A Phase 1/2b, Multiple Dose and 12-Week, Parallel Group, Double Blind, Dose Ranging, Vehicle-Controlled Study of the Safety and Efficacy of ARQ-252 Cream 0.1% and ARQ-252 Cream 0.3% in Subjects With Chronic Hand Eczema
Phase: PHASE1
Conditions: Chronic Hand Eczema
Sponsor: Arcutis Biotherapeutics, Inc.

30 June 2020
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Protocol ARQ-252-205
A Phase 1/2b, Multiple Dose and 12-Week, Parallel Group, Double
Blind, Dose Ranging, Vehicle-Controlled Study of the Safety and
Efficacy of ARQ-252 Cream 0.1% and ARQ-252 Cream 0.3% in
Subjects with Chronic Hand Eczema
Sponsor:
Arcutis Biotherapeutics, Inc.
2945 Townsgate Road, Suite 110
Westlake Village, CA 91361
Sponsor Representative:
David Berk, MD
Vice President, Clinical Development
Tel: +1 (805) 418-5006 Ext. 711
E-mail: dberk@arcutis.com
Medical Monitor:
Maria Marcano Bozo, MD
One Park Drive, Suite 150
Research Triangle Park, NC 27709
Tel: +1 (512) 686-1256
E-mail: ARCU211360@premier-research.com
IND Number:
140409
Protocol Version:
Amendment 2
Protocol Date:
30 June 2020
GCP Statement
This study is to be performed in full compliance with the protocol, International Conference on Harmonisation Good
Clinical Practices (ICH GCP), and applicable regulatory requirements. All required study documentation will be
archived as required by regulatory authorities.
Confidentiality Statement
This document contains confidential information. It contains proprietary information of Arcutis Biotherapeutics,
Inc. Any viewing or disclosure of such information that is not authorized in writing by Arcutis Biotherapeutics, Inc.
is strictly prohibited. Such information may be used solely for the purpose of reviewing or performing this study.

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Amendment 2
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SITE INVESTIGATOR SIGNATURE PAGE
A Phase 1/2b, Multiple Dose and 12-Week, Parallel Group, Double Blind, Dose Ranging,
Vehicle-Controlled Study of the Safety and Efficacy of ARQ-252 Cream 0.1% and ARQ-252 Cream
0.3% in Subjects with Chronic Hand Eczema
ARQ-252-205
SPONSOR:
Arcutis Biotherapeutics, Inc.
2945 Townsgate Road, Suite 110
Westlake Village, CA 91361
ISSUE DATE:
30 June 2020
I have read this protocol, including all appendices, and I agree that it contains all necessary
details for me and my staff to conduct this study as described. I will conduct this study as
outlined herein, in accordance with the current International Conference on Harmonisation Good
Clinical Practices (ICH GCPs) and applicable local and regional regulations.
I will provide all study personnel under my supervision copies of the protocol and access to all
information provided by Arcutis Biotherapeutics, Inc. I will discuss the material with them to
ensure that they are fully informed about ARQ-252 and the study.
I agree that I or my designee will completely inform all subjects in this study concerning the
pertinent details and purpose of the study prior to their agreement to participate in the study in
accordance with cGCPs and regulatory authority requirements. I will be responsible for
maintaining each subject’s consent form in the study file and providing each subject with a
signed copy of the consent form.
I agree to maintain the confidentiality of all information received or developed in connection
with this protocol.
Investigational Site Name: __________________________________
Print Investigator Name:
__________________________________
Investigator Signature: __________________________________ Date: _______________

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SUMMARY OF CHANGES
The following sections have been changed in Amendment 2 of the ARQ-252-205 protocol:
Section
Summary of Changes
1.3
Schedule of Visits and
Assessments (Cohort 2)
Clarified language in the footnote for IP dispensing.
2.4.2
Risks and/or Benefits to
Subjects
Added the potential risks of ARQ-252 cream.
4.2
Number of Sites and
Subjects
Clarified language regarding the replacement of subjects.
4.7.2
Exclusion Criteria
Clarified exclusion criterion for positive patch test with
continued exposure to allergen.
4.8
Removal of Subjects
from Investigational
Product
Updated the reasons for discontinuation of IP.
4.10
Treatment Stopping
Rules
Added additional criteria for treatment discontinuation and
clarified existing criteria.
5.1.1
Screening
Added review of allergies and/or contact dermatitis to the
medical history assessment at the Screening Visit.
5.1.2
Contraception
Requirements
Added statements regarding nonclinical research on fetal
development and the requirement to adhere to the pregnancy
testing and/or contraception requirements of the protocol.
Editorial changes made throughout to improve accuracy or readability

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TABLE OF CONTENTS
1.
PROTOCOL SUMMARY ................................................................................................. 10
Synopsis ......................................................................................................................... 10
Study Schema................................................................................................................ 18
Schedule of Visits and Assessments ............................................................................ 20
2.
INTRODUCTION............................................................................................................... 24
Background................................................................................................................... 24
Nonclinical Safety Summary ....................................................................................... 25
Clinical Studies ............................................................................................................. 26
Oral Administration: Phase 1 ...................................................................................26
Oral Administration: Phase 2 ...................................................................................27
Additional Studies....................................................................................................30
Rationale for Development.......................................................................................... 31
Dose Selection..........................................................................................................31
Risks and/or Benefits to Subjects.............................................................................32
3.
STUDY ENDPOINTS AND OBJECTIVES..................................................................... 32
Study Objectives........................................................................................................... 32
Primary Objectives...................................................................................................32
Study Endpoints............................................................................................................ 33
Primary Endpoints....................................................................................................33
Secondary Endpoints................................................................................................33
Exploratory Endpoints..............................................................................................34
4.
INVESTIGATIONAL PLAN ............................................................................................ 34
Overall Study Design and Plan ................................................................................... 34
Number of Sites and Subjects...................................................................................... 34
Subject Participation.................................................................................................... 35
Randomization.............................................................................................................. 35
Numbering of Subjects................................................................................................. 36
Blinding ......................................................................................................................... 36
Breaking Treatment Codes.......................................................................................36
Selection of Study Population...................................................................................... 37
Inclusion Criteria......................................................................................................37
Exclusion Criteria.....................................................................................................38
Removal of Subjects from Investigational Product................................................... 39
Removal of Subjects from the Study .......................................................................... 40
Treatment Stopping Rules........................................................................................... 40

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Study Restrictions......................................................................................................... 41
Prohibitions and Concomitant Therapy....................................................................41
Treatment...................................................................................................................... 42
Investigational Product Supplies, Packaging and Labeling .....................................42
Treatment Administration ........................................................................................43
Treatment Compliance .............................................................................................43
5.
STUDY PROCEDURES .................................................................................................... 44
Safety Assessments ....................................................................................................... 44
Screening..................................................................................................................44
Contraception Requirements....................................................................................45
Physical Examination...............................................................................................46
Vital Signs, Height and Weight................................................................................46
12-lead ECGs ...........................................................................................................46
Laboratory Tests.......................................................................................................47
Local Tolerability Assessment.................................................................................48
Adverse Events.........................................................................................................49
Efficacy Evaluations..................................................................................................... 49
Investigator’s Global Assessment (IGA) .................................................................49
Body Surface Area (BSA)........................................................................................51
Worst Itch Numerical Rating Scale (WI-NRS)........................................................51
NRS-Pain Scale........................................................................................................51
HECSI ......................................................................................................................52
Quality of Life in Hand Eczema Questionnaire.......................................................53
Nail Dystrophy Assessment .....................................................................................53
Other Evaluations......................................................................................................... 53
Pharmacokinetics Assessment..................................................................................53
Medical Photography ...............................................................................................54
Final Study Visit – End of Study................................................................................. 54
Early Termination Visit............................................................................................... 54
Unscheduled Visit......................................................................................................... 54
Adverse Events.............................................................................................................. 55
Adverse Event Definition.........................................................................................55
Serious Adverse Event Definition............................................................................55
Suspected Unexpected Serious Adverse Reaction (SUSAR) ..................................56
Safety Review with Subject .....................................................................................57
Adverse Event Reporting .........................................................................................57
Reporting Pregnancy.................................................................................................... 58
6.
DATA ANALYSIS.............................................................................................................. 59
Statistical Methods ....................................................................................................... 59
Determination of Sample Size..................................................................................59
Subjects to Analyze..................................................................................................60

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Interim Analysis .......................................................................................................60
Background and Demographic Characteristics........................................................60
Study Disposition.....................................................................................................60
Protocol Deviations and Eligibility Deviations........................................................60
Investigational Product Compliance ........................................................................61
Efficacy Evaluation ...................................................................................................... 61
Primary Efficacy Endpoint.......................................................................................61
Secondary Endpoints................................................................................................61
Exploratory Endpoints..............................................................................................62
Safety Analysis.............................................................................................................. 62
Adverse Events.........................................................................................................62
Local Tolerance Assessment....................................................................................63
Medical History and Physical Examinations ...........................................................63
Clinical Laboratory Results and Vital Signs............................................................63
Prior and Concomitant Medications.........................................................................63
Pharmacokinetic Analysis............................................................................................ 63
7.
STUDY ADMINISTRATION............................................................................................ 63
Ethics ............................................................................................................................. 63
Ethics Review Board................................................................................................63
Ethical Conduct of the Study ...................................................................................64
Subject Information and Consent.............................................................................64
Study Completion and Termination ........................................................................... 64
Study Completion.....................................................................................................64
Study Termination....................................................................................................64
Study Monitoring.......................................................................................................... 65
Data Quality Assurance ............................................................................................... 65
Data Handling and Record Keeping........................................................................... 65
Protocol Amendments and Deviations........................................................................ 66
Confidentiality and Privacy......................................................................................... 66
Conflict of Interest........................................................................................................ 67
Report Format .............................................................................................................. 67
Publication Policy......................................................................................................... 67
8.
REFERENCES.................................................................................................................... 68

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LIST OF TABLES
Table 1.
Proportion of Patients Reaching ACR20/50/70 and Statistical Check
(CMH-FAS-NRI) after 12-week Administration in a Multicenter,
Randomized, Double-blind, Placebo-controlled Phase II Study Evaluating
the Efficacy and Safety of SHR0302 Tables in Patients with Moderate to
Severe Active Rheumatoid Arthritis......................................................................28
Table 2.
Excluded Medications and Treatments..................................................................41
Table 3.
Laboratory Tests ....................................................................................................47
LIST OF FIGURES
Figure 1.
Contraception Requirements for Female Subjects.................................................46
LIST OF APPENDICES
Appendix 1.
Quality Of Life in Hand Eczema Questionnaire (QOLHEQ)................................70

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ABBREVIATIONS
Abbreviation
Definition
ACR20
American College of Rheumatology 20% improvement in rheumatoid
arthritis score
ACR50
American College of Rheumatology 50% improvement in rheumatoid
arthritis score
ACR70
American College of Rheumatology 70% improvement in rheumatoid
arthritis score
AE
Adverse Event
AUC
Area Under the Curve
BID
Twice Daily ("bis in die")
BSA
Body Surface Area
Cmax
Maximum Concentration
Cm
Centimeter
CRF
Case Report Form
CTCAE
Common Terminology Criteria for Adverse Events
DNA
Deoxyribonucleic Acid
EC
Ethics Committee
ECG
Electrocardiogram
FDA
U.S. Food and Drug Administration
FOCBP
Female of Childbearing Potential
FSH
Follicle-Stimulating Hormone
GCP
Good Clinical Practices
Hr
Hour
IB
Investigator’s Brochure
ICF
Informed Consent Form
ICH
International Conference on Harmonisation
ID
Identification
IGA
Investigator’s Global Assessment
IL
Interleukin
IND
Investigational New Drug
IP
Investigational Product
IRB
Institutional Review Board
ITT
Intent to Treat
IRT
Interactive Response Technology

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Abbreviation
Definition
Kg
Kilogram
µg
Microgram
MAD
Multiple ascending dose
MedDRA
Medical Dictionary for Regulatory Activities
Mg
Milligram
Min
Minute
mL
Milliliter
NCI
National Cancer Institute
NIH
National Institutes of Health
NOAEL
No Observed Adverse Effect Level
Ng
Nanogram
NRS
Numerical Rating Scale
P-450
Cytochrome P450
PDE-4
Phosphodiesterase 4
PI
Principal Investigator
PK
Pharmacokinetics
QD
Once Daily ("quaque die")
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SD
Standard Deviation
SUSAR
Suspected Unexpected Serious Adverse Reaction
TCPS
Tri-Council Policy Statement
TEAE
Treatment Emergent Adverse Event
Tmax
Time to Reach Maximum Concentration
US
United States
WI-NRS
Worst Itch – Numeric Rating Score

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1.
PROTOCOL SUMMARY
Synopsis
Protocol Title:
A Phase 1/2b, Multiple Dose and 12-Week, Parallel Group,
Double Blind, Dose Ranging, Vehicle-Controlled Study of the Safety
and Efficacy of ARQ-252 Cream 0.1% and ARQ-252 Cream 0.3% in
Subjects with Chronic Hand Eczema
Clinical Indication:
Chronic Hand Eczema (CHE)
Investigational
Product:
ARQ-252 cream will be supplied as ARQ-252 cream 0.1%
(only applicable in Cohort 2) and ARQ-252 cream 0.3%.
Matching vehicle cream (only applicable in Cohort 2) will contain
only excipients of ARQ-252 cream.
The active ingredient in ARQ-252 cream is SHR0302, a selective
JAK1 inhibitor.
Study Design:
ARQ-252-205 is a Phase 1/2b, Multiple Dose and 12-week, parallel
group, double blind, vehicle-controlled study of the safety and
efficacy of ARQ-252 cream 0.1% and ARQ-252 cream 0.3% in
subjects with chronic hand eczema.
There are 2 cohorts of subjects.
•
Cohort 1 is a multiple dose cohort in which subjects with chronic
hand eczema will be assigned to ARQ-252 cream
0.3% QD x 2 weeks to be applied to both hands (approximately
4% of BSA). PK and tolerability will be evaluated.
•
Cohort 2 is a parallel group, double blind, vehicle-controlled
cohort in which subjects with chronic hand eczema will be
randomized to ARQ-252 cream 0.3% QD, ARQ-252 cream
0.3% BID, ARQ-252 cream 0.1% QD, vehicle cream BID or
vehicle cream QD x 12 weeks to be applied to both hands
(approximately 4% of BSA). Safety and efficacy will be
evaluated.
Study Objectives:
The objectives of this study are as follows:
Phase 1 (Cohort 1)
•
To assess the safety, tolerability and PK of QD application of
ARQ-252 0.3% to both hands for 2 weeks in 6 subjects with
chronic hand eczema (Cohort 1)
Phase 2b (Cohort 2)
•
To assess the safety and efficacy of ARQ-252 cream 0.1% QD and
ARQ-252 cream 0.3% QD and BID, vs vehicle applied QD and
BID for 12 weeks to subjects with chronic hand eczema (Cohort 2)
Study Sites:
Approximately 45 sites in the United States, Canada and Australia.

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Study Population:
For both Cohorts, subjects will be male and female adults (≥18 years
of age), with chronic hand eczema, and an Investigator’s Global
Assessment (IGA) of disease severity of at least Mild (‘2’) at
Baseline. In Cohort 2, subjects with IGA of ‘Mild’ will be limited to
20% of total enrollment, and subjects with IGA of ‘Severe’ will also
be limited to 20% of total enrollment.
•
Cohort 1 will include approximately 6 evaluable subjects,
assigned to ARQ-252 cream 0.3% QD
•
Cohort 2 will include approximately 215 subjects, randomized
2:2:1:1:1 to ARQ-252 cream 0.3% QD : ARQ-252 cream
0.3% BID : ARQ-252 cream 0.1% QD : vehicle cream BID:
vehicle cream QD
Duration of
Participation for
Subjects:
Cohort 1: Screening (up to 4 weeks), Treatment phase (2 weeks),
and follow-up (1 week post-treatment completion) for a total of
7 weeks
Cohort 2: Screening (up to 4 weeks), Treatment phase (12 weeks),
and follow-up (1 week post-treatment completion); for a total of
17 weeks
Inclusion Criteria:
1. Participants legally competent to sign and give informed consent.
2. Males and females 18 years of age and older (inclusive) at the
time of consent.
3. Clinical diagnosis of chronic hand eczema, defined as hand
eczema persistent for more than 3 months, or returned twice or
more within the last 12 months (Diepgen 2009). Generally stable
disease for 6 weeks. Both irritant and non-irritant etiologic forms
are allowed. All morphologic types are allowed,
e.g., vesicular/dyshidrotic, hyperkeratotic, nummular, and other
types.
4. An Investigator’s Global Assessment of disease severity (IGA) of
at least Mild (‘2’) at Baseline (Visit 2). (In Cohort 2, subjects with
IGA of ‘Mild’ will be limited to 20% of total enrollment, and
subjects with IGA of ‘Severe’ subjects will also be limited to 20%
of total enrollment).
5. Chronic hand eczema involving at least 0.3% body surface area
total (i.e., approximately a third of one handprint) lesions on both
hands added together at Baseline (Visit 2).
6. Female subjects of childbearing potential (FOCBP) must have a
negative serum pregnancy test at Screening and negative urine
pregnancy test at Baseline (Visit 2). For FOCBP involved in any
sexual intercourse that could lead to pregnancy: the subject must
agree to use a highly effective contraceptive method for at least
4 weeks prior to Day 1. Additionally, from Day 1 until at least
4 weeks after the last investigational product administration, these

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subjects must agree to use at least 1 highly effective contraceptive
method in addition to 1 barrier method according to Contraception
Requirements (Figure 1).
7. Females of non-childbearing potential must either be post-
menopausal with spontaneous amenorrhea for at least 12 months
(post-menopausal status will be confirmed with FSH testing) or
have undergone surgical sterilization (permanent sterilization
methods include hysterectomy, bilateral oophorectomy,
hysteroscopic sterilization or bilateral salpingectomy) according to
Contraception Requirements (Figure 1).
8. Males, if engaging in sexual intercourse with a female who is
pregnant or a female of childbearing potential, must agree to use a
condom every time during the study and every time subsequently
until 4 weeks after the last investigational product administration.
9. Males must agree not to donate sperm from the first dose of
investigational product until 4 weeks after the last investigational
product administration.
10. Subjects in good health as judged by the Investigator, based on
medical history, physical examination, 12-lead electrocardiogram
(ECG), serum chemistry labs, hematology values, and urinalysis.
11. Subjects are considered reliable and capable of adhering to the
Protocol and visit schedule, according to the judgment of the
Investigator.
Exclusion Criteria:
1. Concurrent skin diseases on the hands which, in the opinion of the
Investigator, could confound the study (e.g., tinnea manuum).
2. Active skin diseases not on the hands such as atopic dermatitis or
psoriasis requiring medical treatment that could significantly
affect hand eczema, in the Investigator’s opinion.
3. Subjects with any presence or history of psoriasis.
4. History of a positive patch test with continued exposure to
allergen. If, in the opinion of the Investigator, there is any
suspected allergic hand eczema with continued exposure to
allergen, subject must undergo diagnostic patch testing to
determine if they meet entry criteria prior to Baseline (Visit 2).
5. Subjects who cannot discontinue systemic and/or topical therapies
for the treatment of chronic hand eczema prior to Baseline
(Visit 2) and during the study according to Excluded Medications
and Treatments (Table 2), (i.e., immunosuppressive drugs,
immunomodulating drugs, retinoids, or corticosteroids).
6. Psoralen ultraviolet A (PUVA) or ultraviolet B (UVB) therapy on
the hands within 4 weeks prior to Baseline (Visit 2).

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7. Cutaneously applied treatment with immunomodulators
(e.g., phosphodiesterase-4 (PDE-4) inhibitors, pimecrolimus,
tacrolimus), topical urea moisturizers, topical antibiotics, or low
or mid potency topical corticosteroids on the hands or elsewhere
within 1 week prior to Baseline (Visit 2). Cutaneously applied
treatment with high potency topical corticosteroids on the hands
or elsewhere within 2 weeks prior to Baseline (Visit 2).
8. Subjects that have significant active systemic or localized
infection, including known actively infected eczema or have had
any infection that required oral or intravenous administration of
antibiotics, antifungal or antiviral agents within 2 weeks prior to
Baseline (Visit 2).
9. Other cutaneously applied therapy on the hands (except for the use
of subject's own non-urea and non-salicylic acid emollients)
within 1 week prior to Baseline (Visit 2).
10. Subjects who are unwilling to refrain from using a tanning bed or
other LEDs as well as outdoor tanning or excessive sun exposure
for 4 weeks prior to Baseline (Visit 2) and during the study.
11. Subjects with a history of chronic alcohol or drug abuse within
6 months prior to Baseline (Visit 2).
12. Current or a history of cancer within 5 years with the exception of
fully treated skin basal cell carcinoma, cutaneous squamous cell
carcinoma or carcinoma in situ of the cervix.
13. Subjects that have received live vaccine therapy less than 4 weeks
prior to Baseline (Visit 2), immunosuppressive drugs less than
4 weeks prior to Baseline (Visit 2), or have known infection with
mycobacterium tuberculosis, hepatitis B or C, or HIV, or have a
diagnosis of an immunodeficiency disorder.
14. Subject had a major surgery within 4 weeks prior to Baseline
(Visit 2) or has a major surgery planned during the study.
15. Known or suspected:
•
severe renal insufficiency or severe hepatic disorders
•
hypersensitivity to component(s) of the investigational product
which include SHR0302, butylated hydroxytoluene (BHT),
benzyl alcohol, dimethyl sulfoxide, cyclomethicone,
dimethicone (350 cst), ST-Elastomer 10, water, propylene
glycol, polyethylene glycol 200, Pemulen TR1, Carbopol
974P, ethylenediaminetetraacetic acid, trolamine and
D-limonene.
16. Pregnant or lactating women or women planning to become
pregnant during the study and / or within 28 days following the
last dose of investigational product.

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17. Subjects who cannot discontinue the use of strong systemic
Cytochrome P-450 3A4 inducers e.g., efavirenz, nevirapine,
glucocorticoids, barbiturates (including phenobarbital), phenytoin,
rifampin and carbamazepine for 2 weeks prior to Baseline
(Visit 2) and during the study period.
18. Subjects who cannot discontinue the use of strong systemic
Cytochrome P-450 3A4 inhibitors e.g., indinavir, nelfinavir,
ritonavir, clarithromycin, itraconazole, ketoconazole, fluconazole,
nefazodone, saquinavir, suboxone and telithromycin for 2 weeks
prior to Baseline (Visit 2) and during the study period.
19. Subjects with any serious medical condition or clinically
significant laboratory, ECG, vital signs or physical examination
abnormality that would prevent study participation or place the
subject at significant risk, as judged by the Investigator.
Key Assessments:
Phase 1 (Cohort 1):
•
Safety will be monitored through application site assessments,
safety labs, AEs, ECGs, physical examinations, and vital
signs.
•
Serial PK sampling will be performed on Day 1 (1, 2, 4, 6,
and 24 hours post-dose administration), and at Day 15
(pre-dose and 1, 2, 4, 6, and 24 hours post-dose
administration). For 24-hour timepoints, subjects return to the
clinic on the following day within 2 hours of the IP application
time from the previous day for PK plasma sample collection.
A pre-dose/trough PK sample will be taken at Day 8.
Phase 2b (Cohort 2):
•
Safety will be monitored through application site assessments,
safety labs, AEs, ECGs, physical examinations, and vital
signs.
•
Efficacy will be evaluated through IGA, HECSI, WI-NRS
Pruritus, NRS Pain, Nail Dystrophy Assessments and
QOLHEQ
•
PK will be evaluated through trough/pre-dose sampling at
Baseline, Day 29, and Day 85.
Study Endpoints:
Phase 1 (Cohort 1):
•
Safety, as measured by the incidence and severity of adverse
events, changes in laboratory parameters, tolerability, and
pharmacokinetics.
Phase 2b (Cohort 2):
The primary endpoint of Cohort 2 is:
•
The rate of an IGA score of ‘clear’ or ‘almost clear’ at
Week 12

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Phase 2b (Cohort 2):
The secondary endpoints of Cohort 2 are:
•
The rate of achievement of IGA of ‘clear’ or ‘almost clear’
PLUS at least a 2-point improvement from Baseline at
Weeks 2, 4, 8 and 12
•
The rate of achievement of at least a 2-point improvement
from Baseline at Weeks 2, 4, 8 and 12
•
Achievement of IGA of ‘clear’ or ‘almost clear’ at Weeks 2, 4,
and 8
•
Time to IGA of ‘clear’ or ‘almost clear’
•
Change in IGA score at Weeks 2, 4, 8, and 12 as compared to
Baseline
•
Change in WI-NRS pruritus score at 2 weeks, 4 weeks,
8 weeks, and 12 weeks compared to Baseline
•
The rate of achievement of ≥4-point reduction from Baseline
in WI-NRS pruritus score at 2 weeks, 4 weeks, 8 weeks, and
12 weeks in subjects with Baseline WI-NRS pruritus score of
at least 4
•
Time to the first achievement of ≥4-point reduction from
Baseline in WI-NRS pruritus score in subjects with Baseline
WI-NRS pruritus score of at least 4
•
Percent change in HECSI (Hand Eczema Severity Index) score
at Weeks 2, 4, 8, and 12 compared to Baseline
•
Change in NRS Pain score at 2 weeks, 4 weeks, 8 weeks, and
12 weeks compared to Baseline
•
The rate of achievement of ≥4-point reduction from Baseline
in Pain NRS score at 2 weeks, 4 weeks, 8 weeks, and
12 weeks in subjects with Baseline Pain NRS score of at least
4
•
Time to the first achievement of ≥4-point reduction from
Baseline in Pain NRS score in subjects with Baseline Pain
NRS score of at least 4
•
Change from Baseline in overall Quality of Life in Hand
Eczema Questionnaire (QOLHEQ) score at each visit
•
Percent BSA affected by disease and % change from baseline
in BSA affected by disease at baseline, 2 weeks, 4 weeks,
8 weeks, and 12 weeks.
The exploratory endpoint of Cohort 2 is:
•
Change from Baseline in Nail Dystrophy at each visit

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Power and Sample
Size:
Cohort 1 will include approximately 6 evaluable subjects, which is
deemed adequate for the purpose of evaluating safety and PK prior to
Cohort 2.
There are approximately 215 subjects planned for Cohort 2.
Approximately 61 subjects will receive ARQ-252 cream 0.3% QD,
approximately 61 subjects will receive ARQ-252 cream 0.3% BID,
approximately 31 subjects will receive ARQ-252 cream 0.1% QD,
approximately 31 subjects will receive matching vehicle cream QD,
and approximately 31 subjects will receive vehicle cream BID.
The randomization scheme will be 2:2:1:1:1 between these
5 treatment groups, stratified by study site and IGA at Baseline.
The primary statistical comparisons will be to assess the ARQ-252
cream 0.3% BID group versus the vehicle BID group, to assess the
ARQ-252 cream 0.3% QD group versus the vehicle QD group, and to
assess the ARQ-252 cream 0.1% QD group versus the vehicle QD
group.
A sample size of 55 per active arm and 28 per vehicle arm will
provide approximately 85% power at the 2-sided 5% significance
level to detect a difference in the percent of subjects with IGA clear or
almost clear at Week 12; for each ARQ-252-treated group versus
vehicle group within the same daily dosing frequency, assuming an
active treatment response rate of 45% and a vehicle response rate of
15%, with a two-sided α = 0.1. This is based on a 2-group X2 test of
equal proportions (without continuity correction). With a 10%
dropout rate, the sample size for the study is increased to 61 subjects
per active arm and 31 subjects per vehicle arm (215 subjects total).
The primary statistical comparisons and evaluation of the secondary
endpoints will not be adjusted for multiplicity.
Statistical Analysis:
Descriptive statistics will be presented for the study endpoints. This
includes the number and percentage of subjects for binary
endpoints/categorical data, and mean, SD, median, minimum, and
maximum for continuous data.
The primary endpoint in Cohort 2 of ‘IGA clear or almost clear at
Week 12’ will be analyzed using a Cochran-Mantel-Haenszel test
stratified by study site and IGA at Baseline. The analysis will be
performed on the Intention-to-Treat (ITT) population and missing
data will be imputed using multiple imputation.
Continuous secondary endpoints measured in Cohort 2 will be
analyzed using Analysis of Covariance with treatment and
stratification factors as independent variables. The ITT population
will be used. Binary secondary endpoints will be analyzed similarly
to the primary endpoint.

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All subjects who are randomized and receive at least one confirmed
dose of investigational product will be included in the safety
population.
Adverse events (AEs) will be summarized within each cohort by
preferred term, system organ class, and treatment group (Cohort 2
only) for all treatment-emergent AEs, serious AEs, related AEs,
AEs leading to withdrawal from investigational product.
Safety laboratory parameters and vital signs will be summarized at
each visit using descriptive statistics or frequencies and percentages,
as appropriate. Changes from Baseline in laboratory values and vital
signs will also be summarized by visit. In addition, changes from
Baseline in weight and laboratory values will be summarized using
shift tables. These summaries will be tabulated by treatment group
for Cohort 2.
All subjects who are enrolled and receive at least one application of
investigational product and have sufficient pharmacokinetic
assessments will be included in the pharmacokinetic population
(Cohorts 1 and 2). When possible, the exposure to SHR0302 will be
calculated based on plasma concentrations versus time profile data.

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Study Schema
Phase 1 (Cohort 1)
Screening
N = 6 Enrolled
Baseline
Treatment Day 1
ARQ-252 0.3% QD (once daily)
Follow Up Period / Visit
2 Week Treatment Period, PK Assessments and Clinic Visits
A Phase 1/2b, Multiple Dose and 12-Week, Parallel Group, Double Blind, Dose
Ranging, Vehicle-Controlled Study of the Safety and Efficacy of ARQ-252 Cream
0.1% and ARQ-252 Cream 0.3% in Subjects with Chronic Hand Eczema
Phase 1/Cohort 1
Approximately 6 subjects with chronic hand eczema will receive ARQ-252 0.3%
cream QD (once daily)

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Phase 2b (Cohort 2)
ARQ-252
0.1% QD
(once daily)
Vehicle Cream
QD
(once daily)
12 Week Treatment Period and Clinic Visits
ARQ-252
0.3% QD
(once daily)
ARQ-252
0.3% BID
(twice daily)
Follow Up Period / Visit
A Phase 1/2b, Multiple Dose and 12-Week, Parallel Group, Double Blind, Dose Ranging,
Vehicle-Controlled Study of the Safety and Efficacy of ARQ-252 Cream 0.1% and ARQ-252 Cream
0.3% in Subjects with Chronic Hand Eczema
Phase 2b/Cohort 2
Approximately 215 subjects with chronic hand eczema will be randomized to receive either:
•
ARQ-252 0.3% cream QD (once daily) N=61
•
ARQ-252 0.3% cream BID (twice daily) N=61
•
ARQ-252 0.1% cream QD (once daily) N=31
•
Vehicle cream QD (once daily) N=31
•
Vehicle cream BID (twice daily) N=31
The randomization scheme will be 2:2:1:1:1 between these 5 treatment groups, stratified by study site,
and IGA at Baseline.
Screening
N = 215 Enrolled
Baseline
Randomization and Treatment Day 1
Vehicle Cream
BID
(twice daily)

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Schedule of Visits and Assessments
A. Cohort 1 (Phase 1)
Study Procedure
Screening
Baseline
Day 1
PK
Collection
Day 2
Day 8
Week 2
Day 15
PK
Collection
Day 16
Week 3
Day 22
Visit
1
2
3
4
5
6
7
Visit Window
-4 Weeks
+/- 2 hrs
+/-1 day
+/- 1 day
+/- 2 hrs
+/- 3 days
Informed Consent
X
Demographics
X
Medical and Surgical History
X
Physical examinationa
X
X
X
X
X
I/E criteria
X
X
Hematology, Serum
Chemistries, Urine Analysis,
TSH, T4b
X
X
X
X
X
Vital signs, weight, heightc
X
X
X
X
X
Local tolerability assessmentd
X
X
X
BSA, IGA, HECSIe
X
X
X
WI-NRS, NRS Painf
X
Completed daily from Day 1-Day 15
Urine pregnancy testg
X
X
X
X
Serum pregnancy testg
X
Follicle-Stimulating Hormone
(FSH)h
X
Resting 12-lead ECG
X
X
PK samplingi
X
X
X
X
X
IP application in clinicj
X
X
X
Dispense IP
X
Weigh investigational product
containerk
X
X
Dispense/review diary
X
X
X
Adverse event assessmentl
X
X
X
X
X
X
X
Concomitant medications
X
X
X
X
X
X
X

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Footnotes from above table:
a Limited physical examination: skin, lungs, and heart only.
b All samples listed to be collected at Visits 1, 2, 4, 5, and 7. If Baseline visit occurs within 14 days of Screening, the
Screening lab results may be utilized. Refer to Table 3.
c Height to be measured only at Visit 2 (Day 1). Weight will be collected at Baseline, Visits 4, 5 and 7.
d Local tolerability assessments to be recorded prior to IP application for the Investigator assessment of skin irritation
(Berger and Bowman skin irritation score) and 10-15 minutes post IP application for the subject’s ‘0-3’
burning/stinging assessment. Note for investigator tolerability assessments: reactions at the site of IP
application, which may occur post-Baseline, should be differentiated from the preexisting inflammation
associated with the subject’s chronic hand eczema.
e BSA will be measured as the affected BSA for each side of each hand. Affected areas of the lateral aspects of the
fingers and hands should be assigned to the palmar surface. IGA will be a 5-point scale ranging from clear (0) to
severe (4). IGA should be completed prior to other physician assessments and by the same Evaluator at each
study visit. HECSI is an instrument used in clinical trials to rate the severity of 6 clinical signs of hand eczema and
the extent of the lesions on each of 5 distinct hand anatomic areas by use of standard scales. The total HECSI score
is based on a 4-point clinical sign severity scale ranging from 0 (none/absent) to 3 (severe) and a 5-point scale rating
the different affected hand anatomic area(s) ranging from 0 (0% affected area) to 4 (76% to 100% affected area).
f Subjects will complete the WI-NRS pruritis assessment and NRS Pain assessment in the clinic during screening and
then daily at home from the Baseline/Day 1 visit through the Day 15 visit.
g A serum pregnancy test will be administered to all females of child-bearing potential at Screening. A urine
pregnancy test will be administered at Visits 2, 4, 5, and 7 to all females of childbearing potential. A negative result
is required for continued participation in the study, and results must be available prior to dispensing of
investigational product.
h FSH will be performed (if indicated) at Screening to confirm post-menopausal status.
i On the first day of dosing (Day 1), PK samples will be collected at 1, 2, 4, 6 (all +/- 10 mins) and 24 hours post-dose
administration (Day 2, +/- 2 hours). On Day 15 (last dose application), PK samples will be collected pre-dose, 1, 2,
4, 6, (all +/- 10 mins) and 24 hours post dose administration (Day 16, +/- 2 hours). For 24-hour timepoints, subjects
return to the clinic on the following day within 2 hours of the IP application time from the previous day for pre-dose
PK plasma sample. A pre-dose PK sample will be taken at Day 8.
j Clinic personnel will apply assigned IP on Visits 2, 4 and 5 (Baseline, Day 8 and Day 15). Every tube should be
weighed before and after IP application and weights recorded. For the 24-hour PK sampling timepoint the
application of investigational product should occur after the PK sample has been collected.
k Subject should return with investigational product kit at each Visit. Every tube should be weighed before and after
use and weights recorded when dispensed and returned.
l Any emergent AEs will be followed in the clinic for up to 1 month at the Investigator’s discretion until resolved or
otherwise judged as clinically stable

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B. Cohort 2 (Phase 2b)
Study Procedure
Screen
Baseline
Day 1
Wk 2
Day 15
Wk 4
Day 29
Wk 8
Day 57
Wk 12
Day 85
Wk 13
Day 92
Visit
1
2
3
4
5
6
7
Visit Window
-4 weeks
+/- 3 days
+/- 5 days
+/- 5 days
+/- 7 days
+/- 3 days
Informed consent
X
Demographics
X
Medical and surgical history
X
Physical examinationa
X
X
X
Vital signs, height, weightb
X
X
X
X
X
X
X
I/E criteria
X
X
Randomization
X
Hematology, Serum Chemistries,
UA, TSH/T4c
X
X
X
X
X
Resting 12-lead ECG
X
X
X
BSA, IGA, HECSId
X
X
X
X
X
X
X
NRS pain, WI-NRSe
X
Completed daily from Day 1 to Week 13 Visit
QOLHEQe
X
X
X
X
X
X
X
Nail dystrophy assessmentf
X
X
X
X
X
X
Local Tolerability Assessmentsg
X
X
X
X
X
Optional Photographyh
X
X
X
X
X
X
Urine pregnancy testi
X
X
X
X
X
Serum pregnancy testi
X
Follicle-Stimulating Hormone
(FSH)j
X
PK samplingk
X
X
X
IP application/Subject training in
clinicl
X
X
X
X
X
Dispense IP kitm
X
X
X
X
X
Dispense/review diary
X
X
X
X
X
Weigh IP tubesn
X
X
X
X
X
Compliance calculationo
X
X
X
X
X
Adverse event assessmentp
X
X
X
X
X
X
X
Concomitant medications
X
X
X
X
X
X
X

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Footnotes from above table:
a Limited physical examination: skin, lungs, and heart only
b Height will be collected at Visit 2 (Baseline/Day 1) only. Weight will be collected at Baseline, Weeks 4, 8 and 12.
c If Baseline visit occurs within 14 days of Screening, the Screening lab results may be utilized.
d BSA will be measured as the affected BSA for each side of each hand. Affected areas of the lateral aspects of the
fingers and hands should be assigned to the palmar surface. IGA will be a 5-point scale ranging from clear (0) to
severe (4). IGA should be completed prior to other physician assessments and by the same Evaluator at each
study visit. HECSI is an instrument used in clinical trials to rate the severity of 6 clinical signs of hand eczema and
the extent of the lesions on each of 5 distinct hand anatomic areas by use of standard scales. The total HECSI score
is based on a 4-point clinical sign severity scale ranging from 0 (none/absent) to 3 (severe) and a 5-point scale rating
the different affected hand anatomic area(s) ranging from 0 (0% affected area) to 4 (76% to 100% affected area).
e Subjects will complete the WI-NRS pruritis assessment and NRS Pain assessment in the clinic during Screening and
then daily at home from the Baseline/Day 1 visit until the Week 13 visit. QOLHEQ = Quality of Life in Hand
Eczema Questionnaire will be completed at each visit.
f Assessment of nail dystrophy including Baseline identification of the nail with the worst dystrophy and
measurement of the millimeters of normal appearing nail distal to the cuticle post Baseline. Sites participating in
optional photography will obtain photos of nail with the worst dystrophy at Baseline/Day 1 and at subsequent visits.
See Section 5.2.7 for details.
g Local tolerability assessments to be recorded prior to IP application for the Investigator assessment of skin irritation
(Berger and Bowman skin irritation score) and 10-15 minutes post IP application for the subject’s ‘0-3’
burning/stinging assessment. Note for investigator tolerability assessments: reactions at the site of IP
application, which may occur post-Baseline, should be differentiated from the preexisting inflammation
associated with the subject’s chronic hand eczema.
h Photography will be performed at selected investigational sites. Photography will be optional. All efforts will be
made to de-identify the subjects. Sites participating in optional photography will obtain photos of nail with the worst
dystrophy at Baseline/Day 1 and at subsequent visits.
i A serum pregnancy test will be administered to all females of childbearing potential at Screening. A urine pregnancy
test will be administered at Baseline, Weeks 4, 8, 12 and 13. A negative result is required for continued participation
in the study, and results must be available prior to dispensing of investigational product.
j FSH will be performed (if indicated) at Screening to confirm post-menopausal status.
k PK assessments will be collected from all subjects at Days 1, 29 and 85. The draws will be pre-dose IP application
in the clinic.
l Subjects to apply assigned IP in clinic at these visits. The time of application will be documented.
m Kits will be dispensed at Baseline, Weeks 2, 4 and 8. Dispensing at Week 12 requires approval from the Medical
Monitor. See IP Handling Manual for details.
n Each IP tube will be weighed prior to dispensing at the Baseline visit and at each follow-up clinic visit according to
the Schedule of Visits and Assessments. When IP is applied in the clinic, the IP tube will be weighed before and
after IP application. See IP Handling Manual for details.
o Compliance calculation is described in the IP Handling Manual.
p Any emergent AEs will be followed in the clinic for up to one month at the Investigator’s discretion until resolved or
otherwise judged as clinically stable.

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2.
INTRODUCTION
Background
Chronic hand eczema is a common condition which occurs in different forms. Chronic hand
eczema may significantly impact quality of life and cause significant costs, e.g., through inability
of patients to work. There is considerable unmet medical need for new therapies for hand eczema
since few treatments are available and/or approved specifically for hand eczema
(e.g., no FDA-approved therapies) and treatment is often unsatisfactory (Diepgen 2009).
Janus kinases (JAKs) are a family of intracellular nonreceptor tyrosine kinases that transduce
cytokine-mediated signals via the JAK-signal transducer and activator of transcription (STAT)
pathway and have a plethora of effects on the immune system, inflammation, and hematopoiesis.
In humans, the JAK family includes JAK1, JAK2, JAK3, and tyrosine kinase 2 (Tyk2). JAK1 is
a human tyrosine kinase which plays a critical role in initiating responses to multiple major
cytokines. It interacts with the common gamma chain of type I cytokine receptors to elicit signals
from the IL-2 receptor family, the IL-4 receptor family, the gp130 receptor family and other
cytokine receptor families. It is also important for transducing a signal by type I and type II
interferons, and members of the IL-10 family via type II cytokine receptors. JAK2 has been
implicated in signaling by the GM-CSF receptor family and controls various functions relating to
hematopoiesis. JAK3 is involved in signal transduction by receptors that employ the common
gamma chain of the type I cytokine receptor family (e.g., IL-2R, IL-4R, IL-7R, IL-9R, IL-15R,
and IL-21R) (Villarino 2017). Finally, Tyk2 is important for Th1 and Th17 responses,
transducing signals by interferons, IL-12, IL-23, IL-22, and IL-6 (O’Shea 2019).
The first demonstration of the clinical efficacy of JAK inhibitors in eczema utilized a topical
formulation of the pan-JAK inhibitor, tofacitinib, which has been approved orally for the
treatment of rheumatoid arthritis, psoriatic arthritis, and ulcerative colitis (Bissonnette 2016a).
Subsequently, several topical JAK inhibitors (delgocitinib, ruxolitinib) (Kim 2019;
Nakagawa 2018, Worm 2019) and oral JAK inhibitors (upadacitinib, PF-04965842, baricitinib)
(Guttman-Yassky 2019a; Gooderham 2019; Guttman-Yassky 2019b) have been reported to have
efficacy in the treatment of eczema. Oral JAK inhibitors can be accompanied by safety issues
including the development of opportunistic infections, lymphoma and other malignancies, and
hematologic and lipid abnormalities. We are pursuing development of ARQ-252 cream, a topical
form of the JAK1 selective inhibitor SHR0302, as a potential treatment for particular forms of
eczema aiming to maintain the efficacy of this class of agents in these diseases while minimizing
systemic exposure and undesirable side effects.
SHR0302 is in Phase 2 development as an oral therapy for rheumatoid arthritis (RA), Crohn’s
disease, ulcerative colitis, and atopic dermatitis by development partners Jiangsu Hengrui
Medicine Company (Hengrui) and Reistone Biopharma. Clinical safety data from these ongoing
programs, as well as extensive nonclinical studies, provide support for Arcutis’ dermal
(ARQ‑252) development program.

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Nonclinical Safety Summary
In vitro pharmacology data supports that SHR0302 is a strong JAK inhibitor, with
JAK1>JAK2>JAK3> Tyk2 inhibitory activity. Additionally, SHR0302 has demonstrated
activity comparable to tofacitinib in various in vivo models of inflammatory conditions,
including the imiquimod-induced murine model of psoriasis, the oxazolone-induced murine
model of atopic dermatitis, the rat and murine models of collagen-induced arthritis, the
adjuvant-induced arthritis rat model, and the murine dextran sulfate sodium-induced colitis
model.
The nonclinical safety profile of orally administered SHR0302 has been well characterized
through the conduct of safety pharmacology, acute and repeat dose toxicity in rats and monkeys,
genetic toxicology (bacterial reverse mutation, in vitro micronucleus, in vivo micronucleus in
rats), and reproductive/developmental toxicology (fertility, embryofetal development) studies.
In safety pharmacology studies, SHR0302 did not cause significant changes in cardiovascular,
CNS or respiratory functions. After oral administration, SHR0302 was well absorbed and
distributed into many tissues.
During the oral dosing program of SHR0302 with dose levels up to 150 mg/kg/day in rats and
15 mg/kg/day in monkeys, the major target organs identified following repeated dosing were
immune system (lymph nodes, spleen, and thymus), bone marrow, reproductive organs and
digestive tract. As SHR0302 is a potent inhibitor of Janus kinases which are known to affect
cytokine-mediated signaling, the immunomodulatory effects observed (mainly in the rat) in the
toxicity studies are consistent with the pharmacological mechanism of action of SHR0302.
The genotoxicity studies on SHR0302 indicate a lack of potential to induce point mutations,
chromosomal aberrations, or to interact with or damage DNA. Therefore, it is unlikely that
SHR0302 poses a genotoxic risk to humans.
Results of a rat fertility study with SHR0302 showed no effects on male fertility and disrupted
early embryonic development in female rats at 10 and 50 mg/kg. The no observed adverse effect
level (NOAEL) was 50 mg/kg for male fertility and 1 mg/kg for female fertility and early
embryonic development. Embryofetal development studies in rats demonstrated maternal and
fetal toxicity and fetal teratogenicity following oral dosing of SHR0302. The NOAEL for rat
dams was 10 mg/kg and 1 mg/kg for embryofetal effects. In the rabbit embryofetal study, no
maternal toxicity was noted at the high dose of 25 mg/kg/day (NOAEL). Rabbit embryo-fetal
developmental toxicity was noted with effects on fetal viability and development, including fetal
visceral and/or skeletal malformations and resulting in a NOAEL of 1 mg/kg/day.
The nonclinical safety profile of SHR0302 was also evaluated topically in mice and minipigs in
support of once-daily topical administration. Dermal toxicology studies conducted to date
include 13-week mouse, 7-day tolerability in minipigs, 4-week and 16-week toxicity in minipigs,
and local tolerance (ocular irritation, skin sensitization, in vitro phototoxicity). Planned studies
include 39-week toxicity in minipigs and a 104-week carcinogenicity study in mice.

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The dermal toxicity of ARQ-252 (SHR0302 cream) has been evaluated and no new risks have
been identified and no target organs were identified. In the 13-week dermal toxicity study in
mice and the 7-day and 16-week dermal toxicity studies in minipigs, no evidence of systemic
toxicity was observed, and no dermal findings were noted. The NOAELs in each of these repeat
dose dermal toxicity studies were the highest doses administered.
Local tolerance studies demonstrated ARQ-252 is not a skin sensitizer or eye irritant, and it does
not have phototoxic potential.
Overall, the results suggest that topical ARQ-252 cream is safe and well tolerated in both mice
an minipigs. Taken together, the results of the nonclinical toxicology studies demonstrated an
acceptable topical safety profile and support the progression of ARQ-252 cream into clinical
studies in patients with hand eczema.
Clinical Studies
This will be the first study of topical ARQ-252 cream in the human population.
Oral administration of SHR0302 has been studied in three Phase 1 pharmacokinetic studies,
including two conducted in healthy volunteers and one conducted in subjects with rheumatoid
arthritis. Oral administration of SHR0302 has also been studied in a 24-week, Phase 2 study in
subjects with rheumatoid arthritis.
Oral Administration: Phase 1
In three Phase 1 pharmacokinetic studies, a total of 94 subjects were exposed to SHR0302 at
various dosages and duration. The single maximum dose of exposure in humans was 100 mg,
and the longest duration of exposure was 7 days of 10 mg SHR0302 in rheumatoid arthritis
patients.
A study on human safety, pharmacokinetics, and pharmacodynamics was conducted on
SHR0302 following single dose oral administration in healthy subjects (SHR0302-101).
This was a randomized, double blind and placebo-controlled study with six dosage groups of
1, 5, 10, 25, 50 and 100 mg. AEs were reported mainly from the high-dose groups (50 mg and
100 mg) in this single ascending dose study. The most common AEs involved the hematologic
system (neutropenia and high lymphocyte count). Adverse reactions included neutropenia in
7 subjects (10.9%), elevated lymphocytes in 6 subjects (9.4%), and leukopenia in 1 subject
(1.6%). At the 25 mg dose and below, there was no obvious difference between the active and
placebo arms. There were no serious adverse events.
Following single oral dose administration, SHR0302 was rapidly absorbed with median Tmax
values of 1.0 hour across all dose groups. Geometric mean Cmax values increased 105-fold over
the 100-fold increase in dose (1 to 100 mg), demonstrating dose proportional kinetics. Similarly,
the geometric mean AUC0-24 values increased 107-fold over the same 100-fold increase in dose.

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A multiple ascending dose (MAD) study of human safety, pharmacokinetics, and
pharmacodynamics was conducted on orally administered SHR0302 in subjects with rheumatoid
arthritis (SHR0302-102). This was a randomized, double-blind, and placebo-controlled study
with four planned dosage groups of 2, 5, 10 and 25 mg. Each dosage group had 12 subjects,
10 receiving active and 2 receiving placebo. Subjects were dosed for 7 days. The 2, 5, and 10 mg
dose groups were completed, for a total of 36 subjects, 30 receiving active drug. No subjects in
the 25 mg dose group were enrolled.
Twenty out of 36 subjects experienced AEs during the study period, with 16 subjects
experiencing AEs reported as causally related to drug. AEs reported in subjects exposed to
SHR0302 included seven cases of elevated TSH, five cases of elevated alanine aminotransferase,
four cases of elevated aspartate aminotransferase, three cases of anemia, three cases of urinary
tract infection, two cases of lowered free thyroxine, and one case each of ear pain, conjunctivitis,
hypoesthesia, constipation and hematuria. Elevated TSH in blood (five cases), urinary tract
infection (three cases) and lowered free thyroxine (two cases) were concentrated in the 10 mg
SHR0302 group. All AEs were Grade 1 or Grade 2, and most reversed within two weeks of drug
discontinuation. No SAEs were reported. Study drug dose was not decreased or suspended in
any subject due to an AE, and no subject withdrew from the trial due to an AE.
Following multiple oral dose administrations of SHR0302, the median Tmax value was 1.0 hour
across the dose groups. Geometric mean Cmax values increased 3.5-fold over the 5-fold increase
in dose (2 to 10 mg), demonstrating less than dose proportional kinetics. Similarly, the geometric
mean AUC0-24 values increased 4.1-fold over the same 5-fold increase in dose from
1130 hr*ng/mL for the 2 mg dose to 4620 hr*ng/mL for the 10 mg dose.
A food effect study of high-fat intake on the pharmacokinetics of SHR0302 has also been
conducted (SHR0302-103). In this study, SHR0302 (10 mg tablet) was safe and well tolerated in
healthy subjects, and administration of SHR0302 after a high-fat meal did not significantly
impact systemic exposure. Except for one AE (soft tissue contusion) unrelated to drug which
was moderate, the other AEs were mild and recovered without treatment. No SAEs were
reported, and no subject withdrew from the trial due to an AE.
Overall, SHR0302 was well-tolerated with no SAEs reported.
Oral Administration: Phase 2
Preliminary results are available from SHR0302-201, a Phase 2, double-blind, randomized study
evaluating 0.5 mg, 1 mg, 2 mg, 4 mg, and 8 mg of SHR0302 as once-daily oral monotherapy for
adults with active rheumatoid arthritis who were naïve to any disease modifying anti-rheumatic
drug (DMARDs) or have had an inadequate response or intolerance to conventional synthetic
DMARDs. The study was placebo-controlled for 12 weeks, followed by a 12-week, open label
maintenance phase. The Primary Endpoint was the response rate of American College of
Rheumatology 20 (ACR20) at Week 12, which is a composite measure defined as 20%
improvement in the number of tender and swollen joints, and 20% improvement in 3 of 5 criteria
including patient global assessment, physician global assessment, functional ability measure,

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visual analog pain scale, and erythrocyte sedimentation rate or C-reactive protein. A total of
194 subjects were randomized. 174 subjects completed the placebo-controlled period.
Preliminary efficacy results include:
•
SHR0302 monotherapy was demonstrated to be effective for treatment of active
rheumatoid arthritis, with improvements in clinical signs and symptoms, as well as
physical function versus placebo.
•
A dose response relationship was observed, with the SHR0302 8 mg group having more
responders than the other groups.
•
The Primary Endpoint was met in the 2 mg, 4 mg, and 8 mg groups (refer to Table 1).
Table 1.
Proportion of Patients Reaching ACR20/50/70 and Statistical Check
(CMH-FAS-NRI) after 12-week Administration in a Multicenter,
Randomized, Double-blind, Placebo-controlled Phase II Study Evaluating
the Efficacy and Safety of SHR0302 Tables in Patients with Moderate to
Severe Active Rheumatoid Arthritis
Indicator
Group
Placebo
0.5 mg
1 mg
2 mg
4 mg
8 mg
(N=37)
(N=25)
(N=24)
(N=23)
(N=40)
(N=45)
ACR20
Percentage
(%)
27.0
44.0
41.7
56.5
67.5
77.8
(95% CI)
(13.8, 44.1)
(24.4, 65.1)
(22.1, 63.4)
(34.5, 76.8)
(50.9, 81.4)
(62.9, 88.8)
% difference
from placebo
-
17.0
14.6
29.5
40.5
50.8
(95% CI)
(-6.6, 39.2)
(-8.8, 37.3)
(4.1, 50.8)
(18.2, 57.5)
(29.5, 65.9)
P value
-
0.1871
0.2884
0.0223
0.0004
<0.0001
ACR50
Percentage
(%)
2.7
12.0
20.8
30.4
27.5
37.8
(95% CI)
(0.1, 14.2)
(2.5, 31.2)
(7.1, 42.2)
(13.2, 52.9)
(14.6, 43.9)
(23.8, 53.5)
% difference
from placebo
-
9.3
18.1
27.7
24.8
35.1
(95% CI)
(-4.3, 27.4)
(2.1, 37.9)
(9.2, 48.3)
(8.9, 40.3)
(18.2, 49.8)
P value
-
0.1661
0.0247
0.0022
0.0031
0.0002
ACR70
Percentage
(%)
0.0
4.0
4.2
13.0
12.5
26.7
(95% CI)
(0.0, 9.5)
(0.1, 20.4)
(0.1, 21.1)
(2.8, 33.6)
(4.2, 26.8)
(14.6, 41.9)
% difference
from placebo
-
4.0
4.2
13.0
12.5
26.7
(95% CI)
(-6.0, 19.5)
(-5.8, 20.2)
(0.4, 32.1)
(0.8, 26.1)
(12.4, 41.0)
P value
-
0.2440
0.1797
0.0267
0.0284
0.0007
Investigator’s Brochure, Edition 1.0, Feb 2020.

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Preliminary safety results include:
•
SHR0302 was generally safe and well tolerated. A higher frequency of infections was
observed in SHR0302-treated subjects, particularly in the 8mg group. The most common
infections included upper respiratory tract infections and urinary tract infections.
•
Mean WBC, neutrophils, lymphocyte, HGB, platelet count, serum lipid level, liver
function, kidney function, and thyroid function parameters remained in the normal range
in all SHR0302 treatment groups.
•
Mean platelet count did not increase during the study.
•
Increases in LDL, HDL, total cholesterol and triglycerides were observed. However,
LDL-to-HDL remained stable.
•
Increase in mean serum creatine kinase (CK) was observed in patients treated with
SHR0302 versus placebo but was within normal range. CK-MB remained stable.
•
Most of the reported abnormal laboratory results were classified as CTCAE grade 1 or 2.
CTCAE grade 3 events included: 1 case of increased alanine aminotransferase (4 mg),
1 case of decreased neutrophils (8 mg), 1 case of decreased lymphocytes (4 mg) and
1 case of anemia (8 mg).
•
From Baseline through Week 12, the most common AEs (≥5% across pooled SHR0302
groups) included upper respiratory infection, hyperlipidemia, swollen joint, urinary tract
infection, hypercholesterolemia, joint pain, and cough. From Baseline to Week 12, other
TEAEs occurring at rates ≥5% in individual SHR0302 groups (although <5% across
pooled SHR0302 groups) included hypothyroidism, anemia, liver dysfunction (although
placebo group had highest rate), elevated serum creatine phosphokinase, diarrhea,
headache, hematuria, abdominal discomfort, urine protein detection, blood in urine,
elevated blood lactic dehydrogenase, and upper abdominal pain. Additional common
AEs (≥5% across pooled SHR0302) seen from Baseline through Week 24 included
elevated serum creatine phosphokinase, anemia, and hypothyroidism.
•
Overall, there were 6 severe AEs in 3 subjects including 4 severe SAEs in a subject in the
0.5 mg group during the placebo-controlled period (Craniocerebral injury, Ventricular
hemorrhage, Occipital fracture and Subarachnoid hemorrhage), appendicitis in a subject
in the 4 mg group during the placebo-controlled period, and elevated liver enzymes in a
subject in the 4 mg group during the extension period.
•
AEs leading to discontinuation were generally uncommon from Baseline through
Week 12 (1 or fewer subjects per group). From Baseline through Week 24, AEs leading
to discontinuation remained generally uncommon (1 or fewer subjects per group, except
for 3 subjects in the 4 mg group, and 3 subjects in 8 mg group including 1 subject in
placebo group then received 8 mg after Week 12).
•
A total of 4 cases of herpes zoster (all in 8 mg group) and 1 case of opportunistic
infection (8 mg group, cryptococcal pneumonia) were reported.
•
No tuberculosis, malignancy, important cardiac events or death were reported.
•
One thrombotic event was reported, a SAE of multiple lacunar infarcts in a 64 year-old
woman in the 0.5mg SHR0302 group, requiring hospitalization, deemed unrelated, with
dose not changed.

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•
From Baseline through Week 12, there were 13 SAEs in 9 subjects overall, including
3 SAEs in 2 subjects in the placebo group, 5 SAEs (Craniocerebral injury, Ventricular
hemorrhage, Occipital fracture and Subarachnoid hemorrhage; Lacunar infarction) in
2 subjects in the 0.5 mg group, 3 SAEs (Hemorrhoids; Pulmonary infection;
Appendicitis) in 3 subjects in the 4 mg group, and 2 SAEs (Epiglottic cyst; Tympanitis)
in 2 subjects in the 8 mg group. From Week 12 through Week 24, there were 4 SAEs in
3 subjects, including Liver dysfunction in a subject in the 4 mg group, Viral
gastroenteritis in a placebo-8 mg subject, and Cryptococcal pneumonia and Ureterolith in
a subject in the 8 mg group.
Additional Studies
An open label, self-controlled study (SHR0302-105) evaluating drug interaction potential
between SHR0302 and methotrexate (MTX) in subjects with rheumatoid arthritis was recently
completed. Subjects were to take MTX 10 mg once daily on Day 1 and Day 8, and SHR0302
10 mg once daily on Days 3 to Day 8. Overall, 15 subjects were enrolled. A total of 18 adverse
events were reported in 8 of 15 subjects (53.3%). Of the 18 adverse events, 3 subjects (20.0%)
reported 5 adverse events after SHR0302 alone, 4 subjects (26.7%) reported 5 adverse events
after MTX alone, and 3 subjects (20.0%) reported 8 adverse events after MTX and SHR0302 in
combination. The adverse events reported in subjects given SHR0302 alone included headache,
back pain, fever, constipation and tachycardia each in 1 subject (6.7%). The adverse events
reported by the subjects after MTX and SHR0302 in combination included anemia, upper
respiratory tract infection, urinary tract infection, elevated blood triglycerides, elevated aspartate
aminotransferase, positive urine leukocytes and tachycardia each in 1 subject (6.7%). No serious
adverse events were reported, and no subjects withdrew prematurely due to adverse event.
Ongoing Studies
Two studies of SHR0302 as an oral treatment of inflammatory bowel disease are ongoing.
RSJ10101 is a phase 2, randomized, placebo-controlled, double-blind, 4 arm, dose-ranging
study to evaluate the efficacy and safety of SHR0302 compared to placebo in adults with
moderate to severe, active ulcerative colitis. Treatment groups include 3 different doses of
SHR0302 (4mg QD, 8mg QD, 4mg BID) or placebo, with 1:1:1:1 randomization. The study
consists of an 8-week blinded treatment phase, followed by an 8-week of blinded, active
extension phase. Planned enrollment is 152 across China, Ukraine, United States, and Poland.
RSJ10201 is a phase 2, randomized, placebo-controlled, double-blind, four arms dose-ranging
study to evaluate the efficacy and safety of SHR0302 compared to placebo in adults with
moderate to severe, active Crohn’s disease. Treatment groups include 3 different doses of
SHR0302 (4mg QD, 8mg QD, 4mg BID) or placebo, with 1:1:1:1 randomization. The study
consists of a 12-week blinded treatment phase, followed by a 12-week of blinded, active
extension phase. Planned enrollment is 144 across China, Ukraine, United States, and Poland.
Analysis of blinded data from these two ongoing studies in IBD (RSJ10101 and RSJ10201) as of
October 19, 2019 has been performed. Based on this analysis, 39 subjects were estimated to be
exposed to SHR0302 in these two clinical trials. One SAE was reported as colitis ulcerative and
the other one was synovitis. The latter SAE was unblinded and confirmed to be on SHR0302.

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Overall, the reported safety data were in line with the known and expected safety profile of
SHR0302.
Finally, two additional studies of SHR0302 recently started, for which no data is currently
available. RSJ10303 is a phase 2 study in China of SHR0302 in atopic dermatitis. The study is
a randomized, double-blind, and placebo-controlled, evaluating the efficacy and safety of
SHR0302 4mg QD, SHR0302 8mg QD, or placebo in adult patients with moderate to severe
atopic dermatitis. RSJ10411 is a phase 1, vehicle-controlled study in Australia and China to
evaluate the safety and pharmacokinetics of SHR0302 base ointment at single dose and multiple
dose in healthy adult subjects.
Rationale for Development
Since the first demonstration of the clinical efficacy of JAK inhibitors for the treatment of
eczema, which utilized a topical formulation of tofacitinib for the treatment of atopic dermatitis,
numerous oral JAK inhibitors and several other topical JAK inhibitors have also demonstrated
efficacy in eczema. We are pursuing the development of ARQ-252 cream as a topical
JAK1-selective inhibitor for the treatment of hand eczema, planning to take advantage of the
efficacy of this class of agents in this disease, while minimizing systemic exposure and
undesirable side effects. Nonclinical and systemic clinical data with SHR0302 to date are
supportive of this plan.
The above data indicate that topical ARQ-252 could provide an important addition to the
dermatologist’s approach for treating hand eczema.
Dose Selection
ARQ-252 cream 0.3% was selected as the high clinical dose because this dose remains in
solution when stored at controlled room temperature.
In Cohort 1 of this study, ARQ-252 cream 0.3% will be applied QD to approximately 4% BSA
in subjects with hand eczema. It is well known that cutaneous disease states can alter drug
permeability as compared to normal human skin. Since eczematous skin may have different drug
permeability characteristics than normal skin (Ortiz 2009; Halling-Overgaard 2017), this study is
planned in patients with hand eczema rather than healthy volunteers. Administration of
ARQ‑252 cream 0.3% once-daily to approximately 4% of BSA at an application rate of
approximately 0.75 mg/cm2 would result in 1.5 mg of total SHR0302 being absorbed per day,
assuming 100% absorption of applied drug, an amount well covered by the oral MAD study
discussed previously (Section 2.3.1). In the oral MAD, daily doses of 2 to 10 mg resulted in
signals for thyroid effects (elevated TSH, decreased free T4), mild LFT abnormalities, and a few
urinary tract infections. These are all easily monitored, and skin absorption is very likely to be
only a small fraction of 100%. Moreover, in the Phase 2 RA study, mean WBC, neutrophils,
lymphocyte, HGB, platelet count, liver function and kidney function remained in the normal
range in all SHR0302 treatment groups.

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Following a review of safety and PK data from Phase 1 (Cohort 1) of this study, Phase 2b
(Cohort 2) can commence. Phase 2b (Cohort 2) is a parallel group, double blind,
vehicle-controlled cohort in which subjects with chronic hand eczema will be randomized to
ARQ-252 cream 0.3% QD, ARQ-252 cream 0.3% BID, ARQ-252 cream 0.1% QD, vehicle
cream BID or vehicle cream QD.
Risks and/or Benefits to Subjects
The potential risks of ARQ-252 cream stem from what is known about the safety of the oral form
of this drug, and risks associated with the JAK inhibitor mechanism. These risks include serious
infections, other infections (e.g., upper respiratory tract infections, opportunistic infections,
herpes), anemia, lymphopenia, natural killer (NK) cell reduction, neutropenia, platelet elevations
or reductions, malignancy and lymphoproliferative disorders, gastrointestinal perforations, liver
function abnormalities, thyroid function abnormalities, lipid elevation, serum creatinine
elevations, creatine phosphokinase elevations, thrombosis, nausea, diarrhea, headache, and
hypertension. In general, topical delivery is expected to carry lower risk than oral administration
at therapeutic doses to the degree that systemic exposure is reduced. Previous nonclinical
research showed that the active ingredient in ARQ-252 can harm fetal development. Please refer
to the Investigator’s Brochure for detailed information.
Phase 1 (Cohort 1)
Subjects in Cohort 1 subjects may see an improvement in their hand eczema, although the study
duration of 2 weeks may limit this possibility.
Phase 2b (Cohort 2)
Subjects randomized to active treatment in Cohort 2 may see an improvement in their hand
eczema with the use of ARQ-252 cream. Those receiving vehicle cream may also see
improvement related to the moisturizing properties of the vehicle
The safety monitoring practices employed in this protocol (i.e., physical examinations,
application site reaction assessments, hematology, serum chemistry, TSH, T4, urinalysis, ECG,
and AE questioning) are adequate to protect the subjects’ safety and should detect expected AEs.
3.
STUDY ENDPOINTS AND OBJECTIVES
Study Objectives
Primary Objectives
The objectives of this study are as follows:
Phase 1 (Cohort 1):
•
To assess the safety, tolerability and PK of QD application of ARQ-252 0.3% to both
hands for 2 weeks in 6 subjects with chronic hand eczema

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Phase 2b (Cohort 2):
•
To assess the safety and efficacy of ARQ-252 cream 0.1% QD and ARQ-252 cream
0.3% QD and BID, vs vehicle applied QD and BID for 12 weeks to subjects with chronic
hand eczema
Study Endpoints
Primary Endpoints
Phase 1 (Cohort 1):
The primary endpoint of Cohort 1 is safety, as measured by the incidence and severity of adverse
events, changes in laboratory parameters, tolerability, and pharmacokinetics.
Phase 2b (Cohort 2):
The primary endpoint of Cohort 2 is:
•
The rate of an IGA score of ‘clear’ or ‘almost clear’ at Week 12
Secondary Endpoints
Phase 2b (Cohort 2):
The secondary endpoints of Cohort 2 are:
•
The rate of achievement of IGA of ‘clear’ or ‘almost clear’ PLUS at least a 2-point
improvement from Baseline at Weeks 2, 4, 8 and 12
•
The rate of achievement of at least a 2-point improvement from Baseline at Weeks 2, 4, 8
and 12
•
Achievement of IGA of ‘clear’ or ‘almost clear’ at Weeks 2, 4, and 8
•
Time to IGA of ‘clear’ or ‘almost clear’
•
Change in IGA score at Weeks 2, 4, 8, and 12 as compared to Baseline
•
Change in WI-NRS pruritus score at 2 weeks, 4 weeks, 8 weeks, and 12 weeks compared
to Baseline
•
The rate of achievement of ≥4-point reduction from Baseline in WI-NRS pruritus score at
2 weeks, 4 weeks, 8 weeks, and 12 weeks in subjects with Baseline WI-NRS pruritus
score of at least 4
•
Time to the first achievement of ≥4-point reduction from Baseline in WI-NRS pruritus
score in subjects with Baseline WI-NRS pruritus score of at least 4
•
Percent change in HECSI (Hand Eczema Severity Index) score at Weeks 2, 4, 8, and 12
compared to Baseline
•
Change in Pain NRS score at 2 weeks, 4 weeks, 8 weeks, and 12 weeks compared to
Baseline

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•
The rate of achievement of ≥4-point reduction from Baseline in Pain NRS score at
2 weeks, 4 weeks, 8 weeks, and 12 weeks in subjects with Baseline Pain NRS score of at
least 4
•
Time to the first achievement of ≥4-point reduction from Baseline in Pain NRS score in
subjects with Baseline Pain NRS score of at least 4
•
Change from baseline in overall Quality of Life in Hand Eczema Questionnaire
(QOLHEQ) score at each visit
•
Percent BSA affected by disease and % change from baseline in BSA affected by disease
at baseline, 2 weeks, 4 weeks, 8 weeks, and 12 weeks.
Exploratory Endpoints
Phase 2b (Cohort 2):
The exploratory endpoint of Cohort 2 is:
•
Change from Baseline in Nail Dystrophy at each visit.
4.
INVESTIGATIONAL PLAN
Overall Study Design and Plan
This is a phase 1/2b, multiple dose and 12-week, parallel group, double blind, dose ranging,
vehicle-controlled study of the safety and efficacy of ARQ-252 cream 0.1% and ARQ-252 cream
0.3% in subjects with chronic hand eczema.
There are 2 cohorts of subjects:
•
Cohort 1 is a multiple dose cohort in which subjects with chronic hand eczema will be
assigned to ARQ-252 cream 0.3% QD x 2 weeks to be applied to both hands. PK and
tolerability will be evaluated.
•
Cohort 2 is a parallel group, double blind, vehicle-controlled cohort in which subjects with
chronic hand eczema will be randomized to ARQ-252 cream 0.3% QD, ARQ-252 cream
0.3% BID, ARQ-252 cream 0.1% QD, vehicle cream BID or vehicle cream QD x 12 weeks
to be applied to both hands. Safety and efficacy will be evaluated.
Number of Sites and Subjects
A total of approximately 6 evaluable subjects will be enrolled in Cohort 1 and a total of
approximately 215 subjects will be enrolled in Cohort 2. Approximately 45 study sites are
planned in the US, Canada and Australia. During the conduct of the study, additional countries
and/or sites may be added if necessary. Subjects will be adults (≥18 years of age) males or
females with chronic hand eczema.
For Cohort 1, evaluable subjects are defined as those that:
•
Complete 2 weeks of treatment

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•
Have PK results for all timepoints required at D1, D2, D15 and D16.
Unevaluable subjects in Cohort 1 may be replaced. Subjects in Cohort 2 will not be replaced.
Subject Participation
Phase 1 (Cohort 1)
Subject participation involves a minimum of 7 clinic visits including Screening, Baseline/Day 1,
Day 2, Day 8, Day 15, Day 16 and Day 22. Subjects will be treated with investigational product
(ARQ-252 cream 0.3% QD) for 2 weeks. The interval between the Screening and Baseline visits
could be up to 4 weeks, therefore the anticipated maximum duration of subject participation is
7 weeks.
Phase 2b (Cohort 2)
Subject participation involves a minimum of 7 clinic visits including Screening, Baseline/Day 1,
Week 2, Week 4, Week 8, Week 12 and Week 13. Subjects will be randomized to a treatment
group and will be treated with investigational product for 12 weeks. The interval between the
Screening and Baseline visits could be up to 4 weeks, therefore the anticipated maximum
duration of subject participation is 17 weeks.
Randomization
Phase 1 (Cohort 1)
Phase 1 (Cohort 1) is open label and all enrolled subjects will be assigned treatment with
ARQ‑252 cream 0.3% QD at the Baseline visit. Subjects will be enrolled at the Baseline visit
after the Investigator confirms that the subject meets all eligibility criteria listed in Section 4.7.
Enrollment will be documented by the completion of the Enrollment Notification Form.
Phase 2b (Cohort 2)
Phase 2b (Cohort 2) is randomized. Randomization will take place at the Baseline visit after the
Investigator confirms that the subject meets all eligibility criteria listed in Section 4.7. Subjects
will be randomly assigned to apply ARQ-252 0.3% QD, ARQ-252 0.3% BID, ARQ-252 0.1%
QD, vehicle cream QD or vehicle cream BID by an interactive response technology system
(IRT).
Assignment of treatment arm will be made at a 2:2:1:1:1 ratio and stratified by study site and
IGA at baseline according to a computer-generated randomization list. Kits containing tubes of
investigational product will be assigned to each subject by the IRT system. A subject may
receive more than one kit for the treatment period. The kits and tubes will be labeled with a
unique number, in a blinded manner.

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Numbering of Subjects
Phase 1 (Cohort 1)
All subjects who sign informed consent will be assigned a unique six-digit subject ID number by
the site. The first three digits will correspond to the site number (assigned by the Sponsor) and
the next three digits correspond to the sequential order in which the subject is screened for the
study.
Phase 2b (Cohort 2)
All subjects who sign informed consent will be assigned a unique six-digit subject ID number by
the IRT system. The first three digits correspond to the site number (assigned by the Sponsor),
the next three digits correspond to the sequential order in which the subject is screened for the
study.
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.).
Blinding
Phase 1 (Cohort 1) is not blinded.
Phase 2b (Cohort 2) is double-blinded, therefore neither the subjects nor the Investigator and
clinical personnel will be aware of which investigational product (ARQ-252 0.1% cream,
ARQ‑252 0.3% cream or vehicle cream) an individual subject receives. The subjects,
Investigator and clinical personnel will be aware of whether IP is to be applied QD (once daily)
or BID (twice daily).
Breaking Treatment Codes
Phase 2b (Cohort 2)
In the event of a medical emergency where breaking the blind is required to provide medical care
to the subject, the Investigator may obtain treatment assignment directly from the IRT system for
that subject. Refer to the current version of the IRT plan for details on unblinding. Treatment
assignment should, however, remain blinded unless the assignment knowledge is necessary to
determine subject emergency medical care. The rationale for unblinding must be clearly
explained in source documentation and on the CRF, along with the date on which the treatment
assignment was obtained. The Investigator is requested to contact the Sponsor promptly in the
event of any treatment unblinding.
Blinding of study treatment is critical to the integrity of this clinical trial and therefore, if a
subject’s treatment assignment is disclosed to the Investigator, the subject will have the study
treatment discontinued. All subjects will be followed until study completion unless consent to do
so is specifically withdrawn by the subject.

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Selection of Study Population
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 18 years of age and older (inclusive) at the time of consent.
3. Clinical diagnosis of chronic hand eczema, defined as hand eczema persistent for more than
3 months, or returned twice or more within the last 12 months (Diepgen 2009). Generally
stable disease for 6 weeks. Both irritant and non-irritant etiologic forms are allowed.
All morphologic types are allowed, e.g., vesicular/dyshidrotic, hyperkeratotic, nummular,
and other types.
4. An Investigator’s Global Assessment of disease severity (IGA) of at least Mild (‘2’) at
Baseline (Visit 2). (In Cohort 2, subjects with IGA of ‘Mild’ will be limited to 20% of total
enrollment, and subjects with IGA of ‘Severe’ subjects will also be limited to 20% of total
enrollment).
5. Chronic hand eczema involving at least 0.3% body surface area total (i.e., approximately a
third of one handprint) lesions on both hands added together at Baseline (Visit 2).
6. Female subjects of childbearing potential (FOCBP) must have a negative serum pregnancy
test at Screening and negative urine pregnancy test at Baseline (Visit 2). For FOCBP
involved in any sexual intercourse that could lead to pregnancy: the subject must agree to use
a highly effective contraceptive method for at least 4 weeks prior to Day 1. Additionally,
from Day 1 until at least 4 weeks after the last investigational product administration, these
subjects must agree to use at least 1 highly effective contraceptive method in addition to
1 barrier method according to Contraception Requirements (Figure 1).
7. Females of non-childbearing potential must either be post-menopausal with spontaneous
amenorrhea for at least 12 months (post-menopausal status will be confirmed with FSH
testing) or have undergone surgical sterilization (permanent sterilization methods include
hysterectomy, bilateral oophorectomy, hysteroscopic sterilization, or bilateral salpingectomy)
according to Contraception Requirements (Figure 1).
8. Males, if engaging in sexual intercourse with a female who is pregnant or a female of
childbearing potential, must agree to use a condom every time during the study and every
time subsequently until 4 weeks after the last investigational product administration.
9. Males must agree not to donate sperm from the first dose of investigational product until
4 weeks after the last investigational product administration.
10. Subjects in good health as judged by the Investigator, based on medical history, physical
examination, 12-lead electrocardiogram (ECG), serum chemistry labs, hematology values,
and urinalysis.
11. Subjects are considered reliable and capable of adhering to the Protocol and visit schedule,
according to the judgment of the Investigator.

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Exclusion Criteria
Subjects who meet any of the following exclusion criteria will be excluded from participation in
this study:
1. Concurrent skin diseases on the hands which, in the opinion of the Investigator, could
confound the study (e.g., tinnea manuum).
2. Active skin diseases not on the hands such as atopic dermatitis or psoriasis requiring medical
treatment that could significantly affect hand eczema, in the Investigator’s opinion.
3. Subjects with any presence or history of psoriasis.
4. History of a positive patch test with continued exposure to allergen. If, in the opinion of the
Investigator, there is any suspected allergic hand eczema with continued exposure to
allergen, subject must undergo diagnostic patch testing to determine if they meet entry
criteria prior to Baseline (Visit 2).
5. Subjects who cannot discontinue systemic and/or topical therapies for the treatment of
chronic hand eczema prior to Baseline (Visit 2) and during the study according to Excluded
Medications and Treatments (Table 2), (i.e., immunosuppressive drugs, immunomodulating
drugs, retinoids, or corticosteroids).
6. Psoralen ultraviolet A (PUVA) or ultraviolet B (UVB) therapy on the hands within 4 weeks
prior to Baseline (Visit 2).
7. Cutaneously applied treatment with immunomodulators (e.g., phosphodiesterase-4 (PDE-4)
inhibitors, pimecrolimus, tacrolimus), topical urea moisturizers, topical antibiotics, or low or
mid potency topical corticosteroids on the hands or elsewhere within 1 week prior to
Baseline (Visit 2). Cutaneously applied treatment with high potency topical corticosteroids
on the hands or elsewhere within 2 weeks prior to Baseline (Visit 2).
8. Subjects that have significant active systemic or localized infection, including known
actively infected eczema or have had any infection that required oral or intravenous
administration of antibiotics, antifungal or antiviral agents within 2 weeks prior to Baseline
(Visit 2).
9. Other cutaneously applied therapy on the hands (except for the use of subject's own non-urea
and non-salicylic acid emollients) within 1 week prior to Baseline (Visit 2).
10. Subjects who are unwilling to refrain from using a tanning bed or other LEDs as well as
outdoor tanning or excessive sun exposure for 4 weeks prior to Baseline (Visit 2) and during
the study.
11. Subjects with a history of chronic alcohol or drug abuse within 6 months prior to Baseline
(Visit 2).
12. Current or a history of cancer within 5 years with the exception of fully treated skin basal cell
carcinoma, cutaneous squamous cell carcinoma or carcinoma in situ of the cervix.
13. Subjects that have received live vaccine therapy less than 4 weeks prior to Baseline (Visit 2),
immunosuppressive drugs less than 4 weeks prior to Baseline (Visit 2), or have known
infection with mycobacterium tuberculosis, hepatitis B or C, or HIV, or have a diagnosis of
an immunodeficiency disorder.

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14. Subject had a major surgery within 4 weeks prior to Baseline (Visit 2) or has a major surgery
planned during the study.
15. Known or suspected:
•
severe renal insufficiency or severe hepatic disorders
•
hypersensitivity to component(s) of the investigational product which include SHR0302,
butylated hydroxytoluene (BHT), benzyl alcohol, dimethyl sulfoxide, cyclomethicone,
dimethicone (350 cst), ST-Elastomer 10, water, propylene glycol, polyethylene glycol
200, Pemulen TR1, Carbopol 974P, ethylenediaminetetraacetic acid, trolamine and
D-limonene.
16. Pregnant or lactating women or women planning to become pregnant during the study and /
or within 28 days following the last dose of investigational product.
17. Subjects who cannot discontinue the use of strong systemic Cytochome P-450 3A4 inducers
e.g., efavirenz, nevirapine, glucocorticoids, barbiturates (including phenobarbital), phenytoin,
rifampin and carbamazepine for 2 weeks prior to Baseline (Visit 2) and during the study
period.
18. Subjects who cannot discontinue the use of strong systemic Cytochome P-450 3A4 inhibitors
e.g., indinavir, nelfinavir, ritonavir, clarithromycin, itraconazole, ketoconazole, fluconazole,
nefazodone, saquinavir, suboxone and telithromycin for 2 weeks prior to Baseline (Visit 2)
and during the study period.
19. Subjects with any serious medical condition or clinically significant laboratory, ECG, vital
signs or physical examination abnormality that would prevent study participation or place
the subject at significant risk, as judged by the Investigator.
Removal of Subjects from Investigational Product
A subject may discontinue investigational product for any of the following reasons:
•
Occurrence of any medical condition or circumstance that, in the opinion of the
Investigator, does not allow the subject to adhere to the requirements for investigational
product as per the protocol.
•
Adverse Events as described in Section 4.10. The Investigator must follow the subject
until the AE resolves or satisfactorily stabilizes.
•
Treatment must be discontinued immediately in the event of a female subject’s
pregnancy.
•
Subject's decision to withdraw from investigational product.
•
Requirement for use of prohibited concomitant medication after consultation with the
Sponsor and Medical Monitor.
•
Subject’s repeated failure to comply with protocol requirements or study related
procedures.

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Removal of Subjects from the Study
A subject may be removed from study participation for any of the following reasons:
•
Subject death.
•
Subject's decision to withdraw from study.
•
Subject is lost to follow-up. A subject will be considered lost to follow-up after three
phone and three email attempts and documentation of a certified letter sent to the
subject’s address.
•
Termination of the study by the Sponsor, FDA, or other regulatory authorities.
Treatment Stopping Rules
If a subject has non-cutaneous adverse events of concern, clinically significant laboratory values
or any condition that the Investigator determines could possibly be related to the investigational
product, the Investigator should immediately contact the Medical Monitor to discuss if the
subject should be discontinued from treatment with investigational product.
Treatment for any individual subject will be discontinued if the subject experiences:
•
A serious adverse event (SAE) or a clinically significant non-serious AE which in the
opinion of the Principal Investigator or Medical Monitor warrants discontinuation from
the study for that subject’s well-being.
•
A treatment-emergent severe (Grade 3 or higher) laboratory abnormality (confirmed by
repeat sample).
•
A severe infection (Grade 3 or higher)
•
An Ischemic or thromboembolic cardiovascular event (regardless of Grade)
•
Any other adverse event that represents an unacceptable risk to the subject (e.g., Grade 3
or higher)
As noted above, study treatment must be discontinued immediately in the event of a female
subject’s pregnancy.
Treatment should be interrupted:
•
If a subject develops an application site reaction with the clinical appearance of an
‘irritation reaction’, and with a severity of a Dermal Response Score of 5 (erythema,
edema and papules) or greater on the scale of Berger and Bowman, treatment should be
interrupted for up to one week and may then be resumed if the reaction has, in the
opinion of the Investigator, adequately resolved.
Treatment should be discontinued:
•
If the application site reaction reoccurs, treatment should be discontinued permanently,
and the subject followed until the reaction resolves.

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For cases of suspected allergic contact dermatitis, the Medical Monitor and Sponsor should be
notified and there should be discussion about performing patch testing to further evaluate.
Patch testing is encouraged in such cases.
Phase 2b (Cohort 2)
In the event of a medical emergency where unblinding is required to provide medical care to the
subject, refer to the most current IRT plan and Breaking Treatment Codes (Section 4.6.1).
Contact the Medical Monitor and the Sponsor promptly.
Study Restrictions
Prohibitions and Concomitant Therapy
Prohibited medications and products are detailed in Table 2 (Excluded Medications and
Treatments).
Generally, the addition of new medications, including nonprescription medications, during the
course of the study is discouraged. However, the short-term use of a medication may be
authorized by the Investigator. The Investigator must make the decision to authorize the use of
any such a medication only after consideration of the clinical situation, the potential for masking
symptoms of a more significant underlying event, and whether the use of the medication will
compromise the outcome or validity of the clinical investigation. If medication is required, the
name, strength, frequency, duration of use, and reason for use will be recorded in source
documents and entered into the CRFs. Medications which have been used chronically by
subjects, in particular statins and anti-hypertensives, are allowed for use during the study,
except as prohibited in Table 2.
Table 2.
Excluded Medications and Treatments
Excluded Medications and Treatments
Washout Period from
Baseline (Visit 2)
Topical calcineurin inhibitors, PDE-4 inhibitors (Eucrisa®), topical urea-containing
emollients, topical salicylic acid-containing emollients, topical antibiotics, topical low
potency corticosteroids, topical mid potency corticosteroids
7 days
Topical high potency corticosteroids
14 days
Systemic antibiotics
14 days
Systemic non-biologic treatments for eczema (e.g., cyclosporine, azathioprine,
corticosteroids, methotrexate)
•
Oral JAK inhibitors will be allowed if stopped for reasons other than safety
concerns (28 day washout required)
28 days or 5 half-lives
(whichever is longer)
Biologics including Dupixent®
3 months or 5 half-lives
(whichever is longer)
Oral retinoids (alitretinoin/Toctino, acitretinin, isotretinoin)
3 months
Cell-depleting biologics such as rituximab
6 months

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Excluded Medications and Treatments
Washout Period from
Baseline (Visit 2)
UVB or PUVA phototherapy, tanning booths
28 days
Strong Cytochrome P-450 3A4 inhibitors and strong Cytochrome P-450 3A4 inducers
14 days
All investigational drugs
3 months (biologics); 1 month
(oral); 2 weeks (topical) - or
5 half-lives (whichever is
longer)
Note:
•
Ear drop, 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 Baseline (Visit 2) and are continued at the same dose throughout the study.
•
Non-medicated emollients, moisturizers and sunscreens will be allowed as normally used by the subjects.
These should not be applied to treatment sites 2 hours before or after investigational product application.
•
There is no washout for sedating or nonsedating antihistamines. During the study, systemic treatment with
sedating antihistamines is prohibited. During the study, systemic treatment with nonsedating antihistamines in a
nonstable regimen is prohibited, while systemic treatment with sedating or nonsedating antihistamines in a
stable regimen is allowed.
•
Live vaccine therapy is not allowed less than 4 weeks prior to Baseline (Visit 2).
Treatment
Investigational Product Supplies, Packaging and Labeling
Phase 1 (Cohort 1)
ARQ-252 cream 0.3% will be in 12-gram tubes. The tubes will be labeled in an open-label
manner. The tubes dispensed to a subject will be labeled with a unique number.
Phase 2b (Cohort 2)
ARQ-252 cream 0.1%, ARQ-252 cream 0.3% or vehicle formulation will be in 12-gram tubes.
The tubes will be packaged in kits, containing 2 tubes of investigational product. The number of
kits dispensed to a subject will be based on the dosing frequency, either BID (twice daily) or QD
(once daily). The kits and tubes will be labeled with a unique number, in a blinded manner.
Phase 1 and 2b (Cohorts 1 and 2)
The Sponsor will supply sufficient quantities of the investigational product to each site to allow
for completion of this study.
Records will be made of the receipt and dispensing of the investigational product supplied.
At the conclusion of the study, any unused investigational product will be returned to the
Sponsor or designee, or destroyed, as per Sponsor instructions.
Refer to the most current version of the IP Handling Plan for details on accountability, storage,
and management of IP.

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Treatment Administration
Initial treatment with the IP will occur on Day 1. At the Baseline visit the study staff will
demonstrate to the subject how to apply IP using the first tube that is assigned to the subject at
enrollment/randomization. Study site staff will demonstrate how two unit doses (two pea size
amounts of IP will cover approximately 4% BSA, i.e., both hands entirely) are properly squeezed
from the tube and applied as a thin film to cover both hands. IP will be applied to the front and
back of both hands, interlacing fingers, rubbing in thoroughly but gently, until the cream has
absorbed. The subject will then practice squeezing a similar amount and applying IP. The study
staff will confirm that the subject’s application technique is correct.
Subjects in Cohort 1 will be instructed to apply IP once daily (QD). Subjects in Cohort 2 will be
instructed to apply IP either once daily (QD) or twice daily (BID), as determined at
randomization.
IP tubes must be returned by subjects at each study visit, both empty and full, and will be
weighed. Re-training will be conducted at subsequent visits as needed (i.e., if the returned tube
weighs substantially different than the expected weight).
Subjects will be instructed to refrain from handwashing for 4 hours after IP application, if
possible. Subjects may use hand sanitizer within 4 hours of IP application, if necessary.
Hand washing and use of hand sanitizer within 4 hours of IP application will be recorded in the
subjects’ diary and CRF.
Treatment Compliance
Each IP tube will be weighed prior to dispensing at the Baseline visit and at each follow-up
clinic visit according to the Schedule of Visits and Assessments (Section 1.3). When IP is
applied in the clinic, the IP tube will be weighed before and after IP application. If the subject’s
actual use is substantially different than the expected use (see IP Handling Plan), the subject will
be retrained on the investigational product application technique.
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,
handwashing or use of hand sanitizer within 4 hours. 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 CRFs. If a subject misses a dose,
they should be instructed to return to the protocol investigational product administration schedule
(i.e., if subject forgets a dose they should wait until the next planned application and apply as
usual).
A subject will be considered compliant with the dosing regimen if the subject applies at least
80% of the expected applications during the investigational product application period and does
not miss more than 3 consecutive doses.

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Compliance will be assessed by review of the dosing diary. Weight of investigational product
applied will be measured for reporting purposes.
If the diary shows less than 80% of expected use, the subject is using too little investigational
product and retraining must be conducted and documented.
Compliance will be documented in source and in CRF.
5.
STUDY PROCEDURES
Safety Assessments
The Schedule of Visits and Assessments (Section 1.3) summarizes the clinical procedures to be
performed at each visit. Individual clinical procedures are described in detail below. Additional
evaluations/testing may be deemed necessary by the PI and/or the Sponsor for reasons related to
subject safety.
This study assesses the safety, efficacy, and PK of ARQ-252 cream 0.1%, ARQ-252 cream 0.3%
and vehicle cream. Safety will be determined by evaluating physical examinations, 12-lead
ECGs, vital signs/weight, clinical laboratory parameters, local tolerability assessments, and AEs
as outlined in the Schedule of Visits and Assessments (Section 1.3). If deemed necessary,
additional safety assessments will be performed at the discretion of the Investigator.
Screening
Before a subject’s participation in the clinical study, the Investigator is responsible for obtaining
written informed consent from the subject after adequate explanation of the study design,
anticipated benefits, and the potential risks. A subject is considered a participant of the trial once
the ICF is completely signed.
The following procedures/assessments will be performed at the Screening Visit (within 4 weeks
after signing the informed consent):
•
Review of medical and surgical history, including any history of allergies and/or contact
dermatitis
•
Review of childbearing potential (subject or partner of male subject) and contraceptive
use (see Section 5.1.2)
•
Collection of demographic data including sex, age, race, ethnicity
•
Vital signs including temperature, heart rate, and blood pressure
•
Chronic Hand Eczema assessments (BSA, IGA, HECSI).
•
Limited physical examination of skin, lungs, and heart
•
ECG

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•
Laboratory tests: hematology, chemistry, urinalysis, TSH, T4, serum pregnancy test
(for female subjects of childbearing potential), FSH (if indicated to confirm
post-menopausal status)
•
Completion of WI-NRS and NRS Pain. Subjects in Cohort 2 will also complete the
QOLHEQ.
•
Collection of concomitant medications and adverse events
Medical history of chronic hand eczema will include the following information, which will be
recorded in the CRF:
•
Morphologic subtype of HE
•
Whether the subject has ever been patch tested and if so, the patch test results and any
positives (e.g., nickel).
•
Distribution on hands (palmar vs dorsal vs interdigital vs pulpitis)
All screened subjects will receive a screening number at the time of informed consent. Subjects
in Cohort 2 will be entered into the IRT system at the time of consent.
Subjects may be re-screened one time, the original assigned Subject ID screening number will be
used for re-screening.
Contraception Requirements
Previous nonclinical research showed that the active ingredient in ARQ-252 can harm fetal
development. Subjects engaging sexual intercourse that could lead to pregnancy must adhere to
the following pregnancy testing and/or contraception requirements.
Female Subjects
Female subjects of childbearing potential (FOCBP) must have a negative serum pregnancy test at
Screening and negative urine pregnancy test at Baseline (Visit 2). For FOCBP involved in any
sexual intercourse that could lead to pregnancy: the subject must agree to use a highly effective
contraceptive method for at least 4 weeks prior to Day 1. Additionally, from Day 1 until at least
4 weeks after the last investigational product administration, these subjects must agree to use at
least 1 highly effective contraceptive method in addition to 1 barrier method of contraception.
The acceptable methods of contraception are listed below in the Figure 1.

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Figure 1.
Contraception Requirements for Female Subjects
Male Subjects:
Males, if engaging in sexual intercourse with a female who is pregnant or a female of
childbearing potential, must agree to use a condom every time during the study and every time
subsequently until 4 weeks after the last investigational product administration.
Physical Examination
Physical examinations will be performed according to the Schedule of Visits and Assessments
(Section 1.3). The physical exam will be limited to skin, lungs and heart only.
Vital Signs, Height and Weight
Vital signs will be performed according to the Schedule of Visits and Assessments (Section 1.3).
Weight, blood pressure, heart rate, and temperature will be collected in seated position after
5 mins. Subjects will be instructed to void prior to weight being taken and to remove any objects
of significant weight (i.e., jackets, outerwear, shoes, cell phones, wallet, key chains, etc.).
Height will be measured at Baseline (Day 1) only.
12-lead ECGs
12-lead ECGs will be performed according to the Schedule of Visits and Assessments
(Section 1.3).
ECGs will be obtained on subjects after 5 minutes in the supine position. All ECG tracings and
readouts will be reviewed by the Investigator and central reader at the ECG laboratory.

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Laboratory Tests
All tests listed in Table 3 below will be performed according to the Schedule of Visits and
Assessments (Section 1.3) unless otherwise noted. The collection of specimens will be in a
non-fasting state (no food restrictions). In addition, laboratory safety tests may be performed at
various unscheduled time points, if deemed necessary by the Investigator.
Table 3.
Laboratory Tests
Hematology
Serum Chemistry
•
Hemoglobin
•
Hematocrit
•
Total and differential leukocyte count
•
Red blood cell count with indices and morphology
•
Platelet count
•
Reticulocyte count1
•
Blood Urea Nitrogen
•
Bilirubin (total and direct)
•
Alkaline phosphatase
•
Aspartate aminotransferase
•
Alanine aminotransferase
•
Albumin
•
Sodium
•
Potassium
•
Chloride
•
Glucose
•
Creatinine
•
Creatine kinase
Urinalysis
Additional Tests
•
pH
•
Specific gravity
•
Protein2
•
Glucose
•
Ketones
•
Bilirubin
•
Blood2
•
Nitrite2
•
Urobilinogen
•
Leukocyte esterase2
•
Thyroid Stimulating Hormone T4 (TSH/T4)
•
Urine pregnancy test3
(for females of childbearing potential only)
•
Serum pregnancy test (hCG)4
•
Follicle-stimulating Hormone (FSH) 5
•
Pharmacokinetic (PK) assessments
1 If red blood cell count, hemoglobin or hematocrit values are below the lower limit of normal, reticulocyte count
will be performed
2 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.
3 Cohort 1: At Baseline, Day 8, Day 15 and Day 22 for FOCBP only. Cohort 2: At Baseline, Week 4, 8, 12 and 13
for FOCBP only.
4 At screening only for FOCBP.
5 If indicated to confirm post-menopausal status

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Local Tolerability Assessment
The Investigator Local Tolerability Assessment will be performed according to the Schedule of
Visits and Assessments (Section 1.3).
Application site reactions will be graded at the timepoints outlined in the Schedule of Visits and
Assessments (Section 1.3). 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 chronic hand eczema.
The Investigator assessments will be conducted by the Investigator prior to investigational
product application in the clinic.
Dermal Response
0 = no evidence of irritation
1 = minimal erythema, barely perceptible
2 = definite erythema, readily visible; minimal edema or minimal papular response
3 = erythema and papules
4 = definite edema
5 = erythema, edema and papules
6 = vesicular eruption
7 = strong reaction spreading beyond application site
Other Effects
A = slight glazed appearance
B = marked glazing
C = glazing with peeling and cracking
D = glazing with fissures
E = film of dried serous exudates
F = small petechial erosions and/or scabs
G = no other effects
The Subject Local Tolerability Assessment will be performed according to the Schedule of Visits
and Assessments (Section 1.3).
This assessment will be administered by the site 10 to 15 minutes after investigational product
application in the clinic.

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Grade
Sensation Following Investigational Product Application
0 (none)
No sensation
1 (mild)
Slight warm, tingling sensation; not really bothersome
2 (moderate)
Definite warm, tingling sensation that is somewhat bothersome
3 (severe)
Hot, tingling/stinging sensation that has caused definite discomfort
Adverse Events
Adverse events (AEs) will be collected continuously during the study beginning at informed
consent and assessed according to the Schedule of Visits and Assessment (Section 1.3).
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 5.7.
Efficacy Evaluations
Investigator’s Global Assessment (IGA)
Investigator’s Global Assessment of chronic hand eczema will be performed according to the
Schedule of Visits and Assessments (Section 1.3).
The IGA is a static evaluation of qualitative overall chronic hand eczema severity. This global
assessment scale is an ordinal scale with five severity grades (reported only in integers of 0 to 4).
Each IGA Severity Score is defined by distinct and clinically relevant morphologic descriptions
that minimizes inter-observer variability.
Every effort must be made for the same Evaluator to complete the IGA for the subject at
every study visit.
IGA will be assessed at clinic visits prior to the subject applying Investigational Product
and other physician assessments.

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Investigator Global Assessment of Disease (IGA)
Score
Grade
Description
0
Clear
Absence of erythema and scaling,
AND
Absence of vesiculation, edema, and fissures.
Note: Post-inflammatory pigmentary changes may be present.
1
Almost clear
Barely perceptible or faint erythema, and/or
Slight flaking over limited areas, mostly fine scales,
AND
Absence of vesiculation, edema, or fissures
2
Mild
Barely perceptible or faint erythema, and/or
Slight flaking over limited areas, mostly fine scales
AND
Scattered vesicles affecting up to 10% of hand, without erosion, and/or
Dermal swelling over less than 10% of hands, and/or
Cracked skin affecting a small area of the hand
3
Moderate
Either barely perceptible or faint erythema, or prominent redness, and/or
Either slight flaking over limited areas, mostly fine scales, or flaking over widespread
area(s), coarser scale
AND
Scattered or clustered vesicles affecting up to 30% of hand, without visible erosion or
excoriation, and/or
Definite dermal swelling over more than 10% of hand, and/or
Cracked skin affecting multiple areas of the hand
4
Severe
Either prominent or deep intense red color, and/or
Either flaking over widespread area(s), coarser scales, or desquamation covering over
30% of the hand, with coarse thick scales
AND
At least one of the following:
High density of vesicles extending over large area(s), or with erosion or excoriation,
and/or
Dermal swelling with skin induration over widespread area(s), and/or
One or more deep fissures and causing bleeding
Adapted from Ruzicka 2008.

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Body Surface Area (BSA)
BSA Assessments will be performed according to the Schedule of Visits and Assessments
(Section 1.3).
The BSA affected by chronic hand eczema 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). Lesions on both hands will be added together. Affected areas of the lateral aspects
of the fingers and hands should be assigned to the palmar surface.
Worst Itch Numerical Rating Scale (WI-NRS)
Subjects will complete the WI-NRS pruritus assessment. WI-NRS Assessments will be
performed according to the Schedule of Visits and Assessments (Section 1.3).
Subjects will complete the WI-NRS pruritis assessment in the clinic during Screening and then
daily at home from the Baseline/Day 1 visit until the last visit. Subjects will record their
WI-NRS on a diary and will return the diary to the clinic at each visit. Sites will review WI-NRS
entries and enter into the CRF.
The WI-NRS has been developed as a simple, single item to assess the patient-reported severity
of this symptom at its highest intensity during the previous 24-hour period. (Naegeli 2015).
The WI‑NRS will be determined by asking the subject’s assessment of worst itch over the past
24 hours. The scale is from ‘0 to 10’ (“no itch” to “worst imaginable itch”).
Copyright © (2017) Eli Lilly and Company. All rights reserved.
NRS-Pain Scale
The Numerical Rating Scale (NRS) for Pain will be performed according to the Schedule of
Visits and Assessments (Section 1.3).
Subjects will complete the NRS Pain assessment in the clinic during screening and then daily at
home from the Baseline/Day 1 visit until the last visit. Subjects will record their NRS-Pain score
on a diary and will return the diary to the clinic at each visit. Sites will review NRS-Pain entries
and enter into the CRF.

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The NRS-Pain Scale is the most widely used instrument for pain screening. Subjects will select
the number between 0 and 10 that fits best to their worst pain intensity over the past 24 hours,
where 0 represents ‘no pain at all’ and 10 ‘the worst pain possible’.
Source: https://www.physio-pedia.com/images/4/47/NRS_pain.jpg
HECSI
The Hand Eczema Severity Index (HECSI) will be performed according to the Schedule of Visits
and Assessments (Section 1.3).
HECSI is an instrument used in clinical trials to rate the severity of 6 clinical signs of hand
eczema and the extent of the lesions on each of 5 hand areas by use of standard scales. The total
HECSI score is based on a 4-point severity scale ranging from 0 (none/absent) to 3 (severe) and
a 5-point scale rating the affected area(s) ranging from 0 (0% affected area) to 4 (76% to 100%
affected area).
Clinical Signs
Fingertips
Fingers
(except tips)
Palm of
hands
Back of
hands
Wrists
Erythema (E)
Infiltration/papulation (I)
Vesicles (V)
Fissures (F)
Scaling (S)
Oedema (O)
SUM (E + I + V + F + S + O)
Extent (Ex)
Total HESCI Score =
Sum x Ex +
Sum x Ex +
Sum x Ex +
Sum x Ex +
Sum x Ex +
Total HECSI score (min 0; max 360). For each location (total of both hands) the affected area was given a score
from 0 to 4: (0, 0%; 1, 1-25%; 2, 26-50%; 3, 51-75%; 4, 76-100%) for the extent of clinical symptoms. Finally the
score given for the extent for each location was multiplied by the total sum of the intensity of each clinical feature
(each contributing equally to the final score) and the total sum called the HESCI score was calculated, varying from
0 to a maximum severity score of 360 points.
Adapted from Held 2005.

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Quality of Life in Hand Eczema Questionnaire
The Quality Of Life in Hand Eczema Questionnaire (QOLHEQ) will be performed according to
the Schedule of Visits and Assessments (Section 1.3) in Phase 2b (Cohort 2). The QOLHEQ is
an instrument to assess disease specific Health Related Quality of Life (HRQOL) in patients
suffering from hand eczema (Appendix 1). The construct HRQOL includes all impairments or
limiting conditions caused by the health state of an individual. The QOLHEQ is a disease
specific instrument, thereby only assessing impairments caused by hand eczema. It consists out
of 30 items which can be summarized according to four domains of HRQOL: Impairments
because of (1) symptoms, (2) emotions, (3) limitations in functioning or (4) because of treatment
and prevention.
Nail Dystrophy Assessment
Phase 2b (Cohort 2)
A Nail Dystrophy Assessment will be performed in Cohort 2 according to the Schedule of Visits
and Assessments (Section 1.3) to identify any alteration of nail morphology. Assessment to
include the following evaluations by the Investigator:
Baseline/Day 1:
•
Does the subject have at least one nail with significant dystrophy extending to the
cuticle? Yes/No
•
If “Yes”, record which nail has the worst dystrophy (indicating left or right)
Subsequent visits according to the Schedule of Visits and Assessments:
•
For the identified fingernail with the worst dystrophy at Baseline/Day 1, is there normal
appearing nail distal to the cuticle, Yes/No
•
If “Yes”, how many millimeters of normal appearing nail distal to the cuticle?
Sites participating in optional photography will obtain photos of nail with the worst dystrophy at
Baseline/Day 1 and at subsequent visits according to the Schedule of Visits and Assessments
(Section 1.3) and Section 5.3.2.
Other Evaluations
Pharmacokinetics Assessment
PK draws will be performed according to the Schedule of Visits and Assessments (Section 1.3)
for all subjects at all sites.
Phase 1 (Cohort 1)
•
Serial PK sampling will be performed on Day 1 (1, 2, 4, 6, and 24 hours post-dose
administration), and at Day 15 (pre-dose and 1, 2, 4, 6, and 24 hours post-dose
administration). For 24-hour timepoints, subjects return to the clinic on the following day

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within 2 hours of the IP application time from the previous day for PK plasma sample
collection. A pre-dose/trough PK sample will be taken at Day 8.
Phase 2b (Cohort 2):
•
PK will be evaluated through trough/pre-dose sampling at Baseline, Day 29, and Day 85.
PK draws will be collected while the subject is having serum chemistries drawn at applicable
visits. The draws will be pre-dose investigational product application in the clinic. Ensure
investigational product is not applied in the area where PK will be drawn.
Medical Photography
Phase 2b (Cohort 2)
Photography will be performed at selected investigational sites using Canfield photography
equipment according to the Schedule of Visits and Assessment (Section 1.3) in Phase 2b
(Cohort 2). Photography will be optional. All efforts will be made to de-identify the subjects.
Sites participating in optional photography will obtain photos of nail with the worst dystrophy at
Baseline/Day 1 and at subsequent visits according to the Schedule of Visits and Assessments
(Section 1.3).
Final Study Visit – End of Study
Phase 1 (Cohort 1)
The approximate final study visit will occur at Week 3 (Day 22).
Phase 2b (Cohort 2):
The approximate final study visit will occur at Week 13 (Day 92).
For both Cohorts, the procedures performed during these visits are as described in the Schedule
of Visits and Assessments (Section 1.3). A 3-day scheduling window is allowed for this visit.
Adverse events will be recorded as reported by the subject and followed to resolution
(as necessary).
Early Termination Visit
If a subject is withdrawn or wishes to exit the study prior to the final study visit, an early
termination visit will be scheduled. This visit should include the procedures and assessments that
would be performed at the final study visit for either Cohort 1 or Cohort 2 (Section 1.3).
Unscheduled Visit
Unscheduled visits may be necessary to repeat testing following abnormal laboratory results, for
follow-up of AEs, or for any other reason, as warranted in the judgement of the Investigator.

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The following information will be collected for all subjects:
•
Concomitant medications/procedures
•
AEs
•
BSA, IGA, HESCI
Adverse Events
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
investigational product through study completion.
Application site reactions will be considered adverse events if they require intervention,
suspension or discontinuation of investigational product.
Serious Adverse Event Definition
The definitions and reporting requirements of Health Canada/the Food and Drug Administration
(FDA)/ Therapeutic Goods Administration (TGA)/ICH Guidelines for Clinical Safety Data
Management, Definitions and Standards for Expedited Reporting, Topic E2A will be adhered to.
If any AEs are serious, as defined by ICH Guidelines for Clinical Safety, required procedures
will be followed.
All SAEs will be reported to the Sponsor (or delegate) via fax or e-mail within 24 hours of
becoming aware of the event, whether or not the serious events are deemed IP-related.
All serious event reporting will adhere to ICH E6: Guideline for Good Clinical Practice and
ICH E2A: Clinical Safety Data Management: Definitions and Standards for Expedited
Reporting.: The ERB/IRB will be notified of the Alert Reports as per HC, FDA, ICH and the
IRB/ERB’s policies and procedures. Refer to the Safety Reporting Instructions for SAE
reporting.
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

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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 history
documentation for the individual subject.
•
Diagnostic and therapeutic procedures, such as surgery, should not be reported as AEs;
however, the medical condition for which the procedure was performed should be
reported if it occurs during the reporting period and meets the definition of an AE. For
example, an acute appendicitis that begins during the AE reporting period should be
reported as an AE, and the resulting appendectomy should be recorded as treatment of the
AE.
Unexpected is defined as an AE that is not listed in the IB or is not listed at the specificity or
severity that has been observed; or is not consistent with the risk information described in the
general investigational plan or elsewhere in the current study documentation.
If a SAE occurs to a subject on this study, contact the Medical Monitor within one business day
of knowledge of event.
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.

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Safety Review with Subject
At each follow-up visit, subjects will be queried with an open-ended question such as:
‘How have you been feeling since your last visit?’ Additionally, the study staff will review
subject 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).
Adverse Event Reporting
AEs will be collected following informed consent of the subject through subject study
completion.
The Investigator will review each event and assess its relationship to investigational product
treatment (unrelated, unlikely, possibly, probably, likely). Each sign or symptom reported will be
graded on the NIH NCI CTCAE (Version 5.0) 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 investigational product will be assessed using the following
definitions:
Unrelated
•
The AE must clearly be caused by the subject’s clinical state, or the study
procedure/conditions.
•
Definitely not related to drug.
•
Temporal sequence of AE onset relative to administration of drug not reasonable.
•
Another obvious cause of an AE.
Unlikely
•
Time sequence is unreasonable.
•
There is another more likely cause for an AE.
Possibly
•
Corresponds to what is known about the drug.
•
Time sequence is reasonable.
•
Could have been due to another equally, likely cause.
Probably
•
Is a known effect of the drug.
•
Time sequence from taking drug is reasonable.
•
Ceases on stopping the drug.
•
Cannot be reasonably explained by the known characteristics of the subject’s clinical state.
Likely
•
Is a known effect of the drug (e.g., listed in Physicians' Desk Reference, Compendium of
Pharmaceuticals and Specialties, IB).
•
Time sequence from taking drug is reasonable.
•
Event stops upon stopping drug, event returns upon restarting drug.

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The following CTCAE toxicity grading scale 5-point severity scale definitions for rating
maximum severity will be used:
Grade 1
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not
indicated.
Grade 2
Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate
instrumental activities of daily living.*
Grade 3
Severe or medically significant but not immediately life-threatening; Hospitalization or
prolongation of hospitalization indicated; disabling; limiting self-care activities of daily living.**
Note: An experience may be severe but may not be serious, e.g., severe headache).
Grade 4
Life-threatening consequences; urgent intervention indicated.
Grade 5
Death related to AE.
Note: A semi-colon indicates ‘or’ within the description of the grade.
*Instrumental activities of daily living refer to preparing meals, shopping for groceries or clothes, using the
telephone, managing money, etc.
**Self-care activities of daily living refer to bathing, dressing and undressing, feeding self, using the toilet, taking
medications, and not bedridden.
AEs will be coded using the most current MedDRA® version available at the start of the study
(e.g., 21.0 or higher).
Reporting Pregnancy
During the study, all subjects should be instructed to contact the Investigator immediately if they
suspect they might be pregnant (e.g., missed or late menstrual period). If pregnancy is
confirmed, Investigational Product must be discontinued immediately, the subject should be
referred to an obstetrician experienced in reproductive toxicity for evaluation and counseling,
and the subject should be followed until conclusion of the pregnancy. Subject may be required to
sign a separate informed consent form to obtain pregnancy follow-up information, per local
requirements.
The Investigator is responsible for reporting all available pregnancy information on the
pregnancy report and submitting to the Medical Monitor within 24 hours of becoming aware of
the event, although pregnancy itself is not considered an AE. Follow-up information detailing
the outcome of the pregnancy and the health of the newborn should be reported as it becomes
available. Any pregnancy resulting in a congenital abnormality or birth defect of the newborn,
or neonatal death occurring within 30 days of the birth must be reported as a SAE, regardless of
causality. Any infant death that occurs after the 30 day reporting period that the Investigator
suspects is related to Investigational Product must also be reported as an SAE.
Partner pregnancies of a male subject will be reported.

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6.
DATA ANALYSIS
Data will be handled and processed according to the Contract Research Organization’s Standard
Operating Procedures, which are written based on the principles of GCP.
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.
Descriptive statistics will be used to provide an overview of the safety, efficacy, and
pharmacokinetic results. For categorical parameters, the number and percentage of subjects in
each category will be presented. The denominator for percentage will be based on the number of
subjects appropriate for the purpose of analysis. For continuous parameters, descriptive statistics
will include n (number of subjects), mean, standard deviation (SD), median, minimum,
and maximum.
Missing efficacy data for IGA will be imputed using multiple imputation.
The primary statistical comparisons and secondary endpoints will be made at the
0.10 significance level and will not be adjusted for multiple comparisons.
Determination of Sample Size
Cohort 1 will include approximately 6 evaluable subjects, which is deemed adequate for the
purpose of evaluating safety and PK prior to Cohort 2.
There are approximately 215 subjects planned for Cohort 2. Approximately 61 subjects will
receive ARQ-252 cream 0.3% QD, approximately 61 subjects will receive ARQ-252 cream 0.3%
BID, approximately 31 subjects will receive ARQ-252 cream 0.1% QD, approximately 31
subjects will receive matching vehicle cream QD, and approximately 31 subjects will receive
vehicle cream BID. The randomization scheme will be 2:2:1:1:1 between these 5 treatment
groups, stratified by study site and IGA at Baseline.
The primary statistical comparisons will be to assess the ARQ-252 cream 0.3% group BID group
versus the vehicle BID group, to assess the ARQ-252 cream 0.3% QC group versus the vehicle
QD group, and to assess the ARQ-252 cream 0.1% QD group versus the vehicle QD group.
A sample size of 55 per active arm and 28 per vehicle arm will provide approximately 85%
power at the 2-sided 10% significance level to detect a difference in the rate of subjects attaining
an IGA score of clear or almost clear (for each ARQ-252-treated group versus vehicle group
within the same daily dosing frequency), assuming an active treatment response rate of 45% and
a vehicle response rate of 15%. This is based on a 2-group X2 test of equal proportions
(without continuity correction). With a 10% dropout rate, the sample size for the study would be
increased to 61 subjects per active arm and 31 subjects per vehicle arm (215 subjects total).

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The primary statistical comparisons and evaluations of secondary endpoints will not be adjusted
for multiplicity.
Subjects to Analyze
Five analysis populations will be defined:
•
The Safety population will include all subjects who are enrolled and received at least one
confirmed dose of study medication. This population will be used for all safety analyses
and will be defined separately for each Cohort.
•
The Intent-to-Treat will include all subjects randomized to Cohort 2. This population
will be the primary analysis for the analysis of efficacy endpoints.
•
The Per-Protocol Population will include all subjects in the safety population, who were at
least 80% compliant with study medication application, and showed no important
deviations from the study protocol that would affect the interpretation of efficacy.
This population will be used as a sensitivity analysis of primary and secondary efficacy
endpoints.
•
The Pruritis population is a subset of the ITT population and include subjects with
WI‑NRS score ≥4 at Baseline. This population will be used for the analysis of WI-NRS.
•
The PK population will include all subjects receiving the active drug with sufficient
plasma concentrations of SHR0302 to define a profile, as determined by the
pharmacokineticist.
Interim Analysis
No interim efficacy analyses are planned. Safety data will be reviewed on an ongoing basis.
Background and Demographic Characteristics
Demographics, baseline disease characteristics, baseline height, weight, and BSA will be
summarized descriptively for all enrolled (Cohort 1) and randomized (Cohort 2) subjects.
Study Disposition
The number of subjects randomized, receiving IP, completing study, and withdrawing
prematurely (with reason for withdrawal) will be summarized by cohort and treatment group.
Protocol Deviations and Eligibility Deviations
The number of subjects with important protocol deviations and/or eligibility deviations will be
summarized by category and by treatment group.

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Investigational Product Compliance
The number of IP applications by each subject based on diary data will be summarized using
descriptive statistics. The amount of IP used by each subject based on product weight will be
summarized by treatment using summary statistics (mean, SD, median, minimum, and
maximum), and categorically. IP compliance will be calculated based on number of applications
divided by the expected number (amount) of IP for each subject. Compliance will be
summarized descriptively by cohort and treatment group.
Efficacy Evaluation
Primary Efficacy Endpoint
The primary efficacy endpoint is the rate of subjects achieving an IGA score of ‘clear’ or ‘almost
clear’ at Week 12.
The primary statistical comparisons will be to assess the ARQ-252 cream 0.3% group BID group
versus the vehicle BID group, to assess the ARQ-252 cream 0.3% QD group versus the vehicle
QD group, and to assess the ARQ-252 cream 0.1% QD group versus the vehicle QD group.
The primary endpoint will be analyzed using a Cochran-Mantel-Haenszel test stratified by IGA
at Baseline and study site. Statistical significance will be concluded at the 2-sided 10%
significance level for each of the primary comparisons. Missing scores will be imputed using
multiple imputation.
Secondary Endpoints
The Secondary Efficacy Endpoints will include:
•
The rate of achievement of IGA of ‘clear’ or ‘almost clear’ PLUS at least a 2-point
improvement from Baseline at Weeks 2, 4, 8 and 12
•
The rate of achievement of at least a 2-point improvement from baseline at Weeks 2, 4, 8
and 12
•
The rate of achievement of IGA of ‘clear’ or ‘almost clear’ at Weeks 2, 4, and 8
•
Time to IGA of ‘clear’ or ‘almost clear’
•
Change in IGA score at Weeks 2, 4, 8, and 12 as compared to Baseline
•
Change in WI-NRS pruritus score at Weeks 2, 4, 8, and 12 as compared to Baseline
•
The rate of achievement of ≥4-point reduction from Baseline in WI-NRS pruritus score at
Weeks 2, 4, 8, and 12, in subjects with Baseline WI-NRS pruritus score of at least 4
•
Time to the first achievement of ≥4-point reduction from Baseline in WI-NRS pruritus
score in subjects with Baseline WI-NRS pruritus score of at least 4
•
Percent change in HECSI (Hand Eczema Severity Index) score at Weeks 2, 4, 8, and 12
compared to Baseline

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•
Change in Pain NRS score from Baseline to Weeks, 2, 4, 8, and 12
•
The rate of achievement of ≥4-point reduction from Baseline in Pain NRS score at
2 weeks, 4 weeks, 8 weeks, and 12 weeks in subjects with Baseline Pain NRS score of at
least 4
•
Time to the first achievement of ≥4-point reduction from Baseline in Pain NRS score in
subjects with Baseline Pain NRS score of at least 4
•
Change from Baseline in overall Quality of Life in Hand Eczema Questionnaire
(QOLHEQ) score at each visit.
•
Percent BSA affected by disease and % change from baseline in BSA affected by disease
at baseline, 2 weeks, 4 weeks, 8 weeks, and 12 weeks.
Exploratory Endpoints
•
Change from Baseline in Nail Dystrophy at each visit (Cohort 2 only)
The binary secondary endpoints will be analyzed using a Cochran-Mantel-Haenszel test stratified
by Baseline IGA and study site as with the primary endpoint. The continuous secondary
endpoints will be analyzed using an analysis of covariance stratified by Baseline IGA and study
site and Baseline values of the endpoint as independent variables. Statistical comparison
between the active treatment arm and vehicle arm will be facilitated by using contrasts.
Analyses may also include pooling the active treatment groups together for comparison against
the vehicle treatment groups; specifications for these analyses will be included in the SAP.
Safety Analysis
Descriptive statistics will be calculated for safety data and presented by visit and treatment group
for quantitative safety data and frequency counts will be compiled for classification of qualitative
safety data. Summaries of local tolerability will be presented by visit and treatment group.
Adverse Events
All treatment-emergent AEs occurring during the study will be recorded and classified on the
basis of MedDRA terminology for the safety population. Treatment-emergent AEs are those AEs
with an onset on or after the date of study treatment. All treatment-emergent AEs will be
summarized by treatment group, the number of subjects reporting treatment-emergent AEs,
system organ class, preferred term, severity, relationship, and seriousness. Serious adverse events
(SAEs) will be listed by subject. SAEs will be summarized by treatment group, severity, and
relationship to study treatment. For AEs, each subject will be counted only once within a system
organ class or a preferred term using the event with the greatest relationship and greatest
severity.
All information pertaining to AEs noted during the study will be listed by subject, detailing the
verbatim description given by the Investigator, preferred term, system organ class, start date,
stop date, severity, action taken regarding IP, corrective treatment, outcome, and IP relatedness.
The event onset will also be shown relative (in number of days) to date of first application.

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In addition, a listing of subjects who prematurely discontinue from the IP due to adverse events
will also be provided.
Local Tolerance Assessment
For the Investigator’s and Subject’s assessment, the numeric application site reaction scores will
be summarized individually by using number and percentage of subjects by visit, as well as
mean/median scores.
Medical History and Physical Examinations
Clinically significant changes observed during physical examination will be captured as adverse
events and included in AE tabulations.
Clinical Laboratory Results and Vital Signs
All clinical laboratory results and ECG measurements and their change from Baseline (pre-dose),
will be summarized descriptively by parameter, along with time point of collection.
A shift table describing out-of-normal range shifts will be provided for clinical laboratory results.
Prior and Concomitant Medications
Prior and concomitant medication information for all enrolled/randomized subjects will be
presented in electronic datasets. Summary tables will be presented by World Health
Organization-Anatomical Therapeutic Chemical Classification System (WHO-ATC) therapeutic
category and product.
Pharmacokinetic Analysis
Plasma drug concentrations at pre-dose will be summarized using descriptive statistics.
A manual for blood sampling, collection, processing, and sample shipment will be provided in a
separate document.
A detailed description of the PK analysis will be presented in the SAP.
7.
STUDY ADMINISTRATION
Ethics
Ethics Review Board
Before enrollment of subjects 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, ICH
GCP regulations and other local/regional regulatory requirements. A letter documenting the IRB
or IEC approval must be received by the Sponsor (or delegate) before the initiation of the study

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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,
Health Canada, local and regional regulations and ICH GCP guidelines.
The Investigator, the Sponsor, or designee shall promptly notify the IRB or IEC of any SAEs,
SUSARs, or any other information that may affect the safe use of the investigational products
during the study, per the IRB or IEC local requirements, and in compliance with FDA and Health
Canada regulations and ICH GCP guidelines.
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 (R2), Nov 2016) and
the applicable regulations of the country(ies) in which the trial is conducted.
Subject Information and Consent
The purpose of the study, the procedures to be carried out and the potential hazards will be
described to the subjects in non-technical terms. Subjects will be required to read, sign and date a
current version of the IRB/EC approved ICF summarizing the discussion prior to enrollment 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.
Study Completion and Termination
Study Completion
The study is considered completed with the last visit of the last subject participating in the study.
The final data from the investigational site will be sent to the Sponsor (or designee) after
completion of the final subject visit at that site, in the time frame specified in the Clinical Trial
Agreement.
Study Termination
The Sponsor reserves the right to close the investigational site or terminate the study at any time
for any reason at the sole discretion of the Sponsor. Investigational sites will be closed upon
study completion. An investigational site is considered closed when all required documents and
study supplies have been collected and a site closure visit has been performed. The Investigator
may initiate site closure at any time, provided there is reasonable cause and sufficient notice is
given in advance of the intended termination.

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Reasons for the early closure of an investigational site by the Sponsor or Investigator may
include but are not limited to:
•
Failure of the Investigator to comply with the protocol, the Sponsor’s procedures, or GCP
guidelines.
•
Inadequate recruitment of subjects by the Investigator.
•
Discontinuation of further IP development
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.
Data Quality Assurance
In order to ensure the collection of accurate, consistent, complete, and reliable data during this
clinical study, Sponsor representatives or designees may conduct audits of participating clinical
study sites at appropriate intervals throughout the study. The results of these periodic clinical
study site audits may be subject to review by independent auditors at completion of the clinical
investigation.
The Clinical Study Report will undergo QC review by the Clinical Research Organization’s
Quality Assurance (QA) department.
All clinical data will undergo a quality control check prior to clinical database lock. Edit checks
are performed for appropriate databases as a validation routine to check for missing data,
data inconsistencies, data ranges etc. Corrections are made prior to database lock.
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

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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 CRFs. 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.
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.
Confidentiality and Privacy
The Investigator must assure that subjects’ anonymity will be strictly maintained and that their
identities are protected from unauthorized parties. Only an identification code and any other
unique identifier(s) as allowed by local law (such as date of birth) will be recorded on any form
or biological sample submitted to the Sponsor.

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The Investigator agrees that all information received from Arcutis Biotherapeutics, Inc.,
including but not limited to the Investigator’s Brochure, this protocol, CRF/eCRF, the IP, and
any other study information, remain the sole and exclusive property of Arcutis Biotherapeutics,
Inc. during the conduct of the study and thereafter. This information is not to be disclosed to any
third party (except employees or agents directly involved in the conduct of the study or as
required by law) without prior written consent from Arcutis Biotherapeutics, Inc. The
Investigator further agrees to take all reasonable precautions to prevent the disclosure by any
employee or agent of the study site to any third party or otherwise into the public domain.
Conflict of Interest
All study investigators will provide documentation of their financial interest or arrangements
with Arcutis Biotherapeutics, Inc., or proprietary interests in the investigational product under
study. This documentation must be provided prior to the Investigator’s participation in the study.
All investigators with reported conflict of interest will be required to have such conflicts
managed in a way that is appropriate to their participation in the design and conduct of this
study.
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).
Publication Policy
The Sponsor is supportive of publishing clinical trial findings. Any form of publication that is
derived from this study must be submitted to Arcutis Biotherapeutics, Inc. for review and
approval. The process of coordinating publication efforts is detailed in the Clinical Trial
Agreement.

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8.
REFERENCES
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.
Bissonnette R, Papp KA, Poulin Y, et al. Topical tofacitinib for atopic dermatitis: a phase IIa
randomized trial. Br J Dermatol. 2016a;175(5):902-911.
Diepgen T, Andersen K, Brandao F, et al. Hand eczema classification: a cross‐sectional,
multicentre study of the aetiology and morphology of hand eczema. British Journal of
Dermatology.2009;160:353-358. doi:10.1111/j.1365-2133.2008.08907.x.
Gooderham n T, Andersen K, Brandao F, et al. Hand eczema classification: a cross‐sectional,
multicentre study of the aetiology and morphology of hand eczema. British Journal of
Dermatology. 2009;160: 353-358. doi:10.1111/j.1365-2133.2008.08907.x.
Gooderham MJ, Forman SB, Bissonnette R, et al. Efficacy and safety of oral Janus kinase 1
inhibitor abrocitinib for patients with atopic dermatitis a phase 2 randomized clinical trial.
JAMA Dermatol. 2019; 155(12):1371-1379.
Guttman-Yassky E, Thaçi D, Pangan A, at al. Upadacitinib in adults with moderate to severe
atopic dermatitis: 16-week results from a randomized, placebo-controlled trial. Journal of
Allergy and Clinical Immunology. 2019a Nov 28, doi: 10.1016/j.jaci.2019.11.025 [article in
press].
Guttman-Yassky E, Silverberg JI, Nemoto O, et al. Baricitinib in adult patients with moderate-
to-severe atopic dermatitis: a phase 2 parallel, double-blinded, randomized placebo-controlled
multiple-dose study. J Am Acad Dermatol. 2019b Apr, 80(4):913-921,
doi:10.1016/j.jaad.2018.01.018.
Halling-Overgaard AS, Kezic S, Jakasa I, et al. Skin absorption through atopic dermatitis skin: a
systematic review. Br J Dermatol. 2017;177: 84-106.
Held E, Skoet R, Johansen J, et al. The hand eczema severity index (HECSI): a scoring system
for clinical assessment of hand eczema. A study of inter- and intraobserver reliability.
Br J Dermatol. 2005 Feb;152(2):302-7.
Investigator’s Brochure, Edition 1.0, Feb 2020.
Kim BS, Howell MD, Sun K, et al. Treatment of Atopic Dermatitis With Ruxolitinib Cream
(JAK1/JAK2Inhibitor) or Triamcinolone Cream, Journal of Allergy and Clinical Immunology.
Published online: October 17, 2019.
Naegeli A, Flood E, Tucker J, et al. The Worst Itch Numeric Rating Scale for patients with
moderate to severe plaque psoriasis or psoriatic arthritis. Int J Dermatol. 2015 Jun;54(6):715-22.

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Nakagawa H, Nemoto, Igarashi A, et al. Efficacy and safety of topical JTE-052, a Janus kinase
inhibitor, in Japanese adult patients with moderate-to severe atopic dermatitis: a phase II,
multicentre, randomized, vehicle-controlled clinical study. Br J Dermatology.
2018;178:424-432.
Ortiz PG, Hansen SH, Shah VP, et al. Impact of adult atopic dermatitis on topical drug
penetration: assessment by cutaneous microdialysis and tape stripping. Acta Derm Venereol.
2009;89:33-38.
O’Shea J, Gadina M. 2019. Selective Janus kinase inhibitors come of age. Nature Reviews
Rheumatology. 2019 Feb;15(2):74-75.
Ruzicka T, Lynde CW, Jemec GB, et al. Efficacy and safety of oral alitretinoin (9‐cis retinoic
acid) in patients with severe chronic hand eczema refractory to topical corticosteroids: results of
a randomized, double‐blind, placebo‐controlled, multicentre trial. British Journal of
Dermatology. 2008;158(4):808‐17.
Villarino AV, Kanno Y, O'Shea JJ. Mechanisms and consequences of Jak-STAT signaling in the
immune system. Nature Immunology. 2017;18:374-384.
Worm M, Bauer A, Elsner P, et al . Efficacy and safety of topical delgocitinib in patients with
chronic hand eczema: data from a randomized, double-blind, vehicle-controlled phase IIa study.
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APPENDICES
Appendix 1.
Quality of Life in Hand Eczema Questionnaire (QOLHEQ)

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© DermIS 2003-2018