A Phase 3, 4-Week, Parallel Group, Double Blind, Vehicle-Controlled Study of the Safety and Efficacy of ARQ-151 Cream 0.05% Administered QD in Subjects With Atopic Dermatitis
Phase: PHASE3
Conditions: Atopic Dermatitis Eczema
Sponsor: Arcutis Biotherapeutics, Inc.

Confidential 
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Protocol ARQ-151-315 
A Phase 3, 4-Week, Parallel Group, Double Blind, Vehicle-Controlled 
Study of the Safety and Efficacy of ARQ-151 Cream 0.05% 
Administered QD in Subjects with Atopic Dermatitis 
 
Sponsor: 
Arcutis Biotherapeutics, Inc. 
 
3027 Townsgate Road, Suite #300 
 
Westlake Village, CA 91361 
 
Sponsor Representative: 
 
 
 
 
 
 
 
 
Medical Monitor:  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
IND Number:  
 
 
Protocol Version: 
Amendment 2 
 
Date:  
10 April 2023 
 
 
GCP Statement 
This study is to be performed in full compliance with the protocol, International Conference on Harmonisation 
GoodClinical Practices (ICH GCP), and applicable regulatory requirements. All required study documentation will 
be archived as required by regulatory authorities. 
 
Confidentiality Statement 
This document contains confidential information. It contains proprietary information of Arcutis Biotherapeutics, 
Inc.. Any viewing or disclosure of such information that is not authorized in writing by Arcutis Biotherapeutics, 
Inc.. is strictly prohibited. Such information may be used solely for the purpose of reviewing or performing this 
study. 

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SITE INVESTIGATOR SIGNATURE PAGE 
 
ARQ-151-315 
A Phase 3, 4-Week, Parallel Group, Double Blind, Vehicle-Controlled Study of the Safety and 
Efficacy of ARQ-151 Cream 0.05% Administered QD in Subjects with Atopic Dermatitis 
 
SPONSOR: 
Arcutis Biotherapeutics, Inc. 
3027 Townsgate Road, Suite #300 
Westlake Village, CA 91361 
 
ISSUE DATE: 
10 April 2023 
 
 
I have read this protocol, including all appendices, and I agree that it contains all necessary 
details for me and my staff to conduct this study as described. I will conduct this study as 
outlined herein, in accordance with the current International Conference on Harmonisation Good 
Clinical Practices (ICH GCPs) and applicable local and regional regulations. 
 
I will provide all study personnel under my supervision copies of the protocol and access to all 
information provided by Arcutis Biotherapeutics, Inc.  I will discuss the material with them to 
ensure that they are fully informed about ARQ-151 and the study. 
 
I agree that I or my designee will completely inform all subjects in this study concerning the 
pertinent details and purpose of the study prior to their agreement to participate in the study in 
accordance with cGCPs and regulatory authority requirements. I will be responsible for 
maintaining each subject’s consent form in the study file and providing each subject with a 
signed copy of the consent form. 
 
I agree to maintain the confidentiality of all information received or developed in connection 
with this protocol. 
 
Investigational Site Name:  
 
 
 
 
 
 
 
 
 
       
 
Print Investigator Name:       
 
 
 
 
 
 
 
 
 
 
Investigator Signature: ________________________________  
  Date:  _______________ 
 
 
 

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1. 
SYNOPSIS 
Name of Sponsor/Company: Arcutis Biotherapeutics, Inc. 
Name of Investigational Product: ARQ-151 will be supplied as an emollient cream at 0.05% strength 
or as a matching vehicle cream containing only excipients of ARQ-151  
Name of Active Ingredient: Roflumilast, a PDE-4 inhibitor 
Protocol Number:  
ARQ-151-315 
Phase: 3 
Country: US, Canada, and 
Poland 
Title of Study:  
A Phase 3, 4-Week, Parallel Group, Double Blind, Vehicle-Controlled Study of the Safety and Efficacy 
of ARQ-151 Cream 0.05% Administered QD in Subjects with Atopic Dermatitis 
Clinical Indication:  Atopic Dermatitis 
Number of Sites: Approximately 109 in the US, Canada, and Poland. During the conduct of the study, 
additional countries and/or sites may be added if necessary. 
Study Population:  
Subjects will be male and female children (2-5 years old, inclusive). Subjects will have mild to 
moderate atopic dermatitis involvement with a vIGA-AD score of ‘2’ (mild) or ‘3’ (moderate) for 
study entry. Approximately 650 subjects are planned to be randomized in this study. 
Objectives:  
Primary: 
To assess the safety and efficacy of ARQ-151 cream 0.05% vs vehicle administered QD x 4 weeks to 
subjects aged 2-5 years with atopic dermatitis. 
Summary of Study Design:  
This is a Phase 3, parallel group, double blind, vehicle-controlled study in which ARQ-151 cream 
0.05% or vehicle is applied QD x 4 weeks to subjects aged 2-5 years with mild to moderate atopic 
dermatitis. 
At entry, subjects will have ≥3% BSA involvement (excluding the scalp, palms, soles) and mild or 
moderate atopic dermatitis (AD) based on vIGA-AD assessment.   
Upon determination of eligibility, subjects will be randomized 2:1 to either ARQ-151 cream 0.05% or 
matching vehicle cream.  The randomization will be stratified by vIGA-AD score at baseline 
(‘Mild’ vs. ‘Moderate’), and by study site. 
Caregivers will apply ARQ-151 cream 0.05% or vehicle cream QD to all AD affected areas and any 
newly appearing AD lesions that arise during the study, except on the scalp. Caregivers should 
maintain treatment of these areas with study drug for the duration of the study regardless of whether 
treatable areas of AD clear prior to Week 4/Day 29. 
At the Week 4 visit, subjects may be eligible to enroll in a 12‑month, open label extension study 
(ARQ-151-313) evaluating ARQ-151 cream 0.15% QD and 0.05% QD. All subjects will have the 
option to enroll into the ARQ-151-313 study. 

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Methodology:  
This is a blinded study with a randomization scheme of 2 to 1 for the following treatment group: 
• 
Approximately 433 subjects will receive ARQ-151 cream 0.05% QD 
• 
Approximately 217 subjects will receive matching cream vehicle QD 
The primary comparison will be performed at the 2.5% significance level and will include: 
• 
ARQ-151 cream 0.05% vs. vehicle cream 
Sample Size Justification: 
Approximately 650 subjects are planned to be randomized in this study. To test the secondary endpoint 
of IGA success in subjects with a vIGA-AD score of ‘Moderate’ at randomization, approximately 
490 of the subjects to be accrued will have vIGA‑AD score of ‘Moderate’ at randomization.  
Randomization will be stratified by vIGA-AD score (‘Mild’ vs. ‘Moderate’), and study site. 
This sample size provides more than 90% power to detect 15% difference between treatment groups on 
vIGA‑AD success at Week 4 at α=0.025 using a 2-sided stratified Cochran-Mantel-Haenszel test.  The 
results from a recent Phase 2 study (ARQ‑151-212) of ARQ-151 cream 0.05% compared to vehicle 
treatment were used to estimate the treatment difference.  The vIGA-AD success rate at Week 4 was 
38% in the ARQ-151 cream 0.05% group compared to 22% in the vehicle.  Similarly, 37% of subjects 
demonstrated vIGA-AD success at Week 4 in the ARQ-151 cream 0.15%. This sample size also 
provides more than 80% power to detect 15% difference between treatment groups on IGA success at 
Week 4 among subjects with vIGA-AD score ‘Moderate’ at randomization.  The same testing method, 
the stratified Cochran-Mantel-Haenszel test, will be used as for the primary endpoint. 
Number of Patients (planned):  
Approximately 650 subjects; randomized 2:1 to ARQ-151 cream 0.05%: vehicle 
Duration of Treatment:  
Screening (up to 30 days) + Treatment phase (4 weeks) for a total of about 8 weeks. 
Upon completion of the treatment phase of the study (Week 4/Day 29) subjects may have the 
opportunity, to participate in an open-label extension study (ARQ‑151-313) of up to 52 weeks 
(12 months). 
Main Criteria for Inclusion:  
1. 
Informed consent of parent(s) or legal guardian as required by local laws. 
2. 
Males and females, ages 2 to 5 years old (inclusive) at time of signing the Informed Consent 
(Screening) and at Baseline/Day 1.  
3. 
Diagnosed with mild to moderate atopic dermatitis according to the criteria of  
Hanifin and Rajka (1980) prior to or at the screening visit.  Subjects must have at least 3 of the 
4 basic features per Hanifin and Rajka (1. Pruritus; 2. Typical morphology and distribution 
[facial and extensor eruptions in infants and children]; 3. Chronic or chronically relapsing 
dermatitis; or 4. Personal or family history of atopy), in addition to 3 or more minor criteria. 
4. 
History of AD for at least 6 weeks as determined by the Investigator through subject interview. 
Stable disease for the past 4 weeks with no significant flares in atopic dermatitis before 
screening. 
5. 
EASI Score >5 at Baseline/Day 1.  EASI is evaluated for the entire body except the scalp, 
palms, and soles. 

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6. 
vIGA-AD score of ‘Mild’ (‘2’) or ‘Moderate’ (‘3’) at Baseline/Day 1. The vIGA-AD is 
evaluated for the entire body except the scalp, palms, and soles. 
7. 
Has AD involvement of >3% BSA at Baseline/Day 1 (excluding the scalp, palms, soles).  
8. 
In good health as judged by the Investigator, based on medical history, physical examination, 
vital signs, serum chemistry labs, and hematology values. 
9. 
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. 
Main Criteria for Exclusion:  
1. 
Subjects with any serious medical condition or clinically significant laboratory, vital signs, or 
physical examination abnormality that would prevent study participation or place the subject at 
significant risk, as judged by the Investigator. 
2. 
Subjects who cannot discontinue medications and treatments prior to the Baseline visit and 
during the study according to Excluded Medications and Treatments (Table 1). 
3. 
Has unstable AD or any consistent requirement for high potency topical steroids to manage AD 
signs or symptoms. 
4. 
Subjects who have significant active systemic or localized infection (e.g., molluscum 
contagiosum), including known actively infected AD, or have had any infection that required 
oral or intravenous administration of antibiotics, antifungal or antiviral agents within 14 days 
prior to Baseline/Day 1 and during the study. 
5. 
Subjects who are unwilling to refrain from prolonged sun exposure for 4 weeks prior to 
Baseline/Day 1 and during the study. 
6. 
Subjects with skin conditions other than AD that would interfere with evaluations of the effect 
of the study medication on AD, as determined by the Investigator.  Subjects with any condition 
on the treatment area which, in the opinion of the Investigator, could confound efficacy 
measurements, e.g., molluscum contagiosum. 
7. 
Subjects with known genetic dermatological conditions that overlap with AD, such as 
Netherton syndrome. 
8. 
Known allergies to excipients in ARQ-151 cream 
 
 
  
9. 
Subjects who cannot discontinue the use of strong cytochrome P-450 CYP3A4 inhibitors 
e.g., indinavir, nelfinavir, ritonavir, clarithromycin, itraconazole, ketoconazole, nefazodone, 
saquinavir, suboxone and telithromycin for 2 weeks prior to the baseline visit and during the 
study period.  
10. Subjects who cannot discontinue the use of strong cytochrome P-450 CYP3A4 inducers 
e.g., efavirenz, nevirapine, glucocorticoids, barbiturates (including phenobarbital), phenytoin, 
and rifampin and carbamazepine for 2 weeks prior to the baseline visit and during the study 
period.  
11. Subjects who have received oral roflumilast (Daxas®, Daliresp®) within the past 4 weeks 
prior to Baseline/Day 1. 
12. Known or suspected:  
a. Severe renal insufficiency  
− 
Severe renal insufficiency is defined as calculated creatinine clearance <30 mL/min 

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b. Moderate to severe hepatic disorders (Child-Pugh B or C) 
13. Previous treatment with ARQ-151. 
14. Subjects currently undergoing allergy testing (e.g., food allergy testing or skin prick testing), 
patch testing, food challenges, or allergy desensitization, or plan to do so during the study. 
15. Subjects with any serious known medical condition or clinically significant laboratory 
abnormality that would prevent study participation or place the subject at significant risk, as 
determined by the Investigator. 
16. Subjects with a history of a major surgery within 4 weeks prior to Baseline/Day 1 or subjects 
who have a major surgery planned during the study. 
17. Any history of cancer.  
18. Parent(s)/legal guardian(s) who are unable to communicate, read, or understand the local 
language(s).  Subjects who display any condition which in the Investigator’s opinion, makes 
them unsuitable for clinical study participation. 
19. 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) living in 
the same house. 
Investigational Product, Dosage and Mode of Administration:  
ARQ-151 cream 0.05% or matching vehicle cream is to be applied topically QD to all atopic dermatitis 
(AD) affected areas and any newly appearing AD lesions that arise during the 4-week study, except on 
the scalp. Caregivers should maintain treatment of these areas with study drug for the duration of the 
study regardless of whether treatable areas of AD clear prior to Week 4. 
Key Assessments:  
• 
Safety will be monitored through local tolerability assessments, vital signs, physical 
examination, safety labs, and AEs. Parents/caregivers will be advised to promptly report any 
changes in behavior that could signal psychological distress or emotional distress. 
o 
After obtaining consent, all SAEs should be collected. After application of the first dose 
of Investigational Product, all AEs should be collected. 
o 
The investigator or a properly trained and designated sub-investigator will perform local 
tolerability assessments at Baseline/Day 1, and Weeks 1, 2, and 4 (Days 8, 15, and 29). 
Subjects will have vital signs measured at each study visit. Height will be collected at 
Visit 1 (Screening) and Week 4/Day29. 
o 
A limited physical exam (skin, lungs, and heart only) will be performed at Screening, 
Baseline/Day 1 and Week 4/Day 29. Blood samples for routine safety laboratory tests 
(hematology, serum chemistry) will be obtained at Screening. 
• 
Efficacy will be assessed using: 
o 
vIGA-AD 
o 
EASI 
o 
WI-NRS 
o 
BSA 
o 
CDLQI (for 4-5 years old) 
o 
IDQoL (for 2-3 years old) 
o 
DFI 

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o 
SCORAD 
o 
POEM 
Study Endpoints:  
Primary Efficacy Endpoint: 
IGA Success, defined as a vIGA-AD score of ‘clear’ or ‘almost clear’ PLUS a 2-grade improvement 
from Baseline at Week 4. 
Secondary Efficacy Endpoints: 
• 
In subjects with vIGA-AD score of ‘Moderate’ at randomization, IGA Success at Week 4 
• 
Achievement of at least 75% reduction in the Eczema Area and Severity Index (EASI-75) at 
Week 4  
• 
vIGA-AD score of ‘clear’ or ‘almost clear’ at Week 4 
• 
vIGA-AD Success at Week 2 
• 
vIGA-AD of ‘clear’ or ‘almost clear’ at Week 2 
• 
vIGA-AD success at Week 1 
• 
vIGA-AD of ‘clear’ or ‘almost clear’ at Week 1 
Criteria for Evaluation: 
Safety: 
The safety population will include all subjects who are randomized 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 incidence of adverse events will be summarized as well as changes from baseline in vital signs. 
Statistical Methods: 
Subjects will be stratified by Baseline vIGA-AD score (‘Mild’ and ‘Moderate’) and by study site. 
• 
The primary endpoint will be tested in all randomized subjects 
The primary endpoint will be analyzed using a Cochran-Mantel-Haenszel (CMH) test stratified by 
baseline vIGA-AD score.  Statistical significance will be concluded at the 2.5% significance level 
(2-sided). 
To control for familywise type I error at level of 0.025, the remaining secondary endpoints will be 
tested sequentially at an alpha level of 0.025 upon successful demonstration of statistical significance 
for the primary endpoint.   
The analysis populations are defined as follows: 
• 
Intent-to-Treat (ITT) population will include all subjects who are randomized. 
• 
Per protocol (PP) population will include all subjects in the ITT population, who are at least 
80% compliant with study medication application, have a vIGA-AD assessment within the 
Week 4 visit window, and show no major deviations from the study protocol that would affect 
the interpretation of efficacy.  
• 
vIGA-AD Moderate ITT population will be a subset of the ITT population with vIGA-AD 
score ‘Moderate’ at randomization. 

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• 
The WI-NRS population will be a subset of the ITT population who: 
o Parent/caregiver completed at least 4 of 7 evaluable daily WI-NRS questionnaires during 
the last 7 days of the Screening period; 
o Have a mean baseline WI-NRS score ≥4.0, defined as the average of all non-missing 
scores reported during the last 7 days of the Screening period. 
• 
Safety population will include all subjects who are enrolled and received at least one 
confirmed dose of study medication. 
Descriptive statistics for continuous variables will include mean, median, standard deviation, Q1, Q3, 
min, max. Descriptive statistics for categorical variables will include frequencies and percentages. For 
missing data, the primary imputation method and sensitivity methods will be detailed in the SAP. The 
primary endpoint and secondary endpoint of vIGA-AD success will be analyzed with a 
Cochran-Mantel-Haenszel test stratified by disease severity determined by baseline vIGA-AD used to 
stratify randomization. 
Categorical efficacy analysis will be analyzed in the same manner as the primary endpoint.   
The incidence of adverse events will be summarized as well as changes in laboratory parameters and 
vital signs. 
 
 
 

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1.1. 
Study Schema 
 
 

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2. 
SCHEDULE OF VISITS AND ASSESSMENTS 
Study Procedure 
Screen 
Baseline 
Day 1 
Week 1 
Day 8 
Week 2 
Day 15 
Week 4 
Day 29/ET 
Visit 
1 
2 
3 
4 
5 
Visit Window 
-30 days 
N/A 
± 3 days 
± 3 days 
± 3 days 
Parents/Caregivers informed consent 
X 
 
 
 
 
Demographics 
X 
 
 
 
 
Medical and surgical history 
X 
 
 
 
 
Physical examinationa 
X 
X 
 
 
X 
I/E criteria 
X 
X 
 
 
 
Hematology and Serum Chemistriesb 
X 
 
 
 
 
Vital signs, weight, heightc 
X 
X 
X 
X 
X 
vIGA-ADd, EASId, BSAd, SCORADd 
X 
X 
X 
X 
X 
WI-NRS prurituse 
X 
X 
X 
X 
X 
POEMf 
X 
X 
X 
X 
X 
Local Tolerability Assessmentsg 
 
X 
X 
X 
X 
CDLQIh, IDQoLh, DFIh 
X 
X 
X 
X 
X 
Medical Photographyi 
 
X 
X 
 
X 
Drug application and 
Parents/Caregivers training in clinicj 
 
X 
X 
X 
 
Dispense/Redispense investigational 
product kitk 
 
X 
X 
X 
Xl 
Weigh investigational product tubesl 
 
X 
X 
X 
X 
Dispense/review diary 
X 
X 
X 
X 
 X 
Compliance determinationm 
 
 
X 
X 
X 
Adverse event assessmentn 
X 
X 
X 
X 
X 
Concomitant medications 
X 
X 
X 
X 
X 
Study Exito 
 
 
 
 
X 
a. Limited physical examination: skin (including assessment of Fitzpatrick skin type at Screening only), lungs, and 
heart only. 
b. To be collected at Screening.  In addition, laboratory safety tests may be performed at various unscheduled time 
points, if deemed necessary by the Investigator. 
c. Height will be collected at Screening and Week 4/Day 29. 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). Measure the weight in triplicate and report the average weight in EDC. A 
5% weight loss (whether or not intentional or other explained) should be reported to the medical monitor in a 
timely manner and before the next clinic visit. 

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Footnotes from above table: 
d. The vIGA-AD assessment will be a 5-point scale ranging from clear (0) to severe (4) and is evaluated for the 
entire body except the scalp, palms, and soles. EASI takes into account overall severity of erythema, 
infiltration/papulation, excoriation, and lichenification, in addition to extent of BSA affected. The 4 clinical signs 
will be graded on a 4-point scale (0 [absent] to 3 [severe]) for 4 body regions (head and neck, upper extremities, 
lower extremities, and trunk). Total EASI score will be calculated as a sum of scores of all 4 body regions. EASI 
total score will range from 0 (absent) to 72 (severe). Total BSA affected by AD will be determined for all body 
surfaces except the scalp, palms and soles. The vIGA-AD assessment should be completed prior to other 
physician assessments. SCORAD total score will range between 0 and 103. 
e. Parents/guardians/caregivers of children will report pruritus at home on a daily basis starting 7 days prior to the 
Baseline/Day 1 visit, and then every day thereafter using a diary. WI-NRS score will be determined by assessing 
worst itch over the past 24 hours. The scale is from 0 (no itch) to 10 (worst itch) and this value will be recorded 
each day.  Caregiver/parents will be given instructions on how to complete this questionnaire.   
f. POEM will be completed for all subjects by proxy completion. 
g. Local tolerability assessments should be recorded prior to study drug application for the Investigator assessment 
of skin irritation (Berger and Bowman skin irritation score) and 10-15 minutes post-drug application for the 
Subject’s ‘0-3’ burning/stinging assessment. Parents/guardians will complete assessment for subjects. Subject’s 
burning stinging assessment at Week 4/Day 29 will be provided by a recall assessment of burning/stinging 
experienced post drug application on the previous day (Day 28). Note for Investigator tolerability 
assessments: reactions at the site of product application, which may occur post-Baseline, should be 
differentiated from the preexisting inflammation associated with the subject’s atopic dermatitis. If a 
subject is entering ARQ-151-313 Open Label Extension study, then the Subject’s ‘0-3’ burning/stinging 
assessment will be performed as described in the ARQ-151-313 protocol for Baseline/Day 1.  
h. The CDLQI will be completed by parents/caregivers for subjects ≥4 years of age. The IDQoL will be completed 
by parents/caregivers for subjects <4 years. The Dermatitis Family Impact Questionnaire (DFI) will be 
completed by parents/caregivers for all subjects. 
i. Photography of AD lesion(s) selected by the Investigator will be performed at all investigational sites. All efforts 
will be made to de-identify the subjects. Canfield equipment will be used to capture photographs. Subjects who 
are unwilling to participate in the medical photography will be allowed to opt out of this procedure, as 
documented on the Informed Consent Form. 
j. Subjects to apply assigned IP during clinic visits, except for the Day 29/ET visit. If a subject is entering 
ARQ-151-313 Open Label Extension study, then subjects will apply IP as described in the ARQ-151-313 
protocol for Baseline/Day 1. 
k. It is expected that kits will be dispensed based on %BSA affected. See IP Handling Manual for details. On Day 8 
and 15, dispensing of IP is optional.  Site should review IP kit to ensure sufficient IP is available until the next 
visit and only dispense additional IP if needed. On Day 29, if the subject is unable to perform the Day 29 clinic 
visit due to COVID-19 restrictions (isolation, quarantine, etc.) then additional IP may need to be dispensed using 
Unscheduled Visits or home delivery of IP, so IP can continue to be applied at home until the subject is able to 
return to the clinic to complete the Day 29 assessments (contact sponsor representative for guidance).   
l. Every tube should be weighed and recorded when dispensed and returned. See IP Handling Manual for details. 
m. Compliance determination is described in the IP Handling Manual and in Section 6.10.4 of this protocol. 
n. All AEs should be collected starting after the first application of the investigational product through the end of 
the study. All SAEs should be collected starting after the signing of informed consent through 30 days after the 
last day of the application of the investigational product or the end of the study (whichever is later). Any AEs 
(whether serious or non-serious) and clinically abnormal laboratory test value(s) will be evaluated by the 
Principal Investigator (PI) and treated and/or followed up for up to 30 days after end of treatment or until 
symptoms or value(s) return to normal, or acceptable level, as judged by the PI (if the subject is continuing into 
the ARQ-151-313 OLE study, then AEs from this study (ARQ-151-315) will only be followed until they exit 
from this study).  
o. Subjects who enroll into the open label extension study (ARQ-151-313) must complete the ARQ-151-315 
Week 4/Day 29 visit as this visit (Week 4/Day 29) is the Day 1 visit for ARQ-151-313. 

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TABLE OF CONTENTS 
1. 
SYNOPSIS ...................................................................................................................6 
1.1. 
Study Schema .............................................................................................................12 
2. 
SCHEDULE OF VISITS AND ASSESSMENTS .....................................................13 
3. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.............................19 
4. 
BACKGROUND AND RATIONALE .......................................................................22 
4.1. 
Introduction .................................................................................................................22 
4.2. 
Nonclinical Studies .....................................................................................................23 
4.3. 
Toxicity Summary ......................................................................................................23 
4.4. 
Clinical Studies ...........................................................................................................23 
4.4.1. 
Psoriasis Phase 2a (ARQ-151-101) ............................................................................23 
4.4.2. 
Psoriasis Phase 2b (ARQ-151-201) ............................................................................25 
4.4.3. 
Atopic Dermatitis Phase 1 PK Study in Adults (ARQ-151-102) ...............................26 
4.4.4. 
Phase 1 Study in Adolescents and Pediatrics (ARQ-151-105) ...................................26 
4.4.5. 
Atopic Dermatitis Phase 2 Dose Ranging Study (ARQ-151-212) .............................27 
4.4.6. 
Oral Roflumilast Tablet ..............................................................................................28 
4.5. 
Rationale for Development .........................................................................................29 
4.5.1. 
Dose Selection ............................................................................................................29 
4.5.2. 
Risks and/or Benefits to Subjects ...............................................................................29 
5. 
STUDY OBJECTIVES AND ENDPOINTS ..............................................................30 
5.1. 
Study Objectives .........................................................................................................30 
5.1.1. 
Primary Objective .......................................................................................................30 
5.2. 
Study Endpoints ..........................................................................................................30 
5.2.1. 
Primary Efficacy Endpoints ........................................................................................30 
5.2.2. 
Secondary Efficacy Endpoints ....................................................................................30 
6. 
INVESTIGATIONAL PLAN .....................................................................................31 
6.1. 
Overall Study Design and Plan ...................................................................................31 
6.2. 
Study Population .........................................................................................................31 
6.3. 
Number of Subjects ....................................................................................................31 
6.4. 
Blinding ......................................................................................................................32 
6.5. 
Breaking Treatment Codes .........................................................................................32 

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6.6. 
Selection of Study Population ....................................................................................32 
6.6.1. 
Inclusion Criteria ........................................................................................................32 
6.6.2. 
Exclusion Criteria .......................................................................................................33 
6.7. 
Removal of Subjects from Study Treatment or from the Study .................................35 
6.7.1. 
Removal of Subjects from Study Treatment ..............................................................35 
6.7.2. 
Removal of Subjects from the Study ..........................................................................35 
6.8. 
Replacement of Subjects that Withdraw or are Discontinued from the Study ...........35 
6.9. 
Prohibitions and Concomitant Therapy ......................................................................35 
6.10. 
Treatment ....................................................................................................................37 
6.10.1. 
Drug Supplies, Packaging, and Labeling ....................................................................37 
6.10.2. 
Numbering of Subjects ...............................................................................................38 
6.10.3. 
Treatment Administration ...........................................................................................38 
6.10.4. 
Treatment Compliance ................................................................................................39 
7. 
STUDY PROCEDURES ............................................................................................40 
7.1. 
Safety Assessments .....................................................................................................40 
7.1.1. 
Screening ....................................................................................................................40 
7.1.2. 
Baseline/Day 1 ............................................................................................................41 
7.1.3. 
Physical Examination .................................................................................................41 
7.1.4. 
Vital Signs, Height and Weight ..................................................................................41 
7.1.5. 
Laboratory Tests .........................................................................................................42 
7.1.6. 
Local Tolerability Assessment ...................................................................................42 
7.1.7. 
Adverse Events ...........................................................................................................43 
7.2. 
Efficacy Evaluations ...................................................................................................44 
7.2.1. 
Validated Investigator Global Assessment Scale for Atopic Dermatitis 
(vIGA-AD) .................................................................................................................44 
7.2.2. 
Eczema Area and Severity Index (EASI) ...................................................................44 
7.2.3. 
Worst Itch-Numerical Rating Scale (WI-NRS) ..........................................................45 
7.2.4. 
Children’s Dermatology Life Quality Index (CDLQI) ...............................................46 
7.2.5. 
Infants' Dermatitis Quality of Life Index (IDQOL) ...................................................46 
7.2.6. 
Dermatitis Family Impact Questionnaire (DFI) .........................................................46 
7.2.7. 
Medical Photography ..................................................................................................46 
7.3. 
Other Evaluations .......................................................................................................47 

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7.3.1. 
Body Surface Area (BSA) ..........................................................................................47 
7.3.2. 
SCORAD ("SCORing Atopic Dermatitis") ................................................................47 
7.3.3. 
Patient-Oriented Eczema Measure (POEM) ...............................................................47 
7.4. 
Final Study Visit – End of Study ................................................................................47 
7.5. 
Early Termination Visit ..............................................................................................47 
7.6. 
Unscheduled Visit .......................................................................................................47 
7.7. 
Adverse Events ...........................................................................................................48 
7.7.1. 
Adverse Event Definition ...........................................................................................48 
7.7.2. 
Serious Adverse Event ................................................................................................49 
7.7.3. 
Suspected Unexpected Serious Adverse Reaction (SUSAR) .....................................50 
7.7.4. 
Safety Review with Subject ........................................................................................50 
7.7.5. 
Adverse Event Reporting ............................................................................................50 
7.8. 
Treatment Stopping Rules ..........................................................................................52 
8. 
DATA ANALYSIS ....................................................................................................53 
8.1. 
Statistical Methods ......................................................................................................53 
8.1.1. 
Determination of Sample Size ....................................................................................53 
8.1.2. 
Subjects to Analyze ....................................................................................................54 
8.1.3. 
Background and Demographic Characteristics ..........................................................54 
8.1.4. 
Investigational Product Application Compliance .......................................................54 
8.2. 
Efficacy Evaluation ....................................................................................................55 
8.2.1. 
Statistical Methods ......................................................................................................55 
8.2.2. 
Children’s Dermatology Life Quality Index (CDLQI), Infant Dermatology 
Quality of Life Index (IDQoL), SCORAD and POEM ..............................................56 
8.3. 
Safety Evaluation ........................................................................................................56 
8.3.1. 
Adverse Events ...........................................................................................................56 
8.3.2. 
Local Tolerance Assessment ......................................................................................57 
8.3.3. 
Medical History and Physical Examinations ..............................................................57 
8.3.4. 
Clinical Laboratory Results and Vital Signs ..............................................................57 
8.3.5. 
Prior and Concomitant Medications ...........................................................................57 
9. 
STUDY ADMINISTRATION ...................................................................................57 
9.1. 
Ethics ..........................................................................................................................57 
9.1.1. 
Ethics Review Board ..................................................................................................57 

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9.1.2. 
Ethical Conduct of the Study ......................................................................................58 
9.1.3. 
Subject Information and Consent ...............................................................................58 
9.2. 
Study Monitoring ........................................................................................................58 
9.3. 
Study Completion/Termination ..................................................................................58 
9.3.1. 
Study Completion .......................................................................................................58 
9.3.2. 
Study Termination ......................................................................................................59 
9.4. 
Data Quality Assurance ..............................................................................................59 
9.5. 
Data Handling and Record Keeping ...........................................................................59 
9.6. 
Protocol Amendments and Deviations .......................................................................60 
9.7. 
Confidentiality and Privacy ........................................................................................60 
9.8. 
Conflict of Interest ......................................................................................................60 
9.9. 
Report Format .............................................................................................................61 
9.10. 
Publication Policy .......................................................................................................61 
10. 
REFERENCES ...........................................................................................................62 
11. 
APPENDICES ............................................................................................................64 
APPENDIX 1. BODY DIAGRAM .............................................................................................64 
APPENDIX 2. VALIDATED INVESTIGATOR GLOBAL ASSESSMENT SCALE 
FOR ATOPIC DERMATITIS ............................................................................65 
APPENDIX 3. CHILDREN’S DERMATOLOGY LIFE QUALITY INDEX ...........................66 
APPENDIX 4. INFANTS’ DERMATITIS QUALITY OF LIFE INDEX (IDQOL) .................68 
APPENDIX 5. DERMATITIS FAMILY IMPACT QUESTIONNAIRE (DFI) ........................70 
APPENDIX 6. SCORAD ............................................................................................................72 
APPENDIX 7. PATIENT-ORIENTED ECZEMA MEASURE (POEM) ..................................73 
APPENDIX 8. NIAID DMID TOXICITY TABLE ...................................................................75 
 
LIST OF TABLES 
Table 1: 
ARQ-151-101:  Skin Toleration Treatment-Emergent Adverse Experiences ............24 
Table 2: 
Excluded Medications and Treatments .......................................................................36 
 

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3. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
AE 
Adverse Event 
AMP 
Adenosine Monophosphate 
AD 
Atopic Dermatitis 
AUC 
Area Under the Curve 
BSA 
Body Surface Area 
CFB 
Change from Baseline 
Cmax 
Maximum Concentration 
Cm 
Centimeter 
CDLQI 
Children's Dermatology Life Quality Index 
CMH 
Cochran-Mantel-Haenszel 
COPD 
Chronic Obstructive Pulmonary Disease 
CRF 
Case Report Form 
CTCAE 
Common Terminology Criteria for Adverse Events 
DNA 
Deoxyribonucleic Acid 
EASI 
Eczema Area and Severity Index 
FDA 
U.S. Food and Drug Administration 
GCP 
Good Clinical Practices 
GLP 
Good Laboratory Practices 
HCA 
Alpha-Hydroxycinnamaldehyde 
HPRT 
Hypoxanthine-guanine Phosphoribosyl Transferase 
Hr 
Hour 
IB 
Investigational Brochure 
IC50 
Half Maximal Inhibitory Concentration 
ICF 
Informed Consent Form 
ICH  
International Conference on Harmonisation 
ID 
Identification  
IDQoL 
Infant Dermatology Quality of Life Index 
IL 
Interleukin 
IND 
Investigational New Drug 

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Abbreviation 
Definition 
IP 
Investigational Product 
IRB 
Institutional Review Board 
ITT 
Intent to Treat 
Kg 
Kilogram 
LED 
Light Emitting Device 
LoE 
Lack of efficacy 
g 
Microgram 
MedDRA 
Medical Dictionary for Regulatory Activities 
Mg 
Milligram 
MH 
Mantel-Haenszel 
Min 
Minute 
mL 
Milliliter 
MMRM 
Mixed Model Repeated Measures  
MTD 
Maximum Tolerated Dose 
MUSE 
Maximal Use Systemic Exposure 
NCI 
National Cancer Institute 
NIH 
National Institutes of Health 
Ng 
Nanogram 
NOAEL 
No Observed Adverse Effect Level 
NRS 
Numeric Rating Score 
NSAID 
Nonsteroidal Anti-Inflammatory Drug 
P-450 
Cytochrome P450 
PDE-4 
Phosphodiesterase 4 
PDMP 
Protocol Deviation Management Plan 
PI 
Principal Investigator  
PK 
Pharmacokinetics 
PP 
Per Protocol  
QD 
Once Daily ("quaque die") 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation  

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Abbreviation 
Definition 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TBD 
To Be Determined 
TCPS 
Tri-Council Policy Statement 
TEAE 
Treatment Emergent Adverse Event 
Tmax 
Time to Reach Maximum Concentration 
TPA 
Target Plaque Area 
TPSS 
Target Plaque Severity Score 
US 
United States 
UVR 
Ultraviolet Radiation 
V79 
Chinese Hamster Cell Line 
vIGA-AD 
Validated Investigator Global Assessment-Atopic Dermatitis 
WI-NRS 
Worst Itch Numeric Rating Score 

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4. 
BACKGROUND AND RATIONALE 
4.1. 
Introduction 
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 
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reducing the levels of tumour necrosis factor-α, IL-12, IL-23, and other signaling effectors 
(Murrell 2015, Nazarian 2009). 
4.2. 
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 (20 mg/kg), the highest dose administered 
and the maximum feasible concentration. Local tolerance studies demonstrated ARQ-151 is not a 
skin sensitizer or eye irritant, and it does not have phototoxic potential. 
4.3. 
Toxicity Summary 
Across the dermal and systemic toxicology programs, the exposure to parent drug and N-oxide 
metabolite differs by route and species. While exposure to roflumilast and its active metabolite 
are likely to be higher following topical administration of ARQ-151 relative to oral 
administration, when the margins from the toxicity studies are considered as a whole, the 
NOAELs across routes and species provide assurance that the anticipated exposures with 
ARQ-151 cream is safe. 
4.4. 
Clinical Studies 
Topical ARQ-151 cream has been evaluated in both plaque psoriasis (through 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 is used in atopic dermatitis.  The safety data from the psoriasis 
studies are relevant to the atopic dermatitis development program. 
4.4.1. 
Psoriasis Phase 2a (ARQ-151-101) 
ARQ-151-101 (NCT03392168) was a Phase 2a study of two active doses of ARQ-151, 0.5% and 
0.15% vs vehicle in the topical treatment of adult patients 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. 

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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 two concentrations of 
ARQ-151 drug product (0.15% and 0.5%) versus vehicle applied QD x 28 days, analyzing target 
psoriatic plaques for efficacy.  Subjects were randomized 1:1:1 to receive 0.5% drug product, 
0.15% drug product or vehicle to psoriatic plaques up to 5.0% of BSA.  In each subject, up to 
3 target plaques were identified for efficacy analysis. 
PK assessments conducted on Day 1: 1, 2, 4 and 6 hours; Day 14: pre-dose (trough) and 1 hour 
post-dose; and Day 28: pre-dose (trough), 1, 2, 4, 6 and 24 hours. 
Safety results follow: 
• 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
       
 
 
 
 
 
       
 
 
 
 
 
       
 
 
 
 
 
       
 
 
 
 
 
       
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 

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Day 28 pharmacokinetic results of ARQ-151-101 are as follows: 
• 
 
 
 
 
 
4.4.2. 
Psoriasis Phase 2b (ARQ-151-201) 
ARQ-151-201 (NCT03638258) was a parallel group, double blind, vehicle-controlled study in 
which ARQ-151 cream 0.15%, ARQ-151 cream 0.3%, or vehicle cream was applied QD for 
12 weeks to over 300 adult subjects with 2% to 20% BSA of chronic plaque psoriasis and 
baseline IGA of Mild or greater.  In this study, both ARQ-151 cream 0.3% and ARQ-151 cream 
0.15% were safe and well tolerated, demonstrating similar safety and tolerability profiles 
compared to each other and compared to vehicle.  The safety data are summarized below: 
• 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 

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Pharmacokinetic results of ARQ-151-201 are as follows: 
 
 
 
 
 
 
 
 
 
4.4.3. 
Atopic Dermatitis Phase 1 PK Study in Adults (ARQ-151-102) 
ARQ-151-102 was an open label, Phase 1, pharmacokinetics and safety study of ARQ-151 
cream 0.15% and ARQ-151 cream 0.05% administered QD in adult subjects with mild to 
moderate AD. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
4.4.4. 
Phase 1 Study in Adolescents and Pediatrics (ARQ-151-105) 
ARQ-151-105 (NCT04156191) is an ongoing open-label, Phase 1, pharmacokinetics, maximal 
usage PK, safety, and efficacy study of ARQ-151 cream 0.15% administered QD in adolescent 
and pediatric subjects with mild to moderate atopic dermatitis.   

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The study is being conducted in three parts, the first two of which are completed.  The first part 
consisted of three cohorts in which subjects aged 2 to 17 years old had 1.5 - 35% BSA 
involvement (excluding the scalp, palms, soles) and mild or moderate atopic dermatitis based on 
vIGA-AD.   
The second part of the study consisted of three cohorts in which subjects were evaluated under 
maximal use conditions (MUSE) and had BSA involvement (excluding the scalp, palms, soles) 
of ≥35% in subjects 2 to 11 years old (inclusive) or ≥25% in subjects 12 to <17 years old with 
mild or moderate atopic dermatitis based on vIGA-AD.  At least 60% of the enrolled subjects 
had moderate atopic dermatitis.  
The third part of the study consists of one cohort (Cohort 7) in which subjects 2 to 5 years of age 
(inclusive) will be administered a lower concentration of ARQ-151 cream (0.05%) and evaluated 
under maximal use conditions (MUSE). Subjects will have BSA involvement (excluding the 
scalp, palms, soles) of ≥35% with mild or moderate atopic dermatitis based on vIGA-AD. At 
least 60% of the enrolled subjects had moderate atopic dermatitis.  This cohort of the study is 
ongoing. 
Preliminary Study Results 
 
 
 
 
 
 
 
   
 
 
4.4.5. 
Atopic Dermatitis Phase 2 Dose Ranging Study (ARQ-151-212) 
ARQ-151-212 (NCT03916081) was a parallel group, double blind, vehicle-controlled, Phase 2 
study that evaluated ARQ-151 cream 0.05% and 0.15% in the treatment of mild to moderate 
atopic dermatitis in 136 adolescent and adult subjects with 1.5 to 35% BSA of involvement.   
Ninety-three female (68.4%) and 43 male (31.6%) subjects with mild to moderate AD 
participated in the study. Overall, the demographic and baseline disease characteristics were 
similar across all study groups. The mean age for all 136 study subjects was 41.6 years, 
including 8 adolescent subjects (between 12-17 years). The mean EASI score at Baseline for all 
study subjects was 9.04. The majority of subjects were in the moderate vIGA-AD category 
(77.9%). The mean BSA involvement was 9.5% for all study subjects. 
 
 
 
 

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4.4.6. 
Oral Roflumilast Tablet 
Oral roflumilast (DALIRESP®) has been approved globally for the treatment of COPD and has 
been evaluated in nine phase III/IV randomized double-blind clinical trials (Wedzicha 2016).  
Overall, the safety of oral roflumilast has been well established in its targeted population of 
mostly middle- and upper-aged individuals who currently smoke cigarettes or have smoked them 
extensively in the past.  Adverse events (AEs) reported with roflumilast tablets have been 
consistent with those expected for oral PDE-4 inhibitors.  In a pooled analysis of safety data 
from 6-month and 1-year clinical trials (N=8630), the most common AEs were diarrhea, weight 
loss and nausea.  Other AEs reported more frequently with roflumilast treatment than with 
placebo were back pain, influenza, insomnia and decreased appetite (Michalski 2012, 
Wedzicha 2016).   
In addition to the self-reported cases of weight loss in the 6-month and 1-year oral trials, 
clinically significant weight loss was also reported in two prospective studies that evaluated 
weight (Michalski 2012). 
Psychiatric-related AEs were also greater in patients treated with roflumilast tablets (5.9%) 
compared to those treated with placebo (3.3%).  The most common psychiatric-related AEs were 
insomnia, depression and anxiety.  A small number of cases of completed suicide and suicide 
ideation have been reported in patients taking oral roflumilast in clinicals trials and also during 
post-marketing experience (Michalski 2012).   
The only contraindication to oral roflumilast is use in patients with moderate to severe liver 
impairment (Child-Pugh B or C), where systemic levels of roflumilast may become elevated. 

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4.5. 
Rationale for Development 
Atopic dermatitis is currently treated with topical calcineurin inhibitors and/or topical 
corticosteroids in combination with emollients.  In 2016, Eucrisa® (crisaborole), a less potent 
PDE-4 inhibitor than roflumilast, was approved for the topical treatment of atopic dermatitis.  
Topical calcineurin inhibitors block the activation of T-lymphocytes and diminish inflammation, 
but are accompanied by a ‘black box’ warning for the development of lymphomas and other 
lymphoproliferative diseases.  Topical corticosteroids can cause skin atrophy and hypothalamic-
pituitary axis suppression, and their use is often accompanied by poor adherence due to 
corticophobia (fear of using corticosteroids in patients or doctors).  Eucrisa provides precedence 
for the effectiveness of topical PDE-4 inhibitors in atopic dermatitis, but it is a twice-daily 
ointment, its efficacy is modest, and its use is often accompanied by burning, stinging, and local 
skin reactions.  In our Phase 2 AD study (ARQ-151-212), we observed excellent local toleration 
of ARQ-151 cream formulations.  Since roflumilast is a more potent PDE-4 inhibitor than 
crisaborole (Hatzelmann 2010), ARQ-151 cream has potential to provide greater efficacy with 
better local toleration than Eucrisa. 
This study will evaluate the safety and efficacy of ARQ-151 cream in children with mild to 
moderate atopic dermatitis. 
4.5.1. 
Dose Selection 
In ARQ-151-212 (conducted in adult and adolescent subjects), results for the primary efficacy 
endpoint, mean absolute change from baseline in EASI score at Week 4, were numerically higher 
in the ARQ-151 cream 0.05% and ARQ-151 cream 0.15% (p= 0.097) groups than in the vehicle 
group. Furthermore, the result of the sensitivity analysis of the primary endpoint at Week 4 was 
statistically significant (ARQ-151 cream 0.15%, p= 0.027). Statistical significance was reached 
for numerous other clinically important efficacy endpoints including percent change from 
baseline in EASI score, EASI-75 responders, and patients achieving vIGA-AD score of clear or 
almost clear. Both doses of topical roflumilast (0.15% and 0.05%) had a similar and favorable 
safety and tolerability profile, with generally more favorable efficacy observed at the ARQ-151 
cream 0.15% dose. Results of this study support the use of ARQ-151 cream 0.15% in further 
studies of adult and adolescent subjects with mild to moderate AD. 
 
 
 
 
 
 
 
 
4.5.2. 
Risks and/or Benefits to Subjects 
A favorable local and systemic benefit-risk profile has been observed in prior studies of 
ARQ‑151 cream. Subjects 2 to 5 years of age enrolled in this study, randomized to active 
treatment, may see an improvement in their atopic dermatitis with ARQ-151 cream 0.05%, based 
on the activity of doses tested in atopic dermatitis (0.05% and 0.15%) and psoriasis 

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(0.15% ‑ 0.5%), and approval of a less potent topical PDE-4 inhibitor (crisaborole) for atopic 
dermatitis.  Subjects may also see some benefit of ARQ-151 cream based on a potentially 
moisturizing effect of the formulation.  
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 4.4.6) 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, and AE reporting). In addition, parents/caregivers of these subjects 2 to 5 years old 
will be advised to promptly report any changes in behavior that could signal psychological 
distress or emotional distress. 
5. 
STUDY OBJECTIVES AND ENDPOINTS 
5.1. 
Study Objectives 
5.1.1. 
Primary Objective 
To assess the safety and efficacy of ARQ-151 cream 0.05% vs vehicle administered 
QD x 4 weeks to children with atopic dermatitis. 
5.2. 
Study Endpoints 
5.2.1. 
Primary Efficacy Endpoints 
IGA Success, defined as a vIGA-AD score of ‘clear’ or ‘almost clear’ PLUS a 2-grade 
improvement from Baseline at Week 4. 
5.2.2. 
Secondary Efficacy Endpoints 
• In subjects with vIGA-AD score of ‘Moderate’ at randomization, IGA Success at 
Week 4 
• Achievement of at least 75% reduction in the Eczema Area and Severity Index 
(EASI-75) at Week 4  
• vIGA-AD score of ‘clear’ or ‘almost clear’ at Week 4 

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• vIGA-AD Success at Week 2 
• vIGA-AD of ‘clear’ or ‘almost clear’ at Week 2 
• vIGA-AD success at Week 1 
• vIGA-AD of ‘clear’ or ‘almost clear’ at Week 1 
6. 
INVESTIGATIONAL PLAN 
6.1. 
Overall Study Design and Plan 
This is a Phase 3, parallel group, double blind, vehicle-controlled study in which ARQ-151 
cream 0.05% or vehicle is applied QD x 4 weeks to subjects with mild to moderate atopic 
dermatitis. 
At entry, subjects will have ≥3% BSA involvement (excluding the scalp, palms, soles) and mild 
or moderate atopic dermatitis (AD) based on vIGA-AD assessment.   
Upon determination of eligibility, subjects will be randomized 2:1 to either ARQ-151 cream 
0.05% cream or matching vehicle cream.  The randomization will be stratified by vIGA-AD 
score at baseline (‘Mild’ vs. ‘Moderate’), and by study site. 
Caregivers will apply ARQ-151 cream 0.05% or vehicle cream QD to all AD affected areas and 
any newly appearing AD lesions that arise during the study, except on the scalp. Caregivers 
should maintain treatment of these areas with study drug for the duration of the study regardless 
of whether treatable areas of AD clear prior to Week 4/Day 29. 
Subject participation involves a minimum of 5 clinic visits including Screening, Baseline/Day 1, 
Week 1/Day 8, Week 2/Day 15, and Week 4/Day 29.  The interval between the Screening and 
Baseline/Day 1 visits could be up to 30 days, therefore the anticipated maximum duration of 
subject participation is approximately 8 weeks. 
At the Week 4/Day 29 visit, subjects may be eligible to enroll in a 12‑month, open label 
extension study (ARQ-151-313) evaluating ARQ-151 cream 0.15% QD and 0.05% QD. All 
subjects will have the option to enroll into the ARQ-151-313. 
6.2. 
Study Population 
Subjects will be male and female children (2-5 years old, inclusive). Subjects will have mild to 
moderate atopic dermatitis involvement with a vIGA-AD score of ‘2’ (Mild) or ‘3’ (Moderate) 
for study entry. Up to 25% of the subjects will have a vIGA-AD score of ‘2’(Mild). 
6.3. 
Number of Subjects 
Approximately 650 subjects are planned to be randomized at approximately 109 study sites in 
the US, Canada, and Poland. During the conduct of the study, additional countries and/or sites 
may be added if necessary. To test the secondary endpoint of IGA success in subjects with a 
vIGA-AD score of ‘Moderate’ at randomization, approximately 490 of the subjects to be accrued 

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will have vIGA‑AD score of ‘Moderate’ at randomization.  Randomization will be stratified by 
Baseline/Day 1 vIGA-AD score (‘Mild’ vs. ‘Moderate’), and by study site. 
6.4. 
Blinding 
This is a double-blind study, therefore neither the subjects nor the Investigator and clinical 
personnel will be aware of which treatment an individual subject receives. 
Randomization will take place at the Baseline/Day 1 visit after the Investigator confirms that the 
subject meets all eligibility criteria listed in Section 6.6. 
Subjects will be randomly assigned to apply ARQ-151 cream 0.05 % QD, or matching vehicle 
QD.  Assignment of drug or vehicle will be made at a 2:1 ratio (drug:vehicle) and stratified by 
Baseline/Day 1 vIGA-AD score (‘Mild’ vs. ‘Moderate’), and by study site according to a 
computer-generated randomization list.  Kits containing tubes of study medication will be 
assigned to each subject using an internet-based response system (IWRS).  A subject may 
receive more than one kit for the treatment period.  The kits and tubes are blinded, and each kit is 
numbered with a unique kit number. 
6.5. 
Breaking Treatment Codes 
In the event of a medical emergency where breaking the blind is required to provide medical care 
to the subject, the Investigator may obtain treatment assignment directly from the IWRS system 
for that subject. Refer to the current version of the ARQ-151-315 IWRS User Manual for details 
on unblinding. Treatment assignment should, however, remain blinded unless the assignment 
knowledge is necessary to determine subject emergency medical care. The rationale for 
unblinding must be clearly explained in source documentation and on the CRF, along with the 
date on which the treatment assignment was obtained. The investigator is requested to contact 
the Medical Monitor promptly in the event of any treatment unblinding. 
Blinding of study treatment is critical to the integrity of this clinical trial and therefore, if a 
subject’s treatment assignment is disclosed to the Investigator, the subject will have the study 
treatment discontinued. All subjects will be followed until study completion unless consent to do 
so is specifically withdrawn by the subject/parent/caregiver. 
6.6. 
Selection of Study Population 
6.6.1. 
Inclusion Criteria 
1. Informed consent of parent(s) or legal guardian as required by local laws. 
2. Males and females, ages 2 to 5 years old (inclusive) at time of signing informed consent 
(Screening) and at Baseline/Day 1.  
3. Diagnosed with mild to moderate atopic dermatitis according to the criteria of 
Hanifin and Rajka (1980) prior to or at the screening visit.  Subjects must have at least 
3 of the 4 basic features per Hanifin and Rajka (1. Pruritus; 2. Typical morphology and 
distribution [facial and extensor eruptions in infants and children]; 

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3. Chronic or chronically relapsing dermatitis; or 4. Personal or family history of atopy), 
in addition to 3 or more minor criteria. 
4. History of AD for at least 6 weeks as determined by the Investigator through subject 
interview. Stable disease for the past 4 weeks with no significant flares in atopic 
dermatitis before screening. 
5. EASI Score ≥5 at Baseline/Day1. EASI is evaluated for the entire body except the scalp, 
palms, and soles. 
6. vIGA-AD score of ‘Mild’ (‘2’) or ‘Moderate’ (‘3’) at Baseline/Day 1. The vIGA-AD is 
evaluated for the entire body except the scalp, palms, and soles. 
7. Has AD involvement of ≥3% BSA at Baseline/Day1 (excluding the scalp, palms, soles).  
8. In good health as judged by the Investigator, based on medical history, physical 
examination, vital signs, serum chemistry labs, and hematology values. 
9. 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. 
6.6.2. 
Exclusion Criteria 
1. Subjects with any serious medical condition or clinically significant laboratory, vital 
signs, or physical examination abnormality that would prevent study participation or 
place the subject at significant risk, as judged by the Investigator. 
2. Subjects who cannot discontinue medications and treatments prior to the Baseline visit 
and during the study according to Excluded Medications and Treatments (Table 2). 
3. Has unstable AD or any consistent requirement for high potency topical steroids to 
manage AD signs or symptoms. 
4. Subjects who have significant active systemic or localized infection (e.g., molluscum 
contagiosum), including known actively infected AD, or have had any infection that 
required oral or intravenous administration of antibiotics, antifungal or antiviral agents 
within 14 days prior to Baseline/Day 1 and during the study. 
5. Subjects who are unwilling to refrain from prolonged sun exposure for 4 weeks prior to 
Baseline/Day 1 and during the study. 
6. Subjects with skin conditions other than AD that would interfere with evaluations of the 
effect of the study medication on AD, as determined by the Investigator.  Subjects with 
any condition on the treatment area which, in the opinion of the Investigator, could 
confound efficacy measurements, e.g., molluscum contagiosum. 
7. Subjects with known genetic dermatological conditions that overlap with AD, such as 
Netherton syndrome. 
8. Known allergies to excipients in ARQ-151 cream 
 
 
  

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9. Subjects who cannot discontinue the use of strong cytochrome P-450 CYP3A4 inhibitors 
e.g., indinavir, nelfinavir, ritonavir, clarithromycin, itraconazole, ketoconazole, 
nefazodone, saquinavir, suboxone and telithromycin for 2 weeks prior to the baseline 
visit and during the study period.  
10. Subjects who cannot discontinue the use of strong cytochrome P-450 CYP3A4 inducers 
e.g., efavirenz, nevirapine, glucocorticoids, barbiturates (including phenobarbital), 
phenytoin, and rifampin and carbamazepine for 2 weeks prior to the baseline visit and 
during the study period. 
11. Subjects who have received oral roflumilast (Daxas®, Daliresp®) within the past 
4 weeks prior to Baseline/Day 1. 
12. Known or suspected:  
• Severe renal insufficiency 
− Severe renal insufficiency is defined as calculated creatinine clearance 
<30 mL/min 
• Moderate to severe hepatic disorders (Child-Pugh B or C) 
13. Previous treatment with ARQ-151. 
14. Subjects currently undergoing allergy testing (e.g., food allergy testing or skin prick 
testing), patch testing, food challenges, or allergy desensitization, or plan to do so during 
the study. 
15. Subjects with any serious known medical condition or clinically significant laboratory 
abnormality that would prevent study participation or place the subject at significant risk, 
as determined by the Investigator. 
16. Subjects with a history of a major surgery within 4 weeks prior to Baseline/Day 1 or 
subjects who have a major surgery planned during the study. 
17. Any history of cancer.  
18. Parent(s)/legal guardian(s) who are unable to communicate, read, or understand the local 
language(s).  Subjects who display any condition which in the Investigator’s opinion, 
makes them unsuitable for clinical study participation. 
19. 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) living in the same house. 

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6.7. 
Removal of Subjects from Study Treatment or from the Study 
6.7.1. 
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 7.7. The Investigator must follow the subject 
until the AE resolves or satisfactorily stabilizes.  
3. Parent/Caregiver decision to discontinue treatment with study drug. 
6.7.2. 
Removal of Subjects from the Study 
A subject may be removed from study participation for any of the following reasons: 
• Subject death. 
• Parent/Caregiver decision to withdraw from the study. 
• Subject is lost to follow-up. A subject will be considered lost to follow-up after three 
phone and three email attempts and documentation of a certified letter sent to the 
subject’s address. 
• Requirement for use of prohibited concomitant medication after consultation with the 
Sponsor and Medical Monitor. 
• Parent/Caregiver repeated failure to comply with protocol requirements or study 
related procedures. 
• Parent/Caregiver interrupts trial study drug application for more than 50% of 
scheduled doses. 
• Termination of the study by the Sponsor, FDA, or other regulatory authorities 
6.8. 
Replacement of Subjects that Withdraw or are Discontinued from 
the Study 
Subjects that withdraw or are discontinued from the study will not be replaced. 
6.9. 
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 

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compromise the outcome or validity of the clinical investigation. Other medications may be 
authorized by the Investigator for conditions other than AD. If medication is required, the name, 
strength, frequency, duration of use, and reason for use will be recorded in source documents and 
entered into the CRFs.  Medications which have been used chronically by subjects, in particular 
statins and anti-hypertensives, are allowed for use during the study, except as prohibited in 
Table 2. No rescue medication for AD is allowed during this study up to Week 4. 
Emollients and Moisturizers: Non-medicated emollients or moisturizers will be allowed once 
daily in a stable regimen as normally used by the subjects. For subjects that apply a 
non-medicated emollient or moisturizer after an evening shower/bath, the study drug must be 
applied first to the treatment areas (after the shower/bath). The non-medicated emollient or 
moisturizer can then be applied but only to other untreated areas of the subject’s skin 
(see Section 6.10.3 for additional details). 
Table 2: 
Excluded Medications and Treatments 
Excluded Medications and Treatment 
Washout Period Prior to 
Baseline/Day 1 
Biologics such as dupilumab  
6 months 
Investigational biologics 
6 months 
• 
Systemic treatments that could affect AD; e.g. corticosteroids, 
retinoids, calcineurin inhibitors, hydroxycarbamide 
(hydroxyurea), methotrexate, cyclosporine, azathioprine, 
hydroxychloroquine, mycophenolate mofetil, or other 
immunosuppressive therapies, or systemic treatment with 
nonsedating antihistamines in a nonstable regimen.   
• 
Systemic treatments with nonsedating antihistamines 
(e.g., cetirizine, desloratadine, loratadine) in a stable regimen is 
allowed. 
4 weeks or 5 half-lives, 
whichever is longer 
PUVA or NBUVB phototherapy 
4 weeks 
Topical products containing urea 
1 week 
Sedating antihistamines and other over the counter remedies containing 
sedating antihistamine, such as sleep aids (e.g., ZzzQuil™ 
LIQUICAPS®SLEEP-AID), and cough/cold remedies (e.g., Theraflu® 
night time, NyQuil™ Cold & Flu Night time) 
1 week 
Topical corticosteroids, calcineurin inhibitors, or Eucrisa®.  Topical 
antibacterial medications or products, including soaps, dilute bleach 
baths, or sodium hypochlorite-based products anywhere on the body. 
2 weeks  
Strong cytochrome P-450 CYP3A4 inhibitors e.g., indinavir, nelfinavir, 
ritonavir, clarithromycin, itraconazole, ketoconazole, nefazodone, 
saquinavir, suboxone and telithromycin 
2 weeks 

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Table 2: 
Excluded Medications and Treatments (Continued) 
Excluded Medications and Treatment 
Washout Period Prior to 
Baseline/Day 1 
Strong cytochrome P-450 CYP3A4 inducers e.g., efavirenz, nevirapine, 
glucocorticoids, barbiturates (including phenobarbital), phenytoin, 
rifampin, and carbamazepine 
2 weeks 
Systemic antibiotics 
≤15 days 
Oral roflumilast (Daxas®, Daliresp®) 
4 weeks 
All other investigational drugs 
4 weeks or 5 half-lives, 
whichever is longer 
Notes: 
• 
Eye / ear drop and nasal corticosteroid preparations are allowed.  Inhaled corticosteroid preparations are 
allowed if used for a stable condition and at a stable dose for > 28 days before screening and are 
continued at the same dose throughout the study. 
• 
Non-medicated emollients or moisturizers will be allowed once daily in a stable regimen as normally 
used by the subjects. For subjects that apply a non-medicated emollient or moisturizer after an evening 
shower/bath, the study drug must be applied first to the treatment areas. The non-medicated emollient or 
moisturizer can then be applied but only to other untreated areas of the subject’s skin.  
• 
Sunscreens will be allowed daily, as needed by the subjects when applied at least 2 hours after 
application of randomized study drug.   
• 
Concomitant other medications for chronic conditions 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. 
6.10. 
Treatment 
6.10.1. 
Drug Supplies, Packaging, and Labeling 
ARQ-151 cream or matching vehicle will be supplied in 45 gram tubes.  The tubes will be 
packaged in kits, containing multiple tubes of investigational product.  The number of kits 
dispensed to a subject will be based on the BSA involvement of atopic dermatitis.  The kits and 
tubes will be labeled in a blinded manner.  The kit(s) dispensed to a subject will be labeled with a 
unique number. 
The Sponsor will supply sufficient quantities of the study drug and matching vehicle to each site 
to allow for completion of this study. 
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. 

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6.10.2. 
Numbering of Subjects 
All subjects who sign an informed consent form will be assigned a unique 6-digit subject 
identification (ID) number by the IWRS system.   
The subject identifier number is 6-digits (SXX-YYY) and will contain the study number-site 
number (where S = 5 and XX is this study site number such as 01, 02, etc.) and the subject 
number (YYY). It will be assigned in numerical order, by site, at the screening visit based on 
chronological order of screening dates. 
Individuals who do not meet the criteria for participation in this trial (screen failure) may be 
rescreened once, if deemed acceptable by the investigator. Rescreened subjects should be 
assigned a different subject number than the initial screening. All procedures planned at the 
screening visit, including signature of a new consent form, will be performed.  
In the case of a screening laboratory value abnormality, the test can be repeated once within the 
original screening time window, if the investigator believes there is a reasonable possibility that 
the subject would be eligible if re-tested. This would not be considered a screen failure and a 
new subject number would not be assigned. 
The clinical site is responsible for maintaining a current log of subject ID number assigned to 
each subject. The subject ID number will be used to identify the subject throughout the study and 
is required to be entered on all clinical study documentation (e.g., case report forms, labeling of 
clinical materials and sample containers, investigational product accountability logs, etc.). 
6.10.3. 
Treatment Administration 
Initial treatment with the IP will occur on Day 1. ARQ-151 cream 0.05% is administered once 
daily as a topical product to cover the skin surface at an application rate of approximately 
2 mg/cm2.   
At Baseline visit, the study staff will demonstrate to the parent(s)/caregiver(s) how to apply 
ARQ-151 cream using the first tube from the kit that is assigned to the subject.  Study site staff 
will be trained to ensure a unit dose (a pea size unit of ARQ-151 cream will cover approximately 
1% BSA) is properly squeezed from the tube and applied to atopic dermatitis lesion(s) as a thin 
film and rubbed in using the index and middle finger, rubbing in thoroughly but gently, until the 
‘white’ has disappeared.  The parent(s)/caregiver will then practice squeezing a similar amount 
onto their index and middle finger and apply a thin film to other areas to be treated.  At 
Baseline/Day 1, the study staff will ensure that the parent/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). 
Parents/caregivers will be instructed to apply investigational product once daily to all treatment 
areas identified by the Investigator at Baseline and any new lesions at subsequent visits using a 
Body Diagram (see Appendix 1). 

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Note: 
• All subjects should receive medication each evening (except on clinic visit days when 
the investigational product will be applied at the clinic). If the subject takes an 
evening shower/bath, the ARQ-151 cream or vehicle can be applied as soon as the 
skin is nearly dry, but no later than 20 minutes before going to bed.  Subjects are not 
to wash areas where ARQ-151 cream or vehicle has been applied until at least 4 hours 
after study drug application. 
• Non-medicated emollients or moisturizers will be allowed once daily in a stable 
regimen as normally used by the subjects. For subjects that apply a non-medicated 
emollient or moisturizer after an evening shower/bath, the study drug must be applied 
first to the treatment areas (after the shower/bath). The non-medicated emollient or 
moisturizer can then be applied but only to other untreated areas of the subject’s skin. 
• Parents/caregivers should wash their hands with soap and water after applying IP to a 
child. 
• Parents/guardians/caregivers who are pregnant, or women of childbearing potential 
who are trying to become pregnant, or who are breastfeeding, or planning to 
breastfeed during the study should avoid accidental exposure by either avoiding 
applying investigational product or by wearing gloves during its application. 
• Subjects should maintain treatment of areas with study drug for the duration of the 
study regardless of whether treatable areas of AD clear prior to Week 4 visit. 
• New lesions that develop during the study should be treated (except scalp).  An 
unscheduled visit is not required for starting treatment of new lesions. 
Each investigational product tube will be weighed prior to dispensing at the Baseline visit and at 
each subsequent visit. Investigational product tubes must be returned by subjects at each study 
visit, both empty and full, and will be weighed. If the subject’s actual use is substantially 
different than the expected use for the subject’s BSA (see IP Handling Plan), the parent/caregiver 
will be retrained on the study drug application technique. 
6.10.4. 
Treatment Compliance 
Investigational product tubes will be weighed at each clinic visit. 
Parents/caregivers will complete a daily diary recording the date and time of each dose applied, 
any missed doses, and a comment section should the subjects have a comment, e.g., record 
potential AEs.  Site personnel will review the diaries and use the information to question the 
Parent/Caregiver 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 for reporting purposes. 
If the diary shows less than 80% of expected daily applications (but not more than 3 consecutive 
missed doses), the subject is using too little study drug and retraining must be conducted and 
documented. 
Compliance will be documented in source and in eCRF. 
7. 
STUDY PROCEDURES 
The Schedule of Visits and Assessments (Section 2) summarizes the clinical procedures to be 
performed at each visit. Individual clinical procedures are described in detail below. 
7.1. 
Safety Assessments 
This study assesses the safety and efficacy of ARQ-151 cream. Safety will be determined by 
evaluating physical examinations, local tolerability assessments, vital signs/weight, clinical 
laboratory parameters, and AEs as outlined in the Schedule of Visits and Assessments 
(Section 2).  
Additional evaluations/testing may be deemed necessary by the PI and/or the Sponsor for 
reasons related to subject safety. 
7.1.1. 
Screening 
Before a subject’s participation in the clinical study, the Investigator is responsible for obtaining 
written informed consent from the subject’s parent(s) or legal guardian(s) after adequate 
explanation of the study design, anticipated benefits, and the potential risks. A subject is 
considered a participant of the trial once the ICF is completely signed.  
During the study, if a subject changes age group, the subject will continue with the assessments 
specific to their age group at the time of consent at Screening. 
The following procedures/assessments will be performed at the Screening Visit (within 30 days 
after signing the informed consent): 
• Review of medical and surgical history 
• Collection of demographic data including sex, age, race, ethnicity 
• Vital signs including temperature, heart rate, and blood pressure 
• Collection of body weight (kg), and height (cm) 

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• Atopic dermatitis assessments (e.g., vIGA-AD, BSA, EASI, SCORAD) 
• Limited physical examination of skin (including assessment of Fitzpatrick skin type 
at Screening only), lungs, and heart 
− Fitzpatrick skin phototype will be rated as follows: 
a. 
Always burns easily; never tans (sensitive) 
b. 
Always burns easily; tans minimally (sensitive) 
c. 
Burns moderately; tans gradually (light brown) (normal) 
d. 
Burns minimally; always tans well (moderate brown) (normal) 
e. 
Rarely burns; tans profusely (dark brown) (insensitive) 
f. 
Never burns, deeply pigmented (insensitive) 
• Laboratory tests: hematology and chemistry 
• Completion of WI-NRS, CDLQI, IDQoL, DFI, and POEM 
• Collection of concomitant medications and serious adverse events 
Subjects may be re-screened one time and the subject will be assigned a new Subject ID. 
7.1.2. 
Baseline/Day 1 
Randomization will take place at the Baseline visit after the subject has been found to be fully 
eligible for participation. A subject will be considered enrolled into the study upon the first IP 
application.    
7.1.3. 
Physical Examination 
Physical examinations will be performed according to the Schedule of Visits and Assessments 
(Section 2). The physical exam will be limited to skin, lungs and heart only. 
7.1.4. 
Vital Signs, Height and Weight 
Vital signs will be performed according to the Schedule of Visits and Assessments (Section 2). 
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 remove any objects of significant 
weight (i.e., jackets, outerwear, shoes, cell phones/tablets, wallet, key chains, etc.). Weight 
should be obtained using a calibrated weight scale and the same scale, whenever possible, should 
be used for a subject throughout the duration of the study.  The subject should stand with both 
feet in the center of the scale with their arms at their side and hold still. Record the weight to the 
nearest decimal fraction (for example, 25.1 kilograms). Weight should be measured in triplicate 
and the average weight reported in EDC. An unexplained, clinically significant weight loss 
should be reported to the Medical Monitor. 
Height will be measured at Screening and Week 4/Day 29. 

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7.1.5. 
Laboratory Tests 
All tests listed below will be performed according to the Schedule of Visits and Assessments 
(Section 2) unless otherwise noted. No food restrictions are required for the collection of 
specimens. In addition, laboratory safety tests may be performed at various unscheduled time 
points, if deemed necessary by the Investigator. 
Hematology 
Serum Chemistry 
Hemoglobin 
Hematocrit  
Total and differential leukocyte count 
Red blood cell count with indices and morphology 
Platelet count 
Blood Urea Nitrogen 
Bilirubin (total and direct) 
Alkaline phosphatase 
Aspartate aminotransferase 
Alanine aminotransferase 
Albumin 
Sodium 
Potassium 
Chloride 
Glucose 
Creatinine (including GFR (Schwartz) or 
Schwartz creatinine clearance)  
7.1.6. 
Local Tolerability Assessment 
The Investigator Local Tolerability Assessment will be performed according to the Schedule of 
Visits and Assessments (Section 2).  
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 sub-investigator prior to study drug application in the clinic. 
Dermal Response: 
0. no evidence of irritation 
1. minimal erythema, barely perceptible 
2. definite erythema, readily visible; minimal edema or minimal papular response 
3. erythema and papules 
4. definite edema 
5. erythema, edema and papules 
6. vesicular eruption 
7. strong reaction spreading beyond application site 

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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 2). 
The parent/caregiver will assess for the subject burning/stinging (0-3 score):  
Grade Sensation Following Drug Application 
0 (none) 
 
No sensation 
1 (mild) 
 
Slight warm, tingling sensation; not really bothersome 
2 (moderate) Definite warm, tingling sensation that is somewhat bothersome 
3 (severe)  
Hot, tingling/stinging sensation that has caused definite discomfort 
This assessment will be administered by the site 10 to 15 minutes after study drug application in 
the clinic at Baseline and at every clinic visit. 
• Note: for subject burning stinging assessment at Week 4/Day 29, Parents/Caregivers 
will provide a recall assessment of burning/stinging experienced post drug application 
on the previous day (Day 28) 
7.1.7. 
Adverse Events 
Adverse events (AEs) will be collected and assessed throughout the study according to the 
Schedule of Visits and Assessments (Section 2). The Investigator is responsible for ensuring that 
all adverse events observed by the clinical staff or reported by the Parent/Caregiver 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 Parent/Caregiver 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 7.7.1). 

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AEs (whether serious or non-serious) and clinically significant abnormal laboratory test value(s) 
will be evaluated by the PI and treated and/or followed up for up to 30 days after end of 
treatment or until the symptoms or value(s) return to normal, or acceptable levels, as judged by 
the PI. Refer to Section 7.7 for further details on Adverse Events. 
7.2. 
Efficacy Evaluations 
For efficacy evaluation subjects will have ≥3% BSA of AD involvement (excluding the scalp, 
palms, soles). Palms and soles may be treated with investigational product in this study, but will 
not be counted towards vIGA-AD, EASI, or BSA assessments. EASI is evaluated for the entire 
body except the scalp, palms, and soles. 
7.2.1. 
Validated Investigator Global Assessment Scale for Atopic Dermatitis 
(vIGA-AD) 
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 2). 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 2). 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, SCORAD). 
• Every effort must be made for the same Evaluator to complete the IGA for the 
subject at every study visit. 
• IGA will be assessed at clinic visits prior to the Investigational Product 
application at the site. 
7.2.2. 
Eczema Area and Severity Index (EASI) 
EASI scores (Hanifin 2001) will be performed according to the Schedule of Visits and 
Assessments (Section 2). 
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 

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• 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% 
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, SCORAD, or BSA assessments. EASI is evaluated for the entire 
body except the scalp, palms, and soles. 
7.2.3. 
Worst Itch-Numerical Rating Scale (WI-NRS) 
The WI-NRS has been developed as a simple, single item to assess the patient-reported severity 
of this symptom at its highest intensity during the previous 24-hour period (Newton 2019). The 
WI-NRS will be determined by the parent/caregiver recording of daily assessment of worst itch 
over the past 24 hours. The scale is from ‘0 to 10’ (“no itch” to “worst itch imaginable” or “worst 
imaginable itch”). 
 

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WI-NRS Assessments will be performed according to the Schedule of Visits and Assessments 
(Section 2) starting 7 days prior to the Baseline/Day 1 clinic visit (during the 7 days prior to 
Baseline/Day 1, the parent/caregiver will record the WI-NRS value every day). 
Parents/guardians will be reminded not to review responses from the previous days when 
completing the WI-NRS. Parent and/or guardian will be trained at the screening visit in the 
accurate completion of the WI-NRS.  
7.2.4. 
Children’s Dermatology Life Quality Index (CDLQI) 
CDLQI will be performed according to the Schedule of Visits and Assessments (Section 2). The 
Children's Dermatology Life Quality Index (CDLQI; ≥4 years old) allows a simple, compact and 
uniform assessment of patients with skin diseases in general, in which higher scores indicate 
poorer disease-related quality of life. Parents/caregivers will complete the CDLQI. 
See Appendix 3 for the CDLQI. 
7.2.5. 
Infants' Dermatitis Quality of Life Index (IDQOL) 
IDQOL will be performed according to the Schedule of Visits and Assessments (Section 2). The 
Infants' Dermatitis Quality of Life Index questionnaire (Appendix 4) is designed to assess the 
impact of atopic dermatitis on the quality of life of infants below the age of four years.  
It is self-explanatory and should be completed by the child’s parent(s) or regular caregiver. 
7.2.6. 
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 (Appendix 5).  
7.2.7. 
Medical Photography 
Photography of AD lesion(s) selected by the Investigator will be performed by all sites at all 
investigational visits, except Week 2/Day 15.  All efforts will be made to de-identify the 
subjects. Canfield equipment will be used to capture photographs. 
Photography should be focused on single lesions or specific body sections (e.g., arm). Body or 
half body photos should only be taken if necessary. Subjects who are unwilling to participate in 
the medical photography will be allowed to opt out of this procedure and documented on the 
informed consent.  
Refer to the current Photography Manual for instructions regarding photography. 

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7.3. 
Other Evaluations 
7.3.1. 
Body Surface Area (BSA) 
BSA assessments will be performed according to the Schedule of Visits and Assessments 
(Section 2). 
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). 
7.3.2. 
SCORAD ("SCORing Atopic Dermatitis") 
SCORAD is a clinical tool for assessing the severity (i.e. extent, intensity) of atopic dermatitis as 
objectively as possible. It gives approximate weights of 60% to intensity and 20% each to spread 
(extent) and subjective signs (pruritus and insomnia, etc.). See Appendix 6. 
7.3.3. 
Patient-Oriented Eczema Measure (POEM) 
The Patient-Oriented Eczema Measure (POEM) is a tool used for monitoring atopic eczema 
severity. It focuses on the illness as experienced by the patient.  
POEM is a 5-point scale measuring the frequency of each of seven AD symptoms (dryness, 
itching, flaking, cracking, sleep loss, bleeding, and weeping) over the past week scored as 
occurring “no days” (0), “1 to 2 days” (1), “3 to 4 days” (2), “5 to 6 days” (3) or “every day” (4). 
Total score ranges from 0–28, with higher score indicating greater symptom impact. 
See Appendix 7. 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). 
7.4. 
Final Study Visit – End of Study 
The approximate final study visit will occur at Week 4/Day 29. The procedures performed 
during this visit are as described in the Schedule of Visits and Assessments (Section 2). A 3-day 
scheduling window is allowed for this visit. Adverse events will be recorded as reported by the 
participant or and followed to resolution or stabilization (as necessary). 
7.5. 
Early Termination Visit 
If a subject is withdrawn or wishes to exit the study, a termination visit will be scheduled. This 
visit should include the procedures and assessments that would be performed at the 
Week 4/Day 29 visit. 
7.6. 
Unscheduled Visit 
Unscheduled visits may be necessary to repeat testing following abnormal laboratory results, for 
follow-up of AEs, or for any other reason, as warranted in the judgement of the Investigator. 

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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.  
7.7. 
Adverse Events 
7.7.1. 
Adverse Event Definition 
An AE is defined as any untoward medical occurrence associated with the use of a drug in 
humans, whether or not considered drug related. An AE can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a medicinal (investigational) product, whether or not related to the 
medicinal (investigational) product.  
A treatment emergent adverse event (TEAE) is defined as an AE that started post application of 
study medication at the Baseline visit or was present at treatment initiation but worsened during 
treatment, through study completion.  
The definition of AEs includes worsening of a pre-existing medical condition.  Worsening 
indicates that the pre-existing medical condition has increased in severity, frequency, and/or 
duration or has an association with a worse outcome.  When recording such events, provide 
descriptions that the pre-existing condition has changed (e.g., 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 treatment 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. 

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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. 
7.7.2. 
Serious Adverse Event 
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) 
• 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 

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• 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. 
7.7.3. 
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. 
7.7.4. 
Safety Review with Subject 
At each subsequent clinic visit after the screening visit, subjects will be queried with an open 
ended question such as: ‘How have you been feeling since your last visit?’  Additionally, the 
study staff will review subject diaries and, if it appears that a potential AE was recorded, study 
staff will query the subject and determine if an AE occurred.   
AEs (whether serious or non-serious) and clinically significant abnormal laboratory test value(s) 
will be evaluated by the PI and treated and/or followed for up to one month after end of 
treatment until the symptoms or value(s) return to normal, or acceptable levels, as judged by the 
Investigator. 
Where appropriate, medical test(s) and/or examination(s) will be performed to document 
resolution of event(s). Outcome may be classified as resolved, improved, unchanged, worse, fatal 
or unknown (lost to follow up). 
7.7.5. 
Adverse Event Reporting 
The Investigator is responsible for recording all adverse events, observed by the clinic staff or 
reported by the subject that occur after the first application of investigational product through the 
end of the study.  All SAEs should be reported starting after the signing of the informed consent 
through 30 days after the last day of the application of the investigational product or the end of 
the study (whichever is later).  
Any AEs (whether serious or non-serious) and clinically abnormal laboratory test 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 symptoms or value(s) return to normal, or acceptable level, as judged by the PI 

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(if the subject is continuing into the ARQ-151-313 OLE study, then AEs from this study, 
ARQ-151-315, will only be followed until they exit from this study). 
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 (modified for pediatric subjects) 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 be noted. 
The relationship of each AE to the Investigational Product will be assessed using the following 
definitions:  
Unrelated 
• 
The AE must clearly be caused by the subject’s clinical state, or the study 
procedure/conditions. 
• 
Definitely not related to drug. 
• 
Temporal sequence of an AE onset relative to administration of drug not 
reasonable. 
• 
Another obvious cause of an AE. 
Unlikely 
• 
Time sequence is unreasonable. 
• 
There is another more likely cause for an AE. 
Possibly 
• 
Corresponds to what is known about the drug. 
• 
Time sequence is reasonable. 
• 
Could have been due to another equally, likely cause. 
Probably 
• 
Is a known effect of the drug. 
• 
Time sequence from taking drug is reasonable. 
• 
Ceases on stopping the drug. 
• 
Cannot be reasonably explained by the known characteristics of the 
subject’s clinical state. 
Likely 
• 
Is a known effect of the drug (e.g., listed in Physicians' Desk Reference, 
Compendium of Pharmaceuticals and Specialties, IB). 
• 
Time sequence from taking drug is reasonable. 
• 
Event stops upon stopping drug, event returns upon restarting drug. 

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The following CTCAE toxicity grading scale 5-point severity scale definitions for rating 
maximum severity will be used: 
Grade 1 
• 
Mild; asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention not indicated. 
Grade 2 
• 
Moderate; minimal, local or noninvasive intervention indicated; limiting 
age-appropriate instrumental activities of daily living. 
Grade 3 
• 
Severe or medically significant but not immediately life-threatening; 
Hospitalization or prolongation of hospitalization indicated; disabling; 
limiting self-care activities of daily living. 
• 
Note: An experience may be severe but may not be serious, e.g., severe 
headache). 
Grade 4 
• 
Life-threatening consequences; urgent intervention indicated. 
Grade 5 
• 
Death related to AE. 
Note:  A semi-colon indicates ‘or’ within the description of the grade. 
AEs will be coded using the most current MedDRA® version 23.0 or later. 
7.8. 
Treatment Stopping Rules 
If a subject has non-cutaneous adverse events of concern, clinically significant laboratory values 
or any condition that the investigator determines could possibly be related to the study drug, the 
Investigator should immediately contact the Medical Monitor to discuss if the subject should be 
discontinued from treatment with investigational product.  
Treatment for any individual subject will be discontinued if the subject experiences:  
• A serious adverse event (SAE) or a clinically significant non-serious AE which in the 
opinion of the Principal Investigator or Medical Monitor warrants discontinuation 
from the study for that subject’s well-being. 
• A treatment-emergent severe (Grade 3) laboratory abnormality (confirmed by repeat 
sample; see Appendix 8 and the Laboratory Toxicity Grading section in the appendix 
for more information). 
Parents/caregivers will be advised to promptly report any changes in behavior that could signal 
psychological distress or emotional distress. 
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.   

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Treatment should be discontinued: 
• If the application site reaction reoccurs, treatment should be discontinued 
permanently, and the subject followed until the reaction resolves.   
For cases of suspected allergic contact dermatitis, the medical monitor and sponsor should be 
notified and there should be discussion about performing patch testing to further evaluate. Patch 
testing is encouraged in such cases. 
In the event of a medical emergency where unblinding is required to provide medical care to the 
subject, refer to the most current IWRS User Manual (Section 6.5). Contact the Medical Monitor 
and the Sponsor promptly. 
8. 
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. 
8.1. 
Statistical Methods 
The methodology presented below is a summary of the more detailed analysis plan that will be 
presented in the Statistical Analysis Plan (SAP).  The SAP will be finalized before the database 
is locked and unblinded. Any changes to the methods described in the final SAP will be 
described and justified in the clinical study report.  
All statistical processing will be performed using SAS® (Version 9.4) unless otherwise stated. 
8.1.1. 
Determination of Sample Size 
Approximately 650 subjects are planned to be randomized in this study. To test the secondary 
endpoint of IGA success in subjects with a vIGA-AD score of ‘Moderate’ at randomization, 
approximately 490 of the subjects to be accrued will have vIGA‑AD score of ‘Moderate’ at 
randomization.  Randomization will be stratified by Baseline vIGA-AD score 
(‘Mild’ vs. ‘Moderate’), and study site. 
This study is designed to differentiate between a vehicle cream treatment that has an IGA 
success rate of 22% or less and ARQ-151 cream treatment with an IGA success rate of 37% or 
more.  The hypothesis is that the IGA success rate among subjects treated with ARQ-151 cream 
0.05% is significantly greater than the IGA success rate among subjects treated with vehicle 
cream. 
This sample size provides more than 90% power to detect 15% difference between treatment 
groups on vIGA‑AD success at Week 4 at α=0.025 using a 2-sided stratified Cochran-Mantel-
Haenszel test.  The results from a recent Phase 2 study (ARQ‑151-212) of ARQ-151 cream 
0.05% compared to vehicle treatment were used to estimate the treatment difference.  The 
vIGA-AD success rate at Week 4 was approximately 38% in the ARQ-151 cream 0.05% group 
compared to 22% in the vehicle.  Similarly, approximately 37% of subjects demonstrated 
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provides more than 80% power to detect an overall 15% difference between treatment groups on 
IGA success at Week 4 in subjects with vIGA-AD score ‘moderate’ at randomization.  The same 
testing method, the stratified Cochran-Mantel-Haenszel test, will be used as for the primary 
endpoint. 
8.1.2. 
Subjects to Analyze 
The analysis populations are defined as follows: 
• Intent-to-Treat (ITT) population will include all subjects who are randomized.  
• Per protocol (PP) population will include all subjects in the ITT population, who are 
at least 80% compliant with study medication application, have a vIGA-AD 
assessment within the Week 4 visit window, and show no major deviations from the 
study protocol that would affect the interpretation of efficacy.  
• vIGA-AD Moderate ITT population will be a subset of the ITT population with 
vIGA-AD score ‘moderate’ at randomization. 
• The WI-NRS population will be a subset of the ITT population who: 
o Parent/caregiver completed at least 4 of 7 evaluable daily WI-NRS questionnaires 
during the last 7 days of the Screening period; 
o Have a mean baseline WI-NRS score ≥4.0, defined as the average of all non-
missing scores reported during the last 7 days of the Screening period. 
• Safety population will include all subjects who are enrolled and received at least one 
confirmed dose of study medication. 
8.1.3. 
Background and Demographic Characteristics 
Descriptive statistics will be used to summarize demographic characteristics (age, sex, ethnicity, 
and race) and background characteristics for the randomized subjects. 
8.1.4. 
Investigational Product Application Compliance 
The number of study drug applications by each subject based on diary data will be summarized 
using summary statistics (mean, standard deviation [SD], median, minimum, and maximum), and 
categorically.  
The number of investigational product applications by each subject based on diary data will be 
summarized using descriptive statistics.  
The amount of investigational product used by each subject based on tube weight will be 
summarized by treatment using descriptive statistics. 
Investigational product application compliance will be calculated based on number of 
applications divided by the expected number (amount) of investigational product applications for 
each subject.  Compliance will be summarized descriptively by treatment group. 

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8.2. 
Efficacy Evaluation 
8.2.1. 
Statistical Methods 
Subjects will be stratified by Baseline vIGA-AD score and by study site, however due to a very 
low number of subjects in many sites, the analysis model will only stratify by vIGA-AD score 
stratum. 
The primary endpoint will be tested using ITT population. 
The primary estimand is described by the following attributes: 
Treatment: Roflumilast cream 0.05% 
Population: Subjects aged 2-5 years with Atopic Dermatitis  
Endpoint: vIGA-AD success at Week 4 
Handling of Intercurrent Events: A hybrid strategy will be used for handling intercurrent 
events. For events other than discontinuation due to AE or lack of efficacy (LoE), the occurrence 
of the intercurrent event will be considered irrelevant in defining the treatment effect of interest, 
i.e., the value for the variable of interest is used regardless of whether the intercurrent event 
occurs. This is the treatment policy strategy.  Discontinuation due to an AE or LoE is considered 
to be informative about the subject’s outcome and is incorporated into the definition of the 
variable.   To that end, subjects who discontinue due to LoE or AE will be treated as non-
responders for an analysis visit if the study day of the subject’s last dose day falls within or prior 
to the relevant analysis visit window. Analysis visit windows will be defined in the SAP.  This is 
a composite variable strategy. 
Population-level Summary: The ratio of the odds of achieving vIGA-AD success after 4 weeks 
of using roflumilast cream 0.05%, relative to the odds of success after 4 weeks using a matching 
vehicle cream in the ITT population.  
Missing data will be handled with multiple imputation methods (MI). A Cochran-Mantel-
Haenszel (CMH) test stratified by the baseline vIGA-AD score used for randomization, will be 
performed separately for each of the multiply imputed analysis data sets, and results will be 
combined into one multiple imputation inference. The CMH test will not be stratified by study 
site as the 650 subjects will be randomized by over 90 sites leading to a low subject to site ratio.  
The common Mantel-Haenszel (MH) odds ratio and common MH proportion difference, 
adjusted for baseline vIGA-AD score used for randomization, will be provided along with their 
associated 97.5% and 95% CIs.  Statistical significance will be concluded at the 
2.5% significance level (2-sided).   
To control for the familywise type I error at level of 0.025, the remaining secondary endpoints 
will be tested sequentially at an alpha level of 0.025 upon successful demonstration of statistical 
significance for the primary endpoint.  The endpoints listed below will be tested in ITT 
population unless otherwise noted.   

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• In subjects with a vIGA-AD score of ‘Moderate’ at randomization, IGA Success at 
Week 4 
• Achievement of at least 75% reduction in the Eczema Area and Severity Index 
(EASI-75) at Week 4  
• vIGA-AD score of ‘clear’ or ‘almost clear’ at Week 4 
• vIGA-AD Success at Week 2 
• vIGA-AD of ‘clear’ or ‘almost clear’ at Week 2 
• vIGA-AD success at Week 1 
• vIGA-AD of ‘clear’ or ‘almost clear’ at Week 1 
The ITT population will be used for the primary and secondary efficacy analyses endpoints 
except the endpoint for subjects with vIGA-AD score of ‘Moderate’ at baseline, in which 
vIGA-AD Moderate ITT population will be used.    
A supplemental analysis of observed data for the PP population will also be performed for the 
primary endpoint, vIGA-AD success at Week 4. Descriptive statistics for continuous variables 
will include mean, median, standard deviation, Q1, Q3, min, max. Descriptive statistics for 
categorical variables will include frequencies and percentages. For missing data, the primary 
imputation method and sensitivity methods will be detailed in the SAP. The secondary endpoint 
of vIGA-AD success in subjects with vIGA-AD of ‘Moderate’ at randomization will be analyzed 
with a  chi-square test .  
Other categorical efficacy endpoints will be analyzed in the same manner as the primary 
endpoint.   
8.2.2. 
Children’s Dermatology Life Quality Index (CDLQI), Infant Dermatology 
Quality of Life Index (IDQoL), SCORAD and POEM 
Children’s Dermatology Life Quality Index (CDLQI), the Infant Dermatology Quality of Life 
Index (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 at Week 4.  These efficacy endpoints will be analyzed descriptively. 
8.3. 
Safety Evaluation 
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. 
8.3.1. 
Adverse Events 
The subject incidence of treatment-emergent adverse events (TEAE) will be summarized overall, 
by severity, and by attribution. 

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8.3.2. 
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. 
8.3.3. 
Medical History and Physical Examinations 
Medical history for all subjects will be presented descriptively by parameter.  
Physical examination for all subjects will be presented descriptively by parameter.  Changes in 
physical examinations will be described in the text of the final report. 
8.3.4. 
Clinical Laboratory Results and Vital Signs 
Clinical safety labs at Week 4 were removed from the study by protocol amendment 1.  All 
clinical laboratory results collected prior to amendment 1 and vital signs measurements, will be 
summarized descriptively by parameter, visit, and treatment group along with time point of 
collection. 
A shift table describing out-of-normal range shifts will be provided for clinical laboratory results.  
A shift table will identify subjects who gain or lose >5% body weight over the course of the 
study. 
8.3.5. 
Prior and Concomitant Medications 
Prior and concomitant medication information for all randomized subjects will be presented in a 
by-subject listing.  Summary tables will be presented by World Health Organization-Anatomical 
Therapeutic Chemical Classification System (WHO-ATC) therapeutic category and product. 
9. 
STUDY ADMINISTRATION 
9.1. 
Ethics 
9.1.1. 
Ethics Review Board 
Before screening of subjects into the study, the current protocol, ICF, and any accompanying 
material to be provided to the subjects will be reviewed and approved by an appropriate IRB, as 
required by FDA (21 CFR § 56) and ICH GCP regulations.  A letter documenting the IRB 
approval must be received by the Sponsor before the initiation of the study at a clinical site. 
Amendments to the protocol will be subject to the same requirements as the original protocol.  
The Investigator, Sponsor, or designee will submit a progress report at least once yearly to the 
IRB. However, the frequency of these reports will depend on IRB requirements. As soon as 
possible after completion or termination of the study, the Investigator will submit a final report to 
the IRB per the IRB requirements, and in compliance with FDA and ICH GCP guidelines. 
The Investigator, the Sponsor, or designee shall promptly notify the IRB of any SAEs, SUSARs, 
or any other information that may affect the safe use of the study drug(s) during the study, per 
the IRB local requirements, and in compliance with FDA regulations and ICH GCP guidelines. 

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9.1.2. 
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). 
9.1.3. 
Subject Information and Consent 
The investigator is responsible for obtaining written informed consent from each individual 
participating and/or their parents/caregivers in this study after adequate explanation 
(in non-technical terms) of the aims, methods, objectives, and potential hazards of the study and 
before undertaking any study-related procedures. The investigator must use the most current 
IRB- or IEC-approved consent form for 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 will be read, appropriately signed and dated by the subject’s legally 
authorized representative and the person conducting the consent discussion, and also by an 
impartial witness if required by IRB or IEC or local requirements. 
Parents/caregivers will be given a signed copy of the signed ICF. 
9.2. 
Study Monitoring 
Prior to the initiation of the clinical investigation, Sponsor representatives or designees may visit 
the clinical site where the investigation is to be conducted.  Sponsor representatives or designees 
shall ensure that the Investigator understands the investigational status of the investigational 
product, all requirements of the investigation to be undertaken, and all of his/her responsibilities 
as an Investigator.  Sponsor representatives or designees will also visit the clinical site at 
appropriate intervals as required to ensure compliance with the protocol and to verify the 
accuracy and completeness of data reported on the CRFs.  The Study Director or designees shall 
be available for consultation with the Investigator and serve as liaisons between the clinical site 
and the Sponsor. 
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. 
9.3. 
Study Completion/Termination 
9.3.1. 
Study Completion 
The study is considered completed with the last visit of the last subject participating in the study. 
The final data from the investigational site will be sent to the Sponsor (or designee) after 
completion of the final subject visit at that site, in the time frame specified in the Clinical Trial 
Agreement. 

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9.3.2. 
Study Termination 
The Sponsor reserves the right to close the investigational site or terminate the study at any time 
for any reason at the sole discretion of the Sponsor. Investigational sites will be closed upon 
study completion. An investigational site is considered closed when all required documents and 
study supplies have been collected and a site closure visit has been performed. The investigator 
may initiate site closure at any time, provided there is reasonable cause and sufficient notice is 
given in advance of the intended termination.  
Reasons for the early closure of an investigational site by the Sponsor or investigator may 
include but are not limited to: 
• Failure of the investigator to comply with the protocol, the Sponsor’s procedures, or 
GCP guidelines. 
• Inadequate recruitment of subjects by the investigator. 
• Discontinuation of further drug development. 
9.4. 
Data Quality Assurance 
In order to ensure the collection of accurate, consistent, complete, and reliable data during this 
clinical investigation, Sponsor representatives or designees may conduct audits of participating 
sites at appropriate intervals throughout the study.  The results of these periodic site audits may 
be subject to review by independent auditors at completion of the clinical investigation.   
All clinical data will undergo a quality control check prior to clinical database lock. Edit checks 
are performed for appropriate databases as a validation routine using SAS version 9.4 to check 
for missing data, data inconsistencies, data ranges etc. Corrections are made prior to database 
lock. 
9.5. 
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.   

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9.6. 
Protocol Amendments and Deviations 
No change or amendment to this protocol may be made by the investigator or Sponsor after the 
protocol has been agreed to and signed by all parties unless such change(s) or amendment(s) has 
(have) been agreed upon by the investigator and Sponsor.  Any change agreed upon will be 
recorded in writing, and the written amendment will be signed by the investigator and Sponsor.  
Institutional review board approval is required prior to the implementation of an amendment, 
unless overriding safety reasons warrant immediate action, in which case the IRB(s) will be 
promptly notified. 
No deviation from the protocol will be made except to protect the life or physical well-being of a 
subject in an emergency.  Except in such emergencies, prior approval of the Sponsor, and the 
IRB, is required before deviations from the planned protocol.  All protocol deviations that occur 
during the study will be documented and reported to Sponsor and to the IRB(s), if applicable, 
according to regulations.  Further details about the documentation, evaluation, and follow-up of 
protocol deviations are detailed in this study’s clinical monitoring plan 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), 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. 
9.7. 
Confidentiality and Privacy 
The investigator must assure that subjects’ anonymity will be strictly maintained and that their 
identities are protected from unauthorized parties. Only an identification code and any other 
unique identifier(s) as allowed by local law (such as date of birth) will be recorded on any form 
or biological sample submitted to the Sponsor. The investigator agrees that all information 
received from Arcutis Biotherapeutics, Inc., including but not limited to the investigator 
brochure, this protocol, CRF/eCRF, the IP, and any other study information, remain the sole and 
exclusive property of Arcutis Biotherapeutics, Inc. during the conduct of the study and thereafter. 
This information is not to be disclosed to any third party (except employees or agents directly 
involved in the conduct of the study or as required by law) without prior written consent from 
Arcutis Biotherapeutics, Inc. The investigator further agrees to take all reasonable precautions to 
prevent the disclosure by any employee or agent of the study site to any third party or otherwise 
into the public domain. 
9.8. 
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. 
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managed in a way that is appropriate to their participation in the design and conduct of this 
study. 
9.9. 
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). 
9.10. 
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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10. 
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. 
DAXAS (roflumilast) film-coated tablets [product monograph]. AstraZeneca Canada, Inc., 
Mississauga, Ontario Canada; 2017. 
EUCRISA™ (crisaborole) ointment, 2%, for topical use [package insert]. Pfizer Laboratories 
Div. Pfizer Inc, NY, USA; 2017. 
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 J.M. and Rajka G. Diagnostic features of atopic dermatitis. Acta Derm Venereol Suppl 
(Stockh). 1980;92:44–47. 
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. 
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. 

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Murrell DF, Gebauer K, Spelman L, et al. Crisaborole topical ointment, 2% in adults with atopic 
dermatitis: a phase 2a, vehicle- controlled, proof-of-concept study. J Drugs Dermatol. 
2015;14:1108–1112. 
Nazarian R, Weinberg JM. AN-2728, a PDE4 inhibitor for the potential topical treatment of 
psoriasis and atopic dermatitis. Curr Opin Investig Drugs. 2009;10:1236–1242. 
Newton et al., Exploring Content and Psychometric Validity of Newly Developed Assessment 
Tools for Itch and Skin Pain in Atopic Dermatitis. Journal of Patient-Reported Outcomes. 
2019;3:42. 
Nygaard U, Deleuran M, Vestergaard C. Emerging treatment options in atopic dermatitis: topical 
therapies. Dermatology. 2017;233:333–343. 
OTEZLA® (apremilast) tablets, for oral use [package insert].  Celgene Corporation, Summit, NJ 
USA; 2017. 
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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11. 
APPENDICES 
APPENDIX 1. BODY DIAGRAM 
Site personnel to mark treatable areas identified by the Investigator. 
(Reminder: Application will be all areas affected (except for the scalp).  Continue to apply even 
if area(s) clears and treat new lesions (except scalp). 
 
 

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APPENDIX 2. VALIDATED INVESTIGATOR GLOBAL ASSESSMENT 
SCALE FOR ATOPIC DERMATITIS 
 

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APPENDIX 3. CHILDREN’S DERMATOLOGY LIFE QUALITY INDEX 
 

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APPENDIX 4. INFANTS’ DERMATITIS QUALITY OF LIFE INDEX 
(IDQOL) 
 
 
 
 

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APPENDIX 5.  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 6. SCORAD 
SCORAD https://www.ncbi.nlm.nih.gov/pubmed/8435513 
 

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APPENDIX 7. PATIENT-ORIENTED ECZEMA MEASURE (POEM) 
 

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