 
Administration of Informed Consent Form ................................................................47 
7.2. 
Interactive Response Technology Procedure ..............................................................47 
7.3. 
Demography and Medical History ..............................................................................48 
7.3.1. 
Demographics and General Medical History .............................................................48 
7.3.2. 
Disease Characteristics and Treatment History ..........................................................48 
7.4. 
Prior and Concomitant Medications and Procedures ..................................................48 
7.5. 
Safety Assessments .....................................................................................................48 
7.5.1. 
Adverse Events ...........................................................................................................48 
7.5.2. 
Physical Examinations ................................................................................................48 
7.5.2.1. 
Comprehensive Physical Examination .......................................................................48 
7.5.2.2. 
Targeted Physical Examination ..................................................................................49 
7.5.3. 
Vital Signs ..................................................................................................................49 
7.5.4. 
Electrocardiograms .....................................................................................................49 
7.5.5. 
Laboratory Assessments .............................................................................................49 
7.5.5.1. 
Chemistry ....................................................................................................................49 
7.5.5.2. 
Hematology .................................................................................................................49 
7.5.5.3. 
Urinalysis ....................................................................................................................50 
7.5.5.4. 
Pregnancy Testing ......................................................................................................50 
7.5.5.5. 
Hepatitis and HIV Screening Tests .............................................................................50 
7.6. 
Efficacy Assessments .................................................................................................50 
7.6.1. 
Vitiligo Area and Severity Index ................................................................................50 
7.6.2. 
Body Surface Area ......................................................................................................51 
7.6.3. 
Vitiligo European Task Force Scale ...........................................................................51 
7.6.4. 
Physician's Global Vitiligo Assessment .....................................................................52 
7.6.5. 
Patient's Global Vitiligo Assessment ..........................................................................52 
7.6.6. 
Patient Global Impression of Change-Vitiligo ...........................................................52 
 
 
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53 
 
53 
 
53 
 
53 
 
53 
7.10. 
Other Study Procedures ..............................................................................................53 
7.10.1. 
Distribution of Subject Diaries ...................................................................................53 
8.
SAFETY MONITORING AND REPORTING .........................................................54 
8.1. 
Adverse Events ...........................................................................................................54 
8.1.1. 
Definitions ..................................................................................................................54 
8.1.2. 
Reporting ....................................................................................................................54 
8.2. 
Laboratory Test Abnormalities ...................................................................................55 
8.3. 
Serious Adverse Events ..............................................................................................56 
8.3.1. 
Definitions ..................................................................................................................56 
8.3.2. 
Reporting ....................................................................................................................56 
8.4. 
Emergency Unblinding of Treatment Assignment .....................................................57 
8.5. 
Pregnancy ...................................................................................................................58 
8.6. 
Warnings and Precautions ..........................................................................................58 
8.7. 
Data Monitoring Committee .......................................................................................58 
8.8. 
Product Complaints ....................................................................................................58 
9.
STATISTICS ..............................................................................................................59 
9.1. 
Study Populations .......................................................................................................59 
9.2. 
Selection of Sample Size ............................................................................................59 
9.3. 
Level of Significance ..................................................................................................59 
9.3.1. 
Primary Analysis ........................................................................................................60 
9.3.2. 
Secondary Analysis ....................................................................................................60 
9.3.2.1. 
Tests in Branch 1 ........................................................................................................61 
9.3.2.2. 
Tests in Branch 2 ........................................................................................................61 
9.4. 
Statistical Analyses .....................................................................................................62 
9.4.1. 
Efficacy Analyses .......................................................................................................62 
9.4.1.1. 
Efficacy Measures for Primary and Secondary Endpoints .........................................62 
9.4.1.2. 
Primary Efficacy Analyses .........................................................................................62 
9.4.1.3. 
Secondary Efficacy Analyses .....................................................................................62 
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9.4.1.4. 
Other Efficacy Analyses .............................................................................................63 
9.4.2. 
Safety Analyses ..........................................................................................................63 
9.4.2.1. 
Adverse Events ...........................................................................................................63 
9.4.2.2. 
Clinical Laboratory Tests ...........................................................................................63 
9.4.2.3. 
Vital Signs ..................................................................................................................63 
 
63 
 
64 
9.5. 
Interim Analysis ..........................................................................................................64 
10. 
ETHICAL CONSIDERATIONS AND ADMINISTRATIVE 
PROCEDURES ..........................................................................................................64 
10.1. 
Investigator Responsibilities .......................................................................................64 
10.2. 
Accountability, Handling, and Disposal of Study Drug .............................................66 
10.3. 
Data Management .......................................................................................................66 
10.4. 
Data Privacy and Confidentiality of Study Records ...................................................67 
10.5. 
Financial Disclosure ...................................................................................................67 
10.6. 
Publication Policy .......................................................................................................68 
11. 
REFERENCES ...........................................................................................................69 
APPENDIX A. INFORMATION REGARDING EFFECTIVENESS OF 
CONTRACEPTIVE METHODS ...............................................................................71 
APPENDIX B. POTENT CYP3A4 INHIBITORS AND FLUCONAZOLE .............................72 
APPENDIX C. VITILIGO AREA SEVERITY INDEX ............................................................73 
APPENDIX D. VITILIGO EUROPEAN TASK FORCE SCALE ............................................74 
76 
APPENDIX F. PROTOCOL AMENDMENT SUMMARY OF CHANGES ............................77 
 
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
The following abbreviations and special terms are used in this clinical study Protocol. 
Abbreviation or Term 
Definition 
AA 
alopecia areata 
AD 
atopic dermatitis 
AE 
adverse event 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
AST 
aspartate aminotransferase 
AUC 
total exposure 
BID 
twice daily 
BSA 
body surface area 
CFR 
Code of Federal Regulations 
CL 
clearance 
CLA 
cutaneous lymphocyte antigen 
Cmax 
maximal plasma concentration 
COMFORT 
Controlled Myelofibrosis Study With Oral Janus-Associated Kinase Inhibitor 
Treatment 
Css 
plasma concentration at steady state 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
cytochrome P450 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EOS 
end of study 
EOT 
end of treatment 
ET 
early termination 
F 
percentage of systemic bioavailability 
F-BSA 
facial body surface area 
FDA 
Food and Drug Administration 
fingertip unit 
The amount of cream applied from the distal skin-crease of the tip of the 
index finger.  The distal skin-crease is the skin-crease over the joint nearest 
the end of the finger. 
F-PaGVA 
facial assessment of the Patient's Global Vitiligo Assessment 
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Abbreviation or Term 
Definition 
F-PhGVA 
facial assessment of the Physician's Global Vitiligo Assessment 
FSH 
follicle-stimulating hormone 
F-VASI 
facial assessment of the Vitiligo Area and Severity Index 
FWER 
familywise error rate 
GCP 
Good Clinical Practice 
GGT 
gamma-glutamyl transferase 
H 
head/neck 
HIPAA 
Health Insurance Portability and Accountability Act of 1996 
HLA-DR 
human leukocyte antigen – antigen D related 
IB 
Investigator's Brochure 
IC50 
half maximal inhibitory concentration 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IgM 
immunoglobulin M 
IL 
interleukin 
IL-2R 
interleukin-2-receptor 
IN 
Investigator Notification 
INF 
interferon 
IRB 
institutional review board 
IRT 
interactive response technology 
ITT 
intent-to-treat 
JAK 
Janus kinase 
LL 
lower limbs 
MHC 
major histocompatibility complex 
MedDRA 
Medical Dictionary for Regulatory Activities 
NOAEL 
no-observed-adverse-effect level 
PaGIC-V 
Patient Global Impression of Change for Vitiligo 
PaGVA 
Patient's Global Vitiligo Assessment 
palmar method of BSA 
assessment 
1% BSA for each subject is approximately equal to the surface area of their 
palm plus 5 digits; handprint may be used interchangeably 
PASI 
Psoriasis Area Severity Index 
PhGVA 
Physician's Global Vitiligo Assessment 
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Abbreviation or Term 
Definition 
PK 
pharmacokinetics 
PV 
polycythemia vera 
QD 
once daily 
RNA 
ribonucleic acid 
SAE 
serious adverse event 
STAT 
signal transducers and activators of transcription 
SUSAR 
Suspected Unexpected Serious Adverse Reactions 
T 
trunk 
T-BSA 
total body surface area 
T-PaGVA 
total body assessment of the Patient's Global Vitiligo Assessment 
T-PhGVA 
total body assessment of the Physician's Global Vitiligo Assessment 
TEAE 
treatment-emergent adverse events 
TNF-α 
tumor necrosis factor-alpha 
TSH 
thyroid-stimulating hormone 
T-VASI 
full body assessment of Vitiligo Area and Severity Index 
UL 
upper limbs 
ULN 
upper limit of normal 
VASI 
Vitiligo Area and Severity Index 
VASI50 
≥ 50% improvement from baseline in Vitiligo Area and Severity Index score 
VASI75 
≥ 75% improvement from baseline in Vitiligo Area and Severity Index score 
VASI90 
≥ 90% improvement from baseline in Vitiligo Area and Severity Index score 
VETF 
Vitiligo European Task Force 
 
 
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HLA-DR, and MHC II and the CLA typical of skin homing.  They also produce cytokines such 
as INF-γ and TNF-α.  Through these mechanisms infiltrating T cells kill melanocytes within the 
skin, thereby causing the loss of pigmentation characteristic for nonsegmental vitiligo 
(Guerra et al 2010). 
Le Poole et al (1996) studied the perilesional skin of patients suffering from inflammatory 
vitiligo (a rare subtype of vitiligo).  In these patients, the perilesional skin is red, itchy, and 
irritated, and the inflammation progresses toward skin with remaining melanocytes.  The 
researchers found that melanocyte densities were 2.5 times greater in control skin than in the 
pigmented nonlesional skin of patients and that in perilesional skin, there was a marked decrease 
in density even when compared with nonlesional skin.  CD3 staining of T cells was significantly 
greater in perilesional skin when compared with nonlesional or lesional skin.  Notably, in 
perilesional skin, T-cell infiltrates were substantially increased in the epidermal compartment 
and were mostly concentrated where melanocyte destruction occurs (at the epidermal basal 
layer).  Overall, it was determined that epidermis-infiltrating T cells demonstrate an increased 
CD8/CD4 ratio and increased IL-2 receptor expression.  Perilesional skin biopsies of 
inflammatory vitiligo had a decreased CD4/CD8 T-cell ratio.  This suggests that the destruction 
of melanocytes could be cytotoxic CD8 T-cell mediated.  All of the patients also exhibited 
perilesional HLA-DR expression (MHC class II receptor), particularly along basal and 
suprabasal keratinocytes, and the authors argued that this finding could be associated with local 
T-cell reactivity.  From an autoimmune perspective, their results suggest that a 
melanocyte-specific immune reaction, involving most notably T cells, among other immune 
mediators, is likely involved in the pathogenesis of vitiligo (Le Poole et al 1996). 
Grimes et al (2004) investigated the potential role of cytokines in a clinical study in which 
vitiligo patients were treated with 0.1% tacrolimus ointment, an immunomodulatory drug 
thought to inhibit T-cell activation and consequently diminish the production and secretion of 
proinflammatory cytokines.  Punch biopsies were performed at baseline from depigmented, 
non-sun-exposed lesional skin and adjacent nonlesional skin, and similar biopsies were taken 
from non–sun-exposed control skin.  Following the 24-week treatment period, repeat biopsies 
were excised.  Some level of repigmentation occurred in 89% of patients, most of which 
significantly occurred in the face and neck regions.  In terms of cytokine expression, patient 
involved and uninvolved skin at baseline demonstrated significantly increased expression of 
IL-10, IFN-c, and TNF-α when compared with expression in control skin.  Post-treatment, the 
only significant difference was the decreased expression of TNF-α in both lesional and 
nonlesional skin of the vitiligo patients.  These findings suggest that a cytokine imbalance is 
likely involved in the pathogenesis of vitiligo and that the apparent suppression of TNF-α by 
tacrolimus is a possible means of facilitating repigmentation.  Also, it is important to note that 
repigmentation with tacrolimus was most noted in sun-exposed areas (ie, the face and neck).  
Thus, it could also be suggested that suppression of cytokines, namely TNF-α, somehow 
facilitates the UV stimulation of melanogenesis and, ultimately, the repopulation of melanocytes 
in vitiliginous skin.  These results clearly indicate a plausible role for cytokines in the 
pathogenesis of vitiligo (Grimes et al 2004). 
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1.6. 
Clinical Experience 
1.6.1. 
Clinical Efficacy With Topical INCB018424 Cream in Vitiligo 
An investigator-initiated, 20-week, open-label POC study with extension up to 52 weeks of 
INCB018424 cream 1.5% BID is currently ongoing.  The primary outcome of the study is 
improvement in VASI from baseline to Week 20.  Eleven patients with vitiligo with a minimum 
of 1% affected BSA were enrolled into the study.  At Week 20, 76% improvement in facial 
VASI score was observed in patients with significant facial vitiligo, and 26% improvement in 
overall VASI from baseline to Week 20 was also observed.  These changes were considered to 
be a clinically meaningful response.  Slower response was observed in acral areas as compared 
with facial areas.  Reported AEs considered related to drug were mild and included erythema, 
hyperpigmentation in skin where drug was applied, and transient acne.  Overall, INCB018424 
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1.6.5. 
Oral INCB018424 (Ruxolitinib) Safety 
In the randomized period of the 2 pivotal studies in myelofibrosis, COMFORT-I and 
COMFORT-II, discontinuation because of AEs regardless of causality was observed in 11.3% of 
subjects.  The most frequently reported adverse drug reactions were thrombocytopenia and 
anemia.  Hematological adverse reactions (any CTCAE grade) included anemia (82.4%), 
thrombocytopenia (69.8%), and neutropenia (16.6%).  Anemia, thrombocytopenia, and 
neutropenia are dose-related effects.  The 3 most frequent nonhematological adverse reactions 
were bruising (21.6%), dizziness (15.3%), and headache (14.0%).  The 3 most frequent 
nonhematological laboratory abnormalities were increased alanine ALT (27.2%), increased AST 
(18.6%), and hypercholesterolemia (16.9%). 
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Long-term follow-up in subjects with myelofibrosis (including 615 subjects treated with 
ruxolitinib during the controlled and extension phases of Studies INCB 18424-251 cutoff 
01 OCT 2012; COMFORT-I:  02 SEP 2012; and COMFORT-II:  01 SEP 2012) has shown that, 
as expected, the numbers and proportions of AEs and SAEs has increased; however, no new 
safety signals have emerged (median duration of exposure for this population is 27.6 months, 
with 1345.78 patient-years of exposure). 
In Study INCB 18424-258, in subjects with myelofibrosis with a platelet count between 50 and 
100 × 109/L, beginning treatment with 5 mg BID was well-tolerated, avoided levels of 
thrombocytopenia associated with a high risk of significant bleeding, and provided an 
opportunity to increase the dose of ruxolitinib in a safe manner. 
Overall, the safety profile of ruxolitinib in the PV population is generally consistent with that 
observed in the myelofibrosis population.  Ruxolitinib was generally well-tolerated in subjects 
with PV, and only a small proportion of subjects discontinued ruxolitinib because of AEs (3.6%).  
Most of the AEs were managed by dose modifications.  Hematological toxicities were less 
frequent and less severe in subjects with PV as compared with those observed in subjects with 
myelofibrosis.  No new safety signals emerged from a study in pancreatic cancer in combination 
with capecitabine.  The AE profile of ruxolitinib was also assessed in 198 healthy subjects, 
subjects with various degrees of renal (n = 32) or hepatic (n = 24) impairment, and subjects with 
RA (n = 59).  Adverse events were, in general, mild and resolved without interventions. 
A thorough QT study was conducted in 50 healthy subjects.  There was no indication of a 
QT/QTc-prolonging effect of ruxolitinib in single doses up to a supratherapeutic dose of 200 mg, 
indicating that ruxolitinib has no effect on cardiac repolarization. 
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3. 
SUBJECT ELIGIBILITY 
Deviations from eligibility criteria are not allowed because they can potentially jeopardize the 
scientific integrity of the study, regulatory acceptability, and/or subject safety.  Therefore, 
adherence to the criteria as specified in the Protocol is essential. 
3.1. 
Subject Inclusion Criteria 
A subject who meets all of the following criteria may be included in the study: 
1. Male and female subjects aged 18 to 75 years, inclusive. 
2. Subjects with a clinical diagnosis of vitiligo. 
3. Subjects with vitiligo with depigmented areas including: 
a. at least 0.5% of the total BSA on the face (0.5% BSA is approximately equal to the 
area of the subject's palm [without digits]) AND 
b. at least 3% of the total BSA on nonfacial areas (3% BSA is approximately equal to 
the area of 3 of the subject's handprints [palm plus 5 digits]). 
4. Subjects who agree to discontinue all agents used to treat vitiligo from screening through 
the final follow-up visit.  Over-the-counter preparations deemed acceptable by the 
investigator and camouflage makeups are permitted. 
5. If receiving concomitant medications for any reason, must be on a stable regimen and 
anticipate staying on a stable regimen. 
6. Willingness to avoid pregnancy or fathering of children based on the following criteria: 
a. Woman of nonchildbearing potential (surgically sterile with a hysterectomy and/or 
bilateral oophorectomy OR postmenopausal, defined by last menstrual period 
> 12 months before screening and confirmed by FSH). 
b. Woman of childbearing potential who has a negative serum pregnancy test at 
screening and a negative urine pregnancy test before the first dose on Day 1 and who 
agrees to take appropriate precautions to avoid pregnancy from screening through 
safety follow-up.  Permitted methods that are highly efficacious in preventing 
pregnancy (see Appendix A) should be communicated to the subject and their 
understanding confirmed. 
c. Man who agrees to take appropriate precautions to avoid fathering children from 
screening through safety follow-up.  Permitted methods that are highly efficacious in 
preventing pregnancy (see Appendix A) should be communicated to the subject and 
their understanding confirmed. 
7. Ability to comprehend and willingness to sign an ICF. 
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3.2. 
Subject Exclusion Criteria 
A subject who meets any of the following criteria will be excluded from the study: 
1. Conditions at baseline that would interfere with evaluation of vitiligo. 
2. Subjects who are receiving any kind of phototherapy, including tanning beds. 
3. Subjects with other dermatologic disease besides vitiligo whose presence or treatments 
could complicate the assessment of repigmentation. 
4. Subjects who have used skin bleaching treatments for past treatment of vitiligo or other 
pigmented areas. 
5. Subjects who have received any of the following treatments within the minimum 
specified timeframes. 
a. Use of any biologic, investigational, or experimental therapy or procedure for vitiligo 
within 12 weeks or 5 half-lives (whichever is longer) of screening.  Investigational 
biologics should be discussed with the sponsor to determine if a longer period of 
discontinuation is required. 
b. Use of laser or light-based vitiligo treatments, including tanning beds, within 8 weeks 
of screening. 
c. Use of immunomodulating oral or systemic medications (eg, corticosteroids, 
methotrexate, cyclosporine) or topical treatments that may affect vitiligo (eg, 
corticosteroids, tacrolimus/pimecrolimus, retinoids) within 4 weeks of screening. 
6. Use of any prior and concomitant therapy not listed above that may interfere with the 
objective of the study as per discretion of the investigator, including drugs that cause 
photosensitivity or skin pigmentation (eg, antibiotics such as tetracyclines, antifungals) 
within 8 weeks of screening. 
7. Subjects with a clinically significant abnormal TSH or free T4 at screening as determined 
by the investigator. 
8. Subjects with cytopenias at screening, defined as follows: 
a. Leukocytes < 3 × 109/L (2.5 × 109/L for subjects who are African-American). 
b. Neutrophils < lower limit of normal. 
c. Lymphocytes < 0.8 × 109/L. 
d. Hemoglobin < 10 g/dL. 
e. Platelets < 100 × 109/L. 
9. Subjects with severely impaired liver function (Child-Pugh Class C) or ALT or 
AST ≥ 1.5 × ULN on repeated assessment. 
10. Subjects with impaired renal function with estimated creatinine clearance less than 
60 mL/min. 
11. Positive serology test results for HIV, for hepatitis B surface antigen or core antibody, or 
for hepatitis C virus antibody with detectable RNA at screening. 
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12. Subjects taking potent systemic CYP3A4 inhibitors or fluconazole within 2 weeks or 
5 half-lives, whichever is longer, before the baseline visit (topical agents with limited 
systemic availability are permitted, see Appendix B). 
13. Subjects who have previously received JAK inhibitor therapy, systemic or topical 
(eg, ruxolitinib, tofacitinib, baricitinib, filgotinib, lestaurtinib, pacritinib). 
14. Women who were pregnant during the 12 months before screening. 
15. Women who are breastfeeding. 
16. Current or recent history (< 30 days before screening and/or < 45 days before 
randomization) of a clinically meaningful bacterial, fungal, parasitic, or mycobacterial 
infection. 
17. History of unstable ischemic heart disease (including percutaneous cardiac intervention, 
myocardial infarction, or anginal acceleration within the past 6 months) or uncontrolled 
hypertension (blood pressure > 150/90 mmHg on at least 2 subsequent readings). 
18. 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 subject's ability 
to comply with the administration schedule and study assessments. 
19. Current treatment or treatment within 30 days or 5 half-lives (whichever is longer) before 
the baseline visit with another investigational medication or current enrollment in another 
investigational drug protocol. 
20. Use of any prohibited medications (see Section 5.6.3) within 14 days or 5 half-lives 
(whichever is longer) of the baseline visit. 
21. Donation of blood within 6 weeks before screening or of plasma within 2 weeks before 
screening and unwillingness to forego further blood product donation during the study. 
22. Receipt of blood products within 2 months before screening. 
23. Subjects with a history of malignancy, except for the following adequately treated, 
nonmetastatic malignancies:  basal cell skin cancer not involving areas with vitiligo, 
squamous cell carcinomas of the skin not involving areas with vitiligo, or in situ cervical 
cancer. 
24. Subjects who anticipate receiving a live or live-attenuated vaccination from screening 
through the final follow-up visit. 
25. Subjects with known allergy or reaction to any component of the study formulation. 
26. Subjects who, in the opinion of the investigator, are unable or unlikely to comply with the 
administration schedule and study evaluations. 
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4. 
INVESTIGATIONAL PLAN 
4.1. 
Overall Study Design 
This is a 3-part, randomized, double-blind, and vehicle-controlled study in subjects with vitiligo 
who have depigmented areas including at least 0.5% of the total BSA on the face and at least 3% 
of the total BSA on nonfacial areas as determined by the palmar or handprint (palm plus 5 digits) 
method.  Approximately 150 subjects, aged 18 to 75 years, will be randomized to 1 of 4 dose 
strengths of INCB018424 cream (1.5% BID, 1.5% QD, 0.5% QD, 0.15% QD) or vehicle in a 
1:1:1:1:1 ratio and stratified by age (≤ 30 or > 30 years).  
Subjects will receive blinded treatment for up to 52 weeks to examine efficacy, safety, and 
tolerability.  The 3 parts of the study include a 24-week, double-blind, vehicle-controlled 
treatment period; a 28-week, continued, double-blind treatment period; and a 104-week, 
open-label extension period (see Figure 1).  The primary endpoint of F-VASI50 will be 
evaluated at Week 24.  After completion of the Week 24 assessments, subjects randomized to 
vehicle will be randomized to 1 of the 3 higher active treatment groups in a 1:1:1 ratio while 
maintaining the blind.  Subjects in the 0.15% QD dose group who do not achieve a ≥ 25% 
improvement from baseline on F-VASI (nonresponders of F-VASI25) will be re-randomized to 
1 of the 3 higher active treatment groups while maintaining the blind.  Subjects randomized to 
INCB018424 0.15% QD who achieve a ≥ 25% improvement from baseline on F-VASI will 
remain on the same dose until Week 52.  Subjects randomized to INCB018424 1.5% BID, 
1.5% QD, and 0.5% QD will remain on the same dose until Week 52. 
At any time during the study, if a subject has expansion of existing areas of depigmentation or 
development of new areas of depigmentation, then after a visit to document the VASI score and 
other measures of vitiligo, subjects are to apply study drug to those areas that are new or 
expanded since baseline in addition to areas treated since baseline as long as the total BSA to be 
treated does not exceed 20%.  This visit may be unscheduled. 
After completion of the Week 52 assessments, subjects who continue to be eligible for the study 
will be offered the opportunity to receive an additional 104 weeks of open-label treatment with 
INCB018424 1.5% cream BID.  To be eligible, subjects must have completed the baseline, 
Week 24, and Week 52 visit assessments, be compliant with study medication, have no clinically 
significant changes in laboratory parameters from baseline (must meet entry criteria regarding 
cytopenias and liver assessments) and, in the opinion of the investigator, have no safety concerns 
regarding the previous 52 weeks of treatment with INCB018424 cream.  In the open-label 
extension, subjects may be offered low-dose narrow band-UVB phototherapy in addition to 
INCB018424 cream in consultation with the investigator and sponsor. 
Subjects who are eligible for the open-label extension who have complete facial repigmentation 
(F-PhGVA score of 0) may stop applying study drug to the face, decrease the application rate to 
QD, or continue BID based on investigator judgement at Weeks 52 and 80 (after Week 80, 
subjects may also be permitted to modify their treatment regimen after the investigator has 
consulted with the sponsor).  Subjects may continue to apply INCB018424 1.5% QD or BID to 
areas of vitiligo on the body; dose will be determined by the investigator based on level of 
repigmentation.  A subject who had decreased the dose to QD or stopped applying INCB018424 
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to the face who has a loss of pigmentation on the face (F-PhGVA of at least 1) may increase the 
dose from QD to BID or restart application of INCB018424 1.5% BID after a visit to document 
the F-VASI score and other measures of vitiligo. 
Sites will remain blinded to study drug, but some personnel at Incyte without direct contact with 
sites will be unblinded for the interim analyses.  This internal committee will be charged with 
evaluating the unblinded interim analysis results (when at least 50% subjects first have Week 12 
and then Week 24 data available).  As full repigmentation is anticipated to be a slow process, the 
interim analysis results will determine preliminary efficacy of the treatment groups for future 
study and planning.  After Week 24, the members of the primary endpoint assessment team from 
Incyte will be unblinded. 
If any other skin products that are permitted under the study Protocol are used, subjects should 
continue these unchanged during the study. 
Figure 1: 
Study Design Schema 
 
4.2. 
Measures Taken To Avoid Bias 
This is a randomized, placebo-controlled study with a 52-week double-blind period.  Subjects 
will be randomized to 1 of 5 dose groups at baseline.  After completion of the Week 24 
assessments, subjects randomized to vehicle will be randomized to 1 of the 3 higher active 
treatment groups while maintaining the blind.  Subjects in the 0.15% QD dose group who do not 
achieve a ≥ 25% improvement from baseline on F-VASI (nonresponders of F VASI25) will be 
re-randomized to 1 of the 3 higher active treatment groups while maintaining the blind.  Subjects 
randomized to INCB018424 0.15% QD who achieve a ≥ 25% improvement from baseline on 
F-VASI will remain on the same dose until Week 52.  Subjects randomized to 
INCB018424 1.5% BID, 1.5% QD, and 0.5% QD will remain on the same dose until Week 52. 
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4.3. 
Number of Subjects 
The study will enroll approximately 150 subjects randomized equally to 1 of 5 treatment groups. 
4.4. 
Duration of Treatment and Subject Participation 
Screening is up to 28 days (4 weeks), the double-blind, vehicle-controlled, treatment period is 
24 weeks, the continued double-blind treatment period is 28 weeks (52 weeks cumulative 
double-blind), the optional open-label extension treatment is 104 weeks, and safety follow-up is 
24 weeks.  Total duration is up to 184 weeks. 
4.5. 
Overall Study Duration 
The study begins when the first subject signs the ICF.  The end of the study will occur when all 
subjects have discontinued study drug and have completed applicable follow-up assessments. 
4.6. 
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 decision.  If the study 
is terminated prematurely, then the sponsor will notify the investigators, the IRBs and IECs, and 
regulatory bodies of the decision and reason for termination of the study. 
5. 
TREATMENT 
5.1. 
Treatment Assignment 
5.1.1. 
Subject Numbering and Treatment Assignment 
The study will use an IRT for management of study enrollment.  The system will assign the 
subject study number, track subject visits, randomize according to the defined parameters, 
maintain the blinding, and manage of study drug inventory. 
5.1.2. 
Randomization and Blinding 
For subjects who have met all study entry criteria and none of the exclusion criteria, the IRT 
should be contacted at baseline to obtain the study drug assignment.  The system will assign the 
subject study number, track subject visits, randomize according to the defined parameters, and 
maintain the blind.  The system will employ a configurable stratification algorithm with limits 
set to subject age (≤ 30 and > 30 years).  Subjects will be randomized to 1 of 4 dose strengths of 
INCB018424 cream (1.5% BID, 1.5% QD, 0.5% QD, 0.15% QD) or vehicle in a 1:1:1:1:1 ratio.  
If any of the limits are reached, then the IRT will stop assigning randomization numbers to that 
group, and no additional subjects will be enrolled in that group.  Subjects, investigators, and the 
sponsor (with the exception of members of the interim analysis and primary endpoint analysis 
assessment teams) will remain blinded to each subject's treatment assignment throughout the 
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study.  Emergency unblinding will occur if an AE requires the investigator to be made aware of 
the subject's treatment assignment (see emergency unblinding procedures in Section 8.4 and refer 
to the Study Reference Manual). 
5.2. 
INCB018424 Cream or Matching Vehicle 
5.2.1. 
Description and Administration 
INCB018424 cream or matching vehicle will be applied as a thin film BID, with applications at 
least 8 hours apart.  The dose strengths for INCB018424 cream are 1.5%, 0.5%, and 0.15% (w/w 
free base equivalent) in a cream formulation along with the matching vehicle cream formulation 
containing only the vehicle. 
Study drug will be applied in the clinic on the day of a study visit.  The application regimen is to 
be determined by weighing a tube before and after the subject applies a thin film of study drug to 
the affected areas.  For the determination of dosage, subjects should remove study drug from the 
tube in fingertip units until all of the areas to be treated are covered by a thin film.  On the day of 
a visit, subjects should not apply the study drug at home and will apply the morning dose of 
study drug from the new kit in the clinic.  If a subject has vitiligo present on more than 20% of 
BSA, the application of study drug will be limited to ≤ 20% of the subject's total BSA.  Subjects 
will be advised to limit use to no more than 1 tube per application.  Application instructions will 
be provided at study visits and via a diary card given to the subjects. 
At each visit, an estimate of the percent BSA to be treated will be used by the IRT system to 
calculate the number of tubes of study drug to be dispensed.  All areas identified at baseline 
should continue to be treated through the end of the double-blind period (Week 52) unless the 
subject meets criteria for stopping study drug because of an AE.  If there are new areas to be 
treated, including expansion of existing areas or development of new areas, study drug should be 
applied to these areas in addition to the areas treated at baseline (up to 20% BSA), and the 
percentage of BSA to be treated will be recalculated and increased.  This new estimate will be 
entered into the IRT system to calculate the number of tubes of study drug to be dispensed. 
5.2.2. 
Supply, Packaging, and Labeling 
INCB018424 drug product will be provided as INCB018424 cream 1.5% (w/w free base 
equivalent), INCB018424 cream 0.5%, INCB018424 cream 0.15%, or vehicle packaged as 
15 g per tube.  Tubes will include labeling for morning or for evening application. 
All Incyte investigational product labels will be in the local language and will comply with the 
legal requirements of each participating country. 
5.2.3. 
Storage 
The INCB018424 drug product and vehicle cream should be stored at room temperature between 
15°C and 30°C (59°F and 86°F). 
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5.3. 
Treatment Compliance 
Compliance will be assessed by the site by reviewing the subject diaries and by weighing the 
study drug tubes.  Subjects will also be questioned regarding study drug application technique, 
missed doses, and use of any additional topical or systemic prescriptions of other products or 
over-the-counter products.  Starting at the Day 1 visit and each visit thereafter, a diary will be 
given to each subject in order to record the use of the study drug.  The completed diary will be 
collected during each visit.  Qualified clinical staff will review the subjects' entries for 
compliance.  Subjects who are noncompliant with study drug (defined as nonuse of study drug 
BID as determined by the diary and < 70% or > 130% compliant based on expected application 
regimen and weight of study drug tubes) will have their administration instructions reinforced by 
the investigator or a qualified designee.  Subjects will be considered compliant with the 
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treatment regimen if they apply at least 70% but no more than 130% of the expected applications 
during participation in the treatment phase of the study.  Subjects who are noncompliant on more 
than 1 occasion will be reinstructed by the investigator or a qualified designee, and the sponsor 
should be consulted by the investigator for instruction on the proper handling of the subject.  
Refer to the Study Reference Manual for additional compliance assessment details. 
5.4. 
Treatment Interruptions and Adjustments 
5.4.1. 
Dose Modifications 
During the study, if the subject develops new areas of vitiligo or has an expansion of existing 
areas of vitiligo, subjects are permitted to apply study drug to the additional areas after a visit to 
document the F-VASI score and other measures of vitiligo (may be unscheduled visit), as long as 
the total treated areas do not exceed 20% BSA. 
Subjects who are eligible for the open-label extension who have complete facial repigmentation 
(F-PhGVA score of clear) may stop applying study drug to the face, decrease the application rate 
to QD, or continue BID, based on investigator judgement, at Weeks 52 and 80.  Subjects who 
have complete facial repigmentation that is first observed after Week 80 may also be permitted 
to modify their treatment regimen after the investigator has consulted with the sponsor about 
potentially modifying the subject's treatment regimen.  Subjects may continue to apply 
INCB018424 1.5% QD or BID to areas of vitiligo on the body; dose will be determined by the 
investigator based on level of repigmentation.  A subject who had decreased the dose to QD or 
stopped applying INCB018424 cream to the face who has a loss of pigmentation on the face 
(F-PhGVA of at least 1) may increase the dose from QD to BID or restart application of 
INCB018424 1.5% BID after a visit to document the F-VASI score and other measures of 
vitiligo. 
5.4.2. 
Criteria and Procedures for Dose Interruptions and Adjustments of Study Drug 
In some circumstances, it may be necessary to temporarily interrupt treatment as a result of AEs 
or laboratory abnormalities that may have an unclear relationship to study drug.  Except in cases 
of emergency, it is recommended that the investigator consult with the sponsor medical monitor 
(or other representative of the sponsor) before temporarily interrupting study drug.  Additionally, 
the investigator must obtain approval from the sponsor before restarting study drug that was 
temporarily interrupted because of an AE or laboratory abnormality. 
Individual subjects may have administration interrupted at the discretion of the investigator, in 
consultation with the sponsor, for AEs or laboratory abnormalities until these have resolved.  
Subjects MUST have administration interrupted in the following situations. 
• The subject develops a Grade 2 increase in ALT (> 3 × ULN) or AST (> 3 × ULN); a 
Grade 2 decrease in ANC (< 1.5 × 109/L) or platelets (< 75 × 109/L); or a Grade 3 
decrease in absolute lymphocyte count (< 0.5 × 109/L).  Laboratory abnormalities 
should be confirmed with repeat testing within 48 hours whenever possible and 
expedited delivery of the laboratory results requested. 
• The subject develops a Grade 3 or higher laboratory abnormality, with the exceptions 
of lipase (in which case a Grade 4, > 5 × ULN, results in discontinuation of study 
medication) or any asymptomatic triglyceride, cholesterol, or amylase elevations.  
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Laboratory abnormalities should be confirmed with repeat testing within a medically 
indicated timeframe, based upon the investigator's judgment and in collaboration with 
the sponsor's medical monitor, and expedited delivery of the laboratory results should 
be requested. 
• The subject had a Grade 3 or 4 drug-related AE as determined by the investigator. 
5.4.3. 
Criteria for Permanent Discontinuation of Study Drug 
Subjects who have administration interrupted based on above criteria will be followed until the 
parameters return to the normal range or to baseline values.  Laboratory evaluations can be 
repeated as frequently as daily.  A subject who has had their dose interrupted based on these 
criteria may resume administration with study drug at a later time if the subject no longer meets 
the criteria for interrupting the dose with the sponsor's approval in consultation with the 
investigator.  Subjects who meet withdrawal criteria (see Section 5.5.1) during study drug 
interruption will be withdrawn from the study and may not resume administration. 
5.4.4. 
Criteria and Procedures for Dose Increases of Study Drug 
A subject who had decreased the dose to QD or stopped applying INCB018424 cream to the face 
at Weeks 52 or 80 (or after Week 80; see Section 5.4.1) who subsequently has a loss of 
pigmentation on the face (F-PhGVA of at least 1) may increase the dose from QD to BID or 
restart application of INCB018424 1.5% BID after a visit to document the F-VASI score and 
other measures of vitiligo. 
5.5. 
Withdrawal of Subjects From Study Treatment 
5.5.1. 
Withdrawal Criteria 
Subjects must be withdrawn from study treatment for the following reasons: 
• The subject becomes pregnant. 
• Consent is withdrawn. 
• Further participation would be injurious to the subject's health or well-being, in the 
investigator's medical judgment. 
• The study is terminated by the sponsor. 
• The study is terminated by the local health authority, IRB, or IEC. 
A subject may be discontinued from study treatment as follows: 
• If, during the course of the study, a subject is found not to have met eligibility 
criteria, then the medical monitor, in collaboration with the investigator, will 
determine whether the subject should be withdrawn from the study. 
• If a subject is noncompliant with study procedures or study drug administration in the 
investigator's opinion, then the sponsor should be consulted for instruction on 
handling the subject. 
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5.5.2. 
Withdrawal Procedures 
In the event that the decision is made to permanently discontinue the study drug, the subject will 
be withdrawn from the study, and the EOT visit should be conducted.  Reasonable efforts should 
be made to have the subject return for a follow-up visit.  These visits are described in Section 6.  
The last date of the last dose of study drug and the reason for subject withdrawal will be recorded 
in the eCRF. 
If a subject is withdrawn from the study: 
• The study monitor or sponsor must be notified. 
• The reason(s) for withdrawal must be documented in the subject's medical record and 
in the eCRF. 
• The EOT visit should be performed. 
• The date of the EOT visit should be recorded in the IRT. 
• Subjects must be followed for safety until the time of the follow-up visit or until 
study drug–related toxicities resolve, return to baseline, or are deemed irreversible, 
whichever is longest. 
If the subject 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, subjects will have the option of withdrawing consent for study treatment 
but continuing in the follow-up period of the study for safety/efficacy assessments. 
5.6. 
Concomitant Medications 
All concomitant medications and treatments must be recorded in the eCRF and ideally should 
remain stable through the end of the treatment portion of the study.  All prior medications or 
treatments for vitiligo, all prior biologic medications, and any prior medications received up to 
30 days before randomization will be recorded in the eCRF.  Concomitant treatments and/or 
procedures that are required to manage a subject's medical condition during the study will also be 
recorded in the eCRF. 
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6. 
STUDY ASSESSMENTS 
All study assessments will be performed as indicated in the schedule of assessments (Table 2, 
Table 3, and Table 4), and all laboratory assessments will be performed as indicated in Table 5. 
 
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Table 2: 
Schedule of Assessments During the Double-Blind, Vehicle-Controlled Treatment Period (Through Week 24) 
Evaluation 
Section 
Screening 
Double-Blind Treatment 
Day -28 to 
-1 
Day 1 
Week 4  
± 3 d 
Week 8 
± 3 d 
Week 12 
 ± 3 d 
Week 18 
± 7 d 
Week 24 
± 7 d 
Administrative procedures 
Informed consent 
7.1 
X 
 
 
 
 
 
 
Contact IRT 
7.2 
X 
X 
X 
X 
X 
X 
X 
Inclusion/exclusion criteria 
3 
X 
X 
 
 
 
 
 
Demography 
7.3 
X 
 
 
 
 
 
 
Medical history 
7.3 
X 
 
 
 
 
 
 
Prior/concomitant medications 
7.4 
X 
X 
X 
X 
X 
X 
X 
Apply study drug 
5.2 
 
X 
X 
X 
X 
X 
X 
Study drug and diary card dispensed 
7.10.1 
 
X 
X 
X 
X 
X 
X 
Collect study drug tubes; collect and review 
diary cards 
5.3 
 
 
X 
X 
X 
X 
X 
Assess compliance 
5.3 
 
 
X 
X 
X 
X 
X 
Safety procedures/assessments 
Comprehensive physical examination
a 
7.5.2.1 
X 
 
 
 
 
 
X 
Targeted physical examination 
7.5.2.2 
 
X 
X 
X 
X 
X 
 
Vital signs 
7.5.3 
X 
X 
X 
X 
X 
X 
X 
Hematology and chemistry assessments 
7.5.5 
X 
X 
X 
X 
X 
X 
X 
Serology and thyroid testing 
7.5.5.5 
X 
 
 
 
 
 
 
Urinalysis 
7.5.5.3 
X 
 
 
 
 
 
 
FSH
b 
7.5.5.4 
X 
 
 
 
 
 
 
Pregnancy test
c 
7.5.5.4 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG 
7.5.4 
X 
 
 
 
 
 
 
Assess AEs 
7.5.1 
X 
X 
X 
X 
X 
X 
X 
Efficacy and other assessments 
VASI (face and total body) 
7.6.1 
X 
X 
X 
X 
X 
X 
X 
BSA (face and total body) 
7.6.2 
X 
X 
X 
X 
X 
X 
X 
VETF 
7.6.3 
X 
X 
X 
X 
X 
X 
X 
Physician – PhGVA (face and total body) 
7.6.4 
 
X 
 
 
X 
 
X 
Patient – PaGVA (face and total body) 
7.6.5 
 
X 
 
 
X 
 
X 
PaGIC-V 
7.6.6 
 
 
 
 
X 
 
X 
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Table 2: 
Schedule of Assessments During the Double-Blind, Vehicle-Controlled Treatment Period (Through Week 24) 
(Continued) 
Evaluation 
Section 
Screening 
Double-Blind Treatment 
Day -28 to 
-1 
Day 1 
Week 4  
± 3 d 
Week 8 
± 3 d 
Week 12 
 ± 3 d 
Week 18 
± 7 d 
Week 24 
± 7 d 
a Height and weight at screening only. 
b Serum FSH to be performed for all postmenopausal women only (defined by last menstrual period > 12 months before screening and confirmation by FSH in the postmenopausal 
range). 
c All women will have a serum pregnancy test conducted at the screening visit and urine pregnancy tests conducted at all other visits (including baseline). 
 
 
 
 
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Table 4: 
Schedule of Assessments for the Open-Label Extension Period (Weeks 52 Through 156) 
Evaluation 
Section 
Open-Label Extension Period  
Follow-Up 
Week 52 
± 7 d 
Week 56 
± 7 d 
Week 68 
± 7 d 
Week 80 
± 7 d 
Weeks 92 
and 104  
± 7 d 
Weeks 116, 
128, 140 
± 7 d 
Week 156 
ET/EOT 
± 7 d 
Months 1 
and 3 
± 7 d 
Month 6 
EOS 
± 7 d 
Administrative procedures 
Contact IRT 
7.2 
 
X 
X 
X 
X 
X 
X 
X 
X 
Prior/concomitant medications 
7.4 
 
X 
X 
X 
X 
X 
X 
X 
X 
Apply study drug 
5.2 
X 
X 
X 
X 
X 
X 
 
 
 
Study drug and diary card dispensed 
7.10.1 
X 
X 
X 
X 
X 
X 
 
 
 
Collect study drug tubes; collect and 
review diary cards 
5.3 
 
X 
X 
X 
X 
X 
X 
 
 
Assess compliance 
5.3 
 
X 
X 
X 
X 
X 
X 
 
 
Safety procedures/assessments 
Comprehensive physical examination  
7.5.2.1 
 
 
 
 
 
 
X 
 
 
Targeted physical examination 
7.5.2.2 
 
X 
X 
X 
X 
X 
 
X 
X 
Vital signs 
7.5.3 
 
X 
X 
X 
X 
X 
X 
X 
X 
Hematology and chemistry assessments 
7.5.5 
 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysis 
7.5.5.3 
 
 
 
 
 
 
X 
 
 
Pregnancy test
a 
7.5.5.4 
 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG 
7.5.4 
 
 
 
 
 
 
X 
 
 
Assess AEs 
7.5.1 
 
X 
X 
X 
X 
X 
X 
X 
X 
Efficacy and other assessments 
VASI (face and total body) 
7.6.1 
 
X 
X 
X 
X 
X 
X 
X 
X 
BSA (face and total body) 
7.6.2 
 
X 
X 
X 
X 
X 
X 
X 
X 
VETF 
7.6.3 
 
X 
X 
X 
X 
 
 
 
 
Physician - PhGVA (face and total body) 
7.6.4 
 
 
X 
X 
X 
X 
X 
 
X 
Patient - PaGVA (face and total body) 
7.6.5 
 
 
X 
X 
X 
X 
X 
 
X 
PaGIC-V 
7.6.6 
 
 
X 
X 
X 
X 
X 
 
X 
a All women will have a urine pregnancy test conducted at all visits in this portion of the study. 
 
 
 
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Table 5: 
Clinical Laboratory Assessments 
Serum Chemistries
a 
Hematology 
Albumin 
Alkaline phosphatase 
ALT 
AST 
Bicarbonate 
Blood urea nitrogen 
Calcium 
Chloride 
Creatinine 
Glucose 
Lactate dehydrogenase 
Phosphorus 
Potassium 
Sodium 
Total bilirubin 
Total serum protein 
Hematocrit 
Hemoglobin 
Mean corpuscular volume 
Platelet count 
Red blood cell count 
Reticulocyte count 
White blood cell count 
White blood cell differential  (5 part): 
• Basophils 
• Eosinophils 
• Lymphocytes 
• Monocytes 
• Neutrophils 
Other 
Serology 
Urinalysis 
Urine pregnancy test (at site) 
Serum pregnancy test 
FSH 
Free T4 
TSH 
Hepatitis B surface antigen 
Hepatitis B core antibody 
Hepatitis B core IgM antibody 
Hepatitis C virus antibody 
HCV-RNA (only performed if antibody positive) 
HIV 
a All serum chemistries will be performed on samples collected without respect to food intake (ie, nonfasting). 
6.1. 
Screening 
Screening is the interval between the signing of the ICF and the day that the subject is 
randomized in the study.  Informed consent must be obtained before performing any 
study-specific procedures.  Assessments that are required to demonstrate eligibility may be 
performed over the course of 1 or more days during screening. 
Results from the screening evaluations will be reviewed to confirm subject eligibility before 
randomization and administration of study drug.  Tests with results that fail eligibility 
requirements may be repeated once during screening if the investigator believes the results to be 
in error.  Additionally, a subject who fails screening may repeat the screening process 1 time if 
the investigator believes that there has been a change in eligibility status (eg, following recovery 
from an infection). 
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6.2. 
Baseline 
The results from the screening evaluations will be reviewed to determine whether the subject 
continues to meet the eligibility requirements as specified in the Protocol. 
Subjects who have signed the ICF and meet all the entry criteria (see Section 3) may be 
randomized in the study. 
6.3. 
Treatment 
For subjects who are randomized and administered study drug on Day 1, the dates for subsequent 
study visits will be determined based on this day and should occur within the visit windows 
outlined in the schedule of assessments (Table 2, Table 3, and Table 4). 
The treatment period begins when the subject receives their first dose of study drug on Day 1, 
which will be administered in the clinic.  Tubes of INCB018424 cream or vehicle cream will be 
dispensed to subjects with detailed application instructions. 
After completion of the Week 24 assessments in the double-blind, vehicle-controlled portion of 
the study, treatment assignment will not be unblinded.  The members of the primary endpoint 
assessment team from Incyte will be unblinded, however. 
Subjects randomized to vehicle will be randomized to 1 of the 3 higher active treatment groups 
while maintaining the blind.  Subjects in the 0.15% QD dose group who do not achieve a ≥ 25% 
improvement from baseline on F-VASI (nonresponders of F-VASI25) will be re-randomized to 
1 of the 3 higher active treatment groups while maintaining the blind.  Subjects randomized to 
INCB018424 0.15% QD who achieve a ≥ 25% improvement from baseline on F-VASI will 
remain on the same dose until Week 52.  Subjects randomized to INCB018424 1.5% BID, 1.5% 
QD, and 0.5% QD will remain on the same dose until Week 52. 
Any increase or new areas of vitiligo may be treated, as long as the additional percent BSA is 
documented in the eCRF and the total BSA treated does not exceed 20%. 
After completion of the Week 52 assessments, subjects who continue to be eligible for the study 
will be offered the opportunity to receive an additional 104 weeks of open-label treatment with 
INCB018424 1.5% cream BID. 
If a decision is made that the subject will permanently discontinue study drug, then the EOT visit 
should be conducted.  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.  The subject should be encouraged to return for the follow-up visits. 
6.4. 
Follow-Up 
Subjects will have follow-up assessments 1, 3, and 6 months after the last application of study 
drug.  Although subjects will be asked not to apply any other medications for vitiligo during the 
follow-up period, if prohibited treatment for vitiligo is started, then an earlier follow-up visit may 
be performed.  A final EOS visit should be performed, ideally no earlier than 30 days after the 
last dose of study drug.  Adverse events and SAEs must be reported up until at least 30 days after 
the last dose of study drug, the date of the follow-up visit, or until toxicities resolve, return to 
baseline, or are deemed irreversible, whichever is longest.  Reasonable efforts should be made to 
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have the subject return for the follow-up visits and report any AEs that may occur during this 
phase. 
6.5. 
Unscheduled Visits 
Unscheduled study visits may occur at any time medically warranted.  Any assessments 
performed at those visits should be recorded in the eCRF.  If there is worsening of vitiligo at an 
unscheduled visit, then an F-VASI score, T-VASI score, and 
 
new areas of vitiligo, and then treatment of such areas may begin if the total 
affected treatment area is less than 20%. 
6.6. 
Early Termination 
In the event that any subject discontinues the study drug and subsequently the study before 
completion, regardless of reason, reasonable efforts should be made to have the subject return for 
an ET visit and have the EOT procedures completed as noted in Table 3 and Table 4. 
Subjects who are noncompliant with study drug (defined as not documenting diary BID use and 
< 70% or > 130% compliant based on prescribed application regimen and weight of study drug 
tubes) will have the administration instructions reinforced by the investigator or a qualified 
designee.  After reinforcement, subjects who again fail to meet 70% or 130% compliance 
benchmarks in a subsequent visit will be considered for withdrawal from the study.  In such 
cases, the sponsor should be consulted by the investigator for instruction on the proper handling 
the subject before withdrawal. 
7. 
CONDUCT OF STUDY ASSESSMENTS AND PROCEDURES 
7.1. 
Administration of Informed Consent Form 
Valid informed consent must be obtained from the study subject before conducting any 
study-specific procedures using an ICF approved by the local IRB/IEC that contains all elements 
required by ICH E6 and describes the nature, scope, and possible consequences of the study in a 
form understandable to the study subject.  Local and institutional guidelines for ICF content and 
administration must be followed; the original signed ICF must be retained by the investigator, 
and a copy of the signed ICF must be provided to the study subject.  The informed consent 
process for each subject must be documented in writing within the subject source documentation. 
7.2. 
Interactive Response Technology Procedure 
The IRT will be contacted to obtain a subject ID number when a subject enters screening.  Upon 
determining that the subject is eligible for study entry, the IRT will be contacted to obtain the 
treatment assignment.  Additionally, the IRT will be contacted at each regular study visit to 
update the study drug supply.  See Section 5.1.1 for details on subject numbering and treatment 
assignment. 
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7.3. 
Demography and Medical History 
7.3.1. 
Demographics and General Medical History 
Demographic data and general medical history will be collected at screening. 
7.3.2. 
Disease Characteristics and Treatment History 
A disease-targeted medical and medication history will be collected at screening. 
7.4. 
Prior and Concomitant Medications and Procedures 
Prior and concomitant medications and procedures will be reviewed to determine subject 
eligibility.  All concomitant medications and measures must be recorded in the eCRF, and any 
medication received or procedure performed within 30 days before randomization and up to the 
EOS will be recorded in the eCRF.  The medication record will be maintained after signing the 
ICF to document concomitant medications, including any changes to the dose or regimen.  
Concomitant medications include any prescription, over-the-counter, or natural/herbal 
preparations taken or administered during the study period.  Concomitant treatments and/or 
procedures that are required to manage a subject's medical condition during the study will also be 
recorded in the eCRF. 
7.5. 
Safety Assessments 
7.5.1. 
Adverse Events 
Adverse events will be monitored from the time the subject signs the ICF.  Subjects will be 
instructed to report all AEs during the study and will be assessed for the occurrence of AEs 
throughout the study.  In order to avoid bias in eliciting AEs, subjects will be asked general, 
nonleading questions such as "How are you feeling?"  All AEs (serious and nonserious) must be 
recorded on the source documents and eCRFs regardless of the assumption of a causal 
relationship with the study drug.  The definition, reporting, and recording requirements for AEs 
are described in Section 8. 
7.5.2. 
Physical Examinations 
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. 
Clinically notable abnormalities that are considered clinically significant in the judgement of the 
investigator are to be reported as AEs. 
7.5.2.1. 
Comprehensive Physical Examination 
The comprehensive physical examination will include height and body weight (at screening) and 
assessment(s) of the following organ or body systems:  skin; head, eyes, ears, nose, and throat; 
thyroid; lungs; cardiovascular system; abdomen (liver, spleen); extremities; and lymph nodes; as 
well as a brief neurological examination. 
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7.5.2.2. 
Targeted Physical Examination 
The targeted physical examination will be a symptom-directed evaluation.  The targeted physical 
examination will include body weight and assessment(s) of the body systems or organs, as 
indicated by subject symptoms, AEs, or other findings. 
7.5.3. 
Vital Signs 
Vital sign measurements will include blood pressure, pulse, respiratory rate, and body 
temperature.  Blood pressure and pulse will be taken with the subject in the recumbent, 
semirecumbent, or sitting position after 5 minutes of rest.  Clinically notable abnormalities that 
are considered clinically significant in the judgment of the investigator are to be reported as AEs. 
7.5.4. 
Electrocardiograms 
All 12-lead ECGs will be performed with the subject in a recumbent or semirecumbent position 
after 5 minutes of rest. 
Interpretation of the 12-lead ECG will be used to determine eligibility at screening.  An 
additional ECG will be performed at the EOT visit (Week 52, Week 156, or if the subject 
discontinues treatment).  Throughout the study, a 12-lead ECG may be conducted if associated 
with an AE or other signs or symptoms. 
7.5.5. 
Laboratory Assessments 
Clinical laboratory tests will be performed using a central laboratory, with the exception of urine 
pregnancy tests.  A detailed description of the procedures for sampling, handling, storage, and 
shipment of the central laboratory samples and all material such as test tubes and labels is 
provided in the central Laboratory Manual.  If unscheduled local laboratory tests are performed 
and those results lead to a dose modification, delay, or dose interruption, or if any additional 
non-Protocol–required test is performed because of an AE, then those results and the normal 
reference ranges for those analytes must be documented in the eCRF.  Otherwise, unscheduled 
local laboratory test results do not need to be entered in the eCRF. 
Tests required at each visit are shown in Table 2, Table 3, and Table 4.  Additional analytes may 
be requested based on emerging data, if indicated for safety of study subjects.  In addition, some 
subjects may receive additional assessments as medically indicated; results of nonrequired tests 
may also be entered in the eCRF. 
7.5.5.1. 
Chemistry 
A panel of standard serum chemistries will be analyzed at times shown in Table 2, Table 3, and 
Table 4.  A list of required analytes is found in Table 5.  All serum chemistries will be performed 
from blood samples collected without respect to food intake (ie, nonfasted). 
7.5.5.2. 
Hematology 
Hematology tests will be performed at each study visit indicated in Table 2, Table 3, and 
Table 4.  A list of required analytes for scheduled visits is provided in Table 5. 
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7.5.5.3. 
Urinalysis 
Urinalysis will be performed by a central laboratory at screening and EOT (Week 52, Week 156, 
or if the subject discontinues treatment, see Table 2, Table 3, and Table 4). 
7.5.5.4. 
Pregnancy Testing 
Pregnancy testing will be performed on all female subjects as noted in the schedules of 
assessments (Table 2, Table 3, and Table 4).  Serum pregnancy test will be obtained at screening.  
A urine pregnancy test will be obtained all other visits.  A positive urine pregnancy test should 
be confirmed by a serum pregnancy test. 
7.5.5.5. 
Hepatitis and HIV Screening Tests 
Hepatitis and HIV tests shown in Table 5 will be conducted during the screening period.  If 
subjects are positive for active disease they should not be enrolled per exclusion criteria. 
7.6. 
Efficacy Assessments 
Efficacy assessments are conducted at the weeks noted in Table 2, Table 3, and Table 4. 
7.6.1. 
Vitiligo Area and Severity Index 
Areas affected by depigmentation due to vitiligo will be assessed using the VASI, which is a 
quantitative clinical tool that is analogous to the PASI used in psoriasis and 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. 
In this study, F-VASI will be determined.  F-VASI will be the percentage of depigmented 
vitiligo skin expressed as a percentage of BSA (hand unit) on the face and estimated by the 
investigator using the palmar or handprint (palm plus 5 digits) method.  This will be an 
additional variable to be analyzed in addition to the vitiligo head/neck subscore. 
The total body VASI is calculated using a formula that includes contributions from all body 
regions (possible range, 0-100). 
 
Briefly, the body is divided into the following 6 separate and mutually exclusive sites:  
head/neck, hands, upper extremities (excluding hands), trunk, lower extremities (excluding feet), 
and feet.  The percentage of vitiligo involvement is estimated in hand units by the same 
investigator during the entire course of the study.  Hand unit is based on subject’s hand size.  
Investigator uses his/her hand to mimic the subject’s hand size to evaluate % BSA vitiligo 
involvement.  The degree of depigmentation for each body site was determined and estimated to 
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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 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 2004, Dicle 2015).  See Appendix C for full 
assessment tool. 
7.6.2. 
Body Surface Area 
At each visit, the BSA affected with vitiligo for each of 4 regions (head/neck [H], upper limbs 
[UL], trunk [T], and lower limbs [LL]) as a percent of the total BSA, as well as the face 
separately (depigmented area as a percent of the total area of the face) will be determined to the 
nearest 0.1% using, as guides, the palm plus 5 digits, with fingers tucked together and thumb 
tucked to the side (handprint), as 1% BSA and the thumb as 0.1% BSA.  
If the subject has areas that exceed 20% that will not be treated with study drug, the BSA of 
these areas should be noted. 
If worsening of vitiligo is present, then new areas, expansion of existing areas, or both are noted 
as present since the prior visit. 
7.6.3. 
Vitiligo European Task Force Scale 
The VETF proposed a system that combines analysis of extent, stage of disease (staging), and 
disease progression (spreading).  Extent is evaluated using the rule of nines, already used in 
assessment of AD.  Staging is based on cutaneous and hair pigmentation in vitiligo patches, and 
the disease is staged 0 to 4 on the largest macule in each body region, except hands and feet, 
which are assessed separately and globally as 1 unique area. 
The staging scale is as follows: 
• Stage 0:  normal pigmentation (no depigmentation in area graded). 
• Stage 1:  incomplete pigmentation (including spotty depigmentation, trichrome, and 
homogeneous lighter pigmentation). 
• Stage 2:  complete depigmentation, a few white hairs do not change stage. 
• Stage 3:  partial hair whitening < 30%. 
• Stage 4:  complete hair whitening. 
"Spreading" in VETF includes a dynamic dimension, since rapidly progressive vitiligo needs 
urgent intervention to stabilize the disease.  The proposed grid allows scoring this dimension on 
a simple scale (+1:  progressive; 0:  stable; −1:  regressive). 
Spreading is assessed by combining Wood's lamp and electric light examinations in a dark room.  
Wood's lamp includes a magnifying lens to assess hairs, especially vellus hairs (Taïeb and 
Picardo 2007, Kawakami and Hashimoto 2011, Komen et al 2015). 
See Appendix D for the full assessment tool. 
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8. 
SAFETY MONITORING AND REPORTING 
8.1. 
Adverse Events 
8.1.1. 
Definitions 
For the purposes of this Protocol, an AE is defined as any untoward medical occurrence 
associated with the use of a drug in humans, whether or not considered drug related, that occurs 
after a subject provides informed consent.  Abnormal laboratory values or test results occurring 
after informed consent constitute AEs only if they induce clinical signs or symptoms, are 
considered clinically meaningful, require therapy (eg, hematologic abnormality that requires 
transfusion), or require changes in the study drug(s). 
8.1.2. 
Reporting 
Adverse events that begin or worsen after informed consent should be recorded on the Adverse 
Events form of the eCRF.  Conditions that were already present at the time of informed consent 
should be recorded on the Medical History form in the eCRF.  Monitoring for the occurrence of 
new AEs should be continued for at least 30 days after the last dose of study drug.  Adverse 
events (including laboratory abnormalities that constitute AEs) should be described using a 
diagnosis whenever possible rather than by individual underlying signs and symptoms.  When a 
clear diagnosis cannot be identified, each sign or symptom should be reported as a separate AE. 
The severity of AEs will be assessed using CTCAE v4.03 Grades 1 through 4.  The CTCAE 
v4.03 severity of Grade 5 will not be used; AEs resulting in death will be graded accordingly 
using Grades 1 through 4 and have the outcome noted as fatal.  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: 
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. 
The occurrence of AEs should be sought by nondirective questioning of the subject during the 
screening process after signing the ICF and at each visit during the study.  Adverse events may 
also be detected when they are volunteered by the subject during the screening process or 
between visits, or through physical examination, laboratory test, or other assessments.  To the 
extent possible, each AE should be evaluated to determine: 
• The severity grade (CTCAE Grade 1 to 4). 
• Whether there is at least a reasonable possibility that the AE is related to the study 
treatment:  suspected (yes) or not suspected (no). 
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• The start and end dates, unless unresolved at final follow-up. 
• The action taken with regard to study drug. 
• The event outcome (eg, not recovered/not resolved, recovered/resolved, 
recovering/resolving, recovered/resolved with sequelae, fatal, unknown). 
• The seriousness, as per SAE definition provided in Section 8.3.1. 
Unlike routine safety assessments, SAEs are monitored continuously and have special reporting 
requirements (see Section 8.3.2). 
All AEs should be treated appropriately.  If an AE is treated with a concomitant medication or 
nondrug therapy, this action should be recorded on Adverse Event form and the treatment should 
be specified on the Prior/Concomitant Medications or Procedures and Non-Drug Therapy form 
in the eCRF. 
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.  For example, 
2 separate AEs will be reported if a subject has Grade 1 diarrhea, meeting the definition of an AE 
that lasts for 3 days before worsening to a Grade 3 severity.  The Grade 1 event will be reported 
as an AE with a start date equal to the day the event met the Grade 1 AE definition and a stop 
date equal to the day that the event increased in severity from Grade 1 to Grade 3.  The Grade 3 
event will also be reported as an AE, with the start date equal to the day the event changed in 
intensity from Grade 1 to Grade 3 and a stop date equal to the day that the event either changed 
severity again or resolved. 
8.2. 
Laboratory Test Abnormalities 
Laboratory abnormalities that constitute an AE in their own right (considered clinically 
meaningful, induce clinical signs or symptoms, require concomitant therapy, or require changes 
in study drug) should be recorded on the Adverse Event form in the eCRF.  Whenever possible, a 
diagnosis rather than a symptom should be provided (eg, "anemia" instead of "low hemoglobin").  
Laboratory abnormalities that meet the criteria for AEs should be followed until they have 
returned to normal or an adequate explanation of the abnormality is found.  When an abnormal 
laboratory test result corresponds to a sign or symptom of a previously reported AE, it is not 
necessary to separately record the laboratory test result as an additional event. 
Laboratory abnormalities that do not meet the definition of an AE should not be reported as AEs.  
A Grade 3 or 4 (severe) AE does not automatically indicate an SAE unless it meets the definition 
of serious, as defined in Section 8.3.1.  A dose modification for the laboratory abnormality may 
be required (see Section 5.4) and should not contribute to the designation of a laboratory test 
abnormality as an SAE. 
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8.3. 
Serious Adverse Events 
8.3.1. 
Definitions 
An SAE is defined as an event that meets at least 1 of the following criteria: 
• Is fatal or life-threatening. 
• Requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is a result of: 
− A routine treatment or monitoring of the studied indication not associated with 
any deterioration in condition. 
− An elective surgery or preplanned treatment for a pre-existing condition that is 
unrelated to the indication under study and has not worsened since signing the 
ICF. 
− A treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE and not resulting in hospital admission. 
− Any social reasons and respite care, in the absence of any deterioration in the 
subject's general condition. 
• Results in persistent or significant disability, incapacity, or a substantial disruption of 
a person's ability to conduct normal life functions. 
• Constitutes a congenital anomaly or birth defect. 
• Is considered to be an important medical event or a medically significant 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 subject or may require medical or surgical intervention to prevent 
1 of the outcomes listed above. 
8.3.2. 
Reporting 
Every SAE, regardless of suspected causality (eg, relationship to study drug(s) or study 
procedure or disease progression), occurring after the subject has signed the ICF through the last 
study visit (or 30 days after the last dose of study drug, whichever is later) must be reported to 
the sponsor (or designee) within 24 hours of learning of its occurrence, unless otherwise 
specified by the Protocol.  Any SAEs occurring more than 30 days after the last dose of study 
drug should be reported to the sponsor or its designee only if the investigator suspects a causal 
relationship to the study drug.  Information about all SAEs is collected and recorded on the 
Adverse Event form of the eCRF.  The investigator must assess and record the causal 
relationship of each SAE to the study treatment.  The investigator must also complete the Incyte 
Serious Adverse Event Report Form, in English, and send the completed and signed form to the 
sponsor or designee within 24 hours of becoming aware of the SAE.  The investigator must 
provide a causality assessment, that is, assess whether there is at least a reasonable possibility 
that the SAE is related to the study treatment:  suspected (yes) or not suspected (no).  Refer to the 
Incyte Reference Guide for Completing the Serious Adverse Event Report Form. 
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The contact information of the sponsor's study-specific representatives is listed in the 
investigator manual provided to each site.  The original copy of the SAE Report Form and the 
confirmation sheet must be kept at the study site. 
Investigational site personnel must report any new information regarding the SAE within 
24 hours of becoming aware of the information in the same manner that the initial SAE Report 
Form was sent.  Follow-up information is recorded on an amended or new SAE 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 
SAE 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 subject 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. 
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 (IN) to inform all investigators involved in any 
study with the same drug that this SAE has been reported.  Suspected Unexpected Serious 
Adverse Reactions (SUSARs) 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. 
8.4. 
Emergency Unblinding of Treatment Assignment 
The procedure for emergency unblinding is provided in the Study Reference Manual.  This 
option may be used ONLY if the subject's well-being requires the investigator to be aware of the 
subject's treatment assignment. 
The investigator has the primary right to break the blind of a subject and should try to contact the 
sponsor's (or its designee's) clinical research physician or medical monitor before unblinding a 
subject's treatment assignment; however, this is not mandatory.  If a subject's treatment 
assignment is unblinded, then the sponsor or its designee must be notified immediately by 
telephone. 
If an investigator, site personnel performing assessments, or subject is unblinded, then the 
subject must be withdrawn from the study treatment.  In cases where there are ethical reasons to 
have the subject remain in the study, then the investigator must obtain specific approval from the 
sponsor's (or its designee's) clinical research physician or medical monitor for the subject to 
continue in the study. 
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8.5. 
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 subject during maternal or paternal exposure to study drug, 
the following procedures should be followed in order to ensure subject safety: 
• The study drug must be discontinued immediately (female subjects only; see 
Section 5.4.2 for the maximum permitted duration of study drug interruption). 
• 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 and breastfeeding 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 must be recorded on the SAE report form and 
submitted to the sponsor or designee. 
8.6. 
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 INs.  Any important new safety 
information should be discussed with the subject during the study, as necessary.  If new 
significant risks are identified, they will be added to the ICF. 
8.7. 
Data Monitoring Committee 
No external data monitoring committee will be used; however, an internal data monitoring 
committee will examine the interim analysis. 
8.8. 
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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9.3.1. 
Primary Analysis 
The primary endpoint is proportion of subjects treated with INCB018424 cream who achieve a 
≥ 50% improvement from baseline in F-VASI score (F-VASI50) at Week 24 compared with 
subjects treated with vehicle.  The comparison of the primary endpoint will be performed for the 
superiority of either INCB018424 1.5% BID or INCB018424 1.5% QD versus vehicle (T11 and 
T21 in Figure 2) using the Bonferroni-Holm procedure at an overall 2-sided α = 0.05 level.  The 
tests on the primary endpoint will be used as a gatekeeper for 6 statistical tests on key secondary 
endpoints (see Figure 2). 
9.3.2. 
Secondary Analysis 
The key secondary endpoint includes 6 comparisons as visualized in Figure 2. 
• T31:  INCB018424 0.5% QD is superior to vehicle at Week 24 on F-VASI50. 
• T41:  INCB018424 0.15% QD is superior to vehicle at Week 24 on F-VASI50. 
• T12:  INCB018424 1.5% BID is superior to vehicle at Week 24 on F-PhGVA 
response. 
• T22:  INCB018424 1.5% QD is superior to vehicle at Week 24 on F-PhGVA 
response. 
• T13:  INCB018424 1.5% BID is superior to 0.5% QD at Week 52 on VASI-50. 
• T23:  INCB018424 1.5% QD is superior to 0.5% QD at Week 52 on VASI-50. 
The initial allocation of the overall significance level to Branch 1 (T12 and T22) and Branch 2 
(T31 and T41) is 0.025, respectively.  The weights of the level to be passed on if 1 hypothesis is 
rejected are specified in Figure 2. 
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Figure 2: 
Illustration of the Statistical Treatment Comparisons 
 
9.3.2.1. 
Tests in Branch 1 
The alternative hypotheses for T12 and T22 will be tested using the Bonferroni-Holm procedure 
at an overall 2-sided α = 0.025 level if the null hypotheses on primary endpoints are rejected. 
If both T12 and T22 are rejected, T13 and T23 will be tested using Bonferroni-Holm procedure 
with overall 2-sided α = 0.025 level. 
9.3.2.2. 
Tests in Branch 2 
T31 (superiority of INCB018424 0.5% QD compared with vehicle) and T41 (superiority of 
INCB018424 0.15% QD compared with vehicle), will be tested sequentially at a 2-sided 
α = 0.025 level if the null hypotheses on the primary endpoints are rejected. 
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9.4. 
Statistical Analyses 
9.4.1. 
Efficacy Analyses 
9.4.1.1. 
Efficacy Measures for Primary and Secondary Endpoints 
9.4.1.1.1. VASI50 and F-VASI50 
The VASI/F-VASI score is specified in Section 7.6.  The categorical variable VASI50 is defined 
to be equal to 1 for percentage improvement from baseline in VASI/F-VASI scores of 50 or 
greater and 0 for less than 50.  This definition is introduced for the purpose of identifying 
subjects who respond to the treatment (1 – responder, 0 – nonresponder). 
9.4.1.1.2. Physician's Global Vitiligo Assessment 
Vitiligo status will be assessed using a PGVA 5-point scale with (clear, almost clear, mild 
disease, moderate disease, and severe disease).  A PGVA response is defined as the subjects with 
clear or almost clear during the treatment periods.  This value will be reported for face and for 
overall (F-PhGVA and T-PhGVA, respectively). 
9.4.1.2. 
Primary Efficacy Analyses 
For the primary analysis, comparisons between each active group and vehicle based on 
F-VASI50 at Week 24 will be performed in the ITT population, with a logistic regression with 
treatment groups and stratification factor of baseline age.  Exact logistic regression (Mehta and 
Patel 1995) will be used for all of the comparisons if any of the dose levels has an expected cell 
count less than 5.  The proportions, along with unadjusted p-values and 95% confidence 
intervals, will be reported.  All nonresponders, as well as all subjects 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. 
9.4.1.3. 
Secondary Efficacy Analyses 
Secondary efficacy analyses will be conducted in the ITT population.  The key secondary 
endpoints, including F-PhGVA response at Week 24 and T-VASI50 at Week 52, will be 
analyzed using the similar logistic regression as specified in the primary analysis.  Unadjusted 
p-value will be reported, and the graphic approach will be used to control FWER.  There will be 
no adjustment for multiple comparisons for secondary endpoints besides key secondary 
endpoints. 
The secondary endpoints on F-PhGVA/T-PhGVA, PhGVA response, F-PaGVA/T-PaGVA, and 
F-VASI50/T-VASI50 at other postbaseline visits besides primary and key secondary endpoints 
will be summarized as categorical variables using descriptive statistics.  Mean, change from 
baseline, and percentage change from baseline in F-VASI/T-VASI scores will be summarized 
using descriptive statistics.  An Emax model will be fit for assessment of the dose response 
relationship on percentage change from baseline of F-VASI scores at Week 24, which will 
provide estimates of the maximum and minimum response levels, ED50 (the concentration 
where the response is the midpoint between the maximum and minimum), and the slope 
parameter.  The 5 dose levels of INCB018424 cream in the model fitting will be vehicle, 
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− 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. 
• Obtaining informed consent and ensuring that the study subjects' questions have been 
answered and the subjects fully understand study procedures: 
− Informed consent must be obtained before any study-related procedures are 
conducted, unless otherwise specified by the Protocol. 
− Informed consent must be obtained using the IRB/IEC-approved version in a 
language that is native and understandable to the subject.  A template will be 
provided by the sponsor or its designee.  The sponsor or its designee must review 
and acknowledge the site-specific changes to the ICF template.  The ICF must 
include a statement that the sponsor or its designee and regulatory authorities have 
direct access to subject records. 
• Obtaining approval from the IRB/IEC before the start of the study and for any 
changes to the clinical study Protocol, important Protocol deviations, routine updates, 
and safety information in accordance with institutional requirements and local law. 
− The investigator is responsible for ensuring that the safety reports provided by the 
sponsor are reviewed and processed in accordance with regulatory requirements 
and with the policies and procedures established by the IRB/IEC. 
• 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 subjects who have met the 
specified eligibility criteria. 
• Retaining records in accordance with all local, national, and regulatory laws, but for a 
minimum period of at least 2 years after the last marketing application approval in an 
ICH region and until there are no pending or contemplated marketing applications in 
an ICH region, or if not approved, 2 years after the termination of the test article for 
investigation to ensure the availability of study documentation should it become 
necessary for the sponsor or a regulatory authority to review. 
− The investigator must not destroy any records associated with the study without 
receiving approval from the sponsor.  The investigator must notify the sponsor or 
its designee in the event of accidental loss or destruction of any study records.  If 
the investigator leaves the institution where the study was conducted, the sponsor 
or its designee must be contacted to arrange alternative record storage options. 
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− All eCRF data entered by the site (including audit trail), as well as computer 
hardware and software (for accessing the data), will be maintained or made 
available at the site in compliance with applicable record retention regulations.  
The sponsor will retain the original eCRF data and audit trail. 
10.2. 
Accountability, Handling, and Disposal of Study Drug 
The investigator is responsible for drug accountability at the study site; however, some of the 
drug accountability duties may be assigned to an appropriate pharmacist or other designee.  
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 to the study site. 
• Inventory of study drug at the site. 
• Subject use of the study drug including unit counts from each supply dispensed. 
• Return of study drug to the investigator or designee by subjects. 
The investigational product must be used only in accordance with the Protocol.  The investigator 
will also maintain records adequately documenting that the subjects 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 subjects. 
Completed accountability records will be archived by the site.  The investigator or designee will 
be expected to collect and retain all used, unused, and partially used containers of study drug 
until verified by the study monitor (unless otherwise agreed to by the sponsor).  At the 
conclusion of the study, the investigator or designee will oversee shipment of any remaining 
study drug back to the sponsor or its designee for destruction according to institutional standard 
operating procedures.  If local procedures mandate on-site destruction of investigational supply, 
the site should (where local procedures allow) maintain the investigational supply until the study 
monitor inspects the accountability records in order to evaluate compliance and accuracy of 
accountability by the investigative site.  At sites where the study drug is destroyed before 
monitor inspection, the monitors rely on documentation of destruction per the site SOP. 
10.3. 
Data Management 
Data management will be performed in a validated database via an Electronic Data Capture 
(EDC) system.  All data entry, verification, and validation will be performed in accordance with 
the current standard operating procedures of the Data Management Department at the sponsor or 
its designee.  The database will be authorized for lock once all defined procedures are completed. 
The investigator will be provided with access to an EDC system so that an eCRF can be 
completed for each subject.  Entries made in the eCRF must be verifiable against source 
documents; if updates to the database are not possible, any discrepancies should be explained 
and documented.  The investigator will be responsible for reviewing all data and eCRF entries, 
and will sign and date the designated forms in each subject's eCRF, verifying that the 
information is true and correct.  The investigator is responsible for the review and approval of all 
query responses. 
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Protocol deviations will be identified and recorded in the Protocol Deviation form of 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. 
10.4. 
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. 
Subject names will not be supplied to the sponsor or its designee, if applicable.  Only the subject 
number and subject's initials (subject's initials will only be recorded if allowable by local 
regulations) will be recorded in the eCRF, where permitted; if the subject'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.  The subjects will be informed that representatives of 
the sponsor or its designee, IRB or IEC, or regulatory authorities may inspect their medical 
records to verify the information collected, and that all personal information made available for 
inspection will be handled in strictest confidence and in accordance with local data protection 
laws. 
10.5. 
Financial Disclosure 
Before study initiation, all clinical investigators participating in clinical studies subject to FDA 
Regulation Title 21 CFR Part 54 – Financial Disclosure by Clinical Investigators (ie, "covered 
studies") are required to submit a completed Clinical Investigator Financial Disclosure form that 
sufficiently details any financial interests and arrangements that apply.  For the purpose of this 
regulation, "clinical investigator" is defined as any investigator or sub investigator who is 
directly involved in the treatment or evaluation of research subjects, including the spouse and 
each dependent child of the clinical investigator or sub investigator.  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. 
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10.6. 
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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11. 
REFERENCES 
Alikhan A, Felsten LM, Daly M, Petronic-Rosic V. Vitiligo: a comprehensive overview Part I. 
Introduction, epidemiology, quality of life, diagnosis, differential diagnosis, associations, 
histopathology, etiology, and work-up. J Am Acad Dermatol 2011;65:473-491. 
Castanet J, Ortonne JP. Pathophysiology of vitiligo. Clin Dermatol 1997:15:845-851. 
Clinical Trial Facilitation Group (CTFG). Recommendations related to contraception and 
pregnancy testing in clinical trials. September 15, 2014. http://www.hma.eu/ctfg.html. Accessed 
November 23, 2106. 
Craiglow B, King BA. Tofacitinib citrate for the treatment of vitiligo. JAMA Dermatol 
2015;151:1110-1112. 
Dicle O. Assessment methods in vitiligo. Pigmentary Disorders 2015;2:160. 
DuBois J, Kempers S, Roberts J, et al.  A study of INCB018424 phosphate topical cream in 
subjects with alopecia areata – open-label treatment period. Oral presentation at the National 
Alopecia Areata Foundation Meeting, New York, NY, November 14-15, 2016. 
Grimes PE, Morris R, Avaniss-Aghajani E, Soriano T, Meraz M, Metzger A. Topical tacrolimus 
therapy for vitiligo: therapeutic responses and skin messenger RNA expression of 
proinflammatory cytokines. J Am Acad Dermatol 2004;51:52-61. 
Guerra L, Dellambra E, Brescia S, Raskovic D. Vitiligo: pathogenetic hypotheses and targets for 
current therapies. Curr Drug Metab 2010;11:451-467. 
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. 
INCB018424 Phosphate Cream Investigator's Brochure (IB). Wilmington, DE: Incyte 
Corporation. 
Kawakami T, Hashimoto T. Disease severity indexes and treatment evaluation criteria in vitiligo. 
Dermatol Res Pract 2011;2011:750342. 
Komen L, da Graça V, Wolkerstorfer A, de Rie MA, Terwee CB, van der Veen JP. Vitiligo Area 
Scoring Index and Vitiligo European Task Force assessment: reliable and responsive instruments 
to measure the degree of depigmentation in vitiligo. Br J Dermatol 2015;172:437-443. 
Le Poole IC, van den Wijngaard RM, Westerhof W, Das PK. Presence of T cells and 
macrophages in inflammatory vitiligo skin parallels melanocyte disappearance. Am J Pathol 
1996;148:1219-1228. 
Lotti T, Gori A, Zanieri F, Colucci R, Moretti S. Vitiligo: new and emerging treatments. 
Dermatol Ther 2008;21:110-117. 
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Mehta CR, Patel NR. Exact logistic regression: theory and examples. Stat Med 
1995;14:2143-2160. 
Mohammed GF, Gomaa AH, Al-Dhubaibi MS. Highlights in the pathogenesis of vitiligo. World 
J Clin Cases 2015;3:221-230. 
Taïeb A, Picardo M, VETF Members. The definition and assessment of vitiligo: a consensus 
report of the Vitiligo European Task Force. Pigment Cell Res 2007;20:27-35. 
van den Boorn JG, Konijnenberg D, Dellemijn TA, et al. Autoimmune destruction of skin 
melanocytes by perilesional T cells from vitiligo patients. J Invest Dermatol 
2009;129:2220-2232. 
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APPENDIX A. INFORMATION REGARDING EFFECTIVENESS OF 
CONTRACEPTIVE METHODS 
For Subjects Participating 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.  Such 
methods include: 
• Combined (estrogen and progestogen containing) hormonal contraception associated 
with inhibition of ovulation1 
− oral 
− intravaginal 
− transdermal 
• Progestogen-only hormonal contraception associated with inhibition of ovulation1 
− oral 
− injectable 
− implantable2 
• Intrauterine device (IUD)2 
• Intrauterine hormone-releasing system (IUS)2 
• Bilateral tubal occlusion2 
• Vasectomised partner2,3 
• Sexual abstinence4 
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 spermicide5 
• cap, diaphragm or sponge with spermicide5 
1  Hormonal contraception may be susceptible to interaction with the IMP, which may reduce the efficacy of the 
contraception method. 
2  Contraception methods that in the context of this guidance are considered to have low user dependency. 
3  Vasectomised partner is a highly effective method provided of avoiding pregnancy that partner is the sole sexual 
partner of the WOCBP trial participant and that the vasectomised partner has received medical assessment of the 
surgical success. 
4  In the context of this guidance, sexual abstinence is considered a highly effective method only if defined as 
refraining from heterosexual intercourse during the entire period of risk associated with the study treatments.  The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and the 
preferred and usual lifestyle of the subject. 
5 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:  CTFG 2014. 
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APPENDIX B. POTENT CYP3A4 INHIBITORS AND FLUCONAZOLE 
In clinical studies with CYP3A4 inhibitors, elevated levels of INCB018424 of approximately 
2-fold have been observed after oral administration.  Additionally, simulations using 
physiologically based PK models suggested that fluconazole (a dual CYP3A4 and CYP2C9 
inhibitor) increases steady-state ruxolitinib AUC by approximately 1- to 3-fold after oral 
administration.  Thus, these concomitant medications should not be taken by subjects beginning 
2 weeks or 5 half-lives (whichever is longer) before the first application of study drug until the 
last administration (either Week 24 or Week 52; however, topical use of these agents if the 
systemic bioavailability is low may be permitted on a case-by-case basis.  The following is a list 
of potent CYP3A4 inhibitors and fluconazole.  The sponsor should be contacted with any 
questions regarding concomitant medications that might be considered potent CYP3A4 inhibitors 
but are not on this list. 
• boceprevir 
• clarithromycin 
• cobicistat 
• conivaptan 
• danoprevir 
• elvitegravir 
• fluconazole 
• grapefruit juice 
• idelalisib 
• indinavir 
• itraconazole 
• ketoconazole 
• LCL161 
• lopinavir 
• mibefradil 
• nefazodone 
• nelfinavir 
• posaconazole 
• ritonavir 
• saquinavir 
• telaprevir 
• telithromycin 
• tipranavir 
• troleandomycin 
• voriconazole 
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APPENDIX C. VITILIGO AREA SEVERITY INDEX 
VASI Score range (0 - 100).  Degree of depigmentation scale: 
1.00 (100%) - Complete depigmentation, no pigment is present. 
0.90 (90%) - Specks of pigment present. 
0.75 (75%) - Depigmented area exceeds the pigmented area. 
0.50 (50%) - Pigmented and depigmented areas are equal. 
0.25 (25%) - Pigmented area exceeds depigmented area. 
0.10 (10%) - Only specks of depigmentation present. 
0.0 (0%) - No depigmentation present. 
 
A 
B 
A*B 
Location 
Area involved 
(in hand prints) 
Degree of 
depigmentation 
Total Handprint Units 
Hands 
 
 
 
Upper extremities 
 
 
 
Trunk 
 
 
 
Lower extremities 
 
 
 
Feet 
 
 
 
Head/Neck 
 
 
 
Body Total VASI 
 
 
0-100 
A handprint unit (palm + 5 digits) is equal to 1% of the BSA. 
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APPENDIX D. VITILIGO EUROPEAN TASK FORCE SCALE 
General Recommendations: 
Hands and feet are included in evaluation of extent in arms and legs, but evaluated separately 
and globally for staging and spreading (ie, hands and feet must be staged separately/globally as 
one area).  Staging and Spreading can be assessed simultaneously using a Wood's lamp.  Use 
largest patch in each territory. 
Recommendation to assess extent:  The subject's palm including digits averages 1% BSA.  
Please draw the patches and mark the evaluated patches on figure below. 
Recommendation to assess stage using Wood's lamp (with magnifying lens):    
• Stage 0:  normal pigmentation (no depigmentation in area graded) 
• Stage 1:  incomplete pigmentation (including spotty depigmentation, trichrome, and 
homogeneous lighter pigmentation) 
• Stage 2:  complete depigmentation, a few white hairs do not change stage 
• Stage 3:  partial hair whitening < 30% 
• Stage 4:  complete hair whitening 
Recommendation to assess spreading: 
• First look at patch limits using natural light. 
• Second compare with Wood's lamp limits. 
Score 0 means similar limits. 
Score 1 means progressive vitiligo (ongoing subclinical depigmentation) 
Score -1 means regressive vitiligo (ongoing subclinical repigmentation) 
 
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Source:  Taïeb and Picardo 2007. 
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APPENDIX F. PROTOCOL AMENDMENT SUMMARY OF CHANGES 
Document 
Date 
Amendment (Version) 1: 
17 MAY 2017 
Amendment (Version) 2: 
08 JAN 2018 
Amendment (Version) 3: 
01 AUG 2019 
Amendment 3 (01 AUG 2019) 
Overall Rationale for the Amendment:  The primary purpose of this amendment is to increase 
the length of the open-label extension period from 52 weeks to 104 weeks and the follow-up 
period from 3 months to 6 months. 
1. Synopsis; Section 1.7, Study Rationale and Justification of Dose; Section 4.1, Overall 
Study Design (including Figure 1: Study Design Schema); Section 4.4, Duration of 
Treatment and Subject Participation; Section 6, Study Assessments; Section 6.3, 
Treatment; Section 6.4, Follow-Up; Section 7.5.4, Electrocardiograms; 
Section 7.5.5.3, Urinalysis 
Description of changes:  The length of the open-label extension period was changed 
from 52 weeks to 104 weeks, with visits added approximately every 12 weeks during the 
extension period.  The length of the follow-up period was changed from 3 months to 
6 months.  Assessments and the description of the duration of the study were updated 
accordingly as appropriate. 
Rationale for change:  The durations of the open-label extension and follow-up periods 
were increased to gather information 
 and maintenance of 
response data as well as longer-term safety information. 
2. Synopsis; Section 4.1, Overall Study Design; Section 5.4.1, Dose Modifications; 
Section 5.4.4, Criteria and Procedures for Dose Increases of Study Drug; 
Section 7.6.4, Physician's Global Vitiligo Assessment 
Description of changes:  Language was updated to permit dose modifications after 
Week 80 for subjects who have complete facial repigmentation that is first observed after 
Week 80. 
Rationale for change:  Since the study treatment duration has increased by an additional 
52 weeks, this allows for possible modification of the dosing at additional timepoints 
during treatment. 
3. 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 (08 JAN 2018) 
Overall Rationale for the Amendment: 
The primary purpose of this amendment is to remove the enrollment cap for subjects over 
30 years of age. 
1. Synopsis, Overall Study Design; Section 4.1, Overall Study Design; Section 5.1.2, 
Randomization and Blinding 
Description of changes:  Removed the enrollment cap for subjects over 30 years of age. 
Rationale for change:  Original enrollment cap (no more than 50% of subjects) for 
subjects over 30 years of age is not operationally feasible and would limit the ability to 
deliver study results within a reasonable timeframe. 
2. Section 7.6.1, Vitiligo Area and Severity Index 
Description of changes:  Updated F-VASI and hand unit definition. 
Rationale for change:  To further clarify the definition of face area and VASI 
measurement. 
3. Section 4.1, Overall Study Design; Section 5.1.2, Randomization and Blinding; 
Section 6.3, Treatment 
Description of changes:  Revised text so that the members of the primary endpoint 
assessment team from Incyte will be unblinded at Week 24. 
Rationale for change:  To facilitate future clinical study planning. 
4. Incorporation of administrative changes.  Other minor, administrative changes have 
been incorporated throughout the Protocol and are noted in the redline version of the 
amendment. 
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Amendment 1 (17 MAY 2017) 
Overall Rationale for the Amendment: 
The primary purpose of this amendment is to remove enrollment of subjects aged 12 to 17 years, 
and update the enrollment cap for subjects over 30 years of age to no more than 50% of subjects. 
This amendment includes the changes to the Protocol INCB 18424-211 (20 JAN 2017) 
summarized below.  A redline version of the amendment depicting the updated and previous text 
is also provided. 
1. Synopsis, Overall Study Design, Study Population, Key Inclusion Criteria; 
Section 1.7, Study Rationale and Justification of Dose; Section 3.1, Subject Inclusion 
Criteria; Section 4.1, Overall Study Design (Figure 1); Section 5.1.2, Randomization 
and Blinding 
Description of changes:  Removed subjects aged 12 to 17 years. 
Rationale for change:  Study population was changed in consideration of FDA concerns 
that there is insufficient information from nonclinical juvenile toxicity studies at this time 
to assess risks in pediatric subjects. 
2. Synopsis, Overall Study Design; Section 4.1, Overall Study Design; Section 5.1.2, 
Randomization and Blinding 
Description of changes:  Updated enrollment cap for subjects over 30 years of age to no 
more than 50% of subjects. 
Rationale for change:  To ensure a disease-appropriate age distribution for enrolled 
subjects.  
3. Section 7.6.3, Vitiligo European Task Force Scale; Appendix D, Vitiligo European 
Task Force Scale 
Description of changes:  Updated stage of disease (staging) in the Vitiligo European 
Task Force (VETF) Scale. 
Rationale for change:  To make Section 7.6.3 and Appendix D consistent. 
4. Section 2.2.2, Other Secondary Endpoints; Section 9.3.2 Secondary Analysis; 
Section 9.4.1.3 Secondary Efficacy Analyses; Section 9.4.2.2 Clinical Laboratory 
Tests; 9.4.2.4 Electrocardiograms.  
Description of changes:  Corrected and updated analysis language.  Shortened the 
Clinical Laboratory Tests section and removed the Electrocardiograms section. 
Rationale for change:  To update statistical analysis language as some sections (eg, 
Clinical Laboratory Tests) are not applicable for a topical INCB018424 study. 
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