Clinical trial NCT03916081
Conditions: Atopic Dermatitis
Sponsor: Arcutis Biotherapeutics, Inc.
Start date: 2019-05-31; Completion date: 2019-11-04
Enrollment: 136 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The study will assess the safety, pharmacokinetics (PK), and efficacy of different doses of roflumilast (ARQ-151) cream (0.05% and 0.15%) vs placebo applied once daily (QD) for 28 days by adolescents and adults with atopic dermatitis.

Detailed description:
This is a parallel group, double blind, vehicle-controlled study in which roflumilast cream 0.05% or 0.15% or vehicle is applied QD x 28 days to adolescent and adult subjects with atopic dermatitis. A subset of subjects will have serial PK testing, which will include the first few adolescents and adults enrolled in the study.

Arms: arm 1: Participants apply roflumilast cream 0.05% QD for 28 days. arm 2: Participants apply roflumilast cream 0.15% QD for 28 days. arm 3: Participants apply vehicle cream QD for 28 days.
Interventions: intervention 1: Roflumilast Cream 0.05% intervention 2: Roflumilast Cream 0.15% intervention 3: Vehicle Cream
Intervention descriptions: intervention 1: Roflumilast 0.05% cream for topical application intervention 2: Roflumilast 0.15% cream for topical application intervention 3: Inactive vehicle cream matched to roflumilast cream for topical application.

Protocol documents:
Prot_000.pdf: 
ARQ-151-212 
 
NCT03916081 
 
Protocol Amendment 2, 05-Aug-2019 






Protocol ARQ-151-212 
Arcutis, Inc. 
Amendment 2.0 
 
 August 5, 2019 
Confidential 
 Page 3 of 84 
(crisaborole) 
 Revised PK testing plan to include only trough PK 
sampling for all new subjects enrolled under this 
amendment 
 Updated number of sites to approximately 30 
 Revised efficacy analysis removing vIGA-AD analyses  
 Editorial and administrative changes throughout the 
protocol to clarify language and formatting to improve 
readability, removed Sponsor and Coordinating PI signature 
page to a separate standalone document. 
 
 
 
 
 






Protocol ARQ-151-212 
Arcutis, Inc. 
Amendment 2.0 
 
 August 5, 2019 
Confidential 
 Page 6 of 84 
3 
TABLE OF CONTENTS 
1 
SITE INVESTIGATOR SIGNATURE PAGE .................................................................. 4 
2 
ADDITIONAL KEY CONTACTS FOR THE STUDY .................................................... 5 
3 
TABLE OF CONTENTS ..................................................................................................... 6 
4 
SYNOPSIS ........................................................................................................................... 10 
5 
SCHEDULE OF VISITS AND ASSESSMENTS ............................................................ 18 
6 
ABBREVIATIONS ............................................................................................................. 20 
7 
BACKGROUND AND RATIONALE .............................................................................. 22 
7.1 
Introduction ................................................................................................................. 22 
7.2 
Preclinical Studies ....................................................................................................... 23 
7.2.1 Repeat-Dose Toxicity ............................................................................................... 23 
7.2.2 Reproductive Toxicity .............................................................................................. 25 
7.2.3 Genotoxicity .............................................................................................................. 25 
7.2.4 Carcinogenicity ......................................................................................................... 25 
7.2.5 Special Toxicity:  Local Tolerance of Topical Formulation ..................................... 26 
7.2.6 Conclusions on Toxicity Findings ............................................................................ 26 
7.3 
Clinical Studies ............................................................................................................ 27 
7.3.1 Topical Roflumilast Cream ....................................................................................... 27 
7.3.2 Oral Roflumilast Tablet ............................................................................................ 29 
7.4 
Rationale for Development......................................................................................... 30 
7.4.1 Dose Selection .......................................................................................................... 30 
7.4.2 Risks and/or Benefits to Subjects ............................................................................. 31 
8 
STUDY ENDPOINTS AND OBJECTIVES ..................................................................... 32 
8.1 
Study Objectives.......................................................................................................... 32 
8.1.1 Primary Objectives.................................................................................................... 32 
8.2 
Study Endpoints .......................................................................................................... 32 
8.2.1 Primary Endpoints .................................................................................................... 32 
8.2.2 Secondary Endpoints ................................................................................................ 32 
9 
INVESTIGATIONAL PLAN ............................................................................................ 33 
9.1 
Overall Study Design and Plan .................................................................................. 33 
9.2 
Subject Participation .................................................................................................. 33 
9.3 
Randomization ............................................................................................................ 33 
9.4 
Numbering of Subjects ............................................................................................... 33 
9.5 
Blinding ........................................................................................................................ 34 
9.6 
Selection of Study Population .................................................................................... 34 
9.6.1 Inclusion Criteria ...................................................................................................... 34 
9.6.2 Exclusion Criteria ..................................................................................................... 35 


Protocol ARQ-151-212 
Arcutis, Inc. 
Amendment 2.0 
 
 August 5, 2019 
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9.7 
Removal of Subjects from the Study ......................................................................... 36 
9.8 
Replacement of Subjects that Withdraw or are Discontinued from the Study..... 37 
9.9 
Prohibitions and Concomitant Therapy ................................................................... 37 
9.10 
Treatment .................................................................................................................... 39 
9.10.1 
Drug Supplies, Packaging and Labeling ............................................................... 39 
9.10.2 
Treatment Administration ..................................................................................... 39 
9.10.3 
Treatment Compliance .......................................................................................... 40 
10 STUDY PROCEDURES .................................................................................................... 41 
10.1 
Safety Assessments ...................................................................................................... 41 
10.1.1 
Screening............................................................................................................... 41 
10.1.2 
Physical Examination............................................................................................ 41 
10.1.3 
Vital Signs, Height and Weight ............................................................................ 41 
10.1.4 
12-lead ECGs ........................................................................................................ 42 
10.1.5 
Laboratory Tests ................................................................................................... 42 
10.1.6 
Patient Health Questionnaire Depression Scale (PHQ-8) ..................................... 43 
10.1.7 
Columbia-Suicide Severity Rating Scale (C-SSRS) ............................................. 43 
10.1.8 
Local Tolerability Assessment .............................................................................. 44 
10.1.9 
Adverse Events ..................................................................................................... 45 
10.2 
Efficacy Evaluations ................................................................................................... 45 
10.2.1 
Eczema Area and Severity Index (EASI) ............................................................. 45 
10.2.2 
Validated Investigator Global Assessment scale for Atopic Dermatitis ............... 46 
10.2.3 
Worst Itch Numerical Rating Scale (WI-NRS) .................................................... 48 
10.3 
Other Evaluations ....................................................................................................... 48 
10.3.1 
Body Surface Area (BSA) .................................................................................... 48 
10.3.2 
Pharmacokinetics Assessment .............................................................................. 49 
10.4 
Final Study Visit .......................................................................................................... 49 
10.5 
Early Termination Visit ............................................................................................. 49 
10.6 
Unscheduled Visit........................................................................................................ 49 
10.7 
Adverse Events ............................................................................................................ 50 
10.7.1 
Adverse Event Definition ..................................................................................... 50 
10.7.2 
Serious Adverse Event .......................................................................................... 50 
10.7.3 
Suspected Unexpected Serious Adverse Reaction (SUSAR) ............................... 51 
10.7.4 
Safety Review with Subject .................................................................................. 51 
10.7.5 
Adverse Event Reporting ...................................................................................... 52 
10.8 
Reporting Pregnancy .................................................................................................. 53 
10.9 
Treatment Stopping Rules ......................................................................................... 54 
11 DATA ANALYSIS .............................................................................................................. 55 
11.1 
Statistical Methods ...................................................................................................... 55 
11.1.1 
Pharmacokinetics Assessment .............................................................................. 55 
11.1.2 
Pharmacokinetic Parameters ................................................................................. 56 


Protocol ARQ-151-212 
Arcutis, Inc. 
Amendment 2.0 
 
 August 5, 2019 
Confidential 
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11.1.3 
Safety Analysis ..................................................................................................... 56 
11.1.4 
Determination of Sample Size .............................................................................. 57 
11.1.5 
Subjects to Analyze............................................................................................... 57 
11.1.6 
Interim Analysis .................................................................................................... 58 
11.1.7 
Background and Demographic Characteristics ..................................................... 58 
11.1.8 
Study Medication Compliance .............................................................................. 58 
11.2 
Efficacy Evaluation ..................................................................................................... 58 
11.2.1 
Primary Endpoint .................................................................................................. 58 
11.2.2 
Secondary Endpoints ............................................................................................ 58 
11.3 
Safety Evaluation ........................................................................................................ 59 
11.3.1 
Adverse Events ..................................................................................................... 59 
11.3.2 
Local Tolerance Assessment................................................................................. 60 
11.3.3 
Medical History and Physical Examinations ........................................................ 60 
11.3.4 
Clinical Laboratory Results and Vital Signs ......................................................... 60 
11.3.5 
Prior and Concomitant Medications ..................................................................... 60 
11.4 
Pharmacokinetic Analysis .......................................................................................... 60 
12 STUDY ADMINISTRATION ........................................................................................... 61 
12.1 
Ethics ............................................................................................................................ 61 
12.1.1 
Ethics Review Board............................................................................................. 61 
12.1.2 
Ethical Conduct of the Study ................................................................................ 61 
12.1.3 
Subject Information and Consent/Assent.............................................................. 61 
12.2 
Study Monitoring ........................................................................................................ 61 
12.3 
Study Completion/Termination ................................................................................. 62 
12.3.1 
Study Completion ................................................................................................. 62 
12.3.2 
Study Termination ................................................................................................ 62 
12.4 
Data Quality Assurance .............................................................................................. 62 
12.5 
Data Handling and Record Keeping ......................................................................... 63 
12.6 
Protocol Amendments and Deviations ...................................................................... 63 
12.7 
Report Format ............................................................................................................. 64 
12.8 
Publication Policy........................................................................................................ 64 
13 REFERENCES .................................................................................................................... 65 
14 APPENDICES ..................................................................................................................... 67 
 
 
 
 


Protocol ARQ-151-212 
Arcutis, Inc. 
Amendment 2.0 
 
 August 5, 2019 
Confidential 
 Page 9 of 84 
 
LIST OF TABLES 
Table 1. 
Excluded Medications and Treatments ................................................................... 38 
 
 
LIST OF FIGURES 
Figure 1. 
TPSS x TPS Fitted Summary Statistics from MMRM (mITT Population) ............ 28 
 
 
LIST OF APPENDICES 
Appendix 1. Body Diagram ......................................................................................................... 67 
Appendix 2. Hanifin and Rajka Diagnostic Criteria for Atopic Dermatitis (AD) ....................... 68 
Appendix 3. Patient Health Questionaire-8 (PHQ-8) .................................................................. 69 
Appendix 4. EASI Scoring Tool .................................................................................................. 69 
Appendix 5. Columbia-Suicide Severity Rating Scale (C-SSRS) Baseline/Screening 
Version .................................................................................................................... 71 
Appendix 6. Columbia-Suicide Severity Rating Scale (C-SSRS) Since Last Visit Version ........ 74 
Appendix 7. NIAID DMID Toxicity Table ................................................................................. 77 
 


Protocol ARQ-151-212 
Arcutis, Inc. 
Amendment 2.0 
 
 August 5, 2019 
Confidential 
 Page 10 of 84 
4 
SYNOPSIS 
Compound: 
ARQ-151 cream 0.05% and ARQ-151 cream 0.15% 
IND 
135681 
Clinical Indication: 
Atopic Dermatitis 
Study Phase and 
Type: 
Phase 2 proof of concept study of the safety and efficacy of ARQ-151 
cream 0.05% and 0.15% administered QD in adolescent and adult 
subjects with atopic dermatitis 
Study Objectives: 
 To assess the safety and efficacy of ARQ-151 cream 0.05% vs 
ARQ-151 cream 0.15% vs vehicle administered QD x 4 weeks to 
adolescent and adult subjects with mild to moderate atopic 
dermatitis. 
 To evaluate the systemic exposure and characterize the plasma 
pharmacokinetic (PK) profile of ARQ-151 cream 0.05% and 
0.15% and its major N-oxide metabolite, in adolescent and adult 
subjects with mild to moderate atopic dermatitis. 
Summary of Study 
Design: 
This is a parallel group, double blind, vehicle-controlled study in 
which ARQ-151 cream 0.05% or ARQ-151 cream 0.15% or vehicle is 
applied QD x 4 weeks to adolescent and adult subjects with atopic 
dermatitis. A subset of subjects that consented under the previous 
amendment will have serial PK testing, while only trough PK 
sampling will be performed for all new subjects enrolled under this 
amendment.  
Blinding: 
This study is double blind and vehicle-controlled 
Countries:  
Canada and United States (for all subjects) 
Number of sites: 
Approximately 30 sites in the US and Canada  
Study Population: 
Subjects will be male and female adolescents (12-17 y/o) and adults 
(>18 y/o). Subjects will have atopic dermatitis involvement with a 
vIGA-AD score of ‘2’ (mild) or ‘3’ (moderate) for study entry. 
Inclusion Criteria 
1. 
Participants legally competent to sign and give informed 
consent or, in the case of adolescents, assent with consent of a 
parent(s) or legal guardian, as required by local laws.  
2. 
Males and females ages 12 years and older (inclusive) at the 
time of consent. 
3. 
Clinical diagnosis of active atopic dermatitis according to the 
criteria of Hanifin and Rajka (1980). Subjects must have at least 
3 of the 4 basic features (1. Pruritus; 2. Typical morphology and 
distribution [flexural lichenification in adults and facial and 
extensor eruptions in infants and children]; 3. Chronic or 
chronically relapsing dermatitis; or 4. Personal or family history 
of atopy), in addition to at least 3 minor criteria. 


Protocol ARQ-151-212 
Arcutis, Inc. 
Amendment 2.0 
 
 August 5, 2019 
Confidential 
 Page 11 of 84 
4. 
History of AD for at least 4 months as determined by the 
Investigator through subject interview. Stable disease for the 
past 3 weeks with no significant flares in atopic dermatitis 
before screening. 
5. 
BSA involvement of at least 1.5% (excluding the scalp, palms, 
and soles) but no more than 35%, at Baseline (Visit 2). 
6. 
vIGA-AD score of ‘mild’ (‘2’) or ‘moderate (‘3’) at Baseline 
(Visit 2).  vIGA-AD is evaluated for the entire body except the 
scalp, palms, and soles. 
7. 
Subject has an EASI score of ≥ 5 at Baseline (Visit 2). EASI is 
evaluated for the entire body except the scalp, palms, and soles. 
8. 
Females of childbearing potential (FOCBP) must have a 
negative serum pregnancy test at Screening (Visit 1) and a 
negative urine pregnancy test at  Baseline (Visit 2). In addition, 
sexually active FOCBP must agree to use at least one form of 
highly effective contraception throughout the duration of the 
trial and for one week after application of the last dose. Highly 
effective forms of contraception include: oral/implant/ 
injectable/transdermal contraceptives, intrauterine device, and 
partner’s vasectomy. If barrier methods are used (e.g., condom 
with spermicide, diaphragm with spermicide), then 2 forms of 
contraception are required in association with spermicide. The 
use of abstinence as a contraceptive measure is acceptable as 
long as this is a consistent part of a lifestyle choice and an 
acceptable backup method has been identified if the subject 
becomes sexually active. 
9. 
Females of non-childbearing potential must either be pre-
menarchal, or post-menopausal with spontaneous amenorrhea 
for at least 12 months (post-menopausal status should be 
confirmed with FSH testing) or have undergone surgical 
sterilization (permanent sterilization methods include 
hysterectomy, bilateral oophorectomy, hysteroscopic 
sterilization, bilateral tubal ligation or bilateral salpingectomy). 
10. Subjects in good health as judged by the Investigator, based on 
medical history, physical examination, vital signs, 12-lead 
electrocardiogram (ECG), serum chemistry labs, hematology 
values, and urinalysis. 
 
11. Subjects are considered reliable and capable of adhering to the 
Protocol and visit schedule, according to the judgment of the 
Investigator. 
Exclusion Criteria 
1. 
Subjects with any serious medical condition or clinically 
significant laboratory, ECG, vital signs, or physical examination 
abnormality that would prevent study participation or place the 
subject at significant risk, as judged by the Investigator 




Protocol ARQ-151-212 
Arcutis, Inc. 
Amendment 2.0 
 
 August 5, 2019 
Confidential 
 Page 13 of 84 
13. Subjects with a history of chronic alcohol or drug abuse within 6 
months of initiation of study medication. 
14. History of and/or concurrent condition of serious hypersensitivity 
(anaphylactic shock or anaphylactoid reaction) to PDE-4 
inhibitors. 
15. Current or a history of cancer within 5 years with the exception 
of fully treated skin basal cell carcinoma, cutaneous squamous 
cell carcinoma or carcinoma in situ of the cervix. 
16. Subjects with a history of a major surgery within 4 weeks prior to 
Baseline (Visit 2) or has a major surgery planned during the 
study. 
17. Subjects who are unable to communicate, read or understand the 
local language, or who display another condition, which in the 
Investigator’s opinion, makes them unsuitable for clinical study 
participation. 
18. Subjects that are family members of the clinical study site, 
clinical study staff, or sponsor, or family members of enrolled 
subjects. 
Number of Subjects: Approximately 90 to 105 subjects; randomized 1:1:1 to ARQ-151 
cream 0.05% : ARQ-151 cream 0.15% : vehicle and stratified based 
on IGA score of ‘2’ (mild) or ‘3’ (moderate).   
Duration of 
Participation for 
Subjects: 
Screening (up to 4 weeks) + Treatment phase (4 weeks) for a total of 
approximately 8 weeks 
Study Products: 
 ARQ-151 will be supplied as a 0.05% emollient cream and a 0.15% 
emollient cream 
 Matching vehicle will contain only excipients of ARQ-151 cream 
Planned Dose Level: 
Subjects will receive ARQ-151 cream 0.05% QD or ARQ-151 cream 
0.15% QD or matching vehicle QD to be applied to all AD affected 
areas and any newly appearing AD lesions that arise during the study, 
except the scalp. 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. 
Safety Assessments: 
 Safety will be monitored through local tolerability assessments, 
vital signs, safety labs, 12 lead ECGs and AEs.  
 After obtaining consent, all AEs and TEAEs should be collected.  
 The investigator, or designee, will perform local tolerability 
assessments at Baseline (Visit 2), and weeks 1, 2, and 4 (Visits 4, 
5, and 7). Subjects will have vital signs measured at each study 
visit, except for the 24-hour PK sampling visits (Visit 3 and 6) for 
subjects who agree to serial PK samples collected during the 
study. Height will be collected at Visit 1 only (Screening). 


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Arcutis, Inc. 
Amendment 2.0 
 
 August 5, 2019 
Confidential 
 Page 14 of 84 
 A limited physical exam (skin, lungs, and heart only) will be 
performed at Visit 1-Screening, Visit 2-Baseline and Visit 7-Day 
29. An ECG will be obtained at Visit 1-Screening and Visit 7-Day 
29. Blood and urine samples for routine safety laboratory tests 
(hematology, serum chemistry, and urinalysis) will be obtained at 
Visit 1-Screening, Visit 2-Baseline and Visit 7-Day 29. For all 
female subjects of childbearing potential, a urine pregnancy test 
will be administered at all clinic visits, except for the 24-hour PK 
sampling visits (Visit 3 and 6) for subjects who agree to serial PK 
samples collected during the study, and except for Visit 1 
(Screening) where a serum pregnancy test will be performed. A 
negative pregnancy result is required for continued participation 
in the study, and results (of the urine pregnancy test) must be 
available prior to dispensing of study drug at study visits.   
 
Safety will also be monitored by PHQ-8 and C-SSRS. 
Safety Analysis: 
The following analyses will be performed; however, no formal 
inferential statistics will be done on safety assessments. 
Descriptive statistics will be calculated for quantitative safety data and 
frequency counts will be compiled for classification of qualitative 
safety data. All subjects who are randomized and receive at least one 
confirmed dose of study drug will be included in the safety 
population.  
Adverse Events: 
All adverse events (AEs) reported during the study will be recorded 
and classified based on MedDRA terminology. Treatment-emergent 
adverse events (TEAEs) are defined as those AEs with an onset on or 
after the time of the first study drug application, or AEs that started 
before but worsened after first drug application. All reported TEAEs 
will be summarized by the number of subjects reporting TEAEs, 
system organ class, preferred term, severity, relationship to study 
drug, and as local to the study drug administration site or as a non-
local TEAE. When summarizing TEAEs by severity or relationship to 
study drug, each subject will be counted only once within a system 
organ class or a preferred term by using the event with the greatest 
severity or causality, respectively, within each category.  
Serious adverse events (SAEs) will be summarized by the number of 
subjects reporting SAEs, system organ class, preferred term, severity, 
and relationship to study drug. 
All information pertaining to AEs reported during the study will be 
listed by subject, detailing verbatim term given by the Investigator, 
preferred term, system organ class, start date, stop date, seriousness, 
severity, action taken regarding study drug, corrective treatment, 
outcome, and relationship to study drug. In addition, a list of subjects 
who prematurely discontinued from the study due to an adverse event 


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Amendment 2.0 
 
 August 5, 2019 
Confidential 
 Page 15 of 84 
will also be provided. 
Subset analysis by age group (adolescents and adults) will be 
conducted. 
Medical History, Physical Examinations, Vital Signs, Safety Labs 
and ECGs: 
Medical history will be listed by subject. Clinically significant 
physical examination parameters will be captured as adverse events. 
Safety laboratory parameters and vital signs will be summarized at 
each visit using descriptive statistics or frequencies and percentages, 
as appropriate. Changes from baseline in laboratory values and vital 
signs will also be summarized by visit. In addition, changes from 
baseline in weight and laboratory values will be summarized using 
shift tables according to normal ranges. 
For ECGs, interval measurements will be summarized by time point 
using descriptive statistics. Changes from screening in interval 
measures will also be summarized. Any ECG abnormalities not 
present at Baseline will be identified in a listing of ECG 
abnormalities. 
Subset analysis by age group (adolescents and adults) will be 
conducted. 
Efficacy Analysis 
The Primary Efficacy Endpoint will be defined as:  
• 
Change from baseline in Eczema Area and Severity Index (EASI) 
Total Score at Week 4 
The Secondary Efficacy Endpoints will include: 
• 
Percent change from baseline in EASI Total Score at each study 
visit 
• 
Change from baseline in EASI Total Score at Weeks 1 and 2 
• 
Achievement of a 75% or greater improvement in Eczema Area 
and Severity Index (EASI75) score from baseline to each study 
visit 
• 
Achievement of a 50% or greater improvement in Eczema Area 
and Severity Index (EASI50) score from baseline to each study 
visit 
• 
Change from baseline in BSA involvement at each study visit 
• 
Change from baseline in WI-NRS pruritus score at each study visit 
• 
Achievement of a ≥ 4-point improvement from Baseline in WI-
NRS pruritus score at each study visit for subjects with a Baseline 
WI-NRS ≥ 4 
Subset analysis by age group (adolescents and adults) will be 


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Amendment 2.0 
 
 August 5, 2019 
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conducted. 
Power and Sample 
Size 
There are approximately 90-105 subjects planned for this study.  
Approximately 30-35 subjects will receive ARQ-151 cream 0.05% 
QD; approximately 30-35 subjects will receive ARQ-151 cream 
0.15% QD;  approximately 30-35 subjects will receive vehicle QD.  
A sample size of 27 per arm will provide at least 80% power to detect 
a difference in the mean change from baseline in EASI Total Score 
of 35% at week 4 (for each ARQ-151-treated group versus vehicle-
treated group), assuming a pooled standard deviation of 40%, with a 
two-sided α = 0.05. This is based on a 2-sample t-test.  This includes 
P value adjustment for multiplicity using Bonferroni correction.  With 
a 10-25% dropout rate, the sample size for the study would be 
increased to 30-35 subjects per arm (90-105 subjects total).  Change 
from baseline in EASI Total Score at Week 4 is expected to provide 
more statistical power than percent change from baseline in EASI 
Total Score at this timepoint (which is a secondary endpoint) and has 
been chosen as the primary endpoint. 
Pharmacokinetic 
Sample Collection:  
 = 
For all subjects enrolling under this amendment: 
 A single pre-dose PK sample will be collected on Days 1 and 
29 (trough). 
 For a subset of subjects: 
 Subjects who consented to optional collection of serial PK 
samples under the previous amendment will participate in 
serial PK sampling. 


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Amendment 2.0 
 
 August 5, 2019 
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Statistical Analysis: 
Four analysis populations will be defined: 
 Safety population will include all subjects who are enrolled 
and received at least one confirmed dose of study medication; 
this population will be defined separately for each cohort. 
 Intent-to-Treat (ITT) population will include all randomized 
subjects. 
 Per-Protocol (PP) Population will include all subjects who are 
in the safety population, were at least 80% compliant with 
study medication, and showed no other serious deviations from 
the study protocol. 
 PK population will include all subjects receiving the active 
drug with sufficient plasma concentrations of roflumilast to 
define a profile, as determined by the pharmacokineticist.  
Pharmacokinetics Assessment 
Plasma levels of circulating roflumilast and its major N-oxide 
metabolite will be measured at the following time points: 
 Prior to study drug application on Days 1 and 29 
 Pre-dose, 1, 2, 4, 6 and 24 hours post-dose administration on 
Days 1 and 15 (PK subset only for subjects enrolled under the 
previous amendment) 
Efficacy Assessment 
Descriptive statistics for continuous variables will include mean, 
median, standard deviation, min, max. Descriptive statistics for 
categorical variables will include frequencies and percents. For 
missing data, a multiple imputation technique will be detailed in the 
SAP. The primary endpoint  ‘EASI CFB’ will be analyzed with Mixed 
Model Repeated Measures (MMRM) analysis with subject as a 
random effect and vIGA-AD strata, visit, treatment, visit by treatment 
interaction as fixed effects and baseline as a covariate.  The week 4 
treatment group comparison will be provided using the appropriate 
contrast.  
Continuous secondary efficacy analysis will be analyzed in the same 
manner as the primary endpoint.   
Categorical variables (such as proportion with EASI50) will be 
analyzed using Cochran-Mantel-Haenszel test adjusting for vIGA-AD 
strata. 
 
 


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Amendment 2.0 
 
 August 5, 2019 
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5 
SCHEDULE OF VISITS AND ASSESSMENTS 
STUDY EVENTS FLOW CHART: 
 
Study Procedure 
Screen 
Baseline 
Day 1 
Day 2, 24-
hour PK 
Collection 
 
Wk 1 
Day 8 
 
Wk 2 
Day 15 
Day 16, 24-
hour PK 
Collection 
 
Wk 4 
Day 29  
Visit 
1 
2 
3 
4 
5 
6 
7 
Visit Window 
-4 weeks 
 
 
+/- 3 days 
+/- 3 days 
 
+/- 3 days 
Informed consent 
X 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
Medical and surgical 
history 
X 
 
 
 
 
 
 
Physical examinationa 
X 
X 
 
 
 
 
X 
I/E criteria 
X 
X 
 
 
 
 
 
Hematology, Serum 
Chemistries, and 
Urine Analysis  
X 
X 
 
 
 
 
 
X 
12 lead ECG 
X 
 
 
 
 
 
X 
Vital signs, height, 
weightb 
X 
X 
 
X 
X 
 
X 
vIGA-ADc, EASIc, 
BSAc 
X 
X 
 
X 
X 
 
X 
WI-NRS pruritusd 
X 
X 
 
X 
X 
 
X 
Local Tolerability 
Assessmente  
 
X 
 
X 
X 
 
X 
PHQ-8, C-SSRS 
X 
X 
 
X 
X 
 
X 
Optional 
photographyf 
 
X 
 
X 
 
 
X 
Serum pregnancy test 
X 
 
 
 
 
 
 
Urine pregnancy testg 
 
X 
 
X 
X 
 
X 
PK drawsh 
 
X 
X 
 
X 
X 
X 
Drug/vehicle 
application in clinici 
 
X 
 
X 
X 
 
 
Dispense study 
medication kitj 
 
X 
 
X 
X 
 
 
Dispense/review diary 
 
X 
 
Xo 
X 
 
Xn 
Weigh study 
medication kitk 
 
X 
 
X 
X 
 
X 
Compliance 
calculationl 
 
X 
 
X 
X 
 
X 
Adverse event 
assessmentm 
X 
X 
X 
X 
X 
X 
X 
Concomitant 
medications 
X 
X 
 
X 
X 
 
X 
a Limited physical examination: skin, lungs, and heart only 
b  Height will be collected at Screening only. Weight will be collected at all study visits. Subject to void prior to weight being 
taken. Remove any jackets, outerwear and shoes. Remove any objects of significant weight (i.e. cell phones, wallet, key 
chains). A 5% weight loss should be reported to the medical monitor. 
c   vIGA-AD 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 


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affected by AD will be determined for all body surfaces except the scalp, palms and soles. vIGA-AD should be completed 
prior to other physician assessments. 
d   Subjects will complete the WI-NRS pruritus questionnaire. 
e   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. 
f Photography of AD lesion(s) selected by the Investigator will be performed at some investigational sites.  Photography will 
be optional.  All efforts will be made to de-identify the subjects. 
g A urine pregnancy test will be administered to all females of child-bearing potential. A negative result is required for 
continued participation in the study, and results must be available prior to dispensing of study drug at each visit. 
h For the subset of subjects who enrolled under the previous amendment and agreed to the serial PK: on the first day of dosing, 
PK draws will be done pre-dose (within 1-hour) and at 1, 2, 4, 6 (all  20 min)  and 24 hours ( 2 hr) post-dose 
administration.  On Day 15, PK draws will be taken at pre-dose (within 1-hour), 1, 2, 4, 6 (all  20 min) and 24 hours ( 2 hr) 
post dose administration. For other subjects: PK draws will be collected at Days 1 and 29. The draws will be pre-dose, ≤ 60 
minutes before drug application in the clinic. Ensure study medication is not applied in the area where PK will be drawn. 
Note: Day 2 and Day 16 visits for 24-hour PK collection only apply to the subset of subjects who agree to the serial PK. 
i   Subjects to apply assigned IP in clinic at every visit.  
j Kits will be dispensed based on %BSA affected. See IP Handling Manual for details.   
k   The entire kit should be weighed and recorded at every visit. See IP Handling Manual for details. 
l Compliance calculation is described in the IP Handling Manual 
m Any emergent AEs will be followed in the clinic for up to one month at the Investigator’s discretion until resolved or 
otherwise judged as clinically stable. 
n  On Day 29, no further IP will be applied or dispensed. 
o On Day 8, 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. 
 
 






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7 
BACKGROUND AND RATIONALE 
7.1 
Introduction 
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.  In 2016, Eucrisa® (crisaborole), a PDE-4 inhibitor was approved for 
the topical treatment of mild to moderate atopic dermatitis in patients 2 years of age and older.   
Topical calcineurin inhibitors block the activation of T-lymphocytes and diminish inflammation, 
but are accompanied by a boxed warning for the development of lymphomas and other 
lymphoproliferative diseases.  Topical corticosteroids can cause skin atrophy and hypothalamic-
pituitary axis suppression, and their use is often accompanied by poor adherence due to 
corticophobia (fear of using corticosteroids in patients or doctors).  Eucrisa provides precedence 
for the effectiveness of topical PDE-4 inhibitors in atopic dermatitis, but it is a twice-daily 
ointment, its efficacy may be modest, and its use may be accompanied by burning, stinging, and 
local skin reactions. As a result, there is a need for the development of new topical products for 
the treatment of atopic dermatitis (Nygaard 2017). 
The therapeutic use of PDE-4 inhibitors in AD is based on the recognized intracellular role of 
PDE-4 in keratinocytes (Dastidar 2007, Hanifin 1996). Circulating leukocytes in AD patients 
have PDE-4 activity, which has been associated with higher production of proinflammatory 
mediators and lower production of the anti-inflammatory mediator IL-10, in part due to 
hydrolyzation of cyclic adenosine monophosphate (cAMP) (Grewe 1982, Furue 2014, 
Baumer 2007).  This consequently diminishes levels of cAMP, which leads to increased 
transcription of numerous cytokines, accelerating a number of intracellular functions involved in 
acute and chronic inflammation (Grewe 1982).  Thus, targeting PDE-4 has been shown to 
directly attenuate inflammation due to inhibition of the breakdown of cAMP, consequently 
reducing the levels of tumour necrosis factor-α, IL-12, IL-23, and other signaling effectors 
(Murrell 2015). 
 
 




















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8 
STUDY ENDPOINTS AND OBJECTIVES 
8.1 
Study Objectives 
8.1.1 Primary Objectives 
 
To assess the safety and efficacy of ARQ-151 cream 0.05% vs ARQ-151 cream 0.15% vs 
vehicle administered QD x 4 weeks to adolescent and adult subjects with mild to moderate atopic 
dermatitis. 
To evaluate the systemic exposure and characterize the plasma pharmacokinetic (PK) profile of 
ARQ-151 cream 0.05% and 0.15% and its major N-oxide metabolite, in adolescent and adult 
subjects with mild to moderate atopic dermatitis. 
8.2 
Study Endpoints 
8.2.1 Primary Endpoints 
The Primary Efficacy Endpoint will be:  
 Change from baseline in Eczema Area and Severity Index (EASI) Total Score at Week 4 
8.2.2 Secondary Endpoints 
 
The Secondary Efficacy Endpoints will include: 
 Percent change from baseline in EASI Total Score at each study visit 
 Change from baseline in EASI Total Score at Weeks 1 and 2 
  
    
 Achievement of a 75% or greater improvement in Eczema Area and Severity Index 
(EASI75) score from baseline to each study visit 
 Achievement of a 50% or greater improvement in Eczema Area and Severity Index 
(EASI50) score from baseline to each study visit 
 Change from baseline in BSA involvement at each study visit 
 Change from baseline in WI-NRS pruritus score at each study visit 
 Achievement of a ≥4-point improvement from Baseline in WI-NRS pruritus score at each 
study visit for subjects with a Baseline WI-NRS ≥ 4 


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9 
INVESTIGATIONAL PLAN 
9.1 
Overall Study Design and Plan 
This is a phase 2, parallel group, double blind, vehicle-controlled study of ARQ-151 cream 
0.15% and ARQ-151 cream 0.05% QD applied for 4 weeks to adolescent and adult subjects with 
1.5% to 35% BSA of mild to moderate atopic dermatitis.  A subset of subjects that consented 
under the previous amendment will have serial PK testing, while only trough PK sampling will 
be performed for all new subjects enrolled under this amendment. 
 
A total of up to approximately 90 to 105 subjects will be enrolled at approximately 30 study sites 
in the United States and Canada.  Subjects will be adolescent (12-17 y/o) or adult (≥18 y/o) 
males or females with atopic dermatitis.  Subjects must have an Investigator’s Global 
Assessment of disease severity (vIGA-AD) of Mild (‘2’) or Moderate (‘3’) at Baseline.  Subjects 
must have at least 1.5% and no more than 35% BSA of atopic dermatitis (excluding scalp, palms, 
and soles).  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). 
9.2 
Subject Participation 
Subject participation involves a minimum of 5 clinic visits including Screening, Baseline, 
Week 1, Week 2, and Week 4.  For the subset of subjects enrolled under the previous amendment 
and consented to participate in serial PK sampling, 2 additional clinic visits include 24 hour PK 
collection after Baseline on Day 2 and 24 hour PK collection after Week 2 on Day 16.  The 
interval between the Screening and Baseline visits could be up to 4 weeks, therefore the 
anticipated maximum duration of subject participation is ~8 weeks. 
9.3 
Randomization 
Subjects will apply ARQ-151 cream 0.15% QD or ARQ-151 cream 0.05% QD or vehicle cream 
QD.  Assignment of drug or vehicle will be made at a 1:1:1 ratio and stratified based on 
vIGA-AD score of ‘2’ (mild) or ‘3’ (moderate) according to a computer-generated randomization 
list.  Randomization will take place at Baseline after the patient has been found to be fully 
eligible for participation.  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. 
 
 
9.4 
Numbering of Subjects 
All screened subjects will be identified by a unique five-digit subject ID number.  The first two 
digits correspond to the site number (assigned by the Sponsor, e.g., 01 to 15), the next three 
digits correspond to the sequential order in which the subject is screened for the study (e.g., 
Subject ID 05001: Site 5, subject number 1 screened by that site).  


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The clinical site is responsible for maintaining a current log of subject ID number assigned to 
that subject.  The subject ID number 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.).  
9.5 
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 has received. 
9.6 
Selection of Study Population 
9.6.1 Inclusion Criteria 
Subjects must fulfill all of the following inclusion criteria to be eligible for participation in the 
study: 
 
1. 
Participants legally competent to sign and give informed consent or, in the case of 
adolescents, assent with consent of a parent(s) or legal guardian, as required by local laws.  
2. 
Males and females ages 12 years and older (inclusive) at the time of consent. 
3. 
Clinical diagnosis of active atopic dermatitis according to the criteria of Hanifin and Rajka 
(1980). Subjects must have at least 3 of the 4 basic features (1. Pruritus; 2. Typical 
morphology and distribution [flexural lichenification in adults and facial and extensor 
eruptions in infants and children]; 3. Chronic or chronically relapsing dermatitis; or 
4. Personal or family history of atopy), in addition to at least 3 minor criteria. 
4. 
History of AD for at least 4 months as determined by the Investigator through subject 
interview. Stable disease for the past 3 weeks with no significant flares in atopic dermatitis 
before screening. 
5. 
BSA involvement of at least 1.5% (excluding the scalp, palms, and soles) but no more than 
35%, at Baseline (Visit 2). 
6. 
vIGA-AD score of ‘mild’ (‘2’) or ‘moderate (‘3’) at Baseline (Visit 2).  vIGA-AD is 
evaluated for the entire body except the scalp, palms, and soles. 
7. 
Subject has an EASI score of ≥ 5 at Baseline (Visit 2). EASI is evaluated for the entire 
body except the scalp, palms, and soles. 
8. 
Females of childbearing potential (FOCBP) must have a negative serum pregnancy test at 
Screening (Visit 1) and a negative urine pregnancy test at Baseline (Visit 2). In addition, 
sexually active FOCBP must agree to use at least one form of highly effective 
contraception throughout the duration of the trial and for one week after application of the 
last dose. Highly effective forms of contraception include: 
oral/implant/injectable/transdermal contraceptives, intrauterine device, and partner’s 
vasectomy. If barrier methods are used (e.g., condom with spermicide, diaphragm with 
spermicide), then 2 forms of conception are required in association with spermicide. The 
use of abstinence as a contraceptive measure is acceptable as long as this is a consistent 
part of a lifestyle choice and an acceptable backup method has been identified if the 
subject becomes sexually active. 




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rifampin, and carbamazepine for two weeks prior to the Baseline (Visit 2) and during the 
study period.  
10. Subjects who have received oral roflumilast (Daxas®, Daliresp®) within the past 4 weeks. 
11. Known or suspected:  
 severe renal insufficiency or moderate to severe liver impairment (Child-Pugh B or C) 
 history of chronic infectious disease (e.g., hepatitis B, hepatitis C, or human 
immunodeficiency virus (HIV)) 
 within last 5 years, a history of severe depression, suicidal ideation 
12. Females who are pregnant, wishing to become pregnant during the study, or are breast-
feeding. 
13. Subjects with a history of chronic alcohol or drug abuse within 6 months of initiation of 
study medication. 
14. History of and/or concurrent condition of serious hypersensitivity (anaphylactic shock or 
anaphylactoid reaction) to PDE-4 inhibitors. 
15. Current or a history of cancer within 5 years with the exception of fully treated skin basal 
cell carcinoma, cutaneous squamous cell carcinoma or carcinoma in situ of the cervix. 
16. Subjects with a history of a major surgery within 4 weeks prior to Baseline (Visit 2) or has 
a major surgery planned during the study. 
17. Subjects who are unable to communicate, read or understand the local language, or who 
display another condition, which in the Investigator’s opinion, makes them unsuitable for 
clinical study participation. 
18. Subjects that are family members of the clinical study site, clinical study staff, or sponsor, 
or family members of enrolled subjects 
9.7 
Removal of Subjects from the Study 
Subject participation in this trial may be discontinued for any of the following reasons: 
1. Occurrence of any medical condition or circumstance that, in the opinion of the 
Investigator, exposes the subject to substantial risk and/or does not allow the subject to 
adhere to the requirements of the Protocol. 
 
 


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2. Occurrence of a treatment-emergent adverse event (TEAE) or considerable worsening of an 
AE that, in the opinion of the investigator in consultation with the Medical Monitor and 
Sponsor, represents an unacceptable risk to the subject if he/she continues in the study.  
The investigator must follow the subject until the AE resolves or satisfactorily stabilizes. 
3. Pregnancy. 
4. Subject's decision to withdraw. 
5. Weight loss of >5% if not dieting and after consultation with the Sponsor, at the 
Investigator’s discretion. 
6. C-SSRS indicative of suicidal ideation or a PHQ-8 score ≥15, after consultation with a 
mental health professional, the Sponsor, and at the Investigator’s discretion. 
7. Requirement for use of prohibited concomitant medication after consultation with the 
Sponsor and Medical Monitor. 
8. Subject’s repeated failure to comply with protocol requirements or study related 
procedures. 
9. The subject interrupts trial study drug application for more than 50% of scheduled doses. 
10. Termination of the study by the Sponsor, FDA, or other regulatory authorities. 
9.8 
Replacement of Subjects that Withdraw or are Discontinued from the Study 
Subjects that withdraw or are discontinued from the study prior to Final Study Visit (see 
Section 10.4), may be replaced.   
9.9 
Prohibitions and Concomitant Therapy 
Prohibited medications and products are detailed in Table 1 (Excluded Medications and 
Treatments).   
 
 


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Table 1. 
Excluded Medications and Treatments 
Excluded Medications and Treatments 
Washout Period Prior to Day 1 
Biologics including dupilumab and investigational biologics 
12 weeks or 5 half-lives, whichever 
is longer 
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 in a stable regimen 
is allowed. 
4 weeks 
PUVA or NBUVB phototherapy 
4 weeks 
Topical products containing urea 
1 week 
Sedating antihistamines 
1 week 
Topical corticosteroids, calcineurin inhibitors, or Eucrisa®.  
Topical antibacterial medications or products, including soaps, 
bleach baths, or sodium hypochlorite-based products anywhere 
on the body. 
1 week  
Strong P-450 cytochrome inhibitors e.g., indinavir, nelfinavir, 
ritonavir, clarithromycin, itraconazole, ketoconazole, 
nefazodone, saquinavir, suboxone and telithromycin 
2 weeks 
Strong P-450 cytochrome inducers e.g., efavirenz, nevirapine, 
glucocorticoids, barbiturates (including phenobarbital), 
phenytoin, rifampin, and carbamazepine 
2 weeks 
Systemic antibiotics 
2 weeks 
Tanning beds, other light emitting devices  
4 weeks  
Oral roflumilast (Daxas®, Daliresp®) 
4 weeks 
All other investigational drugs 
4 weeks or 5 half-lives, whichever is 
longer 
Note:   
• 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, moisturizers and sunscreens will be allowed once daily in a stable 
regimen as normally used by the subjects and applied at least 2 hours after application of 
randomized study drug to untreated areas only. 
• Concomitant other medications for chronic conditions (eg, NSAIDs, statins, anti-hypertensives) 
are permitted unless specifically prohibited in the Protocol. 
• Topical antibiotics or any other topical agents are not allowed to be applied to treated areas.  Only 
study drug should be applied to treated areas. 
 
 
 


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Generally, the addition of new medications, including nonprescription medications, during the 
course of the study is discouraged.  However, the short-term use of a medication may be 
authorized by the Investigator.  The Investigator must make the decision to authorize the use of 
any such a medication only after consideration of the clinical situation, the potential for masking 
symptoms of a more significant underlying event, and whether the use of the medication will 
compromise the outcome or validity of the clinical investigation.  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 Case Report Forms.  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 ‘Exclusions’ (Table 1).  
9.10 Treatment 
9.10.1 Drug Supplies, Packaging and Labeling 
 
ARQ-151 cream or vehicle cream will be in squeeze tubes that dispense approximately 45 grams 
of cream.  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 
AD.  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 (ARQ-151 cream 0.15%, 
ARQ-151 cream 0.05%, and matching vehicle cream) 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 unused study drugs will be returned to the Sponsor or designee, or 
destroyed, as per Sponsor instructions. 
9.10.2 Treatment Administration 
At the randomization visit (Baseline visit), the study staff will demonstrate to the subject how to 
apply ARQ-151 cream or vehicle cream using the first tube from the kit that is assigned to the 
subject at randomization.  Study site staff will be trained to ensure a unit dose (a pea size unit of 
ARQ-151 vehicle cream will cover approximately 1% BSA) is properly squeezed from the tube 
and applied to atopic dermatitis lesion(s) as a thin film and rubbed in using the index and middle 
finger, rubbing in thoroughly but gently, until the ‘white’ has disappeared.  The subject will then 
practice squeezing a similar amount onto their index and middle finger and apply a thin film to 
other areas to be treated.  The study staff will confirm that the subject’s application technique is 
correct. 
Re-training will be conducted at subsequent visits as needed (i.e., if the returned tube(s) weighs 
substantially different than the expected weight). 
 
Subjects will be instructed to apply study medication once daily to all treatment areas identified 
by the investigator at Baseline using a Body Diagram (see Appendix 1). 
 


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Note: 
 All subjects should apply medication each evening (except on clinic visit days) at least 
15 minutes after showering or bathing (if they take an evening shower/bath) and then not 
wash areas where ARQ-151 cream or vehicle has been applied until at least 4 hours after 
study drug application and preferably not until the following morning. Study medication 
should be applied at least 20 minutes before going to bed. 
 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 Day 29. 
 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 study medication tube will be weighed prior to dispensing at the baseline visit or 
subsequent visits. Study medication tubes must be returned by subjects at each study visit, both 
empty and full, and will be weighed. If the subject’s actual use is substantially different than the 
expected use for the subject’s BSA (see IP Handling Plan), the subject will be retrained on the 
study drug application technique. 
9.10.3 Treatment Compliance  
 
Study medication tubes will be weighed at each follow-up clinic visit. 
 
Subjects will complete a daily diary recording the date and time of each dose applied, any missed 
doses, and a comment section should the subjects have a comment, e.g., record potential AEs.  
Site personnel will review the diaries and use the information to question the subject regarding 
compliance and AEs and then record appropriate information in source documents and complete 
Case Report Forms (CRFs). If a subject misses a dose, they should be instructed to return to the 
protocol study medication administration schedule (i.e. if subject forgets a dose they should wait 
until that evening and apply as usual). 
 
A subject will be considered compliant with the dosing regimen if the subject applies at least 
80% of the expected applications during the study drug application period and does not miss 
more than 3 consecutive doses. 
 
Compliance will be assessed by review of the dosing diary. Weight of study medication applied 
will be measured for reporting purposes. 
 
If the diary shows less than 80% of expected use, the subject is using too little study drug and 
retraining must be conducted and documented. 
 
Compliance will be documented in source and in eCRF. 


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10 STUDY PROCEDURES 
10.1 Safety Assessments 
The Schedule of Visits and Assessments (Section 5) summarizes the clinical procedures to be 
performed at each visit. Individual clinical procedures are described in detail below. Additional 
evaluations/testing may be deemed necessary by the PI and/or the Sponsor for reasons related to 
subject safety. 
This study assesses the safety, efficacy, and pharmacokinetics of ARQ-151 cream. Safety will be 
determined by evaluating physical examinations, 12-lead ECGs, local tolerability assessments, 
vital signs/weight, clinical laboratory parameters and AEs as outlined in the Schedule of Visits 
and Assessments (Section 5). If deemed necessary, additional safety assessments will be 
performed at the discretion of the PI. 
10.1.1 Screening 
Within 4 weeks prior to the first dosing, subjects will be provided details of study requirements 
and sign an informed consent.  Medical history and demographic data including sex, age, race, 
ethnicity, body weight (kg), and height (cm) will be recorded. Each subject will undergo atopic 
dermatitis assessments, a physical examination, ECG, vital sign measurements (blood pressure, 
heart rate, and temperature) and laboratory tests: hematology, chemistry, urinalysis and a 
pregnancy test for female subjects of child bearing potential. Abnormal or questionable serum 
chemistry tests may be repeated at the discretion of the Investigator. 
All screened subjects will receive a screening number and be entered into the study tracking 
document. 
10.1.2 Physical Examination 
Physical examinations will be performed as follows:  Screening, Baseline, and Week 4.   
The physical exam will be limited to skin, lungs and heart only. 
10.1.3 Vital Signs, Height and Weight 
Vital signs will be collected (in seated position after 5 mins) at timepoints noted below: 
Weight, blood pressure, heart rate, and temperature will be measured at Screening, Baseline, 
Week 1, Week 2, and Week 4.  
Height will be measured at Screening only.  
 
 


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10.1.4 12-lead ECGs 
12-lead ECGs will be performed as follows:  Screening and Week 4. 
ECGs will be performed on subjects after 5 minutes in the supine position. All ECG tracings and 
readouts will be reviewed by the central reader at the ECG laboratory. 
10.1.5 Laboratory Tests 
All tests listed below will be performed as follows: 
Screening, Baseline, and Week 4.    
All tests listed below will be performed according to the Study Events Flow Chart unless 
otherwise noted. The collection of specimens will be in a non-fasting state (no food restrictions). 
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  
 
Urinalysis 
 
 
Additional Tests 
 
pH 
 
Specific gravity 
 
Protein* 
 
Glucose 
 
Ketones 
 
Bilirubin 
 
Blood* 
 
Nitrite* 
 
Urobilinogen 
 
Leukocyte esterase* 
 
 
Urine pregnancy test** 
(for females of child bearing potential only) 
 
Serum pregnancy test (hCG)*** 
 
FSH test, if indicated 
 
* 
If urinalysis is positive for protein, blood, nitrite and/or leukocyte esterase, a microscopic examination (for red blood 
cells, white blood cells, bacteria, casts, and epithelial cells) will be performed. 
** At baseline, Week 1, Week 2, and Week 4 for FOCBP only  
*** At screening only 
 
 


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10.1.6 Patient Health Questionnaire Depression Scale (PHQ-8) 
 
The 8 item PHQ-8 Assessment (see Appendix 3) will be performed as follows:  Screening, 
Baseline, Week 1, Week 2, and Week 4. 
 
A subject with a PHQ-8 score of ‘15’ or above should be referred promptly to a mental health 
care professional and, if currently applying study drug, consideration be given to discontinuation 
from study drug. 
 
PHQ-8 score is the sum of the responses for the 8 questions. 
 
Five severity categories of depression are defined as follows: 
 
• 
None – Minimal depression (1 to 4) 
• 
Mild depression (5 to 9) 
• 
Moderate depression (10 to 14) 
• 
Moderately severe depression (15 to 19) 
• 
Severe depression (20 to 27) 
10.1.7 
Columbia-Suicide Severity Rating Scale (C-SSRS)  
 
C-SSRS Assessments will be performed as follows:  Screening, Baseline, Weeks 1, 2, and 4. 
 
The administration schedule of the C-SSRS will be: 
 
 
The Baseline-Screening version (Appendix 5) will be used at Screening to provide a pre-
treatment assessment baseline.  
o If a subject has a score greater than 0 in suicidal ideation, this is important and 
may indicate the need for mental health intervention. The investigator should give 
consideration to not enrolling the subject in the study.  
 
 
On all subsequent visits, the Since Last Visit version (Appendix 6) will be used. 
o Any score greater than 0 in the suicidal ideation score is important and may 
indicate the need for mental health intervention and consideration be given to 
discontinuation from study drug. This should result in prompt referral to a mental 
health professional and/or possibly the emergency room. The Medical Monitor 
should be contacted.  
 
Subjects will complete the C-SSRS.   
 
The C-SSRS administer will be trained via the C-SSRS training video. A training certificate for 
the administer(s) will be on file in the trial master file at the site. 
 
The Investigator must review the completed C-SSRS.  A qualified mental health care provider 
must be available, immediately if needed, to refer the subject for further evaluation. 


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10.1.8 Local Tolerability Assessment  
Investigator Local Tolerability Assessment will be performed as follows:  Baseline, Week 1, 
Week 2, and Week 4. 
Application site reactions will be graded at the timepoints outlined in the Schedule of Visits and 
Assessments (Section 5). 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 AD. 
 
The investigator assessments will be conducted by the 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 
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 as follows:  Baseline, Week 1, 
Week 2. 
 
This assessment will be administered by the site 10 to 15 minutes after study drug application in 
the clinic at Baseline and at Weeks 1 and 2. 


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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 
10.1.9 Adverse Events  
Adverse events (AEs) will be collected beginning at informed consent signature.  
Any treatment emergent AEs will be followed in the clinic for up to one month at the 
Investigator’s discretion until resolved or otherwise judged as clinically stable. 
For further details on Adverse Events please see Section 10.7. 
10.2 Efficacy Evaluations 
10.2.1 Eczema Area and Severity Index (EASI) 
 
EASI scores (Hanifin, et al. 2001) will be performed as follows:  Screening, Baseline, Week 1, 
Week 2, and Week 4. 
 
The EASI is a static assessment to measure the severity and extent of AD.  EASI combines the 
assessment of the severity of lesions and the area affected into a single score in the range 0 (no 
disease) to 72 (maximal disease). 
 
The body is divided into four sections (head (h) (10% of a person's skin); arms (a) (20%); trunk 
(t) (30%); legs (l) (40%)).  Each of these areas is scored by itself, and then the four scores are 
combined into the final EASI.  
 
For each section, the percent of area (A) of skin involved is estimated and then transformed into 
a grade from 0 to 6 (A): 
 
0. 
0% of involved area 
1. 
< 10% of involved area  
2. 
10–29% of involved area 
3. 
30–49% of involved area 
4. 
50–69% of involved area 
5. 
70–89% of involved area 
6. 
90–100% of involved area 
 
Note: Palms and soles may be treated with study medication in this study, but will not be 
counted towards IGA, EASI, or BSA assessments. EASI is evaluated for the entire body except 
the scalp, palms, and soles. 


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Within each area, the severity is estimated by four clinical signs: Redness (erythema, 
inflammation), Thickness (induration, papulation, swelling – acute eczema), Scratching 
(excoriation), and Lichenification (lined skin, furrowing, prurigo nodules – chronic eczema). 
Severity parameters are measured on a scale of 0 to 3, from none to severe. 
 
To calculate the EASI, the sum of the severity rating for the four clinical signs are multiplied 
with the numerical value of the area affected and with the various percentages of the four body 
areas (see Appendix 4). 
10.2.2 Validated Investigator Global Assessment scale for Atopic Dermatitis 
Validated Investigator Global Assessment scale for Atopic Dermatitis (vIGA-AD) assessments 
will be performed as follows:  Screening, Baseline, Week 1, Week 2, and Week 4.  
 
The vIGA-AD should be completed prior to other physician assessments. 
 
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 Table below). 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). 


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10.2.3 Worst Itch Numerical Rating Scale (WI-NRS) 
 
WI-NRS Assessments will be performed as follows:  Screening, Baseline, Week 1, Week 2, and 
Week 4. 
 
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. (Naegeli 2015). The 
WI-NRS will be determined by asking the subject’s assessment of worst itch over the past 24 
hours. The scale is from ‘0 to 10’ (“no itch” to “worst imaginable itch”). Subjects will complete 
the WI-NRS pruritus assessment. 
 
 
10.3 Other Evaluations  
10.3.1 Body Surface Area (BSA)  
BSA Assessments will be performed as follows:  Screening, Baseline, Week 1, Week 2, and 
Week 4.  
The BSA affected by 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 
(BSA).   
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, IGA, BSA). 
Body Diagram 
The body diagram (see Appendix 1) will be completed as follows:  Baseline. 
A copy of the body diagram will be provided to the subject for study drug application at home.  
 
 


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10.3.2 Pharmacokinetics Assessment 
 
PK draws will be performed as follows for all subjects at all sites: 
 
 
 For the serial PK subset enrolled under the previous amendment: On the first day of 
dosing, PK draws will be done pre-dose and at 1, 2, 4, 6 and 24 hours post-dose 
administration.  On Day 15, PK draws will be taken at pre-dose, 1, 2, 4, 6, and 24 hours 
post-dose administration 
 For all subsequent subjects enrolled under this amendment: PK draws will be collected at 
Days 1 and 29. The single draw will be pre-dose drug application in the clinic. 
 
 
Ensure study medication is not applied in the area where PK will be drawn. 
10.4 Final Study Visit  
The approximate final study visit will occur at Week 4 (Day 29). The procedures performed 
during these visits are as described in Schedule of Events (Section 5). A 3-day scheduling leeway 
period is allowed for this visit.  
10.5 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 visit 
(Day 29). 
10.6 Unscheduled Visit 
Unscheduled visits may be necessary to repeat testing following abnormal laboratory results, for 
follow-up of AEs, or for any other reason, as warranted in the judgement of the Investigator. 
 
The following information will be collected for all subjects: 
 
 Concomitant medications/procedures 
 AEs 
The following information also will be collected: 
 
 vIGA-AD and EASI 
 BSA affected with AD  
 Local tolerability assessment 


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The rules for how to tally vIGA-AD, BSA or other proportions of categorical responses will be 
described in the Statistical Analysis Plan. 
10.7 Adverse Events 
10.7.1 Adverse Event Definition 
An AE means 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.  
AEs will be collected following informed consent of the subject until one month after treatment.  
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.  
Application site reactions will be considered adverse events if they require intervention, 
suspension or discontinuation of study drug.  
10.7.2 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.  If any AEs are serious, as defined by ICH Guidelines 
for Clinical Safety, required procedures will be followed.  All 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.  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. 
An SAE is any AE that in the view of either the PI or Sponsor, results in any of the following 
outcomes: Death, a life-threatening AE, inpatient hospitalization or prolongation of existing 
hospitalization, a persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions, or a congenital anomaly/birth defect.  Important medical events 
that may not result in death, be life-threatening, or require hospitalization may be considered 
serious when, based upon appropriate medical judgment, they may jeopardize the subject and 
may require medical or surgical intervention to prevent one of the outcomes listed in the above 
definition. Examples of such medical events include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home, blood dyscrasias or convulsions that do not result in 
inpatient hospitalization, or the development of drug dependency or drug abuse.  


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Life-threatening is defined as an AE that in the view of the PI or Sponsor, places the subject at 
immediate risk of death. It does not include an AE that, had it occurred in a more severe form, 
might have caused death. 
Hospitalization does not include the following: 
 Rehabilitation facilities, hospice facilities or respite care (e.g. caregiver relief) 
 Nursing homes or skilled nursing facilities 
 Emergency room visits 
 Same day surgeries (as outpatient/same day/ambulatory procedures) 
 <24 hour admissions for observation or evaluation 
Hospitalization or prolongation of hospitalization in the absence of a precipitating, clinical AE is 
not in itself an SAE.  Examples include: 
 Admission for treatment of a preexisting condition that did not worsen 
 Hospitalizations for cosmetic elective surgery, social, and/or convenience admissions 
 Pre-planned treatments or surgical procedures should be noted in the baseline 
documentation for the individual subject. 
 Diagnostic and therapeutic procedures, such as surgery, should not be reported as AEs; 
however, the medical condition for which the procedure was performed should be 
reported if it occurs during the reporting period and meets the definition of an AE.  For 
example, an acute appendicitis that begins during the AE reporting period should be 
reported as an AE, and the resulting appendectomy should be recorded as treatment of the 
AE. 
Unexpected is defined as an AE that is not listed in the IB or is not listed at the specificity or 
severity that has been observed; or is not consistent with the risk information described in the 
general investigational plan or elsewhere in the current IND. 
If a SAE occurs to a subject on this study, contact the Sponsor personnel listed in Section 2 
within one business day of knowledge of event.  
10.7.3 Suspected Unexpected Serious Adverse Reaction (SUSAR)  
This is defined as a serious adverse reaction, the nature or severity of which is not consistent 
with the known study treatment information. A serious event or reaction is not defined as a 
SUSAR when: ‘it is serious but expected’ or it does not fit the definition of an SAE, whether 
expected or not.  
10.7.4 Safety Review with Subject 
At each follow-up visit, subjects will be queried with an open-ended question such as: ‘How 
have you been feeling since your last visit?’  Additionally, the study staff will review subject 


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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 up 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 
PI. 
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). 
10.7.5 Adverse Event Reporting 
The PI will review each event and assess its relationship to drug treatment (unrelated, unlikely, 
possibly, probably, likely). Each sign or symptom reported will be graded on the NIH NCI 
CTCAE toxicity grading scale 5-point severity scale (Grade 1, 2, 3, 4 and 5). The date and time 
of onset, time relationship to drug dosing, duration, and outcome (resolved, improved, 
unchanged, worse, fatal, or unknown/lost to follow-up) of each event will be noted. 
 The relationship of each AE to the study drug 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. 
* Instrumental activities of daily living refer to preparing meals, shopping for groceries or clothes, using the 
telephone, managing money, etc. 
** Self-care activities of daily living refer to bathing, dressing and undressing, feeding self, using the toilet, 
taking medications, and not bedridden. 
AEs will be coded using the most current MedDRA® version available at the start of the study. 
10.8 Reporting Pregnancy  
During the study, all subjects should be instructed to contact the investigator immediately if they 
suspect they might be pregnant (e.g., missed or late menstrual period).  If pregnancy is 
confirmed, the subject will be withdrawn from the study and followed until the pregnancy comes 
to term.   
The investigator is responsible for reporting all available pregnancy information on the 
pregnancy report within 24 hours of becoming aware of the event, although pregnancy itself is 
not considered an AE.  Study treatment must be discontinued immediately in the event of a 
pregnancy.  The subject should be referred to an obstetrician/gynecologist experienced in 
reproductive toxicity for further evaluation and counseling. Monitoring of the subject should 
continue until the conclusion of the pregnancy.  Follow-up information detailing the outcome of 
the pregnancy and the health of the newborn should be reported as it becomes available.   
Partner pregnancies of a male subject do not need to be reported. 
Any pregnancy complication or premature terminations including miscarriage, spontaneous 
abortion or elective termination of a pregnancy for medical reasons will be reported as an SAE, 
as described in Section 10.7.2.  Should the pregnancy result in a congenital abnormality or birth 
defect, a separate SAE report must be submitted.  Furthermore, all neonatal deaths that occur 
within 30 days of the birth should be reported as SAEs, without regard to causality.  In addition, 


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any infant death that occurs after the 30-day reporting period that the investigator suspects are 
related to the in-utero exposure to the study treatment should also be reported.  
10.9 Treatment Stopping Rules 
If a subject has non-cutaneous adverse events of concern, clinically significant laboratory values 
or any condition that the investigator determines could possibly be related to the study drug, 
the Investigator should immediately contact the Medical Monitor to discuss if the subject should 
be discontinued from the study.   
 
Treatment for any individual subject will be discontinued if the subject:  
 
 
Experiences a serious adverse event (SAE) or a clinically significant non-serious AE 
which in the opinion of the Principal Investigator or Medical Monitor warrants 
discontinuation from the study for that subject’s well-being. 
 
A severe (Grade 3) laboratory abnormality (confirmed by repeat sample and considered 
related to study drug).  
Dosing of study drug for an individual subject may be suspended for safety concerns other than 
those described above, at the discretion of the investigator if he/she feels the subject’s safety may 
be threatened. 
A subject with a PHQ-8 score of ‘15’ or above should be referred promptly to a mental health 
care professional and consideration be given to discontinuation from study drug.   
A subject that is experiencing suicidal ideation and behavior should be referred immediately to a 
qualified mental health care provider and consideration given to discontinuation from study drug. 
As noted above, study treatment must be discontinued immediately in the event of a female 
subject’s pregnancy.   
Treatment should be interrupted: 
 If a subject develops an application site reaction with the clinical appearance of an 
‘irritation reaction’, and with a severity of a Dermal Response Score of 5 (erythema, 
edema and papules) or greater on the scale of Berger and Bowman, treatment should be 
interrupted for up to one week and may then be resumed if the reaction has, in the 
opinion of the Investigator, adequately resolved.   
 
Treatment should be discontinued: 
 
If the 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. 


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11 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. 
11.1 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 or later) unless otherwise 
stated. No interim efficacy analyses are planned. 
Descriptive statistics will be used to provide an overview of the safety, efficacy, and 
pharmacokinetic results.  For categorical parameters, the number and percentage of subjects in 
each category will be presented. The denominator for percentage will be based on the number of 
subjects appropriate for the purpose of analysis.  For continuous parameters, descriptive statistics 
will include n (number of subjects), mean, standard deviation (SD), median, minimum, and 
maximum. 
11.1.1 Pharmacokinetics Assessment  
Plasma levels of circulating roflumilast and its major N-oxide metabolite will be measured at the 
following time points: 
 
Prior to study drug application on Days 1  and 29 
 
Pre-dose, 1, 2, 4, 6 hrs post dose on Days 1 and 15, and 24 hrs post dose on Days 2 and 
16 (serial PK subgroup enrolled under previous amendment only) 
 
 


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11.1.2 Pharmacokinetic Parameters  
All subjects who are enrolled and receive at least one application of study drug, and have 
sufficient pharmacokinetic assessments will be included in the pharmacokinetic population. 
When possible, the exposure of roflumilast and its major N-oxide metabolite will be calculated 
based on plasma concentrations versus time profile data and compared between the treatment 
groups.   
A detailed description of the PK analysis will be presented in the SAP.  
11.1.3 Safety Analysis 
The following analyses will be performed; however, no formal inferential statistics will be done 
on safety assessments. 
Descriptive statistics will be presented by visit for quantitative safety data and frequency counts 
will be compiled for classification of qualitative safety data. Summaries of local tolerability will 
be presented by visit. 
Adverse Events: 
All treatment-emergent AEs occurring during the study will be recorded and classified on the 
basis of MedDRA terminology for the safety population. Treatment-emergent AEs are those AEs 
with an onset on or after application of study medication at the Baseline visit or were present at 
treatment initiation but worsened during treatment, through study completion. All treatment-
emergent AEs will be summarized by treatment group, the number of subjects reporting 
treatment-emergent AEs, system organ class, preferred term, severity, relationship, and 
seriousness. 
Comparisons between treatment groups will be made by tabulating the frequency of subjects 
with one or more treatment-emergent AEs (classified into MedDRA terms) during the study.  
Serious adverse events (SAEs) will be listed by subject. SAEs will be summarized by severity, 
and relationship to study treatment. Each subject will be counted only once within a system 
organ class or a preferred term using the event with the greatest relationship and greatest 
severity. 
All information pertaining to AEs noted during the study will be listed by subject, detailing the 
verbatim description given by the Investigator, preferred term, system organ class, start date, 
stop date, severity, action taken regarding study drug, corrective treatment, outcome, and drug 
relatedness. The event onset will also be shown relative (in number of days) to date of first 
application. In addition, a list of subjects who prematurely discontinue from the study due to 
adverse events will also be provided. 
A subject-by-subject treatment-emergent AE (TEAE) data listing, including verbatim term, 
preferred term, treatment, severity, and relationship to study drug, will be provided.  


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Medical history will be listed by subject. Physical examinations performed at Screening, 
Baseline and Week 4, and 12-lead ECGs will be performed at Screening and Week 4. Both 
physical examination and ECG results will be listed by subject. 
Vital signs will be tabulated by visit and treatment group. 
ECGs will be tabulated by visit and treatment group. 
Laboratory testing will be obtained throughout the study and the results summarized by 
parameter, visit and treatment group. 
11.1.4 Determination of Sample Size 
The sample size will be approximately 90 to 105 subjects.  A subset of subjects enrolled under 
the previous amendment will receive serial PK sampling.  
A sample size of 27 per arm will provide at least 80% power to detect a difference in the mean 
change from baseline in EASI Total Score of 35% at week 4 (for each ARQ-151-treated group 
versus vehicle-treated group), assuming a pooled standard deviation of 40%, with a two-sided 
α  = 0.05. This is based on a 2-sample t-test.  This includes P value adjustment for multiplicity 
using Bonferroni correction.  With a 10-25% dropout rate, the sample size for the study would be 
increased to 30-35 subjects per arm (90-105 subjects total).  Change from baseline in EASI Total 
Score at week 4 is expected to provide more statistical power than percent change from baseline 
in Total EASI Score at this timepoint (which is a secondary endpoint) and has been chosen as the 
primary endpoint.  
This sample size is considered adequate for PK and safety evaluation. 
11.1.5 Subjects to Analyze 
Four analysis populations will be defined: 
 Safety population will include all subjects who are enrolled and received at least one 
confirmed dose of study medication; this population will be defined separately for each 
cohort. 
 Intent-to-Treat (ITT) population will include all randomized subjects. 
 Per-Protocol (PP) Population will include all subjects who are in the safety population, 
were at least 80% compliant with study medication, and showed no other serious 
deviations from the study protocol. 
 PK population will include all subjects receiving the active drug with sufficient plasma 
concentrations of roflumilast and its major N-oxide metabolite to define a profile, as 
determined by the pharmacokineticist.  
 
 


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11.1.6 Interim Analysis 
No interim efficacy analyses are planned. 
11.1.7 Background and Demographic Characteristics 
Descriptive statistics will be used to summarize demographic characteristics (age, sex, ethnicity, 
and race) and background characteristics for the enrolled subjects.  Past/coexistent medical 
history information and physical examination observations and vital signs information for all 
randomized subjects will be presented in a by-subject listing.   
11.1.8 Study Medication Compliance 
The number of study drug applications by each subject based on diary data will be summarized 
using summary statistics (mean, standard deviation [SD], median, minimum, and maximum), and 
categorically.  
The amount of study medication received by each subject based on kit weight will be 
summarized by treatment using summary statistics (mean, SD, median, minimum, and 
maximum), and categorically.   
11.2 Efficacy Evaluation 
11.2.1 Primary Endpoint 
The Primary Efficacy Endpoint will be:  
 
 Change from baseline in Eczema Area and Severity Index (EASI) Total Score at Week 4 
 
The primary efficacy endpoint will be analyzed using a MMRM analysis on change-from-
baseline EASI with subject as a random effect and vIGA-AD strata, visit, treatment group, and 
interaction term for treatment-by-visit as fixed effects and the baseline as a covariate.  
Comparison between treatment groups at Week 4 will be done using the appropriate contrast. An 
unstructured variance-covariance matrix will be used. Additional interaction terms will also be 
included in supportive statistical models and will be detailed in the SAP. For missing data, a 
multiple imputation technique will be detailed in the SAP.  
 
The primary efficacy analysis will be done using the ITT (Intent to Treat) population (all 
randomized subjects)and the PP population will be used as supportive analysis. 
11.2.2 Secondary Endpoints 
 
The Secondary Efficacy Endpoints will include: 
 Percent change from baseline in EASI Total Score at each study visit 
 Change from baseline in EASI Total Score at Weeks 1 and 2 


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 Achievement of a 75% or greater improvement in Eczema Area and Severity Index 
(EASI75) score from baseline to each study visit 
 Achievement of a 50% or greater improvement in Eczema Area and Severity Index 
(EASI50) score from baseline to each study visit 
 Change from baseline in BSA involvement at each study visit 
 Change from baseline in WI-NRS pruritus score at each study visit 
 Achievement of a ≥ 4-point improvement from Baseline in WI-NRS pruritus score at 
each study visit for subjects with a Baseline WI-NRS ≥ 4 
A similar analysis approach as outlined for the primary endpoint will be used for all secondary 
continuous efficacy endpoints. 
 
For categorical efficacy endpoints involving proportions (e.g. proportion of patients with 
vIGA-AD score of ‘clear’ or ‘almost clear’ at each study visit), a Cochran-Mantel-Haenszel test 
(CMH) controlling for the stratification variables will be performed. 
11.3 Safety Evaluation 
The following analyses will be performed; however, no formal inferential statistics will be 
performed on safety assessments. 
Descriptive statistics will be calculated for quantitative safety data and frequency counts will be 
compiled for classification of qualitative safety data.  
11.3.1 Adverse Events 
The assessment of safety will be based mainly on the frequency and percent of subjects who 
reported treatment-emergent AEs.  
Adverse events will be coded using the current version of the Medical Dictionary for Drug 
Regulatory Activities (MedDRA).  Treatment emergent adverse events (i.e. events with onset 
dates on or after the start of study drug or with missing onset dates) will be summarized by 
presenting for each treatment group, the number and percentage of subjects having any AE, 
having an AE in an individual body system, and having an AE in an individual preferred term.  
Any other information collected (e.g. severity or relatedness to study medication) will be listed 
as appropriate. 
 
 


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11.3.2 Local Tolerance Assessment 
 
For the Investigator’s assessment the numeric application site reaction scores will be summarized 
individually by using number and percentage of subjects by visit. 
11.3.3 Medical History and Physical Examinations 
Medical history for all subjects will be presented in a by-subject listing.  
Physical examination findings for all subjects will be presented.  Clinically significant changes in 
physical examinations will be reported as AEs and will be described in the text of the final 
report. 
11.3.4 Clinical Laboratory Results and Vital Signs 
All clinical laboratory results and vital signs measurements and their change from baseline 
(pre-dose), will be summarized 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. 
11.3.5 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. 
11.4 Pharmacokinetic Analysis 
All subjects who are enrolled and receive at least one application of study drug, and have 
sufficient pharmacokinetic assessments will be included in the pharmacokinetic population. 
For all subjects, blood samples for the determination of roflumilast and its N-oxide metabolite 
will be collected at scheduled time points as delineated in the Schedule of Visits and 
Assessments (Section 5). Plasma drug concentrations at each time point will be summarized 
using descriptive statistics, reporting n, mean, standard deviation, median, minimum, and 
maximum. 
Where possible, the exposure of roflumilast and its major N-oxide metabolite (as evidenced by 
the Cmax and AUC) will be calculated based on plasma concentrations obtained within 1 hour 
prior to study drug application, and 1, 2, 4, 6 and 24 hours post-dose administration following 
application on Days 1 and 15 (for serial PK subset subjects enrolled under previous amendment 
only). 
A manual for blood sampling, collection, processing, and sample shipment will be provided in a 
separate document.  


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12 STUDY ADMINISTRATION 
12.1 Ethics 
12.1.1 Ethics Review Board  
Before enrollment of patients into the study, the current protocol and ICF 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. 
12.1.2 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). 
12.1.3 Subject Information and Consent/Assent 
The purpose of the study, the procedures to be carried out and the potential hazards will be 
described to the subjects in non-technical terms. Subjects will be required to read, sign and date 
an ICF summarizing the discussion prior to screening and will be assured that they may 
withdraw from the study at any time without jeopardizing their medical care. Adolescents will 
provide written assent and their parent(s) or legal guardian(s) will provide consent, as required 
by local law. 
Subjects will be given a signed copy of their ICF. 
12.2 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 shall ensure 
that the Investigator understands the investigational status of the investigational product, all 
requirements of the investigation to be undertaken, and all of his/her responsibilities as an 
Investigator.  Sponsor representatives will also visit the clinical site at appropriate intervals as 
required to ensure compliance with the protocol and to verify the accuracy and completeness of 


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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. 
12.3 Study Completion/Termination 
12.3.1 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. 
12.3.2 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. 
12.4 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.   
 
 


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All clinical data will undergo a 100% quality control check prior to clinical database lock. Edit 
checks are then performed for appropriate databases as a validation routine using SAS® to check 
for missing data, data inconsistencies, data ranges etc. Corrections are made prior to database 
lock. 
12.5 Data Handling and Record Keeping 
During the clinical study, the Investigator will maintain adequate records, including medical 
records, records detailing the progress of the study for each subject, laboratory reports, signed 
informed consent forms, investigational product disposition records, correspondence with the 
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.   
12.6 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.  
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. 


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12.7 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).  
12.8 Publication Policy 
The Sponsor is supportive of publishing clinical trial findings.  The process of coordinating 
publication efforts is detailed in the Clinical Trial Agreement. 
 


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13 REFERENCES 
Baumer W, Hoppmann J, Rundfeldt C, Kietzmann M: Highly selective phosphodiesterase 4 
inhibitors for the treatment of allergic skin diseases and psoriasis. Inflamm Allergy Drug Targets 
2007;6:17–26.  
Berger, RS, Bowman JP. A reappraisal of the 21-day Cumulative Irritation Test in man.  
J. Toxicol Ot & Ocular Toxicol 1982:1(2);109-115. 
Bethke, TD, Lahu, G.  High absolute bioavailability of the new oral phosphodiesterase-4 
inhibitor roflumilast.  Int. J Clin Pharmacol Ther.  2011; 49:51-57. 
DALIRESP (roflumilast) tablets [package insert]. AstraZeneca Pharmaceuticals LP, Wilmington, 
DE USA; 2017. 
Dastidar SG, Rajagopal D, Ray A: Therapeutic benefit of PDE4 inhibitors in inflammatory 
diseases. Curr Opin Investig Drugs 2007;8: 364–372.  
Furue M, Kitahara Y, Akama H, Hojo S, Hayashi N, Nakagawa 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.  
Halling-Overgaard AS, Kezic S, Jakasa I, Engebretsen KA, Maibach H, Thyssen JP. Skin 
absorption through atopic dermatitis skin: a systematic review. Br J Dermatol. 2017;177:84-106. 
Hanifin JM, Chan SC, Cheng JB, Tofte SJ, Henderson WR Jr, Kirby DS, 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, J.M. and Rajka, G.: Diagnostic features of atopic dermatitis. Acta Derm Venereol 
Suppl (Stockh) 1980; 92: 44–47. 
Hanifin JM, Thurston M, Omoto M, Cherill R, Tofte SJ, Graeber M. 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, Adnot S, Sanjar S, Beume R, 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 1, March 2019. 


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Michalski JM, Golden G, Ikari J., Rennard, SI. PDE4: A novel target in the treatment of chronic 
obstructive pulmonary disease. Clin Pharmacol Ther. 2012;91:134–142. 
Murrell DF, Gebauer K, Spelman L, Zane LT. 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. 
N. Naegeli, E. Flood, J. Tucker, J. Devlen, E. Edson-Heredia. The Worst Itch Numeric Rating 
Scale for patients with moderate to severe plaque psoriasis or psoriatic arthritis. International 
Journal of Dermatology. 2015; 54: 715-722. 
Nygaard U, Deleuran M, Vestergaard C. Emerging treatment options in atopic dermatitis: topical 
therapies. Dermatology. 2017;233:333-343. 
Ortiz PG, Hansen SH, Shah VP, Menne T, Benfeldt E. Impact of adult atopic dermatitis on 
topical drug penetration: assessment by cutaneous microdialysis and tape stripping. Acta Derm 
Venereol. 2009;89:33-38. 
Wedzicha, JA, Calverley, PMA, Klaus, FR.  Roflumilast: a review of its use in the treatment of 
COPD.  Int J Chron Obstruct Pulmon Dis. 2016;11:81-90. 
 




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Appendix 2. Hanifin and Rajka Diagnostic Criteria for Atopic Dermatitis (AD) 
Major criteria: Must have three or more of: 
1. Pruritus 
2. Typical morphology and distribution  
 
Flexural lichenification or linearity in adults 
 
Facial and extensor involvement in infants and children 
3. Chronic or chronically-relapsing dermatitis 
4. Personal or family history of atopy (asthma, allergic rhinitis, atopic dermatitis) 
Minor criteria: Should have three or more of: 
1. Xerosis 
2. Ichthyosis, palmar hyperlinearity, or keratosis pilaris 
3. Immediate (type 1) skin-test reactivity 
4. Raised serum IgE 
5. Early age of onset 
6. Tendency toward cutaneous infections (especially S aureus and herpes simplex) or 
impaired cell-mediated immunity 
7. Tendency toward non-specific hand or foot dermatitis 
8. Nipple eczema 
9. Cheilitis 
10. Recurrent conjunctivitis 
11. Dennie-Morgan infraorbital fold 
12. Keratoconus 
13. Anterior subcapsular cataracts 
14. Orbital darkening 
15. Facial pallor or facial erythema 
16. Pityriasis alba 
17. Anterior neck folds 
18. Itch when sweating 
19. Intolerance to wool and lipid solvents 
20. Perifollicular accentuation 
21. Food intolerance 
22. Course influenced by environmental or emotional factors 
23. White dermographism or delayed blanch 
 
 
 


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Appendix 3. Patient Health Questionaire-8 (PHQ-8)  
 
 
Appendix 4. EASI Scoring Tool  


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Appendix 5. Columbia-Suicide Severity Rating Scale (C-SSRS) Baseline/Screening 
Version 
 
COLUMBIA-SUICIDE SEVERITY 
RATING SCALE 
(C-SSRS)  
Baseline/Screening Version 
Version 1/14/09 
 
  
Posner, K.; Brent, D.; Lucas, C.; Gould, M.; Stanley, B.; Brown, G.; Fisher, P.; Zelazny, J.; 
Burke, A.; Oquendo, M.; Mann, J.  
 
Disclaimer: 
This scale is intended to be used by individuals who have received training in its administration. The questions contained in 
the Columbia-Suicide Severity Rating Scale are suggested probes. Ultimately, the determination of the presence of suicidal 
ideation or behavior depends on the judgment of the individual administering the scale. 
Definitions of behavioral suicidal events in this scale are based on those used in The Columbia Suicide History Form, 
developed by John Mann, MD and Maria Oquendo, MD, Conte Center for the Neuroscience of Mental Disorders 
(CCNMD), New York State Psychiatric Institute, 1051 Riverside Drive, New York, NY, 10032. (Oquendo M. A., 
Halberstam B. & Mann J. J., Risk factors for suicidal behavior: utility and limitations of research instruments. In M.B. First 
[Ed.] Standardized Evaluation in Clinical Practice, pp. 103 -130, 2003.) 
 
For reprints of the C-SSRS contact Kelly Posner, Ph.D., New York State Psychiatric Institute, 1051 Riverside Drive, New 
York, New York, 10032; inquiries and training requirements contact posnerk@nyspi.columbia.edu 
© 2008 The Research Foundation for Mental Hygiene, Inc. 


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SUICIDAL IDEATION 
Ask questions 1 and 2.  If both are negative, proceed to “Suicidal Behavior” section. If the answer to 
question 2 is “yes”, ask questions 3, 4 and 5.  If the answer to question 1 and/or 2 is “yes”, complete 
“Intensity of Ideation” section below.
Lifetime: Time 
He/She Felt 
Most Suicidal 
Past 
 
Months 
1.  Wish to be Dead
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Have you wished you were dead or wished you could go to sleep and not wake up?  
 
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Yes       No 
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Yes     No 
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2.  Non-Specific Active Suicidal Thoughts 
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Have you actually had any thoughts of killing yourself? 
 
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3.  Active Suicidal Ideation with Any Methods (Not Plan) without Intent to Act 
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ZKRZRXOGVD\“I thought about taking an overdose but I never made a specific plan as to when, where or how I would actually do 
it…and I would never go through with it.” 
Have you been thinking about how you might do this? 
 
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4.  Active Suicidal Ideation with Some Intent to Act, without Specific Plan 
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thoughts but I definitely will not do anything about them.” 
Have you had these thoughts and had some intention of acting on them?  
 
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5.  Active Suicidal Ideation with Specific Plan and Intent 
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Have you started to work out or worked out the details of how to kill yourself? Do you intend to carry out this plan? 
   
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INTENSITY OF IDEATION 
The following features should be rated with respect to the most severe type of ideation (i.e., 1-5 from above, with 1 being 
the least severe and 5 being the most severe).  Ask about time he/she was feeling the most suicidal.  
                                   
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                                                                       Type # (1-5)                                                 Description of  Ideation 
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How many times have you had these thoughts?  
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Duration 
When you have the thoughts how long do they last? 
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Controllability 
Could/can you stop thinking about killing yourself or wanting to die if you want to? 
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Deterrents 
Are there things - anyone or anything (e.g., family, religion, pain of death) - that stopped you from wanting to 
die or acting on thoughts of committing suicide? 
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Reasons for Ideation 
What sort of reasons did you have for thinking about wanting to die or killing yourself?  Was it to end the pain 
or stop the way you were feeling (in other words you couldn’t go on living with this pain or how you were 
feeling) or was it to get attention, revenge or a reaction from others? Or both? 
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SUICIDAL BEHAVIOR
(Check all that apply, so long as these are separate events; must ask about all types) 
 
Lifetime 
Past 
 
Years 
Actual Attempt:
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Have you made a suicide attempt? 
Have you done anything to harm yourself? 
Have you done anything dangerous where you could have died? 
What did you do? 
Did you______ as a way to end your life?  
Did you want to die (even a little) when you_____?  
Were you trying to end your life when you _____? 
Or Did you think it was possible you could have died from_____? 
Or did you do it purely for other reasons / without ANY intention of killing yourself (like to relieve stress, feel better,  
get sympathy, or get something else to happen)?  (6HOI,QMXULRXV%HKDYLRUZLWKRXWVXLFLGDOLQWHQW
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Has subject engaged in Non-Suicidal Self-Injurious Behavior? 
Yes     No 
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have occurred). 
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Has there been a time when you started to do something to end your life but someone or something stopped you before 
you actually did anything? 
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Has there been a time when you started to do something to try to end your life but you stopped yourself before you 
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Preparatory Acts or Behavior: 
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Have you taken any steps towards making a suicide attempt or preparing to kill yourself (such as collecting pills, 
getting a gun, giving valuables away or writing a suicide note)? 
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Yes      No 
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Suicidal Behavior:
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Potential Lethality: Only Answer if Actual Lethality=0 
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Protocol ARQ-151-212 
Arcutis, Inc. 
Amendment 2.0 
 
 August 5, 2019 
Confidential 
 Page 74 of 84 
Appendix 6. Columbia-Suicide Severity Rating Scale (C-SSRS) Since Last Visit Version 
 
 
 
 
 
 
 
 
 
 
COLUMBIA-SUICIDE SEVERITY 
RATING SCALE 
(C-SSRS) 
Since Last Visit 
Version 1/14/09 
 
Posner, K.; Brent, D.; Lucas, C.; Gould, M.; Stanley, B.; Brown, G.; Fisher, P.; Zelazny, J.; 
Burke, A.; Oquendo, M.; Mann, J.  
 
 
Disclaimer: 
This scale is intended to be used by individuals who have received training in its administration. The questions contained 
in the Columbia-Suicide Severity Rating Scale are suggested probes. Ultimately, the determination of the presence of 
suicidal ideation or behavior depends on the judgment of the individual administering the scale. 
 
 
Definitions of behavioral suicidal events in this scale are based on those used in The Columbia Suicide History 
Form, developed by John Mann, MD and Maria Oquendo, MD, Conte Center for the Neuroscience of Mental Disorders 
(CCNMD), New York State Psychiatric Institute, 1051 Riverside Drive, New York, NY, 10032. (Oquendo M. A., 
Halberstam B. & Mann J. J., Risk factors for suicidal behavior: utility and limitations of research instruments. In M.B. First 
[Ed.] Standardized Evaluation in Clinical Practice, pp. 103 -130, 2003.) 
 
For reprints of the C-SSRS contact Kelly Posner, Ph.D., New York State Psychiatric Institute, 1051 Riverside Drive, New 
York, New York, 10032; inquiries and training requirements contact posnerk@nyspi.columbia.edu 
 
© 2008 The Research Foundation for Mental Hygiene, Inc. 


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SUICIDAL IDEATION 
Ask questions 1 and 2.  If both are negative, proceed to “Suicidal Behavior” section. If the answer to question 2 is “yes”, 
ask questions 3, 4 and 5.  If the answer to question 1 and/or 2 is “yes”, complete “Intensity of Ideation” section below.
 
Since Last 
Visit 
1.  Wish to be Dead
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Have you wished you were dead or wished you could go to sleep and not wake up?  
 
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Yes       No 
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2.  Non-Specific Active Suicidal Thoughts 
*HQHUDOQRQVSHFLILFWKRXJKWVRIZDQWLQJWRHQGRQH¶VOLIHFRPPLWVXLFLGHH J “I’ve thought about killing myself”ZLWKRXWWKRXJKWVRIZD\VWRNLOO
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Have you actually had any thoughts of killing yourself? 
 
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3.  Active Suicidal Ideation with Any Methods (Not Plan) without Intent to Act 
6XEMHFWHQGRUVHVWKRXJKWVRIVXLFLGHDQGKDVWKRXJKWRIDWOHDVWRQHPHWKRGGXULQJWKHDVVHVVPHQWSHULRG 7KLVLVGLIIHUHQWWKDQDVSHFLILFSODQZLWKWLPH
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overdose but I never made a specific plan as to when, where or how I would actually do it…and I would never go through with it.” 
Have you been thinking about how you might do this? 
 
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4.  Active Suicidal Ideation with Some Intent to Act, without Specific Plan 
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definitely will not do anything about them.” 
Have you had these thoughts and had some intention of acting on them?  
 
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5.  Active Suicidal Ideation with Specific Plan and Intent 
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Have you started to work out or worked out the details of how to kill yourself? Do you intend to carry out this plan? 
   
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INTENSITY OF IDEATION 
The following features should be rated with respect to the most severe type of ideation (i.e., 1-5 from above, with 1 being the least severe 
and 5 being the most severe).  
                                             
Most Severe Ideation:             _____                      _________________________________________________ 
                                               
                                                                                                           Type # (1-5)                                         Description of  Ideation 
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Frequency 
How many times have you had these thoughts?  
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Duration 
When you have the thoughts, how long do they last? 
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Controllability 
Could/can you stop thinking about killing yourself or wanting to die if you want to? 
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Deterrents 
Are there things - anyone or anything (e.g., family, religion, pain of death) - that stopped you from wanting to die or acting on 
thoughts of committing suicide? 
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Reasons for Ideation 
What sort of reasons did you have for thinking about wanting to die or killing yourself?  Was it to end the pain or stop the way 
you were feeling (in other words you couldn’t go on living with this pain or how you were feeling) or was it to get attention, 
revenge or a reaction from others? Or both? 
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SUICIDAL BEHAVIOR
(Check all that apply, so long as these are separate events; must ask about all types) 
Since Last 
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Actual Attempt:
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Have you done anything to harm yourself? 
 
Have you done anything dangerous where you could have died? 
What did you do? 
Did you______ as a way to end your life?  
Did you want to die (even a little) when you_____?  
Were you trying to end your life when you _____? 
Or did you think it was possible you could have died from_____? 
Or did you do it purely for other reasons / without ANY intention of killing yourself (like to relieve stress, feel better, get 
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actually did anything? 
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Yes      No 
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Yes      No 
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Yes      No 
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Enter Code 
 
 
 
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Potential Lethality: Only Answer if Actual Lethality=0 
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SAP_001.pdf: 
SOP-STAT-03-TOOL.01 Version 4 
Effective Date: 03-Jun-2018 
Innovaderm Proprietary & Confidential 
Page 1 of 40 
Statistical Analysis Plan 
Study Title: 
A Phase 2, 4-Week, Parallel Group, Double Blind, 
Vehicle-Controlled Study of the Safety and Efficacy of 
ARQ-151 Cream 0.05% and ARQ-151 Cream 0.15% 
Administered QD in Adolescent and Adult Subjects with 
Atopic Dermatitis 
Protocol Number and Version: 
ARQ-151-212 Amendment 2.0 dated August 5, 2019 
Product: 
ARQ-151 
Sponsor: 
Arcutis, Inc. 
2945 Townsgate Road, Suite 110 
Westlake Village, CA 91361 
Date: 
25-Nov-2019
Version: 
Final 1.0 
Prepared by: 
Innovaderm Research Inc. 
1851 Sherbrooke St. East, Suite 502 
Montreal (QC) H2K 4L5 
Canada 


STATISTICAL ANALYSIS PLAN, Final V1.0Final 
1.0 
Protocol Number: AQR-151-212 
Sponsor: Arcutis, Inc. 
STATISTICAL ANALYSIS PLAN REVISION SUMMARY 
Version 
Version Date 
Author 
Summary of Changes 
Final V1.0 
25-Nov-2019
Sarah Vahey 
Initial Final Version 






 
STATISTICAL ANALYSIS PLAN, Final V1.0Final 
1.0 
 
Protocol Number: AQR-151-212 
Sponsor: Arcutis, Inc. 
 
TABLE OF CONTENT 
1 
INTRODUCTION.................................................................................................................... 8 
2 
STUDY OBJECTIVES AND ENDPOINTS .......................................................................... 8 
3 
STUDY DESIGN .................................................................................................................... 10 
3.1 
Overall Design ................................................................................................................ 10 
3.2 
Schedule of Events ......................................................................................................... 10 
3.3 
Treatment ....................................................................................................................... 13 
3.4 
Randomization, Replacement, and Unblinding Procedures ...................................... 13 
3.4.1 
Randomization ...............................................................................13 
3.4.2 
Replacement ...................................................................................13 
3.4.3 
Unblinding .....................................................................................13 
3.5 
Changes to the Analysis from the Protocol .................................................................. 13 
4 
POPULATIONS FOR ANALYSIS ...................................................................................... 14 
4.1 
Intent-to-Treat Population ............................................................................................ 14 
4.2 
Per-Protocol Population ................................................................................................ 14 
4.3 
Safety Population ........................................................................................................... 14 
4.4 
Pharmacokinetic Population ......................................................................................... 14 
5 
GENERAL CONSIDERATIONS ........................................................................................ 14 
5.1 
Sample Size ..................................................................................................................... 15 
5.2 
Baseline ........................................................................................................................... 15 
5.3 
Reference Start Date and Analysis Day ....................................................................... 15 
5.4 
Windowing Conventions ................................................................................................ 15 
5.5 
Descriptive Statistics ...................................................................................................... 16 
5.6 
Handling of Retests, Unscheduled Visits, and Early Termination Data ................... 16 
5.7 
Software Version ............................................................................................................ 16 
6 
STATISTICAL CONSIDERATIONS ................................................................................. 17 
6.1 
Adjustments for Covariates .......................................................................................... 17 
6.2 
Handling of Dropouts or Missing data ......................................................................... 17 
6.3 
Interim Analysis and Data Monitoring ........................................................................ 17 
6.4 
Multicenter Studies ........................................................................................................ 17 
6.5 
Statistical Tests ............................................................................................................... 17 
6.6 
Multiple Comparisons/Multiplicity .............................................................................. 17 
6.7 
Examination of Subgroups ............................................................................................ 18 
7 
STUDY SUBJECTS ............................................................................................................... 18 
7.1 
Disposition of Subjects ................................................................................................... 18 


 
STATISTICAL ANALYSIS PLAN, Final V1.0Final 
1.0 
 
Protocol Number: AQR-151-212 
Sponsor: Arcutis, Inc. 
 
7.2 
Protocol Deviations ........................................................................................................ 18 
8 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS ............................ 19 
9 
SURGICAL AND MEDICAL HISTORY ........................................................................... 20 
10 
PRIOR AND CONCOMITANT MEDICATIONS ............................................................. 20 
11 
STUDY TREATMENT EXPOSURE AND TREATMENT COMPLIANCE ................. 21 
12 
EFFICACY ANALYSIS ........................................................................................................ 21 
12.1 
Primary Efficacy Endpoint ........................................................................................... 21 
Primary Endpoint Analysis ..............................................................................22 
12.2 
Secondary Endpoints ..................................................................................................... 23 
Secondary Endpoint Analysis ..........................................................................24 
12.3 
Exploratory Endpoints .................................................................................................. 24 
13 
SAFETY ANALYSIS............................................................................................................. 25 
13.1 
Adverse Events ............................................................................................................... 25 
13.2 
Clinical Laboratory ........................................................................................................ 27 
13.3 
Vital Signs ....................................................................................................................... 27 
13.4 
Electrocardiogram (ECG) ............................................................................................. 27 
13.5 
Local Tolerability Assessments ..................................................................................... 27 
13.6 
Patient Health Questionnaire Depression Scale (PHQ-8) .......................................... 28 
13.7 
Columbia-Suicide Severity Rating Scale (C-SSRS) .................................................... 29 
14 
APPENDICES ........................................................................................................................ 30 
Appendix 1 Output Conventions ............................................................................................... 30 
Appendix 2 Algorithm for Imputation of Start/End Date of Adverse Events and 
Prior/Concomitant Medications ................................................................................... 31 
Appendix 3 EASI Scoring Tool .................................................................................................. 32 
Appendix 4 vIGA-AD ................................................................................................................. 33 
Appendix 5 PHQ-8 ...................................................................................................................... 34 
Appendix 6 Columbia-Suicide Severity Rating Scale (C-SSRS)  ............................................ 35 
 
 


 
STATISTICAL ANALYSIS PLAN, Final V1.0Final 
1.0 
 
Protocol Number: AQR-151-212 
Sponsor: Arcutis, Inc. 
 
ABBREVIATIONS 
AD 
atopic dermatitis 
AE 
adverse event 
ANCOVA 
analysis of covariance 
ATC 
anatomical therapeutic chemical 
AUC 
Area under the curve 
BSA 
body surface area 
CI 
confidence interval 
Cmax 
Maximum Concentration 
CMH 
Cochran Mantel Haenszel 
CRO 
contract research organization 
C-SSRS 
Columbia Suicide Severity Rating Scale 
EASI 
Eczema Area and Severity Index 
EASI50 
improvement of at least 50% in the Eczema Area and Severity Index score 
EASI75 
improvement of at least 75% in the Eczema Area and Severity Index score 
ECG 
electrocardiogram 
ET 
early termination 
IGA 
Investigator’s Global Assessment 
IP 
Investigational product 
IWRS 
Internet-based response system 
MedDRA  
Medical Dictionary for Regulatory Activities  
mITT 
modified intent-to-treat (population) 
MMRM 
mixed model repeated measures 
PHQ-8 
Patient Health Questionnaire - 8 
PK 
pharmacokinetic 
PP 
per-protocol (population) 
PR 
PR interval 
PT 
preferred term 
QD 
Quaque die, once daily 
QRS 
QRS interval 
QT 
QT interval 
QTcB 
Bazett’s correction formula for QT interval 
QTcF 
Fridericia’s correction formula for QT interval 
RR 
RR interval 
SAE  
serious adverse event  
SAP  
statistical analysis plan  
SAS 
statistical analysis system® 
SD 
standard deviation 
SOC 
system organ class 
TEAE 
treatment emergent adverse event  
TLF 
tables, listings, and figures 
vIGA-AD 
Validated Investigator Global Assessment-Atopic Dermatitis 
WHO-DD  
World Health Organization Drug Dictionary  


 
STATISTICAL ANALYSIS PLAN, Final V1.0Final 
1.0 
 
Protocol Number: AQR-151-212 
Sponsor: Arcutis, Inc. 
 
WI-NRS 
Worst Itch Numeric Rating Scale 
 
 


 
STATISTICAL ANALYSIS PLAN, Final V1.0Final 
1.0 
 
Protocol Number: AQR-151-212 
Sponsor: Arcutis, Inc. 
 
1 INTRODUCTION 
This statistical analysis plan (SAP) describes the planned analysis and reporting for Arcutis, Inc. 
clinical protocol ARQ-151-212. The analyses described in the SAP are based upon the protocol 
Amendment 2.0 dated August 5th 2019. 
This SAP has been developed prior to database lock, final unblinding, and final analyses. All final 
analyses will be performed after the clinical trial data are entered into the database, any 
discrepancies in the data are resolved, the database is locked, and following the signature of the 
SAP. 
Analyses related to PK data are not covered in this SAP and will be described in a separate 
document. 
2 STUDY OBJECTIVES AND ENDPOINTS 
OBJECTIVES 
ENDPOINTS 
Safety 
Safety endpoints 
To assess the safety of ARQ-151 
cream 0.05% vs ARQ-151 
cream 0.15% vs vehicle 
administered QD x 4 weeks to 
adolescent and adult subjects 
with mild to moderate atopic 
dermatitis.  
 
• Incidence of local and non-local treatment-emergent 
adverse events (TEAEs) 
• Change from baseline in vital signs 
• Change from baseline in clinical laboratory test results 
• Change from baseline in electrocardiograms (ECG) 
• Patient Health Questionnaire – 8 (PHQ-8) and Columbia 
Suicide Severity Rating Scale (C-SSRS) assessments 
• Local tolerability assessments 
Subset analysis by age group (adolescents and adults) will 
also be conducted. 
Efficacy 
Efficacy endpoints 
To assess the efficacy of ARQ-
151 cream 0.05% vs ARQ-151 
cream 0.15% vs vehicle 
administered QD x 4 weeks to 
adolescent and adult subjects 
with mild to moderate atopic 
dermatitis. 
Primary: 
• Change from baseline in Eczema Area and Severity 
Index (EASI) Total Score at Week 4 


 
STATISTICAL ANALYSIS PLAN, Final V1.0Final 
1.0 
 
Protocol Number: AQR-151-212 
Sponsor: Arcutis, Inc. 
 
 
Secondary: 
• Percent change from baseline in EASI Total Score 
at each study visit 
• Change from baseline in EASI Total Score at weeks 
1 and 2  
• Achievement of a 75% or greater improvement in 
EASI (EASI75) score from baseline to each study 
visit 
• Achievement of a 50% or greater improvement in 
EASI (EASI50) score from baseline to each study 
visit 
• Change from baseline in BSA involvement at each 
study visit 
• Change from baseline in WI-NRS pruritus score at 
each study visit 
• Achievement of a ≥4-point improvement from 
Baseline in WI-NRS pruritus score at each study 
visit for subjects with a Baseline WI-NRS ≥ 4 
Subset analysis by age group (adolescents and adults) 
and baseline EASI score (‘2’ (mild) or ‘3’ (moderate)) 
will also be conducted. 
 
Pharmacokinetic 
Pharmacokinetic endpoints (not covered in this SAP) 
To evaluate the systemic 
exposure and characterize the 
plasma pharmacokinetic (PK) 
profile of ARQ-151 cream 
0.05% and 0.15% and its major 
N-oxide metabolite, in 
adolescent and adult subjects 
with mild to moderate atopic 
dermatitis. 
• Plasma levels of circulating roflumilast and its major N-
oxide metabolite 
• Exposure of roflumilast and its major N-oxide metabolite 
(as evidenced by the Cmax and AUC) for subjects who have 
serial PK data. 


 
STATISTICAL ANALYSIS PLAN, Final V1.0Final 
1.0 
 
Protocol Number: AQR-151-212 
Sponsor: Arcutis, Inc. 
 
3 STUDY DESIGN 
3.1 Overall Design 
This is a phase 2, parallel group, double blind, vehicle-controlled study of ARQ-151 cream 
0.15% and ARQ-151 cream 0.05% QD applied for 4 weeks to adolescent and adult subjects with 
1.5% to 35% BSA of mild to moderate atopic dermatitis. A subset of subjects that consented 
under the previous amendment will have serial PK testing, while only trough PK sampling will 
be performed for all new subjects enrolled under protocol amendment 2.0.  
A total of up to approximately 90 to 105 subjects will be enrolled at approximately 30 study sites 
in the United States and Canada.  Subjects will be adolescent (12-17 y/o) or adult (≥18 y/o) 
males or females with atopic dermatitis.  Subjects must have a vIGA-AD of Mild (‘2’) or 
Moderate (‘3’) at Baseline.    Subjects must have at least 1.5% and no more than 35% BSA of 
atopic dermatitis (excluding scalp, palms, and soles).  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, BSA). 
Subject participation involves a minimum of 5 clinic visits including Screening, Baseline, Week 
1, Week 2, and Week 4.  For the subset of subjects enrolled under amendment 1.0 and consented 
to participate in serial PK sampling, 2 additional clinic visits include the 24-hour PK sample 
collection after Baseline on Day 2 and on Day 16.  The interval between the Screening and 
Baseline visits could be up to 4 weeks, therefore the anticipated maximum duration of subject 
participation is ~8 weeks. 
3.2 Schedule of Events 
Table 1 provides a description of the procedures planned at each visit. 
 
 


 
STATISTICAL ANALYSIS PLAN, Final V1.0Final 
1.0 
 
Protocol Number: AQR-151-212 
Sponsor: Arcutis, Inc. 
 
Table 1: Study Events Flow Chart 
Study Procedure 
Screen 
Baseline 
Day 1 
Day 2, 24-
hour PK 
Collection 
 
Wk 1 
Day 8 
 
Wk 2 
Day 15 
Day 16, 24-
hour PK 
Collection 
 
Wk 4 
Day 29  
Visit 
1 
2 
3 
4 
5 
6 
7 
Visit Window 
-4 weeks 
 
 
+/- 3 days 
+/- 3 days 
 
+/- 3 days 
Informed consent 
X 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
Medical and surgical 
history 
X 
 
 
 
 
 
 
Physical examinationa 
X 
X 
 
 
 
 
X 
I/E criteria 
X 
X 
 
 
 
 
 
Hematology, Serum 
Chemistries, and 
Urine Analysis  
X 
X 
 
 
 
 
 
X 
12 lead ECG 
X 
 
 
 
 
 
X 
Vital signs, height, 
weightb 
X 
X 
 
X 
X 
 
X 
vIGA-ADc, EASIc, 
BSAc 
X 
X 
 
X 
X 
 
X 
WI-NRS pruritusd 
X 
X 
 
X 
X 
 
X 
Local Tolerability 
Assessmente  
 
X 
 
X 
X 
 
X 
PHQ-8, C-SSRS 
X 
X 
 
X 
X 
 
X 
Optional photographyf 
 
X 
 
X 
 
 
X 
Serum pregnancy test 
X 
 
 
 
 
 
 
Urine pregnancy testg 
 
X 
 
X 
X 
 
X 
PK drawsh 
 
X 
X 
 
X 
X 
X 
Drug/vehicle 
application in clinici 
 
X 
 
X 
X 
 
 
Dispense study 
medication kitj 
 
X 
 
X 
X 
 
 
Dispense/review diary 
 
X 
 
Xo 
X 
 
Xn 
Weigh study 
medication kitk 
 
X 
 
X 
X 
 
X 
Compliance 
calculationl 
 
X 
 
X 
X 
 
X 
Adverse event 
assessmentm 
X 
X 
X 
X 
X 
X 
X 
Concomitant 
medications 
X 
X 
 
X 
X 
 
X 
a Limited physical examination: skin, lungs, and heart only 
b  Height will be collected at Screening only. Weight will be collected at all study visits. Subject to void prior to weight being 
taken. Remove any jackets, outerwear and shoes. Remove any objects of significant weight (i.e. cell phones, wallet, key 
chains). A 5% weight loss should be reported to the medical monitor. 
c   vIGA-AD 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 


 
STATISTICAL ANALYSIS PLAN, Final V1.0Final 
1.0 
 
Protocol Number: AQR-151-212 
Sponsor: Arcutis, Inc. 
 
calculated as a sum of scores of all 4 body regions. EASI total score will range from 0 (absent) to 72 (severe). Total BSA 
affected by AD will be determined for all body surfaces except the scalp, palms and soles. vIGA-AD should be completed 
prior to other physician assessments. 
d.  Subjects will complete the WI-NRS pruritus questionnaire. 
e.  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. 
f Photography of AD lesion(s) selected by the Investigator will be performed at some investigational sites.  Photography will 
be optional.  All efforts will be made to de-identify the subjects. 
g A urine pregnancy test will be administered to all females of child-bearing potential. A negative result is required for 
continued participation in the study, and results must be available prior to dispensing of study drug at each visit. 
h For the subset of subjects who enrolled under the previous protocol amendment and agreed to the serial PK: on the first day 
of dosing, PK draws will be done pre-dose (within 1-hour) and at 1, 2, 4, 6 (all  20 min)  and 24 hours ( 2 hr) post-dose 
administration.  On Day 15, PK draws will be taken at pre-dose (within 1-hour), 1, 2, 4, 6 (all  20 min) and 24 hours ( 2 hr) 
post dose administration. For other subjects: PK draws will be collected at Days 1 and 29. The draws will be pre-dose, ≤ 60 
minutes before drug application in the clinic. Ensure study medication is not applied in the area where PK will be drawn. 
Note: Day 2 and Day 16 visits for 24-hour PK collection only apply to the subset of subjects who agree to the serial PK. 
i   Subjects to apply assigned IP in clinic at every visit.  
j Kits will be dispensed based on %BSA affected. See IP Handling Manual for details.   
k.  The entire kit should be weighed and recorded at every visit. See IP Handling Manual for details. 
l Compliance calculation is described in the IP Handling Manual 
m Any emergent AEs will be followed in the clinic for up to one month at the Investigator’s discretion until resolved or 
otherwise judged as clinically stable. 
n  On Day 29, no further IP will be applied or dispensed. 
o On Day 8, 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. 
 
 


 
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3.3 Treatment 
The treatment groups are: 
• ARQ-151 cream 0.05% applied QD (once a day) for 4 weeks 
• ARQ-151 cream 0.15% applied QD for 4 weeks 
• Matching Vehicle cream applied QD for 4 weeks 
3.4 Randomization, Replacement, and Unblinding Procedures 
3.4.1 Randomization 
Subjects will apply ARQ-151 cream 0.15% QD or ARQ-151 cream 0.05% QD or vehicle cream 
QD.  Assignment of drug or vehicle will be made at a 1:1:1 ratio and stratified based on vIGA-
AD score of ‘2’ (mild) or ‘3’ (moderate) according to a computer-generated randomization list.  
Randomization will take place at Baseline after the subject has been found to be fully eligible for 
participation.  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. 
This is a double-blind study, therefore neither the subjects nor the Investigator and clinical 
personnel will be aware of which treatment an individual has received. 
3.4.2 Replacement 
Subjects that withdraw or are discontinued from the study prior to Final Study Visit, may be 
replaced.  
3.4.3 Unblinding 
This is a double-blind study, therefore neither the subjects nor the Investigator and clinical 
personnel will be aware of which treatment an individual has received until after the database 
lock. The SAP and the study populations for analysis will be finalized prior to database lock and 
unblinding occurs. 
3.5 Changes to the Analysis from the Protocol 
The primary method of handling of missing data will be the MMRM method without explicit 
imputations for missing data as opposed to a multiple imputation technique. 
The PHQ-8 scoring in the protocol describes “Severe Depression” as any score between 20 and 
27. The PHQ-8 score has a maximum result of 24, The category has been corrected in section 
13.6 to a score between 20-24. 


 
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4 POPULATIONS FOR ANALYSIS 
4.1 Intent-to-Treat Population 
The Intent-to-Treat (ITT) population will include all randomized subjects. All subjects will be 
analyzed according to the treatment group to which they were randomized, regardless of 
treatment received. 
4.2 Per-Protocol Population 
The Per-Protocol (PP) Population will include all subjects who are in the safety population, are at 
least 80% compliant with study medication and do not miss more than 3 consecutive doses, and 
show no other major deviations (a deviation that affects the interpretation of the primary efficacy 
outcome; Section 6.6) from the study protocol . 
Prior to the database lock, major protocol deviation will be defined and reviewed by the sponsor 
and the CRO in charge of the study follow-up in a blinded fashion. Subjects with major protocol 
deviations will be excluded from the PP population. 
All subjects will be analyzed according to the actual treatment they received. 
4.3 Safety Population 
The Safety population will include all subjects who are enrolled and received at least one 
confirmed dose of study medication. Subjects will be analyzed according to the majority of the 
treatment applications received regardless of the treatment group to which they were 
randomized.   
4.4 Pharmacokinetic Population 
The PK population will include all subjects with serial PK data, receiving the active drug, with 
sufficient plasma concentrations of roflumilast and its major N-oxide metabolite to define a 
profile, as determined by the pharmacokineticist.  
5 GENERAL CONSIDERATIONS 
Formats and layouts of tables, listings, and figures (TLF) will be provided in a separate document 
(output general layout is described in Appendix 1). 


 
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5.1 Sample Size 
There are approximately 90-105 subjects planned for this study. A subset of approximately 18 
adults will receive serial PK sampling.  
Approximately 30-35 subjects will receive ARQ-151 cream 0.05% QD; approximately 30-35 
subjects will receive ARQ-151 cream 0.15% QD; approximately 30-35 subjects will receive 
vehicle QD.  
A sample size of 27 per arm will provide at least 80% power to detect a difference in the mean 
change from baseline in EASI Total Score of 35% at week 4 (for each ARQ-151-treated group 
versus vehicle-treated group), assuming a pooled standard deviation (SD) of 40%, with a two-
sided α = 0.05. This is based on a 2-sample t-test.  This includes P value adjustment for 
multiplicity using Bonferroni correction.  With a 10-25% dropout rate, the sample size for the 
study would be increased to 30-35 subjects per arm (90-105 subjects total).   
Change from baseline in EASI Total Score at week 4 is expected to provide more statistical 
power than percent change from baseline in EASI Total Score at this timepoint (which is a 
secondary endpoint) and has been chosen as the primary endpoint. 
This sample size is considered adequate for PK and safety evaluation. 
5.2 Baseline 
Unless otherwise specified, baseline value will be defined as the last non missing assessment prior 
to or on the first study treatment dose date (including unscheduled assessments). If the last non 
missing assessment is performed on the same date as the first study treatment and time is not 
available, the assessment will be considered as baseline, except for adverse events (AEs) and 
medications starting on the first study treatment dose date which will be considered post-baseline. 
5.3 Reference Start Date and Analysis Day 
Analysis day will be calculated from the first study treatment date (day 1) and will be used to show 
start/end day of assessments or events.  
In the situation where the assessment/event date is partial or missing, Analysis day will be 
missing. 
5.4 Windowing Conventions 
Statistical Windows have been proposed for early termination (ET) visits in this study: 
 
Day 1 (Baseline) 
Day 8 
Day 15 
Day 29 


 
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Visit 
1 
4 
5 
7 
Statistical 
Window 
Latest pre-dose 
measurement 
[Day 2; day 11] 
[Day 12 – Day 21] 
[Day 22 – D32] 
 
If there is more than one assessment for a given timepoint and analysis visit, the assessment 
closest to the target day will be considered. If there is more than one assessment with the same 
target date, then the scheduled assessment result will be considered. 
5.5 Descriptive Statistics 
All continuous variables will be summarized by presenting the number of subjects, mean, SD, 
median, minimum, and maximum. Categorical variables will be presented as frequencies and 
percentages. Summary tables will be presented by treatment and visit, when applicable. 
Change from baseline will be calculated as:  
Assessment value at post-baseline visit X – Baseline value. 
Percent change from baseline will be calculated as: 
(Assessment value at post-baseline visit X – Baseline value) / Baseline value * 100. 
5.6 Handling of Retests, Unscheduled Visits, and Early Termination Data 
When retests measurements are done, the retest measurement will be considered for the summary 
analysis. All data from retest visits will be listed. 
 
Unscheduled measurements will not be summarized in by-visit summary tables or figures. 
However, they will be included in shift summary tables. All data from unscheduled visits will be 
listed. 
 
Early Termination (ET) visit assessments will be re-mapped according to the windowing 
conventions in section 5.4.  
5.7 Software Version 
All analyses will be performed using SAS® software Version 9.4 or higher. 


 
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6 STATISTICAL CONSIDERATIONS 
6.1 Adjustments for Covariates 
For the efficacy parameters analyzed using a mixed-effects model for repeated measures 
(MMRM), the corresponding baseline value and the stratification factor vIGA-AD score (“2” 
(mild) or “3” (moderate)) will be included as covariates in the statistical model. 
6.2 Handling of Dropouts or Missing data 
See Appendix 2 for handling of completely or partially missing dates for prior and concomitant 
medications and adverse events. 
The primary method of handling of missing data will be the MMRM method without explicit 
imputations for missing data. A sensitivity analysis will be carried out on the primary endpoint 
using the last observation carried forward (LOCF) as an imputation for missing data. Only post-
baseline values will be carried forward. 
For secondary endpoints involving proportions, missing data at any post-baseline assessment will 
be imputed using LOCF and they will then be determined as a responder or non-responder based 
on the LOCF value. 
6.3 Interim Analysis and Data Monitoring 
No interim analysis is planned for this study. 
6.4 Multicenter Studies 
This is a multicenter study. Since randomization is not stratified by site, subjects will be analysed 
as if from a single center (i.e. all sites are combined).  
6.5 Statistical Tests 
Unless otherwise specified, all statistical tests will be two-sided and will be performed with a 
significance level of 0.05. Confidence intervals (CIs) will be two-sided with 95% coverage. 
6.6 Multiple Comparisons/Multiplicity 
The statistical test for each ARQ-151 dose level for the primary endpoint of Eczema Area and 
Severity Index (EASI) will be two-sided and will be performed with a significance level of 0.05 
using Dunnett’s method to control the overall alpha level.  


 
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No adjustments will be made to account for multiplicity in secondary and exploratory endpoints 
and multiple assessments through time in the same subjects. P-values presented for these 
endpoints will be nominal p-values.  
6.7 Examination of Subgroups 
Subset analysis by age group (adolescents and adults) will be conducted for both safety and 
efficacy data. Subset analysis by vIGA-AD strata (“2” (mild) and “3” (moderate)) will also be 
conducted on the primary and secondary efficacy endpoints. Details on these analyses are 
described in Sections 12.1, 12.2, and 13.  
7 STUDY SUBJECTS 
7.1 Disposition of Subjects 
All subjects who provide informed consent will be accounted for in this study. The number of 
subjects screened and subjects rescreened will be presented. Screen failures and the reason for 
screen failure will be presented for all screened subjects except for those who were rescreened and 
did not fail the second screening. Moreover, the number of subjects randomized and included in 
each analysis population will be presented. Study completion status and the reason for study 
discontinuation will also be presented. The percentage of subjects with screen failures will be 
calculated using the number of subjects screened as denominator. The percentage of screen failure 
by reasons will be calculated using the number of screen failures as denominator. The percentage 
of subjects with study discontinuation will be calculated by reasons using the number of subjects 
who did not complete study as denominator. Otherwise, percentages will be calculated using the 
number of subjects randomized as denominator. Number of days in the study will be calculated as 
follows and summarized: 
 
Number of days in study = Date of completion/discontinuation – 1st dose date +1 
A listing of subject’s disposition will be provided. Information on first screening for subjects who 
were rescreened, including the rescreened subject identifier, will be presented under the first 
screening subject identifier. A listing of subject’s randomization information and a listing of 
subjects included in each of the study populations will also be provided. 
7.2 Protocol Deviations 
The number of events and the number and percentage of subjects with at least one major protocol 
deviation will be summarized by deviation category using the safety population. A listing of all 


 
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protocol deviations will also be provided. The number of events and the number and percentage 
of subjects with at least one important protocol deviation will be summarized by deviation category 
using the safety population.  A listing of subjects with inclusion and exclusion criteria deviations 
will also be provided. This listing will identify important and major protocol deviations.  
An important protocol deviation is a deviation that might significantly affect the completeness, 
accuracy, and/or reliability of the study data or that might significantly affect a subject’s rights, 
safety, or well-being.  A major protocol deviation is a deviation that is likely to affect the primary 
efficacy data (Total EASI score).  
8 DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
Demographics and baseline characteristics will be summarized with descriptive statistics using the 
safety population. The list of demographics and baseline characteristics to be summarized will 
include:  
• Age (years) – calculated relative to date of consent 
• Sex 
• Ethnicity 
• Race 
• Baseline Height (cm) 
• Baseline Weight (kg) 
• Baseline EASI 
• Baseline vIGA-AD 
• Baseline BSA Involvement 
• WI-NRS Pruritus Score 
A listing of all demographics and baseline characteristics will be provided. 


 
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9 SURGICAL AND MEDICAL HISTORY 
Surgical and Medical history will be coded according to the Medical Dictionary for Regulatory 
Activities (MedDRA), Version 22.0. 
Surgical and medical history will be summarized by system organ class (SOC) and preferred term 
(PT) using the safety population. A subject who experienced the same surgical and medical history 
event multiple times will be counted only once for the corresponding PT. Similarly, if a subject 
experienced multiple surgical and medical history events within the same SOC, the subject will be 
counted only once for that SOC. Surgical and medical history events will be sorted alphabetically 
by SOC and within each SOC the PT will be presented by decreasing order. 
A listing of all surgical and medical history events will be provided. 
10 PRIOR AND CONCOMITANT MEDICATIONS 
Medications will be coded according to the World Health Organization Drug Dictionary (WHO-
DD), GLOBAL B3 March 1, 2019. 
Prior medications are defined as any medication started and discontinued prior to the first study 
treatment dose. Concomitant medications are defined as any medication taken after the first study 
treatment dose, including those starting prior to the first study treatment date and continuing past 
that date. See Appendix 2 for handling of completely or partially missing dates for prior and 
concomitant medications.  
Incidence of prior and concomitant medications will be tabulated by anatomical therapeutic 
chemical (ATC) level 3 and PT using the safety population. A subject with the same medication 
taken multiple times will be counted only once for the corresponding PT. Similarly, if a subject 
has taken more than one medication within the same ATC level, then the subject will be counted 
only once for that ATC. Prior and concomitant medications will be sorted alphabetically by ATC 
level and within each ATC level the PT will be presented by decreasing order.  
A listing of all prior and concomitant medications will be provided. 


 
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11 STUDY TREATMENT EXPOSURE AND TREATMENT 
COMPLIANCE 
A summary of exposure related to ARQ-151 cream and the vehicle will be presented using the 
safety population. It will include descriptive statistics on the number of days treated, as well as the 
number of treatment applications, for each treatment group.  
 
For each treatment, compliance will be calculated as follows: 
Number of treatment applications
Number of expected treatment applications × 100 
Since the study treatment is applied once daily, the number of expected treatment applications is 
28 for all subjects. Descriptive statistics for the compliance as well as the number of missed 
applications, subjects with < 80% and ≥ 80% compliance will be presented by treatment. 
Furthermore, the incidence of subjects who missed more than 3 consecutive doses and compliant 
subjects will be presented by treatment.   
 
A subject will be considered compliant with the dosing regimen if the subject applies at least 80% 
of the expected applications during the study drug application period and does not miss more than 
3 consecutive doses.  
 
Exposure and compliance, including compliance collected at each clinic visit, will be displayed in 
a listing of study treatment administration by subject, for each treatment. A listing of drug 
accountability including the tube number, dispensed and returned weight will also be provided. 
 
12 EFFICACY ANALYSIS 
12.1 Primary Efficacy Endpoint 
The Eczema Area and Severity Index (EASI) is a static assessment to measure the severity and 
extent of atopic dermatitis.  EASI combines the assessment of the severity of lesions and the area 
affected into a single score in the range 0 (no disease) to 72 (maximal disease). 
The body is divided into four sections (head (h) (10% of a person's skin); arms (a) (20%); trunk 
(t) (30%); legs (l) (40%)).  Each of these areas is scored by itself, and then the four scores are 
combined into the final EASI.  


 
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For each section, the percent of area (A) of skin involved is estimated and then transformed into 
a grade from 0 to 6 (A): 
0. 0% of involved area 
1. < 10% of involved area  
2. 10–<30% of involved area 
3. 30–<50% of involved area 
4. 50–<70% of involved area 
5. 70–<90% of involved area 
6. 90–100% of involved area 
EASI is evaluated for the entire body except the scalp, palms, and soles. 
Within each area, the severity is estimated by four clinical signs: Redness (erythema, 
inflammation), Thickness (induration, papulation, swelling – acute eczema), Scratching 
(excoriation), and Lichenification (lined skin, furrowing, prurigo nodules – chronic eczema). 
Severity parameters are measured on a scale of 0 to 3, from none to severe. 
To calculate the EASI, the sum of the severity rating for the four clinical signs are multiplied 
with the numerical value of the area affected and with the various percentages of the four body 
areas (see Appendix 3). The score will be set to missing in case of at least one missing value. 
Descriptive statistics on EASI total score will be presented by visit for each treatment group. 
Change from baseline and percentage change from baseline will be also summarized. 
Primary Endpoint Analysis 
The primary efficacy endpoint is change from baseline in EASI Total Score at Week 4.  
The primary efficacy endpoint will be analyzed using a MMRM analysis on change-from-
baseline EASI with subject as a random effect and vIGA-AD strata, visit, treatment group, and 
interaction term for treatment-by-visit as fixed effects and baseline EASI as a fixed covariate.  
An unstructured variance-covariance matrix will be used. The Kenward-Roger approximation 
will be used to estimate denominator degrees of freedom. The primary treatment comparisons 
will be the contrast between each dose of ARQ-151 with the Vehicle at Week 4.  
Sensitivity Analyses 
The interaction term baseline value-by-treatment will also be included in a supportive statistical 
model.  


 
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Missing data is handled using MMRM without explicit imputations for missing data. To assess 
robustness of the primary method of analysis via MMRM, a sensitivity analyses using LOCF 
will be performed. 
The primary efficacy analysis will be performed using the ITT population and the PP population 
will be used as supportive analysis.  
Subgroup Analyses 
An analysis of variance (ANCOVA) will be performed using LOCF to handle missing data, 
where the absolute change from baseline or the percent change from baseline in EASI score at 
Week 4 will be the dependent variable, the treatment group, vIGA-AD strata and age group 
(adolescents or adults) will be fixed effects. Treatment effect per age group and vIGA-AD strata 
will be presented.  
12.2 Secondary Endpoints 
Eczema Area and Severity Index (EASI) 
EASI score (as a secondary endpoint) will be assessed as: 
• Percent change from baseline in EASI Total Score at each study visit 
• Change from baseline in EASI Total Score at Weeks 1 and 2 
• Proportion of subjects with a 75% or greater improvement in Eczema Area and Severity 
Index (EASI75) score from baseline to each study visit 
• Proportion of subjects with a 50% or greater improvement in Eczema Area and Severity 
Index (EASI50) score from baseline to each study visit 
• Proportion of subjects with a 90% or greater improvement in Eczema Area and Severity 
Index (EASI90) score from baseline to each study visit 
• Proportion of subjects with a 100% or greater improvement in Eczema Area and Severity 
Index (EASI100) score from baseline to each study visit 
 
Body Surface Area (BSA) 
The BSA affected by 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 BSA.   
BSA will be assessed as: 
• Change from baseline in BSA involvement at each study visit 
 


 
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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. The WI-NRS will be 
determined by asking the subject’s assessment of worst itch over the past 24 hours. The scale is 
from ‘0 to 10’ (“no itch” to “worst imaginable itch”). Subjects will complete the WI-NRS 
pruritus assessment. 
 
 
WI-NRS will be assessed as: 
• Change from baseline in WI-NRS pruritus score at each study visit 
• ≥4-point improvement from Baseline in WI-NRS pruritus score at each study visit for 
subjects with a Baseline WI-NRS ≥ 4 
• ≥4-point improvement from Baseline in WI-NRS pruritus score at each study visit for 
subjects with a Baseline WI-NRS ≥ 6 
Secondary Endpoint Analysis 
Descriptive statistics will be presented on all secondary endpoints by visit and treatment group.  
A similar analysis approach as outlined for the primary endpoint will be used for all secondary 
continuous efficacy endpoints. The comparisons of each dose of ARQ-151 with the vehicle will 
be presented. 
 
For categorical efficacy endpoints involving proportions (e.g. achievement of a 75% or greater 
improvement in EASI score from baseline at each study visit), a Cochran Mantel Haenszel test 
(CMH) controlling for the stratification variable will be performed. The comparisons of each 
dose of ARQ-151 with the vehicle will be presented. 
 
Subgroup analyses by vIGA-AD strata and age-group will be performed on all secondary 
endpoints. 
12.3 Exploratory Endpoints 
Validated Investigator Global Assessment scale for Atopic Dermatitis (vIGA-AD) 


 
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The vIGA-AD is a static evaluation of qualitative overall atopic dermatitis 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 4). vIGA-AD is evaluated for the entire body 
except the scalp, palms, and soles. 
 
vIGA-AD will be assessed as:  
• Proportion of subjects with vIGA-AD score of ‘clear’ or ‘almost clear’ at each study visit 
• Proportion of subjects with vIGA-AD score of ‘clear’ or ‘almost clear’ with a 2-point 
improvement from baseline at each study visit  
• Change from baseline in vIGA-AD score at each study visit 
Exploratory Endpoint Analysis 
Descriptive statistics will be presented on vIGA-AD by visit and treatment group.  
A similar analysis approach as outlined for the primary endpoint will be used for the change 
from baseline in vIGA-AD. The comparisons of each dose of ARQ-151 with the vehicle will be 
presented. 
 
For categorical efficacy endpoints involving proportions (e.g. proportion of subjects with vIGA-
AD score of “clear” or “almost clear” at each study visit), a Cochran Mantel Haenszel test 
(CMH) controlling for the stratification variable will be performed. The comparisons of each 
dose of ARQ-151 with the vehicle will be presented. 
13 SAFETY ANALYSIS 
All safety analyses will be conducted using the safety population. Safety analyses will be presented 
for all subjects combined, and for adults and adolescents separately. No formal inferential statistics 
will be performed on safety assessments. 
13.1 Adverse Events 
Adverse events (AEs) will be coded according to the Medical Dictionary for Regulatory Activities 
(MedDRA), Version 22.0. 
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. See Appendix 2 for handling of completely or partially 
missing dates for AEs. In the case where it is not possible to define an AE as treatment emergent 
or not, the AE will be classified as treatment emergent. 


 
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An overall summary table of adverse events will be provided. The number of events and the 
number and percentage of subjects who experienced AE, TEAE, TEAE by greatest reported 
relationship, TEAE by highest reported severity, related TEAE by highest reported severity, 
serious AE (SAE), serious TEAE, TEAE leading to study drug discontinuation, TEAE leading to 
study discontinuation, and AE leading to death will be presented. 
Unless otherwise specified, a subject experiencing the same TEAE multiple times will be counted 
only once for the corresponding PT. Similarly, if a subject experiences multiple TEAEs within the 
same SOC, the subject will be counted only once for that SOC. TEAEs will be sorted by decreasing 
order of SOC and within each SOC the PT will be presented by decreasing order. 
Frequency and percentage of subjects who experience TEAE will be summarized by SOC and PT 
within SOC. 
Frequency and percentage of subjects who experience TEAE will be summarized by SOC, PT, 
and relationship. A treatment-related TEAE is defined as any TEAE that is assessed by the 
investigator as likely, probably, or possibly related to study treatment. TEAE that is assessed as 
unrelated or unlikely will be defined as not treatment-related. If a subject experiences more than 
one TEAE within different relationship categories within the same SOC/PT, only the worst case 
(greatest reported relationship) will be reported. A TEAE with an unknown relationship will be 
considered as treatment-related. 
Frequency and percentage of subjects who experience TEAE will be summarized by SOC, PT, 
and severity (mild/moderate/severe). A severe adverse event is defined as any adverse events with 
a severity grade of 3 or higher. If a subject experiences more than one TEAE within different 
severity categories within the same SOC/PT, only the worst case (highest reported severity) will 
be reported. TEAE with an unknown severity will be considered as severe. 
Frequency and percentage of subjects who experience TEAE will be summarized by SOC, PT, 
relationship, and severity (mild/moderate/severe). Each subject will be counted only once within 
a SOC or PT by using 1) the greatest reported relationship followed by 2) the highest reported 
intensity. 
Frequency and percentage of subjects who experience a serious TEAE will be summarized by SOC 
and PT within SOC.  Furthermore, frequency and percentage of subjects who experience a TEAE 
at the application site will be summarized by SOC and PT within SOC. 
Listings of all AEs, all AEs leading to death, all serious AEs, all TEAEs leading to study or study 
drug discontinuation will be provided. 


 
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13.2 Clinical Laboratory 
Descriptive statistics will be presented for data related to chemistry, hematology, and urinalysis. 
Change from baseline values will be presented for each post-baseline assessment. Frequencies and 
percentages for each result will be provided for qualitative urinalysis data. 
Shift tables from baseline to the worst post-baseline assessment describing shifts to abnormality 
will be provided as well. Only subjects with a baseline result and a post-baseline result for the 
parameter will be considered. 
Separate listings of all data for chemistry, hematology, urinalysis, and pregnancy tests will be 
provided.  
Laboratory data will be presented in SI units. 
13.3 Vital Signs 
Descriptive statistics will be presented for data related to vital signs (systolic blood pressure 
diastolic blood pressure, heart rate, body temperature, and weight). Change from baseline values 
will be presented for each post-baseline assessment.  
A shift table identifying subjects who gain or lose >5% body weight over the course of the study 
will be provided. Only subjects with a baseline result and a result at the specified visit for the 
parameter will be considered. 
A listing of all vital sign assessments will be provided.  
13.4 Electrocardiogram (ECG) 
Descriptive statistics will be presented for data related to ECGs (heart rate, RR duration, PR 
interval, QRS interval, QT interval, QTcB interval, and QTcF interval). Change from baseline 
values will be presented for each post-baseline assessment.  
Shift tables from baseline to the worst post-baseline assessment describing shifts to abnormality 
for investigator overall interpretation will be provided as well. 
A listing of the ECG assessments will be provided.  
 
13.5 Local Tolerability Assessments 
Investigator Local Tolerability Assessments 


 
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Local tolerability assessed by the investigator will be summarized by treatment and visit for 
dermal response on an 8-point scale (0-7).  Furthermore, the frequency of subjects with each 
dermal response score as well as other effects (A to G) will be summarized by treatment and 
visit.  
A sensitivity analysis of investigator local tolerability assessments will be conducted in which 
data from study sites 19, and 21 will be excluded.  Due to a misunderstanding of the data 
collection form, data from both of these sites were initially assessed as disease assessments 
rather than local tolerability assessments.  Data were updated after correct understanding of the 
CRF was attained, however, the effect of this post facto update of these data will be evaluated 
with this sensitivity analysis. 
A listing of investigator local tolerability assessments will be provided. 
 
Subject Local Tolerability Assessments 
 
Local tolerability assessed by the subject will be summarized by treatment and visit for 
tolerability grading on a 4-point scale (0-3).  Furthermore, the frequency of subjects with each 
tolerability score will be summarized by treatment and visit. 
 
A listing of subject local tolerability assessments will be provided. 
13.6 Patient Health Questionnaire Depression Scale (PHQ-8) 
The Patient Health Questionnaire Depression Scale is an 8 question Assessment (see Appendix 
5).  
 
The PHQ-8 score is the sum of the responses for the 8 questions, each question ranging from 0 
(Not at all) to 3 – (Nearly every day). Five severity categories of depression are defined as 
follows: 
 
• None – Minimal depression (1 to 4) 
• Mild depression (5 to 9) 
• Moderate depression (10 to 14) 
• Moderately severe depression (15 to 19) 
• Severe depression (20 to 24) 
 
The score will be set to missing in case of at least one missing value. The PHQ-8 score will be 
summarized by treatment and visit. Furthermore, the frequency of subjects within each severity 
category will be summarized by treatment and visit. 
 


 
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13.7 Columbia-Suicide Severity Rating Scale (C-SSRS) 
The Columbia-Suicide Severity Rating Scale (C-SSRS) is a questionnaire used for suicide 
assessment developed by multiple institutions, including Columbia University (see Appendix 6). 
A listing of the C-SSRS assessments will be provided. In addition, a listing of data will be provided 
for all subjects who answer ‘Yes’ to any question on the C-SSRS questionnaire. 
 
 
 


 
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Sponsor: Arcutis, Inc. 
 
14 APPENDICES 
Appendix 1 Output Conventions 
TLF will be generated using SAS® and will be displayed on letter size paper with landscape 
orientation, 1-inch margins, and 9 pt Courier New font. 
The header section will comprise the sponsor’s name, the protocol number, the delivery 
description, the data cut-off date (if applicable), the TLF number, the TLF title, the analysis 
population, and the page number (Page X of Y). The footer section will include the TLF footnotes, 
the CRO’s name, the date and time of the execution of the program, the reference listings and the 
name of the program. 
P-values equal to and above 0.001 will be reported to 3 decimal places; p-values less than 0.001 
will be reported as “<0.001”; p-values greater than 0.999 will be reported as “>0.999”.  
The mean, median, and quantiles will be displayed to one more decimal place than the original 
value; minimum and maximum will keep the same number of decimal places as the original 
value; SD, standard error, and CI will be displayed to two more decimal places than the original 
value. If derived parameters are to be summarized, the number of decimals of the derived values 
is to be chosen on a case-by-case basis, but the rule above applies. 
For categorical summary tables, percentages will be reported to one decimal place. Percentages 
between 0 and 0.1 (both exclusive) will be displayed as “<0.1”. The denominator for each 
percentage will be the number of subjects within the population per treatment group unless 
otherwise specified. 
Listings will be ordered by treatment group, subject number, date, and visit (where applicable). 
Imputed dates and imputed missing data will not be presented in the listings. 
Dates & Times Format 
Date and time (if available) will be presented in the format yyyy-mm-dd/hh:mm. 
Presentation of Treatment Groups 
When applicable, study treatments will be represented as follows in the different outputs: 
Study Treatment Full Names  
Study Treatment Output Names 
ARQ-151 cream 0.05% 
ARQ-151 0.05% 
ARQ-151 cream 0.15% 
ARQ-151 0.15% 
Vehicle 
Vehicle 


 
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Protocol Number: AQR-151-212 
Sponsor: Arcutis, Inc. 
 
Appendix 2 Algorithm for Imputation of Start/End Date of Adverse Events and 
Prior/Concomitant Medications 
Event Start Date Imputation 
• Imputation of event end date should be done before imputation of event start date.  
• Completely missing: Impute to the first study treatment date. 
• Missing day and month: Impute to January 1st, unless year is the same as year of first study 
treatment dose then impute to the first study treatment date. 
• Missing day: Impute to the 1st of the month, unless month and year are the same as month 
and year of first study treatment dose then impute to the first study treatment date. 
• If imputed event start date is after event end date (imputed or not), set the event start date 
to the imputed event end date. 
 
Event End Date Imputation 
• Completely missing (and not flagged as “ongoing”): Impute to the last contact date. 
• Missing day and month: Impute to December 31st, unless year is the same as last contact 
date then impute to the last contact date. 
• Missing day: Impute to the last day of the month, unless year and month are the same as 
year and month of last contact date then impute to the last contact date. 
 
 


 
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Sponsor: Arcutis, Inc. 
 
Appendix 3 EASI Scoring Tool 
 
 
 
 


 
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Sponsor: Arcutis, Inc. 
 
Appendix 4 vIGA-AD 
  


 
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Sponsor: Arcutis, Inc. 
 
Appendix 5 PHQ-8 
 
 
 


 
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Sponsor: Arcutis, Inc. 
 
Appendix 
6 
Columbia-Suicide 
Severity 
Rating 
Scale 
(C-SSRS) 
COLUMBIA-SUICIDE SEVERITY 
RATING SCALE 
(C-SSRS)  
Baseline/Screening Version 
Version 1/14/09 
 
  
Posner, K.; Brent, D.; Lucas, C.; Gould, M.; Stanley, B.; Brown, G.; Fisher, P.; Zelazny, J.; 
Burke, A.; Oquendo, M.; Mann, J.  
 
Disclaimer: 
This scale is intended to be used by individuals who have received training in its administration. The questions contained in 
the Columbia-Suicide Severity Rating Scale are suggested probes. Ultimately, the determination of the presence of suicidal 
ideation or behavior depends on the judgment of the individual administering the scale. 
Definitions of behavioral suicidal events in this scale are based on those used in The Columbia Suicide History Form, 
developed by John Mann, MD and Maria Oquendo, MD, Conte Center for the Neuroscience of Mental Disorders 
(CCNMD), New York State Psychiatric Institute, 1051 Riverside Drive, New York, NY, 10032. (Oquendo M. A., 
Halberstam B. & Mann J. J., Risk factors for suicidal behavior: utility and limitations of research instruments. In M.B. First 
[Ed.] Standardized Evaluation in Clinical Practice, pp. 103 -130, 2003.) 
For reprints of the C-SSRS contact Kelly Posner, Ph.D., New York State Psychiatric Institute, 1051 Riverside Drive, New 
York, New York, 10032; inquiries and training requirements contact posnerk@nyspi.columbia.edu 
© 2008 The Research Foundation for Mental Hygiene, Inc. 


 
STATISTICAL ANALYSIS PLAN, Final V1.0Final 
1.0 
 
Protocol Number: AQR-151-212 
Sponsor: Arcutis, Inc. 
 
 
SUICIDAL IDEATION 
Ask questions 1 and 2.  If both are negative, proceed to “Suicidal Behavior” section. If the answer to 
question 2 is “yes”, ask questions 3, 4 and 5.  If the answer to question 1 and/or 2 is “yes”, complete 
“Intensity of Ideation” section below. 
Lifetime: Time 
He/She Felt 
Most Suicidal 
Past __ 
Months 
1.  Wish to be Dead  
Subject endorses thoughts about a wish to be dead or not alive anymore, or wish to fall asleep and not wake up.  
Have you wished you were dead or wished you could go to sleep and not wake up?  
 
If yes, describe: 
 
Yes       No 
□    □ 
 
Yes     No 
□   □ 
2.  Non-Specific Active Suicidal Thoughts 
General non-specific thoughts of wanting to end one’s life/commit suicide (e.g., “I’ve thought about killing myself”) without thoughts 
of ways to kill oneself/associated methods, intent, or plan during the assessment period.  
Have you actually had any thoughts of killing yourself? 
 
If yes, describe: 
 
    Yes       No 
   □    □ 
 
Yes     No 
□   □ 
3.  Active Suicidal Ideation with Any Methods (Not Plan) without Intent to Act 
Subject endorses thoughts of suicide and has thought of at least one method during the assessment period. This is different than a 
specific plan with time, place or method details worked out (e.g.  thought of method to kill self but not a specific plan).  Includes person 
who would say, “I thought about taking an overdose but I never made a specific plan as to when, where or how I would actually do 
it…and I would never go through with it.” 
Have you been thinking about how you might do this? 
 
If yes, describe: 
 
 
    Yes      No 
 □    □ 
 
Yes     No 
□   □ 
4.  Active Suicidal Ideation with Some Intent to Act, without Specific Plan 
Active suicidal thoughts of killing oneself and subject reports having some intent to act on such thoughts, as opposed to “I have the 
thoughts but I definitely will not do anything about them.” 
Have you had these thoughts and had some intention of acting on them?  
 
If yes, describe: 
 
 
   Yes      No 
□    □ 
 
Yes     No 
□   □ 
5.  Active Suicidal Ideation with Specific Plan and Intent 
Thoughts of killing oneself with details of plan fully or partially worked out and subject has some intent to carry it out. 
Have you started to work out or worked out the details of how to kill yourself? Do you intend to carry out this plan? 
   
If yes, describe: 
 
 
   Yes       No 
 □    □ 
 
Yes     No 
□   □ 
INTENSITY OF IDEATION 
The following features should be rated with respect to the most severe type of ideation (i.e., 1-5 from above, with 1 being 
the least severe and 5 being the most severe).  Ask about time he/she was feeling the most suicidal.  
                                   
Lifetime -           Most Severe Ideation:  _______                  ________________________________________ 
                                                                       Type # (1-5)                                                 Description of  Ideation 
 
Past X Months - Most Severe Ideation:  _______                   ________________________________________ 
                                                                      Type # (1-5)                                                 Description of  Ideation 
Most  
Severe 
Most 
Severe 
Frequency 
How many times have you had these thoughts?  
(1) Less than once a week    (2) Once a week   (3)  2-5 times in week    (4) Daily or almost daily    (5) Many times each day 
 
 
____ 
 
 
____ 
Duration 
When you have the thoughts how long do they last? 
(1) Fleeting - few seconds or minutes                                                 (4) 4-8 hours/most of day 
(2) Less than 1 hour/some of the time                                                 (5) More than 8 hours/persistent or continuous 
(3) 1-4 hours/a lot of time 
____ 
____ 
Controllability 
Could/can you stop thinking about killing yourself or wanting to die if you want to? 
(1) Easily able to control thoughts                                                      (4) Can control thoughts  with a lot of difficulty 
(2) Can control thoughts with little difficulty                                     (5) Unable to control thoughts 
(3) Can control thoughts with some difficulty                                    (0) Does not attempt to control thoughts 
____ 
____ 
Deterrents 
Are there things - anyone or anything (e.g., family, religion, pain of death) - that stopped you from wanting to 
die or acting on thoughts of committing suicide? 
(1) Deterrents definitely stopped you from attempting suicide            (4) Deterrents most likely did not stop you  
(2) Deterrents probably stopped you                                                    (5) Deterrents definitely did not stop you  
(3) Uncertain that deterrents stopped you                                             (0) Does not apply 
____ 
____ 
Reasons for Ideation 
What sort of reasons did you have for thinking about wanting to die or killing yourself?  Was it to end the pain 
or stop the way you were feeling (in other words you couldn’t go on living with this pain or how you were 
feeling) or was it to get attention, revenge or a reaction from others? Or both? 
(1) Completely to get attention, revenge or a reaction from others       (4) Mostly to end or stop the pain (you couldn’t go on 
(2) Mostly to get attention, revenge or a reaction from others                     living with the pain or how you were feeling) 
(3) Equally to get attention, revenge or a reaction from others               (5) Completely to end or stop the pain (you couldn’t go on  
       and to end/stop the pain                                                                         living with the pain or  how you were feeling) 
                                                                                                                 (0)  Does not apply 
 
 
____ 
 
 
____ 
 
© 2008 Research Foundation for Mental Hygiene, Inc. 
 
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SUICIDAL BEHAVIOR 
(Check all that apply, so long as these are separate events; must ask about all types) 
 
Lifetime 
Past __ 
Years 
Actual Attempt:  
A potentially self-injurious act committed with at least some wish to die, as a result of act. Behavior was in part thought of as method to kill 
oneself. Intent does not have to be 100%.  If there is any intent/desire to die associated with the act, then it can be considered an actual suicide 
attempt. There does not have to be any injury or harm, just the potential for injury or harm. If person pulls trigger while gun is in 
mouth but gun is broken so no injury results, this is considered an attempt.   
Inferring Intent: Even if an individual denies intent/wish to die, it may be inferred clinically from the behavior or circumstances. For example, a 
highly lethal act that is clearly not an accident so no other intent but suicide can be inferred (e.g., gunshot to head, jumping from window of a 
high floor/story). Also, if someone denies intent to die, but they thought that what they did could be lethal, intent may be inferred.  
Have you made a suicide attempt? 
Have you done anything to harm yourself? 
Have you done anything dangerous where you could have died? 
What did you do? 
Did you______ as a way to end your life?  
Did you want to die (even a little) when you_____?  
Were you trying to end your life when you _____? 
Or Did you think it was possible you could have died from_____? 
Or did you do it purely for other reasons / without ANY intention of killing yourself (like to relieve stress, feel better,  
get sympathy, or get something else to happen)?  (Self-Injurious Behavior without suicidal intent) 
If yes, describe: 
 
Has subject engaged in Non-Suicidal Self-Injurious Behavior? 
Yes     No 
□   □ 
 
 
 
 
 
 
 
Total # of 
Attempts 
 
______ 
 
 
 
 
 
 
 
Yes     No 
□   □ 
Yes     No 
□   □ 
 
 
 
 
 
 
Total # of 
Attempts 
 
______ 
 
 
 
 
 
 
 
Yes     No 
□   □ 
Interrupted Attempt:   
When the person is interrupted (by an outside circumstance) from starting the potentially self-injurious act (if not for that, actual attempt would 
have occurred). 
Overdose: Person has pills in hand but is stopped from ingesting.  Once they ingest any pills, this becomes an attempt rather than an interrupted 
attempt. Shooting: Person has gun pointed toward self, gun is taken away by someone else, or is somehow prevented from pulling trigger. Once 
they pull the trigger, even if the gun fails to fire, it is an attempt. Jumping: Person is poised to jump, is grabbed and taken down from ledge. 
Hanging: Person has noose around neck but has not yet started to hang - is stopped from doing so. 
Has there been a time when you started to do something to end your life but someone or something stopped you before 
you actually did anything? 
If yes, describe: 
 
Yes      No 
□   □ 
 
 
 
Total # of 
interrupted 
 
______ 
 
Yes     No 
□   □ 
 
 
Total # of 
interrupted 
 
______ 
 
Aborted Attempt:   
When person begins to take steps toward making a suicide attempt, but stops themselves before they actually have engaged in any self-
destructive behavior. Examples are similar to interrupted attempts, except that the individual stops him/herself, instead of being stopped by 
something else. 
Has there been a time when you started to do something to try to end your life but you stopped yourself before you 
actually did anything? 
If yes, describe: 
 
Yes      No 
□   □ 
 
 
Total # of 
aborted 
 
______ 
Yes     No 
□   □ 
 
Total # of 
aborted 
 
______ 
Preparatory Acts or Behavior: 
Acts or preparation towards imminently making a suicide attempt. This can include anything beyond a verbalization or thought, such as 
assembling a specific method (e.g., buying pills, purchasing a gun) or preparing for one’s death by suicide (e.g., giving things away, writing a 
suicide note).  
Have you taken any steps towards making a suicide attempt or preparing to kill yourself (such as collecting pills, 
getting a gun, giving valuables away or writing a suicide note)? 
If yes, describe: 
 
 
 
Yes      No 
□   □ 
 
 
Yes     No 
□   □ 
Suicidal Behavior: 
Suicidal behavior was present during the assessment period? 
Yes      No 
□   □ 
Yes     No 
□   □ 
Answer for Actual Attempts Only 
Most Recent 
Attempt 
Date: 
Most Lethal        
Attempt 
Date: 
Initial/First 
Attempt 
Date: 
Actual Lethality/Medical Damage:   
0.  No physical damage or very minor physical damage (e.g., surface scratches). 
1.  Minor physical damage (e.g., lethargic speech; first-degree burns; mild bleeding; sprains). 
2.  Moderate physical damage; medical attention needed (e.g., conscious but sleepy, somewhat responsive; second-degree 
burns; bleeding of major vessel). 
3.  Moderately severe physical damage; medical hospitalization and likely intensive care required (e.g., comatose with reflexes 
intact; third-degree burns less than 20% of body; extensive blood loss but can recover; major fractures). 
4.  Severe physical damage; medical hospitalization with intensive care required (e.g., comatose without reflexes; third-degree 
burns over 20% of body; extensive blood loss with unstable vital signs; major damage to a vital area). 
5.  Death 
 
Enter Code 
 
 
 
______ 
 
 
 
 
Enter Code 
 
 
 
______ 
 
 
 
 
Enter Code 
 
 
 
______ 
 
 
 
Potential Lethality: Only Answer if Actual Lethality=0 
Likely lethality of actual attempt if no medical damage (the following examples, while having no actual medical damage, had 
potential for very serious lethality: put gun in mouth and pulled the trigger but gun fails to fire so no medical damage; laying 
on train tracks with oncoming train but pulled away before run over). 
 
0 = Behavior not likely to result in injury 
1 = Behavior likely to result in injury but not likely to cause death 
2 = Behavior likely to result in death despite available medical care 
 
Enter Code 
 
 
 
______ 
 
 
Enter Code 
 
 
 
______ 
 
 
Enter Code 
 
 
 
______ 
 
© 2008 Research Foundation for Mental Hygiene, Inc. 
 
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Sponsor: Arcutis, Inc. 
 
 
 
 
 
 
 
 
 
 
COLUMBIA-SUICIDE SEVERITY 
RATING SCALE 
(C-SSRS) 
Since Last Visit 
Version 1/14/09 
 
Posner, K.; Brent, D.; Lucas, C.; Gould, M.; Stanley, B.; Brown, G.; Fisher, P.; Zelazny, J.; 
Burke, A.; Oquendo, M.; Mann, J.  
 
 
Disclaimer: 
This scale is intended to be used by individuals who have received training in its administration. The questions contained 
in the Columbia-Suicide Severity Rating Scale are suggested probes. Ultimately, the determination of the presence of 
suicidal ideation or behavior depends on the judgment of the individual administering the scale. 
 
 
Definitions of behavioral suicidal events in this scale are based on those used in The Columbia Suicide History 
Form, developed by John Mann, MD and Maria Oquendo, MD, Conte Center for the Neuroscience of Mental Disorders 
(CCNMD), New York State Psychiatric Institute, 1051 Riverside Drive, New York, NY, 10032. (Oquendo M. A., 
Halberstam B. & Mann J. J., Risk factors for suicidal behavior: utility and limitations of research instruments. In M.B. First 
[Ed.] Standardized Evaluation in Clinical Practice, pp. 103 -130, 2003.) 
 
For reprints of the C-SSRS contact Kelly Posner, Ph.D., New York State Psychiatric Institute, 1051 Riverside Drive, New 
York, New York, 10032; inquiries and training requirements contact posnerk@nyspi.columbia.edu 
 
© 2008 The Research Foundation for Mental Hygiene, Inc. 


 
STATISTICAL ANALYSIS PLAN, Final V1.0Final 
1.0 
 
Protocol Number: AQR-151-212 
Sponsor: Arcutis, Inc. 
 
SUICIDAL IDEATION 
Ask questions 1 and 2.  If both are negative, proceed to “Suicidal Behavior” section. If the answer to question 2 is “yes”, 
ask questions 3, 4 and 5.  If the answer to question 1 and/or 2 is “yes”, complete “Intensity of Ideation” section below. 
 
Since Last 
Visit 
1.  Wish to be Dead  
Subject endorses thoughts about a wish to be dead or not alive anymore, or wish to fall asleep and not wake up.  
Have you wished you were dead or wished you could go to sleep and not wake up?  
 
If yes, describe: 
 
 
Yes       No 
 □    □ 
2.  Non-Specific Active Suicidal Thoughts 
General, non-specific thoughts of wanting to end one’s life/commit suicide (e.g., “I’ve thought about killing myself”) without thoughts of ways to kill 
oneself/associated methods, intent, or plan during the assessment period.  
Have you actually had any thoughts of killing yourself? 
 
If yes, describe: 
 
 Yes      No 
 □    □ 
3.  Active Suicidal Ideation with Any Methods (Not Plan) without Intent to Act 
Subject endorses thoughts of suicide and has thought of at least one method during the assessment period. This is different than a specific plan with time, 
place or method details worked out (e.g., thought of method to kill self but not a specific plan).  Includes person who would say, “I thought about taking an 
overdose but I never made a specific plan as to when, where or how I would actually do it…and I would never go through with it.” 
Have you been thinking about how you might do this? 
 
If yes, describe: 
 
 Yes      No 
 □    □ 
4.  Active Suicidal Ideation with Some Intent to Act, without Specific Plan 
Active suicidal thoughts of killing oneself and subject reports having some intent to act on such thoughts, as opposed to “I have the thoughts but I 
definitely will not do anything about them.” 
Have you had these thoughts and had some intention of acting on them?  
 
If yes, describe: 
 
 
Yes       No 
 □    □ 
5.  Active Suicidal Ideation with Specific Plan and Intent 
Thoughts of killing oneself with details of plan fully or partially worked out and subject has some intent to carry it out. 
Have you started to work out or worked out the details of how to kill yourself? Do you intend to carry out this plan? 
   
If yes, describe: 
 
 
 Yes      No 
 □    □ 
INTENSITY OF IDEATION 
The following features should be rated with respect to the most severe type of ideation (i.e., 1-5 from above, with 1 being the least severe 
and 5 being the most severe).  
                                             
Most Severe Ideation:             _____                      _________________________________________________ 
                                               
                                                                                                           Type # (1-5)                                         Description of  Ideation 
Most 
Severe 
Frequency 
How many times have you had these thoughts?  
(1) Less than once a week    (2) Once a week   (3)  2-5 times in week    (4) Daily or almost daily    (5) Many times each day 
 
____ 
Duration 
When you have the thoughts, how long do they last? 
(1) Fleeting - few seconds or minutes                                                 (4) 4-8 hours/most of day 
(2) Less than 1 hour/some of the time                                                 (5) More than 8 hours/persistent or continuous 
(3) 1-4 hours/a lot of time                                                                    
____ 
Controllability 
Could/can you stop thinking about killing yourself or wanting to die if you want to? 
(1) Easily able to control thoughts                                                      (4) Can control thoughts with a lot of difficulty 
(2) Can control thoughts with little difficulty                                     (5) Unable to control thoughts 
(3) Can control thoughts with some difficulty                                    (0) Does not attempt to control thoughts 
____ 
Deterrents 
Are there things - anyone or anything (e.g., family, religion, pain of death) - that stopped you from wanting to die or acting on 
thoughts of committing suicide? 
(1) Deterrents definitely stopped you from attempting suicide            (4) Deterrents most likely did not stop you  
(2) Deterrents probably stopped you                                                    (5) Deterrents definitely did not stop you  
(3) Uncertain that deterrents stopped you                                             (0) Does not apply 
____ 
Reasons for Ideation 
What sort of reasons did you have for thinking about wanting to die or killing yourself?  Was it to end the pain or stop the way 
you were feeling (in other words you couldn’t go on living with this pain or how you were feeling) or was it to get attention, 
revenge or a reaction from others? Or both? 
(1) Completely to get attention, revenge or a reaction from others       (4) Mostly to end or stop the pain (you couldn’t go on 
(2) Mostly to get attention, revenge or a reaction from others                     living with the pain or how you were feeling) 
(3) Equally to get attention, revenge or a reaction from others               (5) Completely to end or stop the pain (you couldn’t go on  
       and to end/stop the pain                                                                         living with the pain or  how you were feeling) 
                                                                                                                 (0)  Does not apply 
 
 
 
 
____ 
© 2008 Research Foundation for Mental Hygiene, Inc. 
 
        C-SSRS—Since Last Visit (Version 1/14/09)    
 
 
                          Page 1 of 2        


 
STATISTICAL ANALYSIS PLAN, Final V1.0Final 
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Protocol Number: AQR-151-212 
Sponsor: Arcutis, Inc. 
 
SUICIDAL BEHAVIOR 
(Check all that apply, so long as these are separate events; must ask about all types) 
Since Last 
Visit 
Actual Attempt:  
A potentially self-injurious act committed with at least some wish to die, as a result of act. Behavior was in part thought of as method to kill oneself. Intent 
does not have to be 100%.  If there is any intent/desire to die associated with the act, then it can be considered an actual suicide attempt. There does not 
have to be any injury or harm, just the potential for injury or harm. If person pulls trigger while gun is in mouth but gun is broken so no injury results, 
this is considered an attempt.   
Inferring Intent: Even if an individual denies intent/wish to die, it may be inferred clinically from the behavior or circumstances. For example, a highly 
lethal act that is clearly not an accident so no other intent but suicide can be inferred (e.g., gunshot to head, jumping from window of a high floor/story). 
Also, if someone denies intent to die, but they thought that what they did could be lethal, intent may be inferred.  
Have you made a suicide attempt? 
Have you done anything to harm yourself? 
 
Have you done anything dangerous where you could have died? 
What did you do? 
Did you______ as a way to end your life?  
Did you want to die (even a little) when you_____?  
Were you trying to end your life when you _____? 
Or did you think it was possible you could have died from_____? 
Or did you do it purely for other reasons / without ANY intention of killing yourself (like to relieve stress, feel better, get 
sympathy, or get something else to happen)?  (Self-Injurious Behavior without suicidal intent) 
If yes, describe: 
 
 
Has subject engaged in Non-Suicidal Self-Injurious Behavior? 
 
Yes      No 
□   □ 
 
 
 
 
 
 
 
Total # of 
Attempts 
 
______ 
 
 
 
 
 
 
 
Yes     No 
□   □ 
Interrupted Attempt:   
When the person is interrupted (by an outside circumstance) from starting the potentially self-injurious act (if not for that, actual attempt would have 
occurred). 
Overdose: Person has pills in hand but is stopped from ingesting.  Once they ingest any pills, this becomes an attempt rather than an interrupted attempt. 
Shooting: Person has gun pointed toward self, gun is taken away by someone else, or is somehow prevented from pulling trigger. Once they pull the trigger, 
even if the gun fails to fire, it is an attempt. Jumping: Person is poised to jump, is grabbed and taken down from ledge. Hanging: Person has noose around 
neck but has not yet started to hang - is stopped from doing so. 
Has there been a time when you started to do something to end your life but someone or something stopped you before you 
actually did anything? 
If yes, describe: 
 
Yes      No 
□   □ 
 
 
Total # of 
interrupted 
 
______ 
Aborted Attempt:   
When person begins to take steps toward making a suicide attempt, but stops themselves before they actually have engaged in any self-destructive behavior. 
Examples are similar to interrupted attempts, except that the individual stops him/herself, instead of being stopped by something else. 
Has there been a time when you started to do something to try to end your life but you stopped yourself before you 
actually did anything? 
If yes, describe: 
 
 
Yes      No 
□   □ 
 
Total # of 
aborted 
 
______ 
Preparatory Acts or Behavior: 
Acts or preparation towards imminently making a suicide attempt. This can include anything beyond a verbalization or thought, such as assembling a 
specific method (e.g., buying pills, purchasing a gun) or preparing for one’s death by suicide (e.g., giving things away, writing a suicide note).  
Have you taken any steps towards making a suicide attempt or preparing to kill yourself (such as collecting pills, getting a gun, 
giving valuables away or writing a suicide note)? 
If yes, describe: 
 
 
Yes      No 
□   □ 
Suicidal Behavior: 
Suicidal behavior was present during the assessment period? 
Yes      No 
□   □ 
Suicide: 
   Yes    No 
□   □ 
Answer for Actual Attempts Only 
Most Lethal 
Attempt 
Date: 
Actual Lethality/Medical Damage:   
0.  No physical damage or very minor physical damage (e.g., surface scratches). 
1.  Minor physical damage (e.g., lethargic speech; first-degree burns; mild bleeding; sprains). 
2.  Moderate physical damage; medical attention needed (e.g., conscious but sleepy, somewhat responsive; second-degree burns; bleeding of major vessel). 
3.  Moderately severe physical damage; medical hospitalization and likely intensive care required (e.g., comatose with reflexes intact; third-degree burns 
less than 20% of body; extensive blood loss but can recover; major fractures). 
4.  Severe physical damage; medical hospitalization with intensive care required (e.g., comatose without reflexes; third-degree burns over 20% of body; 
extensive blood loss with unstable vital signs; major damage to a vital area). 
5.  Death 
 
Enter Code 
 
 
 
______ 
Potential Lethality: Only Answer if Actual Lethality=0 
Likely lethality of actual attempt if no medical damage (the following examples, while having no actual medical damage, had potential for very serious 
lethality: put gun in mouth and pulled the trigger but gun fails to fire so no medical damage; laying on train tracks with oncoming train but pulled away 
before run over). 
 
0 = Behavior not likely to result in injury 
1 = Behavior likely to result in injury but not likely to cause death 
2 = Behavior likely to result in death despite available medical care  
 
Enter Code 
 
 
 
______ 
© 2008 Research Foundation for Mental Hygiene, Inc. 
 
        C-SSRS—Since Last Visit (Version 1/14/09)    
 
 
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