Clinical trial NCT04773600
Conditions: Atopic Dermatitis Eczema
Sponsor: Arcutis Biotherapeutics, Inc.
Start date: 2021-02-24; Completion date: 2022-09-29
Enrollment: 683 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study will assess the safety and efficacy of ARQ-151 cream vs vehicle applied once a day for 4 weeks by subjects with atopic dermatitis (eczema). This is a parallel group, double blind, vehicle-controlled study in which ARQ-151 0.15% cream or vehicle is applied once daily (qd) for 4 weeks by participants with atopic dermatitis.

Detailed description:

Arms: arm 1: Participants apply roflumilast cream 0.15% once daily (qd) for 4 weeks. arm 2: Participants apply vehicle cream qd for 4 weeks.
Interventions: intervention 1: Roflumilast Cream intervention 2: Vehicle cream
Intervention descriptions: intervention 1: Roflumilast cream 0.15% for topical application intervention 2: Vehicle cream for topical application

Protocol documents:
Prot_000.pdf: 


Protocol ARQ-151-312 
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SITE INVESTIGATOR SIGNATURE PAGE 
 
ARQ-151-312 
A Phase 3, 4-Week, Parallel Group, Double Blind, Vehicle-Controlled Study of the Safety and 
Efficacy of ARQ-151 Cream 0.15% Administered QD in Subjects with Atopic Dermatitis 
 
SPONSOR:  
 
Arcutis Biotherapeutics, Inc. 
 
 
 
 
2945 Townsgate Road, Suite 110 
 
 
 
 
Westlake Village, CA 91361 
 
ISSUE DATE: 
 
04 November 2020 
 
I have read this protocol, including all appendices, and I agree that it contains all necessary 
details for me and my staff to conduct this study as described. I will conduct this study as 
outlined herein, in accordance with the current International Conference on Harmonisation Good 
Clinical Practices (ICH GCPs) and applicable local and regional regulations.  
 
I will provide all study personnel under my supervision copies of the protocol and access to all 
information provided by Arcutis Biotherapeutics, Inc. I will discuss the material with them to 
ensure that they are fully informed about ARQ-151 and the study. 
 
I agree that I or my designee will completely inform all subjects in this study concerning the 
pertinent details and purpose of the study prior to their agreement to participate in the study in 
accordance with cGCPs and regulatory authority requirements. I will be responsible for 
maintaining each subject’s consent form in the study file and providing each subject with a 
signed copy of the consent form. 
 
I agree to maintain the confidentiality of all information received or developed in connection 
with this protocol. 
 
Investigational Site Name: 
_
_ 
 
 
Print Investigator Name:  
 
 
 
Investigator Signature: 
  Date:  
 
 
 
 


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TABLE OF CONTENTS 
1. 
PROTOCOL SUMMARY ..........................................................................................11 
1.1. 
Synopsis ......................................................................................................................11 
1.2. 
Study Schema .............................................................................................................19 
1.3. 
Schedule of Visits and Assessments ...........................................................................20 
2. 
INTRODUCTION ......................................................................................................23 
2.1. 
Background .................................................................................................................23 
2.2. 
Conclusions on Toxicity Findings ..............................................................................24 
2.3. 
Clinical Studies ...........................................................................................................24 
2.3.1. 
Topical Roflumilast Cream .........................................................................................24 
2.3.1.1. 
Psoriasis Phase 2a (ARQ-151-101) ............................................................................25 
2.3.1.2. 
Psoriasis Phase 2b (ARQ-151-201) ............................................................................27 
2.3.1.3. 
Atopic Dermatitis Phase 1 PK Study in Adults (ARQ-151-102) ...............................28 
2.3.1.4. 
Phase 1 Study in Adolescents and Pediatrics (ARQ-151-105) ...................................29 
2.3.1.5. 
Atopic Dermatitis Phase 2 Dose Ranging Study (ARQ-151-212) .............................30 
2.3.2. 
Oral Roflumilast Tablet ..............................................................................................30 
2.4. 
Rationale for Development .........................................................................................31 
2.4.1. 
Dose Selection ............................................................................................................31 
2.4.2 
Risks and/or Benefits to Subjects ...............................................................................32 
3. 
STUDY OBJECTIVES AND ENDPOINTS ..............................................................33 
3.1. 
Study Objectives .........................................................................................................33 
3.1.1. 
Primary Objective .......................................................................................................33 
3.2. 
Study Endpoints ..........................................................................................................33 
3.2.1. 
Primary Endpoint ........................................................................................................33 
3.2.2. 
Secondary Endpoints ..................................................................................................33 
3.2.3. 
Pharmacokinetic Endpoint ..........................................................................................33 
4. 
INVESTIGATIONAL PLAN .....................................................................................34 
4.1. 
Overall Study Design and Plan ...................................................................................34 
4.2. 
Number of Sites and Subjects .....................................................................................34 
4.3. 
Subject Participation ...................................................................................................34 
4.4. 
Numbering of Subjects ...............................................................................................35 


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4.5. 
Selection of Study Population ....................................................................................35 
4.5.1. 
Inclusion Criteria ........................................................................................................35 
4.5.2. 
Exclusion Criteria .......................................................................................................36 
4.6. 
Randomization ............................................................................................................38 
4.7. 
Study Restrictions .......................................................................................................39 
4.7.1. 
Prohibitions and Concomitant Therapy ......................................................................39 
4.8. 
Treatment ....................................................................................................................40 
4.8.1. 
Drug Supplies, Packaging and Labeling .....................................................................40 
4.8.2. 
Blinding ......................................................................................................................41 
4.8.3. 
Breaking Treatment Codes .........................................................................................41 
4.8.4. 
Treatment Administration ...........................................................................................41 
4.8.5. 
Treatment Compliance ................................................................................................42 
4.8.6. 
Removal of Subjects from Study Treatment ..............................................................43 
4.8.7. 
Removal of Subjects from the Study ..........................................................................43 
5. 
STUDY PROCEDURES ............................................................................................44 
5.1. 
Safety Assessments .....................................................................................................44 
5.1.1. 
Screening ....................................................................................................................44 
5.1.2. 
Contraception Requirements ......................................................................................45 
5.1.3. 
Baseline (Day 1) .........................................................................................................46 
5.1.4. 
Physical Examination .................................................................................................46 
5.1.5. 
Vital Signs, Height and Weight ..................................................................................46 
5.1.6. 
Laboratory Tests .........................................................................................................46 
5.1.7. 
Patient Health Questionnaire depression scale (PHQ-8) ............................................47 
5.1.8. 
Patient Health Questionnaire Depression Scale (Modified PHQ-A) ..........................48 
5.1.9. 
Children’s Depression Inventory 2 .............................................................................48 
5.1.10. 
Columbia-Suicide Severity Rating Scale (C-SSRS) ...................................................49 
5.1.11. 
Local Tolerability Assessment ...................................................................................49 
5.1.12. 
Adverse Events ...........................................................................................................50 
5.2. 
Efficacy Evaluations ...................................................................................................51 
5.2.1. 
Validated Investigator Global Assessment Scale for Atopic Dermatitis ....................51 
5.2.2. 
Eczema Area and Severity Index (EASI) ...................................................................51 
5.2.3. 
Worst Itch Numerical Rating Scale (WI-NRS) ..........................................................52 


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5.2.4. 
Dermatology Life Quality Index (DLQI) and Children’s Dermatology Life 
Quality Index (CDLQI) ..............................................................................................53 
5.2.5. 
Dermatitis Family Impact Questionnaire (DFI) .........................................................53 
5.3. 
Other Evaluations .......................................................................................................53 
5.3.1. 
Body Surface Area (BSA) ..........................................................................................53 
5.3.2. 
SCORAD ("SCORing Atopic Dermatitis") ................................................................53 
5.3.3. 
Patient-Oriented Eczema Measure (POEM) ...............................................................53 
5.3.4. 
Pharmacokinetics Assessment ....................................................................................54 
5.3.5. 
Medical Photography ..................................................................................................54 
5.4. 
Final Study Visit – End of Study ................................................................................54 
5.5. 
Early Termination Visit ..............................................................................................54 
5.6. 
Unscheduled Visit .......................................................................................................54 
5.7. 
Adverse Events ...........................................................................................................55 
5.7.1. 
Adverse Event Definition ...........................................................................................55 
5.7.2. 
Serious Adverse Event Definition ..............................................................................55 
5.7.3. 
Suspected Unexpected Serious Adverse Reaction (SUSAR) .....................................57 
5.7.4. 
Safety Review with Subject ........................................................................................57 
5.7.5. 
Adverse Event Reporting ............................................................................................57 
5.8. 
Reporting Pregnancy ..................................................................................................59 
5.9. 
Treatment Stopping Rules ..........................................................................................59 
6. 
DATA ANALYSIS ....................................................................................................60 
6.1. 
Statistical Methods ......................................................................................................60 
6.2. 
Determination of Sample Size ....................................................................................61 
6.3. 
Subjects to Analyze ....................................................................................................61 
6.4. 
Background and Demographic Characteristics ..........................................................61 
6.5. 
Study Medication Compliance ...................................................................................62 
6.6. 
Safety Analysis ...........................................................................................................62 
6.7. 
Efficacy Analysis ........................................................................................................62 
6.8. 
Adverse Events ...........................................................................................................63 
6.9. 
Body Surface Area ......................................................................................................64 
6.10. 
Local Tolerance Assessment ......................................................................................64 
6.11. 
Medical History and Physical Examinations ..............................................................64 


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6.12. 
Clinical Laboratory Results and Vital Signs ..............................................................64 
6.13. 
Prior and Concomitant Medications ...........................................................................64 
6.14. 
Subject Reported Outcomes Analyses ........................................................................64 
6.14.1. 
Dermatology Life Quality Indexes, Children’s Dermatology Life Quality 
Index, SCORAD and POEM ......................................................................................65 
6.15. 
Pharmacokinetic Analysis ..........................................................................................65 
7. 
STUDY ADMINISTRATION ...................................................................................65 
7.1. 
Ethics ..........................................................................................................................65 
7.1.1. 
Ethics Review Board ..................................................................................................65 
7.1.2. 
Ethical Conduct of the Study ......................................................................................65 
7.1.3. 
Subject Information and Consent/Assent ...................................................................65 
7.2. 
Study Completion and Termination ............................................................................66 
7.2.1. 
Study Completion .......................................................................................................66 
7.2.2. 
Study Termination ......................................................................................................66 
7.3. 
Study Monitoring ........................................................................................................66 
7.4. 
Data Quality Assurance ..............................................................................................67 
7.5. 
Data Handling and Record Keeping ...........................................................................67 
7.6. 
Protocol Amendments and Deviations .......................................................................67 
7.7. 
Confidentiality and Privacy ........................................................................................68 
7.8. 
Conflict of Interest ......................................................................................................68 
7.9. 
Report Format .............................................................................................................68 
7.10. 
Publication Policy .......................................................................................................69 
8. 
REFERENCES ...........................................................................................................69 
9. 
APPENDICES ............................................................................................................71 
APPENDIX 1. BODY DIAGRAM .............................................................................................71 
APPENDIX 2. PATIENT HEALTH QUESTIONAIRE-8 (PHQ-8) ..........................................72 
APPENDIX 3. PATIENT HEALTH QUESTIONNAIRE DEPRESSION SCALE 
(MODIFIED PHQ-A) .........................................................................................73 
APPENDIX 4. CHILDREN’S DEPRESSION INVENTORY 2 (PARENT REPORT) ............74 
APPENDIX 5. COLUMBIA-SUICIDE SEVERITY RATING SCALE (C-SSRS) 
“BASELINE/SCREENING” VERSION ...........................................................75 
APPENDIX 6. COLUMBIA-SUICIDE SEVERITY RATING SCALE (C-SSRS) 
“SINCE LAST VISIT” VERSION ....................................................................78 


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APPENDIX 7. VALIDATED INVESTIGATOR GLOBAL ASSESSMENT SCALE 
FOR ATOPIC DERMATITIS ............................................................................81 
APPENDIX 8. DERMATOLOGY LIFE QUALITY INDEX ....................................................82 
APPENDIX 9. CHILDREN’S DERMATOLOGY LIFE QUALITY INDEX ...........................84 
APPENDIX 10. DERMATITIS FAMILY IMPACT QUESTIONNAIRE (DFI) ......................86 
APPENDIX 11. SCORAD ..........................................................................................................88 
APPENDIX 12. PATIENT-ORIENTED ECZEMA MEASURE (POEM) ................................89 
APPENDIX 13. NIAID DMID TOXICITY TABLE .................................................................91 
 
LIST OF TABLES 
Table 1: 
ARQ-151-101: Skin Toleration Treatment-Emergent Adverse Experiences ............ 26 
Table 2: 
Excluded Medications and Treatments ...................................................................... 39 
Table 3: 
Laboratory Tests ........................................................................................................ 47 
 
LIST OF FIGURES 
Figure 1: 
Contraception Requirements for Female Subjects .................................................... 45 
 
 
 
 


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ABBREVIATIONS 
Abbreviation 
Definition 
α 
Alpha Level (significance level) 
AE 
Adverse Event 
AMP 
Adenosine Monophosphate 
AD 
Atopic Dermatitis    
AUC 
Area Under the Curve 
BSA 
Body Surface Area 
CDI 
Children’s Depression Inventory  
CDLQI 
Children’s Dermatology Life Quality Index  
Cmax 
Maximum Concentration 
cm 
Centimeter 
COPD 
Chronic Obstructive Pulmonary Disease 
CRF 
Case Report Form 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CTCAE 
Common Terminology Criteria for Adverse Events 
DFI 
Dermatitis Family Impact 
DNA 
Deoxyribonucleic Acid 
DLQI 
Dermatology Life Quality Index 
EASI 
Eczema Area and Severity Index 
FDA 
U.S. Food and Drug Administration 
FOCBP 
Female of Child Bearing Potential 
FSH 
Follicle-Stimulating Hormone  
GCP 
Good Clinical Practices 
GLP 
Good Laboratory Practices 
hr 
Hour 
IB 
Investigational Brochure 
IC50 
Half Maximal Inhibitory Concentration 
ICF 
Informed Consent Form 
ICH  
International Conference on Harmonisation 
ID 
Identification  
IGA 
Investigator Global Assessment 


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Abbreviation 
Definition 
IL 
Interleukin 
IND 
Investigational New Drug 
IP 
Investigational Product 
IRB 
Institutional Review Board 
ITT 
Intent to Treat 
IWRS 
Interactive Web Response System 
kg 
Kilogram 
LED 
Light Emitting Device 
µg 
Microgram 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
Milligram 
min 
Minute 
mL 
Milliliter 
MTD 
Maximum Tolerated Dose 
NCI 
National Cancer Institute 
NIH 
National Institutes of Health 
NOAEL 
No Observed Adverse Effect Level 
ng 
Nanogram 
P-450 
Cytochrome P450 
PDE-4 
Phosphodiesterase 4 
PHQ-8 
Patient Health Questionnaire-8 
PI 
Principal Investigator  
PK 
Pharmacokinetics 
POEM 
Patient-Oriented Eczema Measure 
QD 
Once Daily ("quaque die") 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SCORAD 
Scoring Atopic Dermatitis 
SD 
Standard Deviation  
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TCPS 
Tri-Council Policy Statement 


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Abbreviation 
Definition 
TEAE 
Treatment Emergent Adverse Event 
Tmax 
Time to Reach Maximum Concentration 
TPA 
Target Plaque Area 
TPSS 
Target Plaque Severity Score 
US 
United States 
UVR 
Ultraviolet Radiation 
V79 
Chinese Hamster Cell Line 
vIGA-AD 
Validated Investigator Global Assessment - Atopic Dermatitis 
WI-NRS 
Worst Itch - Numeric Rating Score  
 
 


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1. 
PROTOCOL SUMMARY 
1.1. 
Synopsis 
Protocol Title: 
A Phase 3, 4-Week, Parallel Group, Double Blind, Vehicle-
Controlled Study of the Safety and Efficacy of ARQ-151 Cream 
0.15% Administered QD in Subjects with Atopic Dermatitis 
Clinical Indication: 
Atopic Dermatitis 
Investigational 
Product: 
• ARQ-151 will be supplied as an emollient cream at 0.15% 
strength 
• Matching vehicle cream will contain only excipients of 
ARQ-151  
Study Design: 
This is a Phase 3, parallel group, double blind, vehicle-controlled 
study in which ARQ-151 cream 0.15% or vehicle is applied QD for 
4 weeks to subjects 6 years of age and older with mild to moderate 
atopic dermatitis. 
At entry, subjects will have ≥3% BSA involvement (excluding the 
scalp, palms, soles) and mild or moderate atopic dermatitis (AD) 
based on vIGA-AD assessment.   
Upon determination of eligibility, subjects will be randomized 2:1 to 
either ARQ-151 cream 0.15% cream or matching vehicle cream.  
The randomization will be stratified by vIGA-AD score at 
Baseline/Day 1 (‘Mild’ vs. ‘Moderate’) and by study site. 
Subjects/caregivers will apply ARQ-151 cream 0.15% or vehicle 
cream QD for 28 days to all AD affected areas and any newly 
appearing AD lesions that arise during the study, except on the scalp. 
Subjects/caregivers should maintain treatment of these areas with 
study drug for the duration of the study regardless of whether 
treatable areas of AD clear prior to Week 4/Day29. 
At the Week 4 visit, subjects may be eligible to enroll in a 12‑month, 
open label extension study (ARQ-151-313) evaluating ARQ-151 
cream 0.15% QD.   
Study Objective: 
To assess the safety and efficacy of ARQ-151 cream 0.15% vs 
vehicle administered QD x 4 weeks to individuals with atopic 
dermatitis. 
Study Sites: 
Approximately 40 sites in the US and Canada. 


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Study Population: 
Subjects will be male and female children and adolescents 
(6‑17 years), and adults (>18 years). Subjects will have mild to 
moderate atopic dermatitis involvement with a vIGA-AD score of 
‘2’ (Mild) or ‘3’ (Moderate) for study entry. Up to 25% of the 
subjects will be ≥18 years old. Approximately 650 subjects are 
planned to be randomized in this study. 
Duration of 
Participation for 
Subjects: 
Screening (up to 30 days) + Treatment phase (4 weeks) for a total of 
about 8 weeks. 
Upon completion of the treatment phase of the study 
(Week 4/Day 29) subjects may have the opportunity, subject to 
regulatory approval and enrollment has not been completed, to 
participate in an open-label extension study (ARQ‑151-313) of up to 
12 months. 
Inclusion Criteria: 
1. For adult subjects: Participants legally competent to sign and 
give informed consent.  For pediatric and adolescent subjects: 
Informed consent of parent(s) or legal guardian, and, if age 
appropriate, assent by the subjects, as required by local laws. 
2. Males and females, ages 6 years and older at time of signing 
Informed Consent (Screening). 
3. Diagnosed with mild to moderate atopic dermatitis according to 
the criteria of Hanifin and Rajka (1980) prior to or at the 
screening visit.  Subjects must have at least 3 of the 4 basic 
features per Hanifin and Rajka (1. Pruritus; 2. Typical 
morphology and distribution [flexural lichenification in adults 
and facial and extensor eruptions in infants and children]; 
3. Chronic or chronically relapsing dermatitis; or 4. Personal or 
family history of atopy), in addition to 3 or more minor criteria. 
4. History of AD for at least 3 months in subjects 6-17 years of age 
or 6 months in subjects >18 years of age, as determined by the 
Investigator using information from the subject’s medical chart, 
from the subject’s physician, or through subject/parent/caregiver 
interview. Stable disease for the past 4 weeks with no significant 
flares in atopic dermatitis before screening. 
5. EASI Score >5.  EASI is evaluated for the entire body except the 
scalp, palms, and soles. 
6. vIGA-AD score of ‘Mild’ (‘2’) of ‘Moderate’ (‘3’) at Baseline. 
The vIGA-AD is evaluated for the entire body except the scalp, 
palms, and soles. 
7. Has AD involvement of >3% BSA (excluding the scalp, palms, 
soles).  
 


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8. Females of childbearing potential (FOCBP) must have a 
negative serum pregnancy test at Screening and a negative urine 
pregnancy test at Baseline/Day 1. In addition, sexually active 
FOCBP must agree to use at least one form of a highly effective 
or barrier method of contraception throughout the trial. The use 
of abstinence as a contraceptive measure is acceptable as long as 
this is a consistent part of a lifestyle choice and an acceptable 
backup method has been identified if the subject becomes 
sexually active.  
9. Females of non-childbearing potential should either be pre-
menarchal, or post-menopausal with spontaneous amenorrhea 
for at least 12 months (post-menopausal status should be 
confirmed with FSH testing) or have undergone surgical 
sterilization (permanent sterilization methods include 
hysterectomy, bilateral oophorectomy, hysteroscopic 
sterilization, bilateral tubal ligation or bilateral salpingectomy). 
10. In good health as judged by the Investigator, based on medical 
history, physical examination, vital signs, serum chemistry labs, 
hematology values, and urinalysis. 
11. Subjects and parent(s)/legal guardian(s) are considered reliable 
and capable of adhering to the Protocol and visit schedule, 
according to the judgment of the Investigator. 
Exclusion Criteria: 
1. Subjects with any serious medical condition or clinically 
significant laboratory, vital signs, or physical examination 
abnormality that would prevent study participation or place the 
subject at significant risk, as judged by the Investigator 
2. Liver function tests excursions that exceed: 
• AST or ALT > 2X ULN 
• Total bilirubin: 
− > 1.5 x ULN or 
− > ULN and ≤ 1.5 x ULN AND direct bilirubin is 
> 35% of total bilirubin 
• ALP ≥ 2x ULN 
3. Subjects who cannot discontinue medications and treatments 
prior to the Baseline visit and during the study according to 
Excluded Medications and Treatments (Table 2). 
4. Has unstable AD or any consistent requirement for high potency 
topical steroids to manage AD signs or symptoms. 
5. Subjects who have significant active systemic or localized 
infection (e.g., molluscum contagiosum), including known 
actively infected AD, or have had any infection that required 




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15. Subjects with a PHQ-8 (adults) or modified PHQ-A 
(adolescents, 12-17 years old inclusive) score ≥10 at Screening 
or Baseline/Day 1 visits. 
16. Subjects (6 to 11 years old, inclusive) with a CDI-2 (parent 
report) raw score ≥17 for females and ≥18 for males at 
Screening or Baseline/Day 1 visits. 
17. Females who are pregnant, wishing to become pregnant during 
the study, or are breast-feeding. 
18. Previous treatment with ARQ-151. 
19. Subjects currently undergoing allergy testing (e.g., food allergy 
testing or skin prick testing), patch testing, food challenges, or 
allergy desensitization, or plan to do so during the study. 
20. Subjects with any serious medical condition (e.g., hypo- or 
hyper-thyroidism) or clinically significant laboratory 
abnormality that would prevent study participation or place the 
subject at significant risk, as determined by the Investigator. 
21. Subjects with a history of a major surgery within 4 weeks prior 
to Baseline/Day 1 or subjects who have a major surgery planned 
during the study. 
22. Subjects with a history of chronic alcohol or drug abuse within 
6 months prior to Screening. 
23. Current or a history of cancer within 5 years with the exception 
of fully treated skin basal cell carcinoma, cutaneous squamous 
cell carcinoma or carcinoma in situ of the cervix.  
24. Parent(s)/legal guardian(s) who are unable to communicate, 
read, or understand the local language(s).  Subjects who are 
unable to communicate, read or understand the local language, 
or who display another condition, which in the Investigator’s 
opinion, makes them unsuitable for clinical study participation. 
25. Subjects who are family members of the clinical study site, 
clinical study staff, or sponsor, or family members of enrolled 
subjects living in the same house. 
Key Assessments: 
Safety Assessments 
• Safety will be monitored through local tolerability 
assessments, vital signs, physical examination, safety labs, 
Children's Depression Inventory 2 (CDI-2, parent report for 
children 6-11 years old, inclusive), modified PHQ-A (for 
adolescents 12-17 years old, inclusive), PHQ-8 (for adults), 
C-SSRS (for adolescents and adults 12 years old and older), 
and AEs.  


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• After obtaining consent, all AEs and TEAEs should be 
collected.  
• The investigator or a properly trained and designated 
subinvestigator will perform local tolerability assessments at 
Baseline/Day 1, and Weeks 1, 2, and 4 (Days 8, 15, and 29). 
Subjects will have vital signs measured at each study visit. 
Height will be collected at Visit 1 (Screening) only. 
• A limited physical exam (skin, lungs, and heart only) will be 
performed at Screening, Baseline/Day 1 and Week 4/Day 29. 
Blood and urine samples for routine safety laboratory tests 
(hematology, serum chemistry, and urinalysis) will be 
obtained at Screening, Baseline/Day 1 and Week 4/Day 29. 
For all female subjects of childbearing potential, a urine 
pregnancy test will be administered at all clinic visits except 
for Screening where a serum pregnancy test will be 
performed. A negative pregnancy result is required for 
continued participation in the study, and results (of the urine 
pregnancy test) must be available prior to dispensing of study 
drug at study visits.   
Efficacy Assessments 
• Efficacy assessments will include vIGA-AD (Appendix 7), 
EASI, WI-NRS, BSA, DLQI/CDLQI (Appendix 8 and 
Appendix 9), DFI (Appendix 10), SCORAD (Appendix 11), 
and POEM (Appendix 12). 
Pharmacokinetic Assessment 
• A single PK assessment (trough) will be performed in all 
subjects with a blood sample collected at Week 4/Day 29. 
Study Endpoints: 
1. The Primary Efficacy Endpoint will be tested in all 
randomized subjects and defined as:  
• The proportion of all randomized subjects who attain IGA 
Success, defined as a vIGA-AD score of ‘clear’ or ‘almost 
clear’ PLUS a 2-grade improvement from Baseline at 
Week 4 
2. Upon demonstration of statistical significance for the primary 
endpoint, a hierarchical testing scheme will be used to test the 
Secondary Efficacy Endpoints defined as: 
• The proportion of randomized subjects with a vIGA-AD 
score of ‘Moderate’ at randomization who attain IGA 
Success at Week 4 
• Among subjects with baseline WINRS ≥ 4, the proportion 
who attain a 4‑point reduction on the WI-NRS at Week 4 


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• The proportion of subjects who attain at least a 75% 
reduction in the Eczema Area and Severity Index 
(EASI-75) at Week 4 
• Time to achievement of vIGA-AD success 
• Time to achievement of EASI-75 
3. Pharmacokinetic endpoints include concentrations of 
roflumilast and its N-oxide metabolite. 
Power and Sample 
Size: 
Approximately 650 subjects are planned to be randomized in this 
study. To test the key secondary endpoint of IGA success in subjects 
with a vIGA-AD score of ‘Moderate’ at randomization, 
approximately 488 of the subjects to be accrued will have vIGA‑AD 
score of ‘Moderate’ at randomization.  Randomization will be 
stratified by vIGA-AD score (‘Mild’ vs. ‘Moderate’) and by study 
site. 
This sample size provides approximately 95% power to detect an 
overall 15% difference between treatment groups on vIGA‑AD 
success at Week 4 at α-0.05 using a 2-sided stratified (vIGA-AD at 
randomization and study site) Cochran-Mantel-Haenszel test.  The 
results from a recent phase 2 study (ARQ‑151-212) of ARQ-151 
cream 0.15% compared to vehicle treatment were used to estimate 
the treatment difference.  Specifically, in the phase 2 trial, 
approximately 37% of subjects demonstrated vIGA-AD success at 
Week 4 in the ARQ-151 0.15% group compared to 22% in the 
vehicle group.  This sample size also provides approximately 90% 
power to detect an overall 17% difference between treatment groups 
on IGA success at Week 4 among subjects with vIGA-AD score 
‘Moderate’ at randomization. The same testing method, the stratified 
Cochran-Mantel-Haenszel test, will be used as for the primary 
endpoint. 


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Statistical Analysis: 
The analysis populations are defined as follows: 
• Safety population will include all subjects who are enrolled 
and received at least one confirmed dose of study medication. 
• Intent-to-Treat (ITT) population will include all subjects who 
are randomized.  
• vIGA-AD Moderate ITT population will be a subset of the ITT 
population with vIGA-AD score ‘moderate’ at randomization. 
• WI-NRS population will be a subset of the ITT population 
with a baseline WI-NRS score ≥ 4. 
• PK population will include all subjects receiving the active 
drug with quantifiable plasma concentrations of roflumilast.  
To control for multiple comparisons, the key secondary endpoint 
will only be tested if the primary endpoint demonstrates statistical 
significance.  In addition, the remaining secondary endpoints will be 
inferentially tested only if the primary and key secondary endpoint 
comparisons are statistically significant.  To control for multiple 
comparisons among the remaining secondary endpoints, partitioning 
of alpha and the Holm’s procedure will be used. 
Descriptive statistics for continuous variables will include mean, 
median, standard deviation, min, max. Descriptive statistics for 
categorical variables will include frequencies and percents. For 
missing data, the primary imputation method and sensitivity methods 
will be detailed in the SAP. The primary endpoint and key secondary 
endpoints of vIGA-AD success will be analyzed with a Cochran-
Mantel-Haenszel test stratified by the randomization factors (disease 
severity determined by vIGA-AD and by study site). 
Categorical secondary efficacy analysis will be analyzed in the same 
manner as the primary endpoint.   
Continuous secondary endpoints will be analyzed analysis of 
covariance with treatment, the randomization stratification factors, 
and baseline value as independent variables.  Statistical comparisons 
between the treatment groups will be obtained using contrasts. 
The incidence of adverse events will be summarized as well as 
changes in laboratory parameters and vital signs. 
 
 


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1.2. 
 
Study Schema 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Screening 
ARQ-151 
0.15% 
Matching 
Vehicle Cream 
Treatment Period and Clinic Visits 
Week 1/Day 8, Week 2/Day 15, and Week 4/Day 29 
Randomization and Treatment 
Baseline / Day 1 
(N=650) 
Not Participating in Open 
Label Extension Study 
 
End of Study 
Participating in Open Label 
Extension Study 
 
ARQ-151-313 
 
Enrollment 
A Phase 3, 4-Week, Parallel Group, Double Blind, Vehicle-Controlled Study of 
the Safety and Efficacy of ARQ-151 Cream 0.15% Administered QD in 
Subjects with Atopic Dematitis  
 
Approximately 650 subjects with atopic dermatitis will be randomized 2:1 to receive 
either: 
• 
ARQ-151 cream 0.15% or Vehicle cream 
Subjects will have ≥3% BSA involvement (excluding the scalp, palms, soles) with a 
vIGA-AD score of ‘2’ (mild) or ‘3’ (moderate) for study entry 
Up to 25% of the subjects will be ≥ 18 years old 


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1.3. 
Schedule of Visits and Assessments 
Study Procedure 
Screen 
Baseline 
Day 1 
Wk 1 
Day 8 
Wk 2 
Day 15 
Wk 4 
Day 29 / ET 
Visit 
1 
2 
3 
4 
5 
Visit Window 
-30 days 
N/A 
+/- 3 days 
+/- 3 days 
+/- 3 days 
Informed consent/assent 
X 
 
 
 
 
Demographics 
X 
 
 
 
 
Medical and surgical 
history 
X 
 
 
 
 
Physical examinationa 
X 
X 
 
 
X 
I/E criteria 
X 
X 
 
 
 
Hematology, Serum 
Chemistries, and Urine 
Analysisb 
X 
X 
 
 
 
X 
Vital signs, height, weightc 
X 
X 
X 
X 
X 
vIGA-AD, EASI, BSA, 
SCORADd 
X 
X 
X 
X 
X 
WI-NRS prurituse 
X 
X 
X 
X 
X 
POEMf 
X 
X 
X 
X 
X 
Local Tolerability 
Assessmentg  
 
X 
X 
X 
X 
CDI-2, PHQ-8, PHQ-A, 
C‑SSRSh 
X 
X 
X 
X 
X 
DLQI, CDLQI, DFIi 
X 
X 
X 
X 
X 
Medical Photographyj 
 
X 
X 
 
X 
Serum pregnancy test 
(FOCBP only) 
X 
 
 
 
 
Urine pregnancy testk 
 
X 
X 
X 
X 
PK drawsl 
 
 
 
 
X 
Drug/vehicle application 
in clinicm 
 
X 
X 
X 
 
Dispense/Re-dispense study 
medication kitn 
 
X 
Xo 
Xo 
Xo 
Dispense/review diary 
 
X 
X 
X 
X 
Weigh study medication 
kitp 
 
X 
X 
X 
X 
Compliance 
determinationq 
 
 
X 
X 
X 
Adverse event assessmentr 
X 
X 
X 
X 
X 
Concomitant medications 
X 
X 
X 
X 
X 
Study Exit s 
 
 
 
 
X 
 


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a Limited physical examination: skin (including assessment of Fitzpatrick skin type at Screening only), lungs, and 
heart only 
b To be collected at Screening, Baseline/Day 1, and Week 4/Day 29. For subjects <18 years of age, if 
Baseline/Day 1 is within 3 weeks of Screening, the Screening results will be utilized. 
c Height will be collected at Screening only. Weight should be obtained using a calibrated weight scale and the same 
scale should be used for a subject throughout the duration of the study.  The subject should remove shoes and 
heavy clothing (sweaters or jackets), and empty pockets. The subject should stand with both feet in the center of 
the scale with their arms at their side and hold still. Record the weight to the nearest decimal fraction (for example, 
25.1 kilograms). For subjects <18 years of age, measure the weight in triplicate and report the average weight in 
EDC. A 5% or greater weight loss (whether or not intentional or other explained) should be reported to the 
medical monitor. 
d The vIGA-AD assessment will be a 5-point scale ranging from clear (0) to severe (4) and is evaluated for the 
entire body except the scalp, palms, and soles. EASI takes into account overall severity of erythema, 
infiltration/papulation, excoriation, and lichenification, in addition to extent of BSA affected. The 4 clinical signs 
will be graded on a 4-point scale (0 [absent] to 3 [severe]) for 4 body regions (head and neck, upper extremities, 
lower extremities, and trunk). Total EASI score will be calculated as a sum of scores of all 4 body regions. EASI 
total score will range from 0 (absent) to 72 (severe). Total BSA affected by AD will be determined for all body 
surfaces except the scalp, palms and soles. The vIGA-AD assessment should be completed prior to other 
physician assessments. SCORAD total score will range between 0 and 103.  
e Subjects will self-assess their pruritus at home on a daily basis starting 7 days prior to the Baseline/Day 1 visit, and 
then every day thereafter.  WI-NRS score will be determined by the subject assessing worst itch over the past 
24 hours. The scale is from 0 (no itch) to 10 (worst itch) and this value will be recorded by the subject each day. 
f POEM will be completed by all subjects either by self or by proxy completion (for children unable to read and/or 
understand the POEM questionnaire, the parent/guardian/caregiver will complete the questionnaire). 
g Local tolerability assessments should be recorded prior to study drug application for the Investigator assessment of 
skin irritation (Berger and Bowman skin irritation score). Note for investigator tolerability assessments: 
reactions at the site of product application, which may occur post-Baseline, should be differentiated from 
the preexisting inflammation associated with the subject’s atopic dermatitis. The subject will assess 
burning/stinging (0-3 score) 10-15 minutes post drug application. Note subject burning stinging assessment: at 
Day 29, subjects will provide a recall assessment of burning/stinging experienced post drug application on 
the previous day (Day 28). 
h Adolescents and adults will complete the C-SSRS (12 years of age and older).  Adults will complete the PHQ-8.  
Adolescents (ages 12 to 17, inclusive) will complete the PHQ-A (PHQ-9 modified). Parents/caregivers will 
complete CDI-2 (parent report) for children 6-11 years of age, inclusive. 
i The DLQI will be completed by subjects ≥17 years of age. The CDLQI will be completed for subjects 
6 to 16 years old, inclusive. The Dermatitis Family Impact Questionnaire (DFI) will be completed by 
parents/caregivers for all subjects 6 to ≤17 years of age. 
j Photography of AD lesion(s) selected by the Investigator will be performed at all investigational sites.  All efforts 
will be made to de-identify the subjects. Canfield equipment will be used to capture photographs. Subjects who are 
unwilling to participate in the medical photography will be allowed to opt out of this procedure, as documented on 
the Informed Consent Form. 
k 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. 
l Single PK trough draw will be collected at Day 29. Ensure study medication was not applied in the area where PK 
will be drawn.  
m Subjects to apply assigned IP during clinic visits, except for the Day 29 visit. 
n Kits will be dispensed based on %BSA affected. See IP Handling Manual for details.   
 
 


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o On Day 8 and 15, dispensing of IP is optional.  Site should review IP kit to ensure sufficient IP is available until the 
next visit and only dispense additional IP if needed. On Day 29, if the subject is unable to perform the Day 29 
clinic visit due to COVID-19 restrictions (isolation, quarantine, etc.) then additional IP may need to be dispensed 
so IP can continue to be applied at home until the subject is able to return to the clinic to complete the Day 29 
assessments (see IP Handling Manual for the process to dispense additional IP at or after Day 29). 
p  Every tube should be weighed and recorded when dispensed and returned.. See IP Handling Manual for details. 
q  Compliance determination is described in the IP Handling Manual 
r All AEs should be collected starting after the first application of the investigational product through the end of the 
study. All SAEs should be collected starting after the signing of the informed consent through 30 days after the 
last day of the application of the investigational product or the end of the study (whichever is later). Any AEs 
(whether serious or non-serious) and clinically abnormal laboratory test values(s) will be evaluated by the PI and 
treated and/or followed up for up to 30 days after end of treatment or until symptoms or value(s) return to normal, 
or acceptable level, as judged by the PI 
s Subjects who enroll into the open label extension study (ARQ-151-313) must complete the ARQ-151-312 visit 
requirements at Week 4. 
 
 


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2. 
INTRODUCTION 
2.1. 
Background 
Roflumilast is a phosphodiesterase 4 (PDE-4) inhibitor approved globally to reduce the risk of 
exacerbations in patients with severe chronic obstructive pulmonary disease (COPD) associated 
with chronic bronchitis.  Roflumilast and its active metabolite, roflumilast N-oxide, are high 
affinity selective inhibitors of PDE-4 (a major cyclic-3′,5′-adenosine monophosphate 
(cyclic AMP)-metabolizing enzyme), whose activity leads to accumulation of intracellular cyclic 
AMP.  There are four different subtypes of PDE-4: PDE-4a, PDE-4b, PDE-4c, and PDE-4d, each 
with several isoforms (splicing variants).  IC50 values of both roflumilast and roflumilast N-oxide 
for the different PDE-4 isoforms and subtypes are mostly sub-nanomolar and single digit 
nanomolar (Hatzelmann 2010).  The PDE-4 family of enzymes are the most prevalent 
phosphodiesterases in immune cells and inhibition of PDE-4 subtypes has been associated with 
anti-inflammatory effects in many biological systems. 
Roflumilast was initially developed as a 500 µg tablet for oral therapy in patients with COPD, 
and as such has been thoroughly evaluated in nonclinical studies.  The safety profile is 
well-established.  Oral roflumilast (500 µg tablet) was approved by Health Canada as DAXAS® 
in December 2010 and by the US FDA as DALIRESP® in February 2011 for the treatment of 
COPD.  The study sponsor has conducted nonclinical studies in which roflumilast is applied 
dermally. 
The dermal nonclinical program for ARQ-151 cream followed current International Conference 
on Harmonisation (ICH) guidelines and includes a 13-week dermal toxicity study in minipigs, a 
13-week dermal toxicity study in mice, a 39-week dermal toxicity study in minipigs, a skin 
sensitization study in guinea pigs, a phototoxicity study, an eye irritation study and a 104-week 
carcinogenicity study in mice, the in life portion of which is complete. 
Refer to the current ARQ-151 Investigator’s Brochure (IB) for the most current PDE-4 dermal 
and oral/systemic nonclinical and clinical information.  
Atopic dermatitis is a chronic inflammatory skin disorder affecting children and adults, with the 
majority presenting with disease of mild to moderate severity.  The use of topical corticosteroids 
and/or topical calcineurin inhibitors, in combination with emollients has been the mainstay for 
treating atopic dermatitis.  In 2016, Eucrisa® (crisaborole), a PDE-4 inhibitor was approved for 
the topical treatment of mild to moderate atopic dermatitis in patients 2 years of age and older.   
Topical calcineurin inhibitors block the activation of T-lymphocytes and diminish inflammation, 
but are accompanied by a boxed warning for the development of lymphomas and other 
lymphoproliferative diseases.  Topical corticosteroids can cause skin atrophy and hypothalamic-
pituitary axis suppression, and their use is often accompanied by poor adherence due to 
corticophobia (fear of using corticosteroids in patients or doctors).  Eucrisa provides precedence 
for the effectiveness of topical PDE-4 inhibitors in atopic dermatitis, but it is a twice-daily 
ointment, its efficacy may be modest, and its use may be accompanied by burning, stinging, and 
local skin reactions. As a result, there is a need for the development of new topical products for 
the treatment of atopic dermatitis (Nygaard 2017). 


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The therapeutic use of PDE-4 inhibitors in AD is based on the recognized intracellular role of 
PDE-4 in keratinocytes (Dastidar 2007, Hanifin 1996). Circulating leukocytes in AD patients 
have PDE-4 activity, which has been associated with higher production of proinflammatory 
mediators and lower production of the anti-inflammatory mediator IL-10, in part due to 
hydrolyzation of cyclic adenosine monophosphate (cAMP) (Grewe 1982, Furue 2014, 
Baumer 2007).  This consequently diminishes levels of cAMP, which leads to increased 
transcription of numerous cytokines, accelerating a number of intracellular functions involved in 
acute and chronic inflammation (Grewe 1982).  Thus, targeting PDE-4 has been shown to 
directly attenuate inflammation due to inhibition of the breakdown of cAMP, consequently 
reducing the levels of tumour necrosis factor-α, IL-12, IL-23, and other signaling effectors 
(Murrell 2015, Nazarian 2009). 
2.2. 
Conclusions on Toxicity Findings 
The safety profile of oral roflumilast is well-established.  An extensive systemic toxicity program 
that evaluated both roflumilast and its active N-oxide metabolite in multiple species via the oral 
route of administration was conducted to support registration of the 500 µg tablet for COPD. 
The previously-conducted systemic toxicity program included studies to evaluate reproductive 
toxicity, genotoxicity and carcinogenicity, and the results of those studies are included in the 
labeling for oral roflumilast.  
To support the development of ARQ-151 topical cream a GLP-compliant dermal toxicity 
program is being conducted.  To date, no new risks have been identified through the dermal 
toxicity program.  In 13-week dermal toxicity studies in minipigs and mice, and a 39-week 
dermal toxicity study in minipigs, no evidence of systemic toxicity was observed.  
Histopathological evaluation of skin in the minipig study included very slight to slight erythema 
at all treatment levels, and minor degrees of irritation such as hyperplasia.  The NOAEL in both 
studies was the 1% concentration of ARQ-151 (20 mg/kg), the highest dose administered and the 
maximum feasible concentration. 
Across the dermal and systemic toxicology programs, the exposure to parent drug and N-oxide 
metabolite differs by route and species. While exposure to roflumilast and its active metabolite 
are likely to be higher following topical administration of ARQ-151 relative to oral 
administration, when the margins from the toxicity studies are considered as a whole, the 
NOAELs across routes and species provide assurance that the anticipated exposures with 
ARQ-151 cream will be safe.  
2.3. 
Clinical Studies 
2.3.1. 
Topical Roflumilast Cream 
The formulation of topical roflumilast, ARQ-151 cream, has been evaluated in both plaque 
psoriasis (currently in Phase 3) and atopic dermatitis (through Phase 2). 














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extensively in the past.  Adverse events (AEs) reported with roflumilast tablets have been 
consistent with those expected for oral PDE-4 inhibitors.  In a pooled analysis of safety data 
from 6-month and 1-year clinical trials (N=8630), the most common AEs were diarrhea, weight 
loss and nausea.  Other AEs reported more frequently with roflumilast treatment than with 
placebo were back pain, influenza, insomnia and decreased appetite (Michalski 2012), 
(Wedzicha 2016).   
In addition to the self-reported cases of weight loss in the 6-month and 1-year oral trials, 
clinically significant weight loss was also reported in two prospective studies that evaluated 
weight (Michalski 2012). 
Psychiatric-related AEs were also greater in patients treated with roflumilast tablets (5.9%) 
compared to those treated with placebo (3.3%).  The most common psychiatric-related AEs were 
insomnia, depression and anxiety.  A small number of cases of completed suicide and suicide 
ideation have been reported in patients taking oral roflumilast in clinicals trials and also during 
post-marketing experience (Michalski 2012).   
The only contraindication to oral roflumilast is use in patients with moderate to severe liver 
impairment (Child-Pugh B or C), where systemic levels of roflumilast may become elevated. 
2.4. 
Rationale for Development 
Atopic dermatitis is currently treated with topical calcineurin inhibitors and/or topical 
corticosteroids in combination with emollients.  In 2016, Eucrisa® (crisaborole), a less potent 
PDE-4 inhibitor than roflumilast, was approved for the topical treatment of atopic dermatitis.  
Topical calcineurin inhibitors block the activation of T-lymphocytes and diminish inflammation, 
but are accompanied by a ‘black box’ warning for the development of lymphomas and other 
lymphoproliferative diseases.  Topical corticosteroids can cause skin atrophy and hypothalamic-
pituitary axis suppression, and their use is often accompanied by poor adherence due to 
corticophobia (fear of using corticosteroids in patients or doctors).  Eucrisa provides precedence 
for the effectiveness of topical PDE-4 inhibitors in atopic dermatitis, but it is a twice-daily 
ointment, its efficacy is modest, and its use is often accompanied by burning, stinging, and local 
skin reactions.  In our Phase 2 AD study (ARQ-151-212), we observed excellent local toleration 
of ARQ-151 cream formulations.  Since roflumilast is a more potent PDE-4 inhibitor than 
crisaborole (Hatzelmann 2010), we believe that ARQ-151 has potential to provide greater 
efficacy with better local toleration than Eucrisa. 
This study will evaluate the safety and efficacy of ARQ-151 cream in children, adolescent, and 
adult subjects with mild to moderate atopic dermatitis. 
2.4.1. 
Dose Selection 
In ARQ-151-212, results for the primary efficacy endpoint, mean absolute change from baseline 
in EASI score at Week 4, were numerically higher in the ARQ-151 cream 0.05% and ARQ-151 
cream 0.15% (p= 0.097) groups than in the vehicle group. Furthermore, the result of the 
sensitivity analysis of the primary endpoint at Week 4 was statistically significant (ARQ 151 
cream 0.15%, p= 0.027). Statistical significance was reached for numerous other clinically 
important efficacy endpoints including % change from baseline in EASI score, EASI-75 


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responders, and patients achieving vIGA-AD score of clear or almost clear. Both doses of topical 
roflumilast (0.15% and 0.05%) had a similar and favorable safety and tolerability profile, with 
generally more favorable efficacy observed at the ARQ-151 cream 0.15% dose. Results of this 
study support the use of ARQ-151 cream 0.15% in studies of adult and adolescent subjects with 
mild to moderate AD. PK data from ARQ 151 105 support the use of the same concentration 
(0.15%) in subjects 6 to 11 years old and the use of a lower concentration in subjects 2 to 5 years 
old. 
2.4.2 
Risks and/or Benefits to Subjects 
A favorable local and systemic benefit-risk profile has been observed in prior studies of 
ARQ-151. Subjects 6 years of age and older, included in this study, randomized to active 
treatment group may see an improvement in their atopic dermatitis with ARQ-151 0.15% cream, 
based on the activity of doses tested in atopic dermatitis (0.05%-0.15%) and psoriasis (0.15%-
0.5%), and approval of a less potent topical PDE-4 inhibitor (crisaborole) for atopic dermatitis.  
Subjects may also see some benefit as the cream formulation of ARQ-151 may have a 
moisturizing effect.  
Oral roflumilast has now been used for almost a decade in the treatment of COPD exacerbations 
and its safety record has been well-documented.  The known adverse effects of oral treatment in 
the COPD population (nausea, vomiting, diarrhea, weight loss, psychiatric AEs 
(see Section 2.3.2) may be readily monitored as specified in this protocol. The profile that is 
emerging from studies of topical roflumilast appears different from the safety and tolerability 
profile of oral roflumilast.  While oral PDE-4 inhibitors (DALIRESP, OTEZLA) have been 
associated with, in particular, a moderate incidence of GI AEs, these AEs, and perhaps others, 
appear to be reported far less frequently with topical PDE-4 inhibitors, including EUCRISA®, 
and ARQ-151 cream to date in clinical trials.  For ARQ-151 cream, this may be related to the 
lack of ‘peak to trough’ Cmax variation, lower Cmax values than observed following oral 
administration, or bypassing of the gastrointestinal tract with topical administration.  
This study has been designed with adequate safety monitoring practices (i.e., physical 
examinations, vital signs/weight, local skin toleration assessments, hematology, serum 
chemistry, urinalysis, PHQ-A/PHQ-8, CDI-2, C-SSRS and AE reporting). 


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3. 
STUDY OBJECTIVES AND ENDPOINTS 
3.1. 
Study Objectives 
3.1.1. 
Primary Objective 
The primary objective of this study is to assess the safety and efficacy of ARQ-151 cream 0.15% 
vs vehicle administered QD x 4 weeks to individuals 6 years of age and older with atopic 
dermatitis. 
3.2. 
Study Endpoints 
3.2.1. 
Primary Endpoint 
The primary endpoint of this study is:  
• The proportion of all randomized subjects who attain IGA Success, defined as a 
vIGA-AD score of ‘clear’ or ‘almost clear’ PLUS a 2-grade improvement from 
Baseline at Week 4 
3.2.2. 
Secondary Endpoints 
The secondary endpoints of this study are: 
• The proportion of randomized subjects with a vIGA-AD score of ‘Moderate’ at 
randomization who attain IGA Success at Week 4 
• Among subjects with baseline WINRS ≥ 4, the proportion who attain a 4‑point 
reduction on the WI-NRS at Week 4 
• The proportion of subjects who attain at least a 75% reduction in the Eczema Area and 
Severity Index (EASI-75) at Week 4 
• Time to achievement of vIGA-AD success 
• Time to achievement of EASI-75 
3.2.3. 
Pharmacokinetic Endpoint 
• Pharmacokinetic endpoints include concentrations of roflumilast and its N-oxide 
metabolite. 


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4. 
INVESTIGATIONAL PLAN 
4.1. 
Overall Study Design and Plan 
This is a Phase 3, parallel group, double blind, vehicle-controlled study in which ARQ-151 
cream 0.15% or vehicle is applied QD x 4 weeks to subjects with mild to moderate atopic 
dermatitis. 
• At entry, subjects will have ≥3% BSA involvement (excluding the scalp, palms, 
soles) and mild or moderate atopic dermatitis (AD) based on vIGA-AD assessment.   
• Upon determination of eligibility, subjects will be randomized 2:1 to either ARQ-151 
cream 0.15% or matching vehicle cream.  The randomization will be stratified by 
vIGA-AD score at baseline (‘Mild’ vs. ‘Moderate’) and by study site. 
• Subjects/caregivers will apply ARQ-151 cream 0.15% or vehicle cream QD for 
28 days to all AD affected areas and any newly appearing AD lesions that arise 
during the study, except on the scalp. Subjects/caregivers should maintain treatment 
of these areas with study drug for the duration of the study regardless of whether 
treatable areas of AD clear prior to Week 4. 
• At the Week 4 visit, subjects may be eligible to enroll in a 12‑month, open label 
extension study (ARQ-151-313) in which they will receive ARQ-151 cream 0.15% 
QD.   
4.2. 
Number of Sites and Subjects 
A total of up to approximately 650 subjects will be randomized at approximately 40 study sites 
in the United States and Canada. During the conduct of the study, additional countries and/or 
sites may be added if necessary. Subjects will be male and female children and adolescents 
(6‑17 years), and adults (>18 years). Subjects will have mild to moderate atopic dermatitis 
involvement with a vIGA-AD score of ‘2’ (mild) or ‘3’ (moderate) for study entry. Up to 25% of 
the subjects will be ≥18 years old and up to 25% of subjects will have a vIGA-AD score of ‘2’. 
4.3. 
Subject Participation 
Subject participation involves a minimum of 5 clinic visits including Screening, Baseline, 
Week 1, Week 2, and Week 4.  The interval between the Screening and Baseline visits could be 
up to 30 days, therefore the anticipated maximum duration of subject participation is 
approximately 8 weeks. 
Upon completion of the treatment phase of the study (Week 4) subjects may have the 
opportunity, subject to regulatory approval and enrollment has not been completed, to participate 
in an open-label extension study (ARQ‑151-313) of up to 12 months. 


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4.4. 
Numbering of Subjects 
All subjects who sign an informed consent form will be assigned a unique 6-digit subject 
identification (ID) number by the IWRS system.   
The subject identifier number is 6-digits (SXX-YYY) and will contain the study number-site 
number (where S = 2 and XX is this study site number such as 01, 02, etc.) and the subject 
number (YYY). It will be assigned in numerical order at the screening visit based on 
chronological order of screening dates. 
Individuals who do not meet the criteria for participation in this trial (screen failure) may be 
rescreened once, if deemed acceptable by the investigator. Rescreened subjects should be 
assigned a different subject number than the initial screening. All procedures planned at the 
screening visit, including signature of a new consent form, will be performed.  
In the case of a screening laboratory value abnormality, the test can be repeated once within the 
original screening time window, if the investigator believes there is a reasonable possibility that 
the subject would be eligible if re-tested. This would not be considered a screen failure and a 
new subject number would not be assigned. 
The clinical site is responsible for maintaining a current log of subject ID number assigned to 
each subject. The subject ID number will be used to identify the subject throughout the study and 
is required to be entered on all clinical study documentation (e.g., case report forms, labeling of 
clinical materials and sample containers, investigational product accountability logs, etc.).  
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: 
1. For adult subjects: Participants legally competent to sign and give informed consent.  For 
pediatric and adolescent subjects: Informed consent of parent(s) or legal guardian, and, if 
age appropriate, assent by the subjects, as required by local laws. 
2. Males and females, ages 6 years and older at time of signing Informed Consent 
(Screening). 
3. Diagnosed with mild to moderate atopic dermatitis according to the criteria of 
Hanifin and Rajka (1980) prior to or at the screening visit.  Subjects must have at least 3 
of the 4 basic features per Hanifin and Rajka (1. Pruritus; 2. Typical morphology and 
distribution [flexural lichenification in adults and facial and extensor eruptions in infants 
and children]; 3. Chronic or chronically relapsing dermatitis; or 4. Personal or family 
history of atopy), in addition to 3 or more minor criteria. 


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4. History of AD for at least 3 months in subjects 6-17 years of age or 6 months in subjects 
>18 years of age, as determined by the Investigator using information from the subject’s 
medical chart, from the subject’s physician, or through subject/parent/caregiver 
interview. Stable disease for the past 4 weeks with no significant flares in atopic 
dermatitis before screening. 
5. EASI Score >5.  EASI is evaluated for the entire body except the scalp, palms, and soles. 
6. vIGA-AD score of ‘Mild’ (‘2’) of ‘Moderate’ (‘3’) at Baseline/Day 1. The vIGA-AD is 
evaluated for the entire body except the scalp, palms, and soles. 
7. Has AD involvement of >3% BSA (excluding the scalp, palms, soles).  
8. Females of childbearing potential (FOCBP) must have a negative serum pregnancy test at 
Screening (Visit 1) and a negative urine pregnancy test at Baseline/Day 1. In addition, 
sexually active FOCBP must agree to use at least one form of a highly effective or barrier 
method of contraception throughout the trial. The use of abstinence as a contraceptive 
measure is acceptable as long as this is a consistent part of a lifestyle choice and an 
acceptable backup method has been identified if the subject becomes sexually active.  
9. Females of non-childbearing potential should either be pre-menarchal, or post-
menopausal with spontaneous amenorrhea for at least 12 months (post-menopausal status 
should be confirmed with FSH testing) or have undergone surgical sterilization 
(permanent sterilization methods include hysterectomy, bilateral oophorectomy, 
hysteroscopic sterilization, bilateral tubal ligation or bilateral salpingectomy). 
10. In good health as judged by the Investigator, based on medical history, physical 
examination, vital signs, serum chemistry labs, hematology values, and urinalysis. 
11. Subjects and parent(s)/legal guardian(s) are considered reliable and capable of adhering 
to the Protocol and visit schedule, according to the judgment of the Investigator. 
4.5.2. 
Exclusion Criteria 
Subjects who meet any of the following exclusion criteria will be excluded from participation in 
this study: 
1. Subjects with any serious medical condition or clinically significant laboratory, vital 
signs, or physical examination abnormality that would prevent study participation or 
place the subject at significant risk, as judged by the Investigator 
2. Liver function tests excursions that exceed: 
• AST or ALT > 2X ULN 
• Total bilirubin: 
− > 1.5 x ULN or 
− > ULN and ≤ 1.5 x ULN AND direct bilirubin is > 35% of total bilirubin 
• ALP ≥ 2x ULN 




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15. Subjects with a PHQ-8 (adults) or modified PHQ-A (adolescents, 12-17 years old 
inclusive) score ≥10 at Screening or Baseline visits 
16. Subjects (6 to 11 years old, inclusive) with a CDI-2 (parent report) raw score ≥17 for 
females and ≥18 for males at Screening or Baseline/Day 1 visits 
17. Females who are pregnant, wishing to become pregnant during the study, or are 
breast-feeding. 
18. Previous treatment with ARQ-151. 
19. Subjects currently undergoing allergy testing (e.g., food allergy testing or skin prick 
testing), patch testing, food challenges, or allergy desensitization, or plan to do so during 
the study. 
20. Subjects with any serious medical condition (e.g., hypo- or hyper-thyroidism) or 
clinically significant laboratory abnormality that would prevent study participation or 
place the subject at significant risk, as determined by the Investigator. 
21. Subjects with a history of a major surgery within 4 weeks prior to Baseline/Day 1 or 
subjects who have a major surgery planned during the study. 
22. Subjects with a history of chronic alcohol or drug abuse within 6 months prior to 
Screening. 
23. Current or a history of cancer within 5 years with the exception of fully treated skin basal 
cell carcinoma, cutaneous squamous cell carcinoma or carcinoma in situ of the cervix.  
24. Parent(s)/legal guardian(s) who are unable to communicate, read, or understand the local 
language.  Subjects who are unable to communicate, read or understand the local 
language(s), or who display another condition, which in the Investigator’s opinion, makes 
them unsuitable for clinical study participation. 
25. Subjects who are family members of the clinical study site, clinical study staff, or 
sponsor, or family members of enrolled subjects living in the same house. 
4.6. 
Randomization 
Randomization will take place at the Baseline visit after the Investigator confirms that the subject 
meets all eligibility criteria listed in Section 4.5. 
Subjects will be randomly assigned to apply ARQ-151 cream 0.15 % QD, or matching vehicle 
QD.  Assignment of drug or vehicle will be made at a 2:1 ratio (drug:vehicle) and stratified by 
vIGA-AD score (‘Mild’ vs. ‘Moderate’), and by study site according to a computer-generated 
randomization list.  Kits containing tubes of study medication will be assigned to each subject 
using an internet-based response system (IWRS).  A subject may receive more than one kit for 
the treatment period.  The kits and tubes are blinded and each kit is numbered with a unique kit 
number. 


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4.7. 
Study Restrictions 
4.7.1. 
Prohibitions and Concomitant Therapy 
Prohibited medications and products are detailed in Table 2 (Excluded Medications and 
Treatments).   
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 
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. Other medications may be 
authorized by the Investigator for conditions other than AD. 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. No rescue medication for AD is allowed during this study up to Week 4. 
Table 2: 
Excluded Medications and Treatments 
Excluded Medications and Treatments 
Washout Period Prior to Day 1 
Approved biologics such as dupilumab 
6 months 
Investigational biologics 
6 months 
• 
Systemic treatments that could affect AD; 
e.g. corticosteroids, retinoids, calcineurin inhibitors, 
hydroxycarbamide (hydroxyurea), methotrexate, 
cyclosporine, azathioprine, hydroxychloroquine, 
mycophenolate mofetil, or other immunosuppressive 
therapies, or systemic treatment with nonsedating 
antihistamines in a nonstable regimen.   
• 
Systemic treatments with nonsedating antihistamines 
(e.g., cetirizine, desloratadine, loratadine) in a stable 
regimen is allowed. 
4 weeks or 5 half-lives, whichever is 
longer 
PUVA or NBUVB phototherapy 
4 weeks 
Topical products containing urea 
1 week 
Sedating antihistamines and other over the counter remedies 
containing sedating antihistamine, such as sleep aids 
(e.g., ZzzQuil™ LIQUICAPS®SLEEP-AID), and cough/cold 
remedies (e.g., Theraflu® night time, NyQuil™ Cold & Flu 
Night time) 
1 week 
Topical corticosteroids, calcineurin inhibitors, or Eucrisa®.  
Topical antibacterial medications or products, including 
soaps, dilute bleach baths, or sodium hypochlorite-based 
products anywhere on the body. 
2 weeks  


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Table 2: 
Excluded Medications and Treatments (Continued) 
Excluded Medications and Treatments 
Washout Period Prior to Day 1 
Strong cytochrome P-450 CYP3A4 inhibitors e.g., indinavir, 
nelfinavir, ritonavir, clarithromycin, itraconazole, 
ketoconazole, nefazodone, saquinavir, suboxone and 
telithromycin 
2 weeks 
Strong cytochrome P-450 CYP3A4 inducers e.g., efavirenz, 
nevirapine, glucocorticoids, barbiturates (including 
phenobarbital), phenytoin, rifampin, and carbamazepine 
2 weeks 
Systemic antibiotics 
2 weeks 
Tanning beds, other light emitting devices  
4 weeks  
Oral roflumilast (Daxas®, Daliresp®) 
4 weeks 
All other investigational drugs 
4 weeks or 5 half-lives, whichever is 
longer 
• 
Eye / ear drop and nasal corticosteroid preparations are allowed.  Inhaled corticosteroid preparations are allowed 
if used for a stable condition and at a stable dose for > 28 days before screening and are continued at the same 
dose throughout the study. 
• 
All subjects should apply medication each evening, except on clinic visit days when the study product will be 
applied at the clinical site. If the subject takes an evening shower/bath, the ARQ-151 cream or vehicle can be 
applied as soon as the skin is nearly dry, but no later than 20 minutes before going to bed.  Subjects are not to 
wash areas where ARQ-151 cream or vehicle has been applied until at least 4 hours after study drug application.  
Non-medicated emollients or moisturizers will be allowed once daily in a stable regimen as normally used by 
the subjects. For subjects that apply a non-medicated emollient or moisturizer after an evening shower/bath, the 
study drug must be applied first to the treatment areas. The non-medicated emollient or moisturizer can then be 
applied but only to other untreated areas of the subject’s skin.  
• 
Sunscreens will be allowed daily, as needed by the subjects when applied at least 2 hours after application of 
randomized study drug.   
• 
Concomitant other medications for chronic conditions (e.g., NSAIDs, statins, anti-hypertensives) are permitted 
unless specifically prohibited in the Protocol. 
• 
Topical antibiotics, topical antihistamines, or any other topical agents are not allowed to be applied to treated 
areas. 
4.8. 
Treatment 
4.8.1. 
Drug Supplies, Packaging and Labeling 
ARQ-151 cream or matching vehicle will be supplied in 45 gram tubes.  The tubes will be 
packaged in kits, containing multiple tubes of investigational product.  The number of kits 
dispensed to a subject will be based on the BSA involvement of atopic dermatitis.  The kits and 
tubes will be labeled in a blinded manner.  The kit(s) dispensed to a subject will be labeled with a 
unique number. 
The Sponsor will supply sufficient quantities of the study drug and matching vehicle to each site 
to allow for completion of this study. 


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Records will be made of the receipt and dispensing of the study drugs supplied.  At the 
conclusion of the study, any used/unused study drugs will be returned to the Sponsor or 
designee, or destroyed, as per Sponsor instructions. 
Refer to the most current version of the IP Handling Plan for details on accountability, storage, 
and management of ARQ-151.  
4.8.2. 
Blinding 
This is a double-blind study, therefore neither the subjects nor the Investigator and clinical 
personnel will be aware of which treatment an individual subject receives. 
4.8.3. 
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 IWRS system 
for that subject. Refer to the current version of the ARQ-151-312 IWRS User Manual 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 Medical Monitor 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. 
4.8.4. 
Treatment Administration 
Initial treatment with the IP will occur on Day 1. ARQ-151 cream 0.15% is administered once 
daily as a topical product to cover the skin surface at an application rate of approximately 
2 mg/cm2.   
At Baseline visit, the study staff will demonstrate to the subject/caregiver(s) how to apply 
ARQ-151 cream using the first tube from the kit that is assigned to the subject.  Study site staff 
will be trained to ensure a unit dose (a pea size unit of ARQ-151 cream will cover approximately 
1% BSA) is properly squeezed from the tube and applied to atopic dermatitis lesion(s) as a thin 
film and rubbed in using the index and middle finger, rubbing in thoroughly but gently, until the 
‘white’ has disappeared.  The subject/caregiver will then practice squeezing a similar amount 
onto their index and middle finger and apply a thin film to other areas to be treated.  At 
Baseline/Day 1, the study staff will ensure that the subject/caregiver’s application technique is 
correct and that a thin layer is applied as instructed (which represents an application rate of 
approximately 2 mg/cm2).    
Re-training will be conducted at subsequent visits as needed (i.e., if the returned tube(s) weighs 
substantially different than the expected weight). 


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Subjects/caregivers will be instructed to apply investigational product once daily to all treatment 
areas identified by the Investigator at Baseline using a Body Diagram (see Appendix 1). 
Note: 
• All subjects should apply medication each evening (except on clinic visit days when 
the investigational product will be applied at the clinic). If the subject takes an 
evening shower/bath, the ARQ-151 cream or vehicle can be applied as soon as the 
skin is nearly dry, but no later than 20 minutes before going to bed.  Subjects are not 
to wash areas where ARQ-151 cream or vehicle has been applied until at least 4 hours 
after study drug application. 
• Caregivers should wash their hands with soap and water after applying IP to a child. 
• Parents/guardians/caregivers who are pregnant, or women of childbearing potential 
who are trying to become pregnant, or who are breastfeeding, or planning to 
breastfeed during the study should avoid accidental exposure by either avoiding 
applying investigational product or by wearing gloves during its application. 
• Subjects should maintain treatment of areas with study drug for the duration of the 
study regardless of whether treatable areas of AD clear prior to Week 4 visit. 
• New lesions that develop during the study should be treated (except scalp).  
An unscheduled visit is not required for starting treatment of new lesions. 
Each investigational product tube will be weighed prior to dispensing at the Baseline visit and at 
each subsequent visit. Investigational product tubes must be returned by subjects at each study 
visit, both empty and full, and will be weighed. If the subject’s actual use is substantially 
different than the expected use for the subject’s BSA (see IP Handling Plan), the 
subject/caregiver will be retrained on the study drug application technique. 
4.8.5. 
Treatment Compliance 
Investigational product tubes will be weighed at each clinic visit. 
Subjects/caregivers will complete a daily diary recording the date and time of each dose applied, 
any missed doses, and a comment section should the subjects have a comment, e.g., record 
potential AEs.  Site personnel will review the diaries and use the information to question the 
subject regarding compliance and AEs and then record appropriate information in source 
documents and complete Case Report Forms (CRFs). If a subject misses a dose, they should be 
instructed to return to the protocol investigational product administration schedule (i.e. if subject 
forgets a dose they should wait until that evening and apply as usual). 
A subject will be considered compliant with the dosing regimen if the subject meets both of the 
following requirements: 
• applies at least 80% of the expected applications during the study drug application period 
• does not miss more than 3 consecutive doses 
Compliance will be assessed by review of the dosing diary. Weight of investigational product 
applied (via dispensed and returned tube weights) will be measured for reporting purposes. 


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If the diary shows less than 80% of expected daily applications (but not more than 3 consecutive 
missed doses), the subject is using too little study drug and retraining must be conducted and 
documented. 
Compliance will be documented in source and in eCRF. 
4.8.6. 
Removal of Subjects from Study Treatment 
Subject treatment with study drug in this trial may be discontinued for any of the following 
reasons: 
1. Occurrence of any medical condition or circumstance that, in the opinion of the 
Investigator does not allow the subject to adhere to the requirements of the Protocol. 
2. Adverse Events as described in Section 5.1.12 and Section 5.9. The Investigator must 
follow the subject until the AE resolves or satisfactorily stabilizes.  
3. Treatment must be discontinued immediately in the event of a female subject’s 
pregnancy. 
4. Subject's decision to discontinue treatment with study drug. 
5. C-SSRS (Section 5.1.10) indicative of suicidal ideation  
6. PHQ-8 (Section 5.1.7) or modified PHQ-A (Section 5.1.8) score ≥15 if determined by 
Investigator in consultation with mental health professional 
7. CDI-2 (Section 5.1.9) raw total score of ≥32 if determined by Investigator in consultation 
with mental health professional 
8. Requirement for use of prohibited concomitant medication after consultation with the 
Sponsor and Medical Monitor. 
9. Subject’s repeated failure to comply with protocol requirements or study related 
procedures. 
10. The subject interrupts trial study drug application for more than 50% of scheduled doses. 
11. Termination of the study by the Sponsor, FDA, or other regulatory authorities. 
4.8.7. 
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 the 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  


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5. 
STUDY PROCEDURES 
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.  
5.1. 
Safety Assessments 
This study assesses the safety and efficacy of ARQ-151 cream. Safety will be determined by 
evaluating physical examinations, local tolerability assessments, vital signs/weight, clinical 
laboratory parameters, either PHQ-8 (adults, ≥18 years old) or modified PHQ-A (adolescents, 
12-17 years old) or Children’s Depresssion Inventory 2 (CDI-2, parent report for children 
6-11 years old, inclusive), C-SSRS (12 years and older) and AEs as outlined in the Schedule of 
Visits and Assessments (Section 1.3).  
Additional evaluations/testing may be deemed necessary by the PI and/or the Sponsor for 
reasons related to subject safety. 
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 or written assent from adolescent subjects and consent 
from their parent(s) or legal guardian(s) for children and/or adolescents after adequate 
explanation of the study design, anticipated benefits, and the potential risks.  A subject is 
considered a participant of the trial once the ICF or written assent for adolescent subjects is 
completely signed.  
Subjects must provide informed consent/assent as per their age group at screening. During the 
study, if a subject changes age group, the subject must provide informed consent/assent relative 
to his/her current age group. Subjects will continue with the assessments specific to their age 
group at the time of consent/assent at Screening. 
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 
• Collection of demographic data including sex, age, race, ethnicity 
• Vital signs including temperature, heart rate, and blood pressure 
• Collection of body weight (kg), and height (cm) 
• Atopic dermatitis assessments (e.g., vIGA-AD, BSA, EASI, SCORAD) 
• Limited physical examination of skin (including assessment of Fitzpatrick skin type 
at Screening only), lungs, and heart 
− Fitzpatrick skin phototype will be rated as follows: 
I:  
Always burns easily; never tans (sensitive) 
II:  
Always burns easily; tans minimally (sensitive) 


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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) 
• Laboratory tests: hematology, chemistry, urinalysis, serum pregnancy test (for female 
subjects of child bearing potential) 
• Completion of WI-NRS, CDI-2, DLQI, CDLQI, DFI, C-SSRS, POEM, and PHQ 
(-8 or -A) 
• Collection of concomitant medications and adverse events 
Subjects may be re-screened one time and the subject will assigned a new Subject ID. 
5.1.2. 
Contraception Requirements 
Females of childbearing potential (FOCBP) must have a negative serum pregnancy test at 
Screening and a negative urine pregnancy test at Baseline (Day 1). In addition, sexually active 
FOCBP must agree to use at least one form of an highly effective or barrier method of 
contraception throughout the trial according to Contraception Requirements (Figure 1). 
Figure 1: 
Contraception Requirements for Female Subjects 
 


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5.1.3. 
Baseline (Day 1) 
Randomization will take place at the Baseline visit after the subject has been found to be fully 
eligible for participation. A subject will be considered enrolled into the study upon the first IP 
application.    
If the Baseline visit occurs within 21 days of Screening for subjects < 18 years old, the Screening 
results may be used. 
5.1.4. 
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. 
5.1.5. 
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 5 mins of 
rest. For weight measurement, 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.). Weight should be obtained using a calibrated weight scale and the same scale, 
whenever possible, should be used for a subject throughout the duration of the study.  The 
subject should stand with both feet in the center of the scale with their arms at their side and hold 
still. Record the weight to the nearest decimal fraction (for example, 55.5 pounds or 25.1 
kilograms). For subjects <18 years of age, measure the weight in triplicate and report the average 
weight in EDC. An unexplained, clinically significant weight loss should be reported to the 
Medical Monitor. 
Height will be measured at Screening only.  
5.1.6. 
Laboratory Tests 
All tests listed in Table 3 below will be performed according to the Schedule of Visits and 
Assessments (Section 1.3) unless otherwise noted. No food restrictions are required for the 
collection of specimens. In addition, laboratory safety tests may be performed at various 
unscheduled time points, if deemed necessary by the Investigator. 




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• Moderately severe depression (15 to 19) 
• Severe depression (20 to 24) 
A subject with a PHQ-8 score of 10-14 should be referred to a mental health professional for 
evaluation, regardless of the reason for their change in score. 
A subject with a PHQ-8 score ≥15 should be immediately referred to a mental health 
professional, and Investigators in consultation with the mental health professional should 
consider interruption or discontinuation of the study drug. 
5.1.8. 
Patient Health Questionnaire Depression Scale (Modified PHQ-A) 
The Modified PHQ-A Assessment (Appendix 3) will be performed in adolescent subjects 
(12-17 years old, inclusive). 
Modified PHQ-A score is the sum of the responses for five severity categories of depression 
defined as follows:  
• None – Minimal depression (0 to 4)  
• Mild depression (5 to 9)  
• Moderate depression (10 to 14)  
• Moderately severe depression (15 to 19) 
• Severe depression (20 to 24) 
A subject with a modified PHQ-A score of 10-14 should be referred to a mental health 
professional for evaluation, regardless of the reason for their change in score. 
A subject with a modified PHQ-A score ≥15 should be immediately referred to a mental health 
professional, and Investigators in consultation with the mental health professional should 
consider interruption or discontinuation of the study drug. 
5.1.9. 
Children’s Depression Inventory 2 
The CDI-2 Assessment  will be performed according to the Schedule of Visits and Assessments 
(Section 1.3) for subjects 6 to 11 years old, inclusive. 
The CDI-2 quantifies depressive symptomatology using reports from children/adolescents, 
teachers, and parents or caregivers. It is recommended for use in initial evaluation and is 
appropriate when there is a need for an assessment and robust description of a child’s depressive 
symptoms. 
This study will use the CDI Parent Report Form. An example of the Parent report form is 
presented in Appendix 4. 
A subject with a CDI-2 raw score of ≥21 for females and ≥22 for males should be referred to a 
mental health professional for evaluation.  


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A subject with a CDI-2 raw total score of ≥32 should be referred to a mental health professional, 
and Investigators in consultation with the mental health professional should consider interruption 
or discontinuation of the study drug. 
5.1.10. 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
C-SSRS Assessments will be performed according to the Schedule of Visits and Assessments 
(Section 1.3) for subjects 12-years old and older. 
The administration schedule of the C-SSRS will be: 
• The “Baseline/Screening” version (Appendix 5) will be used at Screening to provide 
a pre-treatment assessment.  
• On all subsequent visits, the “Since Last Visit” version (Appendix 6) will be used 
(Baseline/Day 1, Week 1/Day 8, Week 2/Day 15 or Week 4/Day 29). 
• A score greater than 0 at the Screening or Baseline visit in suicidal ideation may 
indicate the need for mental health intervention. The investigator should not enroll the 
subject in the study. 
• Any score greater than 0 in the suicidal ideation score may indicate the need for 
mental health intervention. The Investigator should give consideration for the subject 
to discontinue from the study drug and prompt referral to an identified mental health 
professional and/or an appropriate emergency room. The Medical Monitor should be 
contacted.    
The C-SSRS administer will be trained via the C-SSRS training video. A training certificate for 
the administer(s) will be on file in the trial master file at the site. 
The Investigator must review the completed C-SSRS.  A qualified mental health care provider 
must be available, immediately if needed, to refer the subject for further evaluation. 
5.1.11. 
Local Tolerability Assessment 
The Investigator Local Tolerability Assessment will be performed according to the Schedule of 
Visits and Assessments (Section 1.3).  
Application site reactions will be graded at each timepoint. Irritation reactions are graded using 
the scale detailed in the following section (Berger 1982). Reactions at the site of product 
application, which may occur post-Baseline, should be differentiated from the preexisting 
inflammation associated with the subject’s atopic dermatitis. 
The investigator assessments will be conducted by the investigator or a properly trained and 
designated subinvestigator prior to study drug application in the clinic. 
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 


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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 Assessment will be performed according to the Schedule of Visits 
and Assessments (Section 1.3). 
The subject will assess burning/stinging (0-3 score):  
Grade 
Sensation Following Drug 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 
This assessment will be administered by the site 10 to 15 minutes after study drug application in 
the clinic at Baseline and at every clinic visit. 
• Note: for subject burning stinging assessment at Day 29, subjects will provide a recall 
assessment of burning/stinging experienced post drug application on the previous day 
(Day 28). 
5.1.12. 
Adverse Events 
Adverse events (AEs) will be collected and assessed throughout the study according to the 
Schedule of Visits and Assessments (Section 1.3). The Investigator is responsible for ensuring 
that all adverse events observed by the clinical staff or reported by the subject that occur after the 
first application of investigational product through the end of the study are recorded in the 
subject’s medical record and the eCRF. 
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 (Section 5.7.5). 


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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. Refer Section 5.7 for further details on Adverse Events. 
5.2. 
Efficacy Evaluations 
For efficacy evaluation subjects will have >3% BSA of AD involvement (excluding the scalp, 
palms, soles). Palms and soles may be treated with investigational product in this study, but will 
not be counted towards vIGA-AD, EASI, or BSA assessments. EASI is evaluated for the entire 
body except the scalp, palms, and soles.. 
5.2.1. 
Validated Investigator Global Assessment Scale for Atopic Dermatitis 
Validated Investigator Global Assessment scale for Atopic Dermatitis (vIGA-AD) 
assessments should be completed prior to other physician assessments. 
vIGA-AD assessment will be performed according to the Schedule of Visits and Assessments 
(Section 1.3). The vIGA-AD is a static evaluation of qualitative overall AD severity. This global 
assessment scale is an ordinal scale with five severity grades (reported only in integers of 0 to 4). 
Each grade is defined by a distinct and clinically relevant morphologic description that 
minimizes inter-observer variability (see Appendix 7). vIGA-AD is evaluated for the entire body 
except the scalp, palms, and soles. 
Note: All atopic dermatitis lesions on a subject will be treated including the face, trunk, 
genitals/skin folds, or limbs (excluding the scalp). The palms and soles will be treated but will 
not be counted towards any measurements of efficacy (EASI, vIGA-AD, BSA). 
Every effort must be made for the same Evaluator to complete the IGA for the subject at 
every study visit. 
IGA will be assessed at clinic visits prior to the subject applying Investigational Product at 
the site.  
5.2.2. 
Eczema Area and Severity Index (EASI) 
EASI scores (Hanifin 2001) will be performed according to the Schedule of Visits and 
Assessments (Section 1.3) 
Four anatomic sites—head, upper extremities, trunk, and lower extremities—are assessed for 
erythema, induration/infiltration (papules), excoriation, and lichenification as seen on the day of 
the examination. The severity of each sign is assessed using a 4-point scale (half steps are 
allowed; e.g. 0.5, 1.5 and 2.5): 
• 0 = none 
• 1 = mild 
• 2 = moderate 
• 3 = severe 


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The area affected by atopic dermatitis within a given anatomic site is estimated as a percentage 
of the total area of that anatomic site and assigned a numerical value according to the degree of 
atopic dermatitis involvement as follows: 
• 0 = no involvement 
• 1 = 1-9% 
• 2 = 10-29% 
• 3 = 30-49% 
• 4 = 50-69% 
• 5 = 70-89% 
• 6 = 90-100% 
The EASI score is obtained by using the formula below for subjects ≥8 years old: 
EASI = 0.1 (Eh + Ih + Exh + Lh) Ah + 0.2 (Eu + Iu + Exu + Lu) Au + 
0.3 (Et + It + Ext + Lt) At + 0.4 (El + Il + Exl + Ll) Al 
The EASI score is obtained by using the formula below for subjects <8 years old: 
EASI = 0.2 (Eh + Ih + Exh + Lh) Ah + 0.2 (Eu + Iu + Exu + Lu) Au +  
0.3 (Et + It + Ext + Lt) At + 0.3 (El + Il + Exl + Ll) Al 
Where E, I, Ex, L, and A denote erythema, induration, excoriation, lichenification and area, 
respectively, and h, u, t, and l denote head, upper extremities, trunk, and lower extremities, 
respectively. 
Note: Palms and soles may be treated with investigational product in this study, but will not be 
counted towards IGA, EASI, or BSA assessments. EASI is evaluated for the entire body except 
the scalp, palms, and soles. 
5.2.3. 
Worst Itch Numerical Rating Scale (WI-NRS) 
The WI-NRS has been developed as a simple, single item to assess the patient-reported severity 
of this symptom at its highest intensity during the previous 24-hour period.  
(Newton 2019). The WI-NRS will be determined by the subject’s recording of daily assessment 
of worst itch over the past 24 hours. The scale is from ‘0 to 10’ (“no itch” to “worst itch 
imaginable” or “worst imaginable itch”). 
WI-NRS Assessments will be performed according to the Schedule of Visits and Assessments 
(Section 1.3) starting 7 days prior to the Baseline/Day 1 clinic visit (during the 7 days prior to 
Baseline/Day 1 the subject will record the WI-NRS value every day). 


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5.2.4. 
Dermatology Life Quality Index (DLQI) and Children’s Dermatology Life 
Quality Index (CDLQI) 
The DLQI (ages 17+ years) and CDLQI (ages 6-16 years, inclusive) will be performed according 
to the Schedule of Visits and Assessments (Section 1.3). The DLQI/CDLQI is a simple, 
self-administered and user-friendly validated questionnaire. The DLQI/CDLQI is designed to 
measure the health-related quality of life of adult patients suffering from a skin disease. The 
DLQI/CDLQI consists of 10 questions concerning patients' perception of the impact of skin 
diseases on different aspects of their health-related quality of life over the last week. 
Subjects/caregivers will complete the CDLQI/DLQI. Refer to Appendix 8 for the DLQI and 
Appendix 9 for the CDLQI. 
5.2.5. 
Dermatitis Family Impact Questionnaire (DFI) 
This questionnaire measures how much having a child with atopic dermatitis affects the quality 
of life of other (adult) members of the family. To be completed by parents/guardians/caregivers 
of subjects ≤17 years of age (Appendix 10).   
5.3. 
Other Evaluations 
5.3.1. 
Body Surface Area (BSA) 
BSA assessments will be performed according to the Schedule of Visits and Assessments 
(Section 1.3). 
The BSA affected for atopic dermatitis will be determined by the subject’s hand method, where 
the subject’s hand (including fingers) surface area is assumed to equal 1% of body surface area 
(excluding the scalp, palms, soles).  
5.3.2. 
SCORAD ("SCORing Atopic Dermatitis") 
SCORAD is a clinical tool for assessing the severity (i.e. extent, intensity) of atopic dermatitis as 
objectively as possible. It gives approximate weights of 60% to intensity and 20% each to spread 
(extent) and subjective signs (insomnia, etc.).  
See Appendix 11. 
5.3.3. 
Patient-Oriented Eczema Measure (POEM) 
The Patient-Oriented Eczema Measure (POEM) is a tool used for monitoring atopic eczema 
severity. It focuses on the illness as experienced by the patient.  
POEM is a 5-point scale measuring the frequency of each of seven AD symptoms (dryness, 
itching, flaking, cracking, sleep loss, bleeding, and weeping) over the past week scored as 
occurring “no days” (0), “1 to 2 days” (1), “3 to 4 days” (2), “5 to 6 days” (3) or “every day” (4). 
Total score ranges from 0–28, with higher score indicating greater symptom impact. 
See Appendix 12. The self/proxy report questionnaire will be used in this study (for children 
unable to read and/or understand the POEM questionnaire, the parent/guardian/caregiver will 
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5.3.4. 
Pharmacokinetics Assessment 
PK draws will be performed according to the Schedule of Visits and Assessments (Section 1.3) 
for all subjects at all sites: 
• A single PK assessment (trough) will be performed in all subjects with a blood 
sample collected at Week 4/Day 29. 
Ensure study medication is not applied in the area where PK will be drawn. 
5.3.5. 
Medical Photography 
Photography of AD lesion(s) selected by the Investigator will be performed by all sites at all 
investigational visits, except Week 2/Day 15.  All efforts will be made to de-identify the 
subjects. Canfield equipment will be used to capture photographs. 
Photography should be focused on single lesions or specific body sections (e.g. arm). Body or 
half body photos should only be taken if necessary. Subjects who are unwilling to participate in 
the medical photography will be allowed to opt out of this procedure and documented on the 
informed consent.  
Refer to the current Photography Manual for instructions regarding photography. 
5.4. 
Final Study Visit – End of Study 
The approximate final study visit will occur at Week 4/Day 29. The procedures performed 
during this visit are as described in the Schedule of Visits and Assessments (Section 1.3). A 
3-day scheduling window is allowed for this visit. Adverse events will be recorded as reported 
by the participant or and followed to resolution or stabilization (as necessary). 
5.5. 
Early Termination Visit 
If a subject is withdrawn or wishes to exit the study, a termination visit will be scheduled. This 
visit should include the procedures and assessments that would be performed at the Week 4/Day 
29 visit. 
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 
The following information also will be collected: 
• vIGA-AD and EASI 
• BSA affected with AD  


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• Local tolerability assessment (by Investigator) 
The rules for how to tally vIGA-AD, BSA or other proportions of categorical responses will be 
described in the Statistical Analysis Plan. 
5.7. 
Adverse Events 
5.7.1. 
Adverse Event Definition 
An AE is defined as any untoward medical occurrence associated with the use of a drug in 
humans, whether or not considered drug related. An AE can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a medicinal (investigational) product, whether or not related to the 
medicinal (investigational) product.  
A treatment emergent adverse event (TEAE) is defined as an AE that started post application of 
study medication at the Baseline visit or was present at treatment initiation but worsened during 
treatment, through study completion.  
The definition of AEs 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.  When recording such events, provide 
descriptions that the pre-existing condition has changed (eg, worsening hypertension for a 
subject with pre-existing hypertension).  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. 
Progression of atopic dermatitis including new or worsening of anticipated clinical signs or 
symptoms, which are collected as clinical efficacy variables and assessed as unequivocally 
associated with the disease progression and /or lack of efficacy, should NOT be reported as 
adverse events unless the disease progression is greater than anticipated in the natural course 
of the disease. 
In general, abnormal laboratory findings without clinical significance (based on the 
investigator’s judgment) are not to be recorded as AEs.  However, abnormal laboratory findings 
that result in new or worsening clinical sequelae, or that require therapy or adjustment in current 
therapy, are considered AEs.  Where applicable, clinical sequelae (not the laboratory 
abnormality) are to be recorded as the AE. 
5.7.2. 
Serious Adverse Event Definition 
The definitions and reporting requirements of 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.  Statements regarding mandatory reporting of all 
serious unexpected adverse drug reactions (SUSARs) to Health Canada [as per C.05.014 (1) of 
the FDR] will be adhered. If any AEs are serious, as defined by ICH Guidelines for Clinical 
Safety, required procedures will be followed.   


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An SAE is defined as any AE that, in the view of either the PI or Sponsor, meets at least 1 of the 
following serious criteria:  
• Fatal  
• Life-threatening (places the subject at immediate risk of death) 
• Requires inpatient hospitalization or prolongation of existing hospitalization 
• Results in a persistent or significant incapacity/disability  
• Congenital anomaly/birth defect.   
• Other important medical events that, based upon appropriate medical judgment, may 
jeopardize the subject and may require medical or surgical intervention to prevent one 
of the outcomes listed in the above definition.  
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 baseline 
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 study document. 
If a SAE occurs to a subject on this study, contact the Medical Monitor within one business day 
of knowledge of event.  


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5.7.3. 
Suspected Unexpected Serious Adverse Reaction (SUSAR) 
SUSAR 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 subsequent clinic visit after the screening 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.   
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 for up to one month after end of 
treatment until the symptoms or value(s) return to normal, or acceptable levels, as judged by the 
Investigator. 
Where appropriate, medical test(s) and/or examination(s) will be performed to document 
resolution of event(s). Outcome may be classified as resolved, improved, unchanged, worse, fatal 
or unknown (lost to follow-up). 
5.7.5. 
Adverse Event Reporting 
The Investigator is responsible for recording all adverse events, observed by the clinic staff or 
reported by the subject that occur after the first application of investigational product through 
one month after treatment permanently discontinues.  Serious adverse events observed by the 
clinic staff or reported by the subject after signing the informed consent form will be recorded.  
All adverse events that meet the criteria for “serious” (i.e., SAEs) will be reported to the Sponsor 
via fax or e-mail within 24 hours of becoming aware of the event, whether or not the serious 
events are deemed drug-related.  Reporting should be done by sending the completed SAE form 
to the following e-mail address (faxing can also be done as a second option in case e-mailing is 
not possible). 
Safety Contact Information: 
 
E-mail: 
 
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 IRB will be notified of the Alert Reports as per FDA, ICH and the IRB’s 
policies and procedures. The sponsor, or delegate, will be responsible for reporting SAEs to 
health authorities per local reporting requirements. The Investigator will be responsible for 
reporting events to their respective IRBs in accordance to the IRB requirements. 
The Investigator will review each adverse event and assess its relationship to Investigational 
Product (unrelated, unlikely, possibly, probably, likely). Each sign or symptom reported will be 
graded on the NIH NCI CTCAE toxicity grading scale 5-point severity scale (Grade 1, 2, 3, 4 


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and 5). The date and time of onset, time relationship to drug dosing, duration, and outcome 
(resolved, improved, unchanged, worse, fatal, or unknown/lost to follow-up) 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 an 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. 
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 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. 


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* 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. 
AEs will be coded using the most current MedDRA® version available at the start of the study. 
5.8. 
Reporting Pregnancy 
During study participation, 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.  
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 complication must be reported as a SAE. In addition, 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 do not need to 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 study drug, 
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 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; see Appendix 13 for more information). 
A subject with a PHQ-8 or modified PHQ-A score ≥15 should receive immediate referral to a 
mental health professional, and Investigators in consultation with the mental health professional 
should consider interruption or discontinuation of the study drug. 
• Subjects with a PHQ-8 or modified PHQ-A score of 10-14 should be referred to a 
mental health professional for evaluation, regardless of the reason for their change in 
score 


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Subjects with a CDI-2 raw total score of ≥32 should be referred to a mental health professional, 
and Investigators in consultation with the mental health professional should consider interruption 
or discontinuation of the study drug 
• Subjects with a CDI-2 raw score of ≥21 for females and ≥22 for males should be 
referred to a mental health professional for evaluation 
A subject that is experiencing suicidal ideation and behavior should be referred immediately to a 
qualified mental health care provider and consideration given to discontinuation from study drug. 
As noted above, study treatment must be discontinued immediately in the event of a female 
subject’s pregnancy.   
Treatment should be interrupted: 
• 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) or greater on the scale of Berger and Bowman, 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.   
Treatment should be discontinued: 
• If the application site reaction reoccurs, treatment should be discontinued 
permanently, and the subject followed until the reaction resolves.   
For cases of suspected allergic contact dermatitis, the medical monitor and sponsor should be 
notified and there should be discussion about performing patch testing to further evaluate. Patch 
testing is encouraged in such cases. 
In the event of a medical emergency where unblinding is required to provide medical care to the 
subject, refer to the most current IWRS User Manual (Section 4.8.3). Contact the Medical 
Monitor and the Sponsor promptly.  
6. 
DATA ANALYSIS 
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.  


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6.2. 
Determination of Sample Size 
There are approximately 650 subjects planned for this study. In order to test the key secondary 
endpoint of IGA success in subjects with a vIGA-AD score of ‘Moderate’ at randomization, 
approximately 488 of the subjects to be accrued will have vIGA‑AD score of ‘Moderate’ at 
randomization.  Randomization will be stratified by vIGA-AD score (‘Mild’ vs. ‘Moderate’) and 
by study site. 
This sample size provides approximately 95% power to detect an overall 15% difference 
between treatment groups on vIGA‑AD success at Week 4 at α-0.05 using a 2-sided stratified 
(vIGA-AD at randomization and study site) Cochran-Mantel-Haenszel test.  The results from a 
recent phase 2 study (ARQ‑151-212) of ARQ-151 cream 0.15% compared to vehicle treatment 
were used to estimate the treatment difference.  Specifically, in the phase 2 trial, approximately 
37% of subjects demonstrated vIGA-AD success at Week 4 in the ARQ-151 0.15% group 
compared to 22% in the vehicle group.  This sample size also provides approximately 90% 
power to detect an overall 17% difference between treatment groups on IGA success at Week 4 
among subjects with vIGA-AD score ‘moderate’ at randomization.  The same testing method, 
the stratified Cochran-Mantel-Haenszel test, will be used as for the primary endpoint. 
To control for multiple comparisons, the key secondary endpoint will only be tested if the 
primary endpoint demonstrates statistical significance.  In addition, the remaining secondary 
endpoints will be inferentially tested only if the primary and key secondary endpoint 
comparisons are statistically significant.  To control for multiple comparisons among the 
remaining secondary endpoints, partitioning of alpha and the Holm’s procedure will be used. 
6.3. 
Subjects to Analyze 
The analysis populations are defined as follows: 
• Safety population will include all subjects who are enrolled and received at least one 
confirmed dose of study medication. 
• Intent-to-Treat (ITT) population will include all subjects who are randomized.  
• vIGA-AD Moderate ITT population will be a subset of the ITT population with 
vIGA-AD score ‘moderate’ at randomization. 
• WI-NRS population will be a subset of the ITT population with WI-NRS score ≥ 4 at 
baseline. 
• Pharmacokinetic (PK) population will include all subjects receiving the active drug 
with quantifiable plasma concentrations of roflumilast.  
6.4. 
Background and Demographic Characteristics 
Descriptive statistics will be used to summarize demographic characteristics (age, sex, ethnicity, 
and race) and background characteristics for the randomized subjects.   


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6.5. 
Study Medication Compliance 
The number of study drug applications by each subject based on diary data will be summarized 
using summary statistics (mean, standard deviation [SD], median, minimum, and maximum), and 
categorically.  
The number of investigational product applications by each subject based on diary data will be 
summarized using descriptive statistics.  
The amount of investigational product used by each subject based on tube weight will be 
summarized by treatment using descriptive statistics, and categorically. 
Investigational product application compliance will be calculated based on number of 
applications divided by the expected number (amount) of investigational product applications for 
each subject.  Compliance will be summarized descriptively by treatment group. 
6.6. 
Safety Analysis 
Descriptive statistics will be calculated for quantitative safety data and frequency counts will be 
compiled for classification of qualitative safety data. The safety population will be used for these 
analyses. 
Adverse Events: 
The subject incidence of treatment-emergent adverse events (TEAE) will be summarized 
overall, by severity, and by attribution.  
Clinical Laboratory Results: 
Shifts in clinical laboratory parameters from baseline to worst post-baseline grade will be 
provided.   
Vital Signs: 
The subject incidence of >5% weight loss or gain on study will be provided, as well as 
whether weight loss was explained or unexplained. 
6.7. 
Efficacy Analysis 
The Primary Efficacy Endpoint will be tested in all randomized subjects and defined as:  
• The proportion of all randomized subjects who attain IGA Success, defined as a 
vIGA-AD score of ‘clear’ or ‘almost clear’ PLUS a 2-grade improvement from 
Baseline at Week 4 
Upon demonstration of statistical significance for the primary endpoint, a hierarchical testing 
scheme will be used to test the key secondary endpoint defined as: 
• The proportion of randomized subjects with a vIGA-AD score of ‘Moderate’ at 
randomization who attain IGA Success at Week 4 
Missing IGA scores will be imputed using multiple imputation. 


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Upon successful demonstration of statistical significance for the secondary endpoint, the 
remaining endpoints will be grouped into secondary endpoint family 1, comprised of the 4‑point 
reduction on the WI-NRS, and secondary endpoint family 2, comprised of the EASI-75 at 
Week 4, vIGA-AD of ‘clear’ or ‘almost clear’ at Week 4, time to achievement of vIGA-AD 
success, and time to achievement of EASI-75.  An alpha level of 0.03 will be used to test the 
4-point reduction in the WI-NRS at Week 4.  An alpha level of 0.02 will be used to test the 
endpoints in secondary endpoint family 2.  The Holm procedure will be used to control for 
multiple comparisons within secondary endpoint family 2.  The endpoints listed below will be 
tested among all randomized subjects, unless otherwise noted.   
Secondary Endpoint Family 1 (α=0.03) 
• Among subjects with baseline WI-NRS ≥ 4, the proportion of subjects who attain a 
4-point reduction in the WI-NRS at Week 4 
Secondary Endpoint Family 2 (α = 0.02, Holm’s procedure) 
• The proportion of subjects who attain at least a 75% reduction in the Eczema Area 
and Severity Index at Week 4 (EASI-75)  
• Proportion of patients with vIGA-AD score of ‘clear’ or ‘almost clear’ at Week 4 
• Time to achievement of vIGA-AD success 
• Time to achievement of EASI-75 
The ITT population will be used for the primary and secondary efficacy analyses, with the 
exception of the key secondary endpoint analysis which will be performed on the vIGA-AD 
Moderate ITT population. 
6.8. 
Adverse Events 
All TEAEs occurring during the study will be recorded and classified on the basis of MedDRA 
terminology for the safety population. TEAEs are defined as those AEs with an onset on or after 
the time of first study drug application. All reported TEAEs will be summarized by treatment 
group. 
Descriptive statistics will be calculated for quantitative safety data and frequency counts will be 
compiled for classification of qualitative safety data.  
Adverse Events: 
The subject incidence of treatment-emergent adverse events (TEAE) will be summarized overall, 
by severity, and by attribution.  
Clinical Laboratory Results: 
Shifts in clinical laboratory parameters from baseline to worst post-baseline grade will be 
provided.   


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Vital Signs: 
The subject incidence of >5% weight loss or gain on study will be provided, as well as whether 
weight loss was explained or unexplained.   
6.9. 
Body Surface Area 
Body surface area (BSA) affected by AD will be analyzed descriptively. 
6.10. 
Local Tolerance Assessment 
For Investigator’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. 
6.11. 
Medical History and Physical Examinations 
Medical history for all subjects will be presented descriptively by parameter.  
Physical examination for all subjects will be presented descriptively by parameter.  Changes in 
physical examinations will be described in the text of the final report. 
6.12. 
Clinical Laboratory Results and Vital Signs 
All clinical laboratory results and vital signs measurements and their change from baseline 
(pre-dose), will be summarized descriptively by parameter, visit, and treatment group along with 
time point of collection. 
A shift table describing out-of-normal range shifts will be provided for clinical laboratory results.  
A shift table will identify subjects who gain or lose >5% body weight over the course of the 
study. 
6.13. 
Prior and Concomitant Medications 
Prior and concomitant medication information for all randomized subjects will be presented in a 
by-subject listing.  Summary tables will be presented by World Health Organization-Anatomical 
Therapeutic Chemical Classification System (WHO-ATC) therapeutic category and product. 
6.14. 
Subject Reported Outcomes Analyses 
WI- WI-NRS scale will be analyzed for change from Baseline (measured as a weekly average 
during the week before the Baseline/Day 1 visit) in itch severity of at least 4 at Week 4/Day 29 
as a weekly average during the week before the Week 4/Day 29 visit.  


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6.14.1. 
Dermatology Life Quality Indexes, Children’s Dermatology Life Quality Index, 
SCORAD and POEM 
Dermatology Life Quality Index (DLQI), Children’s Dermatology Life Quality Index (CDLQI), 
the Dermatitis Family Impact (DFI), the Scoring Atopic Dermatitis (SCORAD), and the 
Patient-oriented Eczema Measure (POEM) will be analyzed by evaluation of the reduction in 
total score at Week 4.  These efficacy endpoints will be analyzed descriptively. 
6.15. 
Pharmacokinetic Analysis 
Plasma drug concentrations will be summarized using descriptive statistics, reporting n, mean, 
standard deviation, median, minimum, and maximum. The PK population will be used for these 
analyses.  
7. 
STUDY ADMINISTRATION 
7.1. 
Ethics 
7.1.1. 
Ethics Review Board 
Before screening of subjects into the study, the current protocol, ICF, and any accompanying 
material to be provided to the subjects will be reviewed and approved by an appropriate IRB, as 
required by FDA (21 CFR § 56) and ICH GCP regulations.  A letter documenting the IRB 
approval must be received by the Sponsor 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. However, the frequency of these reports will depend on IRB requirements. As soon as 
possible after completion or termination of the study, the Investigator will submit a final report to 
the IRB per the IRB requirements, and in compliance with FDA and ICH GCP guidelines. 
The Investigator, the Sponsor, or designee shall promptly notify the IRB of any SAEs, SUSARs, 
or any other information that may affect the safe use of the study drug(s) during the study, per 
the IRB local requirements, and in compliance with FDA 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 Consolidated 
Guidance, April 1996). 
7.1.3. 
Subject Information and Consent/Assent 
The investigator is responsible for obtaining written informed consent from each individual 
participating in this study after adequate explanation (in non-technical terms) of the aims, 
methods, objectives, and potential hazards of the study and before undertaking any study-related 
procedures. The investigator must use the most current IRB- or IEC-approved consent form for 


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documenting written informed consent. Subjects will be assured that they may withdraw from 
the study at any time without jeopardizing their medical care. Each informed consent (or assent 
as applicable) will be read, appropriately signed and dated by the subject or the subject’s legally 
authorized representative and the person conducting the consent discussion, and also by an 
impartial witness if required by IRB or IEC or local requirements. 
Subjects will be given a signed copy of their ICF/assent. 
7.2. 
Study Completion and Termination 
7.2.1. 
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. 
7.2.2. 
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.  
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 drug development. 
7.3. 
Study Monitoring 
Prior to the initiation of the clinical investigation, Sponsor representatives or designees may visit 
the clinical site where the investigation is to be conducted.  Sponsor representatives or designees 
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 or designees 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. 


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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. 
7.4. 
Data Quality Assurance 
In order to ensure the collection of accurate, consistent, complete, and reliable data during this 
clinical investigation, Sponsor representatives or designees may conduct audits of participating 
sites at appropriate intervals throughout the study.  The results of these periodic site audits may 
be subject to review by independent auditors at completion of the clinical investigation.   
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 using SAS version 9.4 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 source records, including 
medical records, records detailing the progress of the study for each subject, laboratory reports, 
signed informed consent forms, IP disposition records, correspondence with the 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 eCRFs.  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, 
unless overriding safety reasons warrant immediate action, in which case the IRB(s) will be 
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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 
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 drug 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. 
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).  


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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 
Baumer W, Hoppmann J, Rundfeldt C, et al. Highly selective phosphodiesterase 4 inhibitors for 
the treatment of allergic skin diseases and psoriasis. Inflamm Allergy Drug Targets. 2007;6: 
17–26.  
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. 
Bethke TD, Lahu G. High absolute bioavailability of the new oral phosphodiesterase-4 inhibitor 
roflumilast.  Int. J Clin Pharmacol Ther. 2011;49:51-57. 
DALIRESP (roflumilast) tablets [package insert]. AstraZeneca Pharmaceuticals LP, Wilmington, 
DE USA; 2018. 
Dastidar SG, Rajagopal D, Ray A. Therapeutic benefit of PDE4 inhibitors in inflammatory 
diseases. Curr Opin Investig Drugs. 2007;8:364–372.  
Furue M, Kitahara Y, Akama H, et al. Safety and efficacy of topical E6005, a phosphodiesterase 
4 inhibitor, in Japanese adult patients with atopic dermatitis: results of a randomized, 
vehicle-controlled, multicenter clinical trial. J Dermatol. 2014;41:577-585.  
Grewe SR, Chan SC, Hanifin JM. Elevated leukocyte cyclic AMP-phosphodiesterase in atopic 
disease: a possible mechanism for cy- clic AMP-agonist hyporesponsiveness. J Allergy Clin 
Immunol. 1982;70:452–457.  
Hanifin JM, Chan SC, Cheng JB, et al. Type 4 phosphodiesterase inhibitors have clinical and in 
vitro anti-inflammatory effects in atopic dermatitis. J Invest Dermatol. 1996;107:51–56. 
Hanifin JM, Thurston M, Omoto M, et al. The eczema area and severity index (EASI): 
assessment of reliability in atopic dermatitis. EASI Evaluator Group. Exp Dermatol. 
2001;10:11-18.  
Hanifin J.M. and Rajka G. Diagnostic features of atopic dermatitis. Acta Derm Venereol Suppl 
(Stockh). 1980;92: 44–47. 
Hatzelmann A, Morcillo EJ, Lungarella G, et al. The preclinical pharmacology of roflumilast – 
a selective, oral phosphodiesterase 4 inhibitor in development for chronic obstructive pulmonary 
disease. Pulm Pharmacol Ther. 2010;23:235–256. 
Investigator’s Brochure, Edition 2.0, 22 October 2020. 
Michalski JM, Golden G, Ikari J, et al. PDE4: A novel target in the treatment of chronic 
obstructive pulmonary disease. Clin Pharmacol Ther. 2012;91:134–142. 


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Murrell DF, Gebauer K, Spelman L, et al. Crisaborole topical ointment, 2% in adults with atopic 
dermatitis: a phase 2a, vehicle- controlled, proof-of-concept study. J Drugs Dermatol. 
2015;14:1108–1112. 
Nazarian R, Weinberg JM. AN-2728, a PDE4 inhibitor for the potential topical treatment of 
psoriasis and atopic dermatitis. Curr Opin Investig Drugs. 2009;10:1236–1242. 
Newton et al., Exploring Content and Psychometric Validity of Newly Developed Assessment 
Tools for Itch and Skin Pain in Atopic Dermatitis. Journal of Patient-Reported Outcomes. 
2019;3:42. 
Nygaard U, Deleuran M, Vestergaard C. Emerging treatment options in atopic dermatitis: topical 
therapies. Dermatology. 2017;233:333-343. 
Wedzicha JA, Calverley PMA, Klaus FR. Roflumilast: a review of its use in the treatment of 
COPD.  Int J Chron Obstruct Pulmon Dis. 2016;11:81-90. 
 
 




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APPENDIX 2. 
PATIENT HEALTH QUESTIONAIRE-8 (PHQ-8) 
 
 


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APPENDIX 3. 
PATIENT HEALTH QUESTIONNAIRE DEPRESSION 
SCALE (MODIFIED PHQ-A) 


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APPENDIX 4. CHILDREN’S DEPRESSION INVENTORY 2 
(PARENT REPORT) 
 


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APPENDIX 5. 
COLUMBIA-SUICIDE SEVERITY RATING SCALE 
(C-SSRS) “BASELINE/SCREENING” VERSION 
 


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APPENDIX 6. 
COLUMBIA-SUICIDE SEVERITY RATING SCALE 
(C-SSRS) “SINCE LAST VISIT” VERSION 
 


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APPENDIX 7. 
VALIDATED INVESTIGATOR GLOBAL ASSESSMENT 
SCALE FOR ATOPIC DERMATITIS 
 
 
 


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APPENDIX 8. 
DERMATOLOGY LIFE QUALITY INDEX  
 
 
 
 
 
 
 
 
 
 
 
 
 
 DLQI 
Site No:  
 
 
 
 
Date: 
 
 
 
 
 
Score: 
Name:  
 
 
 
 
 
 
 
 
 
 
 
Address: 
 
 
 
 
Diagnosis: 
 
 
 
 
 
 
The aim of this questionnaire is to measure how much your skin problem has affected your life OVER 
THE LAST WEEK.  Please tick  one box for each question. 
 
1. 
Over the last week, how itchy, sore,  
 
 
 
Very much 
 
 
painful or stinging has your skin   
 
 
 
A lot 
 
 
 
been?   
 
 
 
 
 
 
A little  
 
 
 
 
 
 
 
 
 
 
Not at all 
 
 
2. 
Over the last week, how embarrassed 
 
 
 
Very much 
 
 
or self conscious have you been because   
 
 
A lot 
 
 
 
of your skin? 
 
  
 
 
 
 
A little  
 
 
 
 
 
 
 
 
 
 
Not at all 
 
 
3. 
Over the last week, how much has your  
 
 
 
Very much 
 
 
skin interfered with you going 
 
  
 
 
A lot 
 
 
 
shopping or looking after your home or   
 
 
A little  
 
 
garden?        
 
 
 
 
 
 
Not at all 
 
 
Not relevant  
 
 
4. 
Over the last week, how much has your  
 
 
 
Very much 
 
 
skin influenced the clothes  
 
 
 
 
A lot 
 
 
 
you wear? 
 
 
 
 
 
 
A little  
 
 
 
 
 
 
 
 
 
 
Not at all 
 
 
Not relevant  
 
 
5. 
Over the last week, how much has your  
 
 
 
Very much 
 
 
skin affected any social or  
 
 
 
 
A lot 
 
 
 
leisure activities? 
 
 
 
 
 
A little  
 
 
 
 
 
 
 
 
 
 
Not at all 
 
 
 
 
 
 
 
 
 
 
Not relevant  
 
 
6. 
Over the last week, how much has your  
 
 
 
Very much 
 
 
skin made it difficult for   
 
 
 
 
A lot 
 
 
 
you to do any sport? 
 
 
 
 
 
A little  
 
 
 
 
 
 
 
 
 
 
Not at all 
 
 
 
 
 
 
 
 
 
 
Not relevant  
 
 
7. 
Over the last week, has your skin prevented 
 
 
Yes 
 
 
 
you from working or studying?  
 
 
 
No 
 
 
 
 
 
 
 
 
 
 
 
Not relevant  
 
 
 
 
If "No", over the last week how much has   
 
 
A lot 
 
 
 
your skin been a problem at  
 
 
 
 
A little  
 
 
work or studying? 
 
 
 
 
 
Not at all 
 


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8. 
Over the last week, how much has your  
 
 
 
Very much 
 
 
skin created problems with your   
 
 
 
A lot 
 
 
 
partner or any of your close friends 
 
 
 
A little  
 
 
or relatives?  
 
 
 
 
 
 
Not at all 
 
 
 
 
 
 
 
 
 
 
Not relevant  
 
 
9. 
Over the last week, how much has your  
 
 
 
Very much 
 
 
skin caused any sexual   
 
 
 
 
A lot 
 
 
 
difficulties? 
 
 
 
 
 
 
A little  
 
 
 
 
 
 
 
 
 
 
Not at all 
 
 
 
 
 
 
 
 
 
 
Not relevant  
 
 
10. 
Over the last week, how much of a  
 
 
 
Very much 
 
 
problem has the treatment for your 
 
 
 
A lot 
 
 
 
skin been, for example by making  
 
 
 
A little  
 
 
your home messy, or by taking up time?   
 
 
Not at all 
 
 
 
 
 
 
 
 
 
 
Not relevant  
 
 
 
Please check you have answered EVERY question. Thank you.  
 
 
 
AY Finlay, GK Khan, April 1992 www.dermatology.org.uk, this must not be copied without the permission of the authors. 
 
 


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APPENDIX 9. 
CHILDREN’S DERMATOLOGY LIFE QUALITY INDEX 
 
 
Site No.: 
Name:  
 
 
Diagnosis: 
 
 
 
 
 
CDLQI  
Age: 
 
 
 
 
 
 
 
 
 
 
SCORE: 
Address: 
 
 
Date: 
 
 
The aim of this questionnaire is to measure how much your skin problem has 
affected you OVER THE LAST WEEK.  Please tick  one box for each question. 
 
1. 
Over the last week, how itchy, "scratchy",  
 
 
Very much 
 
□ 
 
sore or painful has your skin been? 
 
  
 
Quite a lot 
 
□ 
 
 
  
 
 
 
 
 
 
Only a little 
 
□ 
 
 
 
 
 
 
 
 
 
Not at all 
 
□ 
 
2. 
Over the last week, how embarrassed 
 
 
 
Very much 
 
□ 
 
or self conscious, upset or sad have you  
 
 
 
Quite a lot 
 
□ 
 
been because of your skin? 
 
  
 
 
Only a little 
 
□ 
 
 
 
 
 
 
 
 
 
Not at all 
 
□ 
 
3. 
Over the last week, how much has your  
 
 
 
Very much 
 
□ 
 
skin affected your friendships? 
  
 
 
 
Quite a lot 
 
□ 
 
 
 
 
 
 
 
 
 
Only a little 
 
□ 
 
 
 
 
 
 
 
 
 
Not at all 
 
□ 
 
4. 
Over the last week, how much have you changed 
 
 
Very much 
 
□ 
 
or worn different or special clothes/shoes  
 
 
Quite a lot 
 
□ 
 
because of your skin? 
 
 
 
 
 
Only a little 
 
□ 
 
 
 
 
 
 
 
 
 
Not at all 
 
□ 
 
5. 
Over the last week, how much has your  
 
 
 
Very much 
 
□ 
 
skin trouble affected going out, playing, 
 
 
 
Quite a lot 
 
□ 
 
or doing hobbies? 
 
 
 
 
 
Only a little 
 
□ 
 
 
 
 
 
 
 
 
 
Not at all 
 
□ 
 
6. 
Over the last week, how much have you 
  
 
 
Very much 
 
□ 
 
avoided swimming or other sports because  
 
               Quite a lot 
 
□ 
 
of your skin trouble? 
 
 
 
 
 
Only a little 
 
□ 
 
 
 
 
 
 
 
 
 
Not at all 
 
□ 
 
7. 
Last week, 
 
  
If school time: Over the  
Prevented school               □   
 
         
last week, how much did  
Very much 
 
□ 
 
school time?   
 
              your skin problem affect your 
Quite a lot 
 
□ 
 
 
 
 
 
school work? 
 
 
Only a little 
 
□ 
 
   OR 
 
 
 
 
 
 
 
Not at all 
 
□ 
 
 
was it 
 
 
   
If holiday time: How much 
Very much 
 
□ 
 
holiday time?  
   
               over the last week, has your 
Quite a lot 
 
□ 
 
 
 
 
 
skin problem interfered with 
Only a little 
 
□ 
 
 
 
 
 
your enjoyment of the holiday? 
Not at all 
 
□ 
was it 


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8. 
Over the last week, how much trouble  
 
 
 
Very much 
 
□ 
 
have you had because of your skin with 
 
 
 
Quite a lot 
 
□ 
 
other people calling you names, teasing, 
 
 
 
Only a little 
 
□ 
 
bullying, asking questions or avoiding you? 
 
 
Not at all 
 
□ 
 
9. 
Over the last week, how much has your sleep  
 
 
Very much 
 
□ 
 
been affected by your skin problem? 
 
 
 
Quite a lot 
 
□ 
 
 
 
 
 
 
 
 
 
Only a little 
 
□ 
 
 
 
 
 
 
 
 
 
Not at all 
 
□ 
 
10. 
Over the last week, how much of a   
 
 
 
Very much 
 
□ 
 
problem has the treatment for your  
 
 
 
Quite a lot 
 
□ 
 
skin been? 
 
 
 
 
 
 
Only a little 
 
□ 
 
 
 
 
 
 
 
 
  
Not at all 
 
□ 
 
 
 


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APPENDIX 10. DERMATITIS FAMILY IMPACT QUESTIONNAIRE 
(DFI) 
 
Child’s Name:  
 
Mother/Father/Carer Date:  
 
Score 
 
The aim of this questionnaire is to measure how much your child’s skin problem has affected you 
and your family OVER THE LAST WEEK.  Please tick  one box for each question. 
 
1. 
Over the last week, how much effect 
 
 
 
Very much 
 
 
 
has your child having eczema had on  
 
 
 
A lot 
 
 
 
 
housework, e.g. washing, cleaning. 
 
 
 
A little  
 
 
 
 
 
 
 
 
 
 
 
Not at all 
 
 
 
2. 
Over the last week, how much effect 
 
 
 
Very much 
 
 
 
has your child having eczema had on 
 
 
 
A lot 
 
 
 
 
food preparation and feeding.  
 
 
 
A little  
 
 
 
 
 
 
 
 
 
 
 
Not at all 
 
 
 
3. 
Over the last week, how much effect has 
 
 
Very much 
 
 
 
your child having eczema had on the sleep 
 
 
A lot 
 
 
 
 
of others in family. 
 
 
 
 
 
A little  
 
 
 
 
 
 
 
 
 
 
 
Not at all 
 
 
 
4. 
Over the last week, how much effect has 
 
 
Very much 
 
 
 
your child having eczema had on  
 
 
 
A lot 
 
 
 
 
family leisure activities, eg swimming.  
 
 
A little  
 
 
 
 
 
 
 
 
 
 
 
Not at all 
 
 
 
5. 
Over the last week, how much effect has 
 
 
Very much 
 
 
 
your child having eczema had on time spent 
 
 
A lot 
 
 
 
 
on shopping for the family. 
 
 
 
 
A little  
 
 
 
 
 
 
 
 
 
 
 
Not at all 
 
 
 
6. 
Over the last week, how much effect has your 
 
 
Very much 
 
 
 
child having eczema had on your expenditure,  
 
A lot 
 
 
 
 
eg costs related to treatment, clothes, etc. 
 
 
A little  
 
 
 
 
 
 
 
 
 
 
 
Not at all 
 
 
 
7. 
Over the last week, how much effect has your 
 
 
Very much 
 
 
 
child having eczema had on causing tiredness 
 
 
A lot 
 
 
 
 
or exhaustion in your child’s parents/carers. 
 
 
A little  
 
 
 
 
 
 
 
 
 
 
 
Not at all 
 
 
 
8. 
Over the last week, how much effect has your 
 
 
Very much 
 
 
 
child having eczema had on causing emotional  
 
A lot 
 
 
 
 
distress such as depression, frustration or 
 
 
A little  
 
 
 
guilt in your child’s parents/carers. 
 
 
 
Not at all 
 
 
 
 
 


Protocol ARQ-151-312 
Arcutis Biotherapeutics, Inc. 
Original 
 
 
Confidential 
Page 87 of 100 
 
 
 
 
9. 
Over the last week, how much effect has your 
 
 
Very much 
 
 
 
child having eczema had on relationships 
 
 
A lot 
 
 
 
 
between the main carer and partner or  
 
 
A little  
 
 
 
between the main carer and other children 
 
 
Not at all 
 
 
 
in the family. 
 
10. 
Over the last week, how much effect has helping 
 
Very much 
 
 
 
with your child’s treatment had on the  
 
 
A lot 
 
 
 
 
main carer’s life. 
 
 
 
 
 
A little  
 
 
 
 
 
 
 
 
 
 
 
Not at all 
 
 
 
Please check you have answered EVERY question.  Thank you 
© M.S. Lewis-Jones, A.Y. Finlay 1995 


Protocol ARQ-151-312 
Arcutis Biotherapeutics, Inc. 
Original 
 
 
Confidential 
Page 88 of 100 
 
 
 
 
APPENDIX 11. SCORAD 
SCORAD https://www.ncbi.nlm.nih.gov/pubmed/8435513 
 


Protocol ARQ-151-312 
Arcutis Biotherapeutics, Inc. 
Original 
 
 
Confidential 
Page 89 of 100 
 
 
 
 
APPENDIX 12. PATIENT-ORIENTED ECZEMA MEASURE (POEM) 
 


Protocol ARQ-151-312 
Arcutis Biotherapeutics, Inc. 
Original 
 
 
Confidential 
Page 90 of 100 
 
 
 
 
 




Protocol ARQ-151-312 
Arcutis Biotherapeutics, Inc. 
Original 
 
 
Confidential 
Page 92 of 100 
 
 
 
 
ESTIMATING SEVERITY GRADE 
For abnormalities NOT found elsewhere in the Toxicity Tables use the scale below to estimate 
grade of severity: 
GRADE 1 
Mild: 
Transient or mild discomfort (<48 hours); no medical 
intervention/therapy required 
GRADE 2 
Moderate: 
Mild to moderate limitation in activity - some assistance may be 
needed; no or minimal medical intervention/therapy required 
GRADE 3 
Severe:  
Marked limitation in activity, some assistance usually required; 
medical intervention/therapy required hospitalizations possible. 
 
LABORATORY RANGES 
Where discrepancies in the ULN and LLN of laboratory ranges occur between those included in 
this document and those of the laboratory that performs the assays, the values provided by the 
laboratory will be used for assignment of severity grade.  

















SAP_001.pdf: 
 
SOP-STAT-03-TOOL.01 Version 4 
Effective Date: 03-Jun-2018 
        
 
Page 1 of 52 
 
Statistical Analysis Plan 
 
Study Title: 
A Phase 3, 4-Week, Parallel Group, Double Blind, 
Vehicle-Controlled Study of the Safety and Efficacy of 
ARQ-151 Cream 0.15% Administered QD in Subjects 
with Atopic Dermatitis 
Protocol Number and Version: 
ARQ-151-312, Original dated 31 October 2020 
Amendment 1 dated 08 June 2021  
Amendment 2 dated 18 July 2021 
Amendment 3 dated 23 May 2022 
 
Product: 
ARQ-151 Cream 0.15% 
Sponsor: 
Arcutis Biotherapeutics, Inc. 
3027 Townsgate Road, Suite 300 
Westlake Village, CA 91361 
 
Date: 
05 July 2022 
Version: 
Final 1.0  
 
Prepared by: 
 
  
 
 
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STATISTICAL ANALYSIS PLAN, Version 1.0 
Protocol Number: ARQ-151-312 
Sponsor: Arcutis Biotherapeutics, Inc. 
 
SOP-STAT-03-TOOL.01 Version 4 
Effective Date: 03-Jun-2018 
                
 
Page 2 of 52 
 
STATISTICAL ANALYSIS PLAN REVISION SUMMARY 
Version 
Version Date 
Author 
Summary of Changes  
Original V1.0 
05-JUL-2022 
 
Initial version 
 
 
 
This statistical analysis plan will be reviewed and revised as needed. The most recent approved version will 
replace the previous version in place. 
 
 
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STATISTICAL ANALYSIS PLAN, Version 1.0 
Protocol Number: ARQ-151-312 
Sponsor: Arcutis Biotherapeutics, Inc. 
 
SOP-STAT-03-TOOL.01 Version 4 
Effective Date: 03-Jun-2018 
                
 
Page 4 of 52 
TABLE OF CONTENT 
1 
INTRODUCTION.................................................................................................................... 8 
2 
STUDY OBJECTIVES AND ENDPOINTS .......................................................................... 8 
3 
STUDY DESIGN .................................................................................................................... 10 
3.1 
Overall Design ................................................................................................................ 10 
3.2 
Schedule of Events ......................................................................................................... 12 
3.3 
Treatment ....................................................................................................................... 14 
3.4 
Randomization, Replacement, and Unblinding Procedures ...................................... 14 
3.5 
Changes to the Analysis from the Protocol .................................................................. 15 
4 
POPULATIONS FOR ANALYSIS ...................................................................................... 16 
4.1 
Intent-to-Treat (ITT) Population .................................................................................. 16 
4.2 
Modified Intent-to-Treat (mITT) Population .............................................................. 16 
4.3 
Per Protocol (PP) Population ........................................................................................ 16 
4.4 
vIGA-AD Moderate ITT Population ............................................................................ 16 
4.5 
vIGA-AD Moderate PP Population .............................................................................. 16 
4.6 
WI-NRS Population ....................................................................................................... 17 
4.7 
Safety Population ........................................................................................................... 17 
4.8 
Pharmacokinetic (PK) Population ................................................................................ 17 
5 
GENERAL CONSIDERATIONS ........................................................................................ 17 
5.1 
Sample Size ..................................................................................................................... 18 
5.2 
Baseline ........................................................................................................................... 18 
5.3 
Reference Start Date and Analysis Day ....................................................................... 19 
5.4 
Windowing Conventions ................................................................................................ 19 
5.5 
Derived Variables ........................................................................................................... 20 
5.6 
Descriptive Statistics ...................................................................................................... 23 
5.7 
Statistical Tests ............................................................................................................... 23 
5.8 
Handling of Retests, Unscheduled Visits, and Early Termination Data ................... 23 
5.9 
Software Version ............................................................................................................ 23 
6 
STATISTICAL CONSIDERATIONS ................................................................................. 24 
6.1 
Adjustments for Covariates .......................................................................................... 24 
6.2 
Handling of Dropouts or Missing data ......................................................................... 24 
6.2.1 
Multiple Imputation .......................................................................24 
6.2.2 
Non-responder Imputation Analysis ..............................................27 
6.2.3 
Tipping Point Analysis ..................................................................27 
6.3 
Interim Analysis ............................................................................................................. 27 
6.4 
Multicenter Studies ........................................................................................................ 28 
6.5 
Multiple Comparisons/Multiplicity .............................................................................. 28 
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6.6 
Examination of Subgroups ............................................................................................ 30 
7 
STUDY SUBJECTS ............................................................................................................... 31 
7.1 
Disposition of Subjects ................................................................................................... 31 
7.2 
Protocol Deviations ........................................................................................................ 32 
8 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS ............................ 32 
9 
SURGICAL AND MEDICAL HISTORY ........................................................................... 34 
10 
PRIOR AND CONCOMITANT MEDICATIONS ............................................................. 34 
11 
STUDY TREATMENT EXPOSURE AND TREATMENT COMPLIANCE ................. 34 
12 
EFFICACY ANALYSIS ........................................................................................................ 36 
12.1 
Primary Efficacy Endpoint Analysis ............................................................................ 36 
12.1.1 
Primary Efficacy Endpoint and Estimand......................................36 
12.1.2 
Hypothesis Testing.........................................................................36 
12.1.3 
Primary Endpoint Analysis ............................................................37 
12.2 
Secondary Endpoints Analysis ...................................................................................... 38 
12.3 
Exploratory Efficacy Endpoints ................................................................................... 41 
12.4 
Subgroup Analysis ......................................................................................................... 43 
12.5 
Summary of Primary and Secondary Efficacy Analysis ............................................ 44 
13 
SAFETY ANALYSIS............................................................................................................. 45 
13.1 
Adverse Events ............................................................................................................... 45 
13.2 
Clinical Laboratory ........................................................................................................ 47 
13.3 
Vital Signs ....................................................................................................................... 47 
13.4 
Local Tolerability Assessments ..................................................................................... 47 
13.5 
Patient Health Questionnaire Depression Scale (PHQ-8) and Patient Health 
Questionnaire Depression Scale (Modified PHQ-A) ................................................... 48 
13.6 
Children’s Depression Inventory 2 (CDI-2) ................................................................ 48 
13.7 
Columbia-Suicide Severity Rating Scale (C-SSRS) .................................................... 49 
13.8 
Physical Examination .................................................................................................... 49 
14 
PHARMACOKINETICS ANALYSIS ................................................................................. 49 
15 
REFERENCES ....................................................................................................................... 50 
16 
APPENDICES ........................................................................................................................ 51 
 
 
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Sponsor: Arcutis Biotherapeutics, Inc. 
 
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ABBREVIATIONS 
AD 
Atopic Dermatitis 
AE 
Adverse Event 
ANCOVA 
Analysis of Covariance 
ATC 
Anatomical Therapeutic Chemical 
BMI 
Body Mass Index 
BSA 
Body Surface Area 
CDI-2 
Children’s Depression Inventory 2 
CDLQI 
Children’s Dermatology Life Quality Index  
CI 
Confidence Interval 
CMH 
Cochran-Mantel-Haenszel  
COVID-19 
Coronavirus Disease-19 
CRF 
Case Report Form 
CRO 
contract research organization 
C-SSRS 
Columbia-Suicide Severity Rating Scale  
CSR 
Clinical Study Report 
DFI 
Dermatitis Family Impact 
DLQI 
Dermatology Life Quality Index 
EASI 
Eczema Area and Severity Index 
ECG 
Electrocardiogram 
eCRF  
Electronic Case Report Form  
EDC 
Electronic Data Capture 
EM 
Expectation-Maximization 
ET 
Early Termination 
HR 
Heart Rate 
IP 
Investigational Product 
ITT 
Intent to Treat 
IWRS 
Interactive Web Response System 
LOCF 
Last Observation Carried Forward 
MCMC 
Markov-Chain Monte-Carlo  
MedDRA  
Medical Dictionary for Regulatory Activities 
mITT 
Modified Intent to Treat 
PHQ-8 
Patient Health Questionnaire-8 
PHQ-A 
Modified PHQ-9 for Adolescents 
PMM 
Predictive Mean Matching 
POEM 
Patient-Oriented Eczema Measure  
PK 
Pharmacokinetic 
PP 
Per Protocol 
PT 
Preferred Term 
Q1 
First Quartile 
Q3 
Third Quartile 
QD 
Once Daily  
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SAE  
Serious Adverse Event  
SAP  
Statistical Analysis Plan  
SAS 
Statistical Analysis System® 
SCORAD 
Scoring Atopic Dermatitis  
SD 
Standard Deviation 
SOC 
System Organ Class 
TEAE 
Treatment Emergent Adverse Event  
TESAE 
Treatment Emergent Serious Adverse Event  
TLF 
Tables, Listings, and Figures 
WHO-DD  
World Health Organization Drug Dictionary  
WI-NRS 
Worst Itch - Numeric Rating Score 
vIGA-AD 
Validated Investigator Global Assessment scale for Atopic Dermatitis  
 
 
 
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STATISTICAL ANALYSIS PLAN, Version 1.0 
Protocol Number: ARQ-151-312 
Sponsor: Arcutis Biotherapeutics, Inc. 
 
SOP-STAT-03-TOOL.01 Version 4 
Effective Date: 03-Jun-2018 
                
 
Page 11 of 52 
Figure 1 
Study Schema    
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Screening 
Roflumilast 
0.15% 
Matching 
Vehicle Cream 
Treatment Period and Clinic Visits 
Week 1/Day 8, Week 2/Day 15, and Week 4/Day 29 
Randomization and Treatment 
Baseline / Day 1 
(N=650) 
Not Participating in Open 
Label Extension Study 
 
End of Study 
Participating in Open Label 
Extension Study 
 
ARQ-151-313 
 
Enrollment 
A Phase 3, 4-Week, Parallel Group, Double Blind, Vehicle-Controlled Study of 
the Safety and Efficacy of ARQ-151 Cream 0.15% Administered QD in 
Subjects with Atopic Dermatitis  
Approximately 650 subjects with atopic dermatitis will be randomized 2:1 to receive 
either: 
• 
Roflumilast cream 0.15% or Vehicle cream 
Subjects will have ≥3% BSA involvement (excluding the scalp, palms, soles) with a 
vIGA-AD score of ‘2’ (mild) or ‘3’ (moderate) for study entry 
Up to 50% of the subjects will be ≥ 18 years old 
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3.2 Schedule of Events 
Table 1 Schedule of Visits and Assessments  
Study Procedure 
Screen 
Baseline 
Day 1 
Wk 1 
Day 8 
Wk 2 
Day 15 
Wk 4 
Day 29 / ET 
Visit 
1 
2 
3 
4 
5 
Visit Window 
-30 days 
N/A 
+/- 3 days 
+/- 3 days 
+/- 3 days 
Informed consent/assent 
X 
 
 
 
 
Demographics 
X 
 
 
 
 
Medical and surgical 
history 
X 
 
 
 
 
Physical examinationa 
X 
X 
 
 
X 
I/E criteria 
X 
X 
 
 
 
Hematology, Serum 
Chemistries, and Urine 
Analysisb 
Xb 
Xb 
 
 
Xb 
Vital signs, height, weightc 
X 
X 
X 
X 
X 
vIGA-AD, EASI, BSA, 
SCORADd 
X 
X 
X 
X 
X 
WI-NRS prurituse 
X 
X 
X 
X 
X 
POEMf 
X 
X 
X 
X 
X 
Local Tolerability 
Assessmentg  
 
X 
X 
X 
X 
CDI-2, PHQ-8, PHQ-A, 
C‑SSRSh 
X 
X 
X 
X 
X 
DLQI, CDLQI, DFIi 
X 
X 
X 
X 
X 
Medical Photographyj 
 
X 
X 
 
X 
Serum pregnancy test 
(FOCBP only) 
X 
 
 
 
 
Urine pregnancy testk 
 
X 
X 
X 
X 
PK drawsl 
 
 
 
 
X 
Drug/vehicle application 
in clinicm 
 
X 
X 
X 
 
Dispense/Re-dispense study 
medication kitn 
 
X 
Xo 
Xo 
Xo 
Dispense/review diary 
X 
X 
X 
X 
X 
Weigh study medication 
kitp 
 
X 
X 
X 
X 
Compliance 
determinationq 
 
 
X 
X 
X 
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Study Procedure 
Screen 
Baseline 
Day 1 
Wk 1 
Day 8 
Wk 2 
Day 15 
Wk 4 
Day 29 / ET 
Adverse event assessmentr 
X 
X 
X 
X 
X 
Concomitant medications 
X 
X 
X 
X 
X 
Study Exit s 
 
 
 
 
X 
a Limited physical examination: skin (including assessment of Fitzpatrick skin type at Screening only), lungs, and 
heart only 
b For all subjects entering this study under Amendment 2, to be collected at Screening, but subsequent samples will 
be collected only for subjects ≥12 years old (Baseline/Day 1 and Week 4/Day 29/ET). For subjects 12 to 18 years 
of age, if Baseline/Day 1 is within 3 weeks of Screening, the Screening results may be used. 
c Height will be collected at Screening only. Weight should be obtained using a calibrated weight scale and the same 
scale should be used for a subject throughout the duration of the study.  The subject should remove shoes and 
heavy clothing (sweaters or jackets), and empty pockets. The subject should stand with both feet in the center of 
the scale with their arms at their side and hold still. Record the weight to the nearest decimal fraction (for example, 
25.1 kilograms). For subjects <18 years of age, measure the weight in triplicate and report the average weight in 
EDC. A 5% or greater weight loss (whether or not intentional or other explained) should be reported to the 
medical monitor. 
d The vIGA-AD assessment will be a 5-point scale ranging from clear (0) to severe (4) and is evaluated for the 
entire body except the scalp, palms, and soles. EASI takes into account overall severity of erythema, 
infiltration/papulation, excoriation, and lichenification, in addition to extent of BSA affected. The 4 clinical signs 
will be graded on a 4-point scale (0 [absent] to 3 [severe]) for 4 body regions (head and neck, upper extremities, 
lower extremities, and trunk). Total EASI score will be calculated as a sum of scores of all 4 body regions. EASI 
total score will range from 0 (absent) to 72 (severe). Total BSA affected by AD will be determined for all body 
surfaces except the scalp, palms and soles. The vIGA-AD assessment should be completed prior to other 
physician assessments. SCORAD total score will range between 0 and 103.  
e Subjects will self-assess their pruritus at home on a daily basis starting 7 days prior to the Baseline/Day 1 visit, and 
then every day thereafter.  WI-NRS score will be determined by the subject assessing worst itch over the past 
24 hours. The scale is from 0 (no itch) to 10 (worst itch) and this value will be recorded by the subject each day. 
Subjects will be trained at the Screening visit in the accurate completion of the WI-NRS. In addition, 
parents/caregivers of children and adolescent subjects will be trained at the Screening visit by study staff on how 
to assist the subject, if needed, in completing the WI-NRS. 
f POEM will be completed by all subjects either by self or by proxy completion (for children unable to read and/or 
understand the POEM questionnaire, the parent/guardian/caregiver will complete the questionnaire). 
g Local tolerability assessments should be recorded prior to study drug application for the Investigator assessment of 
skin irritation (Berger and Bowman skin irritation score). Note for investigator tolerability assessments: 
reactions at the site of product application, which may occur post-Baseline, should be differentiated from 
the preexisting inflammation associated with the subject’s atopic dermatitis. The subject will assess 
burning/stinging (0-3 score) 10-15 minutes post drug application. Note subject burning stinging assessment: at 
Day 29, subjects will provide a recall assessment of burning/stinging experienced post drug application on 
the previous day (Day 28). 
h Adolescents and adults will complete the C-SSRS (12 years of age and older).  Adults will complete the PHQ-8.  
Adolescents (ages 12 to 17, inclusive) will complete the PHQ-A (PHQ-9 modified). Parents/caregivers will 
complete CDI-2 (parent report) for children 6-11 years of age, inclusive. 
i The DLQI will be completed by subjects ≥17 years of age. The CDLQI will be completed for subjects 
6 to 16 years old, inclusive. The Dermatitis Family Impact Questionnaire (DFI) will be completed by 
parents/caregivers for all subjects 6 to ≤17 years of age. 
j Photography of AD lesion(s) selected by the Investigator will be performed at all investigational sites.  All efforts 
will be made to de-identify the subjects. Canfield equipment will be used to capture photographs. Subjects who are 
unwilling to participate in the medical photography will be allowed to opt out of this procedure, as documented on 
the Informed Consent Form. 
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k   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. 
l For all subjects entering this study under Amendment 2, a single PK trough draw will be collected at Day 29 only 
for subjects ≥12 years old. Ensure study medication was not applied in the area where PK will be drawn.  
m Subjects to apply assigned IP during clinic visits, except for the Day 29/ET visit. 
n It is expected that kits will be dispensed based on %BSA affected. See IP Handling Manual for details.   
o On Day 8 and 15, dispensing of IP is optional.  Site should review IP kit to ensure sufficient IP is available until 
the next visit and only dispense additional IP if needed. On Day 29, if the subject is unable to perform the Day 29 
clinic visit due to COVID-19 restrictions (isolation, quarantine, etc.) then additional IP may need to be dispensed 
so IP can continue to be applied at home until the subject is able to return to the clinic to complete the Day 29 
assessments (see IP Handling Manual for the process to dispense additional IP at or after Day 29). 
p  Every tube should be weighed and recorded when dispensed and returned. See IP Handling Manual for details. 
q  Compliance determination is described in the IP Handling Manual 
r All AEs should be collected starting after the first application of the investigational product through the end of the 
study. All SAEs should be collected starting after the signing of the informed consent through 30 days after the 
last day of the application of the investigational product or the end of the study (whichever is later). Any AEs 
(whether serious or non-serious) and clinically abnormal laboratory test values(s) will be evaluated by the PI and 
treated and/or followed up for up to 30 days after end of treatment or until symptoms or value(s) return to normal, 
or acceptable level, as judged by the PI (if the subject is continuing into the ARQ-151-313 OLE study, then AEs 
from this study (ARQ-151-312) will only be followed until exit from this study). 
s Subjects who enroll into the open label extension study (ARQ-151-313) must complete the ARQ-151-312 visit 
requirements at Week 4. 
3.3 Treatment 
Roflumilast cream 0.15% or vehicle cream will be administered QD for 28 days (+/- 3 days).  
• Roflumilast cream 0.15% 
• Vehicle cream 
3.4 Randomization, Replacement, and Unblinding Procedures 
Randomization will take place at the Baseline visit prior to first dosing. Subjects who meet all 
eligibility criteria will be randomized at a 2:1 ratio (drug:vehicle) to receive Roflumilast cream 
0.15% QD or matching vehicle QD.  The randomization will be stratified by vIGA-AD score at 
baseline (‘Mild’ vs. ‘Moderate’) and by study site according to a computer-generated 
randomization list.  Kits containing tubes of study medication will be assigned to each subject 
using an internet-based response system (IWRS).  A subject may receive more than one kit for the 
treatment period.  The kits and tubes are blinded and each kit is numbered with a unique kit 
number. 
The study is double-blinded, therefore neither the subjects nor the Investigator, sponsor and 
clinical personnel will be aware of which treatment an individual subject receives. 
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3.5 Changes to the Analysis from the Protocol 
Rationale for change 
Description of the change 
A categorical summary was excluded 
from the SAP as it was determined that it 
was not necessary. 
 
Original text:  
The amount of investigational product used by 
each subject based on tube weight will be 
summarized by treatment using descriptive 
statistics, and categorically. 
Changed to:  
The amount of investigational product used by 
each subject based on tube weight will be 
summarized by treatment using descriptive 
statistics. 
To separate COVID patient from Per 
Protocol analysis set. 
Original text: 
Per protocol (PP) population will include all 
subjects in the ITT population, who are at least 
80% compliant with study medication application, 
and show no major deviations from the study 
protocol that would affect the interpretation of 
efficacy. In addition, subjects who miss the Week 
4 vIGA-AD assessment specifically due to novel 
coronavirus disease-19 (COVID-19) disruptions 
will be excluded from per protocol population. 
 
Changed to: 
Per protocol population will include all subjects 
who are randomized, at least 80% compliant with 
study medication application, have a vIGA-AD 
assessment within the Week 4 visit window, and 
show no “major deviations” from the study 
protocol that would affect the interpretation of 
efficacy. 
Added mITT population to address 
COVID-19 impact. 
The mITT population includes all randomized 
subjects with the exception of subjects who missed 
the week 4 vIGA-AD assessment specifically due 
to COVID-19 disruption. This population will be 
used for sensitivity analysis for the primary 
endpoint.  
 
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4 POPULATIONS FOR ANALYSIS 
4.1 Intent-to-Treat (ITT) Population 
Intent-to-Treat population will include all subjects who are randomized, and all subjects will be 
analyzed according to the treatment group and stratum to which they were randomized. 
4.2 Modified Intent-to-Treat (mITT) Population 
The mITT population includes all randomized subjects with the exception of subjects who missed 
the week 4 vIGA-AD assessment specifically due to COVID-19 disruption. This population will 
be used for sensitivity analysis for the primary endpoint. All subjects will be analyzed according 
to the treatment group and stratum to which they were randomized. 
4.3 Per Protocol (PP) Population 
Per protocol population will include all subjects who are randomized, at least 80% compliant with 
study medication application, have a vIGA-AD assessment within the Week 4 visit window and 
show no “major deviations” from the study protocol that would affect the interpretation of efficacy. 
A complete list of major deviations from the study protocol will be created prior to unblinding and 
include a list of all subjects who will be excluded due to those major deviations. See section 7.2 
for more details.  
All subjects will be analyzed according to the actual treatment group they received and the stratum 
they belong to.  Actual and randomized treatment will only differ if the subject received the wrong 
treatment throughout their participation in the study. 
4.4 vIGA-AD Moderate ITT Population 
vIGA-AD Moderate ITT population will be a subset of the ITT population with vIGA-AD score 
(randomized score) ‘Moderate’ at randomization.  
All subjects will be analyzed according to the treatment group and the stratum to which they were 
randomized. 
4.5 vIGA-AD Moderate PP Population 
vIGA-AD Moderate PP population will be a subset of the PP population with vIGA-AD score 
(actual score) ‘Moderate’ at randomization.  
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All subjects will be analyzed according to the actual treatment group they received and the stratum 
they belong to.  Actual and randomized treatment will only differ if the subject received the wrong 
treatment throughout their participation in the study.  
4.6 WI-NRS Population 
WI-NRS population will be a subset of the ITT population among subjects ≥12 years old with 
average weekly baseline WI-NRS score  4.  
The subjects in WI-NRS population are those: 
1. Completed at least 4 of 7 evaluable daily WI-NRS questionnaires during the last 7 days of 
the Screening period; 
2. Have a mean baseline WI-NRS score ≥ 4.0, defined as the average of all non-missing scores 
reported during the last 7 days of the Screening period if at least 4 of 7 evaluable daily 
WINRS questionnaires available.  If 4 or more evaluable daily questionnaires are missing, 
then the data will be treated as missing.   
All subjects will be analyzed according to the treatment group and stratum to which they were 
randomized.  
4.7 Safety Population 
Safety population will include all subjects who are enrolled and received at least one confirmed 
dose of study medication.   
Subjects will be analyzed based on the treatment group received and the stratum they belong to. 
Actual and randomized treatment will only differ if the subject received the wrong treatment 
throughout their participation in the study. 
4.8 Pharmacokinetic (PK) Population 
Pharmacokinetic population will include all subjects receiving the active drug with quantifiable 
plasma concentrations of roflumilast. 
5 GENERAL CONSIDERATIONS 
Formats and layouts of tables, listings, and figures (TLF) will be provided in a separate document 
(output general layout is described in Appendices 
Appendix 1). 
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5.1 Sample Size 
There are approximately 650 subjects planned for this study. In order to have the desired power 
for the secondary endpoint of vIGA-AD Success in subjects with a vIGA-AD score of ‘Moderate’ 
at randomization, approximately 490 of the subjects to be accrued will have vIGA‑AD score of 
‘Moderate’ at randomization.  Randomization will be stratified by vIGA-AD score (‘Mild’ vs. 
‘Moderate’) and by study site. 
The sample size of 650 subjects provides approximately 95% power to detect an overall 15% 
difference (Odds Ratio = 2.1) between treatment groups on vIGA‑AD success at Week 4 at α=0.05 
using a 2-sided stratified Cochran-Mantel-Haenszel (CMH) test.  The results from a recent Phase 
2 study (ARQ‑151-212) of Roflumilast cream 0.15% compared to vehicle treatment were used to 
estimate the treatment difference.  Specifically, in the Phase 2 trial, approximately 37% of subjects 
demonstrated vIGA-AD Success at Week 4 in the ARQ-151 0.15% group compared to 22% in the 
vehicle group.  The sample size of 490 also provides approximately 90% power to detect an overall 
17% difference (Odds Ratio = 2.1) between treatment groups (28% of vIGA-AD Success at Week 
4 in vehicle treatment) on vIGA-AD Success at Week 4 among subjects with vIGA-AD score 
‘moderate’ at randomization.  The same testing method, the stratified CMH test, will be used as 
for the primary endpoint. 
To control for familywise type I error at level of 0.05, the secondary endpoint of vIGA-AD Success 
at Week 4 in subjects with vIGA-AD of ‘Moderate’ at randomization will only be tested if the 
primary endpoint demonstrates statistical significance.  In addition, the remaining secondary 
endpoints will be inferentially tested only if the primary and secondary endpoint (vIGA-AD 
Success at Week 4 for subjects with vIGA-AD score of ‘Moderate’ at randomization) comparisons 
are statistically significant using the hierarchical testing procedure by partitioning of alpha (see 
Section 6.5 for more details). 
5.2 Baseline 
Unless otherwise specified, baseline value will be defined as the last non-missing assessment prior 
to or concurrently with the first study treatment dosing (including unscheduled/retest assessments). 
If the last non-missing assessment is performed on the same date as the first study treatment 
administration and time is not available, it is assumed that the assessment took place prior to IP 
application, per study site training, and the assessment will be considered as baseline, except for 
adverse events (AEs) and medications starting on the first study treatment dose administration date 
which will be considered postbaseline. 
Average weekly baseline WI-NRS is defined as the average of all non-missing scores reported 
during the last 7 days prior to treatment if at least 4 of 7 evaluable daily WI-NRS questionnaires 
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The average weekly WI-NRS results will be presented for analysis visits i.e., Baseline, 
Week 1, Week 2, Week 3, and Week 4 (see Table 1Table 4 for the analysis window).  
• WI-NRS 4-point reduction = achievement of a 4- point reduction in average weekly WI-
NRS pruritus score compared to average weekly WI-NRS baseline, calculated only for the 
subjects ≥12 years old with average weekly WI-NRS score of ≥ 4 at baseline.  
• EASI total score = 0.1 (Eh + Ih + EXh + Lh) Ah + 0.2 (Eu + Iu + EXu + Lu) Au  
+ 0.3 (Et + It + EXt + Lt) At + 0.4 (El + Il + EXl + Ll) Al  
for subjects ‘≥ 8 years old  
and  
0.2 (Eh + Ih + EXh + Lh) Ah + 0.2 (Eu + Iu + EXu + Lu) Au  
+ 0.3 (Et + It + EXt + Lt) At + 0.3 (El + Il + EXl + Ll) Al  
for subjects < 8 years old 
where E, I, Ex, L, and A denote erythema, induration, excoriation, lichenification, and area, 
respectively, and h, u, t, and l denote head, upper extremities, trunk, and lower extremities, 
respectively.  If a subject turns 8 years old during the study, the formula used at Screening 
will continue to be used through the study duration of the subject’s participation in the 
study.  Scalp, palms, and soles may be treated with investigational product in this study but 
will be excluded from the EASI assessment. 
• EASI-50, EASI-75, EASI-90, EASI-100 = Achievement of at least a 50%, 75%, 90%, or 
100% reduction from baseline in the Eczema Area and Severity Index at Week 4  
• DLQI Score = sum of the 10 questions (individual questions scored as Very much=3, A 
lot=2, A little=1, Not at all=0, Not relevant=0, Question 7: Yes=3, if No, then follow the 
same score as A lot, A little, Not at all), ranging from 0 to 30. If 1 item is missing, it is 
scored as 0 for that item. If 2 or more items are missing, the score should not be calculated.  
• CDLQI Score = sum of the 10 questions (individual questions scored as Very much=3, 
Quite a lot=2, Only a little=1, Not at all=0; Question 7: if the last week was school time, 
the question was scored as Very much=3, Quite a lot=2, Only a little=1, Not at all=0, with 
Prevented school recoded to 3, and if the last week was holiday time, the standard responses 
apply), ranging from 0 to 30. If 1 item is missing, that item is scored as 0. If 2 or more 
items are missing, the score should not be calculated.  
• DFI Score = sum of the 10 questions (individual questions scored as Very much=3, A 
lot=2, A little=1; Not at all=0), ranging from 0 to 30. If 1 item is missing, it is scored as 0 
for that item. If 2 or more items are missing, the score should not be calculated.  
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• PHQ-8 = sum of the 8 questions (individual questions scored as Not at all=0, Several 
days=1, More than half the days=2, and Nearly every day=3), ranging from 0 to 24. If more 
than 1 item is missing the score should not be calculated. If 1 item is missing the score is 
calculated as (sum of answered items*8)/number of answered items (=7).  
• Modified PHQ-A = sum of the 8 questions (individual questions scored as Not at all=0, 
Several days=1, More than half the days=2, and Nearly every day=3), ranging from 0 to 
24. If more than 1 item is missing the score should not be calculated. If 1 item is missing, 
the score is calculated as (sum of answered items*8)/number of answered items (=7).  
• CDI-2 total score is a sum of the 17 questions based on the scoring grid (individual 
questions scored as much or most of the time=0, often=1, some of the time=2, Not at all=3 
for questions Q2, Q7, Q13, Q14, and Q16; individual questions scored as much or most of 
the time=3, often=2, some of the time=1, Not at all=0 for all other questions), ranging from 
0 to 51. All CDI-2 raw scores can be prorated using the following formula, rounding to the 
nearest whole number: 
o Prorated score = (Obtained raw score for scale) * (Total # of items on 
scale/subscale) / Total # items on scale/subscale with responses 
o CDI-2 emotional problem scale is a sum of 9 questions (Q1, Q3-6, Q8, Q10-12). If 
more than 1 item is missing the score should not be calculated. If 1 item is missing 
the score is calculated as (sum of answered items*9)/number of answered items 
(=8).  
o CDI-2 functional problem scale is a sum of 8 questions (Q2, Q7, Q9, Q13-17).  If 
more than 1 item is missing the score should not be calculated. If 1 item is missing 
the score is calculated as (sum of answered items*8)/number of answered items 
(=7). 
o CDI-2 total score is a sum of 17 questions. If more than 2 items are missing the 
score should not be calculated. If 1 item is missing the score is calculated as (sum 
of answered items*17)/number of answered items (=16). If 2 items are missing the 
score is calculated as (sum of answered items*17)/number of answered items (=15). 
• POEM = sum of the 7 questions (individual questions scored as No days = 0, 1 to 2 days = 
1, 3 to 4 days = 2, 5 to 6 days = 3, Every day = 4), ranging from 0 to 28. If 1 question is 
left unanswered this is scored 0 and the scores are summarized and expressed as usual out 
of a maximum of 28. If 2 or more questions are left unanswered the questionnaire is not 
scored.  
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• SCORAD = [Overall BSA affected by AD / 5] + [Intensity score*7/2] + subjective 
symptoms score (pruritus + sleep loss); SCORAD score will be set to missing if 
information for any of the three measures is missing.  
5.6 Descriptive Statistics 
All continuous variables will be summarized by presenting the number of subjects, mean, standard 
deviation (SD), median, Q1, Q3, minimum, and maximum. For PK endpoints, geometric statistics 
including geometric mean and coefficient of variation (CV) will also be provided. 
Categorical variables will be presented as frequencies and percentages.  
Summary tables will be presented by visit, when applicable. 
Change from baseline will be calculated as:  
Assessment value at postbaseline visit X – baseline value. 
Percent change from baseline will be calculated as: 
(Assessment value at postbaseline visit X – baseline value) × 100% / (baseline value)  
Percent change from baseline will be missing in situation where baseline value equals to 0. 
5.7 Statistical Tests 
Unless otherwise specified, all statistical tests will be two-sided and will be performed with a 
significant level of 0.05. Confidence intervals (CIs) will be two-sided with 95% coverage. 
5.8 Handling of Retests, Unscheduled Visits, and Early Termination Data 
Retests measurements, Unscheduled measurements, and ET visit assessments will be included in 
analysis and be summarized via analysis visit windowing according to the windowing conventions 
in section 5.4. 
All data from retest, unscheduled measurements and ET visit assessments will be listed. 
5.9 Software Version 
All analyses will be performed using SAS® software Version 9.4 or higher. 
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6 STATISTICAL CONSIDERATIONS 
6.1 Adjustments for Covariates 
Covariates for this study include pooled study site and baseline vIGA-AD (vIGA-AD=2 - Mild vs. 
vIGA-AD=3 - Moderate at randomization). Subgroup analyses will be generated for the baseline 
covariates. 
6.2 Handling of Dropouts or Missing data 
See Appendix 2 for handling of completely or partially missing dates for prior and concomitant 
medications and AEs. 
Unless otherwise specified, missing safety data will not be imputed. 
6.2.1 Multiple Imputation 
For the primary efficacy endpoint of vIGA-AD success at Week 4 and the secondary endpoint of 
vIGA-AD success at Week 4 among subjects with a ‘Moderate’ randomized vIGA-AD score, the 
primary analysis will impute missing values using a Predictive Mean Matching (PMM) sequential-
regression multiple imputation model for the ITT population.  This is a three-step process. 
1. The first step is to understand the pattern of missingness. In order to perform the multiple 
imputation, a monotone missing pattern has to be achieved. For example, if there exist 
values for baseline and Week 4 visits, but missing values for the Week 1 or 2 visits, the 
Markov-Chain Monte-Carlo (MCMC) method will be used to impute the small amount of 
missing data that may be missing at the intermediate visits that is required to make the 
missing data pattern monotone before applying the multiple imputation algorithm. This 
method uses a non-informative Jeffreys prior to derive the posterior mode from the 
expectation-maximization (EM) algorithm as the starting values for the MCMC method. 
The MCMC method will use the seed 6457149. The vIGA-AD score will be treated as a 
continuous variable for this step and the model will include the vIGA-AD scores at 
baseline, Week 1, Week 2, and Week 4. To avoid values that could not be observed in 
practice, imputed values will be rounded to the nearest integer (Round=1 option in PROC 
MI) in the range of 0 to 4. 
To determine the number of multiply-imputed datasets to be created at this step, the 
proportion of datapoints with non-monotone pattern across all visits and subjects will first 
be derived as follows: 
 
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𝑛𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝑛𝑜𝑛 𝑚𝑜𝑛𝑜𝑡𝑜𝑛𝑒 𝑣𝑖𝑠𝑖𝑡𝑠 𝑎𝑐𝑐𝑟𝑜𝑠𝑠 𝑎𝑙𝑙 𝑣𝑖𝑠𝑖𝑡𝑠 𝑎𝑛𝑑 𝑠𝑢𝑏𝑗𝑒𝑐𝑡𝑠
𝑡𝑜𝑡𝑎𝑙 𝑛𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝑒𝑥𝑝𝑒𝑐𝑡𝑒𝑑 𝑣𝑖𝑠𝑖𝑡𝑠 𝑎𝑐𝑟𝑜𝑠𝑠 𝑎𝑙𝑙 𝑠𝑢𝑏𝑗𝑒𝑐𝑡𝑠 
∗100 
 
Then, the following table will be used: 
 
Non-monotone 
Missing Data 
Number of 
Imputed Datasets 
≤ 2% 
1 
> 2% to ≤ 5% 
3 
> 5% 
10 
 
2. Once the monotone pattern is achieved, the next step is to implement the imputation 
algorithm. For this, the PMM regression method will be used. This method is particularly 
helpful if the normality assumption is violated. For subjects with complete data up to a 
particular visit, a PMM regression model will be fit that includes the outcome at that visit 
as the dependent variable and as independent variables, the treatment group, pooled study 
site, and vIGA-AD score outcomes at previous visits, using a seed of 482371. For other 
scales/questionnaires, the actual baseline vIGA score will also be included as an 
independent variable. This process will be repeated 25 times, resulting in a total of 25 to 
250 complete analysis datasets, depending on the number of imputed monotone datasets 
that are required. The seed may be changed after unblinding in case of any issues with the 
imputation process, and it will be documented in the CSR if any change is required. 
 
3. For each completed dataset, compute the necessary derived variables. The dichotomous 
success rate (clear or almost clear with at least a 2-point change from baseline) will be 
derived. For each of the 25 to 250 complete analysis datasets, the results will be analyzed 
using a CMH analysis, adjusted for the pooled study site and randomized vIGA-AD score 
for the primary efficacy endpoint and adjusted for the pooled site for the secondary efficacy 
endpoint. Results will be combined into one multiple imputation inference as follows: 
a. Common proportion of success, common Mantel-Haenszel (MH) proportion 
difference (and associated 95% CI), and common MH odds ratio (and associated 
common 95% CI) will be combined using PROC MIANALYZE based on Rubin’s 
rule.  Common MH odds ratios and associated common 95% CI will first be 
normalized using a log-transformation before being combined using PROC 
MIANALYZE. The resulting combined common MH odds ratio and associated 
combined common 95% CI will be back-transformed to the arithmetic scale before 
being presented in a table. 
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b. For the combined common proportion of success, the associated combined 
common 95% CI will be calculated as per Lott and Reiter multiple imputation 
Wilson interval method1. 
c. Two p-values will be produced for each analysis: 
i. The primary p-value will be obtained from a multiple imputation CMH test, 
where CMH general association statistics and their standard errors obtained 
from the analysis of each multiply-imputed dataset will be transformed as 
per Wilson-Hilferty2 before being combined using PROC MIANALYZE 
based on Rubin’s rule.  Because the Wilson-Hilferty transformation is a 
monotone transformation, the p-value for the CMH test is the one-sided p-
value from the t distribution. This p-value will be the primary p-value used 
to evaluate the result according to the multiple testing strategy described in 
Section 6.5.   
i. 
Should the common MH odds ratio from the analysis of at least one of the 
multiply-imputed datasets be not estimable, combined common MH odds 
ratio and associated combined common 95% CI and p-value will not be 
presented. Under such circumstance, conclusions will be based on the p-
value obtained from a multiple imputation test of the proportion difference, 
where the common proportion difference using MH weights and associated 
common standard errors based on the Sato variance estimator obtained from 
the analysis of each multiply-imputed dataset will be combined using PROC 
MIANALYZE based on Rubin’s rule. 
Similar multiple imputation method will be used for the average weekly WI-NRS and EASI total 
score.  
For the average weekly WI-NRS, it’s the missing average weekly WI-NRS data (i.e., those that 
cannot be computed because only 3 or less non-missing assessments are available during a given 
week) at Weeks 1, 2, 3, and 4 that will be multiply imputed, not the missing daily WI-NRS data. 
Since the missing average weekly WI-NRS values have a precision of 1 decimal place, the MCMC 
imputation for the non-monotone missing data will be restricted to values between 0 and 10, 
rounded to the 1st decimal (i.e., 0.1). Imputation of missing data for WI-NRS will be based on the 
ITT population, i.e., all randomized subjects will be included in the imputation process. 
For the EASI total score, it’s the missing EASI total score data at Weeks 1, 2, and 4 that will be 
imputed, not the missing EASI question score data.  Since the missing EASI total scores have a 
precision of 1 decimal place, the MCMC imputation for the non-monotone missing data will be 
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restricted to values between 0 and 72, rounded to the 1st decimal (i.e., 0.1).  Imputation of 
missing data for EASI total score will be based on the ITT population. 
6.2.2 Non-responder Imputation Analysis 
If assessment of vIGA-AD after baseline is missing, the subject will be considered as non-
responder (for example, no vIGA-AD success in the analysis of vIGA-AD success). For the vIGA-
AD success endpoints, subjects with missing baseline vIGA-AD score will be considered as non-
responder for these endpoints only. That is, for the secondary efficacy endpoints of vIGA-AD 
score of clear (0) or almost clear (1) and vIGA-AD score of clear (0), the post-baseline assessment 
at a specific visit will be established based on the vIGA-AD score at that visit only, regardless of 
the availability of the baseline vIGA-AD score.  
Similar imputation method will be used for 4‑point reduction on the average weekly WI-NRS and 
EASI-75. For EASI-75, subjects with missing baseline EASI total score will be considered as non-
responder.  For 4‑point reduction on the average weekly WI-NRS, subjects with missing baseline 
average weekly WI-NRS will not be imputed since the analysis of WI-NRS endpoints will be 
performed based on the WI-NRS population from which subjects with a missing baseline average 
weekly WI-NRS are excluded. 
6.2.3  Tipping Point Analysis 
As a sensitivity analysis to the multiple imputation analysis as described in Section 6.2.1 for the 
vIGA-AD success primary endpoint and secondary endpoint of vIGA-AD success among 
subjects with Moderate disease at baseline, a tipping point analysis will be performed in order to 
determine the inflection point at which the inference under the missing not at random (MNAR) 
assumption changes substantially.  
The sensitivity analysis for the primary endpoint will be performed by using a specified sequence 
of shift parameters. The range of shift parameters to be included in this analysis are 0 to 2 by 0.2 
for active and -2 to 0 by 0.2 for Vehicle. The values at which the results of the primary analysis 
are shifted from significant (i.e., α ≤ 0.05) to non-significant (i.e., α > 0.05) will be determined. 
Steps 1 and 3 of the analysis will be the same as for the multiple imputation analysis as described 
in Section 6.2.1. However, Step 2 of the analysis is where the shift parameters will be applied.  
6.3 Interim Analysis  
No interim analysis is planned for this study. 
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6.4 Multicenter Studies 
The study will be conducted at approximately 60 study sites in the US, Canada, and Poland. 
During the conduct of the study, additional countries and/or sites may be added if necessary.  
Sites with less than 16 subjects in the ITT population will be pooled within a country:  
a. Sites with less than 16 subjects will be ordered from lowest to highest in terms of number 
of ITT subjects. In case of ties, the ordering for tied sites will be determined according to 
the site identification number (from smallest to largest).  
b. Sites will be combined beginning at the smallest until the resulting pooled site contains at 
least 16 ITT subjects with at least 1 subject in each treatment group. The sites pooled in 
this way will be considered as a single site in the statistical analyses.  
c. The process described above will resume for the remaining sites not meeting the criterion 
of at least 16 ITT subjects with at least 1 subject in each treatment group. If the final set of 
pooled sites does not meet the criterion of at least 16 ITT subjects with at least 1 subject in 
each treatment group, the final set will be pooled with the preceding pooled site.  
d. If there is only one site with less than 16 ITT subjects with at least 1 subject in each 
treatment group, then this site will be combined with the site with the second lowest number 
of subjects. As above, in the case of ties, the ordering for tied sites will be determined 
according to the site identification number (from smallest to largest).  
As a sensitivity analysis of different pooling strategy, sites that have randomized less than 50% of 
the number of randomized subjects at the site with the largest number of randomized subjects, 
those sites will be pooled within each country. The sensitivity analysis of pooling strategy will be 
applied for the primary endpoint only. 
6.5 Multiple Comparisons/Multiplicity 
To control for familywise type I error at level of 0.05, the secondary endpoint of vIGA-AD Success 
at Week 4 for subjects with vIGA-AD score of ‘Moderate’ at randomization will only be tested if 
the primary endpoint demonstrates statistical significance.  In addition, the remaining secondary 
endpoints will be inferentially tested only if the primary and the secondary endpoint (vIGA-AD 
Success at Week 4 for subjects with vIGA-AD score of ‘Moderate’ at randomization) comparisons 
are statistically significant using hierarchical testing procedure by partitioning of alpha. 
Upon successful demonstration of statistical significance for the primary and above secondary 
endpoint, the remaining endpoints will be grouped into secondary endpoint family 1, comprised 
of the 4‑point reduction on the WI-NRS at Week 4, Week 2 and Week 1, and secondary endpoint 
family 2, comprised of the EASI-75 at Week 4, vIGA-AD of ‘clear’ or ‘almost clear’ at Week 4, 
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vIGA-AD of success at Week 2 and Week 1, vIGA-AD of ‘clear’ or ‘almost clear’ at Week 2 and 
Week 1.  An alpha level of 0.03 will be used to test the endpoints in the secondary endpoint family 
1 sequentially.  An alpha level of 0.02 will be used to test the endpoints in secondary endpoint 
family 2 sequentially.  
In addition to the partitioning of the overall 0.05 alpha into two families, the Fallback Method will 
be applied.  The fallback method is a modification of the fixed-sequence method, providing 
opportunity to test an endpoint later in the sequence even if an endpoint tested early in the sequence 
has failed to show statistical significance. The order of the endpoints remains important. The 
appeal of the fallback method is that if an endpoint later in the sequence has a robust treatment 
effect while the preceding endpoint is unsuccessful, there is a modest amount of alpha retained as 
a fallback to allow interpretation of that endpoint without inflating the Type I error rate. Applying 
the fallback method begins by dividing the total alpha (not necessarily equally) among the 
endpoints and maintains a fixed sequence for the testing. In this study, the Fallback Method will 
be applied to the fixed sequence of testing Family 1, and then Family 2. 
As the testing sequence progresses, a successful test preserves its assigned alpha as “saved” 
(“unused” or “accumulated”) alpha that is passed along to the next test in the sequence, as is the 
case for the sequential method. This accumulated alpha is added to the prospectively assigned 
alpha (if any) of that next endpoint and the summed alpha is used for testing that endpoint. Thus, 
as sequential tests are successful, the alpha accumulates for the endpoints later in the sequence; 
these endpoints are then tested with progressively larger alphas. 
In this study, the Fallback Method will be applied following this sequence: 
Family 1:  Testing will proceed at the 0.03 level sequentially within Family 1.  Should all 3 
endpoints in Family 1 be statistically significant at the 0.03 level, then the full 0.03 alpha will be 
carried to Family 2.  Family 2 would then be tested at the full (=0.02+0.03=0.05).  
Should, anywhere during the sequential testing of Family 1, there is a p-value >0.03, the testing 
within Family 1 will stop, and no additional alpha can be carried over to Family 2.   
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• Actual baseline vIGA-AD score (mild (2) vs. moderate (3)),  
• Baseline % BSA (<10% vs. ≥ 10%),  
• %BSA categories based on tertiles,  
• Baseline EASI total score (≤7 vs >7),  
• Baseline EASI total score based on tertiles 
• Fitzpatrick skin type at Screening (Type I, II and III vs. Type IV, V, and VI),  
• 
Prior inadequate response, intolerance, or contraindication to Topical Corticosteroids 
(yes vs. no), 
 
• 
Facial Involvement (yes vs. no) 
For subgroup based on tertiles, tertiles will be derived using pooled data from both treatment group 
based on the ITT population. 
Details on these analyses are described in Section 12.4. 
7 STUDY SUBJECTS 
7.1 Disposition of Subjects 
All subjects who provide informed consent will be accounted for in this study. The number of 
subjects who were screened and who failed screening (screen failures) will be presented. The 
reasons for screen failure will be presented for all screened subjects who failed screening.  
The number of subjects randomized will be presented by treatment group. The number and 
percentage of the subjects included in each analysis population will be provided by treatment 
group. The number and percentage of the subjects who completed the study, who discontinued the 
study, the reasons for study discontinuation, and early termination due to COVID-19 disruption 
will be presented by treatment group. The percentages will be calculated using the number of the 
randomized subjects as denominator.  
Number of days in the study will be summarized with descriptive statistics by treatment group and 
overall. For each subject, the number of days in the study will be calculated as following: 
 
Number of days in study = Date of completion/discontinuation – 1st dose date +1 
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A listing of subject’s disposition and randomization will be provided. Information on first 
screening for subjects who were rescreened, including the rescreened subject identifier and the 
reason for first screening failure, will be presented under the first screening subject identifier. The 
reason for screening failure will be listed as well.  
A table of randomized strata vs. actual strata will be provided if there is any mis-randomization 
discrepancy.  
7.2 Protocol Deviations 
A data review will be conducted before database lock by the Medical Monitor and the Sponsor to 
classify protocol deviations as minor or major. 
The number and percentage of subjects with at least one important protocol deviation (including 
important protocol deviations associated with COVID-19) will be summarized by deviation 
category and treatment group using the safety analysis set.  
A listing of all protocol deviations will also be provided. The protocol deviations associated with 
COVID-19 and major PDs will be flagged. 
8 DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
Demographics and baseline characteristics will be summarized with descriptive statistics using the 
ITT and safety population. The list of demographics and baseline characteristics to be summarized 
will include:  
• Age (years)  
• Age Group: 6-11, 12-17, 6-17 and ≥18, 18-64 and ≥65  
• Child bearing potential 
• Sex at birth 
• Ethnicity 
• Race* 
• Baseline Height (cm) 
• Baseline Weight (kg)  
• Baseline Body Mass Index (BMI) (kg/m2): Adult, Child/Adolescent  
• Fitzpatrick Skin Type 
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• Prior failure of Topical Corticosteroids, Topical Calcineurin Inhibitors, Eucrisa  
• Atopic Dermatitis involvement on the face, on the eyelids 
• Baseline vIGA-AD 
• Average weekly baseline WI-NRS  
• Daily baseline WI-NRS  
• Baseline BSA (%)  
• Baseline BSA (%) Group - <10% and ≥10%, tertile groups  
• Baseline EASI total score  
• Baseline EASI score group - ≤7 and >7, tertile groups 
• Baseline SCORAD 
• Baseline DLQI/CDLQI 
• Baseline DFI 
• Baseline POEM 
• Baseline PHQ-8 
• Baseline PHQ-A 
• Baseline CDI-2 
*Subjects who reported more than one race will be summarized as ‘Multiple’ races in the table. 
All races selected will be displayed in the listing. 
Adult: BMI (kg/m2) = (weight in kg)/ [(height in cm/100)2]. Baseline height will be used to derive 
BMI for each visit since height is not collected at all visits.  
Child and Adolescent (6 to 17 years): After BMI is calculated using the same formula above for 
children and teens, it is expressed as a percentile obtained from either a graph or a percentile 
calculator. Percentiles will be calculated using data files and instructions provided by the CDC 
(https://www.cdc.gov/growthcharts/percentile data files.htm). Baseline height will be used to 
derive BMI for each visit since height is not collected at all visits. 
A listing of all demographics, analysis population flag, reason not included in the efficacy analysis 
will be provided. 
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9 SURGICAL AND MEDICAL HISTORY 
Surgical and medical history will be coded according to the Medical Dictionary for Regulatory 
Activities (MedDRA), Version 23.0 or higher. 
Surgical and medical history will be summarized by system organ class (SOC) and preferred term 
(PT) using the safety analysis set. A subject who experienced the same surgical and medical history 
event multiple times will be counted only once for the corresponding PT. Similarly, if a subject 
experienced multiple surgical and medical history events within the same SOC, the subject will be 
counted only once for that SOC. Surgical and medical history events will be sorted alphabetically 
by SOC and within each SOC the PT will be presented by descending frequency in the safety 
analysis set. 
10 PRIOR AND CONCOMITANT MEDICATIONS 
Medications will be coded according to the World Health Organization Drug Dictionary 
(WHO-DD) B3 September 2020. 
Prior medications are defined as any medication started and discontinued prior to the first study 
treatment dosing. Concomitant medications are defined as any medication taken after the first 
study treatment dosing, including those who started prior to the first study treatment date and 
continued past that date. See Appendix 2 for handling of completely or partially missing dates for 
prior and concomitant medications.  
Incidence of prior and concomitant medications will be tabulated by ATC level 3 and PT using the 
safety analysis set. A subject with the same medication taken multiple times will be counted only 
once for the corresponding PT. Similarly, if a subject has taken more than one medication within 
the same ATC level, then the subject will be counted only once for that ATC. Prior and 
concomitant medications will be sorted alphabetically by ATC level and within each ATC level, 
the PT will be presented by descending order.   
11 STUDY TREATMENT EXPOSURE AND TREATMENT 
COMPLIANCE 
A summary of exposure related to Roflumilast cream and the vehicle will be presented using the 
safety population by treatment group. It will include descriptive statistics on the number of days 
on IP, as well as the number of investigational product applications based on diary, for each 
treatment group. The number of days on IP, will be calculated as follows: 
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STATISTICAL ANALYSIS PLAN, Version 1.0 
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[(last treatment date- first treatment date) + 1]. 
For each subject, investigational product application compliance (%) will be calculated as follows: 
Number of investigational product applications
Number of expected investigational product applications × 100 
Number of investigational product applications will be calculated as number of expected 
investigational product applications minus number of doses missed. Number of doses missed and 
the date that the dose was missed were collected in eCRF. 
Number of expected investigational product applications will be calculated as calculated as last 
treatment/interruption date – first treatment date + 1. If latest treatment date ≥ latest interruption 
date, then the latest treatment date will be used; otherwise, latest interruption date will be used in 
deriving the expected number of IP applications.  
Descriptive statistics for the compliance as well as the number of missed applications, subjects 
with < 80%, [80% - 100%], and >100% compliance will be presented by treatment. Furthermore, 
the incidence of subjects who missed more than 3 consecutive doses and compliant subjects will 
be presented by treatment.   
A subject will be considered compliant with the dosing regimen if the subject meets both of the 
following requirements: 
• applies at least 80% of the expected applications during the study drug application period 
• does not miss more than 3 consecutive doses 
Total weight of study medication applied (determined by weighing the study medication before 
and after use) will be summarized by treatment using descriptive statistics. Weight of study 
medication used will be documented in source documents and in eCRF. Total weight of IP used is 
determined by subtracting minimum of (returned, remained) tube weight from the maximum of 
(dispensed, prepared) tube weight for each tube that was dispensed and summing the weights. 
Calculate Actual IP Used: maximum of (dispensed, prepared) tube weight minus minimum of 
(returned, remained) tube weight = ___ grams  
 If a tube is not returned at the end of the study or a tube weight is missing, actual IP used for the 
tube and total weight of IP applied during study will be missing. 
Number of days on IP and compliance, including compliance collected at each clinic visit, will be 
displayed in a listing of study treatment administration by subject, for each treatment. A listing of 
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drug accountability including the kit number, tube number, dispensed and returned weight will 
also be provided. 
12 EFFICACY ANALYSIS 
12.1 Primary Efficacy Endpoint Analysis 
12.1.1 Primary Efficacy Endpoint and Estimand  
The vIGA-AD is a static evaluation of qualitative overall AD severity. This global assessment 
scale is an ordinal scale with five severity grades (reported only in integers of 0 to 4). Each grade 
is defined by a distinct and clinically relevant morphologic description that minimizes inter-
observer variability. vIGA-AD is evaluated for the entire body except the scalp, palms, and soles.  
The primary efficacy endpoint is vIGA-AD success, defined as an vIGA-AD score of ‘clear’ (0) 
or ‘almost clear’ (1) plus at least a 2-grade improvement from Baseline at Week 4. 
The primary estimand is described by the following attributes: 
Population: Patients with Atopic Dermatitis  
 
Endpoint: vIGA-AD success at Week 4 
Intercurrent events: In the course of the 4-week randomized treatment period, subjects may be 
exposed to possible known or unknown intercurrent events that could possibly impact the estimates 
of the estimand, such as treatment discontinuation due to a specific adverse effect or perhaps a 
lack of effect. The “Treatment Policy Strategy” will be adopted for handling all known or unknown 
intercurrent events in this study. 
Population-level summary: ratio of the odds of achieving vIGA-AD success after 4 weeks of 
using roflumilast cream 0.15%, relative to the odds of success after 4 weeks using a matching 
vehicle cream in the ITT population.  
The supportive population-level summary: the proportion difference between Roflumilast cream 
0.15% and vehicle groups will be provided for the patients who achieve vIGA-AD success at week 
4 in the ITT population. 
12.1.2 Hypothesis Testing 
Primary hypothesis testing on the odds ratio: The null hypothesis is that the vIGA-AD success 
does not differ between roflumilast cream 0.15% and matching vehicle cream. The alternative 
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hypothesis is that the vIGA-AD success does differ between roflumilast cream 0.15% and 
matching vehicle cream. 
 
Null Hypothesis (H0): PR QV / PV QR = 1.0,  
Alternative Hypothesis (HA): PR QV / PV QR  ≠ 1.0, where 
 
PR = the proportion of vIGA-AD success in roflumilast cream 0.15% 
PV = the proportion of vIGA-AD success in matching vehicle cream  
QR = 1 - PR 
QV = 1 – PV. 
12.1.3 Primary Endpoint Analysis 
For the primary analysis, missing vIGA-AD scores will be imputed using multiple imputation as 
described in Section 6.2.1. These imputations will result in a minimum of 25 to a maximum of 250 
complete analysis datasets, depending on the number of imputed monotone datasets that are 
required. 
Percentages of subjects having a vIGA-AD Success (refer to Section 12.1.1) will be presented by 
visit and treatment group based on multiply imputed data in the ITT population along with a 95% 
Wilson CI. The common MH odds ratio and common MH proportion difference, adjusted for the 
randomization factors (i.e., randomized vIGA-AD score and pooled study site) will also be 
provided along with their common associated 95% CIs. Additionally, count and percentage of 
subjects having a vIGA-AD success, count and percentage of subjects in each category of the 
vIGA-AD scale, and descriptive statistics for the vIGA-AD scores, change in vIGA-AD score from 
baseline and percent change in vIGA-AD score from baseline will be presented by visit and 
treatment group based on observed data in the ITT population. 
The primary endpoint (vIGA-AD Success at Week 4) will then be analyzed using multiple 
imputation CMH test stratified by the randomization factors.  To do so, a CMH analysis will be 
performed separately for each of the complete multiply imputed analysis data sets, and results will 
be combined into one multiple imputation inference using the methodology described in Section 
6.2.1. Statistical significance will be concluded at the 5% significance level (2-sided).  Should the 
odds ratio be not estimable for at least one multiply imputed dataset, the conclusion of the study 
will be based on the p-value obtained from a MH test, stratified by the randomization factors, for 
the common MH proportion difference at Week 4. 
The following sensitivity analyses to the primary analysis of the primary endpoint will be 
performed: 
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• Multiply-imputed data (refer to Section 6.2.1) on mITT population (refer to Section 4.2) 
and  
• Tipping Point analysis (refer to Section 6.2.3) on ITT population. 
• Non-responder imputation (refer to Section 6.2.2) on ITT population. 
• Observed data on ITT population (refer to Section 4.1). 
• Observed data on PP population (refer to Section 4.3). 
For the last three sensitivity analyses, count of subjects having vIGA-AD success will also be 
presented by visit and treatment group in addition to the percentage of subjects having vIGA-AD 
success. 
To assess the impact of the pooling of the study sites on the primary analysis of the primary 
endpoint, the following analyses will be performed: 
• The primary analysis of the primary efficacy endpoint will be repeated but with a different 
site pooling strategy (refer to Section 6.4). 
• To assess the impact of site on the primary analysis endpoint, the proportion of subjects 
achieving vIGA-AD success and 95% CI within each site will be tabulated.  No p-values 
will be provided. Forest plots of the proportions (and associated 95% CI) for each site and 
treatment will also be provided. 
 
• An additional analysis to examine the impact of study site will examine the changes in p-
values that occur after removal of subjects from a site.  To do so, the primary analysis of 
the primary efficacy endpoint will be repeated but removing a different pooled study site 
for each iteration. Forest plots of the odds ratio (and associated 95% CI) for each pooled 
site removed will also be provided. 
12.2 Secondary Endpoints Analysis 
Secondary efficacy endpoints are based on the vIGA-AD scale, WI-NRS scale or EASI 
questionnaire. The list of secondary efficacy endpoints can be found in Section 2 and their 
derivation in Section 5.5. 
• For more details about the vIGA-AD scale refers to Section 12.1.1.  
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• The WI-NRS scale is a single item scale assessing the subject-reported worst itch severity 
during the previous 24-hour period.  The scale is from 0 to 10 (‘no itch’ to ‘worst itch 
imaginable’).   
• For the EASI questionnaire, four anatomic sites (head, upper extremities, trunk, and lower 
extremities) are assessed for erythema, induration/infiltration (papules), excoriation, and 
lichenification as seen on the day of the examination.  The severity of each sign is assessed 
using a 4-point scale (half steps are allowed e.g., 0.5): 0 (none), 1 (mild), 2 (moderate), and 
3 (severe).  The area affected by AD within a given anatomic site is estimated as a 
percentage of the total area of that anatomic site and assigned a numerical value according 
to the degree of AD involvement as follows: 0 (no involvement), 1 (1-9%), 2 (10-29%), 3 
(30-49%), 4 (50-69%), 5 (70-89%), and 6 (90-100%).  
For each secondary efficacy endpoint, missing data will be imputed and data will be summarized 
as for the primary efficacy endpoint (refer to Section 12.1.3). 
Upon successful demonstration of statistical significance for the primary efficacy endpoint, the 
secondary efficacy endpoint of vIGA-AD success among subjects with vIGA-AD score of 
‘Moderate’ at randomization will be analyzed as described for the primary efficacy endpoint (refer 
to Section 12.1.3) but based on the vIGA-AD Moderate ITT population (refer to Section 4.4) and 
stratifying by pooled study site only. That is, as per the vIGA-AD Moderate ITT population 
definition all subjects included in this analysis will have a randomized vIGA-AD score of 
Moderate (3) and so, the CMH test cannot be stratified by randomized vIGA-AD score.  
Upon successful demonstration of statistical significance for the primary and above secondary 
efficacy endpoints, the remaining secondary efficacy endpoints will be grouped into secondary 
endpoint family 1, comprised of the 4‑point reduction on the average weekly WI-NRS at Week 4, 
Week 2 and Week 1, and secondary endpoint family 2, comprised of the EASI-75 at Week 4, 
vIGA-AD of ‘clear’ or ‘almost clear’ at Week 4, vIGA-AD of success at week 2 and week 1, 
vIGA-AD of ‘clear’ or ‘almost clear’ at Week 2 and Week 1.  The analysis of secondary endpoint 
family 1 will be performed as described for the primary efficacy endpoint (refer to Section 12.1.3) 
but based on the WI-NRS population (refer to Section 4.6) and an alpha level of 0.03 will be used 
to test these endpoints sequentially as described in Section 6.5.  Similarly, the analysis of secondary 
endpoint family 2 will be performed as described for the primary efficacy endpoint (refer to 
Section 6.2.1) based on the ITT population (refer to Section 4.1) but an alpha level of 0.02 will be 
used to test these endpoints sequentially as described in Section 6.5.  
Secondary Endpoint Family 1 (=0.03, hierarchical testing) 
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• In subjects ≥12 years old with baseline WI-NRS  4, achievement of at least a 4-point 
reduction in the average weekly WI-NRS at Week 4 
• In subjects ≥12 years old with baseline WI-NRS  4, achievement of at least a 4-point 
reduction in the average weekly WI-NRS at Week 2 
• In subjects ≥12 years old with baseline WI-NRS  4, achievement of at least a 4-point 
reduction in the average weekly WI-NRS at Week 1 
Secondary Endpoint Family 2 ( = 0.02, hierarchical testing) 
• Achievement of at least a 75% reduction in the Eczema Area and Severity Index at 
Week 4 (EASI-75)  
• vIGA-AD of ‘clear’ or ‘almost clear’ at Week 4 
• vIGA-AD Success at Week 2 
• vIGA-AD Success at Week 1 
• vIGA-AD of ‘clear’ or ‘almost clear’ at Week 2 
• vIGA-AD of ‘clear’ or ‘almost clear’ at Week 1 
For the secondary efficacy endpoint of vIGA-AD Success at Week 4 based on the vIGA-AD 
moderate ITT population, the following sensitivity analyses to the primary analysis of this efficacy 
endpoint will be performed if and only if the hierarchical testing procedure (refer to Section 6.5) 
allows it: 
• Tipping Point analysis (refer to Section 6.2.3) on vIGA-AD moderate ITT population. 
• Non-responder imputation (refer to Section 6.2.2) on vIGA-AD moderate ITT population.   
• Observed data on vIGA-AD moderate ITT population. 
• Observed data on vIGA-AD moderate PP population (refer to Section 4.5). 
For the last three sensitivity analyses, count of subjects having vIGA-AD success will also be 
presented at Week 4 by treatment group in addition to the percentage of subjects having vIGA-AD 
success. 
For all other secondary efficacy endpoints, the following sensitivity analyses to the primary 
analysis of these secondary endpoints will be performed if and only if the hierarchical testing 
procedure (refer to Section 6.5) allows it: 
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• Non-responder imputation on WI-NRS population for the WI-NRS secondary efficacy 
endpoints and ITT population for all other secondary efficacy endpoints.   
• Observed data on WI-NRS population for the WI-NRS secondary efficacy endpoints and 
ITT population for all other secondary efficacy endpoints. 
The daily WI-NRS score, average weekly WI-NRS, and WI-NRS success flag will be listed.  
  
The EASI total score and EASI-75 flag at each visit will be listed.   
12.3 Exploratory Efficacy Endpoints 
Exploratory efficacy endpoints are based on the vIGA-AD scale, WI-NRS scale, EASI 
questionnaire, %BSA affected by AD, CDLQI/DLQI questionnaires, DFI questionnaire, 
SCORAD tool or POEM tool. The list of exploratory efficacy endpoints can be found in Section 
2 and their derivation in Section 5.5. 
• For more details about the vIGA-AD scale, refer to Sections 12.1.1. 
• For more details about the WI-NRS scale, refer to Section 12.2. 
• For more details about the EASI questionnaire, refer to Section 12.2.  
• The % of BSA affected by AD will be determined by the subject’s hand method, where the 
subject’s hand (including fingers) surface area is assumed to equal 1% of BSA (excluding 
the scalp, palms, and soles). 
• The CDLQI/DLQI is a self-administered validated questionnaire designed to measure the 
health-related quality of life of children/adult subjects suffering from a skin disease.  It 
consists of 10 questions concerning subjects’ perception of the impact of skin disease on 
different aspects of their health-related quality of life over the last week. Questions 1 to 6 
and 8 to 10 are rated from 0 (Not at all) to 3 (Very much).  For children, if last week was a 
school time, question 7 is rated from 0 (Not at all) to (Prevented school) but if the last week 
was a holiday time, question 7 is rated from 0 (Not at all) to 3 (Very much).  For adults, 
question 7 is rated from 0 (Not at all/Not relevant/No) to 3 (Yes). 
• The DFI questionnaire measures how much having a child with AD affects the quality of 
life of other (adult) members of the family over the last week. It is designed to be completed 
by caregivers of subjects ≤ 17 years of age and consists of 10 questions rated from 0 (Not 
at all) to 3 (Very much). 
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• The SCORAD is a clinical tool to assess the severity (i.e., extent, intensity) of AD as 
objectively as possible.  First, the overall %BSA affected by AD is evaluated (from 0% to 
100%, where a subject’s palm represents 1% of his/her total BSA).  Secondly, the AD 
severity is evaluated based on 6 items (erythema, edema/papulation, oozing/crusts, 
excoriation, lichenification, and dryness) graded using a 4-point scale (half steps are not 
allowed): 0 (absence), 1 (mild), 2 (moderate), and 3 (severe). Lastly, 2 subjective items 
(loss of sleep and intensity of pruritus) are evaluated by having the subject indicates on a 
10.0 cm visual analog scale (VAS) the point corresponding to the average value over the 
last 3 days (0 cm = none to 10 cm= maximum). 
• The POEM is a tool used for monitoring atopic eczema severity.  If focus on the illness as 
experience by the subject.  It consists of a 5-point scale measuring the frequency of each 
of 7 AD symptoms (i.e., dryness, itching, flaking, cracking, sleep loss, bleeding, and 
weeping) over the past week scored from 0 (no days), 1 (1 to 2 days), 2 (3 to 4 days), 3 (5 
to 6 days), and 4 (every day). 
For the continuous exploratory efficacy endpoints of change and percent from baseline in average 
weekly WI-NRS, EASI total score, % BSA, DLQI/CDLQI score, DFI score, SCORAD score, and 
POEM score at Week 1, Week 2, and Week 4, descriptive statistics for the score, change from 
baseline and percent change from baseline will be presented by visit and treatment group based on 
observed data in the ITT population. Descriptive statistics will also be presented similarly for the 
average weekly WI-NRS at Week 3.  For the continuous efficacy exploratory endpoint of daily 
WI-NRS, descriptive statistics will be presented similarly but on a daily basis instead of a weekly 
basis. Additionally, a plot of the mean (and standard error) daily WI-NRS scores over time for 
each treatment group will also be provided based on observed data. A similar plot will be provided 
for the percent change from baseline in daily WI-NRS. 
For each categorical exploratory efficacy endpoint, count and percentages of subjects meeting the 
criteria for an exploratory efficacy endpoint will be presented by visit and treatment group based 
on observed data in the ITT population along with a 95% Wilson CI. Additionally, count and 
percentage of subjects meeting the criteria for vIGA-AD of Clear (0), EASI-50, EASI-90, and 
EASI-100 at Week 1 and Week 2 will also be presented by visit and treatment group based on 
observed data in the ITT population along with a 95% Wilson CI. 
 Continuous exploratory efficacy endpoints will be analyzed at Week 1, Week 2, and Week 4 and 
for daily WI-NRS assessments using an analysis of covariance (ANCOVA) with the factors of 
treatment, two stratification variables (pooled study site and randomized vIGA-AD score), and 
baseline of the variable under analysis as covariate.  Statistical comparisons between the treatment 
groups will be obtained using contrasts. The Least Square (LS) mean and its standard error, 
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Sponsor: Arcutis Biotherapeutics, Inc. 
 
SOP-STAT-03-TOOL.01 Version 4 
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difference in LS means between treatment group (i.e., active - vehicle), its standard error and 
associated 95% confidence interval, and p-value for difference from vehicle will be presented at 
each visit. These analyses will be performed based on observed data in the ITT population. 
Categorical exploratory efficacy endpoints at Weeks 1, 2, and 4 will be analyzed using a CMH test 
adjusted for the two stratification variables (pooled study site and randomized vIGA-AD score).  
Common MH odds ratio, common MH proportion difference and their common associated 95% 
CI, adjusted for the randomization factors, will be provided.  The p-value will be from a CMH test 
for the common MH odds ratio, unless the common MH odds ratio is not estimable.  In such 
circumstances, the p-value will be from a MH test for the common MH proportion difference. 
The analysis of these endpoints will be performed on the observed data with no imputation. The 
p-values will be nominal as no formal inferential testing will be done on exploratory efficacy 
endpoints. 
12.4 Subgroup Analysis  
With the following exception, analyses of the primary and secondary efficacy endpoints (refer to 
Sections 12.1 and 12.2, respectively) will be repeated by subgroups (refer to Section 6.6) based on 
the multiple imputation data using mITT, ITT or WI-NRS population, as applicable (refer to 
Section 12.2). The exception is that the subgroup analyses by randomized vIGA-AD score and by 
actual baseline vIGA-AD score will not be performed for the secondary efficacy endpoint of vIGA-
AD Success based on the vIGA-AD Moderate ITT population.   
The following alternatives could be implemented if the odds ratio and/or proportion difference are 
not estimable: 
1. An unstratified model can be used if odds ratios are not estimable due to over-stratification, 
i.e., too few events for the number of strata.  
2. If the between-imputation variance of odds ratios and/or proportion difference is 0, i.e., the 
estimates are equal across all imputations, the estimates from any imputation will be 
reported. 
Should a specific subgroup have less than 10 subjects across both treatment groups, no statistical 
inference will be performed.  Forest plots of subgroup analysis for primary efficacy endpoint and 
secondary efficacy endpoints will also be provided.  
No subgroup analyses will be presented for the exploratory efficacy endpoint (refer to Section 2). 
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12.5 Summary of Primary and Secondary Efficacy Analysis  
Table 5 provides a summary of the primary and sensitivity analyses that will be provided for 
primary and secondary efficacy endpoints.    
Table 6 Summary of Primary and Secondary Efficacy Analyses 
Efficacy Endpoint 
Primary Analysis 
Sensitivity Analysis 
Primary (refer to Section 12.1) 
vIGA-AD Success  
(a score of ‘0’ or ‘1’ plus 
at least a 2-grade 
improvement) at week 4 
ITT, multiple 
imputation (CMH) 
#1 mITT, multiple imputation (CMH) 
#2 ITT, Tipping point (CMH)) 
#3 ITT, non-responder imputation (CMH) 
#4 ITT, observed data (CMH) 
#5 PP, observed data (CMH) 
#6 ITT, multiple imputation (CMH) and a 
different site pooling strategy (CMH) 
#7 ITT, multiple imputation (CMH) by 
pooled study site 
#8 ITT, multiple imputation (CMH) and 
removing one pooled study site at the 
time 
Secondary (refer to Section 12.2) 
vIGA-AD Success  
(a score of ‘0’ or ‘1’ plus 
at least a 2-grade 
improvement) at week 4 
vIGA-AD Moderate 
ITT, multiple 
imputation (CMH) 
 
#1 vIGA-AD Moderate ITT, Tipping point 
(CMH) 
#2 vIGA-AD Moderate ITT, non-
responder imputation (CMH) 
#3 vIGA-AD Moderate ITT, observed data 
(CMH) 
#4 vIGA-AD Moderate PP, observed data 
(CMH) 
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STATISTICAL ANALYSIS PLAN, Version 1.0 
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SOP-STAT-03-TOOL.01 Version 4 
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Family 1 (=0.03): 
Average weekly WI-
NRS Success 
(achievement of at least a 
4-point reduction) at 
weeks 1,2, and 4 
WI-NRS population, 
multiple imputation 
(CMH) 
#1 WI-NRS, non-responder imputation 
(CMH) 
#2 WI-NRS, observed data (CMH) 
Family 2 (=0.02 or 
=0.05): 
EASI-75 at week 4 
ITT, multiple 
imputation (CMH)  
#1 ITT, non-responder imputation (CMH) 
#2 ITT, observed data (CMH) 
Family 2 (=0.02 or 
=0.05): 
vIGA-AD Success  
(a score of ‘0’ or ‘1’ plus 
at least a 2-grade 
improvement) at weeks 1 
and 2 
ITT, multiple 
imputation (CMH) 
#1 ITT, non-responder imputation (CMH) 
#2 ITT, observed data (CMH) 
Family 2 (=0.02 or 
=0.05): 
vIGA-AD score of ‘0’ or 
‘1’ at weeks 1, 2 and 4 
ITT, multiple 
imputation (CMH) 
#1 ITT, non-responder imputation (CMH) 
#2 ITT, observed data (CMH) 
13 SAFETY ANALYSIS 
Safety analyses will be conducted using the safety population. Subjects will be analyzed based on 
the treatment received and the stratum they belong to.   
No formal inferential statistics will be performed on safety assessments.  
Also, treatment-emergent adverse events by SOC and PT table and summary of weight change 
will be presented by treatment groups for age 6 to 17 years and  18 years separately.   
13.1 Adverse Events 
Adverse events (AEs) will be coded according to the latest available version of Medical Dictionary 
for Regulatory Activities (MedDRA) (Version 23.0 or higher). 
Treatment emergent adverse events (TEAEs) are defined as any AEs with onset on or after the 
first study drug application. See Appendix 2 for handling of completely or partially missing dates 
for AEs. In the case where it is not possible to define an AE as treatment emergent or not, the AE 
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will be classified as treatment emergent. All reported TEAEs will be summarized by treatment 
group. 
Overall summary will be presented, which will include the total number of events, and the number 
and percentage of subjects who experienced TEAE, TEAE by the strongest relationship, TEAE by 
the maximum severity, treatment-related TEAE by maximum severity, treatment-emergent serious 
AE (TESAE), treatment-emergent Non-SAE, TEAE leading to study treatment discontinuation, 
TEAE leading to study discontinuation, TEAE on an application site, and TEAE leading to death.   
The number and percentage of subjects who experience TEAE will be summarized by SOC and 
PT within SOC.  In addition, similar table will be presented by treatment groups for age 6 to 17 
years and  18 years separately.  Unless otherwise specified, a subject experiencing the same 
TEAE multiple times will be counted only once for the corresponding PT. Similarly, if a subject 
experiences multiple TEAEs within the same SOC, the subject will be counted only once for that 
SOC. TEAEs will be sorted alphabetically by SOC and within each SOC the PT will be presented 
by descending frequency in the safety analysis set. A treatment-related TEAE is defined as any 
TEAE that is assessed by the Investigator as likely, probably, or possibly related to study treatment. 
TEAE that is assessed as unrelated or unlikely will be defined as not treatment-related. If a subject 
experiences more than one TEAE within different relationship categories within the same SOC/PT, 
only the worst case (the strongest relationship) will be reported. TEAE with an unknown 
relationship will be considered as treatment-related. 
The number and percentage of subjects who experience TEAE will be summarized by SOC, PT 
and the maximum severity (mild/moderate/severe/life threatening/death related to AE). If a subject 
experiences more than one TEAE within different severity categories within the same SOC/PT, 
only the worst case (the maximum severity) will be reported. TEAE with an unknown severity will 
be considered as severe. 
The number and percentage of subjects who had TESAE, treatment-emergent Non-SAE, will be 
summarized by SOC and PT within SOC.  
Frequency and percentage of subjects who experience TEAE on an application site will be 
summarized by SOC and PT. 
A table and plot of most frequent TEAE (‘≥1%) by PT will be provided by treatment arms (overall 
TEAE, overall TESAE will be included in the same plot). 
All the AEs will be listed. Any TEAE leading to death will also be included in the AE listing (if 
there is any). The TEAE related to application site will be flagged in the AE listing.   
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13.2 Clinical Laboratory 
Descriptive statistics for the observed values in chemistry, hematology, and quantitative urinalysis, 
change from baseline and percent change from baseline values will be presented by treatment 
group at each scheduled visit. For qualitative urinalysis data, the number and percentage of the 
subjects for each level of result by treatment at each scheduled visit will be provided. 
Shift tables from baseline to each postbaseline assessments describing shifts to out-of-normal 
range will be provided for chemistry, hematology, and qualitative urinalysis. Only subjects with a 
baseline result and a result at the specified visit for the parameter will be considered. 
Listings of abnormal laboratory will be provided for each parameter where a subject had at least 
one abnormal result. 
Laboratory data will be presented in SI units. 
13.3 Vital Signs 
Descriptive statistics will be presented for vital signs (systolic blood pressure, diastolic blood 
pressure, heart rate, body temperature, and weight). Observed values, change from baseline and 
percent change from baseline values will be presented by treatment group at each scheduled visit.  
The number and percentage of subjects with gain or lose >5% from baseline in body weight over 
the course of the study will be summarized for overall and separately for children and adolescents 
(6 to 17 years) and adults ( 18 years). BMI will be summarized using descriptive statistics (n, 
mean, standard deviation, median, Q1, Q3, minimum, and maximum) on observed values, change 
from baseline and percent change from baseline values separately for children and adolescents (6 
to 17 years) and adults ( 18 years). The BMI percentile rather than BMI kg/m2 will be summarized 
for children and adolescents (6 to 17 years).  
A listing of all vital sign assessments including weight, BMI, and BMI percentile for children and 
adolescents will be provided. 
13.4   Local Tolerability Assessments 
The investigator’s assessment of the application site reaction will be summarized by visit using 
both categorical methods (number and percentage of subject with each score) as well as continuous 
methods (e.g., mean, standard deviation, etc.)  
Local tolerability (burning/stinging sensation) assessed by the subject will be summarized using 
number and percentage similarly. 
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13.5 Patient Health Questionnaire Depression Scale (PHQ-8) and Patient 
Health Questionnaire Depression Scale (Modified PHQ-A) 
The Modified PHQ-A Assessment will be performed in adolescent subjects (12-17 years old, 
inclusive; question 9 has been removed since that is better evaluated by use of the C-SSRS tool). 
The PHQ-8/Modified PHQ-A score is the sum of the responses for the questions, each question 
ranging from 0 (Not at all) to 3 – (Nearly every day). Five severity categories of depression are 
defined as follows: 
• None – Minimal depression (0 to 4) 
• Mild depression (5 to 9) 
• Moderate depression (10 to 14) 
• Moderately severe depression (15 to 19) 
• Severe depression (20 to 24) 
The score will be set to missing in case of at least one missing value. The number and percentage 
of subjects in each category will be summarized by treatment and visit.  A summary of the shifts 
in depression category from baseline to each study visit will also be provided. 
13.6 Children’s Depression Inventory 2 (CDI-2) 
The CDI-2 Assessment will be performed in children subjects (6-11 years old, inclusive). 
The observed values and changes from baseline will be calculated for CDI-2 total score and the 2 
scales, i.e., emotional problems and functional problems, and will be summarized descriptively by 
treatment group and visit.   
 The CDI-2 total score will be categorized as follows: 
1. Normal: Male Score < 22, Female Score < 21 
2. Elevated: 22 ≤ Male Score < 32, 21 ≤ Female Score < 32 
3. Very Elevated: Male or Female Score ≥ 32.  
The proportion of subjects that meeting the criteria will be summarized by treatment group and 
visit.  
A summary of the shifts in CDI-2 category from baseline to each study visit will also be provided. 
 
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13.7 Columbia-Suicide Severity Rating Scale (C-SSRS) 
The Columbia-Suicide Severity Rating Scale (C-SSRS) is a questionnaire used (for adolescents 
and adults 12 years old and older) for suicide assessment developed by multiple institutions, 
including Columbia University. The C-SSRS prospectively assesses Suicidal Ideation and Suicidal 
Behavior. At the Screening study visit, “Baseline/Screening” version of the C-SSRS will be used. 
This version assesses Suicidal Ideation and Suicidal Behavior during the subject’s lifetime and 
during the past 6 months. For the Screening visit, “lifetime” experience of the subject with Suicidal 
Ideation and Suicidal Behavior will be summarized. On all subsequent visits, the “Since Last Visit” 
version will be used (Baseline/Day 1, Week 1/Day 8, Week 2/Day 15 or Week 4/Day 29).  
Tables will include results from the Suicidal Ideation and Suicidal Behavior sections of the C-
SSRS. Frequencies and percentages of subjects with a response of “Yes” at any point on the 
Suicidal Ideation and Suicidal Behavior items will be summarized by study visit and treatment 
group. 
13.8 Physical Examination 
The number and percentage of subjects with normal and abnormal findings in the physical 
examination will be presented by body system and treatment group at each study visit.  
14 PHARMACOKINETICS ANALYSIS 
Concentration data will be summarized by visit by age group (<18 vs. >=18) and overall, for active 
treatment group using descriptive statistics, reporting n, mean, standard deviation, median, Q1, 
Q3, minimum, and maximum, and geometric statistics including geometric mean and coefficient 
of variation. For computation of mean plasma concentrations, data that are below the limit of 
quantification (BLQ) will be set to 0.0001. The PK population will be used for these analyses. 
 
PK data will be presented in the listing.  
 
 
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STATISTICAL ANALYSIS PLAN, Version 1.0 
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15 REFERENCES 
1. Anne Lott & Jerome P. Reiter (2020) Wilson Confidence Intervals for Binomial Proportions 
with Multiple Imputation for Missing Data, The American Statistician, 74:2, 109-
115, DOI: 10.1080/00031305.2018.1473796 
 
2. Ratitch, B., Lipkovich, I., & O’Kelly, M. (2013). Combining Analysis Results from Multiply 
Imputed Categorical Data. 
PharmaSUG. https://www.pharmasug.org/proceedings/2013/SP/PharmaSUG-2013-SP03.pdf 
 
 
 
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Appendix 2 
Algorithm for Imputation of Start/End Date and Time of Adverse Events and 
Prior/Concomitant Medications 
Event Start Date Imputation 
• Imputation of event end date should be done before imputation of event start date.  
• Completely missing: Impute to the first study treatment date. 
• Missing day and month: Impute to January 1st, unless year is the same as year of first study 
treatment dose date then impute to the first study treatment date. 
• Missing day: Impute to the 1st day of the month, unless month and year are the same as 
month and year of first study treatment dose date then impute to the first study treatment 
date. 
• If imputed event start date is after event end date (imputed or not), set the event start date 
to the imputed event end date. 
Event Start Time Imputation (for Adverse Events only) 
Imputation of event end time should be done before imputation of event start date.  
• If the event date is not the same as the first dose date or time part of the first dose date is 
missing, impute to 00:00. 
• If the event date is the same as the first dose date and event occurred prior to study drug 
application (as flagged in CRF), impute to 00:00. 
•  If the event date is the same as the first dose date and event did not occur prior to study 
drug application (as flagged in CRF), impute to time part of first dose date. 
• If the event start date is equal to event end date and imputed event start time is after event 
end time (imputed or not), set the event start time to the imputed event end time. 
Event End Date Imputation 
• Completely missing (and not flagged as “ongoing”): Impute to the last contact date. 
• Missing day and month: Impute to December 31st, unless year is the same as last contact 
date then impute to the last contact date. 
• Missing day: Impute to the last day of the month, unless year and month are the same as 
year and month of last contact date then impute to the last contact date. 
Event End Time Imputation (for Adverse Events only) 
Impute to 23:59. 
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