A Phase 3, Multicenter, Open-Label Extension Study of the Long-Term Safety of ARQ-151 Cream 0.15% and ARQ-151 Cream 0.05% in Subjects With Atopic Dermatitis
Phase: PHASE3
Conditions: Atopic Dermatitis Eczema
Sponsor: Arcutis Biotherapeutics, Inc.



Protocol ARQ-151-313 
Arcutis Biotherapeutics, Inc. 
Amendment 1 
 
 
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STUDY SITE INVESTIGATOR SIGNATURE PAGE 
 
Protocol ARQ-151-313 
A Phase 3, Multicenter, Open-Label Extension Study of the Long-Term Safety of ARQ-151 
Cream 0.15% and ARQ-151 Cream 0.05% in Subjects with Atopic Dermatitis 
 
SPONSOR: 
 
 
Arcutis Biotherapeutics, Inc. 
 
 
 
 
 
3027 Townsgate Road, Suite #300 
Westlake Village, CA 91361 
 
ISSUE DATE: 
 
 
17 September 2021 
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. 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 ..........................................................................................13 
1.1. 
Synopsis ......................................................................................................................13 
1.2. 
Study Schema .............................................................................................................18 
1.3. 
Schedule of Visits and Assessments ...........................................................................19 
2.
INTRODUCTION ......................................................................................................23 
2.1. 
Background .................................................................................................................23 
2.2. 
Nonclinical Studies .....................................................................................................24 
2.3. 
Clinical Studies ...........................................................................................................24 
2.3.1. 
Topical Roflumilast Cream .........................................................................................24 
2.3.2. 
Oral Roflumilast Tablet ..............................................................................................29 
2.4. 
Rationale for Development .........................................................................................29 
2.4.1. 
Dose Selection ............................................................................................................30 
2.4.2. 
Risks and/or Benefits to Subjects ...............................................................................30 
3.
STUDY OBJECTIVES AND ENDPOINTS ..............................................................31 
3.1. 
Study Objectives .........................................................................................................31 
3.1.1. 
Primary Objective .......................................................................................................31 
3.2. 
Study Endpoints ..........................................................................................................31 
3.2.1. 
Primary Endpoints ......................................................................................................31 
3.2.2. 
Secondary Endpoints ..................................................................................................31 
4.
INVESTIGATIONAL PLAN .....................................................................................32 
4.1. 
Overall Study Design and Plan ...................................................................................32 
4.2. 
Number of Study Sites and Subjects ..........................................................................33 
4.3. 
Subject Participation ...................................................................................................33 
4.4. 
Numbering of Subjects ...............................................................................................33 
4.5. 
Selection of Study Population ....................................................................................33 
4.5.1. 
Inclusion Criteria ........................................................................................................33 
4.5.2. 
Exclusion Criteria .......................................................................................................34 
4.6. 
Study Restrictions .......................................................................................................35 
4.6.1. 
Prohibitions and Concomitant Therapy ......................................................................35 
4.7. 
Treatment ....................................................................................................................37 

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4.7.1. 
IP Supplies, Packaging and Labeling .........................................................................37 
4.7.2. 
Blinding ......................................................................................................................37 
4.7.3. 
Treatment Administration ...........................................................................................37 
4.7.4. 
Treatment Compliance ................................................................................................38 
4.7.5. 
Removal of Subjects from Study Treatment ..............................................................39 
4.7.6. 
Removal of Subjects from the Study ..........................................................................39 
5.
STUDY PROCEDURES ............................................................................................40 
5.1. 
Safety Assessments .....................................................................................................40 
5.1.1. 
Day 1 Visit ..................................................................................................................40 
5.1.2. 
Contraception Requirements ......................................................................................41 
5.1.3. 
Day 1 ...........................................................................................................................41 
5.1.4. 
Physical Examination .................................................................................................41 
5.1.5. 
Vital Signs, Height and Weight ..................................................................................41 
5.1.6. 
Laboratory Tests .........................................................................................................42 
5.1.7. 
Patient Health Questionnaire Depression Scale (PHQ-8) ..........................................43 
5.1.8. 
Patient Health Questionnaire Depression Scale (Modified PHQ-A) ..........................43 
5.1.9. 
Children’s Depression Inventory 2 (CDI-2) ...............................................................44 
5.1.10. 
Columbia-Suicide Severity Rating Scale (C-SSRS) ...................................................44 
5.1.11. 
Local Tolerability Assessment ...................................................................................45 
5.1.12. 
Adverse Events ...........................................................................................................46 
5.1.13. 
Phone Follow Up Visit ...............................................................................................46 
5.2. 
Efficacy Evaluations ...................................................................................................46 
5.2.1. 
Validated Investigator Global Assessment scale for Atopic Dermatitis ....................47 
5.2.2. 
Eczema Area and Severity Index (EASI) ...................................................................47 
5.2.3. 
Worst Itch Numerical Rating Scale (WI-NRS) ..........................................................48 
5.2.4. 
Dermatology Life Quality Index (DLQI) and Children’s Dermatology Life 
Quality Index (CDLQI) ..............................................................................................49 
5.2.5. 
Infants’ Dermatitis Quality of Life Index (IDQOL) ...................................................49 
5.2.6. 
Dermatitis Family Impact Questionnaire (DFI) .........................................................49 
5.3. 
Other Evaluations .......................................................................................................49 
5.3.1. 
Body Surface Area (BSA) ..........................................................................................49 
5.3.2. 
SCORAD (“SCORing Atopic Dermatitis”) ................................................................50 

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5.3.3. 
Patient-Oriented Eczema Measure (POEM) ...............................................................50 
5.3.4. 
Pharmacokinetics Assessment ....................................................................................50 
5.3.5. 
Medical Photography ..................................................................................................50 
5.4. 
Final Study Visit – End of Study ................................................................................51 
5.5. 
Early Termination Visit ..............................................................................................51 
5.6. 
Unscheduled Visit .......................................................................................................51 
5.7. 
Adverse Events ...........................................................................................................52 
5.7.1. 
Adverse Event Definition ...........................................................................................52 
5.7.2. 
Serious Adverse Event Definition ..............................................................................52 
5.7.3. 
Suspected Unexpected Serious Adverse Reaction (SUSAR) .....................................53 
5.7.4. 
Safety Review with Subject ........................................................................................54 
5.7.5. 
Adverse Event Reporting ............................................................................................54 
5.8. 
Reporting Pregnancy ..................................................................................................56 
5.9. 
Treatment Stopping Rules ..........................................................................................56 
6. 
DATA ANALYSIS ....................................................................................................57 
6.1. 
Statistical Methods ......................................................................................................58 
6.2. 
Determination of Sample Size ....................................................................................58 
6.3. 
Subjects to Analyze ....................................................................................................58 
6.4. 
Background and Demographic Characteristics ..........................................................58 
6.5. 
Study Medication Compliance ...................................................................................58 
6.6. 
Safety Analysis ...........................................................................................................59 
6.7. 
Adverse Events ...........................................................................................................59 
6.8. 
Local Tolerance Assessment ......................................................................................59 
6.9. 
Clinical Laboratory Results and Vital Signs ..............................................................59 
6.10. 
Prior and Concomitant Medications ...........................................................................59 
6.11. 
vIGA-AD ....................................................................................................................59 
6.12. 
EASI ...........................................................................................................................59 
6.13. 
WI-NRS ......................................................................................................................59 
6.14. 
Body Surface Area ......................................................................................................60 
6.15. 
Subject Reported Outcomes Analyses ........................................................................60 
6.15.1. 
Dermatology Life Quality Index, Children’s Dermatology Life Quality 
Index, IDQOL, SCORAD and POEM ........................................................................60 

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7.
STUDY ADMINISTRATION ...................................................................................60 
7.1. 
Ethics ..........................................................................................................................60 
7.1.1. 
Ethics Review Board ..................................................................................................60 
7.1.2. 
Ethical Conduct of the Study ......................................................................................60 
7.1.3. 
Subject Information and Consent/Assent ...................................................................61 
7.2. 
Study Monitoring ........................................................................................................61 
7.3. 
Study Completion and Termination ............................................................................61 
7.3.1. 
Study Completion .......................................................................................................61 
7.3.2. 
Study Termination ......................................................................................................61 
7.4. 
Data Quality Assurance ..............................................................................................62 
7.5. 
Data Handling and Record Keeping ...........................................................................62 
7.6. 
Protocol Amendments and Deviations .......................................................................62 
7.7. 
Confidentiality and Privacy ........................................................................................63 
7.8. 
Conflict of Interest ......................................................................................................63 
7.9. 
Report Format .............................................................................................................64 
7.10. 
Publication Policy .......................................................................................................64 
8.
REFERENCES ...........................................................................................................65 
9.
APPENDICES ............................................................................................................67 
APPENDIX 1. PATIENT HEALTH QUESTIONAIRE-8 (PHQ-8) ..........................................67 
APPENDIX 2. PATIENT HEALTH QUESTIONNAIRE DEPRESSION SCALE 
(MODIFIED PHQ-A) .........................................................................................68 
APPENDIX 3. CHILDREN’S DEPRESSION INVENTORY 2 (PARENT REPORT) ............69 
APPENDIX 4. COLUMBIA-SUICIDE SEVERITY RATING SCALE (C-SSRS) 
“SINCE LAST VISIT” VERSION ....................................................................70 
APPENDIX 5. VALIDATED INVESTIGATOR GLOBAL ASSESSMENT SCALE 
FOR ATOPIC DERMATITIS ............................................................................73 
APPENDIX 6. DERMATOLOGY LIFE QUALITY INDEX ....................................................74 
APPENDIX 7. CHILDREN’S DERMATOLOGY LIFE QUALITY INDEX ...........................76 
APPENDIX 8. INFANTS' DERMATITIS QUALITY OF LIFE INDEX (IDQOL) .................78 
APPENDIX 9. DERMATITIS FAMILY IMPACT QUESTIONNAIRE (DFI) ........................79 
APPENDIX 10. SCORAD ..........................................................................................................81 
APPENDIX 11. PATIENT-ORIENTED ECZEMA MEASURE (POEM) ................................82 

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APPENDIX 12. NIAID DMID TOXICITY TABLE .................................................................84 
 
LIST OF TABLES 
Table 1: 
ARQ-151-101: Skin Toleration Treatment-Emergent Adverse Experiences .............25 
Table 2: 
Excluded Medications and Treatments .......................................................................36 
Table 3: 
Laboratory Tests .........................................................................................................42 
 
LIST OF FIGURES 
Figure 1. 
Contraception Requirements for Female Subjects .....................................................41 
 

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1. 
PROTOCOL SUMMARY 
1.1. 
Synopsis 
Name of Sponsor/Company: Arcutis Biotherapeutics, Inc. 
Name of Investigational Product:  ARQ-151 will be supplied as an emollient cream at 0.15% or 
0.05% strength 
Name of Active Ingredient: Roflumilast, a PDE-4 inhibitor 
Protocol Number:  
ARQ-151-313 
Phase: 3 
Country: US and Canada 
Title of Study:   
A Phase 3, Multicenter, Open-Label Extension Study of the Long-Term Safety of ARQ-151 Cream 
0.15% and ARQ-151 Cream 0.05% in Subjects with Atopic Dermatitis  
Clinical Indication:  Atopic Dermatitis 
Number of Sites:  Up to approximately 120 study sites in the United States and Canada.  During the 
conduct of the study, additional countries and/or sites may be added if necessary. 
Study Population:   
Up to approximately 1500 subjects that have completed the 4-week treatment period in studies 
ARQ-151-311 or ARQ-151-312 or ARQ-151-315 and are willing and qualified to enroll in this 
long-term extension study will receive ARQ-151 cream 0.15% (ARQ‑151‑311/312 roll-overs) or 
ARQ-151 cream 0.05% (ARQ‑151‑315 roll-overs) QD.  Subjects 6-17 years of age enrolled under 
Amendment 1 will be treated for 24 weeks with ARQ-151 cream 0.15% (Cohort-Week 24). Subjects 
on ARQ-151 cream 0.05% who turn 6 years old during ARQ-151-313 will switch to ARQ-151 cream 
0.15% at their first scheduled post-birthday visit. 
Objectives: 
Primary: 
To assess long-term safety in a multicenter, open-label, single-arm study in subjects with atopic 
dermatitis treated with ARQ-151 cream 0.15% QD (subjects ≥ 6 years of age) or ARQ‑151 cream 
0.05% QD (subjects 2 to 5 years of age) after completing one of three Phase 3 studies (ARQ-151-311, 
ARQ‑151‑312, or ARQ-151-315).   
Summary of Study Design: 
ARQ-151-313 is an open-label, single-arm, long-term safety study of ARQ-151 cream 0.15% and 
ARQ-151 cream 0.05% in subjects with atopic dermatitis. Eligible subjects will enroll into the 
long-term safety study on the same day as the Week 4 visit of the preceding study (ARQ-151-311, 
ARQ‑151‑312, or ARQ-151-315).  Study medication will be applied topically for up to 24 
(Cohort-Week 24) or 52 weeks at home.  All affected areas, except on the scalp, will be treated.  For 
the first 4 weeks of study ARQ-151-313, all subjects will apply study medication QD in the areas 
identified and treated as per the body diagram in the preceding study (ARQ-151-311/312/315).  
Beginning at the Week 4 visit, any subject who achieves vIGA-AD of ‘0-clear’ as confirmed by the 
Investigator at a scheduled or unscheduled clinic visit, will switch to twice weekly (BIW) maintenance 
treatment.  For maintenance therapy, study medication will be applied on two nonconsecutive days per 
week (e.g. Monday and Thursday) to areas commonly and/or most recently affected by AD, and any 

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areas where AD is developing.  Subjects receiving maintenance treatment who experience AD 
worsening (signs and symptoms) for 1 week despite dosing twice weekly will phone the clinical study 
site, resume daily dosing, and complete the subject diary accordingly.  The phone call (but not a clinic 
visit) is required to resume daily dosing.  At clinic visits, subjects receiving maintenance treatment may 
continue twice weekly maintenance dosing if vIGA-AD is either ‘0-clear’ or ‘1-almost clear’.  Subjects 
will resume daily dosing if vIGA-AD ≥2, and can resume daily dosing if signs/symptoms of AD are 
not adequately controlled with maintenance therapy despite vIGA-AD of ‘1-almost clear’.  Periodic 
clinic visits will include assessments for clinical safety, tolerability, and disease severity. 
Sample Size Justification: 
The sample size will provide a sufficient number of subjects to evaluate the long-term safety of 
ARQ-151 cream 0.15% or ARQ‑151 cream 0.05% over 24 or 52 weeks of treatment, and in 
combination with other studies will provide the development program with sufficient numbers of 
subjects to meet ICH E1A safety exposure goals. 
Number of Patients (planned):  
Up to approximately 1500 subjects are planned to be enrolled in this study.   
Duration of Treatment:   
Approximately 24 (Cohort-Week 24) or 52 weeks 
Main Criteria for Inclusion: 
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 2 years and older. (Only subjects 18 years and older will be enrolled 
at sites located in the province of Québec in Canada.)  
3. Subjects with atopic dermatitis who met eligibility criteria for and successfully completed 
ARQ-151-311 or ARQ-151-312 or ARQ-151-315 through Week 4, and are able and eligible to 
enroll into this long-term safety study on the Week 4 visit of the preceding study. 
4. Females of childbearing potential (FOCBP) must have a negative urine pregnancy test at all 
study visits.  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.  
5. Females of non-childbearing potential should either be pre-menarchal, or post-menopausal 
with spontaneous amenorrhea for at least 12 months (post-menopausal status would have been 
confirmed with FSH testing in the preceding study) or have undergone surgical sterilization 
(permanent sterilization methods include hysterectomy, bilateral oophorectomy, or bilateral 
salpingectomy). 
6. 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. 

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Investigational Product, Dosage and Mode of Administration:  
For the first 4 weeks of study ARQ-151-313, all subjects will apply study medication QD in the areas 
identified and treated as per the body diagram in the preceding study (ARQ-151-311/312/315).  
Beginning at the Week 4 visit, any subject who achieves vIGA-AD of ‘0-clear’ as confirmed by the 
Investigator at a scheduled or unscheduled clinic visit, will switch to twice weekly (BIW) maintenance 
treatment.  For maintenance therapy, study medication will be applied on two nonconsecutive days per 
week (e.g. Monday and Thursday) to areas commonly and/or most recently affected by AD, and any 
areas where AD is developing.  Subjects receiving maintenance treatment who experience AD 
worsening (signs and symptoms) for 1 week despite dosing twice weekly will phone the clinical study 
site, resume daily dosing, and complete the subject diary accordingly.  The phone call (but not a clinic 
visit) is required to resume daily dosing.  At clinic visits, subjects receiving maintenance treatment may 
continue twice weekly maintenance dosing if vIGA-AD is either ‘0-clear’ or ‘1-almost clear’.  Subjects 
will resume daily dosing if vIGA-AD ≥2, and can resume daily dosing if signs/symptoms of AD are 
not adequately controlled with maintenance therapy despite vIGA-AD of ‘1-almost clear’.   
Key Assessments: 
Safety will be monitored through local tolerability assessments, vital signs, physical examination, 
safety labs (subjects ≥12 years old), 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 of 12 years old and older), and AEs. 
Parents/caregivers of subjects 2 to 5 years of age will be advised to promptly report any changes in 
behavior that could signal psychological distress or emotional distress. 
Efficacy assessments will include vIGA-AD, EASI, WI-NRS, BSA, CDLQI/DLQI, DFI, IDQOL, 
SCORAD, and POEM. 
Study Endpoints: 
Primary: 
• 
Adverse Events (AEs) 
• 
Serious Adverse Events (SAEs) 
Secondary: 
• 
Validated Investigator Global Assessment-Atopic Dermatitis (vIGA-AD) value 0 or 1 at each 
assessment 
• 
vIGA-AD success (defined as vIGA-AD value of 0 or 1 plus a 2-grade improvement from 
baseline) 
• 
WI-NRS score over time 
• 
EASI score over time 
Criteria for Evaluation: 
Safety: 
The safety population will include all subjects who are enrolled and received at least one confirmed 
dose of study medication. 
Descriptive statistics will be calculated for quantitative safety data and frequency counts will be 
compiled for classification of qualitative safety data. 
The subject incidence of treatment-emergent adverse events (TEAE) will be summarized overall, by 
severity, and by attribution. 

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Statistical Methods: 
Descriptive statistics will be presented for the endpoints and safety data collected in the clinical trial. 
This includes the number and percentage of subjects for binary endpoints/categorical data, and mean, 
SD, median, Q1, Q3, minimum, and maximum for continuous data.   
Adverse Events 
For the primary endpoints, the occurrence of TEAEs and the occurrence of Serious Adverse Events 
(SAEs) will be tabulated by preferred term and system organ class.   
In addition, summary tables of TEAEs by severity, by relationship to investigational product, and those 
leading to withdrawal from investigational product will be created. 
Vital Signs 
Descriptive statistics will be calculated for vital signs over time. 
Clinical Laboratory Results 
Descriptive statistics of the laboratory parameters will be calculated at each scheduled time point.  
Shifts from baseline will be tabulated. 
Patient Health Questionnaires 
CDI-2 (in 6-11 year-olds), PHQ-8 (in adults), a modified version of the PHQ-A (in adolescents), and 
C-SSRS questionnaires (in adolescents and adults) will be completed at all study visits. Descriptive 
statistics will be calculated for the CDI-2, PHQ-8, and Modified PHQ-A. The C-SSRS will be analyzed 
per the Scoring and Data Analysis Guide from the Columbia Lighthouse Project. 
Efficacy Assessments 
Descriptive statistics will be presented for the efficacy data collected in the clinical trial for the subjects 
who enroll in this study and receive at least one day of study drug. For the binary and continuous 
endpoints related to vIGA-AD, WI-NRS, and EASI, descriptive statistics will be provided for the 
endpoints each scheduled visit.  
 
 

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1.2. 
Study Schema 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
** Under Amendment 1, 24 Week Treatment Period for Cohort-Week 24, Clinic Visits, and Phone Contact Weeks 4, 12, 18, 24 
ARQ-151cream 0.15% 
≥ 6 years old on Day 1 of ARQ-151-313 
52 Week Treatment Period, Clinic Visits, and Phone Contact 
Weeks 4, 12, 18, 24, 30, 36, 44, 52** 
Subjects on ARQ-151 cream 0.05% who turn 6 years old during ARQ-151-313 will switch to ARQ-151 cream 0.15% at their 
first scheduled post-birthday visit 
 
From Day 1 Until Week 4 Visit 
• 
All Subjects, whether clear or not, will apply medication QD 
• 
Study drug will be applied to all areas identified and treated as per the body diagram in the preceding study  
(ARQ-151-311/312/315) 
 
At Week 4 Visit Until End of Study 
 
Day 1 (Visit 1) 
Assessments obtained from Week 4/Day 29 of ARQ-151-311 or ARQ-151-312 or ARQ-151-315 
(Assessments common to Week 4 of the preceding study and Day 1 of the ARQ‑151‑313 study will only be performed once.) 
ARQ-151 cream 0.05% 
2-5 years old on Day 1 of ARQ-151-313 
For Subjects Dosing QD 
In between visits: 
• Continue dosing QD until next clinic visit 
• If AD clears, subject may have an 
Unscheduled visit for vIGA-AD to determine 
whether maintenance dosing should begin 
At scheduled or unscheduled clinic visits: 
• If vIGA-AD=0, switch to maintenance 
treatment 
• If vIGA-AD>1, continue dosing QD 
For Subjects Receiving Twice Weekly Maintenance Treatment* 
In between visits: 
• Continue maintenance treatment, unless AD worsens (signs and 
symptoms) for 1 week despite dosing twice weekly, in which 
case subject/caregiver will phone the study site and resume 
dosing QD 
At scheduled or unscheduled clinic visits: 
• If vIGA-AD=0, continue maintenance treatment 
• If vIGA-AD=1, subject will continue maintenance treatment 
unless signs/symptoms of AD are deemed not adequately 
controlled with maintenance therapy, in which case subject will 
resume dosing QD 
• If vIGA-AD>2, resume dosing QD 
*For maintenance therapy, study medication will be applied on 
two  consecutive days per week (e.g. Monday and Thursday) to 
areas commonly and/or most recently affected by AD, and any 
areas where AD is developing 
A Phase 3, Multicenter, Open-Label Extension Study of the Long-Term Safety of ARQ-151 Cream 0.15% and ARQ-151 Cream 
0.05% in Subjects with Atopic Dermatitis  
 
Up to approximately 1500 subjects that have completed the 4-week treatment period in studies ARQ-151-311 or  
ARQ-151-312 or ARQ‑151-315 and are willing and qualified to enroll in this long-term extension study will receive 
ARQ-151 cream 0.15% (ARQ‑151‑311/312 roll-overs) or ARQ-151 cream 0.05% (ARQ‑151‑315 roll-overs).  

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1.3. 
Schedule of Visits and Assessments 
Study Procedure 
Day 1 
Wk 4 
Wk 12 
Wk18 
Wk 24t 
Wk 30 
Wk 36 
Wk 44 
Wk 52/ET 
Visit # 
1(Week 4) of 
ARQ-151-311 or 
ARQ-151-312 or 
ARQ-151-315 
2 
3 
Phone Visit 
4 
Phone Visit 
5 
Phone Visit 
6 
Visit Window 
 
+/- 3 days 
+/- 7 days 
+/- 7 days 
+/- 7 days 
+/- 7 days 
+/- 7 days 
+/- 7 days 
+/- 7 days 
Informed consent/assent 
X 
 
 
 
 
 
 
 
 
Physical examinationa 
Xs 
X 
 
 
X 
 
 
 
X 
I/E criteria 
X 
 
 
 
 
 
 
 
 
Hematology, Serum 
Chemistries, and Urine 
Analysisb 
Xs 
 
 
 
X 
 
 
 
X 
Vital signs, height, weightc 
Xs 
X 
X 
 
X 
 
X 
 
X 
vIGA-AD, EASI, BSA, 
SCORADd 
Xs 
X 
X 
 
X 
 
X 
 
X 
WI-NRS prurituse 
Xs 
 
 
 
 
 
 
 
 
POEMf 
Xs 
X 
X 
 
X 
 
X 
 
X 
Local Tolerability 
Assessmentg 
X 
X 
X 
 
X 
 
X 
 
X 
CDI-2, PHQ-8, PHQ-A, 
C‑SSRSh 
Xs 
X 
X 
 
X 
 
X 
 
X 
DLQI, CDLQI, IDQOL, 
DFIi 
Xs 
X 
X 
 
X 
 
X 
 
X 
Medical Photographyj 
Xs 
X 
X 
 
X 
 
X 
 
X 
Urine pregnancy testk 
Xs 
X 
X 
 
X 
 
X 
 
X 
PK drawsl 
 
 
 
 
 
 
 
 
X 

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Study Procedure 
Day 1 
Wk 4 
Wk 12 
Wk18 
Wk 24t 
Wk 30 
Wk 36 
Wk 44 
Wk 52/ET 
Visit # 
1(Week 4) of 
ARQ-151-311 or 
ARQ-151-312 or 
ARQ-151-315 
2 
3 
Phone Visit 
4 
Phone Visit 
5 
Phone Visit 
6 
Visit Window 
 
+/- 3 days 
+/- 7 days 
+/- 7 days 
+/- 7 days 
+/- 7 days 
+/- 7 days 
+/- 7 days 
+/- 7 days 
Dispense study medication 
kitm 
X 
X 
X 
 
X 
 
X 
 
 
Drug application and 
Parents/Caregivers training 
in clinic 
X 
 
 
 
 
 
 
 
 
Dispense/review diaryn 
X 
X 
X 
 
X 
 
X 
 
X 
Maintenance Dosing 
Determinationo 
 
X 
X 
 
X 
 
X 
 
 
Weigh study medicationp 
X 
X 
X 
 
X 
 
X 
 
X 
Compliance Determinationq 
 
X 
X 
 
X 
 
X 
 
X 
Adverse event assessmentr 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study Exit 
 
 
 
 
Xt 
 
 
 
X 
a Limited physical examination: skin, lungs, and heart only 
b Hematology, Serum Chemistries, and Urine Analysis will only be done in subjects ≥ 12 years of age at time of enrollment in the preceding study.  
c Height will be collected at Day 1 only for subjects ≥18 years old and at every clinic visit for subjects <18 years old. 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 otherwise 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. vIGA-AD should be completed prior to other physician assessments. SCORAD 
total score will range between 0 and 103.  
 
 

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Footnotes from table above: 
e The WI-NRS pruritus questionnaire will be completed once a week at home utilizing a diary.  The WI-NRS will be self-reported by subjects for subjects 
≥ 6 years of age, and reported by parent/guardian for subjects <6 years of age.  During the Phone Visits at Weeks 18, 30, and 44 a reminder will be given 
to subjects to complete the WI-NRS pruritis questionnaire once a week. 
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 At Day 1 only, local tolerability assessments should be recorded prior to study drug application for the Investigator assessment of skin irritation 
(Berger and Bowman skin irritation score) and 10-15 minutes post-drug application for the Subject’s ‘0-3’ burning/stinging assessment. Note for investigator 
tolerability assessments: reactions at the site of product application should be differentiated from the preexisting inflammation associated with 
the subject’s atopic dermatitis.  For subject tolerability assessments after Day 1, the subject will assess burning/stinging (0-3 score) 10-15 minutes post 
drug application based on recall of the last drug application. For subjects <6 years of age, parents will complete.    
h Adolescents and adults (12 years and older) will complete the C-SSRS (12 years old of age and older).  Adults will complete the PHQ-8.  Adolescents 
(ages 12 to 17 years of age, inclusive) will complete the PHQ-A (PHQ-9 modified for Adolescents). Parents/caregivers will complete the parent report (CDI-2) 
for children 6-11 years of age, inclusive. Subjects will continue with the assessments specific to their age group at the time of consent/assent at Screening of the preceding 
study.   
i The DLQI will be completed by subjects ≥17 years of age (based on age at start of preceding studies ARQ-151-311/312). The CDLQI will be completed for 
subjects > 4 years of age and <16 years of age (based on age at start of preceding studies ARQ‑151‑311/312/315). The Infants’ Dermatitis Quality of Life 
(IDQOL) will be completed by parents/caregivers for subjects < 4 years (based on age at start of parent preceding studies ARQ‑151‑315).  The Dermatitis 
Family Impact Questionnaire (DFI) will be completed by parents/caregivers for all subjects ≥ 2 years of age and ≤17 years of age. Subjects will continue with the 
assessments specific to their age group at the time of consent/assent at Screening of the preceding study.  DFI is not to be conducted for subjects who were ≤17 years of 
age in the ARQ-151-311/312 studies and turned 18 years of age prior to enrollment into ARQ-151-313. 
j Photography will be performed using Canfield equipment on all subjects at all study sites. All efforts will be made to de-identify the subjects. 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. See Photography 
Manual for details. 
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 ≥12 years old entering this study under Amendment 1 a single PK trough draw will be collected at Week 52/ET. Ensure study medication was 
not applied in the area where PK will be drawn. 
m It is expected that kits will be dispensed based on %BSA affected and subject’s age.  Subjects who turn 6 years old during the study will switch to ARQ-151 
cream 0.15% at their first scheduled post-birthday visit. See IP Handling Manual for details.  Under Amendment 1, this is the final visit for Cohort-Week 24 
and no kits will be dispensed at this visit. 
n Dispensing of IP is allowed, if needed.  Study site should review IP kit to ensure sufficient IP is available until the next visit and only dispense additional IP if 
needed. All subjects will continue study medication application in the areas identified and treated as per the body diagram in the preceding study for 
the first 4 weeks of the current study (ARQ-151-313).  
 
 

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Footnotes from table above: 
o Beginning at the Week 4 visit, any subject who achieves vIGA-AD of ‘0-clear’ as confirmed by the Investigator at a scheduled or unscheduled clinic visit, will 
switch to twice weekly (BIW) maintenance treatment.  For maintenance therapy, study medication will be applied on two nonconsecutive days per week 
(e.g. Monday and Thursday) to areas commonly and/or most recently affected by AD, and any areas where AD is developing.  Subjects receiving maintenance 
treatment who experience AD worsening (signs and symptoms) for 1 week despite dosing twice weekly will phone the clinical study site, resume daily dosing, 
and complete the subject diary accordingly.  The phone call (but not a clinic visit) is required to resume daily dosing.  At clinic visits, subjects receiving 
maintenance treatment may continue twice weekly maintenance dosing if vIGA-AD is either ‘0-clear’ or ‘1-almost clear’.  Subjects will resume daily dosing if 
vIGA-AD ≥2, and can resume daily dosing if signs/symptoms of AD are not adequately controlled with maintenance therapy despite vIGA-AD of ‘1-almost 
clear’.  Under Amendment 1, maintenance dosing determination will not be conducted at Week 24 for Cohort-Week 24. 
p The entire kit (every tube) should be weighed and recorded at every visit. See IP Handling Manual for details. 
q Compliance calculation is described in the IP Handling Manual 
r Any emergent AEs will be followed in the clinic for up to one month at the Investigator’s discretion until resolved or otherwise judged as clinically stable. 
s  This data will be obtained from Week 4 of ARQ-151-311/312/315 Study and used as the Day 1 data for this long-term safety study (ARQ-151-313).   
t   Under Amendment 1, this is the final visit for Cohort-Week 24 from ARQ-151-311 and ARQ-151-312.

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2. 
INTRODUCTION 
2.1. 
Background 
Refer to the current ARQ-151 Investigator’s Brochure (IB) for the most current PDE-4 dermal 
and oral/systemic nonclinical and clinical information.  
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. 
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.  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 a fear of using steroids termed corticosteroid phobia or corticophobia that has 
been documented in both healthcare providers and patients (Bos 2019).   
More recently, Eucrisa® (crisaborole), a PDE-4 inhibitor was approved for the topical treatment 
of mild to moderate atopic dermatitis in patients 3 months of age and older.  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). 
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). 

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2.2. 
Nonclinical Studies 
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 (DALIRESP PI 2020).  
To support the development of ARQ-151 topical cream, a GLP-compliant dermal toxicity 
program has been conducted.  To date, no new risks have been identified through the dermal 
toxicity program.  In 13-week dermal toxicity studies in mice and minipigs , and a 39-week 
dermal toxicity study in minipigs, no evidence of systemic toxicity was observed.  The NOAEL 
in both studies was the 1% concentration of ARQ-151 cream (20 mg/kg), the highest dose 
administered and the maximum feasible concentration. 
Local tolerance studies demonstrated ARQ-151 cream is not a skin sensitizer or eye irritant, and 
it does not have phototoxic potential. 
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 cream 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 is safe.  
2.3. 
Clinical Studies 
2.3.1. 
Topical Roflumilast Cream 
ARQ-151 cream has been evaluated in both plaque psoriasis (Phase 3 ongoing) and atopic 
dermatitis (through Phase 2).  The 0.3% concentration is used in psoriasis and the 0.15% and 
0.05% concentration are used in atopic dermatitis.  The safety data from the psoriasis studies are 
relevant to the atopic dermatitis development program. 
2.3.1.1. 
Psoriasis Phase 2a (ARQ-151-101) 
ARQ-151-101 (NCT03392168) was a Phase 2a study of two active doses of ARQ-151 cream, 
0.5% and 0.15% vs vehicle in the topical treatment of adult subjects with chronic plaque 
psoriasis of up to 5% BSA involvement.  
An initial cohort (Cohort 1) of 8 adult psoriasis subjects was treated with a single dose 
application of ARQ-151 cream 0.5% to a 25 cm2 area of psoriatic plaque on the trunk or 
extremities (not on the face, genital area, palms or soles. Local tolerability and systemic safety 
labs were monitored.  PK assessments were made at baseline (pre-dose), 1, 2, 4, 6 and 24 hours. 
Skin permeation of topically applied drug was ~0.4%. Local tolerability and systemic safety labs 
were unremarkable. Six Cohort 1 subjects plus 83 additional psoriasis subjects were then 
enrolled into Cohort 2, an inter-individual, parallel group, randomized and blinded assessment of 

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Oral roflumilast has been used for almost a decade in the treatment of COPD exacerbations and 
its safety profile is 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) can 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). In addition, 
parents/caregivers of subjects 2 to 5 years of age will be advised to promptly report any changes 
in behavior that could signal psychological distress or emotional distress. 
3. 
STUDY OBJECTIVES AND ENDPOINTS 
3.1. 
Study Objectives 
3.1.1. 
Primary Objective 
To assess long-term safety in a multicenter, open-label, single-arm study in subjects with atopic 
dermatitis treated with ARQ-151 cream 0.15% QD (subjects ≥6 years of age) or ARQ-151 cream 
0.05% QD (subjects 2 to 5 years of age) after completing one of three Phase 3 studies 
(ARQ-151-311 or ARQ-151-312 or ARQ-151-315).   
3.2. 
Study Endpoints 
3.2.1. 
Primary Endpoints 
The primary safety endpoints of this study are:  
• Adverse Events 
• Serious Adverse Events (SAEs)    
3.2.2. 
Secondary Endpoints 
The secondary endpoints of this study are:  
• Validated Investigator Global Assessment-Atopic Dermatitis (vIGA-AD) value 0 or 1 
at each assessment 
• 
vIGA-AD success (defined as vIGA-AD value of 0 or 1 plus a 2-grade improvement 
from baseline) 

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• WI-NRS score over time 
• EASI score over time 
4. 
INVESTIGATIONAL PLAN 
4.1. 
Overall Study Design and Plan 
This is a Phase 3, open-label, single-arm, long-term safety study in which ARQ-151 cream 
0.15% or ARQ‑151 cream 0.05% is applied QD x 24 (Cohort-Week 24) or 52 weeks to subjects 
with mild to moderate atopic dermatitis (except for time on BIW maintenance therapy).  
• Eligible subjects will enroll into the long-term safety study on the same day as the 
Week 4 visit of the preceding study (ARQ-151-311 or ARQ-151-312 or 
ARQ‑151‑315).  
• Subjects/caregivers will apply ARQ-151 cream 0.15% for subjects ≥ 6 years old or 
ARQ-151 cream 0.05% for subjects 2-5 years old.  
• If a 5 year-old subject turns 6 years-old during this study, the subject will be switched 
from ARQ-151 cream 0.05% to ARQ-151 cream 0.15% at his/her first scheduled 
post-birthday visit.  Dose reduction back to 0.05% is not permitted. 
• The study drug will be applied QD for 24 (Cohort-Week 24) or 52 weeks to all AD 
affected areas and any newly appearing AD lesions that arise during the study, except 
on the scalp (unless entering BIW maintenance therapy, as described below). 
• For the first 4 weeks of study ARQ-151-313, all subjects will apply study 
medication QD in the areas identified and treated as per the body diagram in the 
preceding study (ARQ-151-311/312/315).  Beginning at the Week 4 visit, any 
subject who achieves vIGA-AD of ‘0-clear’ as confirmed by the Investigator at a 
scheduled or unscheduled clinic visit, will switch to twice weekly (BIW) maintenance 
treatment.  For maintenance therapy, study medication will be applied on two 
nonconsecutive days per week (e.g. Monday and Thursday) to areas commonly 
and/or most recently affected by AD, and any areas where AD is developing.  
Subjects receiving maintenance treatment who experience AD worsening (signs and 
symptoms) for 1 week despite dosing twice weekly will phone the clinical study site, 
resume daily dosing, and complete the subject diary accordingly.  The phone call 
(but not a clinic visit) is required to resume daily dosing.  At clinic visits, subjects 
receiving maintenance treatment may continue twice weekly maintenance dosing if 
vIGA-AD is either ‘0-clear’ or ‘1-almost clear’.  Subjects will resume daily dosing if 
vIGA-AD ≥2, and can resume daily dosing if signs/symptoms of AD are not 
adequately controlled with maintenance therapy despite vIGA-AD of ‘1-almost 
clear’. 

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4.2. 
Number of Study Sites and Subjects 
A total of up to approximately 1500 subjects will be enrolled at up to approximately 120 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 males and females 2 years and older. 
Only subjects 18 years and older will be enrolled at sites located in the province of Québec in 
Canada.  Periodic clinic visits will include assessments for clinical safety, application site 
reactions, and disease improvement or progression.   
4.3. 
Subject Participation 
Subject participation involves a minimum of five clinic visits at Week 4, Week 12, Week 24, 
Week 36 and Week 52 of treatment. There will be three phone visits conducted at Weeks 18, 30 
and 44. (For Cohort-Week 24, subject participation involves a minimum of three clinic visits at 
Week 4, Week 12 and Week 24 of treatment. There will be one phone visit conducted at 
Week 18). The Day 1 visit of this study will be Week 4 of the ARQ-151-311 or ARQ-151-312 or 
ARQ-151-315 study. The baseline value for safety and efficacy will be the last observation prior 
to the first dose of ARQ-151 cream in either the ARQ-151 preceding study (ARQ-151-311 or 
ARQ-151-312 or ARQ-151-315), or this study. The anticipated maximum duration of subject 
participation is about 24 or 52 weeks. Subjects in the ARQ-151-311 or ARQ-151-312 or 
ARQ‑151‑315 study that choose to participate in the long-term extension study will transition 
directly into the ARQ-151-313 study at the Day 1 visit (Week 4 of Study ARQ-151-311 or 
ARQ‑151‑312 or ARQ-151-315). 
4.4. 
Numbering of Subjects 
All subjects enrolled will retain their unique six-digit subject ID number previously assigned 
during the ARQ-151-311 or ARQ-151-312 or ARQ-151-315 study.  
The study 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 2 years and older. (Only subjects 18 years and older will be 
enrolled at sites located in the province of Québec in Canada.) 

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8. Known or suspected:  
a. Severe renal insufficiency (defined as calculated creatinine clearance < 30mL/min)  
Refer to the creatinine levels from the following visits: 
• 
ARQ-151-311/ARQ-151-312 studies: Screening Visit for subjects ages 6-11 and 
Baseline/Day 1 for subjects ≥12 years old (for subjects 12-18 years old, if screening 
lab tests were collected within 3 weeks of Baseline/Day 1, screening results will be 
used) 
• 
ARQ-151-315 study: Screening Visit  
b. moderate to severe hepatic disorders (Child-Pugh B or C) 
c. history of severe depression, suicidal ideation or behavior 
9. Females who are pregnant, wishing to become pregnant during the study, or are 
breast-feeding. 
10. Subjects with any known serious medical condition (e.g., uncontrolled 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. 
11. Subjects with a history of chronic alcohol or drug abuse within 6 months of initiation of 
study medication. 
12. 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. 
13. Subjects and parent(s)/legal guardian(s) 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. 
14. Subjects who are family members of the clinical study site, clinical study staff, or 
sponsor, or family members of enrolled subjects (subjects enrolled in other studies of 
ARQ-151 cream) living in the same house. 
4.6. 
Study Restrictions 
4.6.1. 
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, 

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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. 
Non-medicated emollients, moisturizers and sunscreens can be applied to non-lesional and 
lesional skin. Subjects should maintain a stable moisturizer regimen and minimize changes to 
their moisturizer regimens and usual sunscreens. 
Table 2: 
Excluded Medications and Treatments 
Excluded Medications and Treatments 
Biologics including dupilumab and investigational biologics 
Systemic treatments that could affect AD; e.g. corticosteroids, retinoids, calcineurin inhibitors, 
hydroxycarbamide (hydroxyurea), methotrexate, cyclosporine, azathioprine, hydroxychloroquine, mycophenolate 
mofetil, or other immunosuppressive therapies. 
PUVA or NBUVB phototherapy, tanning beds, other light emitting devices 
Topical corticosteroids, calcineurin inhibitors, or Eucrisa® 
Strong cytochrome P-450 CYP3A4 inhibitors e.g., indinavir, nelfinavir, ritonavir, clarithromycin, itraconazole, 
ketoconazole, nefazodone, saquinavir, suboxone and telithromycin 
Strong cytochrome P-450 CYP3A4 inducers e.g., efavirenz, nevirapine, glucocorticoids, barbiturates 
(including phenobarbital), phenytoin, rifampin, and carbamazepine 
Systemic antibiotics, except short courses, e.g., <15 days 
Oral roflumilast (Daxas®, Daliresp®) 
All other investigational drugs 
 
Note:   
• 
No rescue therapy is permitted per protocol. 
• 
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. 
• 
Non-medicated emollients, moisturizers and sunscreens can be applied to non-
lesional and lesional  skin. Subjects should maintain a stable moisturizer regimen 
and minimize changes to their moisturizer regimens and usual sunscreens. 
• 
Concomitant other medications for chronic conditions (eg, 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.   

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4.7. 
Treatment 
4.7.1. 
IP Supplies, Packaging and Labeling 
ARQ-151 cream will be supplied in 45 or 60 gram tubes.  The tubes will be packaged in kits, 
containing multiple tubes of investigational product.  The kit(s) dispensed to a subject will be 
labeled with a unique number. 
The Sponsor will supply sufficient quantities of the study drug to each study site to allow for 
completion of this study. 
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 cream.  
4.7.2. 
Blinding 
This is an open label study, therefore the subjects, the Investigator, clinical personnel, and the 
sponsor will be aware of which treatment an individual subject receives. 
4.7.3. 
Treatment Administration 
Initial treatment with the IP in the ARQ-151-313 will occur on Day 1 (Day 29 from the 
preceding study). ARQ-151 cream 0.15% or ARQ-151 cream 0.05% is administered once daily 
(unless entering BIW maintenance therapy) as a topical product to cover the skin surface at an 
application rate of approximately 2 mg/cm2.   
At Day 1 visit, the study staff will redemonstrate 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 retrained 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 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). 
For the first 4 weeks of study ARQ-151-313, all subjects will apply study medication QD in the 
areas identified and treated as per the body diagram in the preceding study (ARQ-151-311/ 
312/315).  Beginning at the Week 4 visit, any subject who achieves vIGA-AD of ‘0-clear’ as 
confirmed by the Investigator at a scheduled or unscheduled clinic visit, will switch to twice 
weekly (BIW) maintenance treatment.  For maintenance therapy, study medication will be 
applied on two nonconsecutive days per week (e.g. Monday and Thursday) to areas commonly 

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and/or most recently affected by AD, and any areas where AD is developing.  Subjects receiving 
maintenance treatment who experience AD worsening (signs and symptoms) for 1 week despite 
dosing twice weekly will phone the clinical study site, resume daily dosing, and complete the 
subject diary accordingly.  The phone call (but not a clinic visit) is required to resume daily 
dosing.  At clinic visits, subjects receiving maintenance treatment may continue twice weekly 
maintenance dosing if vIGA-AD is either ‘0-clear’ or ‘1-almost clear’.  Subjects will resume 
daily dosing if vIGA-AD ≥2, and can resume daily dosing if signs/symptoms of AD are not 
adequately controlled with maintenance therapy despite vIGA-AD of ‘1-almost clear’.   
Note: 
• For daily dosing from Week 4 onwards, study medication should be applied to any 
areas where AD is active or developing, and areas commonly and/or most recently 
affected by AD.  
• All subjects should apply medication each evening (unless on BIW maintenance 
therapy) except on Day 1 when medication application will be done on site. If the 
subject takes an evening shower/bath, the ARQ-151 cream 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 has been applied until at least 2 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. 
• 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 Day 1 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. 
4.7.4. 
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.  Study 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). 

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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. 
If the diary shows less than 80% of expected 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. 
4.7.5. 
Removal of Subjects from Study Treatment 
A subject may discontinue study treatment for any of the following reasons: 
1. Occurrence of any medical condition or circumstance that, in the opinion of the 
Investigator, exposes the subject to substantial risk and/or does not allow the subject to 
adhere to the requirements for investigational product as per the Protocol. 
2. Adverse Events as described in 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 (score > 0). 
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. 
4.7.6. 
Removal of Subjects from the Study 
A subject may be removed from study participation for any of the following reasons:  
1. Subject death. 
2. Subject's decision to withdraw from study. 
3. 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. 

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4. Requirement for use of prohibited concomitant medication after consultation with the 
Sponsor and Medical Monitor. 
5. Subject’s repeated failure to comply with protocol requirements or study related 
procedures. 
6. The subject interrupts trial study drug application for more than 50% of scheduled doses.  
7. Termination of the study by the Sponsor, FDA, or other regulatory authorities. 
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 long-term safety and efficacy of ARQ-151 cream. Safety will be 
determined by evaluating physical examinations, local tolerability assessments, vital 
signs/weight, clinical laboratory parameters (subjects ≥12 years old), either PHQ-8 
(adults, ≥18 years old) or modified PHQ-A (adolescents, 12-17 years old) or Children’s 
Depression 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. 
Day 1 Visit 
At Day 1 (Week 4 of the ARQ-151-311 or ARQ-151-312 or ARQ-151-315 study) subjects from 
these preceding studies will be provided details of study requirements and sign an informed 
consent.  Subjects will continue with the safety and efficacy assessments specific to their age 
group at the time of consent/assent at Screening of the preceding study.  Medical and surgical 
history collected in the preceding study will be used in the ARQ-151-313 study.  Only new 
information and updates will need to be collected at Day 1 visit. Atopic dermatitis assessments 
(vIGA-AD, BSA, EASI, SCORAD), physical examination, vital sign measurements 
(blood pressure, heart rate, and temperature), WI‑NRS, CDI-2, DLQI, CDLQI, IDQOL, DFI, 
C-SSRS, POEM, and PHQ (-8 or -A), medical photography, laboratory tests: hematology, 
chemistry, urinalysis and a pregnancy test for female subjects of child bearing potential will be 
obtained at Week 4 visit of ARQ-151-311 or ARQ-151-312 or ARQ-151-315 study and will 
serve as the Day 1 for ARQ-151-313 subjects.  The baseline value for safety and efficacy will be 
the last observation prior to the first dose of ARQ-151 cream in either the ARQ-151 preceding study 
(ARQ-151-311 or ARQ-151-312 or ARQ-151-315), or this study.  
All subjects will retain their Subject ID from the preceding study which will be entered into the 
electronic subject tracking system for this long-term safety study.  

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5.1.2. 
Contraception Requirements 
Females of childbearing potential (FOCBP) must have a negative urine pregnancy test at Day 1 
of study ARQ-151-313. 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 according to 
Contraception Requirements (Figure 1). 
Figure 1: 
Contraception Requirements for Female Subjects 
 
5.1.3. 
Day 1 
Enrollment will take place at the Day 1 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.    
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, 

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5.1.7. 
Patient Health Questionnaire Depression Scale (PHQ-8) 
The PHQ-8 Assessment (Appendix 1) will be performed in adult subjects according to the 
Schedule of Visits and Assessments (Section 1.3). 
PHQ-8 score is the sum of the responses for the 8 questions. 
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)
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 2) 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 the Investigator in consultation with the mental health professional should 
consider interruption or discontinuation of the study drug. 

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5.1.9. 
Children’s Depression Inventory 2 (CDI-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 3. 
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. 
A subject with a CDI-2 raw total score of ≥32 should be referred to a mental health professional, 
and the Investigator 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 “Since Last Visit” version (Appendix 4) will be used at all visits.
•
A score greater than 0 at the 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 study 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. 

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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).  
At Day 1 only, local tolerability assessments should be recorded prior to study drug application 
for the Investigator assessment of skin irritation (Berger and Bowman skin irritation score). 
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 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 
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). 
At Day 1 only, local tolerability assessments should be recorded 10-15 minutes post-drug 
application for the Subject’s ‘0-3’ burning/stinging assessment. 

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The subject will assess burning/stinging (0-3 score), (For subjects <6 years of age, parents will 
complete.):  
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 study site at Day 1 and at every clinic visit. 
• Note: for subject burning stinging assessment at every clinic visit after Day 1, 
subjects will provide a recall assessment of burning/stinging experienced at most 
recent dosing. 
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). 
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. 
5.1.13. 
Phone Follow Up Visit 
Phone Follow Up Visits will be conducted according to the Schedule of Visits and Assessments 
(Section 1.3) for all subjects to review any adverse event or concomitant medication changes.  
5.2. 
Efficacy Evaluations 
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. 

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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 5). 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. 
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 
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% 

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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. 
Note: If a subject turns 8 years old during the study, the formula used at Screening of the 
preceding study will continue to be used through the duration of the subject’s participation in this 
study. 
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 once a week by the subject recording their worst itch over the 
past 24 hours. The scale is from ‘0 to 10’ (“no itch” to “worst itch imaginable” or “worst 
imaginable itch”). 
 
 
The WI-NRS will be self-reported by subjects for subjects ≥ 6 years of age, and reported by 
parent/guardian for subjects <6 years of age.  Subjects and/or parent/guardians will be reminded 
not to review responses from the previous weeks when completing the WI-NRS.  Parent and/or 
guardian will be trained at the baseline visit to assist the subject, if needed, in the accurate 

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completion of the WI-NRS. Caregiver/parents will be given instructions on how to complete this 
questionnaire for subjects between 2 and 5 years of age.   
WI-NRS Assessments will be performed according to the Schedule of Visits and Assessments 
(Section 1.3). 
5.2.4. 
Dermatology Life Quality Index (DLQI) and Children’s Dermatology Life 
Quality Index (CDLQI) 
The DLQI (ages 17+ years) and CDLQI (subjects >4 years of age and <16 years of age (based on 
age at start of preceding studies ARQ-151-311/312/315) will be performed according to the 
Schedule of Visits and Assessments (Section 1.3). Subjects who were assessed using CDLQI in 
their preceding study (ARQ-151-311/312/315) will remain on CDLQI in the current study 
(ARQ-151-313). 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 6 for the DLQI and Appendix 7 for the CDLQI.  
5.2.5. 
Infants’ Dermatitis Quality of Life Index (IDQOL) 
IDQOL (Appendix 8) will be performed according to the Schedule of Visits and Assessments 
(Section 1.3). The Infants' Dermatitis Quality of Life Index questionnaire is designed to assess 
the impact of atopic dermatitis on the quality of life of infants below the age of four 
years. Subjects who were assessed using IDQOL in their preceding study (ARQ-151-315) will 
remain on IDQOL in the current study (ARQ-151-313). 
It should be completed by the child’s parent(s) or regular caregiver. 
5.2.6. 
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 9). DFI is not to be conducted for subjects who were 
≤17 years of age in the ARQ-151-311/312 studies and turned 18 years of age prior to 
enrollment into ARQ-151-313.  
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).  

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5.3.2. 
SCORAD (“SCORing Atopic Dermatitis”) 
SCORAD assessments will be performed according to the Schedule of Visits and Assessments 
(Section 1.3). 
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.).  SCORAD total score will range between 
0 and 103.   
See Appendix 10.
5.3.3. 
Patient-Oriented Eczema Measure (POEM) 
POEM assessments will be performed according to the Schedule of Visits and Assessments 
(Section 1.3). 
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 11. 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 complete 
the questionnaire). 
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 under this Amendment 1: 
•
A single PK assessment (trough) will be performed in subjects ≥12 years old with a
blood sample collected at Week 52/ET.
•
No PK sample will be collected at Week 52/ET for subjects 2-11 years old.
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 study sites at 
all investigational visits, except Weeks 18, 30, and 44.  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. 

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5.4. 
Final Study Visit – End of Study 
The approximate final study visit will occur at Week 52, except for subjects in the Cohort-Week 
24, where the final study visit will occur at Week 24. The procedures performed during this visit 
are as described in the Schedule of Visits and Assessments (Section 1.3). A 7-day scheduling 
window is allowed for this visit. Adverse events will be recorded as reported by the 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 52 
visit. 
5.6. 
Unscheduled Visit 
Beginning at the Week 4 visit, any subject who achieves vIGA-AD of ‘0-clear’ as confirmed by 
the Investigator at a scheduled or unscheduled clinic visit, will switch to twice weekly (BIW) 
maintenance treatment.  For maintenance therapy, study medication will be applied on two 
nonconsecutive days per week (e.g. Monday and Thursday) to areas commonly and/or most 
recently affected by AD, and any areas where AD is developing.  Subjects receiving maintenance 
treatment who experience AD worsening (signs and symptoms) for 1 week despite dosing twice 
weekly will phone the clinical study site, resume daily dosing, and complete the subject diary 
accordingly.  The phone call (but not a clinic visit) is required to resume daily dosing.   
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  
• Local tolerability assessment (by Investigator) 
However, if an unscheduled visit is required for reasons other than safety (e.g. procedures such 
as labs or images that were either missed at the regular subject visit or need to be repeated), the 
vIGA-AD and EASI, BSA affected with AD, and Local Tolerability assessment (by Investigator) 
are not required. 
The rules for how to tally vIGA-AD, BSA or other proportions of categorical responses will be 
described in the Statistical Analysis Plan. 

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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 Day 1 visit of study ARQ-151-313 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.   
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) 

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• 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.  
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.  

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5.7.4. 
Safety Review with Subject 
At each subsequent clinic visit after the Day 1 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 in the 
ARQ-151-313 study 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: 
 
 
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 
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 
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• 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. 
 
 
 

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Note:  
*
A semi-colon indicates ‘or’ within the description of the grade.
*
Instrumental activities of daily living refer to preparing meals, shopping for groceries
or clothes, using the telephone, managing money, etc.
** Self-care activities of daily living refer to bathing, dressing and undressing, feeding 
self, using the toilet, taking medications, and not bedridden. 
AEs will be coded using the most current MedDRA® version available at the time of database 
lock. 
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 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 severe (Grade 3) laboratory abnormality (confirmed by repeat sample and
considered related to study drug [Appendix 12]).

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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.  
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. 
A subject 2 to 5 years of age that is exhibiting behavioral changes that may signal psychological 
or emotional distress should be evaluated immediately by the investigator to determine if referral 
to a qualified mental health care provider is necessary, and consideration should be given to 
discontinuing study drug. 
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. 
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. 
Full details of the statistical analysis will be included in the Statistical Analysis Plan (SAP). 
Data from this study may be analyzed prior to the final analysis for regulatory reporting 
purposes. Under Amendment 1, subjects 6-17 years of age that have completed the 4-week 
treatment period in ARQ-151-311 or ARQ-151-312 will be treated for 24 weeks with ARQ-151 
cream 0.15% (Cohort-Week 24).  The rest of the subjects will be treated for up to 52 weeks with 
ARQ-151. The analysis will be performed by cohorts and overall over time.    

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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.  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.  
6.2. 
Determination of Sample Size 
There are approximately 1500 subjects planned for this study.  
The sample size will provide a sufficient number of subjects to evaluate the long-term safety of 
ARQ-151 cream 0.15% or ARQ-151 cream 0.05% over 24 or 52 weeks of treatment, and in 
combination with other studies provide the development program with sufficient numbers of 
subjects to meet ICH exposure goals. 
6.3. 
Subjects to Analyze 
The safety populations are defined as all subjects who are enrolled and received at least one 
confirmed dose of study medication.  
Pharmacokinetic Population (PK): The PK population includes all subjects receiving 
active drug and had a PK draw (concentration data available) post-baseline. This population will 
be used for the analysis of PK concentrations.  
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 enrolled subjects.   
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, Q1, Q3, 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.   

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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. 
6.7. 
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 of the ARQ-151-313 study. 
6.8. 
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. 
6.9. 
Clinical Laboratory Results and Vital Signs 
All clinical laboratory results (subjects ≥12 years old) and vital signs measurements will be 
summarized descriptively by parameter, visit, and treatment group along with time point of 
collection.  
A shift from baseline table describing out-of-normal range shifts will be provided for clinical 
laboratory results.  
A shift from baseline table will identify subjects who gain or lose >5% body weight over the 
course of the study. 
6.10. 
Prior and Concomitant Medications 
Prior and concomitant medication information for all enrolled 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. 
6.11. 
vIGA-AD 
The proportion of subjects who attain IGA scores of 0 or 1 and IGA success at each assessment 
time will be summarized. IGA scores will be summarized descriptively by visits over time. 
6.12. 
EASI 
EASI will be summarized descriptively by visits over time. 
6.13. 
WI-NRS 
WI-NRS will be summarized descriptively by visits over time. 

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6.14. 
Body Surface Area 
Body surface area (BSA) affected by AD will be summarized descriptively by visits over time. 
6.15. 
Subject Reported Outcomes Analyses 
6.15.1. 
Dermatology Life Quality Index, Children’s Dermatology Life Quality Index, 
IDQOL, SCORAD and POEM  
Dermatology Life Quality Index (DLQI), Children’s Dermatology Life Quality Index (CDLQI), 
Infants’ Dermatitis Quality of Life (IDQOL), 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 (change from baseline and percent change 
from baseline) by visits over time.  These efficacy endpoints will be analyzed descriptively. 
7. 
STUDY ADMINISTRATION 
7.1. 
Ethics 
7.1.1. 
Ethics Review Board 
Before screening of subjects into the study, the current protocol, ICF/assent, and any 
accompanying material to be provided to the subjects will be reviewed and approved by an 
appropriate IRB or EC, as required by FDA (21 CFR § 56), Health Canada, and ICH GCP 
regulations.  A letter documenting the IRB or EC approval must be received by the Sponsor 
(or delegate) before the initiation of the study at a clinical study 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 or EC requirements. As soon 
as possible after completion or termination of the study, the Investigator will submit a final 
report to the IRB or EC per the IRB requirements, and in compliance with FDA and Health 
Canada regulations and ICH GCP guidelines. 
The Investigator, the Sponsor, or designee shall promptly notify the IRB or EC 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). 

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7.1.3. 
Subject Information and Consent/Assent 
The investigator is responsible for obtaining written informed consent from each individual 
participating in this study and/or their parents/caregivers 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 EC-approved consent form for 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 EC or local 
requirements. 
Subjects will be given a signed copy of their ICF/assent. 
7.2. 
Study Monitoring 
Prior to the initiation of the clinical investigation, Sponsor representatives or designees may visit 
the clinical study 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 study 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 study site and the Sponsor. 
The Sponsor or authorized designees may inspect all documents and records required to be 
maintained by the Investigator, including but not limited to medical records (office, clinic, or 
hospital) and investigational product dispensation logs for the subjects in this clinical 
investigation.  The Investigator must permit access to such records.  The Investigator must 
obtain, as part of informed consent, permission for an authorized representative of the Sponsor, 
or regulatory authorities, to review, in confidence, any records identifying subjects. 
7.3. 
Study Completion and Termination 
7.3.1. 
Study Completion 
The study is considered completed with the last visit of the last subject participating in the study. 
The final data from the study site will be sent to the Sponsor (or designee) after completion of 
the final subject visit at that study site, in the time frame specified in the Clinical Trial 
Agreement. 
7.3.2. 
Study Termination 
The Sponsor reserves the right to close the study site or terminate the study at any time for any 
reason at the sole discretion of the Sponsor. Study sites will be closed upon study completion. An 
study site is considered closed when all required documents and study supplies have been 

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collected and a study site closure visit has been performed. The investigator may initiate study 
site closure at any time, provided there is reasonable cause and sufficient notice is given in 
advance of the intended termination.  
Reasons for the early closure of a study site by the Sponsor or investigator may include but are 
not limited to: 
• Failure of the investigator to comply with the protocol, the Sponsor’s procedures, or 
GCP guidelines. 
• Inadequate recruitment of subjects by the investigator. 
• Discontinuation of further drug development. 
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 
study sites at appropriate intervals throughout the study.  The results of these periodic study 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.  

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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)/EC(s) will 
be promptly notified. 
No deviation from the protocol will be made except to protect the life or physical well-being of a 
subject in an emergency.  Except in such emergencies, prior approval of the Sponsor, and the 
IRB, is required before deviations from the planned protocol.  All protocol deviations that occur 
during the study will be documented and reported to Sponsor and to the IRB(s)/EC(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 and Protocol 
Deviation Management Plan (PDMP).  
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)/EC(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 and PDMP. 
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. IRB [or] EC. 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. 

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7.9. 
Report Format 
According to the ICH Harmonized Tripartite Guideline (Organization of the Common Technical 
Document for the Registration of Pharmaceuticals for Human Use M4 and the ICH M2 Expert 
Working Group), the final report will be written according to the ICH E3 Guideline 
(Structure and Content of Clinical Study Reports).  
7.10. 
Publication Policy 
The Sponsor is supportive of publishing clinical trial findings.  Any form of publication that is 
derived from this study must be submitted to Arcutis Biotherapeutics, Inc. for review and 
approval. The process of coordinating publication efforts is detailed in the Clinical Trial 
Agreement. 
 
 

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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. 
Bos B, Antonescu I, Osinga H, et al. Corticosteroid phobia (corticophobia) in parents of young 
children with atopic dermatitis and their health care providers. Pediatr Dermatol. 
2019;36(1):100-104.  
DALIRESP (roflumilast) tablets [package insert]. AstraZeneca Pharmaceuticals LP, Wilmington, 
DE USA; 2020. 
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.  
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. 
ICH E1A The Extent of Population Exposure to Assess Clinical Safety: For Drugs Intended for 
Long-term Treatment of Non-Life-Threatening Conditions. FDA Guidance Document. 
March 1995. 
Investigator’s Brochure, Edition 4.0, 22 January 2021. 
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. 
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. 

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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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9.
APPENDICES
APPENDIX 1. 
PATIENT HEALTH QUESTIONAIRE-8 (PHQ-8) 

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APPENDIX 2. 
PATIENT HEALTH QUESTIONNAIRE DEPRESSION 
SCALE (MODIFIED PHQ-A) 

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APPENDIX 3. 
CHILDREN’S DEPRESSION INVENTORY 2 
(PARENT REPORT) 

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APPENDIX 4. 
COLUMBIA-SUICIDE SEVERITY RATING SCALE 
(C-SSRS) “SINCE LAST VISIT” VERSION 

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APPENDIX 5. 
VALIDATED INVESTIGATOR GLOBAL ASSESSMENT 
SCALE FOR ATOPIC DERMATITIS 

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APPENDIX 6. 
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 7. 
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 
□

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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 8. 
INFANTS' DERMATITIS QUALITY OF LIFE INDEX 
(IDQOL) 

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APPENDIX 9. 
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 


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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 
 
 

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APPENDIX 10. SCORAD 
SCORAD https://www.ncbi.nlm.nih.gov/pubmed/8435513

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APPENDIX 11. PATIENT-ORIENTED ECZEMA MEASURE (POEM) 

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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.