Clinical trial NCT04811131
Conditions: Vitiligo
Sponsor: Arcutis Biotherapeutics, Inc.
Start date: 2021-03-04; Completion date: 2021-08-09
Enrollment: 114 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study will assess the safety and efficacy of ARQ-252 cream in combination with NB-UVB phototherapy treatment in individuals with non-segmental facial vitiligo.

Detailed description:
This study is a Phase 2a, parallel group, double blind, vehicle-controlled study of the safety and efficacy of ARQ-252 0.3% cream in combination with NB-UVB phototherapy treatment in subjects with non-segmental facial vitiligo.

This study was prematurely terminated by the sponsor on 30-Jun-2021.

Arms: arm 1: ARQ-252 cream 0.3% BID with phototherapy. arm 2: ARQ-252 cream 0.3% BID with sham phototherapy arm 3: ARQ-252 Vehicle cream BID with active phototherapy arm 4: ARQ-252 Vehicle cream BID with sham phototherapy
Interventions: intervention 1: ARQ-252 cream 0.3% intervention 2: ARQ-252 Vehicle cream intervention 3: NB-UVB phototherapy active treatment intervention 4: NB-UVB phototherapy sham treatment
Intervention descriptions: intervention 1: ARQ-252 cream 0.3% intervention 2: ARQ-252 Vehicle cream intervention 3: NB-UVB phototherapy active treatment intervention 4: NB-UVB phototherapy sham treatment

Protocol documents:
Prot_000.pdf: 




Protocol ARQ-252-213 
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SUMMARY OF CHANGES 
The following sections have been changed in Amendment 1 (US) of the ARQ-252-213 protocol: 
Section 
Summary of Changes 
1.3 Schedule of Visits and 
Assessments  
Added BSA (Full Body) and T-VASI to Screening Visit 
Added subject weight assessment at the Screening Visit.  
Removed Compliance Calculation from Baseline Visit 
Clarified Footnote q to indicate a subject will be issued a 
new USB stick at each visit during the treatment period to 
obtain data from the Phototherapy Unit. 
4.5.1 Inclusion Criteria 
Updated inclusion criterion for age and Fitzpatrick Skin 
Type 
4.5.2 Exclusion Criteria 
Added exclusion criteria for subjects ages 18-21 years with 
first degree family members (parents, children, and/or 
siblings) who have a history of melanoma. 
4.10.2 Treatment Administration 
Added statement that subjects will be instructed to treat 
any new lesions that appear in the treatment areas during 
the treatment period. 
Added requirement for subjects 18-21 years of age with 
pigmented lesions in the treatment field to cover pigmented 
lesions to prevent NB-UVB exposure. 
5.1 Safety Assessments 
Added safety assessments to include monitoring of the 
reactivation of herpes simplex virus or varicella zoster 
virus and changes in the nails following the initiation of 
phototherapy treatment.   
Figure 1: Contraception 
Requirements for Female Subjects 
Added Bilateral tubal occlusion as a Highly Effective 
Method of contraception. 
5.7.1 Adverse Event Definition 
Added definition of an AE to include worsening of a 
pre-existing medical condition.   
5.7.4. Safety Review with Subject 
Updated safety review to classify outcome based on 
current standards (defined in eCRF completion guideline). 
5.7.5 Adverse Event Reporting 
Updated the classification of the event outcome based on 
current standard (define in eCRF completion guideline). 




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TABLE OF CONTENTS 
1. 
PROTOCOL SUMMARY ..........................................................................................13 
1.1. 
Synopsis ......................................................................................................................13 
1.2. 
Study Schema .............................................................................................................23 
1.3. 
Schedule of Visits and Assessments ...........................................................................24 
2. 
BACKGROUND AND RATIONALE .......................................................................27 
2.1. 
Introduction .................................................................................................................27 
2.2. 
Nonclinical Studies .....................................................................................................28 
2.3. 
Toxicity Summary ......................................................................................................29 
2.4. 
Clinical Studies ...........................................................................................................29 
2.4.1. 
Oral Administration ....................................................................................................29 
2.4.1.1. 
Oral Administration: Phase 1 ......................................................................................30 
 
 
 
 
 
 
2.4.2. 
Topical Administration ...............................................................................................35 
2.4.2.1. 
Topical Administration: Phase 1 ................................................................................35 
 
 
 
 
2.5.1. 
Dose Selection ............................................................................................................37 
2.5.2. 
Risks and/or Benefits to Subjects ...............................................................................38 
3. 
STUDY OBJECTIVES AND ENDPOINTS ..............................................................38 
3.1. 
Study Objectives .........................................................................................................38 
3.1.1. 
Primary Objective .......................................................................................................38 
3.1.2. 
Secondary Objective ...................................................................................................38 
3.2. 
Study Endpoints ..........................................................................................................39 
3.2.1. 
Primary Endpoints ......................................................................................................39 
3.2.2. 
Secondary Endpoints ..................................................................................................39 
3.2.3. 
Exploratory Endpoints ................................................................................................40 
4. 
INVESTIGATIONAL PLAN .....................................................................................40 
4.1. 
Overall Study Design and Plan ...................................................................................40 


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4.2. 
Study Population .........................................................................................................40 
4.3. 
Number of Subjects ....................................................................................................41 
4.4. 
Blinding ......................................................................................................................41 
4.4.1. 
Breaking Treatment Codes .........................................................................................41 
4.5. 
Selection of Study Population ....................................................................................41 
4.5.1. 
Inclusion Criteria ........................................................................................................41 
4.5.2. 
Exclusion Criteria .......................................................................................................42 
4.6. 
Removal of Subjects from Investigational Product ....................................................45 
4.7. 
Removal of Subjects from the Study ..........................................................................45 
4.8. 
Replacement of Subjects that Withdraw or are Discontinued from the Study ...........45 
4.9. 
Prohibitions and Concomitant Therapy ......................................................................45 
4.10. 
Treatment ....................................................................................................................47 
4.10.1. 
IP Supplies, Packaging, and Labeling ........................................................................47 
4.10.2. 
Treatment Administration ...........................................................................................48 
4.10.3. 
Treatment Compliance ................................................................................................49 
5. 
STUDY PROCEDURES ............................................................................................50 
5.1. 
Safety Assessments .....................................................................................................50 
5.1.1. 
Screening ....................................................................................................................50 
5.1.2. 
Contraception Requirements ......................................................................................51 
5.1.3. 
Physical Examination .................................................................................................52 
5.1.4. 
Vital Signs, Height and Weight ..................................................................................52 
5.1.5. 
Fitzpatrick Skin Type Assessment ..............................................................................53 
5.1.6. 
12-lead ECGs ..............................................................................................................53 
5.1.7. 
Laboratory Tests .........................................................................................................53 
5.1.8. 
Local Tolerability Assessment ...................................................................................54 
5.1.9. 
Adverse Events ...........................................................................................................55 
5.2. 
Efficacy Evaluations ...................................................................................................55 
5.2.1. 
Independent Rater Requirement .................................................................................55 
5.2.2. 
Body Surface Area ......................................................................................................56 
5.2.3. 
Vitiligo Area Scoring Index (VASI) ...........................................................................56 
5.2.4. 
Vitiligo Quality of Life (VitiQoL) ..............................................................................57 
5.2.5. 
Vitiligo Noticeability Scale (VNS) .............................................................................57 


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5.2.6. 
Facial Static Investigator Global Assessment (FsIGA) ..............................................57 
5.2.7. 
Patient Global Impression of Change-Vitiligo (PaGIC-V) ........................................57 
5.3. 
Other Evaluations .......................................................................................................58 
5.3.1. 
Medical Photography ..................................................................................................58 
5.3.2. 
Pharmacokinetics Assessment ....................................................................................58 
5.4. 
Final Study Visit .........................................................................................................58 
5.5. 
Early Termination Visit ..............................................................................................58 
5.6. 
Unscheduled Visit .......................................................................................................58 
5.7. 
Adverse Events ...........................................................................................................59 
5.7.1. 
Adverse Event Definition ...........................................................................................59 
5.7.2. 
Serious Adverse Event ................................................................................................59 
5.7.3. 
Suspected Unexpected Serious Adverse Reaction (SUSAR) .....................................61 
5.7.4. 
Safety Review with Subject ........................................................................................61 
5.7.5. 
Adverse Event Reporting ............................................................................................61 
5.8. 
Reporting Pregnancy ..................................................................................................63 
5.9. 
Treatment Stopping Rules ..........................................................................................63 
6. 
STATISTICAL METHODS .......................................................................................64 
6.1. 
Statistical Methods ......................................................................................................64 
6.1.1. 
Pharmacokinetics Assessment ....................................................................................65 
6.1.2. 
Determination of Sample Size ....................................................................................65 
6.1.3. 
Subjects to Analyze ....................................................................................................65 
6.1.4. 
Background and Demographic Characteristics ..........................................................66 
6.1.5. 
Study Disposition........................................................................................................66 
6.1.6. 
Investigational Product Application Compliance .......................................................66 
6.2. 
Efficacy Evaluation ....................................................................................................66 
6.2.1. 
Primary Efficacy Endpoint .........................................................................................66 
6.2.2. 
Secondary Efficacy Endpoints ....................................................................................66 
6.2.3. 
Exploratory Endpoints ................................................................................................67 
6.3. 
Safety Evaluation ........................................................................................................68 
6.3.1. 
Adverse Events ...........................................................................................................68 
6.3.2. 
Local Tolerance Assessment ......................................................................................68 
6.3.3. 
Medical History and Physical Examinations ..............................................................68 


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6.3.4. 
Clinical Laboratory Results and Vital Signs ..............................................................68 
6.3.5. 
Prior and Concomitant Medications ...........................................................................69 
6.3.6. 
Pharmacokinetic Analysis ..........................................................................................69 
7. 
STUDY ADMINISTRATION ...................................................................................69 
7.1. 
Ethics ..........................................................................................................................69 
7.1.1. 
Ethics Review Board ..................................................................................................69 
7.1.2. 
Ethical Conduct of the Study ......................................................................................69 
7.1.3. 
Subject Information and Consent ...............................................................................70 
7.2. 
Study Monitoring ........................................................................................................70 
7.3. 
Study Completion/Termination ..................................................................................70 
7.3.1. 
Study Completion .......................................................................................................70 
7.3.2. 
Study Termination ......................................................................................................70 
7.4. 
Data Quality Assurance ..............................................................................................71 
7.5. 
Data Handling and Record Keeping ...........................................................................71 
7.6. 
Protocol Amendments and Deviations .......................................................................71 
7.7. 
Confidentiality and Privacy ........................................................................................72 
7.8. 
Conflict of Interest ......................................................................................................72 
7.9. 
Report Format .............................................................................................................73 
7.10. 
Publication Policy .......................................................................................................73 
8. 
REFERENCES ...........................................................................................................73 
9. 
APPENDICES ............................................................................................................76 
APPENDIX 1. VITILIGO NB-UVB TREATMENT PROTOCOL ...........................................76 
APPENDIX 2. VITILIGO QUALITY OF LIFE QUESTIONNAIRE .......................................79 
APPENDIX 3. VITILIGO NOTICABILITY SCALE (VNS) ....................................................80 
APPENDIX 4. FACIAL STATIC INVESTIGATOR GLOBAL ASSESSMENT 
(FSIGA) ..............................................................................................................81 
APPENDIX 5. PATIENT GLOBAL IMPRESSION OF CHANGE-VITILIGO 
(PAGIC-V) .........................................................................................................83 
 
 




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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
ACR20 
American College of Rheumatology 20 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
AST 
Aspartate Aminotransferase  
AUC 
Area Under the Curve 
BID 
Twice Daily (bis in die) 
BSA 
Body Surface Area 
Cmax 
Maximum Concentration 
Cm 
Centimeter 
CNS 
Central Nervous System 
CRF 
Case Report Form 
CTCAE 
Common Terminology Criteria for Adverse Events 
CXCL 
C-X-C Motif Chemokine Ligand 
DMARD 
Disease Modifying Anti-Rheumatic Drug 
DNA 
Deoxyribonucleic Acid 
ECG 
Electrocardiogram 
FsIGA 
Facial Static Investigator or Global Assessment 
F-BSA 
Facial Body Surface Area 
FDA 
Food and Drug Administration 
F-VASI 
Facial Vitiligo Area Scoring Index 
F/N-VASI 
Face/Neck Vitiligo Area Scoring Index 
F/N-BSA 
Face and Neck Body Surface Area 
FOCBP 
Female of Child-bearing Potential 
GCP 
Good Clinical Practices 
HDL 
High-density Lipoprotein 
HECSI 
Hand Eczema Severity Index  
HGB 
Hemoglobin 
Hr 
Hour 
IB 
Investigational Brochure 
ICF 
Informed Consent Form 


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Abbreviation 
Definition 
ICH  
International Conference on Harmonisation 
ID 
Identification  
IND 
Investigational New Drug 
IP 
Investigational Product 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
ITT 
Intent to Treat 
JAK 
Janus Kinase 
Kg 
Kilogram 
LDL 
Low-density Lipoprotein 
µg 
Microgram 
MAD 
Multiple Ascending Dose 
MedDRA 
Medical Dictionary for Regulatory Activities 
Mg 
Milligram 
Min 
Minute 
mJ 
Millijoule 
MKTP 
Melanocyte-keratinocyte transplantation procedure 
mL 
Milliliter 
MTX 
Methotrexate 
NB-UVB 
Narrowband Ultraviolet B 
NCI 
National Cancer Institute 
NIH 
National Institutes of Health 
Ng 
Nanogram 
NOAEL 
No Observed Adverse Effect Level 
P-450 
Cytochrome P450 
PaGIC-V 
Patient Global Impression of Change-Vitiligo 
PDE-4 
Phosphodiesterase 4 
PI 
Principal Investigator  
PK 
Pharmacokinetics 
PUVA 
Psoralen Ultraviolet A 
QD 
Once Daily ("quaque die") 


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Abbreviation 
Definition 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
T4 
Thyroxine 
TCPS 
Tri-Council Policy Statement 
TEAE 
Treatment Emergent Adverse Event 
Tmax 
Time to Reach Maximum Concentration 
TSH 
Thyroid Stimulating Hormone 
US 
United States 
VASI 
Vitiligo Area Scoring Index 
VitiQoL 
Vitiligo-Specific Quality of Life Instrument 
VNS 
Vitiligo Noticeability Scale 
WBC 
White Blood Cell 


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1. 
PROTOCOL SUMMARY 
1.1. 
Synopsis 
Name of Sponsor/Company: Arcutis Biotherapeutics, Inc. 
Protocol Number:  
ARQ-252-213 
Phase: 2a 
Country: US and Canada 
Title of Study: A Phase 2a, Proof of Concept, 24-Week, Parallel Group, Double Blind, 
Vehicle-Controlled Study of the Safety and Efficacy of ARQ-252 Cream 0.3% in Subjects 
with Non-Segmental Facial Vitiligo 
Clinical Indication: Vitiligo  
Number of Sites: Approximately 50 
Number of Subjects (planned): Approximately 500  
Objectives:  
Primary:  
The purpose of this study is to assess the safety and efficacy of ARQ-252 cream 0.3% BID vs 
vehicle cream BID, with and without NB-UVB phototherapy treatment in individuals with 
non-segmental facial vitiligo. 
Secondary:  
To assess other efficacy measures of ARQ-252 cream 0.3% BID with and without NB-UVB 
phototherapy treatment in subjects with non-segmental vitiligo on the face, in addition to 
vitiligo on the neck, hands, forearms, and elbows.  
Study Population: 
Subjects will be male and female adults (>18 y/o) with non-segmental facial vitiligo.  Subjects 
can have vitiligo in other areas of the body, however the areas to be treated in the study will 
only include the face, neck, hands, forearms, and elbows.  At least 30% of subjects will have 
active vitiligo as defined as new or expanding vitiligo lesions with or without the presence of 
confetti, trichrome, or inflammatory vitiligo lesion patterns or other clinical signs of active 
vitiligo in the past 3 months. At least 65% of subjects will have treatable non-facial vitiligo on 
the hands, forearms, and elbows.  Subjects will have Facial Body Surface Area (BSA) 
≥ 0.25% and F‑VASI ≥ 0.25.  The maximum BSA (total body inclusive of the face, whether or 
not in areas to be treated in this study) is 15%.  At least 50% of subjects will have Fitzpatrick 
skin type IV-VI.   


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Name of Investigational Product: ARQ-252 cream will be supplied as ARQ-252 cream 
0.3%.  Matching vehicle cream will contain only excipients of ARQ-252 cream. 
The study will also include the following devices: 
• 
 NB-UVB Home Phototherapy Unit – Active Units  
• 
 NB-UVB Home Phototherapy Unit – Sham Units  
Name of Active Ingredient: The active ingredient in ARQ-252 cream is SHR0302, a 
selective JAK1 inhibitor. 
Duration of Treatment: The total duration for subjects on study includes up to 5 weeks in 
screening, 24 weeks of treatment with ARQ-252 cream 0.3% or matching vehicle cream plus 
phototherapy/sham phototherapy and 1 week post-treatment follow-up for a total of 30 weeks.   
Endpoints:  
Primary: 
The primary efficacy endpoint is: 
• Proportion of subjects achieving F-VASI75 (≥ 75% improvement from baseline in 
Facial Vitiligo Area Scoring Index (F-VASI) score) at Week 24. 
Secondary: 
The secondary endpoints will include: 
• Proportion of subjects achieving F-VASI75 (≥ 75% improvement from baseline in 
F-VASI score) at visits prior to Week 24. 
• Percent change from baseline in F-VASI score at all visits. 
• Percent change from baseline in facial body surface area (F-BSA) at all visits. 
• Proportion of subjects achieving F-VASI50 (≥ 50% improvement from baseline in 
F-VASI score) at all visits. 
• Proportion of subjects achieving F-VASI90 (≥ 90% improvement from baseline in 
F-VASI score) at all visits. 
• Proportion of subjects in each category of VNS at specified visits. 
• Change from Baseline in the VNS at specified visits. 
• Change from Baseline in the VitiQoL at specified visits. 
• Patient Global Impression of Change-Vitiligo (PaGIC-V), proportion of patients in 
each PaGIC-V category at specified visits. 
• Proportion of subjects who report PaGIC-V of very much improved or much improved 
during the treatment period. 


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• Time to achieve F-VASI50. 
• Time to achieve F-VASI75. 
• Time to achieve FsIGA of clear or almost clear (0 or 1). 
• FsIGA of clear or almost clear (0 or 1). 
• FsIGA of clear or almost clear (0 or 1) plus 2-grade improvement from baseline. 
• Time to achieve a PaGIC-V of very much improved or much improved. 
Exploratory: 
The exploratory endpoints will include: 
• Percent change from baseline in combined face and neck body surface area (F/N-BSA) 
at all visits. 
• Percent change from baseline in surface area BSA (hands/forearms/elbows) at all 
visits. 
• Percent change from baseline in BSA affected across all treatable sites (face, neck, 
hands, forearms, elbows) at all visits. 
• Proportion of subjects achieving F/N-VASI50 (≥ 50% improvement from baseline in 
F/N-VASI score) at all visits. 
• Proportion of subjects achieving F/N-VASI75 (≥ 75% improvement from baseline in 
F/N-VASI score) at all visits. 
• Proportion of subjects achieving F/N-VASI90 (≥ 90% improvement from baseline in 
F/N-VASI score) at all visits. 
• Percent change from baseline in FOREARM-VASI (forearms/elbows) score at all 
visits. 
• Percent change from baseline in HAND-VASI (hands only) score at all visits. 
• Serum levels of ARQ-252. 
• The proportions of subjects who maintain 80% treatment compliance with both 
application of ARQ-252 cream 0.3% or vehicle cream and phototherapy or sham 
phototherapy up through 24 weeks. 


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Study Design:  
ARQ-252-213 is a Phase 2a, Proof of Concept, 24-week, parallel group, double blind, 
vehicle-controlled study of the safety and efficacy of ARQ-252 cream 0.3% in subjects with 
non-segmental facial vitiligo.  Subjects with facial vitiligo will apply either ARQ-252 0.3% 
cream BID or vehicle cream BID for 24 weeks to all affected areas of vitiligo on the face, 
neck, hands, forearms, and elbows (extending 3 cm from the border of the affected area), but 
not vitiligo elsewhere. 
Subjects will be randomized to a blinded treatment group including the 
 Home 
Phototherapy Unit (NB-UVB) active unit or a sham unit to expose the entire face and areas 
affected on the neck, hands, forearms, and elbows for up to 3 times per week per a 
standardized phototherapy protocol. 
Methodology:  
The randomization scheme will be 3:3:3:1 to the following 4 treatment groups: 
• Approximately 150 subjects will receive ARQ-252 cream 0.3% BID with 
phototherapy. 
• Approximately 150 subjects will receive ARQ-252 cream 0.3% BID with sham 
phototherapy. 
• Approximately 150 subjects will receive matching vehicle cream BID with 
phototherapy 
• Approximately 50 subjects will receive matching vehicle cream BID with sham 
phototherapy 
The primary comparisons will be performed at the 5% significance level and will include: 
• ARQ-252 cream 0.3% in combination with phototherapy vs. vehicle cream in 
combination with phototherapy 
• ARQ-252 cream 0.3% in combination with phototherapy vs. ARQ-252 cream 0.3% in 
combination with sham phototherapy 
Sample Size Justification:   
The primary statistical comparisons will be to compare  
• ARQ-252 cream 0.3% in combination with phototherapy vs. vehicle cream in 
combination with phototherapy 
• ARQ-252 cream 0.3% in combination with phototherapy vs. ARQ-252 cream 0.3% in 
combination with sham phototherapy at the 5% significance level.   
A sample size of 500 subjects will provide approximately 84% power to detect an ARQ-252 
cream 0.3% in combination with phototherapy response rate of at least 50% vs. a vehicle 
cream in combination with phototherapy response rate of 30%, and approximately 84% power 


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to detect an ARQ-252 cream 0.3% in combination with phototherapy rate of at least 50% vs. 
an ARQ-252 cream 0.3% in combination with sham phototherapy rate of 30% using a 
stratified Cochran-Mantel-Haenszel test conducted at the 0.025 alpha level for each 
comparison.   
A drop-out rate of 15% (at 24 weeks) is assumed.  
Upon successful testing for the comparisons above, a hierarchical testing scheme will be used 
to test the following secondary comparisons: 
• ARQ-252 cream 0.3% in combination with phototherapy vs. vehicle cream BID in 
combination with the sham phototherapy 
• ARQ-252 cream 0.3% in combination with sham phototherapy vs. vehicle cream BID 
in combination with the sham phototherapy 
• Vehicle cream BID in combination with phototherapy vs. vehicle cream BID in 
combination with the sham phototherapy 
Assuming a vehicle cream BID in combination with the sham phototherapy rate of no more 
than 5%, these comparisons are expected to have at least 74% power.  These comparisons will 
be made at either the 0.025 or 0.05 level, depending on the outcome of the primary statistical 
comparisons. 
Main Criteria for Inclusion:  
1. Subject is legally competent to sign and give informed consent. 
2. Males and females ages 18-21 years with Fitzpatrick Skin Type IV-VI or age 22 years 
and older with Fitzpatrick Skin Type I-VI. 
3. Clinical diagnosis of non-segmental vitiligo involving face. 
4. A Facial Vitiligo Area Severity Index [F-VASI] score of ≥ 0.25 at baseline. 
5. Vitiligo of the face involving at least ≥ 0.25% body surface area (BSA) involvement 
(ie, one quarter of one handprint). Subjects may have non-facial vitiligo elsewhere 
which will not be included in the minimum BSA.  The maximum BSA (total body 
inclusive of the face, whether or not in areas to be treated in this study) permitted is 
15%. 
6. Subjects with vitiligo on the hands, forearms, or elbows agree to treat these areas in 
addition to the face, with investigational product and phototherapy. 
7. Subject agrees to discontinue all agents used to treat vitiligo from screening through 
the final safety follow-up visit. Over-the-counter preparations deemed acceptable by 
the Investigator and camouflage makeups are permitted. 
8. Female subject of childbearing potential (FOCBP) must have a negative serum 
pregnancy test at Screening and negative urine pregnancy test at Baseline (Visit 2).  
For FOCBP involved in any sexual intercourse that could lead to pregnancy: the 
subject must agree to use a highly effective contraceptive method for at least 4 weeks 


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prior to Day 1.  Additionally, from Day 1 until at least 4 weeks after the last 
investigational product administration, these subjects must agree to use at least 
1 highly effective contraceptive method in addition to 1 barrier method. Figure 1  
9. Female subject of non-childbearing potential must either be post-menopausal with 
spontaneous amenorrhea for at least 12 months prior to baseline (post-menopausal 
status will be confirmed with FSH testing) or have undergone surgical sterilization 
(permanent sterilization methods include hysterectomy, bilateral oophorectomy, or 
bilateral salpingectomy). Figure 1 
10.  Males, if engaging in sexual intercourse with a female who is pregnant or a female of 
child-bearing potential, must agree to use a condom every time during the study and 
every time subsequently until 4 weeks beyond the last dose of investigational product. 
11. Males must agree not to donate sperm from the first dose of investigational product 
until 4 weeks after the last dose of investigational product. 
12. Subject is in good health as judged by the Investigator, based on medical history, 
physical examination, 12-lead electrocardiogram (ECG), serum chemistry labs, 
hematology values, and urinalysis. 
Main Criteria for Exclusion:  
1. Males and females ages 18-21 years with first degree family members (parents, 
children, and/or siblings) who have a history of melanoma. 
2. Subjects with any serious medical condition or clinically significant laboratory, ECG, 
vital signs, or physical examination abnormality that would prevent study participation 
or place the subject at significant risk, as judged by the Investigator. 
3. Subjects who have ever used skin bleaching treatments for treatment of vitiligo or 
other pigmented areas, eg, depigmenting agents such as monobenzyl ether of 
hydroquinone, including Benoquin® (Monobenzone) 
4. Use of any other prior and concomitant therapy that is a contraindication to 
phototherapy or may otherwise interfere with the objective of the study as per 
discretion of the Investigator, such as drugs that cause photosensitivity or skin 
pigmentation (eg, antibiotics such as tetracyclines, antifungals) within 8 weeks of 
Baseline (Visit 2). 
5. More than 33% leukotrichia in facial lesions (assessed via dermatoscope). 
6. Other forms of vitiligo (eg, segmental vitiligo); or other skin depigmentation disorder 
that would confound study assessments (eg, piebaldism, pityriasis alba, leprosy, 
post-inflammatory hypopigmentation, progressive macular hypomelanosis, nevus 
anemicus, chemical leukoderma, and tinea versicolor). 
7. Use of oral or systemic immunomodulating medications (eg, corticosteroids, 
azathioprine, methotrexate, cyclosporine) within 8 weeks of Baseline (Visit 2). 
(See Excluded Medications and Treatments, Table 2). 


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8. Use of prescription or over-the-counter topical treatments that may affect vitiligo 
(eg, corticosteroids, tacrolimus/pimecrolimus, retinoids, vitamin D derivates, 
psoralens) within 4 weeks prior to Baseline (Visit 2) (See Excluded Medications and 
Treatments, Table 2).    
9. Use of any biological or experimental therapy for vitiligo within 24 weeks of Baseline 
(Visit 2) (or 5 half-lives, whichever is longer). 
10. Use of phototherapy (including laser and tanning beds) within 8 weeks prior to 
Baseline (Visit 2). 
11. Previous oral or topical JAK inhibitor therapy within 24 weeks prior to Baseline 
(Visit 2), and/or prior non-response to oral or topical JAK inhibitor therapy for vitiligo 
12. History of melanocyte-keratinocyte transplantation procedure (MKTP) or other 
surgical treatment for vitiligo. 
13. Contraindication to phototherapy, such as photosensitivity disorder (eg, lupus, 
polymorphic light eruption, solar urticaria, dermatomyositis) or use of photosensitizing 
or phototoxic medications. 
14. Subjects with clinically significant abnormal thyroid-stimulating hormone or free T4 at 
screening, or otherwise uncontrolled thyroid function at screening as determined by the 
investigator (Note: If the subject has a history of thyroid disease and is on treatment, 
the subject must be on a stable thyroid regimen for at least 3 months prior to baseline) 
15. History of chronic alcohol or drug abuse within 6 months prior to baseline. 
16. Subjects with a cytopenia at screening, defined as follows: Leukocytes < 3 × 10^9/L 
(2.5 × 10^9/L for subjects who are African-American), Neutrophils < lower limit of 
normal (<1.5x10^9/L), Lymphocytes < 0.8 × 10^9/L, Hemoglobin < 10 g/dL, Platelets 
< 100 × 10^9/L. 
17. Subjects with current or a history of non-skin cancer within 5 years with the exception 
carcinoma in situ of the cervix. 
18. Subjects with greater than 3 adequately treated nonmetastatic basal cell carcinomas 
(BCC) or squamous cell carcinomas (SCC) within 12 months prior to Baseline 
(Visit 2), or a previous history of multiple BCC or SCC on any area of the body, which 
may pose additional risks from participation in the study, in the opinion of the 
Investigator. 
19. Subjects with previous history of melanoma anywhere on the body, or basal cell 
carcinoma (BCC), squamous cell carcinoma (SCC), or actinic keratosis (AK) on the 
face, neck, hands, forearms, or elbows. 
20. Subjects that have received live vaccine therapy less than 4 weeks prior Baseline 
(Visit 2), or anticipate receiving a live or live-attenuated vaccination during the course 
of the study, have received immunosuppressive drugs less than 4 weeks prior Baseline, 
or have known infection with mycobacterium tuberculosis, hepatitis B or C, or HIV, or 
have a diagnosis of an immunodeficiency disorder. 




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Key Assessments:  
Safety will be monitored through application site assessments, safety labs, AEs, ECGs, 
physical examinations, and vital signs.   
Efficacy will be evaluated utilizing:   
• F-BSA 
• F/N-BSA 
• BSA (hands, forearms, elbows)  
• BSA (total body) 
• F-VASI 
• F/N-VASI 
• FOREARM-VASI (forearms, elbows)  
• HAND-VASI 
• T-VASI 
• Vitiligo Noticeability Scale (VNS) 
• Vitiligo Quality of Life (VitiQoL) 
• Patient Global Impression of Change-Vitiligo (PaGIC-V) 
• 
Facial Static Investigator Global Assessment (FsIGA) 
Criteria for Evaluation: 
Pharmacokinetics: 
All subjects who are randomized and receive at least one application of investigational product 
and have at least one PK sample draw will be included in the pharmacokinetic population. 
Safety: 
All subjects who are randomized and receive at least one confirmed dose of IP will be 
included in the safety population.  
Adverse events (AEs) will be summarized by preferred term, system organ class, and 
treatment group for all treatment-emergent AEs, serious AEs, related AEs, AEs leading to 
withdrawal from investigational product 
Safety laboratory parameters and vital signs will be summarized at each visit using descriptive 
statistics or frequencies and percentages, as appropriate. Changes from baseline in laboratory 
values and vital signs will also be summarized by visit. In addition, changes from baseline in 
weight and laboratory values will be summarized using shift tables. 


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Statistical Methods: 
Subjects will be stratified by study site, age <30 or >30 years, and Fitzpatrick Skin Type 
(I-III vs. IV-VI).   
Descriptive statistics will be presented for endpoint and safety data collected in the clinical 
trial.  This includes the number and percentage of subjects for binary endpoints/categorical 
data, and mean, SD, median, minimum, and maximum for continuous data. 
The primary endpoint of Proportion of subjects achieving F-VASI75 (≥ 75% improvement 
from baseline in Facial Vitiligo Area Scoring Index (F-VASI) score) at Week 24 will be 
analyzed using a Cochran-Mantel-Haenszel test stratified by the stratification factors study 
site, age <30 or >30 years, and Fitzpatrick Skin Type (I-III vs. IV-VI).   
The analysis will be performed on the Intention-to-Treat (ITT) population and missing data 
will be imputed using multiple imputation.  
Continuous secondary endpoints will be analyzed using Analysis of Covariance with treatment 
and stratification factor as independent variables.  Binary secondary endpoints will be 
analyzed similarly to the primary endpoint. 
Pharmacokinetics Assessment: 
PK will be evaluated through trough/pre-dose sampling at Baseline, Week 4, Week 12, and 
Week 24. 
Pharmacokinetic Parameters:  
Plasma pre-dose values will be compared between treatment conditions.  Values will be 
normalized based on dose applied. 
 




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1.3. 
Schedule of Visits and Assessments 
Study Procedure 
Screen 
Baseline 
Day 1 
Wk 4 
Day 
29 
Wk 8 
Day 
57 
Wk 12 
Day 
85 
Wk 16 
Day 
113 
Wk 
20 
Day 
141 
Wk 
24 
Day 
169 
Wk 
25 
Day 
176 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
Visit Window 
-35 
days 
 
+/- 5 
days 
+/- 5 
days 
+/- 5 
days 
+/- 5 
days 
+/- 5 
days 
+/- 7 
days 
+/- 7   
days 
Informed consent 
X 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
Fitzpatrick skin type 
assessment 
X 
 
 
 
 
 
 
 
 
Medical and surgical 
history 
X 
 
 
 
 
 
 
 
 
Physical examinationa 
X 
X 
 
 
X 
 
 
 
X 
Vital signs, height, weightb 
X 
X 
X 
X 
X 
X 
X 
X 
X 
I/E criteria 
X 
X 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
Hematology, Serum 
Chemistries, UA, TSH/T4  
X 
X 
X 
 
X 
 
 
X 
 
Lipid (Fasting)c  
 
X 
 
 
 
 
 
X 
 
Resting 12-lead ECG 
X 
 
X 
 
X 
 
 
X 
 
BSAd (Full Body), 
T-VASIe 
X 
X 
 
 
X 
 
 
X 
 
F-BSAd, F/N-BSAd, BSA 
(Hands, Forearms, Elbows) 
d, F-VASIe, F/N-VASIe, 
FOREARM-VASIe, 
HAND-VASIe, FsIGAf 
X 
X 
X 
X 
X 
X 
X 
X 
X 
VNSg, PaGIC-Vh 
 
 
X 
X 
X 
X 
X 
X 
 
VitiQoLi 
 
X 
X 
X 
X 
X 
X 
X 
 
Local Tolerability 
Assessmentsj 
 
X 
X 
X 
X 
X 
X 
X 
 
Digital Photographyk 
 
X 
X 
X 
X 
X 
X 
X 
 
Urine pregnancy testl 
 
X 
X 
X 
X 
X 
X 
X 
X 
Serum pregnancy testm 
X 
 
 
 
 
 
 
 
 
Follicle-Stimulating 
Hormone (FSH)n  
X 
 
 
 
 
 
 
 
 


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Study Procedure 
Screen 
Baseline 
Day 1 
Wk 4 
Day 
29 
Wk 8 
Day 
57 
Wk 12 
Day 
85 
Wk 16 
Day 
113 
Wk 
20 
Day 
141 
Wk 
24 
Day 
169 
Wk 
25 
Day 
176 
PK Samplingo 
 
X 
X 
 
X 
 
 
X 
 
NB-UVB Phototherapy in 
clinicp 
 
X 
 
 
 
 
 
 
 
Return of USB stick to site 
for phototherapy data 
uploadingq 
 
 
X 
X 
X 
X 
X 
X 
 
Dispense IP kitr 
 
X 
X 
X 
X 
X 
X 
 
 
IP application in clinics 
 
X 
X 
X 
X 
X 
X 
 
 
Dispense/review diary 
 
X 
X 
X 
X 
X 
X 
 
 
Weigh IP tubest 
 
X 
X 
X 
X 
X 
X 
X 
 
Compliance calculationu 
 
 
X 
X 
X 
X 
X 
X 
 
Adverse event assessmentv 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
a 
Limited physical examination: skin, lungs, and heart only 
b Height will be measured at Baseline only. Weight will be collected at screening, baseline and Week 24. 
c 
Fasting required for a minimum of 8 hours prior to blood draw  
d 
BSA will utilize the subject's handprint method where 1 handprint will approximate 1% of the body surface area 
involved.  F-BSA will include the % BSA of non-segmental vitiligo on the face only.  F/N-BSA will include the 
% of BSA of vitiligo on the face and neck area only.  Full Body BSA will include the % of BSA of vitiligo on all 
areas of the body. This assessment will be performed by an independent rater per Section 5.2.1. 
e 
Vitiligo Area Scoring Index (VASI) per Section 5.2.3:  F-VASI will utilize measuring only the face. “Face” is 
defined as including the area on the forehead to the original hairline, on the check to the jawline vertically to the 
jawline and laterally from the corner of the mouth to the tragus. The area “face” will not include surface areas of 
lips, scalp, ears, or neck but will include the eyelids and nose.  F/N-VASI will utilize VASI measuring the face 
and neck as defined by the Face as defined above in addition to the neck area. FOREARM-VASI will include 
scoring of the forearms and elbows.  HAND-VASI will include scoring of the hands only.  T-VASI will include 
the following sites: (1) head/neck, (2) hands, (3) upper extremities (excluding hands), (4) trunk, (5) lower 
extremities (excluding feet), and (6) feet.  All VASI assessments will be performed by an independent rater per 
Section 5.2.1.  
f 
The Facial Static Investigator Global Assessment (FsIGA) is a global score of vitiligo severity for the face only. 
The outcome measure incorporates location, distribution, size, depigmentation within lesions and presence or 
absence of signs of activity. Examination of skin should be performed with both normal lighting and Woods 
lamp. This assessment will be performed by an independent rater per Section 5.2.1. 
g Vitiligo Noticeability Scale (VNS) is a 5-point scale which compares vitiligo from before treatment to how 
noticeable is the vitiligo at the time of the assessment. The VNS will be completed by subjects with respect to 
vitiligo on the facial target patch. The target patch on the face is selected by the subject as being the patch that 
they would most like to see in an improvement in. The photos taken on the facial target patch at the Baseline visit 
prior to treatment and at the subsequent visits will be used as reference to assess the change. 
h 
The Patient Global Impression of Change-Vitiligo (PaGIC-V) is a 7-point scale on which the subject will rate 
improvement compared to baseline and will be evaluated for the face only. 
i 
The Vitiligo Quality of Life (VitiQoL) is a 16-item questionnaire with a 7-point numerical scale from (0 - Not at 
all) to (6 - All of the time). The VitiQOL is completed by the subject. 
 
 


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Footnotes from table above: 
j 
Tolerability assessments should be recorded prior to study drug application for Investigator assessment and 
10-15 minutes post-drug application for subject (‘0-3’ burning/stinging assessment).  Investigators will specify if 
any application site reaction is due, in whole or in part, to the effects of phototherapy treatment. Only the 
Investigator assessment will take place on Week 24. 
k 
Digital Photography will be conducted at all sites for all subjects.  Required study photos will be taken of the 
treatment areas during the Baseline Visit. In addition, a photo of the facial target patch will be taken as reference 
for the VNS assessment. Fixed, multi-angle photos will be taken at select sites for additional evaluation. 
l 
A urine pregnancy test will be administered to all females of child-bearing potential. A negative result is required 
for continued participation in the study, and results must be available prior to dispensing of study drug at each 
visit.  
m Serum pregnancy testing will be performed at Screening; a negative result is required for participation in the 
study. 
n FSH will be performed (if indicated) at Screening to confirm post-menopausal status. 
o PK samples will be collected from all subjects at Baseline, Week 4, Week 12, and Week 24. The samples will be 
drawn prior to application of the investigation product in the clinic. Subjects should apply investigational product 
11-12 hours before the PK collection time. 
p NB-UVB Phototherapy treatment will occur in the clinic at the Baseline Visit prior to the initial IP application. 
The treatment will be per the NB-UVB Treatment Protocol (Appendix 1) and be tailored per the subject’s 
Fitzpatrick Score. The subject will be provided with the phototherapy unit in addition to a USB stick which will 
be inserted into the unit to obtain phototherapy data during the course of the treatment period.  
q 
Subjects should be instructed return the USB stick from the phototherapy unit to site for the uploading of the 
phototherapy data.  Once the data has been uploaded by the site staff, a new USB stick should be provided to the 
subject to insert into the NB-UVB phototherapy unit.  
r 
IP kits will be dispensed based on % BSA affected. See IP Handling Manual for details. 
s 
Subjects to apply assigned IP in clinic at these visits. The time of application will be documented.  
t 
Each IP tube will be weighed prior to dispensing at the Baseline visit and at each follow-up clinic visit according 
to the Schedule of Visits and Assessments. When IP is applied in the clinic, the IP tube will be weighed before 
and after IP application. See IP Handling Manual for details. 
u 
Compliance calculation is described in the IP Handling Manual.  
v 
Adverse Events (AEs) and clinically significant abnormal laboratory test value(s) will be evaluated by the PI and 
treated and/or followed up for up to 30 days after end of treatment or until the symptoms or value(s) return to 
normal, or acceptable levels, as judged by the PI.  
 


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2. 
BACKGROUND AND RATIONALE 
2.1. 
Introduction 
Vitiligo is a common autoimmune disease affecting 0.5% to 2% of the world’s population. 
Although generally more prominent in patients with darker skin types, vitiligo affects all races 
and both sexes. Vitiligo often presents as acquired, small, asymmetrical lesions that tend to 
increase in size over time and become more numerous, coalescing into larger areas. Although 
vitiligo can occur on any area of the body, the face is commonly affected.  Vitiligo is associated 
with a significant burden of disease, greatly affecting a patient’s quality of life similar to that 
seen in psoriasis and atopic dermatitis (Linthorst 2009).  Vitiligo can be particularly bothersome 
and disfiguring when it affects the face and neck (as well as other exposed areas such as hands 
and forearms) as these areas are visible and may be difficult to camouflage (Elbuluk 2017). 
Numerous studies have demonstrated that quality of life and mental health are more negatively 
impacted in patients with vitiligo on the face and other visible areas (Elbuluk 2017, Amer 2016, 
Eleftheriadou 2012).  The negative impact of face/head/neck involvement on quality of life has 
been reported to be independent of the extent of disease (Bhandarkar 2012). The impact of 
vitiligo may extend to negative treatment by others, with impact on professional prospects and 
relationships.  With respect to treatment, survey data from patients and providers has identified 
repigmentation specifically of the face and hands as particularly important (Eleftheriadou 2012). 
Vitiligo is characterized by a T helper type 1 (Th1)-mediated immune response with increased 
expression of interferon (IFN)-γ and chemokines C-X-C Motif Chemokine Ligand (CXCL) 
9 and CXCL10 which impair the normal function of melanocytes and produce areas of 
depigmentation on the skin (Rashighi 2014). Importantly, after IFN-γ binds to its cell surface 
receptor (IFNGR), signaling is through Janus Kinases (JAKs) especially JAK1 and JAK2.  
JAK1 is also an important mediator of signaling in the IL-15 pathway which has recently also 
been strongly implicated in vitiligo (Frisoli 2020).  As such, JAK inhibition may represent an 
effective strategy for the treatment of vitiligo by decreasing INF-γ signaling and downstream 
chemokine expression (Craiglow 2015, Harris 2016).  Topical JAK inhibitors may be 
particularly well suited for treating vitiligo given the anticipated lower systemic exposures, 
improved safety profile, and more direct cutaneous delivery offered with topical rather than oral 
administration of JAK inhibitors.  Clinical efficacy of JAK inhibition in autoimmune disease is 
well established, with tofacitinib, upadacitinib, and baricitinib approved as oral treatments for 
rheumatoid arthritis (RA), psoriatic arthritis, and/or ulcerative colitis. Over the past few years, 
there have been multiple reports of oral JAK inhibitors prescribed off-label for vitiligo, with 
clinical benefit (Relke 2019).  Recently, topical JAK inhibition has also been demonstrated to be 
a potentially efficacious strategy in the treatment of vitiligo, with the most advanced data coming 
from a 52‑week analysis of an ongoing phase 2 study of topical ruxolitinib cream monotherapy, 
a JAK1/2 inhibitor (Harris 2019, Rosmarin 2020).  Importantly, based on the phase 2 results with 
topical ruxolitinib (Harris 2019) as well as other reports (Rothstein 2017, Rosmarin 2020), 
topical JAK inhibition has demonstrated considerably greater efficacy for vitiligo on the face 
compared to vitiligo elsewhere on the body.  This has been hypothesized to be due to a high 
density of follicular units on the face relative to other parts of the body. Pigmented hair follicles 
are thought to be important reservoirs of melanocytes for repigmentation due to immune 
























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3.2. 
Study Endpoints 
3.2.1. 
Primary Endpoints 
The primary efficacy endpoint is: 
• Proportion of subjects achieving F-VASI75 (≥ 75% improvement from baseline in 
Facial Vitiligo Area Scoring Index (F-VASI) score) at Week 24. 
3.2.2. 
Secondary Endpoints 
The secondary efficacy endpoints will include: 
• Proportion of subjects achieving F-VASI75 (≥ 75% improvement from baseline in 
F-VASI score) at visits prior to Week 24. 
• Percent change from baseline in F-VASI score at all visits. 
• Percent change from baseline in facial body surface area (F-BSA) at all visits. 
• Proportion of subjects achieving F-VASI50 (≥ 50% improvement from baseline in 
F-VASI score) at all visits. 
• Proportion of subjects achieving F-VASI90 (≥ 90% improvement from baseline in 
F-VASI score) at all visits. 
• Proportion of subjects in each category of VNS at specified visits. 
• Change from Baseline in the VNS at specified visits. 
• Change from Baseline in the VitiQoL at specified visits. 
• Patient Global Impression of Change-Vitiligo (PaGIC-V), proportion of patients in 
each PaGIC-V category at specified visits. 
• Proportion of subjects who report PaGIC-V of very much improved or much 
improved during the treatment period. 
• Time to achieve F-VASI50. 
• Time to achieve F-VASI75. 
• Time to achieve FsIGA of clear or almost clear (0 or 1). 
• FsIGA of clear or almost clear (0 or 1). 
• FsIGA of clear or almost clear (0 or 1) plus 2-grade improvement from baseline. 
• Time to achieve a PaGIC-V of very much improved or much improved. 


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3.2.3. 
Exploratory Endpoints 
The exploratory endpoints will include: 
• Percent change from baseline in combined face and neck body surface area 
(F/N-BSA) at all visits. 
• Percent change from baseline in surface area BSA (hands/forearms/elbows) at all 
visits. 
• Percent change from baseline in BSA affected across all treatable sites (face, neck, 
hands, forearms, elbows) at all visits. 
• Proportion of subjects achieving F/N-VASI50 (≥ 50% improvement from baseline in 
F/N-VASI score) at all visits. 
• Proportion of subjects achieving F/N-VASI75 (≥ 75% improvement from baseline in 
F/N-VASI score) at all visits. 
• Proportion of subjects achieving F/N-VASI90 (≥ 90% improvement from baseline in 
F/N-VASI score) at all visits. 
• Percent change from baseline in FOREARM-VASI (forearms/elbows) score at all 
visits. 
• Percent change from baseline in HAND-VASI (hands only) score at all visits. 
• Serum levels of ARQ-252. 
• The proportions of subjects who maintain 80% treatment compliance with both 
application of ARQ-252 cream 0.3% or vehicle cream and phototherapy or sham 
phototherapy up through 24 weeks. 
4. 
INVESTIGATIONAL PLAN 
4.1. 
Overall Study Design and Plan 
ARQ-252 cream 0.3% or matching vehicle cream is to be applied BID to all affected areas of 
vitiligo on the face, neck, forearms, elbows, and hands (extending 3 cm from the border of the 
affected area) including any new lesions that may appear during the course of the 24-week 
treatment period of the study.  Subjects will also receive either an active or indistinguishable 
sham 
 1 NB-UVB Home Phototherapy Unit to be used on aforementioned areas 
for up to 3 times per week per the NB-UVB Phototherapy Treatment Protocol (Appendix 1).  
4.2. 
Study Population 
Subjects will be male and female adults (>18 y/o) with facial non-segmental vitiligo.  At least 
30% of subjects will have active vitiligo defined as new or expanding vitiligo lesions with or 
without the presence of confetti, trichrome, or inflammatory vitiligo lesion patterns or other 
clinical signs of active vitiligo in the past 3 months. At least 65% of subjects will have treatable 
non-facial vitiligo on the hands, forearms, and elbows.  Entry requirements include Facial Body 


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Surface Area (F-BSA) ≥ 0.25% and F‑VASI ≥ 0.25.  The maximum BSA (total body inclusive of 
the face, whether or not in areas to be treated in this study) is 15%.  At least 50% of subjects will 
have Fitzpatrick skin type IV-VI. 
4.3. 
Number of Subjects 
Approximately 500 subjects are planned to be randomized across approximately 50 sites in 
United States and Canada. 
4.4. 
Blinding 
The study is double-blinded, therefore neither the subjects nor the Investigator, Independent 
Rater, or clinical site personnel will be aware of which investigational product (ARQ‑252 0.3% 
cream or vehicle cream) or NB-UVB phototherapy unit (Active or Sham) the subject receives.  
4.4.1. 
Breaking Treatment Codes 
In the event of a medical emergency where breaking the blind is required to provide medical care 
to the subject, the Investigator may obtain treatment assignment directly from the Interactive 
Response Technology (IRT) system for that subject. Refer to the current version of the IRT plan 
for details on unblinding. Treatment assignment should, however, remain blinded unless the 
assignment knowledge is necessary to determine subject emergency medical care. The rationale 
for unblinding must be clearly explained in source documentation and on the CRF, along with 
the date on which the treatment assignment was obtained. The Investigator is requested to 
contact the Sponsor promptly in the event of any treatment unblinding. 
Blinding of study treatment is critical to the integrity of this clinical trial and therefore, if a 
subject’s treatment assignment is disclosed to the Investigator, the subject will have the study 
treatment discontinued. All subjects will be followed until study completion unless consent to do 
so is specifically withdrawn by the subject. 
4.5. 
Selection of Study Population 
4.5.1. 
Inclusion Criteria 
Subjects must fulfill all of the following inclusion criteria to be eligible for participation in the 
study: 
Main Criteria for Inclusion:  
1. Subject is legally competent to sign and give informed consent. 
2. Males and females ages 18-21 years with Fitzpatrick Skin Type IV-VI or age 22 years 
and older with Fitzpatrick Skin Type I-VI. 
3. Clinical diagnosis of non-segmental vitiligo involving face. 
4. A Facial Vitiligo Area Severity Index [F-VASI] score of ≥ 0.25 at baseline. 


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5. Vitiligo of the face involving at least ≥ 0.25% body surface area (BSA) involvement 
(ie, one quarter of one handprint). Subjects may have non-facial vitiligo elsewhere which 
will not be included in the minimum BSA.  The maximum BSA (total body inclusive of 
the face, whether or not in areas to be treated in this study) permitted is 15%. 
6. Subjects with vitiligo on the hands, forearms, or elbows agree to treat these areas in 
addition to the face, with investigational product and phototherapy. 
7. Subject agrees to discontinue all agents used to treat vitiligo from screening through the 
final safety follow-up visit. Over-the-counter preparations deemed acceptable by the 
Investigator and camouflage makeups are permitted. 
8. Female subject of childbearing potential (FOCBP) must have a negative serum pregnancy 
test at Screening and negative urine pregnancy test at Baseline (Visit 2).  For FOCBP 
involved in any sexual intercourse that could lead to pregnancy: the subject must agree to 
use a highly effective contraceptive method for at least 4 weeks prior to Day 1.  
Additionally, from Day 1 until at least 4 weeks after the last investigational product 
administration, these subjects must agree to use at least 1 highly effective contraceptive 
method in addition to 1 barrier method. Figure 1 
9. Female subject of non-childbearing potential must either be post-menopausal with 
spontaneous amenorrhea for at least 12 months prior to baseline (post-menopausal status 
will be confirmed with FSH testing) or have undergone surgical sterilization 
(permanent sterilization methods include hysterectomy, bilateral oophorectomy, or 
bilateral salpingectomy). Figure 1 
10. Males, if engaging in sexual intercourse with a female who is pregnant or a female of 
child-bearing potential, must agree to use a condom every time during the study and 
every time subsequently until 4 weeks beyond the last dose of investigational product. 
11. Males must agree not to donate sperm from the first dose of investigational product until 
4 weeks after the last dose of investigational product. 
12. Subject is in good health as judged by the Investigator, based on medical history, physical 
examination, 12-lead electrocardiogram (ECG), serum chemistry labs, hematology 
values, and urinalysis. 
4.5.2. 
Exclusion Criteria 
Subjects who meet any of the following exclusion criteria will be excluded from participation in 
this study:  
1. Males and females ages 18-21 years with first degree family members (parents, children, 
and/or siblings) who have a history of melanoma. 
2. Subjects with any serious medical condition or clinically significant laboratory, ECG, 
vital signs, or physical examination abnormality that would prevent study participation or 
place the subject at significant risk, as judged by the Investigator. 


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3. Subjects who have ever used skin bleaching treatments for treatment of vitiligo or other 
pigmented areas, eg, depigmenting agents such as monobenzyl ether of hydroquinone, 
including Benoquin® (Monobenzone). 
4. Use of any other prior and concomitant therapy that is a contraindication to phototherapy 
or may otherwise interfere with the objective of the study as per discretion of the 
Investigator, such as drugs that cause photosensitivity or skin pigmentation 
(eg, antibiotics such as tetracyclines, antifungals) within 8 weeks of Baseline (Visit 2). 
5. More than 33% leukotrichia in facial lesions (assessed via dermatoscope). 
6. Other forms of vitiligo (eg, segmental vitiligo); or other skin depigmentation disorder that 
would confound study assessments (eg, piebaldism, pityriasis alba, leprosy, 
post-inflammatory hypopigmentation, progressive macular hypomelanosis, nevus 
anemicus, chemical leukoderma, and tinea versicolor). 
7. Use of oral or systemic immunomodulating medications (eg, corticosteroids, 
azathioprine, methotrexate, cyclosporine) within 8 weeks of Baseline (Visit 2). 
(See Excluded Medications and Treatments, Table 2). 
8. Use of prescription or over-the-counter topical treatments that may affect vitiligo 
(eg, corticosteroids, tacrolimus/pimecrolimus, retinoids, vitamin D derivates, psoralens) 
within 4 weeks prior to Baseline (Visit 2) (See Excluded Medications and Treatments, 
Table 2).    
9. Use of any biological or experimental therapy for vitiligo within 24 weeks of Baseline 
(Visit 2) (or 5 half-lives, whichever is longer). 
10. Use of phototherapy (including laser and tanning beds) within 8 weeks prior to Baseline 
(Visit 2). 
11. Previous oral or topical JAK inhibitor therapy within 24 weeks prior to Baseline (Visit 2), 
and/or prior non-response to oral or topical JAK inhibitor therapy for vitiligo. 
12. History of melanocyte-keratinocyte transplantation procedure (MKTP) or other surgical 
treatment for vitiligo. 
13. Contraindication to phototherapy, such as photosensitivity disorder (eg, lupus, 
polymorphic light eruption, solar urticaria, dermatomyositis) or use of photosensitizing or 
phototoxic medications. 
14. Subjects with clinically significant abnormal thyroid-stimulating hormone or free T4 at 
screening, or otherwise uncontrolled thyroid function at screening as determined by the 
investigator (Note: If the subject has a history of thyroid disease and is on treatment, the 
subject must be on a stable thyroid regimen for at least 3 months prior to baseline). 
15. History of chronic alcohol or drug abuse within 6 months prior to baseline. 
16. Subjects with a cytopenia at screening, defined as follows: Leukocytes < 3 × 10^9/L 
(2.5 × 10^9/L for subjects who are African-American), Neutrophils < lower limit of 
normal (<1.5x10^9/L), Lymphocytes < 0.8 × 10^9/L, Hemoglobin < 10 g/dL, Platelets 
< 100 × 10^9/L. 




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29. Subjects who are family members of the clinical study site, clinical study staff, or 
sponsor, or family members that live in the same house of enrolled subjects. 
4.6. 
Removal of Subjects from Investigational Product 
A subject may discontinue investigational product for any of the following reasons: 
• Occurrence of any medical condition or circumstance that, in the opinion of the 
Investigator, does not allow the subject to adhere to the requirements for 
investigational product as per the protocol. 
• Occurrence of an Adverse Events as described in Section 5.9. The Investigator must 
follow the subject until the AE resolves or satisfactorily stabilizes. 
• Pregnancy: Treatment must be discontinued immediately in the event of a subject’s 
pregnancy.  
• Subject's decision to withdraw from investigational product. 
• Requirement for use of prohibited concomitant medication after consultation with the 
Sponsor and Medical Monitor. 
• Subject’s repeated failure to comply with protocol requirements or study related 
procedures. 
4.7. 
Removal of Subjects from the Study 
A subject may be removed from study participation for any of the following reasons:  
• Subject death. 
• Subject's decision to withdraw from study. 
• Subject is lost to follow-up. A subject will be considered lost to follow-up after three 
phone and three email attempts and documentation of a certified letter sent to the 
subject’s address. 
• Termination of the study by the Sponsor, FDA, or other regulatory authorities. 
4.8. 
Replacement of Subjects that Withdraw or are Discontinued from 
the Study 
Subjects who withdraw or are discontinued from the study will not be replaced.  
4.9. 
Prohibitions and Concomitant Therapy 
Prohibited medications and products are detailed in the Excluded Medications and Treatments 
(Table 2). 
Generally, the addition of new medications, including nonprescription medications, during the 
course of the study is discouraged.  However, the short-term use of a medication may be 
authorized by the Investigator.  The Investigator must make the decision to authorize the use of 


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any such a medication only after consideration of the clinical situation, the potential for masking 
symptoms of a more significant underlying event, and whether the use of the medication will 
compromise the outcome or validity of the clinical investigation.   
If medication is required, the name, strength, frequency, duration of use, and reason for use will 
be recorded in source documents and entered into the CRFs.  Medications which have been used 
chronically by subjects, in particular statins and anti-hypertensives, are allowed for use during 
the study, except as prohibited in (Table 2). 
Table 2: 
Excluded Medications and Treatments 
Excluded Medications and Treatment 
Washout Period Prior to Baseline 
Melanocyte-keratinocyte transplantation 
procedure (MKTP) or other surgical 
treatment for vitiligo 
Lifetime history is prohibited 
Skin bleaching treatments for past 
treatment of vitiligo or other pigmented 
areas, eg, depigmenting agents such as 
monobenzyl ether of hydroquinone, 
including Benoquin® (Monobenzone) 
Lifetime history is prohibited 
Topical treatments that may affect vitiligo 
(eg, corticosteroids, tacrolimus/ 
pimecrolimus, retinoids, vitamin D 
derivatives/preparations, psoralens), 
whether prescription or over-the-counter 
4 weeks 
Immunomodulating oral or systemic 
medications (eg, corticosteroids, 
azathioprine, methotrexate, cyclosporine) 
8 weeks 
Oral or topical JAK inhibitors 
24 weeks (prior lack of response is exclusionary) 
Biological or experimental therapy for 
vitiligo within 12 weeks of screening 
24 weeks or 5 half-lives (whichever is longer) 
Cell-depleting biologics such as rituximab 
6 months 
Strong Cytochrome P-450 3A4 inhibitors 
and strong Cytochrome P-450 3A4 
inducers 
2 weeks 
UVB or PUVA phototherapy (home or 
office-based), Excimer Laser, and tanning 
booths 
8 weeks 
All investigational drugs 
24 weeks (biologics); 8 weeks (oral); 4 weeks 
(topical) - or 5 half-lives (whichever is longer) 
Live vaccine therapy 
4 weeks 
 


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Notes:  
• Ear drop, eye drop and nasal corticosteroid preparations are allowed.   
• Non-medicated emollients should not be applied to treatment sites 2 hours before or 
after study drug application. 
• All topical products should be avoided (with the exception of mineral oil) for 
30 minutes before phototherapy because of the possibility of deactivation or 
interference with transmission of NB-UVB radiation. Mineral oil should only be used 
in unique circumstances of significant dryness and scaling in the treatment area and 
under the direction of the Investigator. 
• Subjects should avoid application of products with SPF on the day of phototherapy, 
prior to treatment. Subjects can apply sunscreen following the phototherapy 
treatment.   
• All subjects regardless of Fitzpatrick skin type, should apply a broad-spectrum 
sunscreen with a SPF > 30, with reapplication as needed when exposed to sunlight, 
and avoid sunlight to decrease the risk of additional UVB exposure and phototoxic 
effect. 
• Subjects must notify the Investigator if they are prescribed or intend to take any new 
medications, supplements, etc as they could be photosensitizing.   
4.10. 
Treatment 
4.10.1. 
IP Supplies, Packaging, and Labeling 
ARQ-252 cream 0.3% or vehicle formulation will be packaged in 12-gram tubes.  These tubes 
will be packaged in kits, containing 2 tubes each of investigational product for dispensation to 
randomized subjects.  The number of kits dispensed to a subject will be based on % BSA at 
baseline.  The kits and tubes will be labeled with a unique number, in a blinded manner. 
Either an active or sham 
 NB-UVB Home Phototherapy unit will be provided to 
the subject for home use based on randomization arm.   
Records will be made of the receipt and dispensation of investigational product and phototherapy 
unit.  At the conclusion of the study, any unused investigational product will be returned to the 
Sponsor or designee, or destroyed, as per Sponsor instructions. Phototherapy units will be 
returned to the designee as per Sponsor instructions.  
Refer to the most current version of the IP Handling Plan for details on accountability, storage, 
and management of IP and the NB-UVB Home Phototherapy Unit.  


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4.10.2. 
Treatment Administration 
Initial treatment with the IP and phototherapy will occur on Day 1 (Baseline) visit.  The 
treatment of IP will occur after the treatment with the phototherapy in the clinic.    
At the Day 1 (Baseline) visit, the study staff will instruct the subject how to apply IP using the 
first tube that is assigned to the subject at randomization.  Study site staff will inform the subject 
that one pea size amount of IP should be used to cover approximately 2% BSA (approximately 
2 hand prints), and instruct the subject to extrude the appropriate amount of investigational 
product based on the vitiligo BSA in each treatment area (face, neck, hands, forearms, and 
elbows).  Subjects will be instructed to treat (with IP and phototherapy), any new lesions that 
appear in the treatment areas during the treatment period. 
Study staff will provide oversight while the subject extrudes and applies the initial dose, 
including how the IP is applied as a thin film and rubbed in thoroughly but gently, until the 
cream has absorbed in the vitiligo areas on the face, neck, hands, forearms, and elbows and 
include 3 cm around the border of the application area. The study staff will confirm that the 
subject’s application technique is correct. 
All dispensed IP tubes must be returned by subjects at each study visit, to be weighed at the 
clinic. Re-training on the application of the IP will be conducted at subsequent visits as needed 
(i.e., if the returned tube weighs substantially different than the expected weight). 
At the Day 1 (Baseline) visit, the initial treatment with the phototherapy unit will occur prior to 
IP application.  The study staff will set up the phototherapy unit and review the instructions for 
use with each subject.  Subjects should avoid application of products with SPF on the day of 
phototherapy, prior to treatment. Subjects can apply sunscreen following the phototherapy 
treatment.  Washing the face and treatment areas is encouraged prior to phototherapy treatment.  
Subjects will be instructed to refrain from use of any topical products on the treated area with the 
exception of mineral oil for 30 minutes before phototherapy because of the possibility of 
deactivation or interference with transmission of NB-UVB.  Mineral oil should only be used in 
unique circumstances of significant dryness and scaling in the treatment area and under the 
direction of the Investigator.  Use of topical products for any reason will be recorded in the 
subjects’ diary and CRF. 
Subjects 18-21 years of age with pigmented lesions (eg, nevi) in the treatment field will be 
instructed to cover pigmented lesions (not areas of vitiligo repigmentation) to prevent NB-UVB 
exposure. 
Each subject will be instructed to complete the initial phototherapy treatment in accordance to 
the Vitiligo NB-UVB Treatment Protocol (Appendix 1) in the clinic.  The phototherapy 
treatment plan will be in alignment with the Fitzpatrick Skin Type.   


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4.10.3. 
Treatment Compliance 
IP Compliance: 
Each IP tube will be weighed prior to dispensing at the Baseline visit and subsequently at each 
follow-up clinic visit according to the Schedule of Visits and Assessments (Section 1.3).  When 
IP is applied at the clinic, the tube will be weighed before and after application.  If the subject’s 
actual use is substantially different than the expected use (see IP Handling Plan), the subject will 
be retrained on the investigational product extrusion and application technique. 
Subjects will complete a daily diary recording the date and time of each dose applied, any missed 
doses, and any relevant comments e.g., to record potential AEs or issues with the study 
medication/investigational product.  Site personnel will review the diaries and use the 
information to question the subject regarding compliance and AEs to record in source documents 
and CRFs.  
If a subject misses a dose of IP, they should be instructed to return to the protocol-specified 
investigational product administration schedule (i.e., if subject forgets a dose they should wait 
until the next planned application and apply as usual). The subject should document the missed 
dose in the subject diary card. 
A subject will be considered compliant with the IP dosing regimen if the subject applies at least 
80% of the expected doses during the treatment period and does not miss more than 
3 consecutive doses.  If the diary shows less than 80% of expected use, the subject is using too 
little investigational product and retraining must be conducted and documented. 
Compliance will be assessed by review of the dosing diary. Weight of investigational product 
applied will be measured for reporting purposes. 
Phototherapy Compliance: 
If a subject misses a phototherapy treatment, the subject should be instructed to document the 
missed treatment in the subject diary.  The subject should follow the guidance in the NB-UVB 
Vitiligo Treatment Protocol (Appendix 1) to determine the phototherapy dose of the next 
treatment. 
A subject will be considered compliant with the phototherapy treatment dosing regimen if the 
subject completes 80% of the required treatments over the total of the 24 week treatment period.  
Compliance will be assessed by review of the subject diary and will be documented in source 
and in CRF. 


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5. 
STUDY PROCEDURES 
5.1. 
Safety Assessments 
The Schedule of Visits and Assessments (Section 1.3) summarizes the clinical procedures to be 
performed at each visit. Individual clinical procedures are described in detail below. Additional 
evaluations/testing may be deemed necessary by the PI and/or the Sponsor for reasons related to 
subject safety. 
This study assesses the safety, efficacy, and PK of ARQ-252 cream 0.3% and vehicle cream in 
combination with active or sham phototherapy.  Safety will be determined by evaluating physical 
examinations, 12-lead ECGs, vital signs/weight, clinical laboratory parameters, local tolerability 
assessments, and AEs as outlined in the Schedule of Visits and Assessments (Section 1.3). 
Subjects will be monitored for the reactivation of herpes simplex virus or varicella zoster virus 
following the initiation of phototherapy treatment.   In addition, subjects who will treat vitiligo 
on the hands will be monitored for changes in the nails following the initiation of phototherapy 
treatment.  Changes noted from these assessments will be recorded in the CRF. 
If deemed necessary, additional safety assessments will be performed at the discretion of the 
Investigator. 
5.1.1. 
Screening 
Before a subject’s participation in the clinical study, the Investigator is responsible for obtaining 
written informed consent from the subject after adequate explanation of the study design, 
anticipated benefits, and the potential risks. 
The following procedures/assessments will be performed at the Screening Visit (within 4 weeks 
after signing the informed consent): 
• Review of medical and surgical history, including any history of allergies  
• Review of childbearing potential (subject or partner of male subject) and 
contraceptive use (Section 5.1.2) 
• Collection of demographic data including sex, age, race, ethnicity 
• Limited physical examination of skin, lungs, and heart 
• Vital signs including weight, temperature, heart rate, and blood pressure 
• ECG 
• Medical history of vitiligo will include the following information, which will be 
recorded in the CRF:   
− Location (ie, face, neck, hands, forearms) 
− Distribution/Characteristics: Presence of confetti, trichrome, or inflammatory 
vitiligo lesion patterns or other clinical signs of active vitiligo 
• Assessment of Fitzpatrick skin type 


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• BSA Assessments (F-BSA, F/N-BSA, BSA (hands, forearms, elbows), 
BSA (total body)  
• Vitiligo assessments (F-VASI, F/N-VASI, FOREARM-VASI, HAND-VASI, 
T-VASI, and FsIGA) 
• Laboratory tests: hematology, chemistry, urinalysis, TSH, T4, serum pregnancy test 
(for female subjects of childbearing potential), FSH (if indicated to confirm 
post-menopausal status) 
• Collection of concomitant medications and adverse events 
All screened subjects will receive a screening number and will be entered into the Interactive 
Response Technology (IRT) system at the time of consent.  
Subjects may be re-screened one time, the original assigned Subject ID screening number will be 
used for re-screening. 
5.1.2. 
Contraception Requirements 
Previous nonclinical research showed that the active ingredient in ARQ-252 can harm fetal 
development. Subjects engaging sexual intercourse that could lead to pregnancy must adhere to 
the following pregnancy testing and/or contraception requirements.  
Female Subjects: 
Female subjects of childbearing potential (FOCBP) must have a negative serum pregnancy test at 
Screening and negative urine pregnancy test at Baseline (Visit 2).  For FOCBP involved in any 
sexual intercourse that could lead to pregnancy: the subject must agree to use a highly effective 
contraceptive method for at least 4 weeks prior to Day 1.  Additionally, from Day 1 until at least 
4 weeks after the last investigational product administration, these subjects must agree to use at 
least 1 highly effective contraceptive method in addition to 1 barrier method of contraception. 
The acceptable methods of contraception are listed below in the Figure 1. 


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Figure 1: 
Contraception Requirements for Female Subjects 
 
 
Male Subjects:  
Males, if engaging in sexual intercourse with a female who is pregnant or a female of 
childbearing potential, must agree to use a condom every time during the study and every time 
subsequently until 4 weeks after the last investigational product administration. 
5.1.3. 
Physical Examination 
Physical examinations will be performed according to the Schedule of Visits and Assessments 
(Section 1.3).  The physical exam will be limited to skin, lungs and heart only. 
5.1.4. 
Vital Signs, Height and Weight 
Vital signs will be performed according to the Schedule of Visits and Assessments (Section 1.3). 
Blood pressure, heart rate, and temperature will be collected in seated position after 
approximately 5 mins. Subjects will be instructed to void prior to weight being taken and to 
remove any objects of significant weight (i.e., jackets, outerwear, shoes, cell phones, wallet, key 
chains, etc.).  
Height will be measured at Baseline (Day 1) only. 


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5.1.5. 
Fitzpatrick Skin Type Assessment 
At screening, Fitzpatrick skin phototype will be rated:  
I: Always burns easily; never tans (sensitive)  
II: Always burns easily; tans minimally (sensitive) 
III: Burns moderately; tans gradually (light brown) (normal)  
IV: Burns minimally; always tans well (moderate brown) (normal)  
V: Rarely burns; tans profusely (dark brown) (insensitive)  
VI: Never burns; deeply pigmented (insensitive) 
5.1.6. 
12-lead ECGs 
12-lead ECGs will be performed according to the Schedule of Visits and Assessments 
(Section 1.3). 
ECGs will be obtained on subjects after approximately 5 minutes in the supine position. All ECG 
tracings and readouts will be reviewed by the Investigator and central reader at the ECG 
laboratory. 
5.1.7. 
Laboratory Tests 
Hematology 
Serum Chemistry 
• 
Hemoglobin 
• 
Hematocrit  
• 
Total and differential leukocyte count 
• 
Red blood cell count with indices and 
morphology 
• 
Platelet count 
• 
Reticulocyte count1 
• 
Blood Urea Nitrogen 
• 
Bilirubin (total and direct) 
• 
Alkaline phosphatase 
• 
Aspartate aminotransferase 
• 
Alanine aminotransferase 
• 
Albumin 
• 
Sodium 
• 
Potassium 
• 
Chloride 
• 
Glucose 
• 
Creatinine 
• 
Creatine kinase 
Urinalysis 
Additional Tests 
• 
pH 
• 
Specific gravity 
• 
Protein2 
• 
Glucose 
• 
Ketones 
• 
Bilirubin 
• 
Blood2 
• 
Nitrite2 
• 
Urobilinogen 
• 
Leukocyte esterase2 
• 
Thyroid Stimulating Hormone T4 (TSH/T4)  
• 
Urine pregnancy test3 
(for females of childbearing potential only) 
• 
Serum pregnancy test (hCG)4 
• 
Follicle-stimulating Hormone (FSH) 5 
• 
Pharmacokinetic (PK) assessments 
• 
Fasting Lipids (cholesterol, triglycerides, HDL, and LDL) 6  
 
 


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From table above: 
1 If red blood cell count, hemoglobin or hematocrit values are below the lower limit of normal, reticulocyte count 
will be performed 
2 If urinalysis is positive for protein, blood, nitrite and/or leukocyte esterase, a microscopic examination (for red 
blood cells, white blood cells, bacteria, casts, and epithelial cells) will be performed. 
3 At Baseline, Week 4, 8, 12, 16, 20, and 24 for FOCBP only.  
4 At screening only for FOCBP. 
5 If indicated to confirm post-menopausal status 
6 Fasting required for a minimum of 8 hours prior to blood draw 
5.1.8. 
Local Tolerability Assessment 
The Investigator Local Tolerability Assessments will be performed according to the Schedule of 
Visits and Assessments (Section 1.3).  Application site reactions are graded using the scale 
detailed in the following section (Berger 1982).  
The Investigator Local Tolerability Assessment will be conducted by the Investigator prior to 
investigational product application in the clinic. 
Investigators will specify if any application site reaction is due, in whole or in part, to the 
effects of phototherapy treatment.  
Dermal Response 
0. no evidence of irritation 
1. minimal erythema, barely perceptible 
2. definite erythema, readily visible; minimal edema or minimal papular response 
3. erythema and papules 
4. definite edema 
5. erythema, edema, and papules 
6. vesicular eruption 
7. strong reaction spreading beyond application site 
Other Effects 
A. = slight glazed appearance 
B. = marked glazing 
C. = glazing with peeling and cracking 
D. = glazing with fissures 
E. = film of dried serous exudates  
F. = small petechial erosions and/or scabs 
G. = no other effects 
The Subject Local Tolerability Assessments will be performed according to the Schedule of 
Visits and Assessments (Section 1.3).   
The Subject Local Tolerability Assessment will be administered by the site 10 to 15 minutes 
after investigational product application in the clinic. 


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The subject will assess burning/stinging (0-3 score): 
Local Tolerability Assessment 
Grade 
Sensation Following Investigational Product Application 
0 (none) 
No sensation 
1 (mild) 
Slight warm, tingling sensation; not really bothersome 
2 (moderate) 
Definite warm, tingling sensation that is somewhat bothersome 
3 (severe) 
Hot, tingling/stinging sensation that has caused definite discomfort 
5.1.9. 
Adverse Events 
Serious adverse events (SAEs) will be collected from the time the Informed Consent Form (ICF) 
is signed through 30 days after the last day of the application of the investigational product or the 
end of study (whichever is later).  
Adverse events (AEs) will be collected following the first application of investigational product 
through the end of the study. 
Please see Section 5.7 for further details regarding the collection and reporting of adverse events.  
5.2. 
Efficacy Evaluations 
5.2.1. 
Independent Rater Requirement 
To reduce possible functional unblinding and bias, independent raters will conduct efficacy 
assessments while separate trained members of the research team will conduct safety 
assessments and other activities of study oversight.  
An independent rater is a trained research team member that is not aware of a subject’s response 
to treatment as it pertains to safety including AEs such as local treatment site reactions.   
The independent rater assigned for a subject: 
• may conduct screening activities.  
• have not participated in any activities prohibited for that role (e.g., safety 
assessments) following initial IP/phototherapy treatment for that subject. 
• is not absolutely required to be the same person for each assessment, although it is 
strongly preferred that the same rater be used consistently wherever possible. 
At the end of the study, the independent rater will be asked to complete an attestation to 
determine if they remain blinded as to the subject’s treatment group. 


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5.2.2. 
Body Surface Area 
BSA assessments will be performed according to the Schedule of Visits and Assessments 
(Section 1.3). 
The BSA affected with vitiligo will be assessed as a percentage of the total BSA, and will be 
determined to the nearest 0.01% 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. 
• Facial BSA (F-BSA) will be evaluated for the purpose of inclusion in the study.  The 
area "Face" is defined as including the area on the forehead to the original hairline, on 
the cheek to the jawline vertically to the jawline and laterally from the corner of the 
mouth to the tragus. The area "Face" will not include surface area of the lips, scalp, 
ears, or neck but will include the eyelids and nose. 
• F/N-BSA includes the BSA of the face and neck. 
• BSA of the hands, forearms and elbows will include BSA affected with vitiligo in 
those aforementioned areas. 
• BSA (total body) will include all areas of the body affected with vitiligo. 
5.2.3. 
Vitiligo Area Scoring Index (VASI) 
Areas affected by depigmentation due to vitiligo will be assessed using the VASI, which is a 
quantitative clinical tool that 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.  
The reliability and validity of F-VASI and T-VASI instruments as measures of treatment 
efficacy were confirmed (Rosmarin 2020). 
VASI is measured by percentage of vitiligo involvement (% of BSA) and the degree of 
depigmentation. The percentage of BSA (hand unit) vitiligo involvement is estimated by the 
Investigator using the Palmar Method. Hand unit is based on subject’s hand size. The 
Investigator uses his/her hand to mimic the subject’s hand size to evaluate percentage of BSA 
vitiligo involvement.  
The following VASI scoring will be completed per the Schedule of Visits and Assessments 
(Section 1.3). 
• F-VASI: The area "Face" is defined as the area included in the validation of F-VASI 
(Rosmarin 2020), with the additional inclusion of the eyelids. “Face” is defined as the 
area on the forehead to the original hairline, on the cheek to the jawline vertically to 
the jawline and laterally from the corner of the mouth to the tragus. The area "Face" 
will not include surface area of the lips, scalp, ears, or neck but will include the 
eyelids and nose.  
• F/N-VASI: Includes the VASI of the face and neck 
• FOREARM-VASI: Includes VASI (total score) of the Forearms and Elbows 
• HAND-VASI: Includes VASI of the hands only 


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• T-VASI: Includes VASI of the following 6 separate and mutually exclusive sites: 
(1) head/neck, (2) hands, (3) upper extremities (excluding hands), (4) trunk, (5) lower 
extremities (excluding feet), and (6) feet. 
The degree of depigmentation foreach vitiligo involvement site is determined and estimated to 
the nearest of the following percentages: 0, 10%, 25%, 50%, 75%, 90%, or 100%. At 100% 
depigmentation, no pigment is present; at 90%, specks of pigment are present; at 75%, the 
depigmented area exceeds the pigmented area; at 50%, the depigmented and pigmented area are 
equal; at 25%, the pigmented area exceeds the depigmented area; at 10%, only specks of 
depigmentation are present.  
The VASI is then derived by multiplying the values assessed for the vitiligo involvement by the 
percentage of affected skin for each site and summing the values of all sites together.  
The percentage of vitiligo involvement is estimated in hand units by the same investigator during 
the entire course of the study.  
5.2.4. 
Vitiligo Quality of Life (VitiQoL) 
The Vitiligo Quality of Life (VitiQOL) will be completed according to the Schedule of Visits 
and Assessments (Section 1.3). The VitiQOL is an instrument designed to assess disease specific 
health-related quality of life (HRQL) in patients suffering from vitiligo and also provide an 
objective measure of disease status, burden of disease, and treatment outcome (Appendix 2). It 
consists of 16-item questionnaire with a 7-point numerical scale from 0 - Not at all to 6 - All of 
the time. 
5.2.5. 
Vitiligo Noticeability Scale (VNS) 
The Vitiligo Noticeability Scale (VNS) is a 5-point scale which compares vitiligo from before 
treatment to how noticeable the vitiligo is at the time the VNS is performed. The VNS will be 
completed by subjects with respect to vitiligo on the facial target patch. The target patch on the 
face is selected by the subjects as being the patch that they would most like to see an 
improvement in. The photos taken of the facial target patch at the Baseline visit prior treatment 
and at the subsequent visits will be used as reference for the assessment (Appendix 3). 
5.2.6. 
Facial Static Investigator Global Assessment (FsIGA) 
The Facial Static Investigator Global Assessment (FsIGA) is a global score of vitiligo severity 
for the face only. The outcome measure incorporates location, distribution, size, depigmentation 
within lesions and presence or absence of signs of activity. Examination of skin should be 
performed with both normal lighting and Woods lamp (Appendix 4).  
5.2.7. 
Patient Global Impression of Change-Vitiligo (PaGIC-V) 
The PaGIC-V is an assessment of improvement by the subject and is to be evaluated in this study 
specifically with respect to facial vitiligo.  It is a 7-point scale comparing facial vitiligo at 
baseline with the subject’s treated facial vitiligo at the study visit. (Appendix 5)    


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5.3. 
Other Evaluations 
5.3.1. 
Medical Photography 
Digital Photography will be conducted at all sites for all subjects according to the Schedule of 
Visits and Assessment (Section 1.3).  Photos will be taken of the facial target patch at the 
Baseline visit prior treatment and at the subsequent visits as reference for the VNS assessment. 
Fixed, multi-angle photos will be taken at select sites for additional evaluation. 
5.3.2. 
Pharmacokinetics Assessment 
PK sampling will be performed according to the Schedule of Visits and Assessments 
(Section 1.3) for all subjects at all sites: 
• PK will be evaluated through trough/pre-dose sampling at Baseline, Week 4, 
Week 12, and Week 24.  
Subjects should apply investigational product 11-12 hours before the PK collection time. 
PK samples will be collected while the subject is having safety labs drawn at applicable visits. 
The PK samples will be completed prior to investigational product application in the clinic. 
Ensure investigational product is not applied in the area where PK will be drawn. 
5.4. 
Final Study Visit 
The final study visit will take place at approximately Week 25. The procedures performed during 
this visit are as described in the Schedule of Visits and Assessments (Section 1.3).  A 7-day 
scheduling window is allowed for this visit. Adverse events will be recorded as reported by the 
subject and followed to resolution (as necessary). 
5.5. 
Early Termination Visit 
If a subject is withdrawn or wishes to exit the study prior to the final study visit, an early 
termination visit will be scheduled. This visit should include the procedures and assessments that 
would be performed at the Week 24 visit as described in the Schedule of Visits and Assessments 
(Section 1.3). 
5.6. 
Unscheduled Visit 
Unscheduled visits may be necessary to repeat testing following abnormal laboratory results, for 
follow-up of AEs, or for any other reason, as warranted in the judgement of the Investigator. 
The following information will be collected for all subjects: 
• Concomitant medications/procedures 
• AEs 
• F-VASI, F/N-VASI, FOREARM-VASI (forearms and elbows), HAND-VASI, and 
T-VASI  


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5.7. 
Adverse Events 
5.7.1. 
Adverse Event Definition 
An adverse event (AE) means any untoward medical occurrence associated with the use of a 
drug in humans, whether or not considered drug or device related. An AE can therefore be any 
unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or 
disease temporally associated with the use of a medicinal (investigational) product or device, 
whether or not related to the medicinal (investigational) product or device.   
The definition of an AE includes worsening of a pre-existing medical condition.  Worsening 
indicates that the pre-existing medical condition has increased in severity, frequency, and/or 
duration or has an association with a worse outcome.  A pre-existing condition that has not 
worsened during the study or involves an intervention, such as elective cosmetic surgery or a 
medical procedure while on study, is not considered an AE. 
Adverse events resulting from device deficiency will also be reported.  A device deficiency is 
inadequacy of a medical device related to its identity, quality, durability, reliability, safety or 
performance, such as malfunction, misuse or use error and inadequate labeling.  
Irradiated site reactions will be considered adverse events if they exceed the expected irradiation 
reaction per the Investigator’s discretion, require medical intervention (e.g. treatment with 
medication or dressings prescribed or applied by a physician) or discontinuation of phototherapy 
treatment. 
5.7.2. 
Serious Adverse Event 
The Investigator is responsible for ensuring that all serious adverse events observed by the 
clinical staff or reported by the subject that occur after signing of the informed consent through 
30 days after the last day of the application of the investigational product or the end of study 
(whichever is later) are recorded in the subject’s medical record and are submitted per SAE 
reporting requirements. 
All SAEs will be reported to the Sponsor (or delegate) within 24 hours of becoming aware of the 
event, whether or not the serious events are deemed IP related. All serious event reporting will 
adhere to ICH E6: Guideline for Good Clinical Practice and ICH E2A: Clinical Safety Data 
Management: Definitions and Standards for Expedited Reporting.:  The ERB/IRB will be 
notified of the Alert Reports as per HC, FDA, ICH and the IRB/ERB’s policies and procedures. 
Refer to the Safety Reporting Instructions for SAE reporting. 
An SAE is any AE that in the view of either the PI or Sponsor, results in any of the following 
outcomes:  Death, a life threatening AE, inpatient hospitalization or prolongation of existing 
hospitalization, a persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions, or a congenital anomaly/birth defect.  Important medical events 
that may not result in death, be life threatening, or require hospitalization may be considered 
serious when, based upon appropriate medical judgment, they may jeopardize the subject and 
may require medical or surgical intervention to prevent one of the outcomes listed in the above 
definition. Examples of such medical events include allergic bronchospasm requiring intensive 


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treatment in an emergency room or at home, blood dyscrasias or convulsions that do not result in 
inpatient hospitalization, or the development of drug dependency or drug abuse.  
Life threatening is defined as an AE that in the view of the PI or Sponsor, places the subject at 
immediate risk of death. It does not include an AE that, had it occurred in a more severe form, 
might have caused death. 
Hospitalization does not include the following: 
• Rehabilitation facilities, hospice facilities or respite care (e.g., caregiver relief) 
• Nursing homes or skilled nursing facilities 
• Emergency room visits 
• Same day surgeries (as outpatient/same day/ambulatory procedures) 
• <24 hour admissions for observation or evaluation 
Hospitalization or prolongation of hospitalization in the absence of a precipitating, clinical AE is 
not in itself an SAE.  Examples include: 
• Admission for treatment of a preexisting condition that did not worsen 
• Hospitalizations for cosmetic elective surgery, social, and/or convenience admissions 
• Pre-planned treatments or surgical procedures should be noted in the history 
documentation for the individual subject 
• Diagnostic and therapeutic procedures, such as surgery, should not be reported as 
AEs; however, the medical condition for which the procedure was performed should 
be reported if it occurs during the reporting period and meets the definition of an AE.  
For example, an acute appendicitis that begins during the AE reporting period should 
be reported as an AE, and the resulting appendectomy should be recorded as 
treatment of the AE. 
Unexpected is defined as an AE that is not listed in the IB or is not listed at the specificity or 
severity that has been observed; or is not consistent with the risk information described in the 
general investigational plan or elsewhere in the current study documentation. 
If an SAE occurs to a subject on this study, contact the Medical Monitor within one business day 
of knowledge of event. 
The definitions and reporting requirements of Health Canada/the Food and Drug Administration 
(FDA)/ICH Guidelines for Clinical Safety Data Management, Definitions and Standards for 
Expedited Reporting, Topic E2A will be adhered to. If any AEs are serious, as defined by 
ICH Guidelines for Clinical Safety, required procedures will be followed.  


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5.7.3. 
Suspected Unexpected Serious Adverse Reaction (SUSAR) 
This is defined as a serious adverse reaction, the nature or severity of which is not consistent 
with the known study treatment information. A serious event or reaction is not defined as a 
SUSAR when: ‘it is serious but expected’ or it does not fit the definition of an SAE, whether 
expected or not. 
5.7.4. 
Safety Review with Subject 
At each follow-up visit, subjects will be queried with an open-ended question such as: 
‘How have you been feeling since your last visit?’  Additionally, the study staff will review 
subject diaries and, if it appears that a potential AE was recorded, study staff will query the 
subject and determine if an AE occurred.   
Where appropriate, medical test(s) and/or examination(s) will be performed to document 
resolution and/or outcome of event(s).  
5.7.5. 
Adverse Event Reporting 
The Investigator is responsible for ensuring that all adverse events observed by the clinical staff 
or reported by the subject that occur after baseline the first application of investigational product 
through the end of the study are recorded in the subject’s medical record and the eCRF.   
AEs (whether serious or non-serious) and clinically significant abnormal laboratory test value(s) 
will be evaluated by the PI and treated and/or followed up for up to 30 days after end of 
treatment or until the symptoms or value(s) return to normal, or acceptable levels, as judged by 
the PI.  
The Investigator will review each event and assess its relationship to investigational product 
treatment (unrelated, unlikely, possibly, probably, likely) or phototherapy treatment (unrelated, 
likely). Each sign or symptom reported will be graded on the NIH NCI CTCAE (Version 5.0) 
toxicity grading scale 5-point severity scale (Grade 1, 2, 3, 4 and 5). The date and time of onset, 
time relationship to drug dosing and/or phototherapy treatment, duration, and outcome of each 
event will be noted.   
The relationship of each AE to the investigational product will be assessed using the following 
definitions: 
Unrelated 
The AE must clearly be caused by the subject’s clinical state, or the study 
procedure/conditions. 
Definitely not related to drug. 
Temporal sequence of AE onset relative to administration of drug not reasonable. 
Another obvious cause of an AE. 
Unlikely 
Time sequence is unreasonable. 
There is another more likely cause for an AE. 
Possibly 
Corresponds to what is known about the drug. 
Time sequence is reasonable. 
Could have been due to another equally, likely cause. 


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Probably 
Is a known effect of the drug. 
Time sequence from taking drug is reasonable. 
Ceases on stopping the drug. 
Cannot be reasonably explained by the known characteristics of the subject’s clinical 
state. 
Likely 
Is a known effect of the drug (e.g., listed in Physicians' Desk Reference, 
Compendium of Pharmaceuticals and Specialties, IB). 
Time sequence from taking drug is reasonable. 
Event stops upon stopping drug, event returns upon restarting drug. 
 
The relationship of each AE to the phototherapy treatment will be assessed using the following 
definitions: 
Unrelated 
The AE must clearly be caused by the subject’s clinical state, or the study 
procedure/conditions. 
Definitely not related to phototherapy treatment. 
Temporal sequence of AE onset relative to phototherapy treatment not reasonable. 
Another obvious cause of an AE. 
Likely 
Is a known effect of the phototherapy treatment (e.g., listed in Fitzpatrick’s 
Dermatology, 9th Edition). (Kang 2019) 
Time sequence from the phototherapy treatment is reasonable. 
Event stops upon cessation of phototherapy treatment, event returns upon restarting 
phototherapy treatment. 
The following CTCAE toxicity grading scale 5-point severity scale definitions for rating 
maximum severity will be used: 
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 instrumental 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.** 
Note: An experience may be severe but may not be serious, e.g., severe headache). 
Grade 4 
Life-threatening consequences; urgent intervention indicated. 
Grade 5 
Death related to AE. 
Note: A semi-colon indicates ‘or’ within the description of the grade. 
* Instrumental activities of daily living refer to preparing meals, shopping for groceries or clothes, using the 
telephone, managing money, etc. 
** Self-care activities of daily living refer to bathing, dressing and undressing, feeding self, using the toilet, taking 
medications, and not bedridden. 


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The Investigator is responsible for the assessment of all adverse events to determine if the event 
is related to the Investigational Product, Phototherapy Treatment, or both. AEs will be coded 
using the most current MedDRA® version available at the start of the study (e.g., 21.0 or higher). 
5.8. 
Reporting Pregnancy 
During the study, all subjects should be instructed to contact the Investigator immediately if they 
suspect they might be pregnant (e.g., missed or late menstrual period).  If pregnancy is 
confirmed, Investigational Product must be discontinued immediately, the subject should be 
referred to an obstetrician experienced in reproductive toxicity for evaluation and counseling, 
and the subject should be followed until conclusion of the pregnancy. Subject may be required to 
sign a separate informed consent form to obtain pregnancy follow-up information, per local 
requirements. 
The Investigator is responsible for reporting all available pregnancy information on the 
pregnancy report and submitting to the Medical Monitor within 24 hours of becoming aware of 
the event, although pregnancy itself is not considered an AE.  Follow-up information detailing 
the outcome of the pregnancy and the health of the newborn should be reported as it becomes 
available.  Any pregnancy resulting in a congenital abnormality or birth defect of the newborn, 
or neonatal death occurring within 30 days of the birth must be reported as a SAE, regardless of 
causality. Any infant death that occurs after the 30-day reporting period that the Investigator 
suspects is related to Investigational Product must also be reported as an SAE. 
Partner pregnancies of a male subject will be reported. 
5.9. 
Treatment Stopping Rules 
If a subject has non-cutaneous adverse events of concern, clinically significant laboratory values 
or any condition that the Investigator determines could possibly be related to the investigational 
product, the Investigator should immediately contact the Medical Monitor to discuss if the 
subject should be discontinued from treatment with investigational product.   
Treatment for any individual subject should be interrupted if the Investigator observes the 
following: 
• If a subject develops an application site reaction with the clinical appearance of an 
‘irritation reaction’, and with a severity of a Dermal Response Score of 5 
(erythema, edema, and papules) on Local Tolerability Assessment (Section 5.1.8), 
treatment should be interrupted for up to one week and may then be resumed if the 
reaction has, in the opinion of the Investigator, adequately resolved.   
For application site reactions treatment should be discontinued: 
• If the application site reaction reoccurs, treatment should be discontinued 
permanently, and the subject followed until the reaction resolves.   


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Treatment for any individual subject will be discontinued if the subject experiences:  
• A serious adverse event (SAE) or a clinically significant non-serious AE which in the 
opinion of the Principal Investigator or Medical Monitor warrants discontinuation 
from the study for that subject’s well-being. 
• A treatment-emergent severe (Grade 3) laboratory abnormality (confirmed by repeat 
sample) which in the opinion of the Principal Investigator or Medical Monitor 
warrants discontinuation from the study for that subject’s well-being. 
• A severe infection (Grade 3 or higher) 
• An ischemic or thromboembolic cardiovascular event (regardless of Grade) 
• A severe adverse event within the system-organ class of Cardiac Disorders (Grade 3 
or higher) 
As noted above, study treatment must be discontinued immediately in the event of a female 
subject’s pregnancy.   
In the event of a medical emergency where unblinding is required to provide medical care to the 
subject, refer to the most current IRT plan and Breaking Treatment Codes (Section 4.4.1). 
Contact the Medical Monitor and the Sponsor promptly. 
6. 
STATISTICAL METHODS 
Data will be handled and processed according to the Contract Research Organization’s Standard 
Operating Procedures, which are written based on the principles of GCP. 
6.1. 
Statistical Methods 
The methodology presented below is a summary of the more detailed analysis plan that will be 
presented in the Statistical Analysis Plan (SAP).  The SAP will be finalized before the database 
is locked and unblinded. Any changes to the methods described in the final SAP will be 
described and justified in the clinical study report. 
All statistical processing will be performed using SAS® (Version 9.4) unless otherwise stated.  
Descriptive statistics will be used to provide an overview of the safety, efficacy, and 
pharmacokinetic results.  For categorical parameters, the number and percentage of subjects in 
each category will be presented. The denominator for percentage will be based on the number of 
subjects appropriate for the purpose of analysis.  For continuous parameters, descriptive statistics 
will include n (number of subjects), mean, standard deviation (SD), median, minimum, 
and maximum. 
Missing efficacy data for F-VASI will be imputed using multiple imputation. 
For statistical comparisons other than those for the primary and hierarchical secondary 
endpoints, the overall 0.05 significance level will be used and no adjustments will be made for 
multiple comparisons. 


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6.1.1. 
Pharmacokinetics Assessment 
Plasma pre-dose concentrations will be compared between treatment groups to evaluate potential 
differences. 
6.1.2. 
Determination of Sample Size 
The primary statistical comparison will be to compare  
• ARQ-252 cream 0.3% in combination with phototherapy vs. vehicle cream in 
combination with NB-UVB 
• ARQ-252 cream 0.3% in combination with phototherapy vs. ARQ-252 cream 0.3% in 
combination with sham phototherapy at the 5% significance level.   
A sample size of 500 subjects will provide approximately 84% power to detect an ARQ-252 
cream 0.3%  in combination with phototherapy response rate of at least 50% vs. a vehicle cream 
in combination with phototherapy response of rate of 30% and approximately 84% power to 
detect an ARQ-252 cream 0.3% in combination with phototherapy rate of at least 50% vs. an 
ARQ-252 cream 0.3% in combination with sham phototherapy  rate of 30% using a stratified 
Cochran-Mantel-Haenszel test conducted at the 0.025 alpha level for each comparison.  A drop 
out rate of 15% at 24 weeks is assumed.  
Upon successful testing for the comparisons above, a hierarchical testing scheme will be used to 
test the following secondary comparisons: 
• ARQ-252 cream 0.3% in combination with phototherapy vs. vehicle cream BID in 
combination with the sham phototherapy 
• ARQ-252 cream 0.3% in combination with sham phototherapy vs. vehicle cream BID 
in combination with the sham phototherapy 
• Vehicle cream BID in combination with phototherapy vs. vehicle cream BID in 
combination with the sham phototherapy 
Assuming a Vehicle cream BID in combination with the sham phototherapy rate of no more than 
5%, these comparisons are expected to have at least 74% power.  These comparisons will be 
made at either the 0.025 or 0.05 level, depending on the outcome of the primary statistical 
comparisons. 
6.1.3. 
Subjects to Analyze 
Three analysis populations will be defined: 
• The Safety population will include all subjects who are enrolled and received at least 
one confirmed dose of investigational product. This population will be used for all 
safety analyses and will be defined separately for each treatment arm. 
• The Intent-to-Treat (ITT) will include all subjects randomized in the study. This 
population will be the primary analysis for the analysis of efficacy endpoints. 


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• The PK population will include all subjects who are randomized and receive at least 
one application of investigational product and have at least one analyzed PK sample. 
6.1.4. 
Background and Demographic Characteristics 
Demographics, baseline disease characteristics, baseline height, weight, and BSA will be 
summarized descriptively for all enrolled subjects. 
6.1.5. 
Study Disposition 
The number of subjects randomized, receiving IP, completing study, and withdrawing 
prematurely (with reason for withdrawal) will be summarized by treatment group. 
6.1.6. 
Investigational Product Application Compliance 
The number of subjects with important protocol deviations and/or eligibility deviations will be 
summarized by category and by treatment group. 
6.2. 
Efficacy Evaluation 
Efficacy endpoints were evaluated by an independent rater as described in Section 5.2.1.  
6.2.1. 
Primary Efficacy Endpoint 
The primary efficacy endpoint will be the proportion of subjects achieving F-VASI75 
(≥ 75% improvement from baseline in Facial Vitiligo Area Scoring Index (F-VASI) score) at 
Week 24. 
The primary endpoint of ‘Proportion of subjects achieving F-VASI75 (≥ 75% improvement from 
baseline in Facial Vitiligo Area Scoring Index (F-VASI) score) at Week 24 will be analyzed 
using a Cochran-Mantel-Haenszel test stratified by the stratification factors study site and 
Fitzpatrick Skin Type (I-III vs. IV-VI).  The analysis will be performed on the Intention-to-Treat 
(ITT) population and missing data will be imputed using multiple imputation.  
6.2.2. 
Secondary Efficacy Endpoints 
Continuous secondary endpoints will be analyzed using Analysis of Covariance with treatment 
and stratification factor as independent variables.  Binary secondary endpoints will be analyzed 
similarly to the primary endpoint. 
The secondary efficacy endpoints will include: 
• Proportion of subjects achieving F-VASI75 (≥ 75% improvement from baseline in 
F-VASI score) at visits prior to Week 24. 
• Percent change from baseline in F-VASI score at all visits. 
• Percent change from baseline in facial body surface area (F-BSA) at all visits. 
• Proportion of subjects achieving F-VASI50 (≥ 50% improvement from baseline in 
F-VASI score) at all visits. 


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• Proportion of subjects achieving F-VASI90 (≥ 90% improvement from baseline in 
F-VASI score) at all visits. 
• Proportion of subjects in each category of VNS at specified visits. 
• Change from Baseline in the VNS at specified visits. 
• Change from Baseline in the VitiQoL at specified visits. 
• Patient Global Impression of Change-Vitiligo (PaGIC-V), proportion of patients in 
each PaGIC-V category at specified visits. 
• Proportion of subjects who report PaGIC-V of very much improved or much 
improved during the treatment period. 
• Time to achieve F-VASI50. 
• Time to achieve F-VASI75. 
• Time to achieve FsIGA of clear or almost clear (0 or 1). 
• FsIGA of clear or almost clear (0 or 1). 
• FsIGA of clear or almost clear (0 or 1) plus 2-grade improvement from baseline. 
• Time to achieve a PaGIC-V of very much improved or much improved. 
The binary secondary endpoints will be analyzed using a Cochran-Mantel-Haenszel test stratified 
by study site, age <30 or >30 years, and Fitzpatrick Skin Type (I-III vs. IV-VI).   
6.2.3. 
Exploratory Endpoints 
• Percent change from baseline in combined face and neck body surface area 
(F/N-BSA) at all visits. 
• Percent change from baseline in surface area BSA (hands/forearms/elbows) at all 
visits. 
• Percent change from baseline in BSA affected across all treatable sites (face, neck, 
hands, forearms, elbows) at all visits. 
• Proportion of subjects achieving F/N-VASI50 (≥ 50% improvement from baseline in 
F/N-VASI score) at all visits. 
• Proportion of subjects achieving F/N-VASI75 (≥ 75% improvement from baseline in 
F/N-VASI score) at all visits. 
• Proportion of subjects achieving F/N-VASI90 (≥ 90% improvement from baseline in 
F/N-VASI score) at all visits. 
• Percent change from baseline in FOREARM-VASI (forearms/elbows) score at all 
visits. 
• Percent change from baseline in HAND-VASI (hands only) score at all visits. 


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• Serum levels of ARQ-252. 
• The proportions of subjects who maintain 80% treatment compliance with both 
application of ARQ-252 cream 0.3% or vehicle cream and phototherapy or sham 
phototherapy up through 24 weeks. 
6.3. 
Safety Evaluation 
Descriptive statistics will be calculated for safety data and presented by visit and treatment group 
for quantitative safety data and frequency counts will be compiled for classification of qualitative 
safety data.  Summaries of local tolerability will be presented by visit and treatment group. 
6.3.1. 
Adverse Events 
All AEs occurring during the study will be recorded and classified on the basis of MedDRA 
terminology for the safety population.  AEs will be summarized by treatment group, the number 
of subjects reporting AEs, system organ class, preferred term, severity, relationship, and 
seriousness.  
Serious adverse events (SAEs) will be listed by subject.  SAEs will be summarized by treatment 
group, severity, and relationship to study treatment. For AEs, each subject will be counted only 
once within a system organ class or a preferred term using the event with the greatest 
relationship and greatest severity. 
All information pertaining to AEs noted during the study will be listed by subject, detailing the 
verbatim description given by the Investigator, preferred term, system organ class, start date, 
stop date, severity, action taken regarding IP, corrective treatment, outcome, and IP and/or 
phototherapy relatedness.  The event onset will also be shown relative (in number of days) to 
date of first application. 
In addition, a listing of subjects who prematurely discontinue from the IP due to adverse events 
will also be provided. 
6.3.2. 
Local Tolerance Assessment 
For the Investigator’s and Subject’s assessment, the numeric application site reaction scores will 
be summarized individually by using number and percentage of subjects by visit, as well as 
mean/median scores. 
6.3.3. 
Medical History and Physical Examinations 
Clinically significant changes observed during physical examination will be captured as adverse 
events and included in AE tabulations. 
6.3.4. 
Clinical Laboratory Results and Vital Signs 
All clinical laboratory results and ECG measurements and their change from Baseline (pre dose), 
will be summarized descriptively by parameter, along with time point of collection. 
A shift table describing out-of-normal range shifts will be provided for clinical laboratory results. 


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6.3.5. 
Prior and Concomitant Medications 
Prior and concomitant medication information for all enrolled/randomized subjects will be 
presented in electronic datasets.   Summary tables will be presented by World Health 
Organization-Anatomical Therapeutic Chemical Classification System (WHO-ATC) therapeutic 
category and product. 
6.3.6. 
Pharmacokinetic Analysis 
Plasma drug concentrations at pre-dose will be summarized using descriptive statistics.   
A manual for blood sampling, collection, processing, and sample shipment will be provided in a 
separate document. 
7. 
STUDY ADMINISTRATION 
7.1. 
Ethics 
7.1.1. 
Ethics Review Board 
Before enrollment of subjects into the study, the current protocol and ICF will be reviewed and 
approved by an appropriate IRB or IEC, as required by FDA (21 CFR § 56), Health Canada, 
ICH GCP regulations and other local/regional regulatory requirements.  A letter documenting the 
IRB or IEC approval must be received by the Sponsor (or delegate) before the initiation of the 
study at a clinical site. Amendments to the protocol will be subject to the same requirements as 
the original protocol.  
The Investigator, Sponsor, or designee will submit a progress report at least once yearly to the 
IRB or IEC. However, the frequency of these reports will depend on IRB or IEC requirements. 
As soon as possible after completion or termination of the study, the Investigator will submit a 
final report to the IRB or IEC per the IRB or IEC requirements, and in compliance with FDA, 
Health Canada, local and regional regulations and ICH GCP guidelines. 
The Investigator, the Sponsor, or designee shall promptly notify the IRB or IEC of any SAEs, 
SUSARs, or any other information that may affect the safe use of the investigational products 
during the study, per the IRB or IEC local requirements, and in compliance with FDA and Health 
Canada regulations and ICH GCP guidelines. 
7.1.2. 
Ethical Conduct of the Study 
This research will be carried out in accordance with the protocol, the principles of the 
Tri Council Policy Statement (TCPS), the ethical principles set forth in the Declaration of 
Helsinki, and the ICH harmonized tripartite guideline regarding GCP (E6 (R2), Nov 2016) and 
the applicable regulations of the country(ies) in which the trial is conducted. 


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7.1.3. 
Subject Information and Consent 
The purpose of the study, the procedures to be carried out and the potential hazards will be 
described to the subjects in non-technical terms. Subjects will be required to read, sign and date a 
current version of the IRB/EC approved ICF summarizing the discussion prior to enrollment and 
will be assured that they may withdraw from the study at any time without jeopardizing their 
medical care. 
Subjects will be given a signed copy of their ICF. 
7.2. 
Study Monitoring 
Prior to the initiation of the clinical investigation, Sponsor representatives or designees will visit 
the clinical site where the investigation is to be conducted.  Sponsor representatives shall ensure 
that the Investigator understands the investigational status of the investigational product, all 
requirements of the investigation to be undertaken, and all of his/her responsibilities as an 
Investigator.  Sponsor representatives will also visit the clinical site at appropriate intervals as 
required to ensure compliance with the protocol and to verify the accuracy and completeness of 
data reported on the CRFs.  The Study Director or designees shall be available for consultation 
with the Investigator and serve as liaisons between the clinical site and the Sponsor. 
The Sponsor or authorized designees may inspect all documents and records required to be 
maintained by the Investigator, including but not limited to medical records (office, clinic, or 
hospital) and investigational product dispensation logs for the subjects in this clinical 
investigation.  The Investigator must permit access to such records.  The Investigator must 
obtain, as part of informed consent, permission for an authorized representative of the Sponsor, 
or regulatory authorities, to review, in confidence, any records identifying subjects. 
7.3. 
Study Completion/Termination 
7.3.1. 
Study Completion 
The study is considered completed with the last visit of the last subject participating in the study. 
The final data from the investigational site will be sent to the Sponsor (or designee) after 
completion of the final subject visit at that site, in the time frame specified in the Clinical Trial 
Agreement. 
7.3.2. 
Study Termination 
The Sponsor reserves the right to close the investigational site or terminate the study at any time 
for any reason at the sole discretion of the Sponsor. Investigational sites will be closed upon 
study completion. An investigational site is considered closed when all required documents and 
study supplies have been collected and a site closure visit has been performed. The Investigator 
may initiate site closure at any time, provided there is reasonable cause and sufficient notice is 
given in advance of the intended termination. 


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Reasons for the early closure of an investigational site by the Sponsor or Investigator may 
include but are not limited to: 
• Failure of the Investigator to comply with the protocol, the Sponsor’s procedures, or 
GCP guidelines. 
• Inadequate recruitment of subjects by the Investigator. 
• Discontinuation of further IP development 
7.4. 
Data Quality Assurance 
In order to ensure the collection of accurate, consistent, complete, and reliable data during this 
clinical study, Sponsor representatives or designees may conduct audits of participating clinical 
study sites at appropriate intervals throughout the study.  The results of these periodic clinical 
study site audits may be subject to review by independent auditors at completion of the clinical 
investigation.   
The Clinical Study Report will undergo QC review by the Clinical Research Organization’s 
Quality Assurance (QA) department.  
All clinical data will undergo a quality control check prior to clinical database lock. Edit checks 
are performed for appropriate databases as a validation routine to check for missing data, data 
inconsistencies, data ranges etc. Corrections are made prior to database lock. 
7.5. 
Data Handling and Record Keeping 
During the clinical study, the Investigator will maintain adequate records, including medical 
records, records detailing the progress of the study for each subject, laboratory reports, signed 
informed consent forms, investigational product disposition records, correspondence with the 
ERB/IRB and Study Monitor/Sponsor, AE reports, and information regarding subject 
discontinuation and completion of the clinical investigation. 
All required study data will be recorded on CRFs.  Any change of data will be recorded on the 
audit trail and a reason for the change will be entered.  
The Principal Investigator must retain all documentation relating to the study for a period of at 
least 2 years after the last marketing application approval or, if not approved, 2 years following 
the discontinuance of the test article for investigation.  If this requirement differs from any local 
regulations, the local regulations will take precedence unless the local retention policy is less 
than 2 years.   
7.6. 
Protocol Amendments and Deviations 
No change or amendment to this protocol may be made by the Investigator or Sponsor after the 
protocol has been agreed to and signed by all parties unless such change(s) or amendment(s) has 
(have) been agreed upon by the Investigator and Sponsor.  Any change agreed upon will be 
recorded in writing, and the written amendment will be signed by the Investigator and Sponsor.  
Institutional review board approval is required prior to the implementation of an amendment, 


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unless overriding safety reasons warrant immediate action, in which case the IRB(s) will be 
promptly notified. 
No deviation from the protocol will be made except to protect the life or physical well-being of a 
subject in an emergency.  Except in such emergencies, prior approval of the Sponsor, and the 
IRB, is required before deviations from the planned protocol.  All protocol deviations that occur 
during the study will be documented and reported to Sponsor and to the IRB(s), if applicable, 
according to regulations.  Further details about the documentation, evaluation, and follow-up of 
protocol deviations are detailed in this study’s clinical monitoring plan.  
No waivers to inclusion/exclusion criteria will be granted; subjects need to meet all criteria, 
exactly as specified, to be enrolled.  Additionally, prospective deviations from the protocol or 
investigational plan are not permitted except to protect the life or physical well-being of a subject 
in an emergency.  Deviations that occur unintentionally or are the result of action by the subject 
must be documented and reported to the IRB(s), if applicable, according to regulations.  Further 
details about the documentation, evaluation, and follow-up of protocol deviations are detailed in 
this study’s clinical monitoring plan. 
7.7. 
Confidentiality and Privacy 
The Investigator must assure that subjects’ anonymity will be strictly maintained and that their 
identities are protected from unauthorized parties. Only an identification code and any other 
unique identifier(s) as allowed by local law (such as date of birth) will be recorded on any form 
or biological sample submitted to the Sponsor.  
The Investigator agrees that all information received from Arcutis Biotherapeutics, Inc., 
including but not limited to the Investigator’s Brochure, this protocol, CRF/eCRF, the IP, and 
any other study information, remain the sole and exclusive property of Arcutis Biotherapeutics, 
Inc. during the conduct of the study and thereafter. This information is not to be disclosed to any 
third party (except employees or agents directly involved in the conduct of the study or as 
required by law) without prior written consent from Arcutis Biotherapeutics, Inc. The 
Investigator further agrees to take all reasonable precautions to prevent the disclosure by any 
employee or agent of the study site to any third party or otherwise into the public domain. 
7.8. 
Conflict of Interest 
All study Investigators will provide documentation of their financial interest or arrangements 
with Arcutis Biotherapeutics, Inc., or proprietary interests in the investigational product under 
study. This documentation must be provided prior to the Investigator’s participation in the study. 
All Investigators with reported conflict of interest will be required to have such conflicts 
managed in a way that is appropriate to their participation in the design and conduct of this 
study. 


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7.9. 
Report Format 
According to the ICH Harmonized Tripartite Guideline (Organization of the Common Technical 
Document for the Registration of Pharmaceuticals for Human Use M4 and the ICH M2 Expert 
Working Group), the final report will be written according to the ICH E3 Guideline 
(Structure and Content of Clinical Study Reports). 
7.10. 
Publication Policy 
The Sponsor is supportive of publishing clinical trial findings.  Any form of publication that is 
derived from this study must be submitted to Arcutis Biotherapeutics, Inc. for review and 
approval. The process of coordinating publication efforts is detailed in the Clinical Trial 
Agreement. 
8. 
REFERENCES 
Amer AA, Gao XH. Quality of life in patients with vitiligo: an analysis of the dermatology life 
quality index outcome over the past two decades. Int J Dermatol. 2016;55(6):608-614. 
doi:10.1111/ijd.13198 
Batchelor JM, Tan W, Tour S, et al. Validation of the Vitiligo Noticeability Scale: a patient-
reported outcome measure of vitiligo treatment success. Br J Dermatol. 2016;174(2):386-394. 
doi:10.1111/bjd.14208 
Berger RS, Bowman JP. A reappraisal of the 21-day Cumulative Irritation Test in man.  
J. Toxicol Ot & Ocular Toxicol. 1982;1(2):109-115. 
Bhandarkar SS, Kundu RV. Quality-of-life issues in vitiligo. Dermatol Clin. 2012;30(2):255-viii. 
doi:10.1016/j.det.2011.11.013 
Caron-Schreinemachers AL, Kingswijk MM, Bos JD, et al. UVB 311 nm tolerance of vitiligo 
skin increases with skin photo type. Acta Derm Venereol. 2005;85(1):24-26. 
doi:10.1080/00015550410022203 
Craiglow BG, King BA. Tofacitinib citrate for the treatment of vitiligo: a pathogenesis-directed 
therapy. JAMA Dermatol. 2015;151(10):1110-1112. 
Elbuluk N, Ezzedine K. Quality of Life, Burden of Disease, Co-morbidities, and Systemic 
Effects in Vitiligo Patients. Dermatol Clin. 2017;35(2):117-128. doi:10.1016/j.det.2016.11.002 
Eleftheriadou V, Thomas KS, Whitton ME, et al. Which outcomes should we measure in 
vitiligo? Results of a systematic review and a survey among patients and clinicians on outcomes 
in vitiligo trials. Br J Dermatol. 2012;167(4):804-814. doi:10.1111/j.1365-2133.2012.11056.x 
Fajuyigbe D, Young AR. The impact of skin colour on human photobiological 
responses. Pigment Cell Melanoma Res. 2016;29(6):607-618. doi:10.1111/pcmr.12511 
Frisoli ML, Essien K, Harris JE. Vitiligo: Mechanisms of Pathogenesis and Treatment. Annu Rev 
Immunol. 2020;38:621-648. doi:10.1146/annurev-immunol-100919-023531 


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Harris JE, Pandya A, Lebwohl M, et al.  Efficacy and Safety of a 52-Week, Randomized, 
Double-Blind Trial of Ruxolitinib Cream for the Treatment of Vitiligo.  Presented at the 28th 
European Academy of Dermatology and Venereolgy (EADV) Congress; October 9-13, 2019; 
Madrid, Spain.  
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(2):370-371.  
Investigator’s Brochure, Edition 2.0, Nov, 2020 
Joshipura D, Alomran A, Zancanaro P, et al. Treatment of vitiligo with the topical Janus kinase 
inhibitor ruxolitinib: A 32-week open-label extension study with optional narrow-band 
ultraviolet B. J Am Acad Dermatol. 2018;78(6):1205-1207.e1. doi:10.1016/j.jaad.2018.02.023 
Kang S, Amagai M, Bruckner AL, et al. Fitzpatrick’s Dermatology, 9th Edition.2019. 
Lee JH, Kwon HS, Jung HM, et al. Treatment Outcomes of Topical Calcineurin Inhibitor 
Therapy for Patients With Vitiligo: A Systematic Review and Meta-analysis [published online 
ahead of print, 2019 May 29]. JAMA Dermatol. 2019;155(8):929-938. 
doi:10.1001/jamadermatol.2019.0696 
Lilly E, Lu PD, Borovicka JH, et al. Development and validation of a vitiligo-specific quality-of-
life instrument (VitiQoL). J Am Acad Dermatol. 2013;69(1):e11-e18. 
doi:10.1016/j.jaad.2012.01.038 
Linthorst MW, Spuls PI, de Korte J, et al. The burden of vitiligo: patient characteristics 
associated with quality of life. J Am Acad Dermatol. 2009;61:411-420. 
Liu LY, Strassner JP, Refat MA, et al. Repigmentation in vitiligo using the Janus kinase inhibitor 
tofacitinib may require concomitant light exposure. J Am Acad Dermatol. 2017;77(4):675-682. 
Mohammad TF, Al-Jamal M, Hamzavi IH, et al. The Vitiligo Working Group recommendations 
for narrowband ultraviolet B light phototherapy treatment of vitiligo. J Am Acad Dermatol. 
2017;76(5):879-888. doi:10.1016/j.jaad.2016.12.041 
Peterson D, King B.J. UVL in combination with other therapies for vitiligo: synergy or 
necessity? Am Acad Dermatol. 2020 Sep 3:S0190-9622(20)32584-6.  
doi: 10.1016/j.jaad.2020.08.120. Online ahead of print. PMID: 32891783 
Rashighi M, Agarwal P, Richmond JM, et al. CXCL10 is critical for the progression and 
maintenance of depigmentation in a mouse model of vitiligo. Sci Transl Med. 
2014;6(223):223ra23. 
Relke N, Gooderham M. The Use of Janus Kinase Inhibitors in Vitiligo: A Review of the 
Literature. J Cutan Med Surg. 2019;23(3):298-306. doi:10.1177/1203475419833609 
Rosmarin D, Pandya AG, Lebwohl M, et al. Ruxolitinib cream for treatment of vitiligo: a 
randomised, controlled, phase 2 trial. Lancet. 2020;396(10244):110-120.  
doi:10.1016/S0140-6736(20)30609-7 


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Rothstein B, Joshipura D, Saraiya A, et al. Treatment of vitiligo with the topical Janus kinase 
inhibitor ruxolitinib. J Am Acad Dermatol. 2017;76(6):1054-1060.e1. 
doi:10.1016/j.jaad.2017.02.049 
Taieb A, Alomar A, Böhm M, et al. Guidelines for the management of vitiligo: the European 
Dermatology Forum consensus. Br J Dermatol. 2013;168(1):5-19. doi:10.1111/j.1 
Urso B. Jak-inhibitors and UV-B: Potential combined therapy for vitiligo. Dermatol Ther. 
2017;30(5):10.1111/dth.12531. doi:10.1111/dth.12531 
Ware OR, Guiyab J, Okoye GA. Phototherapy in Skin of Color. Dermatol Clin. 
2020;38(1):63-69. doi:10.1016/j.det.2019.08.006 








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APPENDIX 2. VITILIGO QUALITY OF LIFE QUESTIONNAIRE 
 
 
The validation of this instrument is described in (Lilly 2013). 


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APPENDIX 3. VITILIGO NOTICABILITY SCALE (VNS) 
The Vitiligo Noticeability Scale (VNS) is a 5-point scale which compares vitiligo from before 
treatment to how noticeable the vitiligo is at the time the VNS is performed. The VNS will be 
completed by subjects with respect to vitiligo on the facial target patch. The target patch on the 
face is selected by the subjects as being the patch that they would most like to see an 
improvement in. The photos taken of the facial target patch at the Baseline visit prior treatment 
and at the subsequent visits will be used as reference for the assessment.  
"Compared to before treatment, how noticeable is the vitiligo now? 
More noticeable (1) 
As noticeable (2) 
Slightly less noticeable (3) 
A lot less noticeable (4) 
No longer noticeable (5) 
 
• VNS score of 1 or 2 = treatment not successful 
• VNS score of 3 = treatment partially successful 
• VNS score of 4 or 5 = treatment successful 
Validation of this instrument is described in (Batchelor 2016). 
 






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APPENDIX 5. PATIENT GLOBAL IMPRESSION OF CHANGE-
VITILIGO (PAGIC-V) 
The PaGIC-V is an assessment of improvement by the subject, and is to be evaluated in this 
study specifically with respect to facial vitiligo.  It is a 7-point scale comparing facial vitiligo at 
baseline with the subject’s treated facial vitiligo at the study visit.  
The subject will answer the following:  
Since the start of the treatment you’ve received in the study, the vitiligo on your face treated with 
the study drug is:  
(1) very much improved 
(2) much improved 
(3) minimally improved 
(4) no change 
(5) minimally worse 
(6) much worse 
(7) very much worse 

SAP_001.pdf: 
 
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   Statistical Analysis Plan 
Sponsor 
Arcutis Biotherapeutics, Inc. 
Protocol Title: 
A Phase 2a, Proof of Concept, 24-Week, Parallel Group, 
Double  Blind, Vehicle-Controlled Study of the Safety and 
Efficacy of ARQ-252 Cream 0.3% in Subjects with Non-
Segmental Facial Vitiligo 
Protocol Number: 
ARQ-252-213 
Premier Research PCN: 
ARCU213242 
Document Version: 
Final 1.0 
Document Date:  
28-Sep-2021 
Approvals 
Role 
Signatures 
Biostatistician 
Print Name:
 
 
 
Sign Name: 
 
 
 
 
Peer Reviewer 
Print Name: 
 
 
Sign Name: 
 
 
 
 
 
 


 
Statistical Analysis Plan,  
 
Sponsor Arcutis Biotherapeutics, Inc.  
 
Protocol Number ARQ-252-213  
 
PCN Number ARCU213242 
 
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Role 
Signatures 
Arcutis 
Biotherapeutics, 
Inc. Representative 
Print Name: 
 
Sign Name: 
 
 
 
 
 
Arcutis 
Biotherapeutics, 
Inc. Representative 
Print Name: 
 
Sign Name: 
 
 
 
 
 
 
 


 
Statistical Analysis Plan,  
 
Sponsor Arcutis Biotherapeutics, Inc.  
 
Protocol Number ARQ-252-213  
 
PCN Number ARCU213242 
 
AD-ST-33.06  Effective date: 12-Nov-2020 
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Document History 
Not applicable. 
 
 


 
Statistical Analysis Plan,  
 
Sponsor Arcutis Biotherapeutics, Inc.  
 
Protocol Number ARQ-252-213  
 
PCN Number ARCU213242 
 
AD-ST-33.06  Effective date: 12-Nov-2020 
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Table of Contents 
Approvals ........................................................................................................................................ 1 
Document History ........................................................................................................................... 3 
Table of Contents ............................................................................................................................ 4 
List of Tables .................................................................................................................................. 5 
List of Abbreviations ...................................................................................................................... 6 
1. 
Overview ........................................................................................................................... 10 
2. 
Study Objectives and Endpoints ....................................................................................... 10 
2.1. 
Study Objectives ......................................................................................................... 10 
2.1.1. Primary Objective ....................................................................................................... 10 
2.1.2. Secondary Objectives.................................................................................................. 10 
2.2. 
Study Endpoints .......................................................................................................... 11 
2.2.1. Efficacy Endpoints ...................................................................................................... 11 
2.2.2. Safety Endpoints ......................................................................................................... 12 
3. 
Overall Study Design and Plan ......................................................................................... 13 
3.1. 
Overall Design ............................................................................................................ 13 
3.2. 
Sample Size and Power ............................................................................................... 13 
3.3. 
Study Population ......................................................................................................... 14 
3.4. 
Treatments Administered ............................................................................................ 14 
3.5. 
Method of Assigning Subjects to Treatment Groups .................................................. 14 
3.6. 
Blinding and Unblinding............................................................................................. 14 
3.7. 
Schedule of Events ...................................................................................................... 15 
4. 
Statistical Analysis and Reporting .................................................................................... 19 
4.1. 
Introduction ................................................................................................................. 19 
4.2. 
Interim Analysis and Data Monitoring ....................................................................... 19 
5. 
Analysis Populations ......................................................................................................... 19 
6. 
General Issues for Statistical Analysis .............................................................................. 20 
6.1. 
Statistical Definitions and Algorithms ........................................................................ 20 
6.1.1. Baseline ....................................................................................................................... 20 
6.1.2. Adjustments for Covariates......................................................................................... 20 
6.1.3. Multiple Comparisons ................................................................................................. 20 
6.1.4. Handling of Dropouts or Missing Data ....................................................................... 20 
6.1.5. Analysis Visit Windows ............................................................................................. 20 
6.1.6. Pooling of Sites ........................................................................................................... 20 


 
Statistical Analysis Plan,  
 
Sponsor Arcutis Biotherapeutics, Inc.  
 
Protocol Number ARQ-252-213  
 
PCN Number ARCU213242 
 
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6.1.7. Derived Variables ....................................................................................................... 20 
6.1.8. Data Adjustments/Handling/Conventions .................................................................. 21 
7. 
Study Subjects and Demographics.................................................................................... 22 
7.1. 
Disposition of Subjects and Withdrawals ................................................................... 22 
7.2. 
Demographics and Other Baseline Characteristics ..................................................... 22 
7.3. 
Exposure and Compliance .......................................................................................... 23 
8. 
Efficacy Analysis .............................................................................................................. 23 
9. 
Safety and Tolerability Analysis ....................................................................................... 23 
9.1. 
Adverse Events ........................................................................................................... 23 
9.1.1. Adverse Events Leading to Withdrawal ..................................................................... 24 
9.1.2. Deaths and Serious Adverse Events ........................................................................... 24 
9.2. 
Local Tolerability Assessments .................................................................................. 24 
9.3. 
Clinical Laboratory Evaluations ................................................................................. 24 
9.4. 
Vital Signs ................................................................................................................... 25 
9.5. 
12-Lead Electrocardiograms ....................................................................................... 25 
9.6. 
Physical Examination.................................................................................................. 25 
9.7. 
Concomitant Medications ........................................................................................... 25 
10. 
Changes from Planned Analysis ....................................................................................... 25 
11. 
Other Planned Analysis..................................................................................................... 26 
11.1. Pharmacokinetic Analysis ........................................................................................... 26 
12. 
References ......................................................................................................................... 26 
 
List of Tables 
Table 1: 
Schedule of Events ...................................................................................................... 15 
 
 
 


 
Statistical Analysis Plan,  
 
Sponsor Arcutis Biotherapeutics, Inc.  
 
Protocol Number ARQ-252-213  
 
PCN Number ARCU213242 
 
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List of Abbreviations 
Abbreviation 
Definition 
aCRF  
annotated case report form 
ADR 
adverse drug reactions 
AE 
adverse event 
AESI 
adverse events special interest 
ANCOVA 
analysis of covariance 
ATC 
anatomical therapeutic chemical 
BID  
Twice daily 
BLQ 
below limit of quantification 
BMI 
body mass index 
CI 
confidence interval 
CRF 
case report form 
CS 
clinically significant 
CSR 
clinical study report 
COVID-19 
Novel coronavirus disease 
DBL 
database lock 
DBP 
diastolic blood pressure 
DLT 
dose limiting toxicity 
DMC 
data monitoring committee 


 
Statistical Analysis Plan,  
 
Sponsor Arcutis Biotherapeutics, Inc.  
 
Protocol Number ARQ-252-213  
 
PCN Number ARCU213242 
 
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Abbreviation 
Definition 
DOB 
date of birth 
DSMB  
data safety monitoring board 
DSUR 
development safety update report 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EDC 
electronic data capture 
EMA 
European medicines agency 
FDA 
food and drug administration 
FSIGA 
Facial Static Investigator Global Assessment 
GCP 
good clinical practice 
HR 
heart rate 
IB 
investigator’s brochure 
IP 
investigational product 
IRB 
institutional review board 
IRR 
infusion related reactions 
IRT 
interactive response technology 
ITT 
intent-to-treat 
LLOQ 
lower limit of quantification 
MedDRA 
medical dictionary for regulatory activities 


 
Statistical Analysis Plan,  
 
Sponsor Arcutis Biotherapeutics, Inc.  
 
Protocol Number ARQ-252-213  
 
PCN Number ARCU213242 
 
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Abbreviation 
Definition 
MI 
multiple imputation 
MMRM 
mixed model for repeated measurements 
MTD 
maximum tolerated dose 
NA 
not applicable 
NCS 
non-clinically significant 
PAGIC 
Patient Global Impression of Change 
PD 
protocol deviation 
PK 
pharmacokinetic 
PKAP 
pharmacokinetic analysis plan 
PP 
per-protocol 
RR 
respiratory rate or relative rate 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SBP 
systolic blood pressure 
SD 
standard deviation 
SE 
standard error 
SOC 
system organ class 
SOP 
standard operating procedure 
SUSAR 
suspected, unexpected, serious adverse (drug) reaction 


 
Statistical Analysis Plan,  
 
Sponsor Arcutis Biotherapeutics, Inc.  
 
Protocol Number ARQ-252-213  
 
PCN Number ARCU213242 
 
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Abbreviation 
Definition 
TEAE 
treatment-emergent adverse event 
VASI 
Vitiligo Area Scoring Index 
VITIQOL 
Vitiligo Quality of Life Questionnaire 
VNS 
Vitiligo Noticeability Scale  
WHO-DD 
world health organization drug dictionary 


 
Statistical Analysis Plan,  
 
Sponsor Arcutis Biotherapeutics, Inc.  
 
Protocol Number ARQ-252-213  
 
PCN Number ARCU213242 
 
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1. 
Overview 
This statistical analysis plan (SAP) describes the planned analysis and reporting for Arcutis 
Biotherapeutics, Inc. protocol number ARQ-252-213 A Phase 2a, Proof of Concept, 24-Week, Parallel 
Group, Double Blind, Vehicle-Controlled Study of the Safety and Efficacy of ARQ-252 Cream 0.3% 
in Subjects with Non-Segmental Facial Vitiligo), dated 14-Apr-2021 Amendment Version 1 (US) and 
30-Apr-2021 Amendment Version 1 (CAN). Reference materials for this statistical plan include the 
protocol and the accompanying sample data collection documents. Operational aspects related to 
collection and timing of planned clinical assessments are not repeated in this SAP unless relevant to 
the planned analysis. 
The structure and content of this SAP provides sufficient detail to meet the requirements identified by 
the Food and Drug Administration (FDA), European Medicines Agency (EMA), and International 
Conference on Harmonization (ICH) of Technical Requirements for Registration of Pharmaceuticals 
for Human Use: Guidance on Statistical Principles in Clinical Trials (ICH, 1998). All work planned 
and reported for this SAP will follow internationally accepted guidelines, published by the American 
Statistical Association (ASA, 2018) and the Royal Statistical Society (RSS, 2014), for statistical 
practice. 
The planned analyses identified in this SAP may be included in clinical study reports (CSRs), 
regulatory submissions, or future manuscripts. Also, post-hoc exploratory analyses not necessarily 
identified in this SAP may be performed to further examine study data. Any post-hoc or unplanned, 
exploratory analysis performed will be clearly identified as such in the final CSR. 
Upon sponsor discretion, this study was terminated before the enrolled subjects could finish their 
treatment period. The statistical plan described hereafter is an a priori plan. It will be approved before 
any inferential or descriptive analysis of data pertaining to Arcutis Biotherapeutics, Inc.’s study ARQ-
252-213. 
2. 
Study Objectives and Endpoints  
2.1. 
Study Objectives 
2.1.1. Primary Objective 
The purpose of this study is to assess the safety and efficacy of ARQ-252 cream 0.3% twice daily 
(BID) vs vehicle cream BID, with and without Narrowband Ultraviolet B (NB-UVB) phototherapy 
treatment in individuals with non-segmental facial vitiligo. 
2.1.2. Secondary Objectives 
The secondary objective of this study is to assess other efficacy measures of ARQ-252 cream 
0.3% BID with and without NB-UVB phototherapy treatment in subjects with non-segmental 


 
Statistical Analysis Plan,  
 
Sponsor Arcutis Biotherapeutics, Inc.  
 
Protocol Number ARQ-252-213  
 
PCN Number ARCU213242 
 
AD-ST-33.06  Effective date: 12-Nov-2020 
Version Final 1.0    |    Date 28-Sep-2021      |    AD-PR-109.02  Effective date: 17-Aug-2020 
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vitiligo on the face, in addition to vitiligo on the neck, hands, forearms, and elbows. 
2.2. 
Study Endpoints 
2.2.1. Efficacy Endpoints 
Upon sponsor discretion, this study was terminated before the enrolled subjects could finish 
their treatment period. As a result, only descriptive summaries are provided for in  Facial 
Vitiligo Area Scoring Index (F-VASI), and no additional efficacy analyses are conducted. 
2.2.1.1. 
Primary Efficacy Endpoint 
The primary efficacy endpoint of this study is proportion of subjects achieving F-VASI75 
(≥ 75% improvement from baseline F-VASI score) at Week 24. 
2.2.1.2. 
Secondary Efficacy Endpoint(s) 
The secondary efficacy endpoints of this study include the following:  
 
Proportion of subjects achieving F-VASI75 (≥ 75% improvement from baseline in F-VASI 
score) at visits prior to Week 24.  
 Percent change from baseline in F-VASI score at all visits. 
 Percent change from baseline in facial body surface area (F-BSA) at all visits. 
 Proportion of subjects achieving F-VASI50 (≥ 50% improvement from baseline in  
F-VASI score) at all visits. 
 Proportion of subjects achieving F-VASI90 (≥ 90% improvement from baseline in F-VASI 
score) at all visits. 
 Proportion of subjects in each category of Vitiligo Noticeability Scale (VNS) at specified 
visits. 
 Change from Baseline in the VNS at specified visits. 
 Change from Baseline in the Vitiligo-Specific Quality of Life Instrument (VitiQoL) at 
specified visits. 
 Patient Global Impression of Change-Vitiligo (PaGIC-V), proportion of patients in 
each PaGIC-V category at specified visits. 
 Proportion of subjects who report PaGIC-V of very much improved or much 
improved during the treatment period. 
 Time to achieve F-VASI50. 
 Time to achieve F-VASI75. 


 
Statistical Analysis Plan,  
 
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Protocol Number ARQ-252-213  
 
PCN Number ARCU213242 
 
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 Time to achieve FsIGA of clear or almost clear (0 or 1). 
 FsIGA of clear or almost clear (0 or 1). 
 FsIGA of clear or almost clear (0 or 1) plus 2-grade improvement from baseline. 
 Time to achieve a PaGIC-V of very much improved or much improved. 
2.2.1.3. 
Exploratory Efficacy Endpoint(s) 
The exploratory efficacy endpoints of this study include the following:  
 Percent change from baseline in combined face and neck body surface area 
(F/N-BSA) at all visits. 
 Percent change from baseline in surface area BSA (hands/forearms/elbows) at all 
visits. 
 Percent change from baseline in BSA affected across all treatable sites (face, neck, 
hands, forearms, elbows) at all visits. 
 Proportion of subjects achieving F/N-VASI50 (≥ 50% improvement from baseline in 
F/N-VASI score) at all visits. 
 Proportion of subjects achieving F/N-VASI75 (≥ 75% improvement from baseline in 
F/N-VASI score) at all visits. 
 Proportion of subjects achieving F/N-VASI90 (≥ 90% improvement from baseline in 
F/N-VASI score) at all visits. 
 Percent change from baseline in FOREARM-VASI (forearms/elbows) score at all 
visits. 
 Percent change from baseline in HAND-VASI (hands only) score at all visits. 
 Serum levels of ARQ-252. 
 The proportions of subjects who maintain 80% treatment compliance with both 
application of ARQ-252 cream 0.3% or vehicle cream and phototherapy or sham 
phototherapy up through 24 weeks. 
2.2.2. Safety Endpoints 
The safety endpoints of this study include the following and will be conducted: 
 Adverse events (AEs) 
 Local tolerability assessments 
 Clinical laboratory parameters 
 Vital signs 


 
Statistical Analysis Plan,  
 
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Protocol Number ARQ-252-213  
 
PCN Number ARCU213242 
 
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 Physical examinations 
 12-lead electrocardiograms (ECGs) 
 Prior and concomitant medications  
3. 
Overall Study Design and Plan 
This is a 24-week, parallel group, double blind, vehicle-controlled study for the treatment of subjects 
with non-segmental facial vitiligo. This study was planned to include both male and female adults 
having a facial BSA ≥ 0.25% and F-VASI ≥ 0.25. A total of 500 subjects were planned to be 
randomized. After having met all inclusion criteria, and none of the exclusion criteria, subjects were to be 
randomized in a 3:3:3:1 ratio as mentioned below in Section 3.4. Screening for up to 5 weeks followed by 
24 weeks of treatment phase was planned for this study. In addition to the study drug ARQ-252 cream and 
vehicle cream, subjects were randomized to receive Daavlin series NB-UVB active or sham units. Subjects 
have to record the date and time each dose has been applied, any missed doses, and any additional 
comments. There was a follow-up visit approximately 1 week after treatment has been completed. 
Upon the sponsor discretion, this study was terminated and none of the subjects could finish the entire 
treatment period. All the subjects that were currently enrolled have been early terminated and subjects 
that are in screening have been screen failed. Emergency unblinding was performed after following 
Premier Research SOPs. 
3.1. 
Overall Design 
3.2. 
Sample Size and Power 
The primary statistical comparisons will be to compare 
 ARQ-252 cream 0.3% in combination with phototherapy vs. vehicle cream in combination 
with NB-UVB. 
 ARQ-252 cream 0.3% in combination with phototherapy vs. ARQ-252 cream 0.3% in 
combination with sham phototherapy at the 5% significance level. 
A sample size of 500 subjects was planned to provide approximately 84% power to detect an ARQ-
252 cream 0.3% in combination with phototherapy response rate of at least 50% vs. a vehicle cream  in 
combination with phototherapy response of rate of 30%, and approximately 84% power to detect an 
ARQ-252 cream 0.3% in combination with phototherapy rate of at least 50% vs. an ARQ-252 cream 
0.3% in combination with sham phototherapy rate of 30%, using a stratified Cochran-Mantel-
Haenszel test conducted at the 0.025 alpha level for each comparison. A drop out rate of 15% at 24 
weeks was assumed.  
Upon successful testing for the comparisons above, a hierarchical testing scheme will be used to test 
the following secondary comparisons: 
 ARQ-252 cream 0.3% in combination with phototherapy vs. vehicle cream BID in 
combination with the sham phototherapy. 


 
Statistical Analysis Plan,  
 
Sponsor Arcutis Biotherapeutics, Inc.  
 
Protocol Number ARQ-252-213  
 
PCN Number ARCU213242 
 
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 ARQ-252 cream 0.3% in combination with sham phototherapy vs. vehicle cream BID in 
combination with the sham phototherapy. 
 Vehicle cream BID in combination with phototherapy vs. vehicle cream BID in combination 
with the sham phototherapy. 
Assuming a vehicle cream BID in combination with the sham phototherapy rate of no more than 5%, 
these comparisons are expected to have at least 74% power. These comparisons will be made at either 
the 0.025 or 0.05 level, depending on the outcome of the primary statistical comparisons. 
3.3. 
Study Population 
The study population consists of male and female adults (>18 y/o) with facial non-segmental vitiligo 
having F-BSA ≥ 0.25% and F-VASI ≥ 0.25, with a maximum BSA (total body inclusive of the face,  
whether or not in areas to be treated in this study) of 15%. 
3.4. 
Treatments Administered 
Subjects who meet the eligibility criteria will be randomized to 1 of the 4 following treatment groups 
in a 3:3:3:1 ratio: 
 ARQ-252 cream 0.3% BID with NB-UVB  phototherapy 
 ARQ-252 cream 0.3% BID with sham NB-UVB  phototherapy 
 Vehicle cream BID with NB-UVB  phototherapy 
 Vehicle cream BID with sham NB-UVB phototherapy 
3.5. 
Method of Assigning Subjects to Treatment Groups 
Subjects will be randomized and assigned to treatment arm in a 3:3:3:1 ratio according to a computer-
generated randomization list. Randomization will be stratified by study site and FitzPatrick skin type 
(I-III or IV-VI), with at least 50% of subjects having Fitzpatrick skin type IV-VI. 
3.6. 
Blinding and Unblinding 
The study was planned to be double-blinded, therefore neither the subjects nor the Investigator, 
Independent Rater, or clinical site personnel were aware of which investigational product (ARQ‑ 252 
0.3% cream or vehicle cream) or NB-UVB phototherapy unit (Active or Sham) the subject receives. 
However, upon the sponsor discretion, the study was terminated and treatment unblinding was 
performed following Premier Research SOPs. 
 
 


 
Statistical Analysis Plan,  
 
Sponsor Arcutis Biotherapeutics, Inc.  
 
Protocol Number ARQ-252-213  
 
PCN Number ARCU213242 
 
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3.7. 
Schedule of Events 
A detailed schedule of events for the study is provided in Table 1. 
Table 1: 
Schedule of Events 


 
Statistical Analysis Plan,  
 
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Protocol Number ARQ-252-213  
 
PCN Number ARCU213242 
 
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Study Procedure 
Screen 
Baseline 
Day 1 
Wk 
4 
Day 
29 
Wk 
8 
Day 
57 
Wk 12 
Day 
85 
Wk 
16 
Day 
113 
Wk 
20 
Day 
141 
Wk 
24 
Day 
169 
Wk 
25 
Day 
176 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
Visit Window 
-35 
days 
+/- 5 
days 
+/- 5 
days 
+/- 5 
days 
+/- 5 
days 
+/- 5 
days 
+/- 7 
days 
+/- 7 
days 
Informed consent 
X 
Demographics 
X 
Fitzpatrick skin type 
assessment 
X 
Medical and surgical history 
X 
Physical examinationa 
X 
X 
X 
X 
Vital signs, height, weightb 
X 
X 
X 
X 
X 
X 
X 
X 
X 
I/E criteria 
X 
X 
Randomization 
X 
Hematology, Serum Chemistries, 
UA, TSH/T4 
X 
X 
X 
X 
X 
Lipid (Fasting)c 
X 
X 
Resting 12-lead ECG 
X 
X 
X 
X 
BSAd (Full Body), T-
VASIe 
X 
X 
X 
X 
F-BSAd, F/N-BSAd, BSA 
(Hands, Forearms, Elbows) d, F-
VASIe, F/N-VASIe, FOREARM-
VASIe, HAND-VASIe, FsIGAf 
X 
X 
X 
X 
X 
X 
X 
X 
X 
VNSg, PaGIC-Vh 
X 
X 
X 
X 
X 
X 
VitiQoLi 
X 
X 
X 
X 
X 
X 
X 
Local Tolerability 
Assessmentsj 
X 
X 
X 
X 
X 
X 
X 
Digital Photographyk 
X 
X 
X 
X 
X 
X 
X 
Urine pregnancy testl 
X 
X 
X 
X 
X 
X 
X 
X 
Serum pregnancy testm 
X 


 
Statistical Analysis Plan,  
 
Sponsor Arcutis Biotherapeutics, Inc.  
 
Protocol Number ARQ-252-213  
 
PCN Number ARCU213242 
 
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Study Procedure 
Screen 
Baseline 
Day 1 
Wk 
4 
Day 
29 
Wk 
8 
Day 
57 
Wk 12 
Day 
85 
Wk 
16 
Day 
113 
Wk 
20 
Day 
141 
Wk 
24 
Day 
169 
Wk 
25 
Day 
176 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
Visit Window 
-35 
days 
+/- 5 
days 
+/- 5 
days 
+/- 5 
days 
+/- 5 
days 
+/- 5 
days 
+/- 7 
days 
+/- 7 
days 
Follicle-Stimulating Hormone 
(FSH)n 
X 
PK Samplingo 
 
X 
X 
X 
X 
NB-UVB Phototherapy in clinicp 
 
X 
Return of USB stick to site for 
phototherapy data uploadingq 
 
X 
X 
X 
X 
X 
X 
Dispense IP kitr 
 
X 
X 
X 
X 
X 
X 
IP application in clinics 
 
X 
X 
X 
X 
X 
X 
Dispense/review diary 
 
X 
X 
X 
X 
X 
X 
Weigh IP tubest 
 
X 
X 
X 
X 
X 
X 
X 
Compliance calculationu 
 
X 
X 
X 
X 
X 
X 
Adverse event assessmentv 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
a 
Limited physical examination: skin, lungs, and heart only 
b 
Height will be measured at Baseline only. Weight will be collected at screening, baseline and Week 24. 
c 
Fasting required for a minimum of 8 hours prior to blood draw 
d 
BSA will utilize the subject's handprint method where 1 handprint will approximate 1% of the body surface area 
involved. F-BSA will include the % BSA of non-segmental vitiligo on the face only. F/N-BSA will include the 
% of BSA of vitiligo on the face and neck area only. Full Body BSA will include the % of BSA of vitiligo on all 
areas of the body. This assessment will be performed by an independent rater per the protocol. 
e 
Vitiligo Area Scoring Index (VASI) per the protocol: F-VASI will utilize measuring only the face. “Face” is 
defined as including the area on the forehead to the original hairline, on the check to the jawline vertically to the 
jawline and laterally from the corner of the mouth to the tragus. The area “face” will not include surface areas of 
lips, scalp, ears, or neck but will include the eyelids and nose. F/N-VASI will utilize VASI measuring the face 
and neck as defined by the Face as defined above in addition to the neck area. FOREARM-VASI will include 
scoring of the forearms and elbows. HAND-VASI will include scoring of the hands only. T-VASI will include 
the following sites: (1) head/neck, (2) hands, (3) upper extremities (excluding hands), (4) trunk, (5) lower 
extremities (excluding feet), and (6) feet. All VASI assessments will be performed by an independent rater per 
the protocol. 
f 
The Facial Static Investigator Global Assessment (FsIGA) is a global score of vitiligo severity for the face only. 
The outcome measure incorporates location, distribution, size, depigmentation within lesions and presence or 
absence of signs of activity. Examination of skin should be performed with both normal lighting and Woods 
lamp. This assessment will be performed by an independent rater per the protocol. 
g Vitiligo Noticeability Scale (VNS) is a 5-point scale which compares vitiligo from before treatment to how 


 
Statistical Analysis Plan,  
 
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Protocol Number ARQ-252-213  
 
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noticeable is the vitiligo at the time of the assessment. The VNS will be completed by subjects with respect to 
vitiligo on the facial target patch. The target patch on the face is selected by the subject as being the patch that 
they would most like to see in an improvement in. The photos taken on the facial target patch at the Baseline visit 
prior to treatment and at the subsequent visits will be used as reference to assess the change. 
h 
The Patient Global Impression of Change-Vitiligo (PaGIC-V) is a 7-point scale on which the subject will rate 
improvement compared to baseline and will be evaluated for the face only. 
i 
The Vitiligo Quality of Life (VitiQoL) is a 16-item questionnaire with a 7-point numerical scale from (0 - Not at 
all) to (6 - All of the time). The VitiQOL is completed by the subject. 
j 
Tolerability assessments should be recorded prior to study drug application for Investigator assessment and 
10-15 minutes post-drug application for subject (‘0-3’ burning/stinging assessment). Investigators will specify if 
any application site reaction is due, in whole or in part, to the effects of phototherapy treatment. Only the 
Investigator assessment will take place on Week 24. 
k 
Digital Photography will be conducted at all sites for all subjects. Required study photos will be taken of the 
treatment areas during the Baseline Visit. In addition, a photo of the facial target patch will be taken as reference 
for the VNS assessment. Fixed, multi-angle photos will be taken at select sites for additional evaluation. 
l 
A urine pregnancy test will be administered to all females of child-bearing potential. A negative result is required 
for continued participation in the study, and results must be available prior to dispensing of study drug at each 
visit. 
m  Serum pregnancy testing will be performed at Screening; a negative result is required for participation in the 
study. 
n 
FSH will be performed (if indicated) at Screening to confirm post-menopausal status. 
o  PK samples will be collected from all subjects at Baseline, Week 4, Week 12, and Week 24. The samples will be 
drawn prior to application of the investigation product in the clinic. Subjects should apply investigational product 
11-12 hours before the PK collection time. 
p     NB-UVB Phototherapy treatment will occur in the clinic at the Baseline Visit prior to the initial IP application. 
The treatment will be per the NB-UVB Treatment Protocol and be tailored per the subject’s Fitzpatrick Score. 
The subject will be provided with the phototherapy unit in addition to a USB stick which will be inserted into 
the unit to obtain phototherapy data during the course of the treatment period. 
q 
Subjects should be instructed return the USB stick from the phototherapy unit to site for the uploading of the 
phototherapy data. Once the data has been uploaded by the site staff, a new USB stick should be provided to the 
subject to insert into the NB-UVB phototherapy unit. 
r 
IP kits will be dispensed based on % BSA affected. See IP Handling Manual for details. 
s 
Subjects to apply assigned IP in clinic at these visits. The time of application will be documented. 
t 
Each IP tube will be weighed prior to dispensing at the Baseline visit and at each follow-up clinic visit according 
to the Schedule of Visits and Assessments. When IP is applied in the clinic, the IP tube will be weighed before 
and after IP application. See IP Handling Manual for details. 
u 
Compliance calculation is described in the IP Handling Manual. 
v 
Adverse Events (AEs) and clinically significant abnormal laboratory test value(s) will be evaluated by the PI and 
treated and/or followed up for up to 30 days after end of treatment or until the symptoms or value(s) return to 
normal, or acceptable levels, as judged by the PI. 
 


 
Statistical Analysis Plan,  
 
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Protocol Number ARQ-252-213  
 
PCN Number ARCU213242 
 
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4. 
Statistical Analysis and Reporting 
4.1. 
Introduction 
Data processing, tabulation of descriptive statistics, calculation of inferential statistics, and 
graphical representations will primarily use SAS (release 9.4 or higher). If the use of other 
software is warranted, the final statistical methodology report will detail what software was used 
for what purposes. 
Continuous (quantitative) variable summaries will include the number of subjects (n) with 
non-missing values, mean, standard deviation (SD), median, Q1, Q3, minimum, and maximum.  
Categorical (qualitative) variable summaries will include the frequency and percentage of 
subjects who are in the particular category or each possible value. In general, the denominator 
for the percentage calculation will be based upon the total number of subjects in the study 
population for the treatment group, unless otherwise specified. The denominator for by-visit 
displays will be the number of subjects in the relevant study population with non-missing data at 
each visit. 
The minimum and maximum will be reported with the same degree of precision (i.e., the same 
number of decimal places) as the observed data. Measures of location (mean, median, Q1, and 
Q3) will be reported to 1 degree of precision more than the observed data and measures of spread 
(SD) will be reported to 2 degrees of precision more than the observed data. 
Percentages will be presented to 1 decimal place, unless otherwise specified. 
No formal hypothesis testing was done for this study. 
4.2. 
Interim Analysis and Data Monitoring 
No interim analyses are planned. 
5. 
Analysis Populations 
The following analysis populations are planned for this study:  
 Safety Population (SAF): The Safety population includes all subjects who are enrolled 
and received at least 1 confirmed dose of investigational product (IP). This population 
will be used for all safety analyses. 
 Intent-To-Treat Population (ITT): The ITT population includes all randomized 
subjects in the study. This population will be used for efficacy descriptive summaries 
along with disposition.  
 Pharmacokinetic Population (PK): The PK population will include all subjects 
who are randomized and receive at least 1 application of IP and have at least 1 
analyzed PK sample. 


 
Statistical Analysis Plan,  
 
Sponsor Arcutis Biotherapeutics, Inc.  
 
Protocol Number ARQ-252-213  
 
PCN Number ARCU213242 
 
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6. 
General Issues for Statistical Analysis 
The study was terminated based on sponsor’s decision. All the analysis are in descriptive nature. 
No formal test will be performed.  
6.1. 
Statistical Definitions and Algorithms 
6.1.1. Baseline 
For assessments where time was recorded (e.g., ECG), the last observation recorded before the 
first application of study drug will be used as the baseline observation for all calculations of 
change from baseline. For assessments where time was not recorded, the last observation 
recorded on or before the day of first application of study drug will be used as the baseline 
observation for all calculations of change from baseline.   
For subject tolerability assessments, baseline is derived as the last non-missing measurement 
taken on the day of first application of study drug. 
6.1.2. Adjustments for Covariates 
No adjustment for covariates will be made for this study. All the analyses are descriptive, and no 
subgroup analysis will be performed.  
6.1.3. Multiple Comparisons 
No adjustments will be made for multiple comparisons because there will be no formal 
hypothesis testing, nor any inferential statistical analyses, only descriptive summaries. 
6.1.4. Handling of Dropouts or Missing Data 
No inferential statistical analyses are planned for this study. 
6.1.5. Analysis Visit Windows 
Safety and efficacy data will not be windowed and will be analyzed as per the nominal visit present 
in the database.  
6.1.6. Pooling of Sites 
Not applicable. 
6.1.7. Derived Variables 
 Weight of IP (g) = dispensed tube weight – returned tube weight. 


 
Statistical Analysis Plan,  
 
Sponsor Arcutis Biotherapeutics, Inc.  
 
Protocol Number ARQ-252-213  
 
PCN Number ARCU213242 
 
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 Number of expected IP applications = calculated as 2 * (last treatment date - first 
treatment date + 1). 
 Number of IP applications = number of expected IP applications – missed IP 
applications as collected in the case report form (CRF). As the time of missing dose is not 
captured in the CRF, only the dates will be used in determining number of missed doses; 
if 2 records exist for the same date, that will be considered as 2 missed IP applications. 
 Days on IP = Calculated as last treatment date – first treatment date + 1. For subjects 
who are missing the date of last study drug application, for any reason, the last known 
contact date from subject visits CRF will be used in the calculation of treatment duration. 
 BMI (kg/m2) = (weight in kg)/[(height in cm/100)2]. For all visits, baseline height will 
be used to derive BMI since height is collected only at baseline.  
 Change from baseline = value at current time point – value at baseline.  
 Percent change from baseline = (value at current time point – value at baseline)/value at 
baseline.  
 TEAE = any AE with an onset date/time after the first application of IP. If time is 
unavailable, any AE occurring on or after the date of first application of IP will be 
considered treatment emergent. 
6.1.8. Data Adjustments/Handling/Conventions 
Upon the sponsor discretion, only safety and limited efficacy will be presented in Clinical Data 
Interchange Standards Consortium (CDISC) datasets. Data not subject to analysis according to this 
plan will not appear in any tables or graphs or listings or the CDISC datasets. 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
version 23.1 thesaurus. 
A treatment-related AE to study drug is any AE with a relationship to the study drug of possibly, 
probably, likely, or missing. 
A treatment-related AE to phototherapy treatment is any AE with a relationship to the 
phototherapy treatment of likely or missing. 
For partial AE and medication start dates: 
 If the year is unknown, then do not impute the date but assign a missing value. 
 If the year is known, but the month or month and day is unknown, then: 
o If the year matches the year of first dose date and the end date (if present) is after 
first dose date, then impute as the month and day of the first dose date. 


 
Statistical Analysis Plan,  
 
Sponsor Arcutis Biotherapeutics, Inc.  
 
Protocol Number ARQ-252-213  
 
PCN Number ARCU213242 
 
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o Otherwise, assign 01 January. 
 If the year and month are known, but the day is unknown, then: 
o If the month and year match the month and year of the first dose date, then impute 
as the day of the first dose date. 
o Otherwise, assign 01. 
For partial AE and medication end dates: 
 If the year is unknown, then do not impute the date but assign as missing value. 
 If the year is known, but the month or month and day is unknown, then: 
o If the year matches the year of the last date of the study (date of last contact if 
subject lost to follow-up; date of completion or early termination otherwise), then 
impute as the month and day of the last date of the study. 
o Otherwise, assign 31 December. 
 If the year and month are known, but the day is unknown, then: 
o If the month and year match the month and year of the last date of the study, then 
impute as the day of the last date of the study. 
o Otherwise, assign the last day of the month. 
7. 
Study Subjects and Demographics 
7.1. 
Disposition of Subjects and Withdrawals 
Disposition will include tabulations of the number of subjects randomized into each treatment 
group, the number of subjects who received treatment, subjects completing the study, tabulated 
reasons for discontinuation from the study overall and due to COVID-19 disruption, and number 
of subjects in each analysis population. Disposition will be summarized for all subjects who were 
entered into database by treatment group and overall. 
7.2. 
Demographics and Other Baseline Characteristics 
Summary statistics for age, age group ( age ≤ 30, age > 30), gender (including child-bearing 
potential), race, ethnicity, height, weight, baseline disease characteristics (F-VASI, Fitzpatrick 
skin type), percent total BSA affected by vitiligo, percent BSA affected by vitiligo on face, and 
BMI will be presented by treatment group and overall.    
For the continuous variables, the number of non-missing values and the mean, standard 
deviation, minimum, Q1, median, Q3, and maximum will be tabulated.  
For the categorical variables, the counts and proportions of each value will be tabulated.    


 
Statistical Analysis Plan,  
 
Sponsor Arcutis Biotherapeutics, Inc.  
 
Protocol Number ARQ-252-213  
 
PCN Number ARCU213242 
 
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These analyses will be conducted for the Safety population.  
7.3. 
Exposure and Compliance 
The number of IP applications by each subject based on diary data will be summarized using 
descriptive statistics appropriate for continuous variables.  
The amount of IP used by each subject based on tube weight will be summarized descriptively 
by treatment group using continuous methods.    
The number of days on IP will be summarized descriptively by treatment group using continuous 
methods.  
8. 
 Efficacy Analysis 
Due to the study termination, it was the sponsor decision to not execute any efficacy analyses. 
Though the protocol indicates primary and secondary endpoints, upon the sponsor decision only 
F-VASI summaries will be provided based on observed value. Hence, observed, change and 
percent change from baseline in F-VASI scores will be summarized descriptively by treatment 
group using ITT population.  
9. 
Safety and Tolerability Analysis 
Safety will be evaluated from reported AEs, physical examinations, local tolerability 
assessments, and changes in 12-lead ECGs, clinical laboratory values, and vital signs/weight. No 
inferential statistical tests will be performed. 
All safety analyses will be performed on the Safety population. 
9.1. 
Adverse Events 
All AEs, TEAEs, and SAEs will be coded using the MedDRA dictionary version 23.1.  
A TEAE is defined as an AE with an onset date/time on or after the first application of IP. An 
overall summary of TEAEs will be provided; this will present number and percent of subjects 
who reported at least 1 of the following: TEAE (including all TEAEs, TEAEs by maximum 
severity, and related TEAEs to study drug and phototherapy), SAE, discontinued the study due to 
a TEAE, discontinued the study drug due to a TEAE, and discontinued the phototherapy due to a 
TEAE. 
The number and percent of subjects reporting TEAEs, grouped by MedDRA system organ class 
(SOC) and preferred term, will be tabulated by severity or greatest relationship to study drug and 
treatment group. In the case of multiple occurrences of the same TEAE within the same subject, 
each subject will only be counted once for each preferred term. In addition, summary by greatest 
relationship to the phototherapy treatment will be tabulated similarly. 


 
Statistical Analysis Plan,  
 
Sponsor Arcutis Biotherapeutics, Inc.  
 
Protocol Number ARQ-252-213  
 
PCN Number ARCU213242 
 
AD-ST-33.06  Effective date: 12-Nov-2020 
Version Final 1.0    |    Date 28-Sep-2021      |    AD-PR-109.02  Effective date: 17-Aug-2020 
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In the summaries showing severity and relationship to study medication the event with the 
maximum severity (mild < moderate < severe < life-threatening < death) will be reported. If a 
particular event is missing the severity, then the strongest possible severity will be assumed for 
analysis (severity = severe). 
In the AE data listings, all AEs will be displayed. Any AEs that are treatment emergent will be 
flagged. 
9.1.1. Adverse Events Leading to Withdrawal 
AEs leading to withdrawal of study drug will be flagged in the AE listing, displaying details of 
the event(s) captured on the CRF. 
9.1.2. Deaths and Serious Adverse Events 
No deaths occurred during the course of study. 
9.2. 
Local Tolerability Assessments 
The investigator’s assessment of the application site reaction will be summarized by study visit 
and treatment group using both categorical methods (number and percentage of subject with each 
score) as well as continuous methods (e.g., mean, median, etc.). Categorical summaries will be 
provided for dermal response as well as other effects. No inferential statistical tests will be 
performed. This assessment should be performed prior to the application of IP in the study site. 
Subjects not meeting this condition on baseline visit are completely removed from the table 
summary. 
The subject’s assessment of the application site reaction will be summarized similarly. This 
assessment should be performed 10 – 15 minutes after the application of IP in the study site. 
Subjects not meeting this condition on baseline visit are completely removed from the table 
summary.  
9.3. 
Clinical Laboratory Evaluations 
Laboratory test results will be summarized descriptively by treatment and study visit as both 
observed values, changes, and percent changes from baseline values for continuous hematology, 
chemistry, and urinalysis results. Categorical urinalysis results will be summarized using 
frequencies by study visit and treatment. 
Abnormal results will be flagged in the listings.  


 
Statistical Analysis Plan,  
 
Sponsor Arcutis Biotherapeutics, Inc.  
 
Protocol Number ARQ-252-213  
 
PCN Number ARCU213242 
 
AD-ST-33.06  Effective date: 12-Nov-2020 
Version Final 1.0    |    Date 28-Sep-2021      |    AD-PR-109.02  Effective date: 17-Aug-2020 
 Page 25 of 26 
 
 
9.4. 
Vital Signs 
Descriptive summaries of observed values, changes, and percent changes from baseline will be 
calculated for systolic blood pressure, diastolic blood pressure, heart rate, weight, BMI, and oral 
body temperature by treatment group and study visit.   
9.5. 
12-Lead Electrocardiograms 
Descriptive summaries for observed values and change from baseline will be presented for 
12-lead ECG measures of PR interval, QRS interval, QT interval, QTc interval (Fridericia’s 
[QTcF] correction method), and heart rate. These summaries will be presented by study visit and 
treatment group. 
The number and percentage of subjects with each ECG investigator interpretation (normal; 
abnormal, not clinically significant; or abnormal, clinically significant) will be displayed for each 
treatment group and study visit. If the interpretation results are different in CRF and external 
data, only the CRF data will be summarized in the tables. If the interpretation results are just 
collected in one source, that will be used for table summaries. 
9.6. 
Physical Examination 
The number and percentage of subjects with normal; abnormal, not clinically significant; or 
abnormal, clinically significant findings in the physical examination will be displayed at each 
study visit by body system and treatment group. Subjects having abnormal findings with 
description of Vitiligo are removed from table summary upon the sponsor request. 
9.7. 
Concomitant Medications 
Prior and concomitant medications will be summarized descriptively by treatment group, 
Anatomical Therapeutic Chemical (ATC) Class Level 4, and Preferred Term using counts and 
percentages. 
Prior medications will be presented separately from concomitant medications. Medications that 
started before the first application of IP will be considered prior medications whether or not they 
were stopped before the first application of study drug. Any medications continuing or starting 
after the first application of study drug will be considered to be concomitant. If a medication 
starts before the first application of study drug and continues after the first application of study 
drug it will be considered both prior and concomitant. 
Medications will be coded using WHODrug Enhance Global B3G, version September 2020. 
10. 
Changes from Planned Analysis 
This study was planned for 24 weeks to evaluate safety and efficacy ARQ-252 Cream 0.3% in 
Subjects with Non-Segmental  Facial Vitiligo. However, upon the sponsor discretion the study 


 
Statistical Analysis Plan,  
 
Sponsor Arcutis Biotherapeutics, Inc.  
 
Protocol Number ARQ-252-213  
 
PCN Number ARCU213242 
 
AD-ST-33.06  Effective date: 12-Nov-2020 
Version Final 1.0    |    Date 28-Sep-2021      |    AD-PR-109.02  Effective date: 17-Aug-2020 
 Page 26 of 26 
 
 
terminated and all the subjects that were currently enrolled are early terminated. Due to this 
decision, the following actions were taken which deviates from the planned analyses in the 
protocol: 
 Emergency unblinding was done after following Premier Research SOPs. 
 Only summary statistics are provided for F-VASI and other safety endpoints.  
 No statistical testing is performed and none of secondary endpoints are summarized. 
 The SAP and shells are developed to provide only summary statistics and frequency 
distributions. 
11. 
Other Planned Analysis 
11.1. Pharmacokinetic Analysis 
Plasma drug concentrations will be summarized using descriptive statistics by treatment group 
and time point. 
12. 
References 
ASA. (2018) Ethical Guidelines for Statistical Practice. Prepared by the Committee on 
Professional Ethics, April 2018. http://www.amstat.org/about/ethicalguidelines.cfm 
ICH (1998). ICH Harmonised Tripartite Guideline. Statistical Principles for Clinical Trials E9; 
1998. https://database.ich.org/sites/default/files/E9_Guideline.pdf 
RSS. (2014) The Royal Statistical Society: Code of Conduct, 2014. 
https://rss.org.uk/about/policy-and-guidelines/code-of-conduct/.