A Phase 2b 12-Week Parallel Group, Double Blind, Vehicle-Controlled Study of the Safety, Efficacy and Pharmacokinetics of ARQ-151 Cream 0.3% and ARQ-151 Cream 0.15% Administered Once Daily in Subjects With Chronic Plaque Psoriasis
Phase: PHASE2
Conditions: Plaque Psoriasis
Sponsor: Arcutis Biotherapeutics, Inc.

 
 
Study 
Number: 
ARQ-151-201 
NCT #: 
NCT03638258 
Official 
Title: 
A Phase 2b 12-Week Parallel Group, Double 
Blind, Vehicle- 
Controlled Study of the Safety, Efficacy and 
Pharmacokinetics of 
ARQ-151 Cream 0.3% and ARQ-151 Cream 
0.15% 
Administered QD in Subjects with Chronic 
Plaque Psoriasis 
 
Protocol 
Date: 
02-Aug-2018 
 

 
 
 
Protocol ARQ-151-201 
Amendment 1 
A Phase 2b 12-Week Parallel Group, Double Blind, Vehicle-
Controlled Study of the Safety, Efficacy and Pharmacokinetics of 
ARQ-151 
Cream 
0.3% 
and ARQ-151 
Cream 
0.15% 
Administered QD in Subjects with Chronic Plaque Psoriasis 
 
 
 
 
GCP Statement 
This study is to be performed in full compliance with the protocol, Good Clinical Practices 
(GCP), and applicable regulatory requirements. All required study documentation will be 
archived as required by regulatory authorities. 
 
Confidentiality Statement 
This document is confidential. It contains proprietary information of Arcutis, Inc. Any 
viewing or disclosure of such information that is not authorized in writing by Arcutis, Inc. is 
strictly prohibited. Such information may be used solely for the purpose of reviewing or 
performing this study. 

Protocol ARQ-151-201 
Arcutis, Inc. 
Amendment 1.0  
 
November 8, 2018 
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PROTOCOL REVISION HISTORY 
Version/Date 
Description 
ARQ-151-201 Version 1 
August 2, 2018 
Original protocol 
ARQ-151-201 Amendment 1.0 
November 8, 2018 
• 
Added protocol revision history section. 
• 
Added the Dermatology Life Quality Index (DLQI) to visits 
1 through 7. 
• 
Updated modified Intent to Treat (mITT) population to 
Intent to Treat (ITT) population.  
• 
Added footnote “b” in the Study Events Flowchart to clarify 
routine blood chemistries if Baseline is within 14 days of 
Screening, the Screening results may be utilized for 
Baseline. The other footnotes were updated accordingly.  
• 
Footnote “m” has been revised to include collection of the 
tube weight prior to the application and after the application. 
• 
Added footnote “r” to the Study Events Flowchart to update 
the duration of subject participation for the study.  Subjects 
who enroll into the open label extension study (ARQ-151-
202) will complete the study at Week 12; subjects that do 
not enroll into ARQ-151-202 will return at Week 16 to 
complete the study. 
• 
Revised Inclusion Criterion #8 to more completely define 
Females of Non-Child Bearing Potential to include those 
who are post-menopausal or surgically sterile.  
• 
Revised Exclusion Criterion #5 to clarify subjects with 
palmoplantar only involvement are to be excluded. 
• 
Clarified the optional PK draws will be applicable only to 
subjects who enter the 4-week follow up period. 
• 
Added text in Data Analysis section relevant to the PSD and 
addition of the DLQI; changed primary analysis population 
from mITT to ITT per FDA advice; rearranged order of 
subsections under Data Analysis to improve organization. 
• 
Editorial and administrative changes throughout the protocol 
to clarify language and formatting to improve readability. 
  
 

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Amendment 1.0  
 
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2 
ADDITIONAL KEY CONTACTS FOR THE STUDY 
Sponsor Contact for Serious Adverse 
Event Reporting 
 
 
 
 
 
 
Medical Monitor 
 
 
 
 
 
  
 
Managing CRO 
Cu-Tech, LLC 
333 US Highway 46 West 
Mountain Lakes, NJ 07046 
  
 
 
 
Certified Clinical Laboratory 
ACM Global Laboratories 
160 Elmgrove Park 
Rochester, NY 14624, USA  
 
 
Bioanalytical Laboratory 
Q Squared Solutions BioSciences, LLC 
19 Brown Road 
Ithaca, NY 14850 
 
 
 
Pharmacokinetic Analysis 
 
ADME Solutions, Inc. 
 
 
  

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Arcutis, Inc. 
Amendment 1.0  
 
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ADDITIONAL KEY CONTACTS FOR THE STUDY (Cont.) 
 
Data Management / Statistical 
Analysis 
 
QST Consultations, Ltd. 
11275 Edgewater Drive 
Allendale, MI 49401 
  
 

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Arcutis, Inc. 
Amendment 1.0  
 
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3 
TABLE OF CONTENTS 
1 
PRINCIPAL INVESTIGATOR AND SPONSOR – SIGNATORIES ............................. 2 
2 
ADDITIONAL KEY CONTACTS FOR THE STUDY .................................................... 4 
3 
TABLE OF CONTENTS ..................................................................................................... 6 
4 
SYNOPSIS ........................................................................................................................... 10 
5 
SCHEDULE OF VISITS AND ASSESSMENTS ............................................................ 15 
6 
ABBREVIATIONS ............................................................................................................. 17 
7 
BACKGROUND AND RATIONALE .............................................................................. 19 
7.1 
Introduction ................................................................................................................. 19 
7.2 
Preclinical Studies ....................................................................................................... 19 
7.2.1 Repeat-Dose Toxicity ............................................................................................... 20 
7.2.2 Oral (Systemic) Studies of Roflumilast and N-Oxide Metabolite ............................ 21 
7.2.3 Reproductive Toxicity .............................................................................................. 22 
7.2.4 Genotoxicity .............................................................................................................. 22 
7.2.5 Carcinogenicity ......................................................................................................... 22 
7.2.6 Special Toxicity:  Local Tolerance of Topical Formulation ..................................... 23 
7.2.7 Conclusions on Toxicity Findings ............................................................................ 23 
7.3 
Clinical Studies ............................................................................................................ 24 
7.3.1 Topical Roflumilast Cream ....................................................................................... 24 
7.3.2 Oral Roflumilast Tablet ............................................................................................ 26 
7.4 
Rationale for Development......................................................................................... 27 
7.4.1 Dose Selection .......................................................................................................... 27 
7.4.2 Risks and/or Benefits to Subjects ............................................................................. 28 
8 
STUDY ENDPOINTS AND OBJECTIVES ..................................................................... 29 
8.1 
Study Objectives.......................................................................................................... 29 
8.1.1 Primary Objectives.................................................................................................... 29 
8.2 
Efficacy Endpoints ...................................................................................................... 29 
8.2.1 Primary Endpoint ...................................................................................................... 29 
8.2.2 Secondary Endpoints ................................................................................................ 30 
8.2.3 Exploratory Endpoints .............................................................................................. 30 
9 
INVESTIGATIONAL PLAN ............................................................................................ 31 
9.1 
Overall Study Design and Plan .................................................................................. 31 
9.2 
Subject Participation .................................................................................................. 31 
9.2.1 Randomization .......................................................................................................... 32 
9.2.2 Numbering of Subjects ............................................................................................. 32 
9.3 
Selection of Study Population .................................................................................... 32 
9.3.1 Inclusion Criteria ...................................................................................................... 32 
9.3.2 Exclusion Criteria ..................................................................................................... 33 

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Amendment 1.0  
 
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9.3.3 Removal of Subjects from the Study ........................................................................ 34 
9.4 
Study Restrictions ....................................................................................................... 35 
9.4.1 Prohibitions and Concomitant Therapy .................................................................... 35 
9.5 
Treatment .................................................................................................................... 36 
9.5.1 Drug Supplies, Packaging and Labeling ................................................................... 36 
9.5.2 Blinding..................................................................................................................... 36 
9.5.3 Treatment Administration ......................................................................................... 36 
9.5.4 Treatment Compliance .............................................................................................. 37 
10 STUDY PROCEDURES .................................................................................................... 38 
10.1 
Safety Assessments ...................................................................................................... 38 
10.1.1 
Screening............................................................................................................... 38 
10.1.2 
Physical Examination............................................................................................ 38 
10.1.3 
Vital Signs, Height and Weight ............................................................................ 38 
10.1.4 
12-Lead ECGs ....................................................................................................... 39 
10.1.5 
Laboratory Tests ................................................................................................... 39 
10.1.6 
Patient Health Questionnaire depression scale (PHQ-8) ...................................... 40 
10.1.7 
Columbia-Suicide Severity Rating Scale (C-SSRS) ............................................. 42 
10.1.8 
Local Tolerability Assessments ............................................................................ 42 
10.1.9 
Adverse Events ..................................................................................................... 43 
10.2 
Efficacy Evaluations ................................................................................................... 44 
10.2.1 
Investigator’s Global Assessment (IGA) .............................................................. 44 
10.2.2 
Modified Psoriasis Area and Severity Index (mPASI) ......................................... 45 
10.2.3 
Body Surface Area (BSA) .................................................................................... 46 
10.2.4 
Worst Itch Numerical Rating Scale (WI-NRS) .................................................... 46 
10.2.5 
Fatigue NRS .......................................................................................................... 46 
10.2.6 
Work Productivity and Activity Impairment (WPAI) .......................................... 47 
10.2.7 
Itch-Related Sleep Loss ........................................................................................ 47 
10.2.8 
Psoriasis Symptom Diary (PSD) ........................................................................... 47 
10.2.9 
Dermatology Life Quality Index (DLQI) ............................................................. 48 
10.2.10 Dermal Imaging .................................................................................................... 48 
10.3 
Pharmacokinetics Assessment ................................................................................... 48 
10.4 
Adverse Events ............................................................................................................ 48 
10.4.1 
Adverse Event Definition ..................................................................................... 48 
10.4.2 
Serious Adverse Event .......................................................................................... 49 
10.4.3 
Suspected Unexpected Serious Adverse Reaction (SUSAR) ............................... 50 
10.4.4 
Safety Review ....................................................................................................... 50 
10.4.5 
Adverse Event Reporting ...................................................................................... 50 
10.5 
Reporting Pregnancy .................................................................................................. 52 
10.6 
Treatment Stopping Rules ......................................................................................... 52 
10.6.1 
Emergency Unblinding ......................................................................................... 53 
11 DATA ANALYSIS .............................................................................................................. 53 

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Amendment 1.0  
 
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11.1 
Statistical Methods ...................................................................................................... 53 
11.1.1 
Determination of Sample Size .............................................................................. 54 
11.1.2 
Subjects to Analyze............................................................................................... 54 
11.1.3 
Interim Analysis .................................................................................................... 54 
11.1.4 
Background and Demographic Characteristics ..................................................... 54 
11.1.5 
Study Medication Compliance .............................................................................. 55 
11.2 
Efficacy Evaluation ..................................................................................................... 55 
11.2.1 
Primary Efficacy Endpoint ................................................................................... 55 
11.2.2 
Secondary Endpoints ............................................................................................ 55 
11.2.3 
Exploratory Endpoints .......................................................................................... 56 
11.3 
Safety Evaluation ........................................................................................................ 56 
11.3.1 
Adverse Events ..................................................................................................... 56 
11.3.2 
Local Tolerance Assessments ............................................................................... 57 
11.3.3 
Medical History and Physical Examinations ........................................................ 57 
11.3.4 
PHQ-8 ................................................................................................................... 57 
11.3.5 
C-SSRS ................................................................................................................. 58 
11.3.6 
Clinical Laboratory Results and Vital Signs/Weight Measurements ................... 58 
11.3.7 
Prior and Concomitant Medications ..................................................................... 58 
11.4 
Patient Reported Outcomes Analyses ....................................................................... 58 
11.4.1 
WI-NRS, Fatigue NRS, Itch-Related Sleep Loss ................................................. 58 
11.4.2 
Work Productivity and Activity Impairment (WPAI) Questionnaire ................... 58 
11.4.3 
Dermatology Life Quality Index (DLQI) ............................................................. 58 
11.4.4 
Psoriasis Symptom Diary (PSD) ........................................................................... 58 
11.5 
Pharmacokinetic Analysis .......................................................................................... 59 
12 STUDY ADMINISTRATION ........................................................................................... 59 
12.1 
Ethics ............................................................................................................................ 59 
12.1.1 
Ethics Review Board............................................................................................. 59 
12.1.2 
Ethical Conduct of the Study ................................................................................ 59 
12.1.3 
Subject Information and Consent.......................................................................... 60 
12.2 
Study Monitoring ........................................................................................................ 60 
12.3 
Data Quality Assurance .............................................................................................. 60 
12.3.1 
Verification of Blinding ........................................................................................ 60 
12.4 
Data Handling and Record Keeping ......................................................................... 61 
12.5 
Protocol Amendments and Deviations ...................................................................... 61 
12.6 
Report Format ............................................................................................................. 62 
12.7 
Publication Policy........................................................................................................ 62 
13 REFERENCES .................................................................................................................... 63 
14 APPENDICES ..................................................................................................................... 64 
 
 
 

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Arcutis, Inc. 
Amendment 1.0  
 
November 8, 2018 
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LIST OF TABLES 
 
Table 1: Excluded Medications and Treatments ........................................................................... 35 
Table 2.: Laboratory Tests ............................................................................................................ 39 
 
 
LIST OF FIGURES 
 
Figure 1: TPSS x TPS Fitted Summary Statistics from MMRM (mITT Population) .................. 25 
 
 
LIST OF APPENDICES 
 
Appendix 1: Work Productivity and Activity Impairment Questionnaire (WPAI) ...................... 64 
Appendix 2: Columbia-Suicide Severity Rating Scale (C-SSRS) Baseline/Screening 
Version .................................................................................................................... 66 
Appendix 3: Columbia-Suicide Severity Rating Scale (C-SSRS) Since Last Visit Version ........ 69 
Appendix 4: Psoriasis Symptom Diary (PSD) .............................................................................. 72 
Appendix 5: Dermatology Life Quality Index (DLQI)................................................................. 75 
Appendix 6: National Institute of Allergy and Infectious Diseases, Division of 
Microbiology and Infectious Diseases (DMID) Toxicity Table for Use in 
Trials Enrolling Healthy Adults (2014) Modified ................................................... 77 
 
 
 

Protocol ARQ-151-201 
Arcutis, Inc. 
Amendment 1.0  
 
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4 
SYNOPSIS 
Compound: 
ARQ-151 cream 0.3% and ARQ-151 cream 0.15% 
IND 
135681 
Clinical Indication: 
Chronic Plaque Psoriasis 
Study Phase and 
Type: 
Phase 2b Parallel Group, Double Blind, Vehicle-Controlled Study  
Study Objectives: 
To assess the safety and efficacy of ARQ-151 cream 0.3% and ARQ-151 
cream 0.15% vs. vehicle administered QD for 84 days to individuals with 
2 - 20% BSA of chronic plaque psoriasis.  
Summary of Study 
Design: 
This is a parallel group, double blind, vehicle-controlled study in which 
ARQ-151 cream 0.3% or ARQ-151 cream 0.15% or vehicle cream is 
applied QD for 84 days to subjects with chronic plaque psoriasis involving 
between 2 and 20% BSA. 
Blinding: 
This study is double blind and vehicle controlled 
Countries:  
Canada and United States  
Number of sites: 
Approximately 30 sites  
Study Population: 
Subjects will be male and female 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. 
Subjects with an IGA of ‘Mild’ (2) will be limited to 20% of total 
enrollment and subjects with IGA of ‘Severe” (4) will be limited to 15% of 
total enrollment. 
Main Inclusion 
Criteria 
1. Participants legally competent to sign and give informed consent 
2. Males and females ages 18 years and older  
3. Clinical diagnosis of psoriasis vulgaris of at least 6 months duration as 
determined by the Investigator 
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 mPASI score of at least 2 (excluding the scalp, palms and soles) at 
Baseline  
7. Females of childbearing potential (FOCBP) must have a negative urine 
pregnancy test at Screening (Visit 1) and Baseline (Visit 2). In addition, 
sexually active FOCBP must agree to use at least one form of highly 
effective contraception throughout the trial.  Highly effective forms of 
contraception include: oral/implant/injectable/transdermal 
contraceptives, intrauterine device, and partner’s vasectomy.  If barrier 
methods are used (e.g., condom with spermicide, diaphragm with 
spermicide), then 2 forms of conception are required. The use of 
abstinence as a contraceptive measure is acceptable as long as this is a 

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Arcutis, Inc. 
Amendment 1.0  
 
November 8, 2018 
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consistent part of a lifestyle choice and an acceptable backup method 
has been identified if the subject becomes sexually active. 
8. Females of non-childbearing potential should be post-menopausal with 
spontaneous amenorrhea for at least 12 months or have undergone 
surgical sterilization (permanent sterilization methods include 
hysterectomy, bilateral oophorectomy, hysteroscopic sterilization, 
bilateral tubal ligation or bilateral salpingectomy). 
Main Exclusion 
Criteria 
1. Subjects who cannot discontinue medication and treatments  prior to the 
Baseline visit and during the study according to Excluded Medications 
and Treatments (Table 1). 
2. Planned excessive exposure of treated area(s) to either natural or 
artificial sunlight, tanning bed or other LED. 
3. Subjects currently taking lithium or antimalarial drugs. 
4. Planned initiation or changes to concomitant medication that could, in 
the opinion of the Investigator, affect psoriasis vulgaris (e.g. beta 
blockers, ACE inhibitors).  
5. Current diagnosis of guttate, erythrodermic/exfoliative, palmoplantar 
only involvement, or pustular psoriasis.  
6. Subjects with any condition on the treatment area which, in the opinion 
of the Investigator, could confound efficacy measurements. 
7. Known allergies to excipients in ARQ-151 cream
 
 
 
  
8. Subjects who cannot discontinue the use of strong P-450 cytochrome 
inhibitors (e.g., indinavir, nelfinavir, ritonavir, clarithromycin, 
itraconazole, ketoconazole, nefazodone, saquinavir, suboxone and 
telithromycin) for two weeks prior to the baseline visit and during the 
study period.  
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. 
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 severe hepatic disorders  
• 
hypersensitivity to component(s) of the investigational products  
• 
history of severe depression, suicidal ideation 
14. 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. 

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Amendment 1.0  
 
November 8, 2018 
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Number of 
Subjects: 
Approximately 300 subjects; randomized 1:1:1 to ARQ-151 cream 0.3% 
QD : ARQ-151 cream 0.15% QD : vehicle QD 
Duration of 
Participation for 
Subjects: 
All subject will participate in Screening (up to 5 weeks) and Treatment 
phases (12 weeks).  
Upon completion of this study, participants may have the opportunity, 
subject to regulatory approval, to participate in an open-label extension 
study of up to 12 months, receiving the 0.3% concentration of drug product 
(ARQ-151-202). 
For subjects who enroll in ARQ-151-202, the week 12 visit will complete 
this study.  Subjects who do not enroll in ARQ-151-202 will return for a 
follow-up visit (4 weeks post-treatment completion). 
Study Products: 
• ARQ-151 drug product will be supplied as a 0.3% and 0.15% cream 
• Matching vehicle cream will contain only excipients of ARQ-151 cream 
Planned Dose 
Level: 
Subjects will receive ARQ-151 cream 0.3% QD or ARQ-151 cream 0.15% 
QD or matching vehicle cream QD applied to all psoriatic lesions up to and 
including an area of 20% BSA. Application will be all areas affected 
including the face and intertriginous/genital regions (except for the scalp).   
Safety Assessments: 
Safety will be monitored through application site assessments, safety labs, 
12-lead ECGs, PHQ-8, C-SSRS and AEs. 
Safety Analysis: 
The following analyses will be performed; however, no formal inferential 
statistics will be done on safety assessments. 
Descriptive statistics will be calculated for quantitative safety data and 
frequency counts will be compiled for classification of qualitative safety 
data.  
Descriptive statistics will be calculated for the PHQ-8. 
The C-SSRS will be analyzed per the Scoring and Data Analysis Guide 
from the Columbia Lighthouse Project.  
Adverse Events: 
A subject-by-subject treatment-emergent AE (TEAE) data listing, including 
verbatim term, preferred term, treatment, severity, and relationship to study 
drug, will be provided. 
The number of subjects experiencing AEs and number of AEs will be 
summarized by treatment using frequency counts. 
Medical History and Physical Examinations: 
Medical history will be listed by subject.  Physical examinations and 
12-lead ECGs will be performed at screening, Week 4 and end-of-study. 
Vital signs will be collected at all study visits.  
Clinical Laboratory Results: 
Routine blood chemistries will be obtained at screening, baseline, week 4 
and week 12.  If Baseline is within 14 days of Screening, the Screening 
results may be utilized.  Urine pregnancy tests will be obtained at screening, 
baseline, weeks 4, 8, and 12. 

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Amendment 1.0  
 
November 8, 2018 
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Efficacy Analysis 
The Primary Efficacy Endpoint will be an IGA score of ‘clear’ or ‘almost 
clear’ at week 6. 
The secondary efficacy endpoints will include: 
• 
IGA score of ‘clear’ or ‘almost clear’ at weeks 4, 8 and 12.  
• 
Percent reduction in mPASI at weeks 4, 6, 8, and 12 as compared to 
Baseline. 
• 
Decrease in percent BSA affected at weeks 4, 6, 8, and 12 as 
compared to baseline. 
• 
IGA score of ‘clear’ or ‘almost clear’ PLUS a 2-grade improvement 
from Baseline at weeks 4, 6, 8 and 12. 
• 
For subjects with intertriginous area involvement, and with severity of 
the intertriginous lesions at least ‘mild’ (intertriginous IGA (I-IGA) 
≥2) at Baseline, ‘I-IGA’ score of ‘clear’ or ‘almost clear’ at weeks 4, 
6, 8 and 12. 
• 
Reduction in WI-NRS pruritus score at weeks 4, 6, 8, and 12 as 
compared to Baseline. 
• 
In subjects with WI-NRS pruritus score ≥ 6 at baseline, a 4-point 
reduction in WI-NRS pruritus score at weeks 4, 6, 8, and 12 as 
compared to Baseline. 
• 
Modified Psoriasis Area Severity Index-75 (mPASI-75; subjects who 
achieve a 75% reduction in mPASI from Baseline) improvement at 
weeks 4, 6, 8, and 12 as compared to Baseline. 
• 
Modified Psoriasis Area Severity Index-90 (mPASI-90; subjects who 
achieve a 90% reduction in mPASI from Baseline) improvement at 
weeks 4, 6, 8, and 12 as compared to Baseline. 
• 
Total PSD at weeks 4, 6, 8, and 12 as compared to Baseline. 
• 
Reduction in Itch-related Sleep Loss score at weeks 4, 6, 8, and 12 as 
compared to Baseline. 
• 
Reduction in Dermatology Life Quality Index (DLQI) score at weeks 
4, 6, 8, and 12 as compared to Baseline. 
• 
Responses to the questions of PSD analyzed as improvement at weeks 
4, 6, 8, and 12 as compared to Baseline. 
Exploratory Endpoints are as follows:  
• 
Reduction in Fatigue NRS score at weeks 4, 6, 8, and 12 as compared 
to Baseline. 
• 
Reduction in WPAI score at weeks 4, 6, 8, and 12 as compared to 
Baseline. 
 

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Amendment 1.0  
 
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Power and Sample 
Size 
Approximately 300 subjects are planned for this study.   
Approximately 100 subjects will receive ARQ-151 cream 0.3% QD; 
approximately 100 subjects will receive ARQ-151 cream 0.15% QD; 
approximately 100 subjects will receive matching vehicle cream QD. 
The randomization scheme will be 1:1:1 (ARQ-151 cream 0.3% QD : 
ARQ-151 cream 0.15% QD : matching vehicle QD. 
The sample size was not powered based on data for the primary endpoint 
to provide statistical significance because of the absence of previous 
primary endpoint data. However, based on efficacy data from the proof of 
concept study, this Phase 2b study is expected to provide reliable 
information regarding the efficacy and safety of the drug products. 
Pharmacokinetic 
Sample Collection:  
PK draws will be done on days 1 (baseline), 29 (week 4) and 85 
(week 12) pre-dose (trough) for all subjects.  
Approximately 30 subjects who enter the 4 week follow up period with 
greater than or equal to 5% BSA involvement will have the option to have 
additional PK draws at 72 hr (3 days), 120 hr (5 days), 168 hr (7 days), 
and 216 hr (9 days) after the last dose of drug.   
For the 72 hour timepoint, the PK draw should be +/- 2 hours of the last 
study drug application.  The 5, 7 and 9 day draws should be completed in 
the morning before noon at the site.  
Statistical Analysis: 
Four analysis populations will be defined: 
• 
Safety population will include all subjects who are enrolled and 
received at least one confirmed dose of study medication; this 
population will be defined separately for each cohort. 
• 
Intent-to-Treatment (ITT) population will include all randomized 
subjects. 
• 
Per-Protocol (PP) Population will include all subjects who are in 
the safety population, were at least 80% compliant with study 
medication, and showed no other serious deviations from the 
study protocol. 
• 
PK population will include all subjects receiving the active drug 
with quantifiable plasma concentrations of roflumilast. 
Descriptive statistics will be presented for the endpoint data collected in 
the clinical trial. Missing efficacy data will be estimated by a mixture of 
linear interpolation and last observation carried forward for the cases were 
linear interpolation is not computationally possible. The week 6 ‘IGA 
success’ endpoint will be analyzed with a logistic regression.  Statistical 
comparison between the active treatment arms and vehicle arms will be 
facilitated by using contrasts. 

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Amendment 1.0  
 
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5 
SCHEDULE OF VISITS AND ASSESSMENTS 
STUDY EVENTS FLOW CHART: 
 
Study Procedure 
Screen 
Baseline 
Day 1 
 
Wk 2  
Day 15 
 
Wk 4 
Day 29 
 
Wk 6 
Day 43 
 
Wk 8 
Day 57 
 
Wk 12 
Day 85  
 
Wk 16 
Day 113 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
Visit Window 
-35 
days 
 
+/- 3 
days 
+/- 5 
days 
+/- 5 
days 
+/- 5 
days 
+/- 7 days 
+/- 7 
days 
Informed consent 
X 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
Physical examinationa 
X 
X 
 
 
 
 
X 
 
I/E criteria 
X 
X 
 
 
 
 
 
 
Hematology, Serum 
Chemistries, and Urine 
Analysisb 
X 
X 
 
X 
 
 
 
X 
 
12-lead ECG 
X 
 
 
X 
 
 
X 
 
Vital signs, height, weightc 
X 
X 
X 
X 
X 
X 
X 
X 
IGAd, BSAd, mPASId 
X 
X 
X 
X 
X 
X 
X 
X 
Intertriginous area IGA 
(I-IGA)e 
 
X 
X 
X 
X 
X 
X 
X 
WI-NRSf, Fatigue NRSg, 
WPAIh, Itch-related sleep loss 
and DLQIi 
X 
X 
X 
X 
 
X 
X 
X 
 
Local Tolerability Assessmentsj 
 
X 
 
X 
 
X 
X 
 
C-SSRS, PHQ-8  
X 
X 
 
X 
 
X 
X 
 
PSD 
X 
X 
X 
X 
X 
X 
X 
X 
Optional Photographyk 
 
X 
 
X 
X 
X 
X 
 
Urine pregnancy testl 
X 
X 
 
X 
 
X 
X 
 
PK drawsm 
 
X 
 
X 
 
 
X 
 
IP application in clinicn 
 
X 
X 
X 
X 
X 
X 
 
Assign study medication kito 
 
X 
 
 
 
 
 
 
Dispense/review diary 
 
X 
X 
X 
X 
X 
X 
 
Weigh study medication tubesp 
 
X 
X 
X 
X 
X 
X 
 
Compliance calculationp 
 
X 
X 
X 
X 
X 
X 
 
Adverse event assessmentq 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
Study Exitr 
 
 
 
 
 
 
 
X 
a Limited physical examination: skin, lungs, and heart only 
b  To be collected at Screening, Baseline, Week 4 and Week 12. If Baseline is within 14 days of Screening, the Screening results 
may be utilized. 
c Height will be collected at Baseline only. Weight will be collected at baseline, week 4, 6, 8 and 12. Subject to void prior to 
weight being taken. Remove any jackets, outerwear and shoes. Remove any objects of significant weight (i.e. cell phones, 
wallet, key chains). A 5% weight loss should be reported to the medical monitor. 
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. Total BSA affected by psoriasis will be determined. mPASI will be 
determined by standard PASI methods for subjects with ≥ 10% BSA involvement; for subjects with < 10% BSA involvement 
the mPASI will be calculated using the actual percentage of the anatomical area involved (e.g. for 5% of an anatomical area 
involved 0.5 would be used for the calculation). PASI-75 and PASI-90 responses will be determined. 
 
 

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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 
(I-IGA) will be recorded at weeks 2, 4, 6, 8, 12 and 14.  This ‘intertriginous area IGA’ should be done AFTER the 
‘standard whole body IGA’ (primary endpoint) in subjects who qualify. 
f   Subjects will complete WI-NRS pruritus assessment. 
g   Subjects will complete Fatigue NRS assessment. 
h   Subjects will complete WPAI (work impairment) assessment.  
i    Subjects will complete Itch-related sleep loss assessment and DLQI. 
j Tolerability assessments should be recorded prior to study drug application for Investigator assessment (Berger and Bowman 
skin irritation score) and 10-15 minutes post-drug application for subject ‘0-3’ burning/stinging assessment.  
k Photography will be performed at selected investigational sites.  Photography will be optional.  All efforts will be made to 
de-identify the subjects. 
l A urine pregnancy test will be administered to all females of child-bearing potential. A negative result is required for 
continued participation in the study, and results must be available prior to dispensing of study drug at each visit. 
m PK draws will be collected from all subjects at Days 1, 29 and 85. The draws will be pre-dose drug application in the clinic 
(i.e., trough levels). The tube weight will be collected prior to the application and after the application. Ensure study 
medication is not applied in the area where PK will be drawn. Approximately 30 subjects, continuing to the Week 16 visit, 
with greater than or equal to 5% BSA involvement, will have additional PK draws at 72 hr (3 days), 120 hr (5 days), 168 hr 
(7 days), and 216 hr (9 days) timepoints post the last treatment application. For the 72 hour timepoint, the PK draw should be 
+/- 2 hours of the last study drug application.  The 5, 7 and 9 day draws should be completed in the morning, before noon at 
the site. 
n   Subjects to apply assigned IP in clinic at every visit. The time of application will be documented.  
o Kits will be dispensed based on %BSA affected. See IP Handling Manual for details.   
p.  Each tube should be weighed and recorded at every visit. See IP Handling Manual for details. 
q 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. 
r    Subjects who enroll into the open label extension study (ARQ-151-202) will complete the study at Week 12; subjects that do 
not enroll into ARQ-151-202 will return at Week 16 to complete the study. 
 
 

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6 
 
ABBREVIATIONS 
AE 
Adverse Event 
AMP 
Adenosine Monophosphate 
AUC 
Area Under the Curve 
BSA 
Body Surface Area 
Cmax 
Maximum Concentration 
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 
mPASI-75 
Modified Psoriasis Area and Severity Index-75; subjects who achieve a 75% reduction in 
mPASI from Baseline 
mPASI-90 
Modified Psoriasis Area and Severity Index-90; subjects who achieve a 90% reduction in 
mPASI from Baseline  

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MTD 
Maximum Tolerated Dose 
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 
PDE-4 
Phosphodiesterase 4 
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 
WPAI 
Work Productivity and Activity Impairment Questionnaire 
WI-NRS 
Worst Itch – Numeric Rating Score 
 
 
 

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7 
BACKGROUND AND RATIONALE 
7.1 
Introduction 
Roflumilast is a phosphodiesterase 4 (PDE-4) inhibitor approved globally to reduce the risk of 
exacerbations in patients with severe chronic obstructive pulmonary disease (COPD) associated 
with chronic bronchitis.  Roflumilast and its active metabolite, roflumilast N-oxide, are high 
affinity selective inhibitors of PDE-4 (a major cyclic-3′,5′-adenosine monophosphate 
(cyclic AMP)-metabolizing enzyme), whose activity leads to accumulation of intracellular cyclic 
AMP.  There are four different subtypes of PDE-4: PDE-4a, PDE-4b, PDE-4c, and PDE-4d, each 
with several isoforms (splicing variants).  IC50 values of both roflumilast and roflumilast N-oxide 
for the different PDE-4 isoforms and subtypes are mostly sub-nanomolar and single digit 
nanomolar (Hatzelmann 2010).  The PDE-4 family of enzymes are the most prevalent 
phosphodiesterases in immune cells and inhibition of PDE-4 subtypes has been associated with 
anti-inflammatory effects in many biological systems. 
 
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 really has not 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 2a results suggest that 
ARQ-151 may be a highly efficacious and well-tolerated topical treatment for psoriasis. 
7.2 
Preclinical Studies  
Roflumilast was initially developed as a 500 µg tablet for oral therapy in patients with COPD, 
and as such has been thoroughly evaluated in nonclinical studies.  The safety profile is 
well-established and the results of those studies are relevant to the dermal roflumilast (ARQ-151 
cream) development program.  Oral roflumilast (500 µg tablet) was approved by Health Canada 
as DAXAS® in December 2010 and by the US FDA as DALIRESP® in February 2011 for the 
treatment of COPD.  
 

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Based on the data from this study, the NOAEL in this strain of mice is the 20 mg/kg dose 
(2 mL/kg of a 1% w/w formulation). 
7.2.2 
Oral (Systemic) Studies of Roflumilast and N-Oxide Metabolite 
The repeat-dose toxicity studies of roflumilast has been evaluated in five animal species, with the 
longest duration being 6 months in mice, 6 months in rats, 3 months in hamsters, 12 months in 
dogs and 9-months in monkeys.  The N-oxide metabolite has been studied for 6 months in mice, 
1 month in rats and 12 months in dogs.  Below is a summary of the drug-related effects seen in 
these studies. 
 
Dose-related changes in rodent olfactory mucosa consisted of disorganization and degeneration 
accompanied by basal cell hyperplasia and inflammatory changes of Bowman’s capsule and 
submucosa.  The rat was the most sensitive species (NOAEL of 0.8 mg/kg/day), while mice and 
hamsters were less sensitive (NOAEL of 4 mg/kg/day).  No equivalent changes were observed in 
the olfactory mucosa of dogs and monkeys, despite high systemic exposures to roflumilast and 
roflumilast N-oxide.  Nasal mucosa lesions in the olfactory region are attributed to a rodent-
specific metabolite.  Humans do not have the corresponding olfactory-specific enzyme. 
 
Gastrointestinal effects in rats (erosion, ulceration and/or inflammation) were seen primarily in 
the 4-week studies with roflumilast and roflumilast N-oxide at the highest doses.  
Gastrointestinal effects seen in monkeys (inflammation in the pyloric region) were minimal and 
transient as they occurred after one month of treatment, but were absent after 9 months of dosing.  
In relation to the approved 500 µg dose, the safety margins (plasma AUC of free drug fraction) 
for any potential gastrointestinal effects are 3.7- and 7.4-fold for rats, and 15- and 9.3-fold for 
monkeys, for roflumilast and roflumilast N-oxide, respectively.  For mice, hamsters and dogs, 
the safety margins at the highest dose tested are 628-, 22- and 47-fold for roflumilast and 249-, 
56- and 3.8-fold for roflumilast N-oxide, respectively. While these margins based on AUC may 
be somewhat less with topical administration if exposure to roflumilast and roflumilast N-oxide 
is increased with topical administration at high BSAs, gastrointestinal effects are likely to be 
Cmax-mediated and thus should be mitigated by a lower, and slower ascent to, Cmax that occurs 
with topical administration. 
 
Epididymal spermiogenic granuloma as well as tubular dilation and degeneration of the testes 
were observed in rats treated with roflumilast and roflumilast N-oxide at doses >0.8 mg/kg/day 
or >1.2 mg/kg/day, respectively.  No drug-related changes in the testis or epididymis were noted 
in the other species. 
 
Cardiac lesions such as focal hemorrhages, hemosiderin deposits and lympho-histiocytic cell 
infiltration in the right atria/auricles were found in repeat dose toxicity with roflumilast and 
roflumilast N-oxide in dogs.  In a 6-month study in mice, peri-arteritis was seen in 1-2/40 mice at 
doses > 12 mg/kg/day.  In a 1-month study in monkeys, myocarditis was seen in 1/3 monkeys at 
0.25 mg/kg/day, but was not seen in a subsequent 9-month study at 0.5 mg/kg/day. The effects 
seen in the latter two species are not considered treatment related. 
 

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Decreased food consumption, reduced body weight gain and adrenal hypertrophy (in mice 
accompanied by a premature involution of the juxtamedullary x-zone) occurred in mice, rats and 
hamsters at high doses of roflumilast that produced exposure ratios exceeding 9- to 650-fold the 
human plasma levels of unbound roflumilast and roflumilast N-oxide compared to the 500 µg 
oral dose.. 
7.2.3 
Reproductive Toxicity 
 
Roflumilast was not teratogenic in rats and rabbits following oral administration up to the highest 
doses of 1.8 mg/kg/day in rats and 0.8 mg/kg/day in rabbits.  Administered at the same doses, 
roflumilast has been shown to induce mild retardation of embryo-fetal development (incomplete 
ossification) in the rat, but not in the rabbit.  Exposure of pregnant rats to unbound roflumilast 
and roflumilast N-oxide was 1.7 and 10.8 times higher, respectively, than exposure of women at 
the 500 µg oral roflumilast dose.  In one of three rat studies on fertility and embryo-fetal 
development, post-implantation losses were observed at oral doses of 0.8 mg/kg/day.  Post-
implantation losses were not seen in rabbits up to doses of 0.8 mg/kg/day.  Rat and rabbit fetuses 
were exposed to roflumilast and the permeability of the placental barrier for drug-related 
material increased with the progression of pregnancy.  Prolongation of gestation was seen in 
mice due to a potential tocolytic effect. 
 
There was no effect on female fertility up to the highest roflumilast dose of 1.5 mg/kg/day in 
rats.  Slight reduction in male fertility was seen in conjunction with epididymal toxicity in rats 
dosed with 1.8 mg/kg/day.  This finding is not considered relevant to humans. 
7.2.4 
Genotoxicity 
 
Roflumilast tested positive in an in vivo mouse micronucleus test, but negative in the following 
assays: Ames test for bacterial gene mutation, in vitro chromosome aberration assay in human 
lymphocytes, in vitro HPRT test with V79 cells, in vitro micronucleus test with V79 cells, DNA 
adduct formation assay in rat nasal mucosa, liver and testes, and in vivo mouse bone marrow 
chromosome aberration assay.  Roflumilast N-oxide was negative in the Ames test and the in 
vitro micronucleus test with V79 cells.  
7.2.5 
Carcinogenicity 
In a 2-year carcinogenicity study in mice, roflumilast was administered by gavage at doses up to 
18 mg/kg/day in males and 12 mg/kg/day in females.  No compound-related tumors occurred.  
In the two 2-year carcinogenicity studies in hamsters, roflumilast was administered by gavage at 
doses up to 16 mg/kg/day.  Nasal neoplasms (undifferentiated carcinomas of the olfactory 
epithelium and adenocarcinoma of Bowman’s gland) were observed at the high doses of 
roflumilast.  No other treatment-related neoplastic findings were observed.  Overall, the tumor-
free level in the animals was 4 mg/kg/day.  The significance of this finding to humans is 
unknown.  

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7.2.6 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
  
 
 
 
 
  
7.2.7 
Conclusions on Toxicity Findings 
 
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.   
 
The previously-conducted systemic toxicity program included studies to evaluate reproductive 
toxicity, genotoxicity and carcinogenicity, and the results of those studies are included in the 
labeling for oral roflumilast.  
 
 
 
 
 
 
 
  

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7.3 
Clinical Studies 
7.3.1 
Topical Roflumilast Cream 
 
This will be the second study of topical ARQ-151 cream in the human population. 
 
ARQ-151 cream 0.5% and 0.15% have been studied in a Phase 2a study (protocol # 
ARQ-151-101; NCT03392168) in patients with mild to moderate chronic plaque psoriasis in the 
United States and Canada.  The study included two cohorts.  Cohort 1 was a single dose study to 
25 cm2 of psoriatic plaque(s) in 8 psoriasis subjects.  Cohort 1 subjects were then enrolled, if 
they met entry criteria, into Cohort 2 of the study. Cohort 2 was a parallel group, double blind, 
vehicle-controlled study in which ARQ-151 cream 0.5%, ARQ-151 cream 0.15% or vehicle 
cream was applied QD for 28 days to 89 subjects with at least 0.5% BSA of chronic plaque 
psoriasis; area for application was not to exceed 5.0% BSA. Cohort 2 subjects had at least one 
target plaque of psoriasis of at least 9 cm2 Target Plaque Area (TPA) in size and with a Target 
Plaque Severity Score (TPSS) ≥ 4. However, all body psoriasis plaques were treated except for 
the face, scalp, intertriginous areas and palms/soles.  Only safety and pharmacokinetics were 
evaluated for the single dose Cohort 1 subjects.  
 
In the parallel group assessment (Cohort 2), the Primary Efficacy Endpoint was:  
 
• Difference in mean percent change from baseline at week 4 in the product of 
TPSS x TPA between each dose concentration level of ARQ-151 cream and vehicle 
control.  This was assessed as a sum of up to 3 target plaques per subject. 
 
Efficacy and safety results of ARQ-151-101 are as follows: 
 
• Figure 1 shows evaluation of the primary efficacy endpoint at Weeks 1, 2, 3 and 4, with 
p values and standard error bars: 
 

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Day 28 pharmacokinetic results of ARQ-151-101 are as follows: 
 
 
 
 
 
 
 
 
7.3.2 
Oral Roflumilast Tablet 
 
Oral roflumilast (DALIRESP®, DAXAS®, a 500 µg tablet) has been approved globally for the 
treatment of COPD and has been evaluated in nine Phase III/IV randomized double-blind clinical 
trials (Wedzicha 2016).  Overall, the safety of oral roflumilast has been well established in its 
targeted population of mostly middle- and upper-aged individuals who currently smoke 
cigarettes or have smoked them extensively in the past.  Adverse events (AEs) reported with 
roflumilast tablets have been consistent with those expected for oral PDE-4 inhibitors.  
In a pooled analysis of safety data from 6-month and 1-year clinical trials (N=8630), the most 
common AEs were diarrhea, weight loss and nausea.  Other AEs reported more frequently with 
roflumilast treatment than with placebo were back pain, influenza, insomnia and decreased 
appetite (Michalski 2012, Wedzicha 2016). 
 
In addition to the self-reported cases of weight loss in the 6-month and 1-year oral trials, 
clinically significant weight loss was also reported in two prospective studies that evaluated 
weight (Michalski 2012). 
 
 
 

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Psychiatric-related AEs were also greater in patients treated with roflumilast tablets (5.9%) 
compared to those treated with placebo (3.3%).  The most common psychiatric-related AEs were 
insomnia, depression and anxiety.  A small number of cases of completed suicide and suicide 
ideation have been reported in patients taking oral roflumilast in clinicals trials and also during 
post-marketing experience (Michalski 2012).   
 
The only contraindication to oral roflumilast, other than hypersensitivity to components of the 
product, is in patients with moderate to severe liver impairment (Child-Pugh B or C), 
where systemic levels of roflumilast may become highly elevated. 
7.4 
Rationale for Development 
In 2016, Snape and colleagues performed a Phase 1 randomized clinical trial to assess the effect 
on skin inﬁltrate thickness and tolerability of topical phosphodiesterase inhibitors, including 
roflumilast, in the treatment of psoriasis vulgaris using a modiﬁed psoriasis plaque test.  
The products evaluated were the active comparators calcipotriol 0.005% and betamethasone 
valerate 0.1% (both in their marketed cream formulations), and investigational cream 
formulations of roﬂumilast 0.5%, TAK-084 0.5% and 5%.  A vehicle cream was used as a 
control (the vehicle cream and roflumilast formulations in this study were different from the 
ARQ-151 cream formulation).  Each treatment was applied daily to different test sites located on 
a single psoriasis plaque of an individual for 3 weeks.  Fifteen patients with psoriasis were 
studied.  The primary endpoint of mean change from baseline in skin inﬁltrate thickness after 
3 weeks of treatment showed statistically signiﬁcant improvements for all treatments: 
betamethasone valerate (-286.9 μm), the selective PDE-4 inhibitors roﬂumilast 0.5% 
(-237.1 μm), TAK-084 0.5% (-153.6 μm), TAK-084 5% (-216.7 μm) and calcipotriol 0.005% 
(-187.7 μm) when compared with vehicle cream control (all p < 0.001) (Snape 2016).  
 
 
   
7.4.1 
Dose Selection 
 
 
 
 
 
 
 

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7.4.2 
Risks and/or Benefits to Subjects 
 
Based on the Phase 2a study results, subjects randomized to active treatment groups are likely to 
see an improvement in their psoriasis with ARQ-151 cream at both the 0.3% and 0.15% dose 
levels.  Subjects randomized to the vehicle arm may also see some improvement as the 
excipients in the vehicle appeared to have some benefit, likely because of a moisturizing effect 
on the subject’s psoriatic plaques.  
 
The safety monitoring practices employed in this protocol (i.e., physical examinations, vital 
signs/weight, 12-lead ECGs, local skin toleration assessments, hematology, serum chemistry, 
urinalysis, PHQ-8, C-SSRS and AE questioning) are adequate to protect the subjects’ safety and 
should detect expected AEs. 
 
Oral roflumilast has now been used for almost a decade in the treatment of COPD exacerbations 
and its safety record has been well-documented.  The known adverse effects of oral treatment in 
the COPD population (nausea, diarrhea, weight loss, psychiatric AEs; see Section 7.3.2) are 
monitorable, the current protocol is designed to detect these adverse events and others should 
they occur, and provides guidance for management, as necessary, to ensure patient safety. 
 

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8 
STUDY ENDPOINTS AND OBJECTIVES 
8.1 
Study Objectives 
8.1.1 
Primary Objectives 
 
To assess the safety, pharmacokinetics and efficacy of ARQ-151 cream 0.3% and ARQ-151 
cream 0.15% vs. vehicle applied QD for 12 weeks to individuals treated with 2 to 20% 
(inclusive) BSA of chronic plaque psoriasis. 
8.2 
Efficacy Endpoints 
8.2.1 
Primary Endpoint 
 
The parallel groups will have analyses for safety, pharmacokinetics, and efficacy. 
 
The Primary Efficacy Endpoint will be:  
 
• IGA score of ‘clear’ or ‘almost clear’ at Week 6.  
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. 

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8.2.2 
Secondary Endpoints 
 
The secondary efficacy endpoints will include: 
 
• IGA score of ‘clear’ or ‘almost clear’ at weeks 4, 8 and 12. 
• Percent reduction in mPASI at weeks 4, 6, 8, and 12 as compared to Baseline. 
• Decrease in Percent BSA affected at weeks 4, 6, 8, and 12 as compared to Baseline. 
• IGA score of ‘clear’ or ‘almost clear’ PLUS a 2-grade improvement from Baseline at 
weeks 4, 6, 8 and 12. 
• For subjects with intertriginous area involvement, and with severity of the intertriginous 
lesions at least ‘mild’ (I-IGA≥2) at Baseline, ‘I-IGA’ score of ‘clear’ or ‘almost clear’ at 
weeks 4, 6, 8 and 12. 
• Reduction in WI-NRS pruritus score at weeks 4, 6, 8, and 12 as compared to Baseline. 
• In subjects with WI-NRS pruritus score ≥ 6 at baseline, a 4-point reduction in WI-NRS 
pruritus score at 4, 6, 8, and 12 weeks as compared to Baseline. 
• Modified Psoriasis Area Severity Index-75 (mPASI-75) improvement at weeks 4, 6, 8, 
and 12 as compared to Baseline. 
• Modified Psoriasis Area Severity Index-90 (mPASI-90) improvement at weeks 4, 6, 8, 
and 12 as compared to Baseline. 
• Total PSD at weeks 4, 6, 8, and 12 as compared to Baseline 
• Reduction in Itch-related Sleep Loss score at weeks 4, 6, 8, and 12 as compared to 
Baseline. 
• Reduction in Dermatology Life Quality Index (DLQI) score at weeks 4, 6, 8, and 12 as 
compared to Baseline. 
• Responses to the questions of PSD analyzed as improvement at weeks 4, 6, 8, and 12 as 
compared to Baseline. 
8.2.3 
Exploratory Endpoints 
 
Exploratory Endpoints are as follows:  
 
• Reduction in Fatigue NRS score at weeks 4, 6, 8, and 12 as compared to Baseline. 
• Reduction in WPAI score at weeks 4, 6, 8, and 12 as compared to Baseline. 
 
 
 

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9 
INVESTIGATIONAL PLAN 
9.1 
Overall Study Design and Plan 
This is a parallel group, double blind, vehicle-controlled study in which ARQ-151 cream 0.3%, 
ARQ-151 cream 0.15% or vehicle cream QD is applied for 84 days to subjects with between 2% 
to 20% (inclusive) BSA of chronic plaque psoriasis. 
 
A total of up to approximately 300 subjects will be enrolled at approximately 30 study sites in 
the United States and Canada.  Subjects will be adult (≥18 y/o) 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 with an IGA of ‘Mild’ (2) will be limited to 
20% of total enrollment. Subjects with an IGA of ‘Severe’ (4) will be limited to 15% of total 
enrollment. 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, 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 weeks 4, 6, 8 and 12.  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.   
9.2 
Subject Participation 
Subject participation involves a minimum of seven clinic visits:eight clinic visits including 
Screening, Baseline and five visits at Week 2, Week 4, Week 6, Week 8 and Week 12 of 
treatment and a week 14 follow-up visit (2 weeks after last dose).  The interval between the 
Screening and Baseline visits could be up to 35 days, therefore the anticipated maximum 
duration of subject participation is ~19 weeks. 
 
Upon completion of this study, participants may have the opportunity, subject to regulatory 
approval, to participate in an open-label extension study of up to 12 months, receiving the 0.3% 
concentration of drug product. The week 12 visit will be the Day 1 visit for ARQ-151-202. 
 
For subjects who do not enter ARQ-151-202 there will be a minimum of eight clinic visits: 
Screening, Baseline, five visits at Week 2, Week 4, Week 6, Week 8 and Week 12 of treatment, 
and a week 16 follow-up visit (4 weeks after last dose).  The interval between the Screening and 
Baseline visits could be up to 35 days, therefore the anticipated maximum duration of subject 
participation is ~21 weeks. 
 
 

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9.2.1 
Randomization 
Subjects will apply ARQ-151 cream 0.3% QD or ARQ-151 cream 0.15% QD or vehicle cream 
QD to psoriatic plaques of 2% BSA up to a maximum application area of 20% BSA.   
 
Assignment of drug or vehicle will be made at a 1:1:1 ratio according to a computer-generated 
randomization list.   
 
Randomization will take place at Baseline after the patient has been found to be fully eligible for 
participation.  Kits containing tubes of study medication will be assigned to each subject using an 
internet-based 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 numbered with a unique kit number.  
9.2.2 
Numbering of Subjects 
All screened subjects will be identified by a unique five-digit subject ID number.  The first two 
digits correspond to the site number (assigned by the Sponsor), the next three digits correspond 
to the sequential order in which the subject is screened for the study (e.g., Subject ID 10001: 
Site 10, first subject screened 001 for that site). Site number 10 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.).  
9.3 
Selection of Study Population 
9.3.1 
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 
2. Males and females ages 18 years and older (inclusive) 
3. Clinical diagnosis of psoriasis vulgaris of at least 6 months duration as determined by the 
Investigator 
4. Psoriasis vulgaris on the face, extremities, trunk, and/or intertriginous areas involving 2-20% 
(inclusive) 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 mPASI score of at least 2 (excluding the scalp, palms and soles) at Baseline.  

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7. Females of childbearing potential (FOCBP) must have a negative urine pregnancy test at 
Screening (Visit 1) and Baseline (Visit 2). In addition, sexually active FOCBP must agree to 
use at least one form of highly effective contraception throughout the trial.  Highly effective 
forms of contraception include: oral/implant/injectable/transdermal contraceptives, 
intrauterine device, and partner’s vasectomy.  If barrier methods are used (e.g., condom with 
spermicide, diaphragm with spermicide), then 2 forms of conception are required. The use of 
abstinence as a contraceptive measure is acceptable as long as this is a consistent part of a 
lifestyle choice and a backup method has been identified if the subject becomes sexually 
active. 
8. Females of non-childbearing potential should be post-menopausal with spontaneous 
amenorrhea for at least 12 months or have undergone surgical sterilization (permanent 
sterilization methods include hysterectomy, bilateral oophorectomy, hysteroscopic 
sterilization, bilateral tubal ligation or bilateral salpingectomy). 
9. In good health as judged by the Investigator, based on medical history, physical examination, 
serum chemistry labs, hematology values, and urinalysis. 
10. Subjects agree not to have prolonged sun exposure during the course of the study.  
Tanning bed use or use of other LEDs is not allowed. 
11. Subjects are considered reliable and capable of adhering to the Protocol and visit schedule, 
according to the judgment of the Investigator. 
9.3.2 
Exclusion Criteria 
 
1. Subjects who cannot discontinue medications and treatments prior to the Baseline visit and 
during the study according to Excluded Medications and Treatments (Table 1). 
2. Planned excessive exposure of treated area(s) to either natural or artificial sunlight, 
tanning bed or other LED.   
3. Subjects currently taking lithium or antimalarial drugs. 
4. Planned initiation or changes to concomitant medication that could, in the opinion of the 
Investigator, affect psoriasis vulgaris (e.g. beta blockers, ACE inhibitors). 
5. Current diagnosis of guttate, erythrodermic/exfoliative, palmoplantar only involvement, or 
pustular psoriasis.  
6. Subjects with any condition on the treatment area which, in the opinion of the Investigator, 
could confound efficacy measurements. 
7. Known allergies to excipients in ARQ-151 cream
 
 
  
8. Subjects who cannot discontinue the use of strong P-450 cytochrome inhibitors 
e.g., indinavir, nelfinavir, ritonavir, clarithromycin, itraconazole, ketoconazole, nefazodone, 
saquinavir, suboxone and telithromycin for two weeks prior to the baseline visit and during 
the study period.   

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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. Subjects who have received oral roflumilast (Daxas®, Daliresp®) within the past 4 weeks.  
11. Known or suspected:  
• severe renal insufficiency or severe hepatic disorders  
• hypersensitivity to component(s) of the investigational products  
• history of severe depression, suicidal ideation 
 
12. Females who are pregnant, wishing to become pregnant during the study, or are breast-
feeding. 
13. Previous treatment with ARQ-151. 
14. 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. 
15. Subjects with a history of chronic alcohol or drug abuse within 6 months of initiation of 
study medication. 
16. History of and/or concurrent condition of serious hypersensitivity (anaphylactic shock or 
anaphylactoid reaction) to PDE-4 inhibitors. 
17. 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. 
18. Subjects with active infection that required oral or intravenous administration of antibiotics, 
antifungal or antiviral agents within 7 days of Baseline/Day 1. 
19. 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. 
9.3.3 
Removal of Subjects from the Study 
 
Subject participation in this trial may be discontinued for any of the following reasons: 
1. Occurrence of any medical condition or circumstance that, in the opinion of the Investigator, 
exposes the subject to substantial risk and/or does not allow the subject to adhere to the 
requirements of the Protocol. 
2. Occurrence of a treatment-emergent adverse event (TEAE) or considerable worsening of an 
AE that, in the opinion of the investigator in consultation with the Medical Monitor and 
Sponsor, represents an unacceptable risk to the subject if he/she continues in the study.  
The investigator must follow the subject until the AE resolves or satisfactorily stabilizes. 
3. Pregnancy. 
4. Subject's decision to withdraw. 

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5. Weight loss of >5% if not dieting and after consultation with the Sponsor, at the 
Investigator’s discretion. 
6. C-SSRS indicative of suicidal ideation or a PHQ-8 score ≥15, after consultation with a 
mental health professional, the Sponsor, and at the Investigator’s discretion. 
7. Requirement for use of prohibited concomitant medication after consultation with the 
Sponsor and Medical Monitor. 
8. Subject’s repeated failure to comply with protocol requirements or study related procedures. 
9. The subject interrupts trial study drug application for more than 50% of scheduled doses. 
10. Termination of the study by the Sponsor, FDA, or other regulatory authorities. 
9.4 
Study Restrictions 
9.4.1 
Prohibitions and Concomitant Therapy 
 
Prohibited medications and products are detailed in Table 1.   
Table 1: Excluded Medications and Treatments 
 
Excluded Medications and treatments 
Wash out 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 
• Systemic treatment with all other therapies with a possible effect on psoriasis vulgaris 
Oral 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 phototherapy 
4 weeks 
UVB  
2 weeks  
Systemic retinoids 
12 weeks 
Investigational drugs 
12 weeks (biologics); 
5 half-lives (orals);  
2 weeks (topical) 
Notes:   
(1) Eye 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) Study medication 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. 

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Generally, the addition of new medications, including nonprescription medications, during the 
course of the study is discouraged.  However, the short-term use of a medication may be 
authorized by the Investigator.  The Investigator must make the decision to authorize the use of 
any such a medication only after consideration of the clinical situation, the potential for masking 
symptoms of a more significant underlying event, and whether the use of the medication will 
compromise the outcome or validity of the clinical investigation.  If medication is required, 
the name, strength, frequency, duration of use, and reason for use will be recorded in source 
documents and 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).  
9.5 
Treatment 
9.5.1 
Drug Supplies, Packaging and Labeling 
 
ARQ-151 cream 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 will be labeled with a unique number. 
 
The Sponsor will supply sufficient quantities of the study drug (ARQ-151 cream 0.3%, 
ARQ-151 cream 0.15%, and matching vehicle cream) to each site to allow for completion of this 
study. 
 
Records will be made of the receipt and dispensing of the study drugs supplied. At the 
conclusion of the study, any unused study drugs will be returned to the Sponsor or designee, or 
destroyed, as per Sponsor instructions. 
9.5.2 
Blinding 
This is a double-blind study, therefore neither the subjects nor the Investigator and clinical 
personnel will be aware of which treatment an individual has received. 
9.5.3 
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-151 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 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.  
 

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Re-training will be conducted at subsequent visits (weeks 2, 4, 6 and 8) as needed (i.e., if the 
returned tube(s) weighs substantially different than the expected weight). 
Subjects will be instructed to apply study medication once daily.  All subjects should apply 
medication each evening (except on clinic visit days) at least 15 minutes after showering or 
bathing (if they take an evening shower/bath) and then not wash areas where ARQ-151 cream or 
vehicle has been applied until at least 4 hours after study drug application and preferably not 
until the following morning.  Study medication should be applied at least 20 minutes before 
going to bed.   
 
Subjects should continue to apply study medication 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 study medication tube will be weighed prior to dispensing at the baseline visit or 
subsequent visits. Study medication tubes must be returned by subjects at each study visit, both 
empty and full, and will be weighed. If the subject’s actual use is substantially different than the 
expected use for the subject’s BSA (see IP Manual), the subject will be retrained on the study 
drug application technique. 
9.5.4 
Treatment Compliance  
Study medication tubes will be weighed at each follow-up clinic visit.   
Subjects will complete a daily diary recording the date and time of each dose applied, any missed 
doses, and a comment section should the subjects have a comment, e.g., record potential AEs. 
Site personnel will review the diaries and use the information to question the subject regarding 
compliance and AEs and then record appropriate information in source documents and complete 
Case Report Forms (CRFs).  If a subject misses a dose, they should be instructed to return to the 
protocol study medication administration schedule (i.e. if subject forgets a dose they should wait 
until that evening and apply as usual).   
A subject will be considered compliant with the dosing regiment if the subject applies at least 
80% of the expected applications during the study drug application period and does not miss 
more than 3 consecutive doses.  
Compliance will be assessed by review of the dosing diary. Weight of study medication applied 
will be measured for reporting purposes.  
If the diary shows less than 80% of expected use, the subject is using too little study drug and 
retraining must be conducted and documented.  
Compliance will be documented in source and in eCRF. 

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10 STUDY PROCEDURES 
10.1 Safety Assessments 
The Schedule of Visits and Assessments (Section 5) summarizes the clinical procedures to be 
performed at each visit. Individual clinical procedures are described in detail below. Additional 
evaluations/testing may be deemed necessary by the PI and/or the Sponsor for reasons related to 
subject safety. 
This study assesses the safety and efficacy of ARQ-151 cream. Safety will be determined by 
evaluating physical examinations, 12-lead ECGs, local tolerability assessments, vital 
signs/weight, clinical laboratory parameters, PHQ-8, C-SSRS and AEs as outlined in the 
Schedule of Visits and Assessments (Section 5). If deemed necessary, additional safety 
assessments will be performed at the discretion of the PI. 
10.1.1 
Screening 
Within 35 days prior to the first dosing, subjects will be provided details of study requirements 
and sign an informed consent.  Medical history and demographic data including sex, age, race, 
ethnicity, body weight (kg), and height (cm) will be recorded. Each subject will undergo 
psoriatic plaque assessments, a physical examination, vital sign measurements (blood pressure, 
heart rate, and temperature), PHQ-8, C-SSRS, and laboratory tests: hematology, chemistry, 
urinalysis and a pregnancy test for female subjects of child bearing potential. 
All screened subjects will receive a screening number and be entered into the electronic subject 
tracking system. 
10.1.2 
Physical Examination 
 
Physical examinations will be performed as follows: 
 
Screening, Baseline and Week 12.   
The physical exam will be limited to skin, lungs and heart only. 
10.1.3 
Vital Signs, Height and Weight 
 
Vital signs will be collected at timepoints noted below: 
 
Blood pressure, heart rate, and temperature will be measured at Screening, Baseline, Weeks 2, 4, 
6, 8, 12 and 16 (if applicable).  
 
Height will be collected at Baseline only.  
 
 
 

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Weight will be collected at Baseline, Weeks 4, 6, 8 and 12. 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% weight loss should be reported to the medical 
monitor. 
10.1.4 
12-Lead ECGs 
 
12-lead ECGs will be performed as follows: 
 
Screening, Week 4 and 12. 
 
ECGs will be performed on subjects after 5 minutes in the supine position. All ECG tracings and 
readouts will be reviewed by the central reader at the ECG laboratory. 
10.1.5 
Laboratory Tests 
All tests listed below will be performed as follows: 
Screening, Baseline, Weeks 4 and 12.    
All tests listed in Table 2 below will be performed according to the Study Events Flow Chart 
unless otherwise noted. The collection of specimens will be in a non-fasting state. 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  
 
 

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Laboratory Tests, continued 
 
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) 
* If urinalysis is positive for protein, blood, nitrite and/or leukocyte esterase, a microscopic examination (for red blood cells, 
white blood cells, bacteria, casts, and epithelial cells) will be performed. 
** At screening, baseline, Weeks 4, 8 and 12 for FOCBP only  
10.1.6 
Patient Health Questionnaire depression scale (PHQ-8)  
 
The 8 item PHQ-8 Assessment will be performed as follows: 
 
Screening, Baseline, Weeks 4, 8, and 12 
 
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 study drug, consideration be given to discontinuation 
from study drug.   
 

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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) 
 

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10.1.7 
Columbia-Suicide Severity Rating Scale (C-SSRS)  
 
C-SSRS Assessments will be performed as follows: 
 
Screening, Baseline, Weeks 4, 8, and 12. 
 
The administration schedule of the C-SSRS will be: 
 
• 
The Baseline-Screening version (Appendix 2) 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 3) will be used. 
o Any score greater than 0 in the suicidal ideation score is important and may 
indicate the need for mental health intervention and consideration be given to 
discontinuation from study drug. This should result in prompt referral to a mental 
health professional and/or possibly the emergency room. The Medical Monitor 
should be contacted.  
 
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. 
10.1.8 
Local Tolerability Assessments  
The Investigator Local Tolerability Assessment will be performed as follows: 
Baseline, Weeks 4, 8 and 12 
Application site reactions will be graded at the timepoints outlined in the Schedule of Visits and 
Assessments (Section 5).  Irritation reactions are graded using the scale detailed in the following 
section (Berger-1982).  Reactions at the site of product application, which may occur post-
Baseline, should be differentiated from the preexisting inflammation associated with the 
subject’s psoriasis.   
 
The investigator assessments will be conducted by the investigator prior to study drug 
application in the clinic.  
 

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Dermal Response 
0 = no evidence of irritation 
1 = minimal erythema, barely perceptible 
2 = definite erythema, readily visible; minimal edema or minimal papular response 
3 = erythema and papules 
4 = definite edema 
5 = erythema, edema and papules 
6 = vesicular eruption 
7 = strong reaction spreading beyond application site 
Other Effects 
 
A = slight glazed appearance 
 
B = marked glazing 
 
C = glazing with peeling and cracking 
 
D = glazing with fissures 
 
E = film of dried serous exudates  
 
F = small petechial erosions and/or scabs 
G = no other effects 
 
The Subject Local Tolerability Assessment will be performed as follows: 
Baseline, Weeks 4, 8 and 12 
This assessment will be administered by the site 10 to 15 minutes after study drug application in 
the clinic at Baseline and at Weeks 4, 8 and 12.  
Grade 
Sensation Following Drug Application 
0 (none) 
No sensation 
1 (mild)  
Slight warm, tingling sensation; not really bothersome 
2 (moderate) 
Definite warm, tingling sensation that is somewhat 
bothersome 
3 (severe) 
Hot, tingling/stinging sensation that has caused definite 
discomfort  
 
10.1.9 
Adverse Events  
 
Adverse events (AEs) will be collected beginning at informed consent and assessed as follows: 
Screening, Baseline, Weeks 2, 4, 6, 8, 12 and 16 (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 10.4. 

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10.2 Efficacy Evaluations  
10.2.1 
Investigator’s Global Assessment (IGA) 
 
Investigator’s 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, 12 and 16 (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 study medication, but will not be counted 
towards IGA, 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. 
 

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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 
whole body involvement), an IGA for the intertriginous region alone (I-IGA) will be recorded at 
weeks 2, 4, 6, 8, 12 and 16 (if applicable).   
This ‘intertriginous area IGA’ (I-IGA) should be done AFTER the ‘standard whole body 
IGA’ (primary endpoint) in subjects who qualify.  
10.2.2 
Modified Psoriasis Area and Severity Index (mPASI) 
mPASI Assessments will be performed as follows: 
Screening, Baseline, Weeks 2, 4, 6, 8, 12 and 16 (if applicable) 
Every effort should be made for the same Evaluator to complete the mPASI for the subject 
at every study visit. 
 
Modified Psoriasis Area and Severity Index (mPASI) is used for the measurement of severity of 
psoriasis.  
 
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 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 - see below for Modified PASI (mPASI) for this grade 
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 study medication in this study, but will not be 
counted towards IGA, mPASI, or BSA assessments. 
 
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. 

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To calculate the 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 
10.2.3 
Body Surface Area (BSA) 
BSA Assessments will be performed as follows: 
Screening, Baseline, Weeks 2, 4, 6, 8, 12 and 16 (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 study medication, but will not be counted towards 
IGA, mPASI, or BSA assessments. 
10.2.4 
Worst Itch Numerical Rating Scale (WI-NRS)  
WI-NRS Assessments will be performed as follows: 
Screening, Baseline, Weeks 2, 4, 6, 8 and 12 
 
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). The 
WI-NRS will be determined by asking the subject’s assessment of worst itch over the past 
24 hours. The scale is from ‘0 to 10’ (“no itch” to “worst imaginable itch”). Subjects will 
complete the WI-NRS pruritus assessment. 
 
 
 
10.2.5 
Fatigue NRS 
 
Fatigue NRS Assessments will be performed as follows: 
 
Screening, Baseline, Weeks 2, 4, 6, 8 and 12 
 
 
 

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Subjects will complete circle the number on the Fatigue NRS assessment that best fits their 
fatigue severity. Fatigue severity will be measured using a unidimensional 11-point numeric 
rating scale (NRS) with anchors of 0 (No Fatigue) and 10 (Fatigue as bad as it can be) for the 
intensity during the previous 24-hour period. The words ‘no fatigue’ and ‘Fatigue as bad as it can 
be’ corresponding to the anchors 0 and 10, respectively, will be placed under the NRS scale.   
No
Fatigue as 
     fatigue
bad as it can be 
10.2.6 
Work Productivity and Activity Impairment (WPAI) 
WPAI Assessments will be completed at the following: 
Screening, Baseline, Weeks 2, 4, 6, 8 and 12 
Subjects will complete the WPAI questionnaire.  Please see Appendix 1 for the WPAI. 
10.2.7 
Itch-Related Sleep Loss  
Itch-Related Sleep Loss Assessments will be performed as follows: 
Screening, Baseline, Weeks 2, 4, 6, 8 and 12  
Subjects will complete the itch-related sleep loss numerical rating scale (NRS) assessment. Itch-
related sleep loss severity will be measured using a unidimensional rating scale (NRS) with 
anchors at 0 (no itch-related sleep loss) and 10 (itch-related sleep loss as bad as it could be) for 
the intensity during the previous 24-hour period. The words ‘no itch-related sleep loss’ and 
‘itch-related sleep loss as bad as it could be’ correspond to the anchors or 0 and 10, respectively, 
and will be placed on the NRS scale.  
      No itch-related
Sleep loss 
 sleep loss
as bad as it can be 
10.2.8 
Psoriasis Symptom Diary (PSD) 
The PSD will be completed as follows: 
Screening, Baseline, Weeks 2, 4, 6, 8, 12 and 16 (if applicable) 
Subjects will complete the PSD. See Appendix 4 for the PSD.  

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10.2.9 
Dermatology Life Quality Index (DLQI)  
 
The DLQI will be completed as follows: 
 
Screening, Baseline, Weeks 2, 4, 6, 8 and 12  
 
Subjects will complete the DLQI. See Appendix 5 for the DLQI. 
10.2.10 Dermal Imaging 
 
Optional photography will be performed at selected centers only at Baseline, Weeks 4, 6, 8 
and 12. 
10.3 Pharmacokinetics Assessment 
PK draws will be performed as follows for all subjects at all sites: 
 
Baseline, Weeks 4 and 12 
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 drug application in the clinic. The tube weight will be collected prior to the 
application and after the application. Ensure study medication is not applied in the area where 
PK will be drawn. 
 
Approximately 30 subjects, continuing to the Week 16 visit, with greater than or equal to 5% 
BSA at the Baseline visit, will have the option to participate in additional PK draws at 72 hours 
(3 days), 120 hours (5 days), 168 hours (7 days) and 216 hours (9 days) post the last treatment 
application.  For the 72 hour timepoint, the PK draw should be +/- 2 hours of the last study drug 
application.  The 5, 7 and 9 day draws should be completed in the morning, before noon at the 
site. 
10.4 Adverse Events 
10.4.1 
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.  
AEs will be collected following informed consent of the subject through subject study 
completion.  
A treatment emergent adverse event (TEAE) is defined as an AE that started post application of 
study medication at the Baseline visit through study completion.  

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Application site reactions will be considered adverse events if they require intervention, 
suspension or discontinuation of study drug.  
10.4.2 
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 via fax or e-mail within 24 hours of becoming aware of the event, whether or not 
the serious events are deemed drug-related. All serious event reporting will adhere to ICH E6: 
Guideline for Good Clinical Practice and ICH E2A: Clinical Safety Data Management: 
Definitions and Standards for Expedited Reporting.:  The 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.  
 
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. 

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• Diagnostic and therapeutic procedures, such as surgery, should not be reported as AEs; 
however, the medical condition for which the procedure was performed should be 
reported if it occurs during the reporting period and meets the definition of an AE.  
For example, an acute appendicitis that begins during the AE reporting period should be 
reported as an AE, and the resulting appendectomy should be recorded as treatment of the 
AE. 
 
Unexpected is defined as an AE that is not listed in the IB or is not listed at the specificity or 
severity that has been observed; or is not consistent with the risk information described in the 
general investigational plan or elsewhere in the current IND/CTA. 
If a SAE occurs to a subject on this study, contact the Sponsor personnel listed in Section 2 
within one business day of knowledge of event.  
10.4.3 
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.  
10.4.4 
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 
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). 
10.4.5 
Adverse Event Reporting 
 
The PI will review each event and assess its relationship to drug treatment (unrelated, unlikely, 
possibly, probably, likely). Each sign or symptom reported will be graded on the NIH NCI 
CTCAE toxicity grading scale 5-point severity scale (Grade 1, 2, 3, 4 and 5). The date and time 
of onset, time relationship to drug dosing, duration, and outcome (resolved, improved, 
unchanged, worse, fatal, or unknown/lost to follow-up) of each event will be noted. 
 
The relationship of each AE to the study drug will be assessed using the following definitions: 

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Unrelated 
• The AE must clearly be caused by the subject’s clinical state, or the study 
procedure/conditions. 
• Definitely not related to drug. 
• Temporal sequence of an AE onset relative to administration of drug not 
reasonable. 
• Another obvious cause of an AE. 
Unlikely 
• Time sequence is unreasonable. 
• There is another more likely cause for an AE. 
Possibly 
• Corresponds to what is known about the drug. 
• Time sequence is reasonable. 
• Could have been due to another equally, likely cause. 
Probably 
• Is a known effect of the drug. 
• Time sequence from taking drug is reasonable. 
• Ceases on stopping the drug. 
• Cannot be reasonably explained by the known characteristics of the 
subject’s clinical state. 
Likely 
• Is a known effect of the drug (e.g., listed in Physicians' Desk Reference, 
Compendium of Pharmaceuticals and Specialties, IB). 
• Time sequence from taking drug is reasonable. 
• Event stops upon stopping drug, event returns upon restarting drug. 
 
The following CTCAE toxicity grading scale 5-point severity scale definitions for rating 
maximum severity will be used: 
Grade 1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated. 
Grade 2 
Moderate; minimal, local or noninvasive intervention indicated; limiting age-
appropriate instrumental activities of daily living.* 
Grade 3 
Severe or medically significant but not immediately life-threatening; 
Hospitalization or prolongation of hospitalization indicated; disabling; limiting 
self-care activities of daily living.** 
Note: An experience may be severe but may not be serious, e.g., severe 
headache). 
Grade 4 
Life-threatening consequences; urgent intervention indicated. 
Grade 5 
Death related to AE. 
Note:  A semi-colon indicates ‘or’ within the description of the grade. 
*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. 

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AEs will be coded using the most current MedDRA® version available at the start of the study 
(e.g., 21.0 or higher). 
10.5 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, the subject will be withdrawn from the study and followed until the pregnancy comes 
to term.   
The investigator is responsible for reporting all available pregnancy information on the 
pregnancy report within 24 hours of becoming aware of the event, although pregnancy itself is 
not considered an AE.  Study treatment must be discontinued immediately in the event of a 
pregnancy.  The subject should be referred to an obstetrician/gynecologist experienced in 
reproductive toxicity for further evaluation and counseling. Monitoring of the subject should 
continue until the conclusion of the pregnancy.  Follow-up information detailing the outcome of 
the pregnancy and the health of the newborn should be reported as it becomes available.   
Partner pregnancies of a male subject do not need to be reported. 
Any pregnancy complication or premature terminations including miscarriage, spontaneous 
abortion or elective termination of a pregnancy for medical reasons will be reported as an SAE, 
as described in Section 10.4.2. Should the pregnancy result in a congenital abnormality or birth 
defect, a separate SAE report must be submitted.  Furthermore, all neonatal deaths that occur 
within 30 days of the birth should be reported as SAEs, without regard to causality.  In addition, 
any infant death that occurs after the 30-day reporting period that the investigator suspects is 
related to the in-utero exposure to the study treatment should also be reported.  
10.6 Treatment Stopping Rules 
If a subject has non-cutaneous adverse events of concern, clinically significant laboratory values 
or any condition that the investigator determines could possibly be related to the study drug, 
the Investigator should immediately contact the Medical Monitor to discuss if the subject should 
be discontinued from the study.   
 
Treatment for any individual subject will be discontinued if the subject:  
• 
Experiences a serious adverse event (SAE) or a clinically significant non-serious AE 
which in the opinion of the Principal Investigator or Medical Monitor warrants 
discontinuation from the study for that subject’s well-being. 
• 
A severe (Grade 3) laboratory abnormality (confirmed by repeat sample and considered 
related to study drug).  
o See Appendix 6 for details. 
Dosing of study drug for an individual subject may be suspended for safety concerns other than 
those described above, at the discretion of the investigator if he/she feels the subject’s safety may 
be threatened. 

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A subject with a PHQ-8 score of ‘15’ or above should be referred promptly to a mental health 
care professional and consideration be given to discontinuation from study drug.   
A subject that is experiencing suicidal ideation and behavior should be referred immediately to a 
qualified mental health care provider and consideration given to discontinuation from study drug. 
As noted above, study treatment must be discontinued immediately in the event of a female 
subject’s pregnancy.   
Treatment should be interrupted: 
• If a subject develops an application site reaction with the clinical appearance of an 
‘irritation reaction’, and with a severity of a Dermal Response Score of 5 (erythema, 
edema and papules) or greater on the scale of Berger and Bowman, treatment should be 
interrupted for up to one week and may then be resumed if the reaction has, in the 
opinion of the Investigator, adequately resolved.   
 
Treatment should be discontinued: 
• 
If the reaction reoccurs, treatment should be discontinued permanently, and the subject 
followed until the reaction resolves.  Given the excellent local toleration in the Phase 1/2a 
study, such reactions are possible, but unlikely. 
10.6.1 
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.  
11 DATA ANALYSIS 
Data will be handled and processed according to the Contract Research Organization’s Standard 
Operating Procedures, which are written based on the principles of GCP. 
11.1 Statistical Methods 
The methodology presented below is a summary of the more detailed analysis plan that will be 
presented in the Statistical Analysis Plan (SAP).  The SAP will be finalized before the database 
is locked and unblinded.  Any changes to the methods described in the final SAP will be 
described and justified in the clinical study report.  
All statistical processing will be performed using SAS® (Version 9.4) unless otherwise stated. 
No interim efficacy analyses are planned. 
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 

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will include n (number of subjects), mean, standard deviation (SD), median, minimum, 
and maximum. 
Missing efficacy data will be estimated by a mixture of linear interpolation and last observation 
carried forward for the cases were linear interpolation is not computationally possible. 
P-values of less than 0.05 will be considered statistically significant based on a two-sided test 
unless otherwise specified. No adjustment will be made for multiplicity. 
11.1.1 
Determination of Sample Size 
A sample size of approximately 300 subjects are planned for the study.  
Approximately 100 subjects will receive ARQ-151 cream 0.3% QD; approximately 100 subjects 
will receive ARQ-151 cream 0.15% QD; and approximately 100 subjects will receive matching 
vehicle cream QD.  The randomization scheme will be 1:1:1 (ARQ-151 cream 0.3% QD: 
ARQ-151 cream 0.15% QD: matching vehicle QD). 
The sample size was not powered based on data for the primary endpoint to provide statistical 
significance because of the absence of previous primary endpoint data. However, based on 
efficacy data from the Phase 1/2a study, this Phase 2b study is expected to provide reliable 
information regarding the efficacy and safety of the drug products. 
11.1.2 
Subjects to Analyze 
Safety population will include all subjects who are enrolled and received at least one confirmed 
dose of study medication. This population will be defined separately for each cohort. 
The Intent-to-Treatment (ITT) population will include all randomized subjects. 
Per-Protocol (PP) Population will include all subjects who are in the safety population, were at 
least 80% compliant with study medication application, and showed no other serious deviations 
from the study protocol. 
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 defined separately for each cohort. 
11.1.3 
Interim Analysis 
No interim efficacy analyses are planned. 
11.1.4 
Background and Demographic Characteristics 
Descriptive statistics will be used to summarize demographic characteristics (age, sex, and race) 
and background characteristics for the enrolled subjects.  Past/coexistent medical history 
information and physical examination observations and vital signs information for all 
randomized subjects will be presented in a by-subject listing.   

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11.1.5 
Study Medication Compliance 
The number of study drug applications by each subject based on diary data will be summarized 
using summary statistics (mean, standard deviation [SD], median, minimum, and maximum), 
and categorically.  
The amount of study medication used by each subject based on tube weight will be summarized 
by treatment using summary statistics (mean, SD, median, minimum, and maximum), 
and categorically.   
11.2 Efficacy Evaluation 
11.2.1 
Primary 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’ at Week 6. 
 
The primary endpoint will be analyzed with a logistic regression with a factor of treatment 
group. Statistical comparison between the active treatment arms and vehicle arms will be 
facilitated by using contrasts. 
11.2.2 
Secondary Endpoints 
 
The secondary efficacy endpoints will include: 
• 
IGA score of ‘clear’ or ‘almost clear’ at weeks 4, 8 and 12.  
• Percent reduction in mPASI at weeks 4, 8, and 12 as compared to Baseline. 
• Decrease in Percent BSA affected at weeks 4, 6, 8, and 12 as compared to baseline. 
• IGA score of ‘clear’ or ‘almost clear’ PLUS a 2-grade improvement from Baseline at 
weeks 4, 6, 8 and 12. 
• For subjects with intertriginous area involvement, and with severity of the 
intertriginous lesions at least ‘mild’ (I-IGA≥2) at Baseline, ‘I-IGA’ score of ‘clear’ or 
‘almost clear’ at weeks 4, 6, 8 and 12. 
• Reduction in WI-NRS pruritus score at weeks 4, 6, 8, and 12 as compared to 
Baseline. 
• In subjects with WI-NRS pruritus score ≥ 6 at baseline, a 4-point reduction in WI-
NRS pruritus score at 4, 6, 8, and 12 weeks as compared to Baseline. 
• Modified Psoriasis Area Severity Index-75 (mPASI-75) improvement at weeks 4, 6, 
8, and 12 as compared to Baseline. 
• Modified Psoriasis Area Severity Index-90 (mPASI-90) improvement at weeks 4, 6, 
8, and 12 as compared to Baseline. 
• Total PSD at weeks 4, 6, 8, and 12 as compared to Baseline. 

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• Reduction in Itch-related Sleep Loss score at weeks 4, 6, 8, and 12 as compared to 
Baseline. 
• Reduction in Dermatology Life Quality Index (DLQI) score at weeks 4, 6, 8, and 12 
as compared to Baseline. 
• Responses to the questions of PSD analyzed as improvement at weeks 4, 6, 8, and 12 
as compared to Baseline. 
The dichotomized IGA analyses will be analyzed with logistic regression similar to the primary 
endpoint. The remainder of the endpoints will be considered continuous and analyzed with an 
analysis of variance with a factor of treatment group. Statistical comparison between the active 
treatment arms and vehicle arms will be facilitated by using contrasts.  
mPASI will be analyzed for all subjects with the modification that, for subjects with < 10% of an 
involved anatomic area, the actual percentage of the anatomical area involved is used rather than 
a ‘0’ or ‘1’ (e.g. for 5% area involved, 0.5 would be used for the calculation).   
11.2.3 
Exploratory Endpoints 
 
Exploratory Endpoints are as follows:  
• Reduction in Fatigue NRS score at weeks 4, 6, 8, and 12 as compared to Baseline. 
• Reduction in WPAI score at weeks 4, 6, 8, and 12 as compared to Baseline. 
Only descriptive statistics will be used to analyze these endpoints. 
11.3 Safety Evaluation 
The following analyses will be performed; however, no formal inferential statistics will be done 
on safety assessments. 
Descriptive statistics will be presented by visit and treatment group for quantitative safety data 
and frequency counts will be compiled for classification of qualitative safety data. Sumaries of 
local tolerability will be presented by visit and treatment group. 
11.3.1 
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. 
Comparisons between treatment groups will be made by tabulating the frequency of subjects 
with one or more treatment-emergent AEs (classified into MedDRA terms) during the study.  

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Serious adverse events (SAEs) will be listed by subject. SAEs will be summarized by treatment 
group, severity, and relationship to study treatment. Each subject will be counted only once 
within a system organ class or a preferred term using the event with the greatest relationship and 
greatest severity. 
All information pertaining to AEs noted during the study will be listed by subject, detailing the 
verbatim description given by the Investigator, preferred term, system organ class, start date, 
stop date, severity, action taken regarding study drug, corrective treatment, outcome, and drug 
relatedness. The event onset will also be shown relative (in number of days) to date of first 
application. In addition, a list of subjects who prematurely discontinue from the study due to 
adverse events will also be provided. 
A subject-by-subject treatment-emergent AE (TEAE) data listing, including verbatim term, 
preferred term, treatment, severity, and relationship to study drug, will be provided.  
Medical history will be listed by subject. Physical examinations and 12-lead ECGs will be 
performed at screening, baseline and end-of-study which will be listed by subject. 
Vital signs will be tabulated by visit and treatment group. 
ECGs will be tabulated by visit and treatment group. 
Routine blood chemistries will be obtained throughout the study and the results summarized by 
parameter, visit and treatment group. 
11.3.2 
Local Tolerance Assessments 
For the Investigator’s assessment the numeric application site reaction scores will be summarized 
individually by using number and percentage of subjects by visit.   
11.3.3 
Medical History and Physical Examinations 
Medical history for all subjects will be presented in a by-subject listing.  
Physical examination findings for all subjects will be presented in a by-subject listing.  
Changes in physical examinations will be described in the text of the final report. 
11.3.4 
PHQ-8 
Data 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) 

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11.3.5 
C-SSRS 
The C-SSRS will be analyzed per the Columbia–Suicide Severity Rating Scale Scoring and Data 
Analysis Guide. 
11.3.6 
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 along with time point of collection. 
A shift table describing out-of-normal range shifts will be provided for clinical laboratory results.  
A shift table will identify subjects who gain or lose >5% body weight over the course of the 
study. 
11.3.7 
Prior and Concomitant Medications 
Prior and concomitant medication information for all randomized subjects will be presented in a 
by-subject listing.  Summary tables will be presented by World Health Organization-Anatomical 
Therapeutic Chemical Classification System (WHO-ATC) therapeutic category and product. 
11.4 Patient Reported Outcomes Analyses 
11.4.1 
WI-NRS, Fatigue NRS, Itch-Related Sleep Loss  
The NRS scales will be analyzed for change from baseline in itch severity (WI-NRS), fatigue  
NRS, and itch-related sleep loss.  
11.4.2 
Work Productivity and Activity Impairment (WPAI) Questionnaire 
The WPAI yields four types of scores:   
1.  Absenteeism (work time missed) 
2.  Presenteeism (impairment at work / reduced on-the-job effectiveness) 
3.  Work productivity loss (overall work impairment / absenteeism plus presenteeism) 
4.  Activity Impairment  
11.4.3 
Dermatology Life Quality Index (DLQI) 
The DLQI will be analyzed by evaluation of the reduction in total score at weeks 4, 6, 8, and 12 
as compared to Baseline. 
11.4.4 
Psoriasis Symptom Diary (PSD) 
The PSD will be analyzed as the improvement in responses to the questions of PSD weeks 4, 6, 
8, and 12 as compared to Baseline.  

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11.5 Pharmacokinetic Analysis 
Plasma drug concentrations at pre-dose will be summarized using descriptive statistics, reporting 
n, mean, standard deviation, median, minimum, and maximum. 
 
For all subjects, blood samples for the determination of roflumilast and its N-oxide metabolite 
will be collected at scheduled time points as delineated in the Schedule of Visits and 
Assessments (Section 5).   
A manual for blood sampling, collection, processing, and sample shipment will be provided in a 
separate document.  
12 STUDY ADMINISTRATION 
12.1 Ethics 
12.1.1 
Ethics Review Board  
Before enrollment of patients into the study, the current protocol and ICF will be reviewed and 
approved by an appropriate IRB 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 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 study drug(s) during the 
study, per the IRB or IEC local requirements, and in compliance with FDA and Health Canada 
regulations and ICH GCP guidelines. 
12.1.2 
Ethical Conduct of the Study 
 
This research will be carried out in accordance with the protocol, the principles of the Tri-
Council Policy Statement (TCPS), the ethical principles set forth in the Declaration of Helsinki, 
and the ICH harmonized tripartite guideline regarding GCP (E6 Consolidated Guidance, 
April 1996). 
 
 

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12.1.3 
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 
an ICF summarizing the discussion prior to screening and will be assured that they may 
withdraw from the study at any time without jeopardizing their medical care. 
Subjects will be given a signed copy of their ICF. 
12.2 Study Monitoring 
Prior to the initiation of the clinical investigation, Sponsor representatives or designees 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. 
12.3 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 QST’s Research’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 using SAS® to check 
for missing data, data inconsistencies, data ranges etc. Corrections are made prior to database 
lock. 
12.3.1 
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. 

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12.4 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.  
 
The principal investigator must retain all documentation relating to the study for a period of at 
least 2 years after the last marketing application approval or, if not approved, 2 years following 
the discontinuance of the test article for investigation.  If this requirement differs from any local 
regulations, the local regulations will take precedence unless the local retention policy is less 
than 2 years.   
12.5 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. 
 
 

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12.6 Report Format 
According to the ICH Harmonized Tripartite Guideline (Organization of the Common Technical 
Document for the Registration of Pharmaceuticals for Human Use M4 and the ICH M2 Expert 
Working Group), the final report will be written according to the ICH E3 Guideline (Structure 
and Content of Clinical Study Reports).  
12.7 Publication Policy 
The Sponsor is supportive of publishing clinical trial findings.  The process of coordinating 
publication efforts is detailed in the Clinical Trial Agreement. 
 

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13 REFERENCES 
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; 2017. 
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 2.1, October 2018 
Michalski, J. M., Golden, G., Ikari, J. and Rennard, S. I. (2012), PDE4: A Novel Target in the 
Treatment of Chronic Obstructive Pulmonary Disease. Clinical Pharmacology & Therapeutics, 
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. 
Snape SD, Wigger-Alberti W, Goehring, UM.  A phase I randomized trial to assess the effect on 
skin inﬁltrate thickness and tolerability of topical phosphodiesterase inhibitors in the treatment of 
psoriasis vulgaris using a modiﬁed psoriasis plaque test.  Br J Dermatol.  2016; 175:479-486. 
Tang-Liu DD, Matsumoto RM, Usansky JI. Clinical pharmacokinetics and drug metabolism of 
tazarotene: a novel topical treatment for acne and psoriasis. Clin Pharmacokinet. 1999; 
37:273-287. 
Wedzicha, JA, Calverley, PMA, Klaus, FR.  Roflumilast: a review of its use in the treatment of 
COPD.  International Journal of Chronic Obstructive Pulmonary Disease (2016) 11:81-90. 

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14 APPENDICES 
Appendix 1: Work Productivity and Activity Impairment Questionnaire (WPAI) 
 
Work Productivity and Activity Impairment Questionnaire: 
Specific Health Problem V2.0 (WPAI:SHP) 
 
The following questions ask about the effect of your psoriasis on your ability to work and 
perform regular activities.  Please fill in the blanks or circle a number, as indicated. 
 
1.  Are you currently employed (working for pay)?  
_____ NO ___ YES 
  If NO, check “NO” and skip to question 6. 
The next questions are about the past seven days, not including today. 
 
 
2. During the past seven days, how many hours did you miss from work because of 
problems associated with your psoriasis?  Include hours you missed on sick days, 
times you went in late, left early, etc., because of your psoriasis.  Do not include time 
you missed to participate in this study. 
 
_____ HOURS 
 
 
3. During the past seven days, how many hours did you miss from work because of 
any other reason, such as vacation, holidays, time off to participate in this study? 
 
_____HOURS 
 
 
4. During the past seven days, how many hours did you actually work? 
 
_____HOURS  (If “0”, skip to question 6.) 
 
 
5. During the past seven days, how much did your psoriasis affect your productivity 
while you were working?   
Think about days you were limited in the amount or kind of work you could do, days 
you accomplished less than you would like, or days you could not do your work as 
carefully as usual.  If psoriasis affected your work only a little, choose a low number.  
Choose a high number if psoriasis affected your work a great deal.   
Consider only how much psoriasis affected  
productivity while you were working. 

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Psoriasis had 
no effect on my 
work 
 
 
 
 
 
 
 
 
 
 
 
Psoriasis 
completely 
prevented me 
from working 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
CIRCLE A NUMBER 
 
6. During the past seven days, how much did your psoriasis affect your ability to do 
your regular daily activities, other than work at a job?   
 
By regular activities, we mean the usual activities you do, such as work around the 
house, shopping, childcare, exercising, studying, etc.  Think about times you were 
limited in the amount or kind of activities you could do and times you accomplished 
less than you would like.  If psoriasis affected your activities only a little, choose a 
low number.  Choose a high number if psoriasis affected your activities a great deal.   
 
Consider only how much psoriasis affected your ability  
to do your regular daily activities, other than work at a job. 
Psoriasis had 
no effect on my 
daily activities 
 
 
 
 
 
 
 
 
 
 
 
Psoriasis 
completely 
prevented me 
from doing my 
daily activities 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
 
                           
CIRCLE A NUMBER 
 
WPAI:SHP  V2.0 (US English)      
  
 

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Appendix 2: Columbia-Suicide Severity Rating Scale (C-SSRS) Baseline/Screening Version 
 

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Appendix 3: Columbia-Suicide Severity Rating Scale (C-SSRS) Since Last Visit Version 
 

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

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If "No", over the last week how much has   
 
 
A lot 
 
 
 
your skin been a problem at  
 
 
 
 
A little  
 
 
work or studying? 
 
 
 
 
 
Not at all 
 
 
8. 
Over the last week, how much has your  
 
 
 
Very much 
 
 
skin created problems with your   
 
 
 
A lot 
 
 
 
partner or any of your close friends 
 
 
 
A little  
 
 
or relatives?  
 
 
 
 
 
 
Not at all 
 
 
 
 
 
 
 
 
 
 
Not relevant  
 
9. 
Over the last week, how much has your  
 
 
 
Very much 
 
 
skin caused any sexual   
 
 
 
 
A lot 
 
 
 
difficulties? 
 
 
 
 
 
 
A little  
 
 
 
 
 
 
 
 
 
 
Not at all 
 
 
 
 
 
 
 
 
 
 
Not relevant  
 
10. 
Over the last week, how much of a  
 
 
 
Very much 
 
 
problem has the treatment for your 
 
 
 
A lot 
 
 
 
skin been, for example by making  
 
 
 
A little  
 
 
your home messy, or by taking up time?   
 
 
Not at all 
 
 
 
 
 
 
 
 
 
 
Not relevant  
 
 
Please check you have answered EVERY question. Thank you.  
 
 
 
¤AY Finlay, GK Khan, April 1992 www.dermatology.org.uk, this must not be copied without the permission of the authors. 
 
 

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Appendix 6: National Institute of Allergy and Infectious Diseases, Division of Microbiology 
and Infectious Diseases (DMID) Toxicity Table for Use in Trials Enrolling 
Healthy Adults (2014) Modified 
 
ABBREVIATIONS USED IN FOLLOWING TABLES:  
 
Abbreviation/Ter
m 
Definition/Explanation 
 
Abbreviation/Ter
m 
Definition/Explanation 
ALT 
alanine aminotransferase 
 
LO 
Low 
aPTT 
activated partial 
thromboplastin time 
mEq 
Milliequivalent 
AST 
aspartate aminotransferase 
mmHg 
millimeter of mercury 
AV block 
atrioventricular block 
Ms 
Millisecond 
bpm 
beats per minute 
N 
Normal 
BUN 
blood urea nitrogen 
PT 
prothrombin time 
CK 
creatine kinase 
PTT 
partial thromboplastin time 
CPK 
creatine phosphokinase 
QTc 
QT-interval corrected for 
heart rate 
FEV1 
forced expiratory volume in 1 
second 
QTcB 
Bazett’s corrected QT 
interval 
g 
Gram 
QTcF 
Fridericia’s corrected QT 
interval 
HI 
High 
RBC 
red blood cell 
HPF 
high power field 
Rx 
Therapy 
IU 
international unit 
S 
Second 
IV 
Intravenous 
U 
Unit 
K/CUMM 
x103/mm3 
ULN 
upper limit of normal 
LLN 
lower limit of normal 
 
 
 
ESTIMATING SEVERITY GRADE 
 
For abnormalities NOT found elsewhere in the Toxicity Tables use the scale below to estimate 
grade of severity: 
GRADE 1 
Mild: 
Transient or mild discomfort (<48 hours); no medical 
intervention/therapy required 
GRADE 2 
Moderate: 
Mild to moderate limitation in activity - some assistance may be 
needed; no or minimal medical intervention/therapy required 
GRADE 3 
Severe:  
Marked limitation in activity, some assistance usually required; 
medical intervention/therapy required hospitalizations possible. 
LABORATORY RANGES 
 
Where discrepancies in the ULN and LLN of laboratory ranges occur between those included in 
this document and those of the laboratory that performs the assays, the values provided by the 
laboratory will be used for assignment of severity grade.  
 

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CLINICAL ADVERSE EVENTS 
Cardiovascular 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Arrhythmia 
 
Asymptomatic, transient signs, no Rx 
required  
Recurrent/persistent; symptomatic 
Rx required  
Hemorrhage, blood loss  
Estimated blood loss ≤100 mL  
Estimated blood loss >100 mL, no 
transfusion required 
Transfusion required 
QTcF (Fridericia’s correction) 
a or QTcB (Bazett’s 
correction) 
Asymptomatic, QTc interval 450-479 
ms, OR  
Increase in interval<30 ms above 
baseline 
Asymptomatic, QTc interval 480-499 
ms, OR  
Increase in interval 30-59 ms above 
baseline 
Asymptomatic, QTc interval ≥500 
ms, OR  
Increase in interval ≥60 ms above 
baseline 
PR interval (prolonged) 
PR interval 0.20-0.25 s 
PR interval >0.25 s 
Type II 2nd degree AV block OR 
Ventricular pause >3.0 s 
Respiratory 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Cough 
Transient-no treatment  
Persistent cough  
Interferes with daily activities 
Bronchospasm, acute 
Transient wheeze; no treatment;  
  
Requires treatment; normalizes with 
bronchodilator and   
FEV1 < 80% predicted before 
bronchodilator  
Minimal  normalization with 
bronchodilator and FEV1 <80% 
predicted after bronchodilator 
Dyspnea  
Does not interfere with usual and social 
activities 
Interferes with usual and social 
activities, no treatment 
Prevents daily and usual social 
activity or requires treatment 
Nasal discharge (rhinitis 
infective per CTCAE 4.0) 
- 
Localized; local intervention indicated 
(e.g. topical antibiotic, antifungal, or 
antiviral) 
- 
Pharyngitis (CTCAE 4.0) 
- 
Localized; local intervention indicated 
(e.g. topical antibiotic, antifungal, or 
antiviral) 
IV antibiotic, antifungal, or antiviral 
intervention indicated; radiologic or 
operative intervention indicated 
Pneumonitis (rales or rhonchi) 
(CTCAE 4.0) 
Asymptomatic; clinical or diagnostic 
observations only; intervention not 
indicated 
Symptomatic; medical intervention 
indicated; limiting instrumental ADL 
Severe symptoms; limiting self-care 
ADL; oxygen indicated 
Lung infection (CTCAE 4.0) 
- 
Moderate symptoms; oral intervention 
indicated (e.g. antibiotic, antifungal, 
antiviral) 
IV antibiotic, antifungal, or antiviral 
intervention indicated; radiologic, 
endoscopic, or operative intervention 
indicated 
a Inclusion dependent upon protocol requirements 

Protocol ARQ-151-201 
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Amendment 1.0  
 
November 8, 2018 
Confidential 
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Gastrointestinal 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Nausea  
No interference with activity 
Some interference with activity 
Prevents daily activities 
Vomiting  
No interference with activity or 
1-2 episodes/24 hours 
Some interference with activity or 
>2 episodes/24 hours 
Prevents daily activity or requires 
IV hydration 
Diarrhea  
2-3 loose or watery stools or  
<400 g/24 hours 
4-5 loose or watery stools or  
400-800 g/24 hours 
6 or more loose or watery stools or 
>800 g/24 hours or requires 
IV hydration 
Urinary Tract 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Urinary tract infection 
(CTCAE 4.0) 
- 
Localized; local intervention indicated 
(e.g., oral or topical antibiotic, 
antifungal, antiviral) 
IV antibiotic, antifungal, or antiviral 
intervention indicated; radiologic or 
operative intervention indicated 
Reactogenicity 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Local reactions 
Pain 
Does not interfere with activity 
Repeated use of non-narcotic pain 
reliever >24 hours or interferes with 
activity 
Any use of narcotic pain reliever or 
prevents daily activity 
Tenderness 
Discomfort only to touch 
Discomfort with movement 
Significant discomfort at rest 
Erythema/redness a 
2.5-5 cm 
5.1-10 cm 
>10 cm 
Induration/swelling b 
2.5-5 cm and does not interfere with 
activity 
5.1-10 cm or interferes with activity 
>10 cm or prevents daily activity 
Systemic reactions 
Allergic reaction  
Pruritus without rash  
Localized urticaria  
Generalized urticaria; angioedema or 
anaphylaxis  
Headache  
No interference with activity 
Repeated use of non-narcotic pain 
reliever >24 hours or some 
interference with activity 
Significant; any use of narcotic pain 
reliever or prevents daily activity 
Fatigue  
No interference with activity 
Some interference with activity 
Significant; prevents daily activity 
Myalgia 
No interference with activity 
Some interference with activity 
Significant; prevents daily activity 

Protocol ARQ-151-201 
Arcutis, Inc. 
Amendment 1.0  
 
November 8, 2018 
Confidential 
 Page 80 of 83 
All other conditions 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Illness or clinical adverse 
event (as defined according to 
applicable regulations) 
No interference with activity 
Some interference with activity not 
requiring medical intervention 
Prevents daily activity and requires 
medical intervention 
a  In addition to grading the measured local reaction at the greatest single diameter, the measurement should be recorded as a continuous variable. 
b  Induration/swelling should be evaluated and graded using the functional scale as well as the actual measurement. 
 
LABORATORY AND VITAL SIGNS TOXICITY GRADING (Some laboratory values have been modified to be consistent with the normal ranges of 
the ACM laboratory used in the present study) 
 
Blood, Serum, or Plasma Chemistries a 
LO/HI/N b 
Mild  
(Grade 1) c 
Moderate  
(Grade 2) 
Severe  
(Grade 3) 
Sodium (mEq/L or mmol/L) 
LO 
131-<LLN  
130  
<130 
HI 
>ULN-148 
149-150 
>150 
Potassium (mEq/L or mmol/L)  
LO 
<LLN-3.2 
<3.2-3.1 
<3.1 
HI 
>ULN-5.6 
>5.6-5.7 
>5.7 
Glucose (mg/dL) 
LO mmol/L 
<LLN-3.0 
<3.0-2.2 
<2.2 
HI mmol/L 
>ULN-8.9 
>8.9-13.9 
>13.9 
Blood urea nitrogen  
HI mmol/L 
>8.9-17.8 
>17.8-35.5 
>35.5 
Creatinine  
N 
115-151 (µmol/L) 
152-177 (µmol/L) 
> 177 (µmol/L) 
Calcium  (CTCAE 4.0) 
LO mmol/L 
<LLN-2.0 
<2.0-1.75 
<1.75 
HI mmol/L 
>ULN-2.9 
>2.9-3.1 
>3.1 
Magnesium  (CTCAE 4.0) 
LO mmol/L 
<LLN-0.5 
<0.5-0.4 
<0.4 
Phosphorous  (CTCAE 4.0) 
LO mmol/L 
<LLN-0.8 
<0.8-0.6 
<0.6 
Creatine kinase (CPK or CK) (CTCAE 4.0) 
HI 
>ULN-2.5xULN 
>2.5xULN-5xULN 
>5xULN 

Protocol ARQ-151-201 
Arcutis, Inc. 
Amendment 1.0  
 
November 8, 2018 
Confidential 
 Page 81 of 83 
Blood, Serum, or Plasma Chemistries a 
LO/HI/N b 
Mild  
(Grade 1) c 
Moderate  
(Grade 2) 
Severe  
(Grade 3) 
Albumin  
LO g/L 
<30-28 
<28-25 
<25 
Total protein  
LO g/L 
<LLN-52 
<52-50 
<50 
Alkaline phosphatase (U/L) (CTCAE 4.0) 
HI 
>ULN-2.5xULN 
>2.5xULN-5xULN 
>5xULN 
AST (U/L) (CTCAE 4.0) 
HI 
>ULN-3xULN 
>3xULN-5xULN 
>5xULN 
ALT (U/L) (CTCAE 4.0) 
HI 
>ULN-3xULN 
>3xULN-5xULN 
>5xULN 
Bilirubin, serum total (mmol/L) (CTCAE 4.0) 
HI mmol/L 
>ULN-1.5xULN 
>1.5xULN-3xULN 
>3xULN 
Bilirubin, serum total (mg/dL) when ALT ≥105 (Hy’s 
law) 
HI 
1.3-1.5 
1.6-2.0  
>2.0  
Bilirubin, serum direct (mmol/L) (CTCAE 4.0) 
HI mmol/L 
>ULN-1.5xULN 
>1.5xULN-3xULN 
>3xULN 
Amylase (U/L) (CTCAE 4.0) 
HI 
>ULN-1.5xULN 
>1.5xULN-2xULN 
>2xULN 
Lipase (U/L) (CTCAE 4.0)  
HI 
>ULN-1.5xULN 
>1.5xULN-2xULN 
>2xULN 
Uric acid (mg/dL/mmol/L) (CTCAE 4.0) 
HI 
>ULN – 10 mg/dL 
(0.59 mmol/L) without 
physiologic 
consequences 
- 
>ULN – 10 mg/dL 
(0.59 mmol/L) with 
physiologic 
consequences 
a   Depending upon the laboratory used, references ranges, eligibility ranges and grading may be split out by sex and/or age. 
b   Low, High, Not Graded (N). 
c   If initial boundary of grade 1 has gap from reference range or eligibility range, calculations based on the New England Journal of Medicine (NEJM) reference 
ranges. 
 
 

Protocol ARQ-151-201 
Arcutis, Inc. 
Amendment 1.0  
 
November 8, 2018 
Confidential 
 Page 82 of 83 
Hematology 
LO/HI/N a 
Mild 
(Grade 1) b 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Hemoglobin (women) (g/dL) 
Hemoglobin (men) (g/dL) 
LO 
10.8-11.3 
9.2-10.7 
<9.2  
LO 
12.0-12.5 
10.0-11.9 
<10.0 
White blood cell count (K/CUMM) 
HI 
11.00-15.00 
15.00-20.00 
>20.00 
LO 
2.50-3.50 
1.50-2.49 
<1.50 
Lymphocytes (K/CUMM) 
LO 
0.76-0.90  
0.50-0.75 
<0.5 
Neutrophils (K/CUMM) 
LO 
1.50-1.95  
1.00-1.49 
<1.00 
Eosinophils (K/CUMM) 
HI 
0.58-0.74  
0.75-1.50 
>1.50 
Platelets (K/CUMM) 
LO 
120-130 
100-120 
<100 
Coagulation 
 
 
 
 
Prothrombin time (PT, seconds) 
HI 
> ULN-14.4 
14.5-15.7 
>15.7 
Partial thromboplastin time  
(PTT or aPTT, seconds) 
HI 
>ULN-42.1 
42.2-50.0 
>50.0 
Fibrinogen (mg/dL) (CTCAE 4.0) 
HI 
>ULN-500 
501-600 
>600 
LO 
<LLN-0.75xLLN 
<0.75xLLN-0.5xLLN 
<0.5xLLN 
Urine  
 
 
 
 
Protein (dipstick) 
HI 
1+ 
2+ 
>2+ 
Glucose (dipstick) 
HI 
1+ 
2+ 
>2+ 
Blood (microscopic) - red blood cells per high power field 
(RBC/HPF) 
HI 
5-10 for males 
9-10 for females  
11-50  
>50 and/or gross blood 
a  Low, High, Not Graded. 
b  If initial boundary of grade 1 has gap from reference range or eligibility range, calculations based on the New England Journal of Medicine (NEJM) reference 
ranges. 
 
 
 

Protocol ARQ-151-201 
Arcutis, Inc. 
Amendment 1.0  
 
November 8, 2018 
Confidential 
 Page 83 of 83 
Vital Signs 
LO/HI/N a 
Mild 
(Grade 1 ) b 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Fever (°C) c 
HI 
38.0-38.4 
38.5-38.9 
>38.9 
Fever (°F)  
HI 
100.4-101.1 
101.2-102.0 
>102.1  
Tachycardia - beats per minute 
HI 
101-115 
116-130 
>130 or ventricular 
dysrhythmias 
Bradycardia - beats per minute 
LO 
40-45  
35-40 
<35 
Hypertension (systolic) - mm Hg d 
HI 
141-150 
151-160 
>160 
Hypertension (diastolic) - mm Hg 
HI 
91-95 
96-100 
>100 
Hypotension (systolic) - mm Hg 
LO 
85-89 
80-84 
<80 
Tachypnea - breaths per minute 
HI 
23-25 
26-30 
>30 
a  Low, High, Not Graded. 
b  If initial boundary of grade 1 has gap from reference range or eligibility range, calculations based on the New England Journal of Medicine (NEJM) reference 
ranges. 
c  Oral temperature; no recent hot or cold beverages or smoking. A protocol should select either °C or °F for inclusion. 
d  Assuming subject is awake, resting, and supine; for adverse events, 3 measurements on the same arm with concordant results.