Clinical trial NCT04211363
Conditions: Chronic Plaque Psoriasis
Sponsor: Arcutis Biotherapeutics, Inc.
Start date: 2019-12-20; Completion date: 2020-11-16
Enrollment: 439 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a double-blind, parallel group, vehicle-controlled study to assess the safety and efficacy of roflumilast (ARQ-151) 0.3% cream vs vehicle (placebo) cream for treatment of chronic plaque psoriasis (CPP) in adult participants with 2 to 20% body surface area (BSA) of CPP.

Detailed description:

Arms: arm 1: Participants receive roflumilast cream 0.3% once daily for 8 weeks. arm 2: Participants receive vehicle cream once daily for 8 weeks.
Interventions: intervention 1: Roflumilast 0.3% cream intervention 2: Vehicle Cream
Intervention descriptions: intervention 1: Roflumilast 0.3% cream for topical application. intervention 2: Vehicle cream for topical application.

Protocol documents:
Prot_000.pdf: 








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6.6.2 
Blinding ................................................................................................................. 36 
6.6.3 
Treatment Administration ..................................................................................... 36 
6.6.4 
Treatment Compliance .......................................................................................... 37 
7 
STUDY PROCEDURES .................................................................................................... 37 
7.1 
Safety Assessments ...................................................................................................... 37 
7.1.1 
Screening ............................................................................................................... 38 
7.1.2 
Physical Examination ............................................................................................ 38 
7.1.3 
Vital Signs, Height and Weight ............................................................................ 38 
7.1.4 
Laboratory Tests ................................................................................................... 39 
7.1.5 
Children’s Depression Inventory 2 ....................................................................... 40 
7.1.6 
Patient Health Questionnaire depression scale (PHQ-8) ...................................... 40 
7.1.7 
Patient Health Questionnaire depression scale (Modified PHQ-A) ..................... 41 
7.1.8 
Columbia-Suicide Severity Rating Scale (C-SSRS) ............................................. 42 
7.1.9 
Local Tolerability Assessments ............................................................................ 43 
7.1.10 
Adverse Events ..................................................................................................... 44 
7.2 
Efficacy Evaluations ................................................................................................... 45 
7.2.1 
Investigator Global Assessment (IGA) ................................................................. 45 
7.2.2 
Psoriasis Area and Severity Index (PASI) and Modified Psoriasis Area and 
Severity Index (mPASI) ........................................................................................................ 46 
7.2.3 
Body Surface Area (BSA) .................................................................................... 47 
7.2.4 
Worst Itch Numerical Rating Scale (WI-NRS) .................................................... 47 
7.2.5 
Psoriasis Symptom Diary (PSD) ........................................................................... 47 
7.2.6 
Dermatology Life Quality Index (DLQI) and Children’s Dermatology Life 
Quality Index (CDLQI) ......................................................................................................... 48 
7.2.7 
Dermal Imaging .................................................................................................... 48 
7.3 
Pharmacokinetics Assessment ................................................................................... 48 
7.4 
Adverse Events ............................................................................................................ 48 
7.4.1 
Adverse Event Definition ..................................................................................... 48 
7.4.2 
Serious Adverse Event .......................................................................................... 49 
7.4.3 
Suspected Unexpected Serious Adverse Reaction (SUSAR) ............................... 50 
7.4.4 
Safety Review ....................................................................................................... 50 
7.4.5 
Adverse Event Reporting ...................................................................................... 51 
7.5 
Reporting Pregnancy .................................................................................................. 52 
7.5.1 
Emergency Unblinding ......................................................................................... 53 
8 
DATA ANALYSIS .............................................................................................................. 53 
8.1 
Statistical Methods ...................................................................................................... 53 
8.1.1 
Determination of Sample Size .............................................................................. 53 
8.1.2 
Subjects to Analyze ............................................................................................... 54 
8.1.3 
Interim Analysis .................................................................................................... 54 
8.1.4 
Background and Demographic Characteristics ..................................................... 54 
8.1.5 
Study Disposition .................................................................................................. 54 
8.1.6 
Protocol Deviations and Eligibility Deviations .................................................... 54 
8.1.7 
Investigational Product Application Compliance ................................................. 55 


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8.2 
Efficacy Evaluation ..................................................................................................... 55 
8.2.1 
Primary Efficacy Endpoint ................................................................................... 55 
8.2.2 
Secondary Endpoints ............................................................................................ 55 
8.3 
Safety Evaluation ........................................................................................................ 57 
8.3.1 
Adverse Events ..................................................................................................... 58 
8.3.2 
Local Tolerance Assessments ............................................................................... 58 
8.3.3 
Medical History and Physical Examinations ........................................................ 58 
8.3.4 
PHQ-8 and Modified PHQ-A ............................................................................... 59 
8.3.5 
C-SSRS ................................................................................................................. 59 
8.3.6 
Clinical Laboratory Results and Vital Signs/Weight Measurements ................... 59 
8.3.7 
Prior and Concomitant Medications ..................................................................... 59 
8.4 
Patient Reported Outcomes Analyses ....................................................................... 59 
8.4.1 
WI-NRS ................................................................................................................ 59 
8.4.2 
Dermatology Life Quality Index (DLQI) and Children’s Dermatology Life 
Quality Index (CDLQI) ......................................................................................................... 60 
8.4.3 
Psoriasis Symptom Diary (PSD) ........................................................................... 60 
8.5 
Pharmacokinetic Analysis .......................................................................................... 60 
9 
STUDY ADMINISTRATION ............................................................................................ 60 
9.1 
Ethics ............................................................................................................................ 60 
9.1.1 
Ethics Review Board ............................................................................................. 60 
9.1.2 
Ethical Conduct of the Study ................................................................................ 61 
9.1.3 
Subject Information and Consent .......................................................................... 61 
9.2 
Study Completion and Termination .......................................................................... 61 
9.2.1 
Study Completion ................................................................................................. 61 
9.2.2 
Study Termination ................................................................................................ 61 
9.3 
Study Monitoring ........................................................................................................ 62 
9.4 
Data Quality Assurance .............................................................................................. 62 
9.4.1 
Verification of Blinding ........................................................................................ 62 
9.5 
Data Handling and Record Keeping ......................................................................... 62 
9.6 
Protocol Amendments and Deviations ...................................................................... 63 
9.7 
Confidentiality and Privacy ....................................................................................... 63 
9.8 
Conflict of Interest ...................................................................................................... 64 
9.9 
Report Format ............................................................................................................. 64 
9.10 
Publication Policy ........................................................................................................ 64 
10 REFERENCES .................................................................................................................... 65 
11 APPENDICES ..................................................................................................................... 66 
 
 
 




Protocol ARQ-151-301 
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21 February 2020 
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1 
PROTOCOL SYNOPSIS 
Protocol Title: 
A Phase 3, 8-Week, Parallel Group, Double Blind, Vehicle-Controlled 
Study of the Safety and Efficacy of ARQ-151 Cream 0.3% Administered 
QD in Subjects with Chronic Plaque Psoriasis 
Investigational 
Product: 
ARQ-151 investigational product will be supplied as a 0.3% cream 
Matching vehicle cream will contain only excipients of ARQ-151 cream 
Planned Dose 
Level: 
Subjects will be randomized 2:1 to receive ARQ-151 cream 0.3% QD or 
matching vehicle cream QD applied to all psoriatic lesions up to and 
including an area of 20% BSA. Application will be to all areas affected 
including the face and intertriginous/genital regions (except for the scalp).   
IND: 
135681 
Clinical Indication: Chronic Plaque Psoriasis 
Study Design: 
This is a phase 3, randomized, parallel group, double blind, vehicle-
controlled study in which ARQ-151 cream 0.3% or vehicle cream is applied 
QD for 8 weeks to subjects with chronic plaque psoriasis involving between 
2 and 20% BSA 
Study Objectives: 
To assess the safety and efficacy of ARQ-151 cream 0.3% vs. vehicle 
administered QD for 8 weeks to individuals with 2 - 20% BSA of chronic 
plaque psoriasis.  
Study Sites:   
Approximately 40 sites in Canada and United States  
Study Population: 
Approximately 400 subjects; randomized 2:1 to ARQ-151 cream 0.3% QD 
or vehicle QD.  
Subjects will be male and female children (2 -11 y/o), adolescents (12-17 
y/o) and adults (>18 y/o).  
Subjects will have 2% to 20% total BSA of chronic plaque psoriasis.  
Subjects will have a minimum IGA of ‘Mild’ (2) for study entry. 
Main Inclusion 
Criteria 
1. Participants legally competent to sign and give informed consent and if 
age appropriate (for children and adolescents) assent, as required by 
local laws 
2. Males and females ages 2 years and older  
3. Clinical diagnosis of psoriasis vulgaris of at least 6 months duration (3 
months for children) as determined by the Investigator.  Stable disease 
for the past 4 weeks. 
4. Psoriasis vulgaris on the face, extremities, trunk, and/or intertriginous 
areas involving 2% to 20% of BSA (excluding the scalp, palms and 
soles) 
5. An Investigator’s Global Assessment of disease severity (IGA) of at 
least Mild (‘2’) at Baseline   
6. A PASI score of at least 2 (excluding the scalp, palms and soles) at 
Baseline  
7. Females of childbearing potential (FOCBP) must have a negative serum 
pregnancy test at Screening (Visit 1) and a negative urine pregnancy test 




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10. Females who are pregnant, wishing to become pregnant during the 
study, or are breast-feeding. 
11. Previous treatment with ARQ-151 or ARQ-154. 
12. Subjects who have received oral roflumilast (Daliresp®, Daxas®) or 
other PDE4 inhibitors (apremilast) within the past 4 weeks. 
13. Known or suspected:  
• 
severe renal insufficiency or moderate to severe liver impairment 
(Child-Pugh B or C) 
• 
known HIV infection  
• 
hypersensitivity to component(s) of the investigational products  
• 
history of severe depression, suicidal ideation, Baseline/Screening 
C-SSRS (12 years and older) indicative of suicidal ideation, whether 
lifetime or recent/current 
14. Subjects with PHQ-8 (18 y/o and older) or modified PHQ-A (12 to 17 
y/o) >10 at Screening or Baseline visits. Subjects (6 to 11 years old, 
inclusive) with a CDI-2 (parent report) raw score >20 at 
Screening/Baseline 
15. Subjects with a history of chronic alcohol or drug abuse within 6 months 
of initiation of study medication. 
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 who are family members of the clinical study site, clinical study 
staff, or sponsor, or family members that live in the same house of 
enrolled subjects. 
19. Subjects with any serious medical condition or laboratory abnormality 
that would prevent study participation or place the subject at significant 
risk, as determined by the Investigator. 
20. 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. 
21. Subjects with active infection that required oral or intravenous 
administration of antibiotics, antifungal or antiviral agents within 7 days 
of Baseline/Day 1. 
Duration of 
Participation for 
Subjects: 
Screening (up to 5 weeks), Treatment phases (8 weeks), and a follow up 
(1 week post-treatment completion) for subjects who do not enroll in 
ARQ-151-306.  
Upon completion of the treatment phase of this study (week 8), subjects  
may have the opportunity, subject to regulatory approval, to participate in an 
open-label extension study (ARQ-151-306) of up to 6 months. 


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Key Assessments: 
Safety will be monitored through AEs, application site assessments, vital 
signs, physical examinations, safety labs, C-SSRS (12 years and older), 
either PHQ-8 (in adults), modified version of the PHQ-A (in adolescents) or 
Children's Depression Inventory 2 (CDI-2), parent report for children (6-11 
years old, inclusive), assessments. 
Efficacy assessments will include IGA, I-IGA, PASI/mPASI, BSA, WI-NRS 
(12 years and older), PSD (adults only), and DLQI (>17 years of age 
)/CDLQI (subjects 2 to 16 inclusive).  
Pharmacokinetic (PK) samples will be collected at pre-dose (trough) on days 
1 (baseline), 29 (week 4), and 57 (week 8) for all subjects. Refer to the 
Schedule of Visits and Assessments (Section 2) for detailed schedules of the 
study assessments. 
Study Endpoints 
The Primary Efficacy Endpoint is IGA success, defined as an IGA score of 
‘clear’ or ‘almost clear’ PLUS a 2-grade improvement from Baseline at 
week 8. 
The secondary efficacy endpoints will include: 
• 
Achievement of Psoriasis Area Severity Index 75 (PASI-75; subjects 
who achieve a 75% reduction in PASI from Baseline) at week 8 
• 
For subjects with intertriginous area involvement, and with severity of 
the intertriginous lesions at least ‘mild’ (intertriginous IGA (I-IGA) ≥2) 
at Baseline, achievement of ‘I-IGA’ score of ‘clear’ or ‘almost clear’ 
PLUS a 2-grade improvement from Baseline at week 8. 
• 
In subjects with WI-NRS pruritus score ≥ 4 at baseline, achievement of a 
4-point reduction in WI-NRS pruritus score at week 8  
• 
In subjects with WI-NRS pruritus score ≥ 4 at baseline, achievement of a 
4-point reduction in WI-NRS pruritus score at week 4  
• 
In subjects with WI-NRS pruritus score ≥ 4 at baseline, achievement of a 
4-point reduction in WI-NRS pruritus score at week 2 
• 
Change from Baseline in total Psoriasis Symptoms Diary (PSD) score at 
week 8. 
• 
Change from Baseline in PSD score at week 4. 
• 
Time to achieving Psoriasis Area Severity Index-50 (PASI-50) 
• 
For subjects with intertriginous area involvement, and with severity of 
the intertriginous lesions at least ‘mild’ (I-IGA ≥2) at Baseline, 
achievement of ‘I-IGA’ score of ‘clear’ at week 8. 
• 
Achievement of Psoriasis Area Severity Index-90 (PASI-90; subjects 
who achieve a 90% reduction in PASI from Baseline) at week 8. 
Statistical 
Considerations: 
Approximately 400 subjects are planned for this study.   
Approximately 267 subjects will receive ARQ-151 cream 0.3% QD; 
approximately 133 subjects will receive matching vehicle cream QD. 
The randomization scheme will be 2:1 (ARQ-151 cream 0.3% QD : 
matching vehicle QD) stratified by study site, baseline IGA (IGA=2 vs. 
IGA≥3), and intertriginous involvement at baseline (I-IGA>2, yes vs no). 
This sample size provides >99% power to detect a 22.4% difference between 
treatment groups on IGA success at α=0.05 using a 2-sided Chi-squared test.  
The results from a recent phase 2b study (ARQ-151-201) of ARQ-151 


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compared to vehicle treatment were used to estimate the treatment 
difference.  Specifically, in the phase 2b trial, 32.2% of subjects 
demonstrated IGA success in the ARQ-151 0.3% group and 9.8% of subjects 
demonstrated IGA success in the vehicle group. 
The number of subjects to be enrolled will also provide sufficient power for 
the first 5 secondary endpoints.  Additionally, the larger study size is 
included in order to provide additional/sufficient numbers of subjects on 
ARQ-151 treatment for a safety database. 
Descriptive statistics will be presented for the endpoint and safety data 
collected in the clinical trial. This includes the number and percentage of 
subjects for binary endpoints/categorical data, and mean, SD, median, 
minimum, and maximum for continuous data. 
The primary endpoint of ‘IGA success at week 8’ will be analyzed using a 
Cochran-Mantel-Haenszel test stratified by study site, IGA at baseline, and 
intertriginous involvement at baseline. The analysis will be performed on the 
Intention-to-Treat (ITT) population and missing data will be imputed using 
multiple imputation. 
Continuous secondary endpoints will be analyzed using Analysis of 
Covariance with treatment and stratification factors as independent variables.  
The ITT population will be used and missing data will be imputed using 
multiple imputation.  Binary secondary endpoints will be analyzed similarly 
to the primary endpoint.  Time-to-event endpoints will be analyzed using the 
Kaplan-Meier estimator. Treatment group comparisons will be performed 
using the log-rank statistic. 
Secondary endpoints will only be tested statistically if the primary endpoint 
is considered statistically significant.  To control for multiple comparisons 
among the secondary endpoints, the following multiplicity procedure will be 
used: 
• 
Upon successful testing of the primary endpoint, the alpha will be 
partitioned to test secondary endpoints families 1 and 2 (partition 1) 
and to test additional WI-NRS timepoints (partition 2) 
• 
Partition 1 of alpha = 0.03 will be allocated to test secondary 
endpoint family 1 and secondary endpoint family 2.  The endpoints 
in family 1 will be tested independently using a Bonferroni split of 
the alpha; the next 5 secondary endpoints (secondary endpoint 
family 2) will be tested using the alpha available after testing 
endpoint family 1.  The Holm procedure will be used to control for 
multiple comparisons in secondary endpoint family 2. 
• 
Partition 2 of alpha = 0.02 will be allocated to sequentially test WI-
NRS success at week 4 and WI-NRS success at week 2. 
All subjects who are randomized and receive at least one confirmed dose of 
investigational product or vehicle cream will be included in the safety 
population.  
Adverse events (AEs) will be summarized by preferred term, system organ 
class, and treatment group for all treatment-emergent AEs, serious AEs, 
related AEs, AEs leading to withdrawal from investigational product, and 
AEs leading to withdrawal from study.  


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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. 
Descriptive statistics will be calculated for the PHQ-8 (adults) or Modified 
PHQ-A (adolescents) and CDI-2 (children). 
The C-SSRS will be analyzed per the Scoring and Data Analysis Guide from 
the Columbia Lighthouse Project. 
 
 
 


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1.1 
Study Schema 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Screening (Visit 1) 
Baseline (Visit 2) 
Randomization and Treatment Day 1 
ARQ-151 0.3% 
Vehicle Cream 
 8-Week Treatment Period (Visits 3, 4, 5 & 6) 
Follow Up Period / Visit 7 
A Phase 3, 8-Week, Parallel Group, Double Blind, Vehicle-Controlled Study of the 
Safety and Efficacy of ARQ-151 Cream 0.3% Administered QD in Subjects with 
Chronic Plaque Psoriasis  
 
Approximately 400 subjects with chronic plaque psoriasis will be randomized 
2:1 to receive either: 
• 
ARQ-151 cream 0.3%,  
• 
Vehicle cream 


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2 
SCHEDULE OF VISITS AND ASSESSMENTS 
Study Procedure 
Screen 
Baseline 
Day 1 
 
Wk 2  
Day 15 
 
Wk 4 
Day 29 
 
Wk 6 
Day 43  
 
Wk 8r 
Day 57  
 
Wk 9 
Day 64 
Visit 
1 
2 
3 
4 
5 
6 
7 
Visit Window 
-35 days 
 
+/- 3 days +/- 5 days +/- 5 days +/- 7 days +/- 7 days 
Informed consent/assent 
X 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
Physical examinationa 
X 
X 
 
 
 
X 
 
I/E criteria 
X 
X 
 
 
 
 
 
Hematology, Serum 
Chemistries, and Urine 
Analysisb 
X 
X 
 
X 
 
 
X 
 
Vital signs, height, weightc 
X 
X 
X 
X 
X 
X 
X 
IGAd, BSAd, PASI/mPASId 
X 
X 
X 
X 
X 
X 
X 
Intertriginous area IGA 
(I-IGA)e 
 
X 
X 
X 
X 
X 
X 
WI-NRSf 
X 
X 
X 
X 
X 
X 
 
DLQI/CDLQIg 
X 
X 
X 
X 
 
X 
 
Local Tolerability 
Assessmentsh 
 
X 
 
X 
 
X 
 
C-SSRS, PHQ-8 / modified 
PHQ-A (12 years and older) 
X 
X 
 
X 
 
X 
 
CDI-2 parent report (6-11 y/o 
inclusive) 
X 
X 
 
X 
 
X 
 
PSDi 
X 
X 
X 
X 
X 
X 
 
Photographyj 
 
X 
X 
X 
X 
X 
 
Serum pregnancy test 
X 
 
 
 
 
 
 
Urine pregnancy testk 
 
X 
 
X 
 
X 
 
PK drawsl 
 
X 
 
X 
 
X 
 
IP application in clinicm 
 
X 
X 
X 
X 
X 
 
Assign investigational 
product kitn 
 
X 
 
 
 
 
 
Dispense/review diary 
 
X 
X 
X 
X 
X 
 
Weigh investigational product 
tubesn 
 
X 
X 
X 
X 
X 
 
Compliance calculationo 
 
X 
X 
X 
X 
X 
 
Adverse event assessmentp 
X 
X 
X 
X 
X 
X 
X 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
Study Exitq 
 
 
 
 
 
 
X 
a Limited physical examination: skin, lungs, and heart only 
b  If Baseline visit occurs within 14 days of Screening, the Screening lab results may be utilized. 
c Height will be collected at Baseline only. Weight will be collected at every visit. 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% unintentional weight loss should be reported to the medical monitor on Page 1. 
d   IGA (based on whole body involvement) will be a 5-point scale ranging from clear (0) to severe (4). IGA should be 
completed prior to other physician assessments and by the same Evaluator at each study visit. Total BSA affected by 
psoriasis will be determined by the subject’s hand method, where the subject’s hand (including fingers) surface area is 
assumed to equal 1% of the BSA. PASI/mPASI will be determined by standard methods. NOTE: while palms and soles will 
be treated with IP, they are not counted towards IGA, PASI/mPASI, or BSA assessments.  
e  For subjects with intertriginous area involvement of at least ‘mild’ severity by IGA (IGA≥2) at Baseline (using the IGA scale 
but evaluating intertriginous areas ONLY and NOT whole body involvement), an IGA for the intertriginous region alone 


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(I-IGA) will be recorded.  This ‘intertriginous area IGA’ should be done AFTER the ‘standard whole body IGA’ 
(primary endpoint) in subjects who qualify. 
f   Subjects 12 years and older will complete WI-NRS pruritus assessment. 
g   Subjects >17 years of age will complete DLQI.  For subjects 2-16 years of age, CDLQI will be completed. 
h Tolerability assessments should be recorded prior to investigational product application for Investigator assessment (Berger 
and Bowman skin irritation score) and 10-15 minutes post-investigational product application for subject ‘0-3’ 
burning/stinging assessment. Parents may report for children. Note for investigator tolerability assessments: reactions at 
the site of product application, which may occur post-Baseline, should be differentiated from the preexisting 
inflammation associated with the subject’s Psoriasis. 
I     Adult subjects only 
j Photography will be performed using Canfield equipment on all subjects at all sites.  All efforts will be made to de-identify 
the subjects. Subjects who are unwilling to participate in the medical photography will be allowed to opt out of this procedure 
and documented on the informed consent. See Photography Manual for details. 
k A urine pregnancy test will be administered to all females of child-bearing potential. A negative result is required for 
continued participation in the study, and results must be available prior to dispensing of investigational product at each visit. 
l PK draws will be collected from all subjects at Days 1, 29 and 57. The draws will be pre-dose investigational product 
application in the clinic (i.e., trough levels). Ensure investigational product is not applied in the area where PK will be drawn. 
m   Subjects to apply assigned IP in clinic at every visit. The time of application will be documented.  
n Kits will be dispensed based on % BSA affected. See IP Handling Manual for details.   
o    Each IP tube should be weighed and recorded at every visit. See IP Handling Manual for details. 
p 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. 
q    Subjects who consent to/enroll into the open label extension study (ARQ-151-306) will complete the study at Week 8; 
subjects that do not consent to/enroll into ARQ-151-306 will return at Week 9 to complete the study. 
r    Subjects that terminate early should return to the clinic for the week 8 assessments. 
 
 
 
 


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3 
 
ABBREVIATIONS 
AE 
Adverse Event 
AMP 
Adenosine Monophosphate 
AUC 
Area Under the Curve 
BSA 
Body Surface Area 
Cmax 
Maximum Concentration 
CDI-2 
Children's Depression Inventory 2 
CDLQI 
Children’s Dermatology Life Quality Index 
COPD 
Chronic Obstructive Pulmonary Disease 
CRF 
Case Report Form 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CTCAE 
Common Terminology Criteria for Adverse Events 
DLQI 
Dermatology Life Quality Index 
DNA 
Deoxyribonucleic Acid 
ERB 
Ethics Review Board 
FDA 
U.S. Food and Drug Administration 
FOCBP 
Female of Child Bearing Potential 
GCP 
Good Clinical Practices 
HC 
Health Canada 
HCA 
Alpha-Hydroxycinnamaldehyde 
HPRT 
Hypoxanthine-guanine Phosphoribosyl Transferase 
IB 
Investigational Brochure 
IC50 
Half Maximal Inhibitory Concentration 
ICF 
Informed Consent Form 
ICH  
International Conference on Harmonisation 
IGA 
Investigator Global Assessment 
I-IGA 
Intertriginous IGA  
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
ITT 
Intent to Treat 
IWRS 
Interactive Web Response System  
LED 
Light Emitting Device 
µg 
Microgram 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
Modified Intent to Treat 
mL 
Milliliter 
MMRM 
Mixed effect Model Repeat Measurement  
mPASI 
Modified Psoriasis Area and Severity Index 
MTD 
Maximum Tolerated Dose 


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NCI 
National Cancer Institute 
NIH 
National Institutes of Health 
NOAEL 
No Observed Adverse Effect Level 
Ng 
Nanogram 
NRS 
Numerical Rating Score  
PASI 
Psoriasis Area and Severity Index 
PASI-75 
Psoriasis Area and Severity Index-75; subjects who achieve a 75% reduction in PASI from 
Baseline 
PASI-90 
Psoriasis Area and Severity Index-90; subjects who achieve a 90% reduction in PASI from 
Baseline  
PASI-100 
Psoriasis Area and Severity Index-100; subjects who achieve a 100% reduction in PASI 
from Baseline  
PDE-4 
Phosphodiesterase 4 
PHQ-A 
Modified PHQ-9 for Adolescents 
PHQ-8 
Patient Health Questionnaire depression scale 
PI 
Principal Investigator  
PK 
Pharmacokinetics 
PP 
Per Protocol  
PSD 
Psoriasis Symptoms Diary 
QD 
Once Daily ("quaque die") 
SAE 
Serious Adverse Event 
TEAE 
Treatment Emergent Adverse Event 
Th1 
Type 1 T Helper Cell 
Th17 
Type 17 T Helper Cell 
Tmax 
Time to reach maximum concentration 
V79 
Chinese hamster cell line 
WI-NRS 
Worst Itch – Numeric Rating Score 
 
 
 


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4 
BACKGROUND AND RATIONALE 
4.1 
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. 
 
Psoriasis is a chronic inflammatory skin disease characterized by raised, well-demarcated, 
erythematous oval plaques with adherent silvery scales.  Numerous past reports have suggested a 
deficiency of cyclic AMP-dependent protein kinases in human psoriatic skin (Brion 1986).  
More recently, various cytokines produced by Th1 and Th17 cells have been shown to play a 
crucial role in the pathogenesis of psoriasis.  It has been postulated that the anti-inflammatory 
effects of PDE-4 inhibitors may provide a beneficial therapeutic intervention in the treatment of 
chronic plaque psoriasis, and recently Otezla® (apremilast) a PDE-4 inhibitor has been approved 
for the oral treatment of chronic plaque psoriasis. 
 
The past 15 years have witnessed a transformation in the systemic treatment of moderate to 
severe psoriasis with the advent of biological therapies.  However, for patients with milder forms 
of disease, best treated with topical options, the therapeutic landscape has not significantly 
changed in several decades.  Topical steroids come in all shapes and forms, but the lower 
potency steroids are not effective and the higher potency steroids are beset with issues of local 
skin atrophy and the potential for hypothalamic-pituitary axis suppression when applied over 
larger body surface areas and for prolonged periods of time.  Vitamin D has been the other staple 
of topical psoriasis treatment but it is irritating, not suitable for use on the face or intertriginous 
areas, and its efficacy is rather modest.  Hence, there is substantial medical need for additional 
topical approaches in the treatment of psoriasis.  The study sponsor is developing a topical 
formulation of roflumilast for the treatment of chronic plaque psoriasis.  Our Phase 2 results 
suggest that ARQ-151 may be a highly efficacious and well-tolerated topical treatment for 
psoriasis. 
4.2 
Nonclinical Studies  
4.2.1 
Toxicology Summary  
Oral roflumilast is approved globally for COPD, and its safety profile is well-established. 
An extensive systemic toxicity program that evaluated both roflumilast and its active N-oxide 
metabolite in multiple species via the oral route of administration was conducted to support 
registration. 


















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Investigator Global Assessment of Disease (IGA) 
Scale Grade 
Description 
0 
Clear  
Plaque thickening = no elevation or thickening over normal skin 
Scaling = no evidence of scaling 
Erythema = none (no residual red coloration but post-inflammatory 
hyperpigmentation may be present) 
1 
Almost 
Clear 
Plaque thickening = none or possible thickening but difficult to ascertain 
if there is a slight elevation above normal skin level 
Scaling = none or residual surface drying and scaling 
Erythema = light pink coloration 
2 
Mild  
Plaque thickening = slight but definite elevation 
Scaling = fine scales partially or mostly covering the lesions 
Erythema = light red coloration 
3 
Moderate 
Plaque thickening = moderate elevation with rounded or sloped edges 
Scaling = most lesions at least partially covered 
Erythema = definite red coloration 
4 
Severe 
Plaque thickening = marked or very marked elevation typically with hard 
or sharp edges 
Scaling = non-tenacious or thick tenacious scale, covering most or all of 
lesions 
Erythema = very bright red coloration; extreme red coloration; deep red 
coloration  
This IGA (whole body) will be the first efficacy endpoint measured at clinic visits and prior 
to the application of any Investigational Product. 
5.2.2 
Secondary Endpoints 
The secondary efficacy endpoints will include: 
• Achievement of Psoriasis Area Severity Index 75 (PASI-75; subjects who achieve a 75% 
reduction in PASI from Baseline) at week 8. 
• For subjects with intertriginous area involvement, and with severity of the intertriginous 
lesions at least ‘mild’ (intertriginous IGA (I-IGA) ≥2) at Baseline, achievement of 
‘I-IGA’ score of ‘clear’ or ‘almost clear’ PLUS a 2-grade improvement from Baseline at 
week 8. 
• In subjects with WI-NRS pruritus score ≥ 4 at baseline, achievement of a 4-point 
reduction in WI-NRS pruritus score at week 8 as compared to Baseline. 
• In subjects with WI-NRS pruritus score ≥ 4 at baseline, achievement of a 4-point 
reduction in WI-NRS pruritus score at week 4 as compared to Baseline. 
• In subjects with WI-NRS pruritus score ≥ 4 at baseline, achievement of a 4-point 
reduction in WI-NRS pruritus score at week 2 as compared to Baseline. 
 


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• Change from Baseline in total Psoriasis Symptoms Diary (PSD) score at week 8. 
• Change from Baseline in total PSD score at week 4. 
• Time to achieving Psoriasis Area Severity Index-50 (PASI-50; subjects who achieve a 
50% reduction in PASI from Baseline). 
• For subjects with intertriginous area involvement, and with severity of the intertriginous 
lesions at least ‘mild’ (intertriginous IGA (I-IGA) ≥2) at Baseline, achievement of 
‘I-IGA’ score of ‘clear’ at week 8. 
• Psoriasis Area Severity Index-90 (PASI-90; subjects who achieve a 90% reduction in 
PASI from Baseline) at week 8. 
6 
INVESTIGATIONAL PLAN 
6.1 
Overall Study Design and Plan 
This is a parallel group, double blind, vehicle-controlled study in which ARQ-151 cream 0.3% or 
vehicle cream QD is applied for 8 weeks to subjects with between 2% to 20% (inclusive) BSA of 
chronic plaque psoriasis. 
 
Approximately 400 subjects will be enrolled at approximately 40 study sites in the United States 
and Canada.  Subjects will be children, adolescent and adult males or females with chronic 
plaque psoriasis.  Subjects must have an Investigator’s Global Assessment of disease severity 
(IGA) of at least Mild (‘2’) at Baseline.  Subjects must have at least 2% and no more than 20% 
Body Surface Area (BSA) of chronic plaque psoriasis.  All psoriasis 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 (IGA, 
BSA, PASI/mPASI).  For subjects with intertriginous area involvement, and with severity of the 
intertriginous area lesions at least ‘mild’ (IGA≥2) at Baseline, ‘I-IGA’ score will be recorded at 
subsequent visits.  The same IGA used for the primary endpoint (whole body) will also be used 
for ‘intertriginous area lesion IGA score’ (I-IGA), but only intertriginous areas will be evaluated 
for I-IGA, not the rest of the body.   
6.2 
Subject Participation 
Upon completion of this study, participants may have the opportunity, subject to regulatory 
approval, to participate in an open-label extension study (ARQ-151-306) of up to 6 months. 
The Week 8 visit of the present study would be the Day 1 visit for ARQ-151-306 and there 
would not be a Week 9 follow-up visit. 
 
For subjects who do not enter ARQ-151-306 there will be a minimum of 7 clinic visits, including 
Screening, Baseline, Week 2, Week 4, Week 6, and Week 8 of treatment, as well as a Week 9 
follow-up visit (1 week after last dose).  Since the interval between the Screening and Baseline 
visits may be up to 35 days, the anticipated maximum duration of subject participation is 
~14 weeks. 


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6.2.1 
Randomization 
Randomization will take place at Baseline after the patient has been found to be fully eligible for 
participation.  The subject is considered enrolled into the study once randomization occurs and 
the subject has been assigned to one of the treatment groups. 
 
Assignment of drug or vehicle will be made at a 2:1 ratio to ARQ-151 cream 0.3% or vehicle 
cream QD according to a computer-generated randomization list.  Randomization will be 
stratified by study site, baseline IGA (IGA=2 vs. IGA≥3), and intertriginous involvement at 
baseline (I-IGA>2, yes vs no). 
 
Kits containing tubes of investigational product will be assigned to each subject using an 
internet-based randomization system (IWRS). A subject may receive more than one kit for the 
treatment period. The kits and tubes are blinded and each kit is assigned a unique kit number.  
 
Subjects will apply ARQ-151 cream 0.3% QD or vehicle cream QD to psoriatic plaques of 
2% BSA up to a maximum application area of 20% BSA.   
6.2.2 
Numbering of Subjects 
All subjects who are randomized will be assigned a unique six-digit subject ID number by the 
IWRS system.  The first three digits correspond to the site number (assigned by the Sponsor), the 
next three digits correspond to the sequential order in which the subject is screened for the study 
(e.g., Subject ID 101001: Site 101, first subject screened 001 for that site). Site number 101 will 
be the first site in the study.   
 
The clinical site is responsible for maintaining a current log of subject ID number assignments 
and the kit 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.). 
6.3 
Selection of Study Population 
6.3.1 
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 and, if age appropriate (for 
children and adolescents) assent, as required by local laws. 
2. Males and females ages 2 years and older (inclusive). 
3. Clinical diagnosis of psoriasis vulgaris of at least 6 months duration (3 months for children) as 
determined by the Investigator.  Stable disease for the past 4 weeks. 
4. Psoriasis vulgaris on the face, extremities, trunk, and/or intertriginous areas involving 2% to 
20% BSA (excluding the scalp, palms and soles). 




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9. Subjects who cannot discontinue the use of strong P-450 cytochrome inducers 
(e.g., efavirenz, nevirapine, glucocorticoids, barbiturates including phenobarbital, phenytoin, 
and rifampin) for two weeks prior to the baseline visit and during the study period. 
10. Females who are pregnant, wishing to become pregnant during the study, or are breast-
feeding. 
11. Previous treatment with ARQ-151 or ARQ-154. 
12. Subjects who have received oral roflumilast (Daxas®, Daliresp®) or other PDE4 inhibitors 
(apremilast) within the past 4 weeks.  
13. Known or suspected:  
• severe renal insufficiency or moderate to severe liver impairment (Child-Pugh B or C) 
• known HIV infection 
• hypersensitivity to component(s) of the investigational products  
• history of severe depression, suicidal ideation, Baseline/Screening C-SSRS indicative of 
suicidal ideation, whether lifetime or recent/current 
 
11. Subjects with PHQ-8 (18 y/o and older) or modified PHQ-A (12 to 17 y/o) >10 at Screening 
or Baseline visits. Subjects (6 to 11 years old, inclusive) with a CDI-2 (parent report) raw 
score >20 at Screening/Baseline 
14. Subjects with a history of chronic alcohol or drug abuse within 6 months of initiation of 
investigational product. 
15. 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. 
16. 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. 
17. Subjects who are family members of the clinical study site, clinical study staff, or sponsor, or 
family members that live in the same household of enrolled subjects. 
18. Subjects with any serious medical condition or laboratory abnormality that would prevent 
study participation or place the subject at significant risk, as determined by the Investigator. 
19. 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. 
20. Subjects with active infection that required oral or intravenous administration of antibiotics, 
antifungal or antiviral agents within 7 days of Baseline (Visit 2). 


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6.3.3 
Removal of Subjects from Investigational Product 
A subject may discontinue investigational product for any of the following reasons: 
• Occurrence of any medical condition or circumstance that, in the opinion of the 
Investigator, exposes the subject to substantial risk and/or does not allow the subject to 
adhere to the requirements for investigational product as per the protocol. 
• 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 
investigational product.  The investigator must follow the subject until the AE resolves or 
satisfactorily stabilizes. 
• Pregnancy. 
• Subject's decision to withdraw from investigational product. 
• Weight loss of >5% if not dieting and after consultation with the Sponsor, at the 
Investigator’s discretion. 
• C-SSRS indicative of suicidal ideation or a PHQ-8 or modified PHQ-A score ≥15, 
after consultation with a mental health professional, the Sponsor, and at the Investigator’s 
discretion. 
• CDI-2 raw total score of 34, after consultation with a mental health professional, 
the Sponsor, and at the Investigator’s discretion. 
• Requirement for use of prohibited concomitant medication after consultation with the 
Sponsor and Medical Monitor. 
• Subject’s repeated failure to comply with protocol requirements or study related 
procedures. 
• The subject interrupts trial investigational product application for more than 50% of 
scheduled doses. 
6.3.4 
Removal of Subjects from Study 
1. Subject death. 
2. Subject's decision to withdraw from study. 
3. Subject is lost to follow-up. A subject will be considered lost to follow-up after three phone 
and three email attempts and documentation of a certified letter sent to the subject’s address. 
4. Termination of the study by the Sponsor, FDA, or other regulatory authorities. 
6.4 
Treatment Stopping Rules 
If a subject has non-cutaneous adverse events of concern, clinically significant laboratory values 
or any condition that the investigator determines could possibly be related to the investigational 


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product, the Investigator should immediately contact the Medical Monitor to discuss if the 
subject should be discontinued from the investigational product. 
 
Treatment for any individual subject will be discontinued if the subject:  
• Experiences a serious adverse event (SAE) or a clinically significant non-serious AE 
which in the opinion of the Principal Investigator or Medical Monitor warrants 
discontinuation from the investigational product for that subject’s well-being. 
• A severe (Grade 3) laboratory abnormality (confirmed by repeat sample and considered 
related to investigational product).  
o See Appendix 5 for details. 
Dosing of investigational product 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 or Modified PHQ-A score of ‘15’or above, CDI-2 raw total score of 34 
and/or is experiencing suicidal ideation or behavior, should be referred promptly to a mental 
health care professional and consideration be given to discontinuation from investigational 
product.  
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.  Given the excellent local toleration in the Phase 1/2a 
and Phase 2b studies, such reactions are possible, but unlikely. 
6.5 
Study Restrictions 
6.5.1 
Prohibitions and Concomitant Therapy 
Prohibited medications and products are detailed in Table 1. 


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Table 1. 
Excluded Medications and Treatments 
 
Excluded Medications and treatments 
Washout period prior to Day 1 
Systemic treatment with biological therapies with a possible effect on psoriasis vulgaris within the 
following time periods prior to randomization 
Etanercept 
4 weeks 
Adalimumab, infliximab 
8 weeks 
All other biologics 
12 weeks or 5 half-lives, 
whichever is longer 
Systemic treatment with all other therapies with a possible effect on psoriasis vulgaris 
Oral/systemic corticosteroids, retinoids, apremilast, 
methotrexate, cyclosporine and other systemic 
immunosuppressants 
4 weeks 
Topical anti-psoriasis medications (e.g., topical corticosteroids, 
vitamin D analogs, prescription shampoos) (except for 
emollients) 
2 weeks 
PUVA or UVB phototherapy 
4 weeks 
Investigational drugs 
12 weeks or 5 half-lives, 
whichever is longer (biologics); 
5 half-lives (orals);  
2 weeks (topical) 
Antihistamines – if prescribed for pruritus associated with 
psoriasis 
2 weeks 
Strong P-450 cytochrome inhibitors and strong P-450 
cytochrome inducers 
2 weeks 
Notes:   
(1) Eye and 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. 
(2) Non-medicated emollients, moisturizers and sunscreens will be allowed as used normally by the subjects. 
These can be applied to non-treated areas as needed and should not be used within 12 hours of a study 
visit. 
(3) Investigational product should be applied at least 20 minutes before going to bed. No emollients or 
moisturizers should be applied on treated areas.   
(4) A tar-containing or dandruff shampoo (zinc pyrithione or selenium sulfide) is allowed for treatment of the 
scalp. 
 
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 transcribed to 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).  


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6.6 
Treatment 
6.6.1 
Investigational Product Supplies, Packaging and Labeling 
ARQ-151 cream 0.3% or vehicle cream will be in 45 gram squeeze tubes.  The tubes will be 
packaged in kits, each containing 4 tubes of investigational product. The number of kits 
dispensed to a subject will be based on the BSA involvement of psoriasis.  It is anticipated that 
the maximum number of kits dispensed to a subject will be four. The kits and tubes will be 
labeled in a blinded manner.  The kit(s) dispensed to a subject/caregiver will be labeled with a 
unique number. 
 
The Sponsor will supply sufficient quantities of the investigational product (ARQ-151 cream 
0.3%, 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 investigational product supplied. 
At the conclusion of the study, any unused investigational product will be returned to the 
Sponsor or designee, or destroyed, as per Sponsor instructions. 
 
Refer to the current version of the IP Handling Manual for details on the accountability, storage, 
and management of the IP. 
6.6.2 
Blinding 
This is a double-blind study, therefore neither the subjects nor the Investigator, clinical 
personnel, or the Sponsor will be aware of which treatment an individual has received. 
6.6.3 
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-151or vehicle cream will cover approximately 1% BSA) is properly squeezed from the 
tube and applied to psoriatic lesion(s) as a thin film and rubbed in using the index and middle 
finger, rubbing in thoroughly but gently, until the ‘white’ has disappeared.  The subject/caregiver 
will then practice squeezing a similar amount onto their index and middle finger and apply a thin 
film to other psoriatic 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 (weeks 2, 4, and 6) as needed (i.e., if the 
returned tube(s) weighs substantially different than the expected weight). 
Subjects/caregivers will be instructed to apply investigational product once daily.  All subjects 
should apply investigational product 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 investigational 
product application and preferably not until the following morning.  Investigational product 
should be applied at least 20 minutes before going to bed. 


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Subjects/caregivers should continue to apply investigational product to all treatment areas 
identified by the investigator at Baseline, using a Body Diagram, even if that area has cleared 
during the treatment period.  New plaques that develop during the study should be treated as 
well. 
 
Each investigational product tube will be weighed prior to dispensing at the baseline visit and 
subsequent visits.  Investigational product tubes must be returned by subjects at each study visit, 
both empty and full, and will be weighed.  If the subject’s actual use is substantially different 
than the expected use for the subject’s BSA (see IP Manual), the subject will be retrained on the 
investigational product application technique. 
6.6.4 
Treatment Compliance  
Investigational product tubes will be weighed at each follow-up clinic visit. 
Subjects/caregivers will complete a daily diary recording the date and time of each dose applied, 
any missed doses, and a comment section should the subjects have a comment, e.g., record 
potential AEs. Site personnel will review the diaries and use the information to question the 
subject regarding compliance and AEs and then record appropriate information in source 
documents and complete Case Report Forms (CRFs).  If a subject misses a dose, they should be 
instructed to return to the protocol investigational product administration schedule (i.e. if subject 
forgets a dose they should wait until that evening and apply as usual). 
A subject will be considered compliant with the dosing regimen if the subject applies at least 
80% of the expected applications during the investigational product application period and does 
not miss more than 3 consecutive doses.  
Compliance will be assessed by review of the dosing diary.  Weight of investigational product 
applied will be measured for reporting purposes. The site will document the weight of the tube 
prior to dispensing to the subject and the weight of the tube when the subject returns for the next 
visit.  
If the diary shows less than 80% of expected use, the subject is using too little investigational 
product and retraining must be conducted and documented.  
Compliance will be documented in source and in eCRF. 
7 
STUDY PROCEDURES 
7.1 
Safety Assessments 
The Schedule of Visits and Assessments (Section 2) summarizes the clinical procedures to be 
performed at each visit. Individual clinical procedures are described in detail below. Additional 
evaluations/testing may be deemed necessary by the PI and/or the Sponsor for reasons related to 
subject safety. 


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This study assesses the safety and efficacy of ARQ-151 cream. Safety will be determined by 
evaluating physical examinations, local tolerability assessments, vital signs/weight, clinical 
laboratory parameters, either PHQ-8 (adults)/modified PHQ-A (adolescents) ) or Children’s 
Depresssion Inventory 2 (CDI-2), C-SSRS (12 years and older) and AEs as outlined in the 
Schedule of Visits and Assessments (Section 2). If deemed necessary, additional safety 
assessments will be performed at the discretion of the PI. 
7.1.1 
Screening 
Within 35 days prior to the first dosing, subjects will be provided details of study requirements 
and sign a current IRB/EC approved informed consent/assent (if appropriate).  Medical history 
and demographic data including sex, age, race, ethnicity, body weight (kg), and height (cm) will 
be recorded. Each subject will undergo psoriatic plaque assessments, a physical examination, 
vital sign measurements (blood pressure, heart rate, and temperature), PHQ-8 (adults)/modified 
PHQ-A (adolescents) or CDI-2 (children), C-SSRS (12 years and older), and laboratory tests: 
hematology, chemistry, urinalysis and serum (Screening) and urine (Baseline) pregnancy tests 
for female subjects of child bearing potential. 
Therapies the subject has used in the last twelve months prior to the Screening (Visit 1) for 
psoriasis will be recorded. 
All screened subjects will be entered into the electronic IWRS system at the time of informed 
consent.  
Subjects may be re-screened one time, the original assigned Subject ID screening number will be 
used for re-screening. 
7.1.2 
Physical Examination 
Physical examinations will be performed as follows: 
 
Screening, Baseline and Week 8. 
The physical exam will be limited to skin, lungs and heart only. 
7.1.3 
Vital Signs, Height and Weight 
Vital signs will be collected at timepoints noted below: 
 
Blood pressure, heart rate, and temperature will be measured at Screening, Baseline, Weeks 2, 4, 
6, 8, and 9 (if applicable).  
 
Height will be collected at Baseline only.  
 
Weight will be collected at Baseline, Weeks 2, 4, 6, 8 and 9 (if applicable).  Subject to void prior 
to weight being taken and remove any jackets, outerwear and shoes.  Remove any objects of 
significant weight (i.e. cell phones, wallet, key chains).  A 5% unintentional weight loss should 
be reported to the medical monitor. 


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7.1.4 
Laboratory Tests 
All tests listed below will be performed as follows and sent to ACM the central laboratory for the 
study for processing: 
Screening, Baseline, Weeks 4 and 8.  If the Baseline visit occurs within 14 days of Screening, 
the Screening lab results may be utilized. 
 
All tests listed in Table 2 below will be performed according to the Schedule of Visits and 
Assessments (Section 2) unless otherwise noted. The collection of specimens will be in a non-
fasting state. In addition, laboratory safety tests may be performed at various unscheduled time 
points, if deemed necessary by the Investigator.  
Table 2.  
Laboratory Tests 
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)*** 
* 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. 
** Baseline, Weeks 4, and 8, for FOCBP only  
*** At Screening, for FOCBP only 


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7.1.5 Children’s Depression Inventory 2 
The CDI-2 Assessment will be performed only for subjects 6-11 years old (inclusive) as follows: 
• Screening, Baseline, Week 4, and Week 8  
The CDI-2 quantifies depressive symptomatology using reports from children/adolescents, 
teachers, and parents or caregivers. It is recommended for use in initial evaluation and is 
appropriate when there is a need for an assessment and robust description of a child’s depressive 
symptoms. 
CDI-2 is available as a self report long and short form, and a parent report form:  
• CDI 2: Self-Report (Short) version (CDI 2:SR[S]). The CDI 2:SR(S) Form is an efficient 
screening measure that contains 12 items and takes about half the time of the full-length 
version to administer (5-10 minutes).The CDI 2:SR(S) has excellent psychometric 
properties and yields a Total Score that is generally very comparable to the one produced 
by the full-length version.  
• CDI: Parent (CDI:P) Forms consist of items that correspond to the self-report version and 
are suitably rephrased. Item selection for the parent form was guided to maximize 
validity, and thus focused on observable manifestations of depression. 
This study will use the CDI Parent Report Form. An example of the Parent report form is 
presented in Appendix 6. 
7.1.6 
Patient Health Questionnaire depression scale (PHQ-8)  
The 8 item PHQ-8 Assessment will be performed in adult subjects as follows: 
 
Screening, Baseline, Weeks 4 and Week 8 
 
Only adult subjects will complete PHQ-8 questionnaire. 
 
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 investigational product, consideration be given to 
discontinuation from investigational product.   
 


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The PHQ-8 
 
 
PHQ-8 score is the sum of the responses for the 8 questions. 
 
Five severity categories of depression are defined as follows:  
• None – Minimal depression (0 to 4)  
• Mild depression (5 to 9)  
• Moderate depression (10 to 14)  
• Moderately severe depression (15 to 19)  
• Severe depression (20 to 24) 
7.1.7 
Patient Health Questionnaire depression scale (Modified PHQ-A)  
The 8 item Modified PHQ-A Assessment will be performed in adolescent subjects as follows: 
 
Screening, Baseline, Weeks 4 and Week 8 
 


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Only adolescent subjects will complete the Modified PHQ-A questionnaire. 
 
A subject with a Modified PHQ-A score of ‘15’ or above should be referred promptly to a 
mental health care professional and, if currently applying investigational product, consideration 
be given to discontinuation from investigational product.  
 
 
Modified PHQ-A score is the sum of the responses for the 8 questions. 
 
Five severity categories of depression are defined as follows:  
• None – Minimal depression (0 to 4)  
• Mild depression (5 to 9)  
• Moderate depression (10 to 14)  
• Moderately severe depression (15 to 19)  
• Severe depression (20 to 24) 
7.1.8 
Columbia-Suicide Severity Rating Scale (C-SSRS)  
C-SSRS Assessments will be performed for subjects 12 and older as follows: 
 


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Screening, Baseline, Week 4 and Week 8. 
 
The administration schedule of the C-SSRS will be: 
 
• The Baseline-Screening version (Appendix 1) 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 2) 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 investigational product. This should result in prompt referral 
to a mental health professional and/or possibly the emergency room. The Medical 
Monitor should be contacted.  
 
The trained administrator will conduct the C-SSRS.  The C-SSRS administrator 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. 
7.1.9 
Local Tolerability Assessments  
The Investigator Local Tolerability Assessment will be performed as follows: 
Baseline, Weeks 4, and 8  
Application site reactions will be graded at the timepoints outlined in the Schedule of Visits and 
Assessments (Section 2).  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 psoriasis. 
 
The investigator assessments will be conducted by the investigator prior to investigational 
product application in the clinic. 
 
Dermal Response 


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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, Weeks 4, and 8 
This assessment will be administered by the site 10 to 15 minutes after investigational product 
application in the clinic at Baseline and at Weeks 4, and 8. Parents may report for children. 
Grade 
Sensation Following Investigational Product Application 
0 (none) 
No sensation 
1 (mild)  
Slight warm, tingling sensation; not really bothersome 
2 (moderate) 
Definite warm, tingling sensation that is somewhat 
bothersome 
3 (severe) 
Hot, tingling/stinging sensation that has caused definite 
discomfort  
7.1.10 
Adverse Events  
 
Adverse events (AEs) will be collected beginning at informed consent and assessed throughout 
the study including at the following visits: 
Screening, Baseline, Weeks 2, 4, 6, 8, and 9 (if applicable) 
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 7.4. 


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7.2 
Efficacy Evaluations  
7.2.1 
Investigator Global Assessment (IGA) 
Investigator Global Assessments (‘whole body’ and ‘intertriginous area’) will be performed at 
the following study visits.  The IGA should be completed prior to other physician assessments. 
 
Screening, Baseline, Weeks 2, 4, 6, 8, and 9 (if applicable) 
 
The IGA is a static evaluation of qualitative overall psoriasis 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.  
 
Note: Palms and soles will be treated in this study with investigational product, but will not be 
counted towards IGA, PASI/mPASI, or BSA assessments. 
 
Every effort should be made for the same Evaluator to complete the IGA for the subject at 
every study visit. 
 
Investigator Global Assessment of Disease (IGA) 
 
Scale 
Grade 
Description 
0 
Clear  
Plaque thickening = no elevation or thickening over normal skin 
Scaling = no evidence of scaling 
Erythema = none (no residual red coloration but post-inflammatory 
hyperpigmentation may be present) 
1 
Almost 
Clear 
Plaque thickening = none or possible thickening but difficult to ascertain 
if there is a slight elevation above normal skin level 
Scaling = none or residual surface drying and scaling 
Erythema = light pink coloration 
2 
Mild  
Plaque thickening = slight but definite elevation 
Scaling = fine scales partially or mostly covering the lesions 
Erythema = light red coloration 
3 
Moderate 
Plaque thickening = moderate elevation with rounded or sloped edges 
Scaling = most lesions at least partially covered 
Erythema = definite red coloration 
4 
Severe 
Plaque thickening = marked or very marked elevation typically with hard 
or sharp edges 
Scaling = non-tenacious or thick tenacious scale, covering most or all of 
lesions 
Erythema = very bright red coloration; extreme red coloration; deep red 
coloration  
 
The standard ‘whole body’ IGA shown above will be recorded for every subject in the 
study. 
For subjects with intertriginous area involvement of at least ‘mild’ severity by IGA (I-IGA≥2) at 
Baseline (using the IGA scale shown above but evaluating intertriginous areas ONLY and NOT 


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whole body involvement), an IGA for the intertriginous region alone (I-IGA) will be recorded at 
weeks 2, 4, 6, 8, and 9 (if applicable). 
This ‘intertriginous area IGA’ (I-IGA) should be done AFTER the ‘standard whole body 
IGA’ (primary endpoint) in subjects who qualify.  
7.2.2 
Psoriasis Area and Severity Index (PASI) and Modified Psoriasis Area and 
Severity Index (mPASI) 
Assessments will be performed as single assessments at each timepoint, from which both PASIs 
and mPASIs will be calculated. 
PASI/mPASI assessments will be performed as follows: 
Screening, Baseline, Weeks 2, 4, 6, 8, 9 (if applicable) 
Every effort should be made for the same Evaluator to complete the PASI/mPASI for the 
subject at every study visit. 
 
Psoriasis Area and Severity Index (PASI)/Modified Psoriasis Area and Severity Index (mPASI) 
is used for the measurement of severity of psoriasis.  
 
PASI/mPASI 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 PASI/mPASI. 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 
 
mPASI: for subjects with < 10% of an involved anatomic area, the mPASI will be calculated 
using the actual percentage of the anatomical area involved (e.g. 0.1 for 1%, 0.2 for 2%, 0.3 for 
3%, … 0.9 for 9%), corresponding to the actual percentage of that particular anatomical area of 
involvement. 
 
Note: Palms and soles may be treated with investigational product in this study, but will not be 
counted towards IGA, PASI/mPASI, or BSA assessments. 
 


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Within each area, the severity is estimated by three clinical signs: erythema (‘E’; redness), 
induration (‘T’; thickness) and desquamation (‘S’; scaling). Severity parameters are measured on 
a scale of 0 to 4, from none to maximum severity possible. 
 
To calculate the PASI/mPASI, the sum of the severity rating for the three main signs are 
multiplied with the numerical value of the area affected and with the various percentages of the 
four body areas. These values are then added to complete the formula as follows: 
 
PASI = 0.1 (Eh + Th + Sh) Ah + 0.2 (Ea + Ta + Sa) Aa + 0.3 (Et + Tt + St) At + 
0.4 (El + Tl + Sl) Al 
7.2.3 
Body Surface Area (BSA) 
BSA Assessments will be performed as follows: 
Screening, Baseline, Weeks 2, 4, 6, 8, and 9 (if applicable)  
The BSA affected by psoriasis 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: Palms and soles will be treated with investigational product, but will not be counted 
towards IGA, PASI/mPASI, or BSA assessments. 
7.2.4 
Worst Itch Numerical Rating Scale (WI-NRS)  
WI-NRS Assessments will be performed for subjects 12 years and older as follows: 
Screening, Baseline, Weeks 2, 4, 6, 8 and 9 (if applicable) 
 
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. 
 
 
 
7.2.5 
Psoriasis Symptom Diary (PSD)  
The PSD will be completed, by adult subjects (>18 years old at Screening), as follows: 
 
Screening, Baseline, Weeks 2, 4, 6 and 8 


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Subjects will complete the PSD. See Appendix 3 for the PSD. 
7.2.6 
Dermatology Life Quality Index (DLQI) and Children’s Dermatology Life Quality 
Index (CDLQI) 
The DLQI (age >17 years) and CDLQI (age 2-16 years) will be completed as follows: 
 
Screening, Baseline, Weeks 2, 4, and 8 
 
Subjects/caregivers will complete the CDLQI/DLQI. See Appendix 4 for the DLQI and CDLQI. 
7.2.7 
Dermal Imaging 
Medical photography will be performed at all sites using Canfield photography equipment at 
Baseline, Weeks 2, 4, 6, and 8. 
 
Photography should be focused on single lesions or specific body sections (e.g. arm). Subjects 
with intertriginous involvement will have also photos of the intertriginous area.  
 
Body or half body photos should only be taken if necessary. All efforts will be made to de-
identify the subjects. Subjects who are unwilling to participate in the medical photography will 
be allowed to opt out of this procedure and documented on the informed consent.  
 
Refer to the current Photography Manual for instructions regarding photography. 
7.3 
Pharmacokinetics Assessment 
PK draws will be performed as follows for all subjects at all sites: 
 
Baseline, Weeks 4 and 8 
Plasma PK assessments will be performed on all subjects.  
PK draws will be collected while the subject is having serum chemistries drawn. The draws will 
be pre-dose investigational product application in the clinic. Ensure investigational product is not 
applied in the area where PK will be drawn. 
7.4 
Adverse Events 
7.4.1 
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.  


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A treatment emergent adverse event (TEAE) is defined as an AE that emerges during treatment, 
having been absent pretreatment, or worsens relative to the pretreatment state.  
 
The definition of AEs includes worsening of a pre-existing medical condition.  Worsening 
indicates that the pre-existing medical condition has increased in severity, frequency, and/or 
duration or has an association with a worse outcome.  When recording such events, provide 
descriptions that the pre-existing condition has changed (e.g., worsening hypertension for a 
subject with pre-existing hypertension).  A pre-existing condition that has not worsened during 
the study or involves an intervention, such as elective cosmetic surgery or a medical procedure 
while on study, is not considered an AE. 
In general, abnormal laboratory findings without clinical significance (based on the 
investigator’s judgment) are not to be recorded as AEs.  However, abnormal laboratory findings 
that result in new or worsening clinical sequelae, or that require therapy or adjustment in current 
therapy, are considered AEs.  Where applicable, clinical sequelae (not the laboratory 
abnormality) are to be recorded as the AE. 
Application site reactions will be considered adverse events if they require intervention, 
suspension or discontinuation of study investigational product. 
7.4.2 
Serious Adverse Event  
The definitions and reporting requirements of Health Canada/the Food and Drug Administration 
(FDA)/ICH Guidelines for Clinical Safety Data Management, Definitions and Standards for 
Expedited Reporting, Topic E2A will be adhered to.  If any AEs are serious, as defined by ICH 
Guidelines for Clinical Safety, required procedures will be followed.   
All SAEs will be reported to the Sponsor (or delegate) via fax or e-mail within 24 hours of 
becoming aware of the event, whether or not the serious events are deemed IP-related.  All 
serious event reporting will adhere to ICH E6: Guideline for Good Clinical Practice and ICH 
E2A: Clinical Safety Data Management: Definitions and Standards for Expedited Reporting.:  
The ERB/IRB will be notified of the Alert Reports as per HC, FDA, ICH and the IRB/ERB’s 
policies and procedures. 
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/CTA. 
If a SAE occurs to a subject on this study, contact the Medical Monitor within one business day 
of knowledge of event. 
7.4.3 
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.  
7.4.4 
Safety Review 
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 


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subject diaries and, if it appears that a potential AE was recorded, study staff will query the 
subject and determine if an AE occurred. 
 
AEs (whether serious or non-serious) and clinically significant abnormal laboratory test value(s) 
will be evaluated by the PI and treated and/or followed 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). 
7.4.5 
Adverse Event Reporting 
 
AEs will be collected following informed consent of the subject through subject study 
completion.  
The PI will review each event and assess its relationship to investigational product 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 investigational product dosing, duration, and 
outcome (resolved, improved, unchanged, worse, fatal, or unknown/lost to follow-up) of each 
event will be noted. 
 
The relationship of each AE to the investigational product will be assessed using the following 
definitions: 
Unrelated 
• The AE must clearly be caused by the subject’s clinical state, or the study 
procedure/conditions. 
• Definitely not related to investigational product. 
• Temporal sequence of an AE onset relative to administration of 
investigational product 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 investigational product. 
• Time sequence is reasonable. 
• Could have been due to another equally, likely cause. 
Probably 
• Is a known effect of the investigational product. 
• Time sequence from taking investigational product is reasonable. 
• Ceases on stopping the investigational product. 


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• Cannot be reasonably explained by the known characteristics of the 
subject’s clinical state. 
Likely 
• Is a known effect of the investigational product (e.g., listed in Physicians' 
Desk Reference, Compendium of Pharmaceuticals and Specialties, IB). 
• Time sequence from taking investigational product is reasonable. 
• Event stops upon stopping investigational product, event returns upon 
restarting investigational product. 
 
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 
(e.g., 21.0 or higher). 
7.5 
Reporting Pregnancy 
During the study, all subjects should be instructed to contact the investigator immediately if they 
suspect they might be pregnant (e.g., missed or late menstrual period).  If pregnancy is 
confirmed, Investigational Product must be discontinued immediately. The subject should be 
referred to an obstetrician/gynecologist experienced in reproductive toxicity for further 
evaluation and counseling and the subject will be followed until the conclusion of the pregnancy.   
The investigator is responsible for reporting all available pregnancy information on the 
pregnancy report to the Medical Monitor within 24 hours of becoming aware of the event, 
although pregnancy itself is not considered an AE.  Follow-up information detailing the outcome 
of the pregnancy and the health of the newborn should be reported as it becomes available.  In 
addition, any pregnancy resulting in a congenital abnormality or birth defect of the newborn, or 
neonatal death occurring within 30 days of the birth must be reported as a SAE, regardless of 
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Partner pregnancies of a male subject do not need to be reported. 
 
7.5.1 
Emergency Unblinding 
If the situation requires emergency unblinding this will be done by investigator using the study  
IWRS system after discussion with Medial Monitor and the Sponsor’s CMO.  
8 
DATA ANALYSIS 
Data will be handled and processed according to the Contract Research Organization’s Standard 
Operating Procedures, which are written based on the principles of GCP. 
8.1 
Statistical Methods 
The methodology presented below is a summary of the more detailed analysis plan that will be 
presented in the Statistical Analysis Plan (SAP).  The SAP will be finalized before the database 
is locked and unblinded.  Any changes to the methods described in the final SAP will be 
described and justified in the clinical study report. 
All statistical processing will be performed using SAS® (Version 9.4 or later) unless otherwise 
stated.  
Descriptive statistics will be used to provide an overview of the efficacy, safety and 
pharmacokinetic results.  For categorical parameters, the number and percentage of subjects in 
each category will be presented.  The denominator for percentage will be based on the number of 
subjects appropriate for the purpose of analysis.  For continuous parameters, descriptive statistics 
will include n (number of subjects), mean, standard deviation (SD), median, minimum, 
and maximum. 
Missing IGA scores will be imputed using multiple imputation. 
8.1.1 
Determination of Sample Size 
A sample size of approximately 400 subjects are planned for the study.  
Approximately 267 subjects will receive ARQ-151 cream 0.3% QD; approximately 133 subjects 
will receive vehicle cream QD.  The randomization scheme will be 2:1 (ARQ-151 cream 0.3% 
QD: matching vehicle QD). 
This sample size provides >99% power to detect a 22.4% difference between treatment groups 
on IGA success at α=0.05 using a 2-sided Chi-squared test.  The results from a recent phase 2b 
study (ARQ-151-201) of ARQ-151 compared to vehicle treatment were used to estimate the 
treatment difference.  Specifically, in this trial 32.2% of subjects reported IGA success in the 
ARQ-151 0.3% group and 9.8% of subjects reported IGA success in the vehicle group. 
 


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The number of subjects to be enrolled will also provide sufficient power for the first 5 secondary 
endpoints.  Additionally, the larger study size is included in order to provide additional/sufficient 
numbers of subjects on ARQ-151 treatment for a safety database. 
8.1.2 
Subjects to Analyze 
Safety population will include all subjects who are enrolled and received at least one confirmed 
dose of investigational product or vehicle cream.  This population will be used for all safety 
analyses. 
The Intention-to-Treat (ITT) population will include all randomized subjects.  This population 
will be the primary analysis population for the analysis of efficacy endpoints. 
The I-IGA population is a subset of the ITT population and includes subjects with intertriginous 
area involvement, and with severity of the intertriginous lesions at least ‘mild’ (intertriginous 
IGA (I-IGA) ≥2) at Baseline.  This population will be used for the analysis of I-IGA endpoints. 
The Pruritis population is a subject of the ITT population and includes subjects with WI-NRS 
pruritus score ≥ 4 at Baseline.  This population will be used for the analysis of achievement of a 
4-point reduction in WI-NRS pruritus score as compared to Baseline. 
The 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.  
This population will be used for analyses of PK parameters. 
8.1.3 
Interim Analysis 
No interim efficacy analyses are planned. 
8.1.4 
Background and Demographic Characteristics 
Baseline disease characteristics and vital sign information will be summarized descriptively for 
all randomized subjects.  
8.1.5 
Study Disposition 
Number of subjects randomized, receiving investigational product, completing treatment, 
completing study, and withdrawing prematurely (with reason for withdrawal) will be 
summarized by treatment group. 
8.1.6 
Protocol Deviations and Eligibility Deviations 
The number of subjects with important protocol deviations and/or eligibility deviations will be 
summarized by treatment group. 


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8.1.7 
Investigational Product Application Compliance 
The number of investigational product applications by each subject based on diary data will be 
summarized using descriptive statistics.  
The amount of investigational product used by each subject based on tube weight will be 
summarized by treatment using descriptive statistics, and categorically. 
Investigational product application compliance will be calculated based on number of 
applications divided by the expected number (amount) of  investigational product applications 
for each subject.  Compliance will be summarized descriptively by treatment group.  
8.2 
Efficacy Evaluation 
8.2.1 
Primary Efficacy Endpoint 
The primary efficacy variable in this study is success in Investigator Global Assessment (IGA) of 
disease severity, defined as an IGA of ‘Clear’ or ‘Almost Clear’ plus a 2-grade improvement 
from Baseline at Week 8. 
 
The primary endpoint will be analyzed using a Cochran-Mantel-Haenszel test stratified by site, 
baseline IGA, and baseline intertriginous involvement.  Statistical significance will be concluded 
at the 5% significance level (2-sided). 
 
Missing IGA scores will be imputed using multiple imputation. 
8.2.2 
Secondary Endpoints 
The secondary efficacy endpoints will include: 
• Achievement of Psoriasis Area Severity Index-75 (PASI-75; subjects who achieve a 
75% reduction in PASI from Baseline) at week 8. 
• For subjects with intertriginous area involvement, and with severity of the intertriginous 
lesions at least ‘mild’ (intertriginous IGA (I-IGA) ≥2) at Baseline, achievement of 
‘I-IGA’ score of ‘clear’ or ‘almost clear’ PLUS a 2-grade improvement from Baseline at 
week 8. 
• In subjects with WI-NRS pruritus score ≥ 4 at baseline, achievement of a 4-point 
reduction in WI-NRS pruritus score at week 8. 
• In subjects with WI-NRS pruritus score ≥ 4 at baseline, achievement of a 4-point 
reduction in WI-NRS pruritus score at week 4. 
• In subjects with WI-NRS pruritus score ≥ 4 at baseline, achievement of a 4-point 
reduction in WI-NRS pruritus score at week 2. 
• Change from Baseline in total Psoriasis Symptoms Diary (PSD) score at week 8. 
• Change from Baseline in total PSD score at week 4. 
• Time to achieving Psoriasis Area Severity Index-50 (PASI-50). 


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• For subjects with intertriginous area involvement, and with severity of the intertriginous 
lesions at least ‘mild’ (I-IGA ≥2) at Baseline, achievement of ‘I-IGA’ score of ‘clear’ at 
week 8. 
• Achievement of PASI-90 (subjects who achieve a 90% reduction in PASI from Baseline) 
at week 8. 
Secondary endpoints will only be tested statistically if the primary endpoint is considered 
statistically significant.  To control for multiple comparisons among the secondary endpoints, the 
following multiplicity procedure will be used: 
Upon successful testing of the primary endpoint the alpha will be partitioned to test secondary 
endpoints families 1 and 2 (partition 1) and to test additional WI-NRS timepoints (partition 2) 
Partition 1 of alpha = 0.03 will be allocated to test secondary endpoint family 1 and secondary 
endpoint family 2.  The endpoints in family 1 will be tested independently using a Bonferroni 
split of the alpha; the next 5 secondary endpoints (secondary endpoint family 2) will be tested 
using the alpha available after testing endpoint family 1.  The Holm procedure will be used to 
control for multiple comparisons in secondary endpoint family 2. 
Partition 2 of alpha = 0.02 will be allocated to sequentially test WI-NRS success at week 4 and 
WI-NRS success at week 2.   
 
 
 
 
 
 
 
 
 
 
 
 
 




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8.3.1 
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 the date of study treatment.  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. 
Serious adverse events (SAEs) will be listed by subject.  SAEs will be summarized by treatment 
group, severity, and relationship to study treatment. 
For AEs, each subject will be counted only once within a system organ class or a preferred term 
using the event with the greatest relationship and greatest severity. 
All information pertaining to AEs noted during the study will be listed by subject, detailing the 
verbatim description given by the Investigator, preferred term, system organ class, start date, 
stop date, severity, action taken regarding investigational product, corrective treatment, outcome, 
and investigational product relatedness.  The event onset will also be shown relative (in number 
of days) to date of first application.  In addition, a listing of subjects who prematurely 
discontinue from the investigational product due to adverse events will also be provided. 
8.3.2 
Local Tolerance Assessments 
 
For the Investigator’s and Subject’s assessment, the numeric application site reaction scores will 
be summarized individually by using number and percentage of subjects by visit, as well as 
mean/median scores.  
8.3.3 
Medical History and Physical Examinations 
Medical history for all subjects will be presented in a by-subject listing. 
Clinically significant changes observed during physical examination will be captured as adverse 
events and included in AE tabulations. 


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8.3.4 
PHQ-8 and Modified PHQ-A 
Data for PHQ-8 and Modified PHQ-A will be analyzed by a shift in state of severity using the 
following scoring system: 
• None – Minimal depression (0 to 4) 
• Mild depression (5 to 9) 
• Moderate depression (10 to 14) 
• Moderately severe depression (15 to 19) 
• Severe depression (20 to 24) 
8.3.5 
C-SSRS 
The C-SSRS will be analyzed per the Columbia–Suicide Severity Rating Scale Scoring and 
Data Analysis Guide. 
8.3.6 
Clinical Laboratory Results and Vital Signs/Weight Measurements 
All clinical laboratory results and vital signs measurements and their change from baseline 
(pre-dose), will be summarized by treatment group along with time point of collection. 
A shift table summarizing out-of-normal range shifts by treatment group will be provided for 
clinical laboratory results.  
Shift tables by treatment group will summarize the number of subjects who gain or lose 
>5% body weight over the course of the study, as well as subjects who gain or lose >10% body 
weight over the course of the study. 
8.3.7 
Prior and Concomitant Medications 
Prior and concomitant medication information for all randomized subjects will be presented in a 
by-subject listing.  Summary tables by treatment group will be presented by World Health 
Organization-Anatomical Therapeutic Chemical Classification System (WHO-ATC) therapeutic 
category and product. 
8.4 
Patient Reported Outcomes Analyses 
8.4.1 
WI-NRS  
Change from baseline in itch severity will be analyzed by treatment group and over time using 
the WI-NRS scale.  For subjects with WI-NRS pruritus score ≥ 4 at baseline, the proportion of 
subjects with a 4-point reduction in WI-NRS pruritus score at weeks 2, 4, and 8 as compared to 
Baseline will be calculated by treatment group and analyzed using a Cochran-Mantel-Haenszel 
test stratified by site, baseline IGA, and intertriginous involvement at baseline (see secondary 
endpoints). 


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8.4.2 
Dermatology Life Quality Index (DLQI) and Children’s Dermatology Life Quality 
Index (CDLQI) 
Both the DLQI and CDLQI will be analyzed by evaluation of the reduction in total score at 
weeks 2, 4, and 8 as compared to Baseline. 
8.4.3 
Psoriasis Symptom Diary (PSD) 
The PSD will be analyzed as the change from baseline in responses to the questions of PSD 
weeks 2, 4, and 8 as compared to Baseline.  
8.5 
Pharmacokinetic Analysis 
Plasma drug concentrations at pre-dose will be summarized using descriptive statistics at each 
visit. 
 
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 2). 
A manual for blood sampling, collection, processing, and sample shipment will be provided in a 
separate document. 
9 
STUDY ADMINISTRATION 
9.1 
Ethics 
9.1.1 
Ethics Review Board  
Before enrollment of patients into the study, the current protocol and ICF will be reviewed and 
approved by an appropriate IRB or IEC, as required by FDA (21 CFR § 56), Health Canada, 
and ICH GCP regulations.  A letter documenting the IRB or IEC approval must be received by 
the Sponsor (or delegate) before the initiation of the study at a clinical site. Amendments to the 
protocol will be subject to the same requirements as the original protocol. 
The Investigator, Sponsor, or designee will submit a progress report at least once yearly to the 
IRB or IEC. However, the frequency of these reports will depend on IRB or IEC requirements. 
As soon as possible after completion or termination of the study, the Investigator will submit a 
final report to the IRB or IEC per the IRB or IEC requirements, and in compliance with FDA and 
Health Canada regulations and ICH GCP guidelines. 
The Investigator, the Sponsor, or designee shall promptly notify the IRB or IEC of any SAEs, 
SUSARs, or any other information that may affect the safe use of the investigational product 
during the study, per the IRB or IEC local requirements, and in compliance with FDA and 
Health Canada regulations and ICH GCP guidelines. 


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9.1.2 
Ethical Conduct of the Study 
This research will be carried out in accordance with the protocol, the principles of the 
Tri Council Policy Statement (TCPS), the ethical principles set forth in the Declaration of 
Helsinki, and the ICH harmonized tripartite guideline regarding GCP (E6 Consolidated 
Guidance, April 1996). 
9.1.3 
Subject Information and Consent 
The purpose of the study, the procedures to be carried out and the potential hazards will be 
described to the subjects in non-technical terms. Subjects will be required to read, sign and date a 
current version of the IRB/EC approved ICF/assent (if appropriate) 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. 
Subjects will be given a signed copy of their ICF. 
9.2 
Study Completion and Termination 
9.2.1 
Study Completion 
The study is considered completed with the last visit of the last subject participating in the study. 
The final data from the investigational site will be sent to the Sponsor (or designee) after 
completion of the final subject visit at that site, in the time frame specified in the Clinical Trial 
Agreement. 
9.2.2 
Study Termination 
The Sponsor reserves the right to close the investigational site or terminate the study at any time 
for any reason at the sole discretion of the Sponsor. Investigational sites will be closed upon 
study completion. An investigational site is considered closed when all required documents and 
study supplies have been collected and a site closure visit has been performed. The investigator 
may initiate site closure at any time, provided there is reasonable cause and sufficient notice is 
given in advance of the intended termination. 
  
Reasons for the early closure of an investigational site by the Sponsor or investigator may 
include but are not limited to: 
• Failure of the investigator to comply with the protocol, the Sponsor’s procedures, or GCP 
guidelines. 
• Inadequate recruitment of subjects by the investigator. 
• Discontinuation of further IP development 


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9.3 
Study Monitoring 
Prior to the initiation of the clinical investigation, Sponsor representatives or designees will visit 
the clinical site where the investigation is to be conducted.  Sponsor representatives shall ensure 
that the Investigator understands the investigational status of the investigational product, 
all requirements of the investigation to be undertaken, and all of his/her responsibilities as an 
Investigator.  Sponsor representatives will also visit the clinical site at appropriate intervals as 
required to ensure compliance with the protocol and to verify the accuracy and completeness of 
data reported on the CRFs.  The Study Director or designees shall be available for consultation 
with the Investigator and serve as liaisons between the clinical site and the Sponsor. 
The Sponsor or authorized designees may inspect all documents and records required to be 
maintained by the Investigator, including but not limited to medical records (office, clinic, 
or hospital) and investigational product dispensation logs for the subjects in this clinical 
investigation.  The Investigator must permit access to such records.  The Investigator must 
obtain, as part of informed consent, permission for an authorized representative of the Sponsor, 
or regulatory authorities, to review, in confidence, any records identifying subjects. 
9.4 
Data Quality Assurance 
In order to ensure the collection of accurate, consistent, complete, and reliable data during this 
clinical investigation, Sponsor representatives or designees may conduct audits of participating 
sites at appropriate intervals throughout the study.  The results of these periodic site audits may 
be subject to review by independent auditors at completion of the clinical investigation.  
The Clinical Study Report will be audited by the Clinical Research Organization’s Quality 
Assurance (QA) department and the QA audit certificate will be included in the study report. 
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 to check for 
missing data, data inconsistencies, data ranges etc. Corrections are made prior to database lock. 
9.4.1 
Verification of Blinding 
The treatment assignments for all enrolled subjects will be unblinded only after the conclusion of 
the study. Specifically, the blind will be broken only after all data are verified, entered into the 
database, and validated; subject evaluability assessments are performed and entered into the 
database; and the database is locked. 
9.5 
Data Handling and Record Keeping 
During the clinical study, the Investigator will maintain adequate records, including medical 
records, records detailing the progress of the study for each subject, laboratory reports, signed 
informed consent forms, investigational product disposition records, correspondence with the 
ERB/IRB and Study Monitor/Sponsor, AE reports, and information regarding subject 
discontinuation and completion of the clinical investigation. 
 
All required study data will be recorded on eCRFs.  Any change of data will be recorded on the 
audit trail and a reason for the change will be entered. 


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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. 
9.6 
Protocol Amendments and Deviations  
No change or amendment to this protocol may be made by the investigator or Sponsor after the 
protocol has been agreed to and signed by all parties unless such change(s) or amendment(s) has 
(have) been agreed upon by the investigator and Sponsor.  Any change agreed upon will be 
recorded in writing, and the written amendment will be signed by the investigator and Sponsor.  
Institutional review board approval is required prior to the implementation of an amendment, 
unless overriding safety reasons warrant immediate action, in which case the IRB(s) will be 
promptly notified. 
 
No deviation from the protocol will be made except to protect the life or physical well-being of a 
subject in an emergency.  Except in such emergencies, prior approval of the Sponsor, and the 
IRB, is required before deviations from the planned protocol.  All protocol deviations that occur 
during the study will be documented and reported to Sponsor and to the IRB(s), if applicable, 
according to regulations.  Further details about the documentation, evaluation, and follow-up of 
protocol deviations are detailed in this study’s clinical monitoring plan.  
 
No waivers to inclusion/exclusion criteria will be granted; subjects need to meet all criteria, 
exactly as specified, to be enrolled.  Additionally, prospective deviations from the protocol or 
investigational plan are not permitted except to protect the life or physical well-being of a subject 
in an emergency.  Deviations that occur unintentionally or are the result of action by the subject 
must be documented and reported to the IRB(s), if applicable, according to regulations.  
Further details about the documentation, evaluation, and follow-up of protocol deviations are 
detailed in this study’s clinical monitoring plan. 
9.7 
Confidentiality and Privacy 
The investigator must assure that subjects’ anonymity will be strictly maintained and that their 
identities are protected from unauthorized parties. Only an identification code and any other 
unique identifier(s) as allowed by local law (such as date of birth) will be recorded on any form 
or biological sample submitted to the Sponsor. 
 
The investigator agrees that all information received from Arcutis Inc., including but not limited 
to the investigator brochure, this protocol, CRF/eCRF, the IP, and any other study information, 
remain the sole and exclusive property of Arcutis Inc. during the conduct of the study and 
thereafter. This information is not to be disclosed to any third party (except employees or agents 
directly involved in the conduct of the study or as required by law) without prior written consent 
from Arcutis Inc. The investigator further agrees to take all reasonable precautions to prevent the 
disclosure by any employee or agent of the study site to any third party or otherwise into the 
public domain. 


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9.8 
Conflict of Interest 
All study investigators will provide documentation of their financial interest or arrangements 
with Arcutis Inc., or proprietary interests in the IP under study. This documentation must be 
provided prior to the investigator’s participation in the study. All investigators with reported 
conflict of interest will be required to have such conflicts managed in a way that is appropriate to 
their participation in the design and conduct of this study. 
9.9 
Report Format 
According to the ICH Harmonized Tripartite Guideline (Organization of the Common Technical 
Document for the Registration of Pharmaceuticals for Human Use M4 and the ICH M2 Expert 
Working Group), the final report will be written according to the ICH E3 Guideline (Structure 
and Content of Clinical Study Reports).  
9.10 Publication Policy 
The Sponsor is supportive of publishing clinical trial findings.  The process of coordinating 
publication efforts is detailed in the Clinical Trial Agreement. 


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10 REFERENCES 
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. 
Brion DE, Raynaud F, Plet A, Laurent P, Leduc B, and Anderson W.  Deficiency of cyclic 
AMP-dependent protein kinases in human psoriasis.  Proc. Natl. Acad. Sci.  1986; 83:5272-5276. 
DALIRESP (roflumilast) tablets [package insert]. AstraZeneca Pharmaceuticals LP, Wilmington, 
DE USA; 2018. 
DAXAS (roflumilast) film-coated tablets [product monograph]. AstraZeneca Canada, Inc., 
Mississauga, Ontario Canada; 2017. 
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 3.0, 08 October 2019. 
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. 
Naegeli, AN, Flood, E, Tucker, J, Devlen, J, Edson-Heredia, E. The Worst Itch Numeric Rating 
Scale for patients with moderate to severe plaque psoriasis or psoriatic arthritis. Int J Dermatol. 
2015; 54(6):715–22. 
Wedzicha, JA, Calverley, PMA, Klaus, FR.  Roflumilast: a review of its use in the treatment of 
COPD.  Int. J. Chron. Obstruct. Pulmon. Dis. 2016; 11:81-90. 


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11 APPENDICES 
Appendix 1. 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  
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. 
 
        C-SSRS—Baseline/Screening (Version 1/14/09)    
 
 
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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  
 
        C-SSRS—Baseline/Screening (Version 1/14/09)    
 
 
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Appendix 2.  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  
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       


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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)    
 
 
                          Page 2 of 2                  


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Appendix 3. Psoriasis Symptom Diary (PSD) 
 
  
 
 Psoriasis Symptom Diary (PSD) 
 
 
 
 
 
 1 Overall, how severe was 
your psoriasis-related 
itching over the past 
24 hours? 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10   
 
 No itching 
Itching as bad as you  
can imagine 
 
  
 
 2 Overall, how bothered  
were you by your psoriasis-
related itching over the 
past 24 hours? 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10   
 
Not bothered  
at all 
As bothered as you  
can imagine 
 
  
 
 3 Overall, how severe was 
your psoriasis-related 
stinging over the past 
24 hours? 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10   
 
No stinging 
Stinging as bad as you  
can imagine 
 
  
 
 4 Overall, how bothered  
were you by your psoriasis-
related stinging over the 
past 24 hours? 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10   
 
Not bothered  
at all 
As bothered as you  
can imagine 
 
  
 
 5 Overall, how severe was 
your psoriasis-related 
burning over the past 
24 hours? 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10   
 
No burning 
Burning as bad as you  
can imagine 
 
 
 
 
 
 
 
 
 
 
 


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 6 Overall, how bothered  
were you by your psoriasis-
related burning over the 
past 24 hours? 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10   
 
Not bothered  
at all 
As bothered as you  
can imagine 
 
  
 
 7 Overall, how severe was 
your psoriasis-affected skin 
cracking over the past 
24 hours? 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10   
 
 No pain 
Pain as bad as you  
can imagine 
 
  
 
 8 Overall, how bothered  
were you by your psoriasis-
affected skin cracking over 
the past 24 hours? 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10   
 
Not bothered  
at all 
As bothered as you  
can imagine 
 
  
 
 9 Overall, how severe was 
your psoriasis-related pain 
over the past 24 hours? 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10   
 
No pain 
Pain as bad as you  
can imagine 
 
  
 
 10 Overall, how bothered  
were you by your psoriasis-
related pain over the past 
24 hours? 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10   
 
Not bothered  
at all 
As bothered as you  
can imagine 
 
  
 
 11 Overall, how severe was 
your psoriasis scaling over 
the past 24 hours? 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10   
 
No scaling  
Scaling as bad as you  
can imagine 
 
 
 
 
 
 
 
 
 


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 12 Overall, how bothered were 
you by your psoriasis 
scaling over the past 
24 hours? 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10   
 
Not bothered  
at all 
As bothered as you  
can imagine 
 
  
 
 13 Overall, how noticeable did 
you think the color of your 
psoriasis-affected skin was 
over the past 24 hours? 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10   
 
Not at all  
noticeable 
As noticeable as you  
can imagine 
 
  
 
 14 Overall, how much did you 
try to hide your psoriasis-
affected skin over the past 
24 hours? 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10   
 
Did not try to  
hide at all 
Totally avoided being seen 
by others 
 
  
 
 15 Overall, how much did  
your psoriasis cause you  
to avoid activities with other 
people over the past  
24 hours? 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10   
 
You did not avoid  
other people  
Avoided other people as 
much as you ever have 
 
  
 
 16 Overall, how embarrassed 
were you because of your 
psoriasis over the past  
24 hours? 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10   
 
No embarrassment 
As embarrassed as you  
can imagine 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
© Novartis 2018 
 
 
 
 


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


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


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CHILDREN'S DERMATOLOGY LIFE QUALITY INDEX 
 
Subject Number:  
 
Diagnosis: 
 
 
 
 
 
CDLQI  
Age: 
 
 
 
Date: 
 
 
 
 
 
 
SCORE: 
 
The aim of this questionnaire is to measure how much your skin problem has 
affected you OVER THE LAST WEEK.  Please tick ü one box for each question. 
 
1. 
Over the last week, how itchy, "scratchy",  
 
 
              Very much 
□ 
 
sore or painful has your skin been? 
 
  
 
              Quite a lot 
□ 
 
 
  
 
 
 
 
 
 
 
Only a little 
□ 
 
 
 
 
 
 
 
 
 
 
Not at all 
□ 
 
2. 
Over the last week, how embarrassed 
 
 
 
             Very much 
□ 
 
or self conscious, upset or sad have you  
 
 
 
             Quite a lot 
□ 
 
been because of your skin? 
 
  
 
 
 
Only a little 
□ 
 
 
 
 
 
 
 
 
 
 
Not at all 
□ 
 
3. 
Over the last week, how much has your  
 
 
 
             Very much 
□ 
 
skin affected your friendships? 
  
 
 
 
             Quite a lot 
□ 
 
 
 
 
 
 
 
 
 
 
Only a little 
□ 
 
 
 
 
 
 
 
 
 
 
Not at all 
□ 
 
4. 
Over the last week, how much have you changed 
 
 
             Very much 
□ 
 
or worn different or special clothes/shoes  
 
 
             Quite a lot 
□ 
 
because of your skin? 
 
 
 
 
 
             Only a little 
□ 
 
 
 
 
 
 
 
 
 
 
Not at all 
□ 
 
5. 
Over the last week, how much has your  
 
 
 
            Very much 
□ 
 
skin trouble affected going out, playing, 
 
 
 
             Quite a lot 
□ 
 
or doing hobbies? 
 
 
 
 
 
 
Only a little 
□ 
 
 
 
 
 
 
 
 
 
 
Not at all 
□ 
 
6. 
Over the last week, how much have you 
  
 
 
          
Very much 
□ 
 
avoided swimming or other sports because  
 
                           Quite a lot 
□ 
 
of your skin trouble? 
 
 
 
 
 
 
Only a little 
□ 
 
 
 
 
 
 
 
 
 
 
Not at all 
□ 
 
7. 
Last week, 
 
  
If school time: Over the  
           
Prevented school            □  
             
last week, how much did  
               Very much 
□ 
 
school time?   
 
            your skin problem affect your 
             Quite a lot 
□ 
 
 
 
 
 
school work? 
 
 
 
Only a little 
□ 
 
   OR 
 
 
 
 
 
 
 
 
Not at all 
□ 
 
 
was it 
 
 
   
If holiday time: How much 
 
Very much 
□ 
 
holiday time?  
   
               over the last week, has your 
 
Quite a lot 
□ 
 
 
 
 
 
skin problem interfered with 
 
Only a little 
□ 
 
 
 
 
 
your enjoyment of the holiday? 
              Not at all 
□ 
 
8. 
Over the last week, how much trouble  
 
 
 
             Very much 
□ 
 
have you had because of your skin with 
 
 
 
             Quite a lot 
□ 
 
other people calling you names, teasing, 
 
 
 
            Only a little 
□ 
was it 


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bullying, asking questions or avoiding you? 
 
 
             Not at all 
□ 
 
9. 
Over the last week, how much has your sleep  
 
 
             Very much 
□ 
 
been affected by your skin problem? 
 
 
 
              Quite a lot 
□ 
 
 
 
 
 
 
 
 
 
 
Only a little 
□ 
 
 
 
 
 
 
 
 
 
 
Not at all 
□ 
 
10. 
Over the last week, how much of a   
 
 
 
              Very much 
□ 
 
problem has the treatment for your  
 
 
 
              Quite a lot 
□ 
 
skin been? 
 
 
 
 
 
 
 
Only a little 
□ 
 
 
 
 
 
 
 
 
  
 
Not at all 
□ 
Please check that you have answered EVERY question. Thank you.  
 
ãM.S. Lewis-Jones, A.Y. Finlay, May 1993, This must not be copied without the permission of the authors. 
 
 




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LABORATORY RANGES 
 
Where discrepancies in the ULN and LLN of laboratory ranges occur between those included in 
this document and those of the laboratory that performs the assays, the values provided by the 
laboratory will be used for assignment of severity grade.  
 
For pediatric subjects the National Institute of Allergy and Infectious Diseases, Division of 
Microbiology and Infectious Diseases (DMID) Pediatric Toxicity Tables (2007)  
 
https://www.niaid.nih.gov/sites/default/files/dmidpedtox.pdf 
 
 














Protocol ARQ-151-301 
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21 February 2020 
Confidential 
 Page 87 of 87 
 
 
 
Appendix 6. Children’s Depression Inventory 2 (Parent Report) 
 

SAP_001.pdf: 


Statistical Analysis Plan, 
Sponsor Arcutis Biotherapeutics, Inc.
Protocol Number ARQ-151-301
PCN Number ARCU9902
AD-ST-33.05  Effective date: 22-Jan-2018
Version 1.0   |    16-Dec-2020    |    AD-PR-109.01 Effective date: 26-Jun-2017
Page 2 of 42


Statistical Analysis Plan, 
Sponsor Arcutis Biotherapeutics, Inc.
Protocol Number ARQ-151-301
PCN Number ARCU9902
AD-ST-33.05  Effective date: 22-Jan-2018
Version 1.0   |    16-Dec-2020    |    AD-PR-109.01 Effective date: 26-Jun-2017
Page 3 of 42
Document History
Not applicable.


Statistical Analysis Plan, 
Sponsor Arcutis Biotherapeutics, Inc.
Protocol Number ARQ-151-301
PCN Number ARCU9902
AD-ST-33.05  Effective date: 22-Jan-2018
Version 1.0   |    16-Dec-2020    |    AD-PR-109.01 Effective date: 26-Jun-2017
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Table of Contents
Approvals........................................................................................................................................ 1
Document History........................................................................................................................... 3
Table of Contents............................................................................................................................ 4
List of Tables .................................................................................................................................. 5
1.
Overview............................................................................................................................. 7
2.
Study Objectives and Endpoints......................................................................................... 7
2.1.
Study Objectives ........................................................................................................... 7
2.1.1. Primary Objective......................................................................................................... 7
2.2.
Study Endpoints............................................................................................................ 8
2.2.1. Safety Endpoints........................................................................................................... 8
2.2.2. Efficacy Endpoints........................................................................................................ 8
3.
Overall Study Design and Plan........................................................................................... 9
3.1.
Overall Design .............................................................................................................. 9
3.2.
Sample Size and Power................................................................................................. 9
3.3.
Study Population........................................................................................................... 9
3.4.
Treatments Administered.............................................................................................. 9
3.5.
Method of Assigning Subjects to Treatment Groups.................................................... 9
3.6.
Blinding and Unblinding............................................................................................... 9
3.7.
Schedule of Events...................................................................................................... 10
4.
Statistical Analysis and Reporting.................................................................................... 13
4.1.
Introduction................................................................................................................. 13
4.2.
Interim Analysis and Data Monitoring ....................................................................... 13
5.
Analysis Populations......................................................................................................... 13
6.
General Issues for Statistical Analysis.............................................................................. 14
6.1.
Statistical Definitions and Algorithms........................................................................ 14
6.1.1. Baseline....................................................................................................................... 14
6.1.2. Adjustments for Covariates......................................................................................... 14
6.1.3. Multiple Comparisons................................................................................................. 15
6.1.4. Handling of Dropouts or Missing Data....................................................................... 16
6.1.5. Analysis Visit Windows ............................................................................................. 19
6.1.6. Pooling of Sites........................................................................................................... 19
6.1.7. Derived Variables ....................................................................................................... 19
6.1.8. Data Adjustments/Handling/Conventions .................................................................. 22
6.2.
Special Handling for COVID-19 Disruptions............................................................. 23
7.
Study Patients/Subjects and Demographics...................................................................... 24
7.1.
Disposition of Patients/Subjects and Withdrawals ..................................................... 24


Statistical Analysis Plan, 
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7.2.
Protocol Violations and Deviations ............................................................................ 24
7.3.
Demographics and Other Baseline Characteristics..................................................... 25
7.4.
Exposure and Compliance .......................................................................................... 25
8.
Efficacy Analysis.............................................................................................................. 25
8.1.
Primary Efficacy Analysis .......................................................................................... 26
8.2.
Secondary Efficacy Analysis ...................................................................................... 27
8.3.
Other Efficacy Analysis.............................................................................................. 29
8.4.
Patient Reported Outcomes......................................................................................... 30
9.
Safety and Tolerability Analysis....................................................................................... 31
9.1.
Adverse Events ........................................................................................................... 31
9.1.1. Adverse Events Leading to Withdrawal ..................................................................... 31
9.1.2. Deaths and Serious Adverse Events ........................................................................... 32
9.1.3. Adverse Events of Special Interest (AESIs) ............................................................... 32
9.2.
Local Tolerance Assessments..................................................................................... 32
9.3.
Clinical Laboratory Evaluations ................................................................................. 32
9.4.
Vital Signs................................................................................................................... 32
9.5.
PHQ and Modified PHQ-A......................................................................................... 33
9.6.
CDI-2 .......................................................................................................................... 33
9.7.
C-SSRS ....................................................................................................................... 33
9.8.
Physical Examination.................................................................................................. 33
9.9.
Concomitant Medication............................................................................................. 34
10.
Changes from Planned Analysis ....................................................................................... 34
11.
Other Planned Analysis..................................................................................................... 36
11.1.
Pharmacokinetic Analysis........................................................................................... 36
11.2.
Intertriginous Subjects ................................................................................................ 36
12.
References......................................................................................................................... 36
13.
Tables, Listings, and Figures ............................................................................................ 37
13.1.
Planned Table Descriptions ........................................................................................ 37
13.2.
Efficacy Data .............................................................................................................. 37
13.3.
Safety Data.................................................................................................................. 37
13.4.
Pharmacokinetic/Pharmacodynamic Data .................................................................. 38
13.5.
Other Data Summary Tables....................................................................................... 38
13.6.
Planned Listing Descriptions ...................................................................................... 38
13.7.
Planned Figure Descriptions....................................................................................... 39
Appendix 1: Premier Research Library of Abbreviations ............................................................ 40
List of Tables


Statistical Analysis Plan, 
Sponsor Arcutis Biotherapeutics, Inc.
Protocol Number ARQ-151-301
PCN Number ARCU9902
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Table 1: Schedule of Events ......................................................................................................... 11
Table 2: Analysis Visit Windows ................................................................................................. 19
Table 3: Demographic Data Summary Tables and Figures .......................................................... 37
Table 4: Efficacy Data .................................................................................................................. 37
Table 5: Safety Data...................................................................................................................... 37
Table 6: Pharmacokinetic/Pharmacodynamic Data...................................................................... 38
Table 7: Other Data Summary Tables .......................................................................................... 38
Table 8: Planned Listings.............................................................................................................. 39
Table 9: Planned Figures .............................................................................................................. 39


Statistical Analysis Plan, 
Sponsor Arcutis Biotherapeutics, Inc.
Protocol Number ARQ-151-301
PCN Number ARCU9902
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1.
Overview
This statistical analysis plan (SAP) describes the planned analysis and reporting for Arcutis, Inc.
protocol number ARQ-151-301 (A Phase 3, 8-Week, Parallel Group, Double Blind, Vehicle-
Controlled Study of the Safety and Efficacy of ARQ-151 Cream 0.3% Administered QD in 
Subjects with Chronic Plaque Psoriasis), Amendment 1 version dated 21-Feb-2020. Reference 
materials for this statistical plan include the protocol and the accompanying sample data 
collection documents. Operational aspects related to collection and timing of planned clinical 
assessments are not repeated in this SAP unless relevant to the planned analysis.
The structure and content of this SAP provides sufficient detail to meet the requirements 
identified by the Food and Drug Administration (FDA), European Medicines Agency (EMA), 
and International Conference on Harmonization (ICH) of Technical Requirements for 
Registration of Pharmaceuticals for Human Use: Guidance on Statistical Principles in Clinical 
Trials1. All work planned and reported for this SAP will follow internationally accepted 
guidelines, published by the American Statistical Association2 and the Royal Statistical Society3, 
for statistical practice.
The planned analyses identified in this SAP may be included in clinical study reports (CSRs), 
regulatory submissions, or future manuscripts. Also, post-hoc exploratory analyses not 
necessarily identified in this SAP may be performed to further examine study data. Any post-hoc 
or unplanned, exploratory analysis performed will be clearly identified as such in the final CSR.
The statistical plan described hereafter is an a priori plan. It will be submitted to file prior to any 
unblinded inferential or descriptive analysis of data pertaining to Arcutis, Inc.
ARQ-151-
301.
2.
Study Objectives and Endpoints
2.1.
Study Objectives
Psoriasis is a chronic inflammatory skin disease characterized by raised, well-demarcated, 
erythematous oval plaques with adherent silvery scales.  
The advent of biological therapies has caused a transformation in the systemic treatment of 
moderate to severe psoriasis.  However, for patients with milder forms of disease, the therapeutic 
landscape has not significantly changed in several decades. Lower potency topical steroids are 
not effective and the higher potency steroids can cause local skin atrophy and the potential for 
hypothalamic-pituitary axis suppression. Another typical therapy, vitamin D, is irritating and is
not suitable for use on the face or intertriginous areas. There is substantial medical need for 
additional topical approaches in the treatment of mild to moderate psoriasis.  The Phase 2 results 
suggest that ARQ-151 (Roflumilast Cream 0.3%) may be a highly efficacious and well-tolerated 
topical treatment for psoriasis.
2.1.1. Primary Objective
The primary objective is to assess the safety and efficacy of ARQ-151 cream 0.3% (Roflumilast 
Cream 0.3%) vs. vehicle administered QD for 8 weeks to individuals with 2-20% BSA of 
chronic plaque psoriasis.


Statistical Analysis Plan, 
Sponsor Arcutis Biotherapeutics, Inc.
Protocol Number ARQ-151-301
PCN Number ARCU9902
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2.2.
Study Endpoints
2.2.1. Safety Endpoints
The safety endpoints of this study include the following:
Adverse events (AEs)
Local tolerance assessments
Patient Health Questionnaire depression scale (PHQ-8) and Modified PHQ-9 for 
Adolescents (PHQ-A)
Columbia-Suicide Severity Rating Scale (C-SSRS)
nd Edition (CDI-2)
Clinical laboratory results
Vital signs
Physical examination
2.2.2. Efficacy Endpoints
2.2.2.1.
Primary Efficacy Endpoint
The primary efficacy endpoint of this study is success in Investigator Global Assessment (IGA) of 
disease severity, defined as an IGA of
o
Almost
-grade improvement 
from Baseline at Week 8.
2.2.2.2.
Secondary Efficacy Endpoints
The secondary efficacy endpoints of this study include the following:
Achievement of Psoriasis Area Severity Index-75 (PASI-75; subjects who achieve a 75% 
reduction in PASI from Baseline) at week 8.
For subjects with intertriginous area involvement, and with severity of the intertriginous 
-
-
-grade improvement from Baseline at 
week 8.
In subjects with Worst Itch Numeric Rating Score (WI-NRS)
at 
baseline, achievement of a 4-point reduction in WI-NRS pruritus score at week 8 as 
compared to Baseline.
In subjects with WI-
-point 
reduction in WI-NRS pruritus score at week 4 as compared to Baseline.
In subjects with WI-
-point 
reduction in WI-NRS pruritus score at week 2 as compared to Baseline.
Change from Baseline in total Psoriasis Symptoms Diary (PSD) score at week 8.
Change from Baseline in total PSD score at week 4.
Time to achieving Psoriasis Area Severity Index-50 (PASI-50; subjects who achieve a 
50% reduction in PASI from Baseline)
For subjects with intertriginous area involvement, and with severity of the intertriginous 
-
-
week 8.


Statistical Analysis Plan, 
Sponsor Arcutis Biotherapeutics, Inc.
Protocol Number ARQ-151-301
PCN Number ARCU9902
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Achievement of PASI-90 (subjects who achieve a 90% reduction in PASI from Baseline) 
at week 8.
3.
Overall Study Design and Plan
3.1.
Overall Design
3.2.
Sample Size and Power
A sample size of approximately 400 subjects are planned for the study. 
Approximately 267 subjects will receive ARQ-151 cream 0.3% (Roflumilast Cream 0.3%) QD; 
approximately 133 subjects will receive vehicle cream QD.  The randomization scheme will be 
2:1 (ARQ-151 cream 0.3% (Roflumilast Cream 0.3%) QD: matching vehicle QD).
This sample size provides >99% power to detect a 22.4% difference between treatment groups 
-sided Chi-squared test.  The results from a recent phase 2b 
study (ARQ-151-201) of ARQ-151 (Roflumilast Cream 0.3%) compared to vehicle treatment 
were used to estimate the treatment difference.  Specifically, in this trial 32.2% of subjects 
reported IGA success in the ARQ-151 0.3% (Roflumilast Cream 0.3%) group and 9.8% of 
subjects reported IGA success in the vehicle group.
The number of subjects to be enrolled will also provide sufficient power for the first 5 secondary 
endpoints.  Additionally, the larger study size is included in order to provide additional/sufficient 
numbers of subjects on ARQ-151 (Roflumilast Cream 0.3%) treatment for a safety database.
3.3.
Study Population
Males and females ages 12 years and older with a clinical diagnosis of psoriasis vulgaris on the 
face, extremities, trunk, and/or intertriginous areas involving 2% to 20% BSA (excluding the 
scalp, palms and soles) of at least 6 months duration that has been stable for the past 4 weeks, 
with a
and a
PASI score of at least 2 (excluding the scalp, palms and soles) at Baseline.
3.4.
Treatments Administered
Subjects will be randomized to one of the two following treatment groups in a 2:1 ratio 
(active:vehicle):
ARQ-151 cream 0.3% (Roflumilast Cream 0.3%) QD
vehicle cream QD.
3.5.
Method of Assigning Subjects to Treatment Groups
Subjects will be randomized and assigned to active drug or vehicle in a 2:1 ratio (active:vehicle)
according to a computer-generated randomization list.  The randomization schedule will be 
olvement at 
baseline (I-IGA 2, yes vs no).
3.6.
Blinding and Unblinding
This study is double-blind. In the event of a serious safety concern where the situation requires 
emergency unblinding this will be done by investigator using the study IWRS system after 
d


Statistical Analysis Plan, 
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3.7.
Schedule of Events
A detailed schedule of events for the study is provided in Table 1.


Statistical Analysis Plan, 
Sponsor Arcutis Biotherapeutics, Inc.
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Table 1: Schedule of Events
Study Procedure
Screen
Baseline
Day 1
Wk 2 
Day 15
Wk 4
Day 29
Wk 6
Day 43 
Wk 8r
Day 57
Wk 9
Day 64
Visit
1
2
3
4
5
6
7
Visit Window
-35 days
+/- 3 days +/- 5 days +/- 5 days +/- 7 days +/- 7 days
Informed consent/assent
X
Medical history
X
Physical examinationa
X
X
X
I/E criteria
X
X
Hematology, Serum 
Chemistries, and Urine 
Analysisb
X
X
X
X
Vital signs, height, weightc
X
X
X
X
X
X
X
IGAd, BSAd, PASI/mPASId
X
X
X
X
X
X
X
Intertriginous area IGA 
(I-IGA)e
X
X
X
X
X
X
WI-NRSf
X
X
X
X
X
X
DLQI/CDLQIg
X
X
X
X
X
Local Tolerability
Assessmentsh
X
X
X
C-SSRS, PHQ-8 / modified 
PHQ-A (12 years and older)
X
X
X
X
CDI-2 parent report (6-11 y/o
inclusive)
X
X
X
X
PSDi
X
X
X
X
X
X
Photographyj
X
X
X
X
X
Serum pregnancy test
X
Urine pregnancy testk
X
X
X
PK drawsl
X
X
X


Statistical Analysis Plan, 
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Protocol Number ARQ-151-301
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IP application in clinicm
X
X
X
X
X
Assign investigational 
product kitn
X
Dispense/review diary
X
X
X
X
X
Weigh investigational product 
tubesn
X
X
X
X
X
Compliance calculationo
X
X
X
X
X
Adverse event assessmentp
X
X
X
X
X
X
X
Concomitant medications
X
X
X
X
X
X
X
Study Exitq
X
a Limited physical examination: skin, lungs, and heart only
b  If Baseline visit occurs within 14 days of Screening, the Screening lab results may be utilized.
c Height will be collected at Baseline only. Weight will be collected at every visit. 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% unintentional weight loss should be reported to the medical monitor on Page 1.
d   IGA (based on whole body involvement) will be a 5-point scale ranging from clear (0) to severe (4). IGA should be 
completed prior to other physician assessments and by the same Evaluator at each study visit. Total BSA affected by 
psoriasis will be determined
assumed to equal 1% of the BSA. PASI/mPASI will be determined by standard methods. NOTE: while palms and soles will 
be treated with IP, they are not counted towards IGA, PASI/mPASI, or BSA assessments. 
e  
2) at Baseline (using the IGA scale 
but evaluating intertriginous areas ONLY and NOT whole body involvement), an IGA for the intertriginous region alone 
(I-IGA) will be recorded.  
(primary endpoint) in subjects who qualify.
f   Subjects 12 years and older will complete WI-NRS pruritus assessment.
g   Subjects >17 years of age will complete DLQI.  For subjects 2-16 years of age, CDLQI will be completed.
h Tolerability assessments should be recorded prior to investigational product application for Investigator assessment (Berger 
and Bowman skin irritation score) and 10-15 minutes post-investigational product application
-
burning/stinging assessment. Parents may report for children. Note for investigator tolerability assessments: reactions at 
the site of product application, which may occur post-Baseline, should be differentiated from the preexisting 
inflammation associated with the
I     Adult subjects only
j
Photography will be performed using Canfield equipment on all subjects at all sites.  All efforts will be made to de-identify 
the subjects. Subjects who are unwilling to participate in the medical photography will be allowed to opt out of this procedure 
and documented on the informed consent. See Photography Manual for details.
k A urine pregnancy test will be administered to all females of child-bearing potential. A negative result is required for 
continued participation in the study, and results must be available prior to dispensing of investigational product at each visit.
l
PK draws will be collected from all subjects at Days 1, 29 and 57. The draws will be pre-dose investigational product 
application in the clinic (i.e., trough levels). Ensure investigational product is not applied in the area where PK will be drawn.
m   Subjects to apply assigned IP in clinic at every visit. The time of application will be documented.
n Kits will be dispensed based on % BSA affected. See IP Handling Manual for details.  
o    Each IP tube should be weighed and recorded at every visit. See IP Handling Manual for details.
p
otherwise judged as clinically stable.


Statistical Analysis Plan, 
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Protocol Number ARQ-151-301
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q   Subjects who consent to/enroll into the open label extension study (ARQ-151-306) will complete the study at Week 8; 
subjects that do not consent to/enroll into ARQ-151-306 will return at Week 9 to complete the study.
r   Subjects that terminate early should return to the clinic for the week 8 assessments.
4.
Statistical Analysis and Reporting
4.1.
Introduction
Data processing, tabulation of descriptive statistics, calculation of inferential statistics, and 
graphical representations will be performed primarily using SAS (release 9.4 or higher). If the 
use of other software is warranted, the final clinical study report will detail what software was 
used for what purposes.
Continuous (quantitative) variable summaries will include the number of subjects (n) with 
non-missing values, mean, standard deviation (SD), median, minimum, and maximum.
Categorical (qualitative) variable summaries will include the frequency and percentage of 
subjects who are in the particular category or each possible value. In general, the denominator 
for the percentage calculation will be based upon the total number of subjects in the study 
population for the treatment group, unless otherwise specified. 
The minimum and maximum will be reported with the same degree of precision (ie, the same 
number of decimal places) as the observed data. Measures of location (mean and median) will be 
reported to 1 degree of precision more than the observed data and measures of spread (SD) will 
be reported to 2 degrees of precision more than the observed data, unless otherwise specified.
Percentages will be presented to 1 decimal place, unless otherwise specified.
Unless otherwise indicated, all statistical tests will be conducted at the 0.05 significance level 
using 2-tailed tests, and P values will be reported. Corresponding 95% confidence intervals (CIs) 
will be presented for statistical tests where appropriate.
A p-value of 
0.10 but > 0.05 will be considered evidence of a trend. 
4.2.
Interim Analysis and Data Monitoring
No interim analyses or data safety monitoring are planned.
5.
Analysis Populations
The following analysis populations are planned for this study:
Safety Population (SAF): The Safety Population includes all subjects who are enrolled 
and received at least one confirmed dose of investigational product. This population will 
be used for all safety analyses.
Intent-To-Treat Population (ITT): The ITT population includes all randomized 
subjects. This population will be the primary analysis population for the analysis of 
efficacy endpoints.


Statistical Analysis Plan, 
Sponsor Arcutis Biotherapeutics, Inc.
Protocol Number ARQ-151-301
PCN Number ARCU9902
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Modified Intent-To-Treat Population (mITT): The mITT population includes all 
randomized subjects with the exception of subjects who missed the week 8 IGA
assessment specifically due to COVID-19 disruption. This population will be used for 
sensitivity of the primary endpoint.
I-IGA ITT Population (I-IGA-ITT): The I-IGA population is a subset of the ITT 
population and includes subjects with intertriginous area involvement, and with severity 
(I-
I-IGA mITT Population (I-IGA-mITT): The I-IGA population is a subset of the mITT 
population and includes subjects with intertriginous area involvement, and with severity 
-
Pruritus ITT Population (PRU4-ITT): The PRU4 population is a subset of the ITT 
population and includes subjects with WI-
4 at Baseline.  This 
population will be used for the analysis of achievement of a 4-point reduction in WI-NRS 
pruritus score as compared to Baseline.
Pruritus mITT Population (PRU4-mITT): The PRU4 population is a subset of the 
mITT population and includes subjects with WI-
4 at Baseline.  This 
population will be used for the analysis of achievement of a 4-point reduction in WI-NRS 
pruritus score as compared to Baseline.
Pharmacokinetic Population (PK): The PK population includes all subjects receiving 
active drug and had a PK draw (concentration data available) at Baseline Day 0 visit.  
This population will be used for the analysis of PK concentrations.
6.
General Issues for Statistical Analysis
6.1.
Statistical Definitions and Algorithms
6.1.1. Baseline
The last observation recorded prior to the first dose of investigational product being administered 
will be used as the baseline observation for all calculations of change from baseline except 
subject tolerability, WI-NRS, DLQI and PSD. The value for date and time of IP administration 
recorded in the EDC database will be used as the anchor for baseline. For assessments where no 
time is recorded (e.g., DLQI/CDLQI and PHQ/mPHQ-A) and the date of the assessment is the 
same as the date of first IP, it is assumed that the assessment took place prior to IP application, 
per study site training, and the last assessment taken on or before the date of first IP is used as 
the baseline.
For subject tolerability assessments, baseline is derived as the last non-missing measurement 
taken on the day of first application of study drug.
6.1.2. Adjustments for Covariates
If there is a statistical difference among treatment groups with respect to baseline characteristics, 
that variable may be added to the statistical models as a blocking factor or covariate to determine 
the effect on treatment.


Statistical Analysis Plan, 
Sponsor Arcutis Biotherapeutics, Inc.
Protocol Number ARQ-151-301
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6.1.3. Multiple Comparisons
all secondary efficacy endpoints included 
in the hierarchical testing strategy by assigning the endpoints into families and only proceeding 
to the next family in accordance with the rules of the pre-specified sequential testing strategy.
Secondary endpoints will only be tested statistically if the primary endpoint is considered 
statistically significant. To control for multiple comparisons among the secondary endpoints, the 
following multiplicity procedure will be used:
Upon successful testing of the primary endpoint (Family 1) the alpha will be partitioned to test 
secondary endpoint Families 2 and 3 (Partition 1) and to test WI-NRS timepoints (Partition 2).
Partition 1 of alpha = 0.03 will be allocated to test Family 2 and Family 3. The endpoints in 
Family 2 will be tested hierarchically in the order depicted below; the next 3 secondary 
endpoints (Family 3) will be tested using the alpha available after testing endpoint Family 2.  
The Holm procedure will be used to control for multiple comparisons in endpoint Family 3.
Partition 2 of alpha = 0.02 will be allocated to sequentially test WI-NRS success at week 8, then 
week 4 and subsequently week 2.


Statistical Analysis Plan, 
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No adjustments will be made for multiple comparisons for other endpoints.
6.1.4. Handling of Dropouts or Missing Data
Any subject who prematurely withdraws from the study will have their last available data 
assigned to an analysis window as described in Section 6.1.5. 
6.1.4.1.
Imputation of Missing Data
For the primary efficacy endpoint of IGA score and tested secondary endpoints, the primary
analysis will impute missing values using a regression-based multiple imputation model.  This is 
a three step process.
1. The first step is to understand the pattern of missingness. In order to perform the multiple
imputation, a monotone missing pattern has to be achieved. For example, if there exists 
values for baseline and Week 8 visits, but missing values for the Week 2 or 4 visits, the 
Markov-Chain Monte-Carlo (MCMC) method will be used to impute the small amount of 
missing data that may be missing at the intermediate visits that is required to make the 
missing data pattern monotone before applying the multiple imputation algorithm. This 
method uses a non-informative Jeffreys prior to derive the posterior mode from the 
expectation-maximization (EM) algorithm as the starting values for the MCMC method. 
The MCMC method will use the seed 59726314. The IGA score will be treated as a 
continuous variable for this step. To avoid values that could not be observed in practice, 
imputed values will be constrained to be integers in the range of 0 to 4.




Statistical Analysis Plan, 
Sponsor Arcutis Biotherapeutics, Inc.
Protocol Number ARQ-151-301
PCN Number ARCU9902
AD-ST-33.05  Effective date: 22-Jan-2018
Version 1.0   |    16-Dec-2020    |    AD-PR-109.01 Effective date: 26-Jun-2017
Page 18 of 42
proc mi data=example seed=59726314 nimpute=XX round=1 out=example_1;
  mcmc impute=monotone;
  var <baseline score>
;
run;
Step 2:
proc mi data=example_1 seed=461903 nimpute=XX  out=example_2;
  class <treatment> <site>;
  monotone regpmm(<baseline score>
);
  var <treatment> <country> <baseline score>
;
run;
XX will be the determined based on the proportion of missing data across visits.
Step 3: This step involves running CMH test stratified by baseline IGA score, and site on each 
completed dataset and combining the results using PROC MIANALYZE.
proc freq data=example noprint;
  by <imputationnumber> <visit>;
  tables <site> * <BL IGA> * <treatment> * 
         <outcome> / cmh alpha=0.05;
  output out=example_stat cmh;
run;
In order to apply PROC MIANALYZE, normalizing transformations have to be applied to the 
odds ratio. P values are obtained using the Wilson Hilferty transformation4.
6.1.4.2.
Tipping Point Analysis
As a sensitivity analysis to the multiple imputation analysis as described in Section 6.1.4.1 for 
the IGA primary endpoint, a tipping point analysis will be performed in order to determine the 
inflection point at which the inference under the MNAR assumption changes substantially. This 
will be used to check the robustness of the imputation.
The sensitivity analysis will be performed by using a specified sequence of shift parameters, 
which will adjust the imputed values for observations in the active treatment group. The range of 
shift parameters to be included in this analysis are -1.5 to 1.5 by 0.2. Once the likely point of the 
shift is determined, the analysis will be rerun using an expanded range around the suspected 
tipping point, with greater precision (i.e., to 2 decimal places, by 0.01). Thus, the value at which 
-si
0.05) will be determined. 
Steps 1 and 3 of the analysis will be the same as for the multiple imputation analysis as described 
in Section 6.1.4.1. However, Step 2 of the analysis is where the shift parameters will be applied. 
Pseudo-code for Step 2 is as follows:
proc mi data=example_1 seed=461903 nimpute=XX  out=example_2;
  class <treatment> <site> <BL IGA>;
  monotone regpmm(<baseline score>
);
  var <treatment> <site> <baseline score>
;
  
Roflumilast 
Cream 0.3%




Statistical Analysis Plan, 
Sponsor Arcutis Biotherapeutics, Inc.
Protocol Number ARQ-151-301
PCN Number ARCU9902
AD-ST-33.05  Effective date: 22-Jan-2018
Version 1.0   |    16-Dec-2020    |    AD-PR-109.01 Effective date: 26-Jun-2017
Page 20 of 42
Worst Itch 
Numeric Rating Score (WI-NRS) 4-point reduction = achievement of a 4-
point reduction in WI-NRS pruritus score compared to baseline, calculated only for 
PASI = 0.1 (Eh + Th + Sh) Ah + 0.2 (Ea + Ta + Sa) Aa + 0.3 (Et + Tt + St) At + 0.4 (El + Tl + 
Sl) Al where E, T, and S are erythema (redness), thickness (induration), and scaling
(desquamation), respectively, scored on a scale of 0 to 4, A is estimated area of skin 
involved, graded on a scale of 0 to 6, and h, e, t, and l are head, arms, trunk, and legs, 
respectively (range for total score 0 to 72). If any one of the components/scores is missing, 
the PASI score is set to missing.
mPASI = same as PASI above, except that for subjects with < 10% of any particular 
involved anatomic area, the mPASI will be calculated using the actual percentage of the 
anatomical area involved rather than the 0 to 6 estimated area score (e.g. 0.1 for 1%, 0.2 
If any one of the components/scores is missing, the 
mPASI score is set to missing.
PASI-50(mPASI-50) = achievement of a 50% reduction in PASI(mPASI) from Baseline.
Time to PASI-50 Success (days) = date of PASI-50 achievement
Day 1 date + 1.
PASI-75(mPASI-75) = achievement of a 75% reduction in PASI(mPASI) from Baseline.
PASI-90(mPASI-90) = achievement of a 90% reduction in PASI(mPASI) from Baseline.
PASI-100(mPASI-100) = achievement of a 100% reduction in PASI(mPASI) from 
Baseline.
PSD Total Score = sum of the 16 questions (individual questions scored 0 to 10; range for 
total score 0 to 160). If 1 or more items are missing, the score is not calculated. 
DLQI Score = sum of the 10 questions (individual questions scored as Very much=3, A 
lot=2, A little=1, Not at all=0, Not relevant=0, Question 7: Yes=3; range for score 0 to 30).
If 1 item is missing, it is scored as 0 for that item. If 2 or more items are missing, the score 
should not be calculated.
must be converted to 0 for the calculation of the total score.
CDLQI Score = sum of the 10 questions (individual questions scored as Very much=3, 
Quite a lot=2, Only a little=1, Not at all=0; Question 7: if the last week was school time, 
the question was scored as Very much=3, Quite a lot=2, Only a little=1, Not at all=0, with 
Prevented school recoded to 3, and if the last week was vacation, the standard responses 
apply; range for score 0 to 30). If 1 item is missing, that item is scored as 0. If 2 or more 
items are missing, the score should not be calculated.
PHQ-8 = sum of the 8 questions (individual questions scored as Not at all=0, Several 
days=1, More than half the days=2, and Nearly every day=3, (range for score 0 to 24). If 


Statistical Analysis Plan, 
Sponsor Arcutis Biotherapeutics, Inc.
Protocol Number ARQ-151-301
PCN Number ARCU9902
AD-ST-33.05  Effective date: 22-Jan-2018
Version 1.0   |    16-Dec-2020    |    AD-PR-109.01 Effective date: 26-Jun-2017
Page 21 of 42
more than 1 item is missing the score should not be calculated.  If 1 item is missing the 
score is calculated as (sum of answered items*8)/number of answered items.
Modified PHQ-A = sum of the 8 questions (individual questions scored as Not at all=0, 
Several days=1, More than half the days=2, and Nearly every day=3, (range for score 0 to 
24). If 1 or more items are missing the score should not be calculated.  If 1 item is missing,
the score is calculated as (sum of answered items*8)/number of answered items.
CDI-2 total score is a sum of the 17 questions (individual questions scored as much or most 
of the time=3, often=2, some of the time=1, Not at all=0; range for score 0 to 51).
CDI-2 emotional problem scale is a sum of 9 questions (Q1, Q3-6, Q8, Q10 -12)
CDI-2 function problem scale is a sum of 8 questions ( Q2, Q7, Q9, Q13-17)
Change from baseline = value at current time point value at Baseline. 
TEAE = any adverse event with an onset date/time after the first application of 
investigational product through study completion; or onset date at/after date of the first IP 
when time is missing
C-SSRS Suicidal ideation
five suicidal ideation questions (Categories 1-5: Wish to be Dead, Non-specific Active 
Suicidal Thoughts, Active Suicidal Ideation with Any Methods (Not Plan) without Intent 
to Act, Active Suicidal Ideation with Some Intent to Act, without Specific Plan Active 
Suicidal Ideation with Specific Plan and Intent).
C-SSRS Suicidal behavior
five suicidal behavior questions (Categories 6-10: Preparatory Acts or Behavior, Aborted 
Attempt, Interrupted Attempt, Actual Attempt (non-fatal), Completed Suicide).
C-SSRS Suicidal ideation or behavior =
any one of the ten suicidal ideation and behavior questions (Categories 1-10) on the C-
SSRS.
Weight of IP (g) = dispensed can weight returned can weight.
Compliance = number of applications divided by the expected number of IP applications 
for each subject. Compliance will be calculated using drug accountability data over the 
entire treatment period for each subject, up to treatment completion or discontinuation. 
Both the EDC and ERT databases will be used to determine missed doses, etc.
Number of expected IP applications = calculated as the last treatment date first treatment 
date +1.


Statistical Analysis Plan, 
Sponsor Arcutis Biotherapeutics, Inc.
Protocol Number ARQ-151-301
PCN Number ARCU9902
AD-ST-33.05  Effective date: 22-Jan-2018
Version 1.0   |    16-Dec-2020    |    AD-PR-109.01 Effective date: 26-Jun-2017
Page 22 of 42
Number of IP applications = number of expected IP applications
missed IP applications 
as collected on the CRF.
BMI (kg/m2) = (weight in kg)/[(height in cm/100)2]. Baseline height will be used to derive 
BMI for each visit since height is not collected at all visits.
BMI Categories
Underweight:   BMI < 18.5
Normal:           18.5 <= BMI <= 24.9
Overweight:     25.0 <= BMI < = 29.9
Obese:             BMI >= 30.0  
Intentional Weight Loss = for the analyses of subjects losing >=5%/>=10% of their 
baseline body weight, 
each visit.
Completion of Study = Completion of the primary efficacy assessment (IGA) at Week 8. 
This may differ from what was recorded in the eCRF.
BSA (body surface area) = sum of coverage areas of head, limbs, upper limbs and 
trunk/genitalia.
6.1.8. Data Adjustments/Handling/Conventions
All collected data will be presented in listings or CDISC datasets. Data not subject to analysis 
according to this plan will not appear in any tables or graphs but will be included only in the data 
listings or CDISC datasets.
All P values will be displayed in four decimals and rounded using standard scientific notation (eg, 
0.XXXX). If a P value less than 0.0001 occurs it will be shown in tables as <0.0001.
All analyses that include the stratification factors (site, baseline IGA, and baseline intertriginous 
involvement) will use the data as collected in the IVR system.  If the overall number of 
discrepancies between the IVR and the eCRF database exceeds 10%, a sensitivity analysis will be 
conducted in which the stratification will be based on the stratification values as collected in the 
eCRF database.
In the event that data from a questionnaire for a particular visit is present in both the EDC database 
and the ERT database, the values present in the ERT database will be used for all analyses. If a 
questionnaire for a visit is only present in the ERT database, then the ERT values will be used, and 
similarly if only present in the EDC database then the EDC values will be used.


Statistical Analysis Plan, 
Sponsor Arcutis Biotherapeutics, Inc.
Protocol Number ARQ-151-301
PCN Number ARCU9902
AD-ST-33.05  Effective date: 22-Jan-2018
Version 1.0   |    16-Dec-2020    |    AD-PR-109.01 Effective date: 26-Jun-2017
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For laboratory values that are < X (X = a number), <= X, > X or >=X then X will be used in the 
analysis.
Adverse events will be coded using the MedDRA version 23.0 thesaurus.
A treatment related AE is any AE with a relationship to IP of possibly, probably, or likely.
For partial AE and medication start dates:
If the year is unknown, then do not impute the date but assign a missing value.
If the year is known, but the month or month and day is unknown, then:
o
If the year matches the year of first dose date and the end date is missing or after 
first dose date, then impute as the month and day of the first dose date.
o
Otherwise, assign 01 January.
If the year and month are known, but the day is unknown, then:
o
If the month and year match the month and year of the first dose date, then impute 
as the day of the first dose date.
o
Otherwise, assign 01.
For partial AE and medication end dates:
If the year is unknown, then do not impute the date but assign as missing value.
If the year is known, but the month or month and day is unknown, then:
o
If the year matches the year of the last date of the study (date of last contact if 
subject lost to follow-up; date of completion or early termination otherwise), then 
impute as the month and day of the last date of the study.
o
Otherwise, assign 31 December.
If the year and month are known, but the day is unknown, then:
o
If the month and year match the month and year of the last date of the study, then 
impute as the day of the last date of the study.
o
Otherwise, assign the last day of the month.
6.2.
Special Handling for COVID-19 Disruptions
In some cases, study visits will have to be delayed/not performed as a result of COVID-19 
disruptions (e.g., sites were closed or subjects were under stay-at-home orders). Where possible, 
study sites may collect post-baseline data from subjects remotely by telephone, traditional mail, 
and/or email; this will be clearly documented in the source. If possible, sites should adhere to the 
protocol visit window for remote data collection.


Statistical Analysis Plan, 
Sponsor Arcutis Biotherapeutics, Inc.
Protocol Number ARQ-151-301
PCN Number ARCU9902
AD-ST-33.05  Effective date: 22-Jan-2018
Version 1.0   |    16-Dec-2020    |    AD-PR-109.01 Effective date: 26-Jun-2017
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Investigator assessments and subject questionnaires normally completed directly in the electronic 
patient reported outcomes (ePRO) tablet during on-site visits should be completed on the 
appropriate paper source documents. The following assessments/questionnaires are approved to 
be collected via telemedicine/remotely:
WI-NRS
DLQI/CDLQI
C-SSRS
PHQ-8/PHQ-A
Subject Local Tolerability
The following assessments cannot be completed via telemedicine/remotely:
IGA/I-IGA
BSA
Investigator Local Tolerability
PASI/mPASI
PSD
Subject Weight
Study visits and procedures must be followed per protocol whenever possible. Any specific 
changes in study conduct that deviate from the protocol should be communicated to the 
institutional review board and Sponsor. All protocol deviations which occurred as a result of 
COVID-19 disruptions (e.g., visits out of window, missed assessments, etc.) will be 
differentiated from other protocol deviations. 
Subjects who were affected by COVID-19 disruptions by either missing their Week 8 visit or 
being discontinued before having a Week 8 visit due to COVID-19 related disruptions will be 
excluded from the mITT population, as described in Section Error! Reference source not 
found..
7.
Study Patients/Subjects and Demographics
7.1.
Disposition of Patients/Subjects and Withdrawals
Disposition will include tabulations of the number of subjects randomized into each treatment 
group, the number of subjects who received treatment, tabulated reasons for discontinuation from 
the study, and number of subjects in each analysis population.
7.2.
Protocol Violations and Deviations
The number of subjects with major protocol deviations will be summarized in categories by 
treatment group and overall for subjects in Safety population.
Protocol deviations will be listed.


Statistical Analysis Plan, 
Sponsor Arcutis Biotherapeutics, Inc.
Protocol Number ARQ-151-301
PCN Number ARCU9902
AD-ST-33.05  Effective date: 22-Jan-2018
Version 1.0   |    16-Dec-2020    |    AD-PR-109.01 Effective date: 26-Jun-2017
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7.3.
Demographics and Other Baseline Characteristics
Summary statistics for age, age groups ( 2- 11, 12 17 and >18 years old), gender, race, 
ethnicity, height, weight, percent BSA covered with plaque psoriasis, IGA, I-IGA, PASI, 
mPASI, WI-NRS, number of subject with WI-NRS >= 4, DLQI, CDLQI, PSD, PHQ-8, PHQ-A
and BMI will be presented by treatment group and overall.
For the continuous variables, the number of non-missing values and the mean, standard 
deviation, minimum, median and maximum will be tabulated. 
For the categorical variables, the counts and proportions of each value will be tabulated.   
These analyses will be conducted for the ITT, mITT, I-IGA-ITT, PRU4-ITT, and Safety 
populations.
Medical history will be listed.
The number and percent of subjects reporting inadequate response, intolerance or 
contraindication to topical corticosteroids, vitamin D Derivatives, Apremilast (Otezla), taken 
conventional systemic therapy or been on phototherapy will be tabulated by treatment group and 
overall. 
The number and percent of subjects reporting psoriasis involvement in knee, elbow, knee and/or 
elbow, facial and genitalia will be tabulated by treatment group and overall.
7.4.
Exposure and Compliance
The number of investigational product applications by each subject based on diary data will be 
summarized using descriptive statistics appropriate for continuous variables. 
The amount of investigational product used by each subject based on tube weight will be 
summarized descriptively by treatment using continuous methods.  
A subject will be considered compliant with the dosing regimen if the subject applies at least 
80% of the expected applications during the investigational product application period and does
not miss more than 3 consecutive doses. The number of subjects that missed more than 3 
consecutive doses will also be displayed. The number and percent of subjects that missed more 
than 3 consecutive doses will be tabulated by treatment group and overall.
Investigational product application compliance will be calculated as described in section 6.1.7.  
Compliance will be summarized descriptively by treatment group using the following categories:
> 100%
-
< 80%.
8.
Efficacy Analysis
All efficacy analyses that include the stratification factors (site, baseline IGA, and baseline 
intertriginous involvement) will use the data as collected in the IVR system.  If the overall 


Statistical Analysis Plan, 
Sponsor Arcutis Biotherapeutics, Inc.
Protocol Number ARQ-151-301
PCN Number ARCU9902
AD-ST-33.05  Effective date: 22-Jan-2018
Version 1.0   |    16-Dec-2020    |    AD-PR-109.01 Effective date: 26-Jun-2017
Page 26 of 42
number of discrepancies between the IVR and the eCRF database exceeds 10%, a sensitivity 
analysis will be conducted in which the stratification will be based on the stratification values as 
collected in the eCRF database.
8.1.
Primary Efficacy Analysis
For this study, the primary estimand is the ratio of the odds of achieving IGA success after 8 
weeks of using ARQ-151 (Roflumilast Cream 0.3%), relative to the odds of success after 8 
weeks of using a matching vehicle cream. In the course of the 8-week randomized treatment 
period, subjects may be exposed to possible known or unknown inter-current events that could 
possibly impact the estimand, such as treatment discontinuation due to a specific adverse effect 
or perhaps a lack of effect. T
been adopted for handling all 
known or unknown inter-current events in this study. To this end, the intent-to-treat (ITT) 
principle will serve as the analytical basis for interpreting the estimand. In other words, the odds 
ratio of achieving IGA success for ARQ-151 (Roflumilast Cream 0.3%) relative to vehicle after 8 
weeks will be evaluated regardless of the occurrence of any such inter-current event. This 
estimand shall be estimated using the CMH approach. This approach produces an estimate which 
is the combined odds ratio resulting from adjusting for the possible confounding effects of three 
classification factors investigative site, baseline IGA and baseline intertriginous involvement.
The primary efficacy endpoint is success in IGA of disease severity, defined as an IGA of
o
Almost
-grade improvement from Baseline at Week 8.
The primary endpoint will be analyzed using a Cochran-Mantel-Haenszel (CMH) test stratified 
by site, baseline IGA, and baseline intertriginous involvement.  Statistical significance will be 
concluded at the 5% significance level (2-sided).
For the primary analysis, missing IGA scores will be imputed using multiple imputation as 
described in Section 6.1.4.   These imputations will result in a minimum of 25 to a maximum of 
250 complete analysis datasets, depending on the number of imputed monotone datasets that are 
required.
The CMH analyses will be performed separately for each of the complete analysis data sets, and 
the results will be combined into one multiple imputation inference (estimated treatment effect 
and associated confidence interval and p-value).
Sensitivity analyses of the primary endpoint will also be performed using the original (non-
imputed, observed data) dataset. These will include a repeated measures logistic regression 
model (GEE) with IGA success as the dependent variable and treatment, and visit as the 
independent variables, and a tipping point analysis. The tipping point analysis will be performed 
as described in Section 6.1.4.26.1.4.2. For the tipping point analysis, a figure will be provided 
that displays the P values in the analysis plotted against the range of shift parameters; included in 
this figure will be the shift parameters and P values for the range of shift parameters to provide 
information on where the analysis tips from significant to non-significant.
All other missing data for all other analyses and summaries will remain missing and will not be 
imputed.  Only observed data will be included in the summaries showing descriptive statistics.
The primary efficacy analysis and the sensitivity analyses will be based on the ITT/mITT
population.  The analysis of the mITT population will use the MI datasets already created for the 


Statistical Analysis Plan, 
Sponsor Arcutis Biotherapeutics, Inc.
Protocol Number ARQ-151-301
PCN Number ARCU9902
AD-ST-33.05  Effective date: 22-Jan-2018
Version 1.0   |    16-Dec-2020    |    AD-PR-109.01 Effective date: 26-Jun-2017
Page 27 of 42
ITT population (i.e. no new MI datasets will be generated).
8.2.
Secondary Efficacy Analysis
The secondary endpoints are:
Time to achieving Psoriasis Area Severity Index-50 (PASI-50; subjects who achieve a 
50% reduction in PASI from Baseline)Achievement of Psoriasis Area Severity Index-75
(PASI-75; subjects who achieve a 75% reduction in PASI from Baseline) at week 8.
For subjects with intertriginous area involvement, and with severity of the intertriginous 
-
-
2-grade improvement from Baseline at 
week 8.
In subjects with Worst Itch Numeric Rating Score (WI-
baseline, achievement of a 4-point reduction in WI-NRS pruritus score at week 8 as 
compared to Baseline.
In subjects with WI-NRS
-point 
reduction in WI-NRS pruritus score at week 4 as compared to Baseline.
In subjects with WI-
-point 
reduction in WI-NRS pruritus score at week 2 as compared to Baseline.
Change from Baseline in total Psoriasis Symptoms Diary (PSD) score at week 8.
Change from Baseline in total PSD score at week 4.
For subjects with intertriginous area involvement, and with severity of the intertriginous 
lesions at le
-
-
week 8.
For the continuous variables, the number of non-missing values and the mean, standard 
deviation, minimum, median and maximum will be tabulated by treatment group and visit and 
similarly, categorical variables will have the counts and proportions of each value will be 
tabulated by treatment group and visit.
Each of the binary endpoints - achievement of PASI-75/50 at week 8, achievement of PASI-90 at 
week 8, 
I-
-grade improvement 
from Baseline at week 8 in the I-IGA-ITT population, achievement of a 4-point reduction in WI-
NRS pruritus score from baseline to weeks 8, 4, and 2 in the PRU4-ITT population, and
-
-IGA population - will be analyzed 
using CMH tests stratified by site, and baseline IGA, similar to the primary analysis above, with 
the exception that missing data will not be imputed.  Analyses of variables mentioned above with 
no population specified will be performed on the ITT population. Only observed data will be 
included in the descriptive statistics.
The continuous endpoints change from baseline in total PSD score at week 4 and at week 8 will 
be analyzed using an analysis of covariance (ANCOVA: total score only) with the factors 
treatment, site, baseline IGA, baseline intertriginous involvement, and baseline of the variable 
under analysis . Statistical comparisons between the treatment groups will be obtained using 
contrasts. The LS Means, standard errors, 95% confidence intervals, and p-values will be 
presented. These analyses will be performed on the ITT population.


Statistical Analysis Plan, 
Sponsor Arcutis Biotherapeutics, Inc.
Protocol Number ARQ-151-301
PCN Number ARCU9902
AD-ST-33.05  Effective date: 22-Jan-2018
Version 1.0   |    16-Dec-2020    |    AD-PR-109.01 Effective date: 26-Jun-2017
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The secondary endpoint time to achieving PASI-50 will be summarized using Kaplan-Meier 
methods and the difference between treatment groups evaluated using the log-rank statistic and 
95% confidence intervals of the median for each treatment group will be presented.  In addition, 
a Cox proportional hazards model that includes the stratification factors will be run and the 
hazard ratio and associated 95% confidence interval will be presented. These analyses will be 
performed on the ITT population.
Secondary endpoints will only be tested statistically if the primary endpoint is considered 
statistically significant.  To control for multiple comparisons among the secondary endpoints, the 
following multiplicity procedure will be used:
Upon successful testing of the primary endpoint (Family 1) the alpha will be partitioned to test 
secondary endpoint Families 2 and 3 (Partition 1) and to test WI-NRS timepoints (Partition 2).
Partition 1 of alpha = 0.03 will be allocated to test Family 2 and Family 3. The endpoints in 
Family 2 will be tested hierarchically in the order depicted below; the next 3 secondary 
endpoints (Family 3) will be tested using the alpha available after testing endpoint Family 2.  
The Holm procedure will be used to control for multiple comparisons in endpoint Family 3.
Partition 2 of alpha = 0.02 will be allocated to sequentially test WI-NRS success at week 8, then 
week 4 and subsequently week 2.
A figure summarizing the endpoint testing is presented below.




Statistical Analysis Plan, 
Sponsor Arcutis Biotherapeutics, Inc.
Protocol Number ARQ-151-301
PCN Number ARCU9902
AD-ST-33.05  Effective date: 22-Jan-2018
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For the primary endpoint of IGA success (IGA of
o
Almost
-grade 
improvement from Baseline at Week 8), subgroup analysis will be performed on the following:
Topical Corticosteroids
Inadequate Response, intolerance or contraindication (Y/N)
Topical Vitamin D Derivatives Inadequate Response, intolerance or contraindication
(Y/N)
Apremilast (Otezla) subjects with any prior use/no prior use
Psoriasis involvement on the elbow (yes)
Psoriasis involvement on the knee (yes)
Psoriasis involvement on the knee or elbow (either one)
By site
By age categories ( 2- 11, 12 -17, >= 18)
Subgroups based on baseline BSA severity, grouped into mild, moderate, and severe categories 
will be analyzed for the following variables:
IGA and I-IGA success
PASI-50, PASI-75, PASI-90
investigator local tolerability and subject local tolerability assessments
WI-NRS
where the BSA groups are defined as follows:
1.
Mild BSA Severity: up to 5% BSA at baseline
2.
Moderate BSA Severity: >=5-10% BSA at baseline
3. Severe BSA Severity: >=10% BSA at baseline
For the subgroup of subjects with intertriginous area involvement or face involvement (defined 
medical history assessment of psoriasis) analyses of the following variables will be performed:
IGA and I-IGA success
PASI-50, PASI-75, PASI-90
Investigator local tolerability and subject local tolerability assessments
WI-NRS
All analyses of these endpoints will be performed on the observed data with no imputation.
8.4.
Patient Reported Outcomes  
The continuous endpoints change from baseline in WI-NRS, change from baseline in PSD, 
change from baseline in total DLQI score, and change from baseline in total CDLQI will be 
analyzed using an analysis of covariance (ANCOVA: total score only) with the factors treatment, 
site, baseline IGA, baseline intertriginous involvement, and baseline of the variable under 
analysis. Statistical comparisons between the treatment groups will be obtained using contrasts. 


Statistical Analysis Plan, 
Sponsor Arcutis Biotherapeutics, Inc.
Protocol Number ARQ-151-301
PCN Number ARCU9902
AD-ST-33.05  Effective date: 22-Jan-2018
Version 1.0   |    16-Dec-2020    |    AD-PR-109.01 Effective date: 26-Jun-2017
Page 31 of 42
The LS Means, standard errors, 95% confidence intervals, and p-values will be presented. These 
analyses will be performed on the ITT population.
Observed and change from baseline scores in WI-NRS itch severity, the total and individual PSD 
items, and the total and individual for both DLQI and CDLQI items will be summarized 
descriptively by treatment group and time point using continuous summary statistics.  These 
summaries will be presented for both the ITT and mITT populations. 
All analyses will be performed on the observed data with no imputation.
9.
Safety and Tolerability Analysis
Safety will be evaluated from reported AEs, local tolerability assessments, changes in clinical 
laboratory values, changes in vital signs, C-SSRS, PHQ-8/modified PHQ-A and CDI-2 results.
All safety analyses will be performed on the Safety population.
9.1.
Adverse Events
All AEs, TEAEs, and SAEs will be coded using the MedDRA dictionary v. 23.0.
An overall summary of TEAEs will be provided; this will present number and percent of subjects 
who reported at least 1: TEAE (including all TEAEs, TEAEs by maximum severity, and TEAEs 
by greatest relationship), SAE, discontinued IP due to a TEAE, or had a TEAE resulting in death.
The number and percent of subjects reporting treatment emergent AEs, grouped by MedDRA 
system organ class and preferred term, will be tabulated by severity or greatest relationship to 
study IP and treatment group. In the case of multiple occurrences of the same TEAE within the 
same subject, each subject will only be counted once for each preferred term.
In the summaries showing severity and relationship to study medication the event with the 
maximum severity (death related to AE > life-threatening consequences > severe > moderate > 
mild) or strongest relationship (unrelated < unlikely < possibly < probably < likely) will be 
reported. If a particular event is missing the severity and/or relationship, then the strongest 
possible severity or relationship will be assumed for analysis (severity = severe, relationship = 
likely). The number and percent of subjects reporting related treatment emergent AEs will be 
tabulated by preferred term and severity. 
In the AE data listings, all AEs will be displayed. AEs that are not treatment-emergent will be 
flagged.
9.1.1. Adverse Events Leading to Withdrawal
A summary of incidence rates (frequencies and percentages) of TEAEs leading to withdrawal of 
IP, by treatment group, SOC, and preferred term will be prepared for the Safety Population. No 
inferential statistical tests will be performed.
A data listing of AEs leading to withdrawal of IP will also be provided, displaying details of the 
event(s) captured on the CRF.


Statistical Analysis Plan, 
Sponsor Arcutis Biotherapeutics, Inc.
Protocol Number ARQ-151-301
PCN Number ARCU9902
AD-ST-33.05  Effective date: 22-Jan-2018
Version 1.0   |    16-Dec-2020    |    AD-PR-109.01 Effective date: 26-Jun-2017
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9.1.2. Deaths and Serious Adverse Events
Any deaths that occur during the study will be listed.
Serious adverse events will be listed and also tabulated by system organ class and preferred term 
and presented by treatment as well as by relationship to IP and maximum severity.
9.1.3. Adverse Events of Special Interest (AESIs)
AESIs may be identified and multiple MedDRA preferred terms may be grouped together to 
calculate the subject incidence of adverse events of interest.
9.2.
Local Tolerance Assessments
will be summarized by visit using 
both categorical methods (number and percentage of subject with each score) as well as 
continuous methods (e.g., mean, standard deviation, etc.). No inferential statistical tests will be 
performed.
of the application site reaction will be summarized similarly.
9.3.
Clinical Laboratory Evaluations
Laboratory test results will be summarized descriptively by treatment and time point as both 
observed values and changes from baseline.
The number of subjects with clinical laboratory values below, within, or above the normal range 
by time point and in relation to baseline will be tabulated for each clinical laboratory analyte by 
treatment group (shift table).
9.4.
Vital Signs
Descriptive summaries of observed values and changes from baseline will be calculated for body 
weight, height, BMI, systolic blood pressure, diastolic blood pressure, heart rate, and oral body 
temperature by treatment group and time point.
Shift table (overall, subjects who indicated weight loss was intentional and subjects weight loss 
was not intentional at each visit) by treatment group will summarize the number of subjects who 
gain or lose >=5% of their baseline body weight during the course of the study, as well as 
subjects who gain or lose >=10% of their baseline body weight over the course of the study.
BMI is derived as specified in Section Error! Reference source not found.. Shift tables
(overall, subjects who indicated weight loss was intentional and subjects weight loss was not 
intentional at each visit) by treatment group for subjects who shift from their baseline BMI 
category (underweight, normal, overweight, obese) to a different BMI category throughout the 
course of the study will be provided by treatment group and visit. 


Statistical Analysis Plan, 
Sponsor Arcutis Biotherapeutics, Inc.
Protocol Number ARQ-151-301
PCN Number ARCU9902
AD-ST-33.05  Effective date: 22-Jan-2018
Version 1.0   |    16-Dec-2020    |    AD-PR-109.01 Effective date: 26-Jun-2017
Page 33 of 42
9.5.
PHQ and Modified PHQ-A
Data for PHQ-8 and Modified PHQ-
point into a category based on the following scoring system: 
None Minimal depression (0 to 4)
Mild depression (5 to 9)
Moderate depression (10 to 14)
Moderately severe depression (15 to 19)
Severe depression (20 to 24)
Shift tables showing the category of severity at each time point by treatment group will be 
presented.
9.6.
CDI-2 
For Children
-2), descriptive summaries of observed values and 
changes from baseline will be calculated for the total score and the 2 scales emotional problems 
and functional problems by treatment group and visit.
All CDI-2 data will be listed.
9.7.
C-SSRS
The C-SSRS is a questionnaire that prospectively assesses Suicidal Ideation and Suicidal 
-SSRS will be 
Suicidality data collected on the C-SSRS will be listed for all subjects. Tables will include results 
from the Suicidal Ideation and Suicidal Behavior sections of the C-SSRS. Frequencies and 
Suicidal Behavior items will be summarized by study visit and treatment group. 
All C-SSRS data will be listed.
9.8.
Physical Examination
The number and percentage of subjects with normal and abnormal findings in the physical 
examination will be displayed at each study visit and treatment group.


Statistical Analysis Plan, 
Sponsor Arcutis Biotherapeutics, Inc.
Protocol Number ARQ-151-301
PCN Number ARCU9902
AD-ST-33.05  Effective date: 22-Jan-2018
Version 1.0   |    16-Dec-2020    |    AD-PR-109.01 Effective date: 26-Jun-2017
Page 34 of 42
9.9.
Concomitant Medication
Prior and concomitant medications will be summarized descriptively by treatment group, overall, 
ATC level 4, and preferred term using counts and percentages.
Prior medications will be presented separately from concomitant medications. Medications that 
started prior to the first application of IP will be considered prior medications whether or not 
they were stopped prior to the first application of IP. Any medications continuing or starting post 
the first application of IP will be considered to be concomitant. If a medication starts prior to the 
first application of IP and continues after the first application of IP it will be considered both 
prior and concomitant.
Medications will be coded using WhoDrug Global B3, vSep2019.
10.
Changes from Planned Analysis
Per Protocol population is described in the protocol however that population and the associated 
analyses have been removed as they were considered to be uninformative.
Modified Intent-To-Treat Population has been added into account for COVID-19 disruption.
Additional exploratory endpoints have been added in the SAP which are not specified in the 
protocol.  They are:


Statistical Analysis Plan, 
Sponsor Arcutis Biotherapeutics, Inc.
Protocol Number ARQ-151-301
PCN Number ARCU9902
AD-ST-33.05  Effective date: 22-Jan-2018
Version 1.0   |    16-Dec-2020    |    AD-PR-109.01 Effective date: 26-Jun-2017
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For the primary endpoint of IGA success (IGA of
o
Almost
-
grade improvement from Baseline at Week 8), subgroup analysis will be performed on 
the following, only summary statistics:
o
Topical Corticosteroids
Inadequate Response, intolerance or contraindication
(Y/N)
o
Topical Vitamin D Derivatives Inadequate Response, intolerance or 
contraindication (Y/N)
o
Prior Apremilast (Otezla) Use subjects with any prior use / no prior use
o
Psoriasis involvement on the elbow (yes)
o
Psoriasis involvement on the knee (yes)
o
Psoriasis involvement on the knee or elbow (either one)
o
By site
o
By age categories (2- 11, 12- 17, >= 18)
Subgroups based on baseline BSA severity, grouped into mild, moderate, and severe 
categories will be analyzed for the following variables, only summary statistics:
o
IGA and I-IGA success
o
PASI-50, PASI-75, PASI-90
o
investigator local tolerability and subject local tolerability assessments
o
WI-NRS
      where the BSA groups are defined as follows:
1.
Mild BSA Severity: up to 5% BSA at baseline
2.
Mod BSA Severity: >=5-10% BSA at baseline
3. Severe BSA Severity: >=10% BSA at baseline
For the subgroup of subjects with intertriginous area involvement or face involvement 
(defined medical history assessment of psoriasis) analyses of the following variables will 
be performed only summary statistics:
o
IGA and I-IGA success
o
PASI-50, PASI-75, PASI-90
o
Investigator local tolerability and subject local tolerability assessments
o
WI-NRS
For PSD, DLQI and CDLQI individual questions will be summarized descriptively by 
treatment group and time point using both continuous summary statistics for the ITT 
population.
Shift tables by treatment group for subjects who shift from their baseline BMI category 
(underweight, normal, overweight, obese) to a different BMI category throughout the 
course of the study will be provided by treatment group and visit. 
The number and percentage of subjects with normal and abnormal findings in the physical 
examination will be displayed at each study visit and treatment group.


Statistical Analysis Plan, 
Sponsor Arcutis Biotherapeutics, Inc.
Protocol Number ARQ-151-301
PCN Number ARCU9902
AD-ST-33.05  Effective date: 22-Jan-2018
Version 1.0   |    16-Dec-2020    |    AD-PR-109.01 Effective date: 26-Jun-2017
Page 36 of 42
Tipping point analysis has been included as a sensitivity analysis for the primary 
endpoint
The mITT population will also be used as a sensitivity analysis for the primary endpoint
Analysis of covariance (ANCOVA) analyses of the following:
o
change and percent change from baseline in PASI
o
change from baseline in affected percent BSA
o
change and percent change from baseline in mPASI
o
change and percent change in WI-NRS
o
change and percent change in DLQI
o
change and percent change in CDLQI
Achievement of PASI-90 (subjects who achieve a 90% reduction in PASI from Baseline) 
at week 8 was a planned secondary endpoint in the protocol and has been moved to an
exploratory endpoint
The testing of the secondary endpoints in section 6.1.3 has been modified from what is in 
in the protocol.
Shift from baseline in Weight and BMI tables are repeated based on the 
intentional/nonintentional or missing weight loss question captured in the CRF at each 
visit.
Incidence of TEAEs leading to study discontinuation by SOC and preferred term
Incidence of related TEAEs by preferred term
11.
Other Planned Analysis
11.1.
Pharmacokinetic Analysis
Concentration data will be summarized by timepoint and treatment group using summary 
statistics.
Data will be listed in the data listing. 
11.2.
Intertriginous Subjects
Only a small percentage of subjects enrolled into the ARQ-151-301 and ARQ-151-302 studies 
have intertriginous involvement. Since these small numbers make drawing conclusions about this 
population difficult, it is planned to pool the data for the subjects with intertriginous involvement 
from these two studies together for a subgroup analysis of this population in the integrated 
summary of efficacy.
12.
References
1. US Federal Register. (1998) International Conference on Harmonization; Guidance on