Clinical trial NCT03260595
Conditions: Healthy Atopic Dermatitis
Sponsor: Pfizer
Start date: 2017-09-13; Completion date: 2017-11-27
Enrollment: 32 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a Phase 1 parallel-cohort study of crisaborole ointment 2% to evaluate the skin irritation potential in adult Japanese healthy subjects in Cohort 1, and to evaluate the safety, tolerability and PK in adult Japanese subjects with mild to moderate AD in Cohort 2.

Detailed description:

Arms: arm 1: None arm 2: None
Interventions: intervention 1: Crisaborole ointment 2% intervention 2: Vehicle
Intervention descriptions: intervention 1: Crisaborole ointment 2% intervention 2: Vehicle

Protocol documents:
Prot_000.pdf: 
Crisaborole (PF-06930164 [AN2728])
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A PHASE 1, SINGLE-CENTER, RANDOMIZED, VEHICLE-CONTROLLED,
PARALLEL-COHORT STUDY OF CRISABOROLE OINTMENT 2%
TO EVALUATE THE SKIN IRRITATION POTENTIAL
IN ADULT JAPANESE HEALTHY SUBJECTS,
AND TO EVALUATE THE SAFETY, TOLERABILITY AND
PHARMACOKINETICS IN ADULT JAPANESE SUBJECTS 
WITH MILD TO MODERATE ATOPIC DERMATITIS
Investigational Product Number:
PF-06930164
Investigational Product Name:
crisaborole
United States (US) Investigational New 
Drug (IND) Number:
Not applicable (N/A)
European Clinical Trials Database 
(EudraCT) Number:
N/A
Protocol Number:
C3291029
Phase:
1


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Document History
Document
Version Date
Summary of Changes and Rationale
Amendment 1
14 July 2017
1. Section 4.2. Exclusion Criteria, 
Cohort 2-2:
Clarify the strong potency topical 
corticosteroids.
2. Section 4.2. Exclusion Criteria, 
Cohort 2-8:
Remove “cryosurgery or”.
3. Section 7.1.1. Laboratory Tests, 
Table 3:
Remove “Total CO2 (bicarbonate)”.
4. Appendix 2. Diagnostic Criteria for 
Atopic Dermatitis (Cohort 2):
Incorporate administrative edits.
Original Protocol
23 June 2017
N/A


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TABLE OF CONTENTS
LIST OF TABLES.....................................................................................................................7
APPENDICES ...........................................................................................................................7
SCHEDULE OF ACTIVITIES..................................................................................................8
1. INTRODUCTION ...............................................................................................................12
1.1. Mechanism of Action/Indication.............................................................................12
1.2. Background .............................................................................................................12
1.3. Drug Development ..................................................................................................13
1.3.1. Nonclinical Safety Studies..........................................................................13
1.3.2. Pharmacokinetics (PK)...............................................................................14
1.3.3. Cutaneous Sensitization, Irritancy Potential and Tolerability....................15
1.3.3.1. Local Tolerability in Sensitive Skin Areas ...............................15
1.3.3.2. Sensitizing and Cumulative Irritation Potential ........................15
1.3.4. Clinical Experience.....................................................................................16
1.4. Rationale..................................................................................................................18
1.4.1. Study Rationale...........................................................................................18
1.4.2. Dose Rationale............................................................................................19
2. STUDY OBJECTIVES AND ENDPOINTS.......................................................................19
3. STUDY DESIGN.................................................................................................................20
3.1. Study Overview.......................................................................................................20
3.2. Number of Sites.......................................................................................................21
3.3. Duration of Study....................................................................................................21
4. SUBJECT ELIGIBILITY CRITERIA.................................................................................22
4.1. Inclusion Criteria.....................................................................................................22
4.2. Exclusion Criteria....................................................................................................24
4.3. Randomization Criteria ...........................................................................................28
4.4. Lifestyle Requirements ...........................................................................................28
4.4.1. Alcohol .......................................................................................................28
4.4.2. Activity .......................................................................................................28
4.4.3. Contraception (Cohort 2)............................................................................28
4.5. Sponsor’s Qualified Medical Personnel..................................................................29
5. STUDY TREATMENTS.....................................................................................................30


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5.1. Allocation to Treatment ..........................................................................................30
5.2. Blinding of Site Personnel.......................................................................................31
5.3. Blinding of the Sponsor...........................................................................................32
5.4. Breaking the Blind ..................................................................................................32
5.5. Subject Compliance.................................................................................................32
5.6. Investigational Product Supplies.............................................................................32
5.6.1. Dosage Form and Packaging ......................................................................32
5.6.2. Preparation and Dispensing........................................................................32
5.7. Administration.........................................................................................................33
5.7.1. Administration for Cohort 1 .......................................................................33
5.7.2. Administration for Cohort 2 .......................................................................33
5.7.2.1. Study Treatment Regimen.........................................................33
5.7.2.2. Calculation of Subject’s Total BSA..........................................33
5.7.2.3. Calculation of Treatable %BSA................................................34
5.7.2.4. Calculation of Per Application Dose.........................................34
5.7.2.5. Dispensing of Investigational Product ......................................34
5.7.2.6. Application of Investigational Product .....................................34
5.8. Investigational Product Storage ..............................................................................35
5.9. Investigational Product Accountability...................................................................36
5.9.1. Destruction of Investigational Product Supplies ........................................36
5.10. Concomitant Treatment(s).....................................................................................36
5.10.1. Washout Periods for Medications/Therapies Prior to Day 1 (Cohort 
2) ......................................................................................................................37
5.10.2. Medications/Therapies Prohibited During the Study (Cohort 2)..............38
5.10.3. Medications/Therapies Allowed During the Study (Cohort 2).................39
6. STUDY PROCEDURES .....................................................................................................39
6.1. Screening (Days –28 to –2).....................................................................................39
6.1.1. Cohort 1 ......................................................................................................40
6.1.2. Cohort 2 ......................................................................................................40
6.2. Study Period ............................................................................................................42
6.2.1. Cohort 1 ......................................................................................................42
6.2.1.1. Day –1 .......................................................................................42


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6.2.1.2. Day 1 .........................................................................................42
6.2.1.3. Day 2 .........................................................................................43
6.2.1.4. Day 3 .........................................................................................43
6.2.1.5. Day 4 .........................................................................................43
6.2.2. Cohort 2 ......................................................................................................44
6.2.2.1. Day –1 .......................................................................................44
6.2.2.2. Day 1 .........................................................................................45
6.2.2.3. Day 2 .........................................................................................45
6.2.2.4. Day 3 to 6 ..................................................................................46
6.2.2.5. Day 7 .........................................................................................46
6.2.2.6. Day 8 .........................................................................................46
6.2.2.7. Day 9 .........................................................................................47
6.3. Follow-up ................................................................................................................48
6.3.1. Follow-up Contact ......................................................................................48
6.4. Subject Withdrawal/Early Termination ..................................................................48
7. ASSESSMENTS..................................................................................................................50
7.1. Safety.......................................................................................................................50
7.1.1. Laboratory Tests .........................................................................................50
7.1.2. Pregnancy Testing (Cohort 2).....................................................................52
7.1.3. Physical Examinations................................................................................52
7.1.4. Blood Pressure and Pulse Rate ...................................................................52
7.1.5. Electrocardiogram.......................................................................................52
7.1.6. Skin Irritation Assessment (Cohort 1)........................................................53
7.2. Pharmacokinetics ....................................................................................................54
7.2.1. Plasma for Analysis of crisaborole and main metabolites (Cohort 2)........54
...........................................................................54
....................................................................................55
7.4. Blood Volume .........................................................................................................55
8. ADVERSE EVENT REPORTING......................................................................................56
8.1. Requirements...........................................................................................................56
8.1.1. Additional Details on Recording Adverse Events on the CRF...................57
8.1.2. Eliciting Adverse Event Information..........................................................57
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8.1.3. Withdrawal From the Study Due to Adverse Events (see also the 
Subject Withdrawal section)............................................................................57
8.1.4. Time Period for Collecting AE/SAE Information......................................57
8.1.4.1. Reporting SAEs to Pfizer Safety...............................................58
8.1.4.2. Recording Non-serious AEs and SAEs on the CRF .................58
8.1.5. Causality Assessment .................................................................................58
8.1.6. Sponsor’s Reporting Requirements to Regulatory Authorities ..................58
8.2. Definitions...............................................................................................................59
8.2.1. Adverse Events...........................................................................................59
8.2.2. Abnormal Test Findings .............................................................................59
8.2.3. Serious Adverse Events ..............................................................................60
8.2.4. Hospitalization............................................................................................60
8.3. Severity Assessment................................................................................................62
8.4. Special Situations ....................................................................................................62
8.4.1. Protocol-Specified Serious Adverse Events...............................................62
8.4.2. Potential Cases of Drug-Induced Liver Injury............................................62
8.4.3. Exposure to the Investigational Product During Pregnancy or 
Breastfeeding, and Occupational Exposure.....................................................64
8.4.3.1. Exposure During Pregnancy......................................................64
8.4.3.2. Exposure During Breastfeeding ................................................65
8.4.3.3. Occupational Exposure .............................................................65
8.4.4. Medication Errors .......................................................................................66
8.4.4.1. Medication Errors......................................................................66
9. DATA ANALYSIS/STATISTICAL METHODS...............................................................67
9.1. Sample Size Determination.....................................................................................67
9.2. Efficacy Analysis ....................................................................................................67
9.3. Pharmacokinetic Analysis (Cohort 2) .....................................................................67
...................................................................................68
9.5. Safety Analysis........................................................................................................68
9.5.1. Electrocardiogram Analysis (Cohort 2)......................................................69
9.5.2. Skin Irritation Analysis (Cohort 1).............................................................69
9.6. Interim Analysis ......................................................................................................70
9.7. Data Monitoring Committee ...................................................................................70
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10. QUALITY CONTROL AND QUALITY ASSURANCE.................................................70
11. DATA HANDLING AND RECORD KEEPING .............................................................71
11.1. Case Report Forms/Data Collection Tools/Electronic Data Record.....................71
11.2. Record Retention...................................................................................................71
12. ETHICS..............................................................................................................................72
12.1. Institutional Review Board/Ethics Committee......................................................72
12.2. Ethical Conduct of the Study ................................................................................72
12.3. Subject Information and Consent..........................................................................72
12.4. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH 
GCP ...........................................................................................................................73
13. DEFINITION OF END OF TRIAL...................................................................................73
14. SPONSOR DISCONTINUATION CRITERIA ................................................................73
15. PUBLICATION OF STUDY RESULTS..........................................................................73
15.1. Communication of Results by Pfizer ....................................................................73
15.2. Publications by Investigators ................................................................................74
16. REFERENCES ..................................................................................................................76
LIST OF TABLES
Table 1.
Key Pharmacokinetic Parameters in AD Subjects (2–17 years) 
(AN2728-AD-102) ...............................................................................................15
Table 2.
Randomization sequence for Cohort 1 .................................................................31
Table 3.
Safety Laboratory Tests........................................................................................51
Table 4.
Skin Irritation Assessment Grades and Scores .....................................................53
Table 5.
Safety Criteria of Skin irritation index .................................................................69
Table 6.
Hanifin and Rajka’s Diagnostic Criteria for Atopic Dermatitis...........................81
Table 7.
Investigator’s Static Global Assessment ..............................................................82
APPENDICES
Appendix 1. Abbreviations......................................................................................................78
Appendix 2. Diagnostic Criteria for Atopic Dermatitis (Cohort 2).........................................81
Appendix 3. Investigator’s Static Global Assessment (Cohort 2)...........................................82


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SCHEDULE OF ACTIVITIES
The schedule of activities table provides an overview of the protocol visits and procedures.  Refer to the STUDY PROCEDURES
and ASSESSMENTS sections of the protocol for detailed information on each procedure and assessment required for compliance with 
the protocol. 
The investigator may schedule visits (unplanned visits) in addition to those listed in the schedule of activities table, in order to conduct 
evaluations or assessments required to protect the well-being of the subject.
Cohort 1
Daya
–28 to –2
–1
1
2
3
4/ET
29 (+7 days)
Screening
FU Contactb
(EOS)
Informed Consent
X
CRU confinement
Xc



Xd
Inclusion/Exclusion Criteria
X
X
X
Medical History
X
X
Physical Examination
X
X
X
Safety laboratory
X
Xe
Demographics
X
Height and Weight
X
Vital Signsf
X
ECGg
X
HIV, HepBsAg, HepBcAb, HCVAb and 
syphilis testing
X
Urine drug testing
X
Xh
Visual Assessment of application field
X
X
Treatments/patch application
Xi
i
i
Patch removal
X
Skin irritation assessment
Xj
Xj
Review and record prior and concomitant 
medications
Xk
X
X
X
X
X
Assess for AEs and SAEsl
X
X
X
X
X
X
X
Abbreviations: = ongoing/continuous event; CRU=clinical research unit; ECG=electrocardiogram; EOS=End of Study; ET=Early Termination; FU= Follow-up; HIV=human 
immunodeficiency virus; HepBsAg=hepatitis B surface antigen; HepBcAb=hepatitis B core antibody; HCVAb=hepatitis C antibody; AE=adverse event; SAE=serious adverse 
event; 


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a.
Day relative to start of study treatment (Day 1).
b.
Follow-up contact will be completed on Day 29 (28+7 calendar days after the application of the investigational product patches on Day 1) to capture any potential adverse 
events.
c.
Subjects will be admitted to the Clinical Research Unit (CRU) on Day –1.
d.
Subjects will discharge from CRU on Day 4 after completion of all assessment on Day 4.
e.
Day –1 clinical labs do not have to be repeated if clinical labs are completed within 7 days prior to Day –1.
f.
Vital signs (pulse rate and blood pressure) taken supine position after subject has been calmly lying for 5 minutes.
g.
Single ECG will be collected.
h.
Day –1 urine drug testing does not have to be repeated if urine drug testing is completed within 7 days prior to Day –1.
i.
Day 1 patches remains in place through Day 3.
j.
Skin irritation assessment of the patch sites will be conducted on Day 3 (approximately 30 minutes after removal of the patches) and Day 4 (approximately 24 hours after 
removal of the patches).
k.
All medications and non-medication therapies used within 28 days prior to the planned first dose.
l.
If AEs/SAEs occur at a patch site, the patch site location must be recorded.


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Cohort 2
Daya
–28 to –2
–1
1
2
3
4
5
6
7
8/ET
9
36 (+7 days)
Screening
FU Contactb
(EOS)
Informed Consent
X
CRU confinement
Xc








Xd
Inclusion/Exclusion Criteria
X
X
X
Medical History
X
X
Confirmation of Diagnosis 
of AD
X
Physical Examination
X
X
Xe
X
Physical Examinationf
(skin examination)
X
X
X
Assess ISGA
X
X
Record treatable AD areas
X
Calculate and Record 
Treatable %BSAg
X
X
Safety laboratory
X
X
X
Demographics
X
Height and Weight
X
Xh
Vital Signsi
X
X
X
ECG
Xj
Xj
Xj
Urine Pregnancy test
X
X
Contraception check
X
X
X
X
FSHk
X
HIV, HepBsAg, HepBcAb, 
HCVAb and syphilis testing
X
Urine drug testing
X
Xl
AM Dosing: Weigh dose 
and apply
X
X
X
X
X
X
X
X
PM Dosing: Weigh dose 
and apply
X
X
X
X
X
X
Obtain PK samples
Xm
Xn
Xn
Xm
Xn


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Daya
–28 to –2
–1
1
2
3
4
5
6
7
8/ET
9
36 (+7 days)
Screening
FU Contactb
(EOS)
Review and record prior 
and concomitant 
medications
Xo
X
X
X
X
X
X
X
X
X
X
Assess for AEs and SAEs
X
X
X
X
X
X
X
X
X
X
X
X
X
Abbreviations: = ongoing/continuous event; AD=atopic dermatitis; CRU=clinical research unit; ISGA=investigator’s static global assessment; %BSA=percent of body surface 
area; ECG=electrocardiogram; EOS=End of Study; ET=Early Termination; FSH=follicle-stimulating hormone; FU= Follow-up; HIV=human immunodeficiency virus;
HepBsAg=hepatitis B surface antigen; HepBcAb=hepatitis B core antibody; HCVAb=hepatitis C antibody; PK=pharmacokinetic; AE=adverse event; SAE=serious adverse event;
a.
Day relative to start of study treatment (Day 1).
b.
Follow-up contact will be completed on Day 36 (28 +7 calendar days after the last application of the investigational product) to capture any potential adverse events and to 
confirm appropriate contraception usage.
c.
Subjects will be admitted to the Clinical Research Unit (CRU) on Day –1.
d.
Subjects will discharge from CRU on Day 9 after completion of all assessment on Day 9.
e.
A physical examination will be conducted at ET.
f.
A skin examination will be conducted by dermatologist.
g.
Treatable percent body surface area (%BSA) is defined as the percent of a subject’s total body surface area that is AD-involved, excluding the scalp and venous access areas.
h.
Only weight will be measured on Day 1.
i.
Vital signs (pulse rate and blood pressure) taken supine position after subject has been calmly lying face up for 5 minutes.
j.
ECG will be collected in single.
k.
Any female subject who has been amenorrheic for at least 12 consecutive months.
l.
Day –1 urine drug testing does not have to be repeated if urine drug testing is completed within 7 days prior to Day –1.
m.
Obtain PK samples at predose, 3 hours and 12 hours post Day 1 and Day 8 AM dose.
n.
Obtain PK samples prior to AM dose on Day 2 and Day 7 (at 24 hours post Day 1 and Day 6 AM dose). Obtain PK samples on Day 9 at 24 hours post Day 8 AM dose.  
o.
All medications and non-medication therapies used within 28 days prior to Screening.
p.
If not collected on the designated collection day, collect at the next available time point when 
 in conjunction with a subject visit.
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1. INTRODUCTION
1.1. Mechanism of Action/Indication
Crisaborole, also referred to as PF-06930164 and AN2728, is a low molecular weight 
benzoxaborole anti-inflammatory phosphodiesterase-4 (PDE-4) inhibitor that penetrates into 
the skin to the sites of inflammation.  PDE-4 inhibition results in increased intracellular 
cyclic adenosine monophosphate (cAMP) levels.  While the specific mechanism(s) by
which crisaborole exerts its therapeutic action is not well defined, crisaborole reduces the
production of several inflammatory cytokines implicated in the pathophysiology of atopic
dermatitis (AD).
Crisaborole is currently being developed for the treatment of mild to moderate AD in patients 
2 years of age and older. On 14 Dec, 2016, crisaborole ointment 2% received its first 
approval from United States (US) Food and Drug Administration (FDA) for the topical 
treatment of mild to moderate AD in patients 2 years of age and older.
1.2. Background
AD, also referred to as atopic eczema or in layperson terms as eczema, is a chronic and 
relapsing disease affecting an increasing number of patients.  Although AD affects patients of 
all ages, it is one of the most common, chronic, relapsing childhood dermatoses, impacting 
15%-30% of all children in the US with 85% of affected individuals showing signs of the 
disease before 5 years of age.1,2  Over the past 50 years, AD has become more prevalent, 
especially in industrialized, temperate countries such as the US and Japan.3,4,5
AD is an inflammatory, highly pruritic, chronic eczematous condition that usually occurs in 
people who have a personal or family history of other atopic conditions such as asthma or 
allergic rhinitis.1, 4  The majority of patients (up to 90%) with AD present with mild to 
moderate disease.6 Manifestation of the disease includes intense pruritus, erythematous 
papules, excoriation, exudation, and lichenification.7 Continuous scratching during 
exacerbations can lead to lichenification, excoriations, and serious skin infections. AD is 
often associated with other conditions including asthma, allergic rhinitis, and food allergy. 
AD has been cited as a major risk factor for the development of asthma in a number of 
longitudinal studies, and children with AD are at increased odds in developing asthma 
compared to children without AD.8,9 The burden of the clinical symptoms of AD coupled 
with the stigma associated with highly visible skin lesions correlates with significant 
morbidity and extensive impairments on health related quality of life measures (HRQoL) for 
patients, especially in children, and caregivers.1,10,11,12  Psychosocial problems, depression, 
and anxiety are associated with AD in both adults and children.13
AD has a significant impact on day to day functioning, as evidenced by its impact on the 
overall well-being of the patient and their family on multiple levels; medical management 
and treatment, HRQoL, and psycho-social implications. AD may also be a source of 
significant economic burden14 as this relapsing disease is often misdiagnosed, misunderstood, 
and ineffectively treated.4  AD is a condition associated with significant morbidity. 
Currently, there is no cure for AD. AD is a chronic disease with treatment focused on the 


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management of flares and maintenance of remissions. Due to the chronic, relapsing nature of 
the disease, treatment may be needed for many years. 
In summary, AD is a disease with multiple comorbidities and significant impact on the 
health, day to day functioning, and HRQoL of AD patients, their caregivers, and family 
members.
1.3. Drug Development
Crisaborole is a novel, non-steroidal, topical anti-inflammatory PDE-4 inhibitor that will 
serve an unmet need in the treatment of AD.  Supporting evidence of the safety and efficacy 
of this product in patients 2 years and older represent a major advancement in the treatment 
of AD given the challenges of managing this common, chronic dermatologic condition and 
the treatment-limiting effects of currently available therapies.  All primary and secondary 
efficacy endpoints were statistically significant in favor of crisaborole ointment 2% BID 
versus vehicle BID in the two Phase 3 registration studies in the US.  Across the 
development program, crisaborole demonstrated an acceptable safety profile, with no 
crisaborole treatment-related serious adverse events (SAE) (except 1 case of drug eruption in 
a Phase 2 study which was classified as possibly related) and with the majority of adverse 
events (AE) being mild and deemed unlikely or not related to investigational product.  Safety 
has not yet been evaluated in patients younger than 2 years of age.
The Investigator’s Brochure (IB) contains summaries of nonclinical and clinical studies 
performed with crisaborole.  A brief summary as background to this study protocol is 
presented here.
1.3.1. Nonclinical Safety Studies
Crisaborole demonstrates inhibitory capacity against human leukocyte cytokine release with 
half maximal effective concentration (EC50) values ranging from high nanomolar to low 
micromolar concentrations.  Crisaborole also inhibits the release of chemokines that are 
important inflammatory mediators.  The primary mechanism of the anti-inflammatory effect 
of crisaborole is through inhibition of PDE-4, which causes elevation of cAMP in leukocytes 
and subsequent protein kinase a (PKA)-mediated phosphorylation of transcription factors that 
are important for cytokine-, chemokine-, or prostaglandin-forming enzyme synthesis and 
release from cells.  Crisaborole proved efficacious against an inflammatory challenge in vivo 
in a mouse phorbol 12-myristate 13-acetate (PMA)-induced ear edema model.  AN7602 and 
AN8323, main metabolites of crisaborole, lack anti-inflammatory activities against PDE-4
and a panel of cytokines.
Crisaborole was generally well tolerated in all species studied in toxicology studies,
including a single-dose intravenous (IV) study in dogs, a 3-month study in mice using dermal 
application of ointment, up to 6-month oral studies in rats, and up to 9-month dermal studies 
in minipigs. Toxicokinetic data were collected as part of various toxicology studies.
Crisaborole was not identified as a reproductive toxicant or a teratogenic agent. Based on 
exposure in a maximal use systemic exposure (MUSE) study (Study AN2728-AD-102) 
conducted in pediatric subjects (2–17 years old) with mild to moderate AD, calculated safety 


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margins for crisaborole are 2× to 13× for embryo-fetal development and reproductive 
toxicity, 215× for acute (eg, cardiovascular) effects, and 11× for chronic effects. Refer to the 
IB for further information on the nonclinical experience with crisaborole ointment 2%.
1.3.2. Pharmacokinetics (PK)
The efficacy of crisaborole for the treatment of AD is not dependent on systemic exposure. 
The development program evaluated systemic exposure to crisaborole and its main
metabolites relative to establishing the safety of topically applied crisaborole. Clinical 
studies in healthy adult volunteers, in pediatric and adolescent subjects with AD, and in 
adults with psoriasis demonstrated similar PK profiles and systemic exposure, irrespective of 
underlying disease or age, and establish that following topical application, crisaborole 
penetrated through the stratum corneum, epidermis, and dermis of human skin, as evidenced 
by the presence of crisaborole and its main metabolites in plasma. Upon reaching the 
systemic circulation, biotransformation of crisaborole is rapid and extensive and primarily 
consists of oxidative deboronation/hydrolysis to produce AN7602 by CYP3A4 and 
CYP1A1/2, followed by subsequent downstream oxidation of this metabolite to form 
AN8323, without notable species-related qualitative differences. These two main
metabolites of crisaborole observed in plasma following topical application to several 
species, including humans, were found to be inactive against PDE-4. Further, as a result of 
rapid biotransformation, systemic exposure of crisaborole is limited following topical 
application of crisaborole.
In the clinical PK study conducted under maximal use conditions (maximal use systemic 
exposure [MUSE] study) in children and adolescents aged 2-17 years with extensive AD 
(mean treatable percent body surface area [Treatable %BSA] 48.7%; range 27%-92%), 
absorption across the skin was rapid, with a median of time to reach maximum observed 
concentration (Tmax) of 3.0 hours on both Day 1 and Day 8 (Study AN2728-AD-102).
Steady state was achieved within the first 8 days of dosing, with a mean crisaborole of 
maximum observed concentration (Cmax) of 127 ng/mL. Minimal plasma accumulation of 
crisaborole and AN7602 was observed at steady state whereas AN8323 displayed an 
approximately 3-4-fold accumulation based on Cmax and area under the concentration-time 
curve from time zero to the 12 hours (AUC12).


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Table 1.
Key Pharmacokinetic Parameters in AD Subjects (2–17 years) 
(AN2728-AD-102)
Analyte
Study Day
Mean Parameter (SD)
(N = 23)
Cmax
(ng/mL)
Tmax
(median [range]) (h)
AUC12
(ng∙h/mL)
Crisaborole
Day 1
111
(113)
3.00
(3.00–12.0)
759a
(730)
Day 8
127b
(196)
3.00b
(3.00–24.0)
949a
(1,240)
AN7602
Day 1
37.8
(35.0)
3.00
(3.00–12.0)
247a
(224)
Day 8
40.8b
(48.6)
3.00b
(0.00–12.0)
290a
(313)
AN8323
Day 1
2,270
(2,640)
12.00
(3.00–24.0)
16,800a
(16,900)
Day 8
6150b
(4790)
3.00b
(0.00–24.0)
63,400a
(49,000)
Abbreviations: AD=atopic dermatitis; AUC12 = area under the plasma concentration-time curve from 0–12 hours after 
dosing; Cmax = maximum observed plasma concentration; SD = standard deviation; Tmax = time to reach maximum 
observed plasma concentration.
a: N = 32;   b: N = 33.
1.3.3. Cutaneous Sensitization, Irritancy Potential and Tolerability
1.3.3.1. Local Tolerability in Sensitive Skin Areas
In a study of healthy subjects (16 men and 16 women) who applied crisaborole ointment 
2% or vehicle for 21 days to sensitive area application sites (including extensor areas,
intertriginous areas, genitals, and face/hairline), 99% of assessments of local tolerability 
were graded as 0 (none), and only 0.1% of assessments graded higher than 1 (mild), with an 
overall maximum grade of 2 (moderate) (Study AN2728-PSR-107). There were no marked 
differences in burning/stinging, erythema, or pruritus at any of the application sites over the 
course of the study between subjects who received crisaborole ointment 2% or vehicle.
Overall, crisaborole ointment 2% was well tolerated over 21 days of dosing in sensitive skin
areas of healthy subjects.
1.3.3.2. Sensitizing and Cumulative Irritation Potential
In a repeat-insult patch test (RIPT) and cumulative irritation study in healthy subjects (Study 
AN2728-RIPT-101), the potential for inducing cutaneous sensitization was assessed in 
238 subjects randomized in Cohort 1.  None of the subjects demonstrated cutaneous evidence 
of sensitization potential (a reaction of at least Grade 4 [definite edema] or a pattern 
suggestive of contact sensitization in the opinion of the Investigator) to the investigational 
products, crisaborole ointment 2% or vehicle.  The potential for causing cutaneous irritation 
was evaluated among 40 subjects randomized in Cohort 2 with daily patch applications for 
21 consecutive days.  There were no statistically significant differences in irritation between 
the crisaborole ointment 2% and vehicle.  Crisaborole ointment 2% and vehicle showed no 
evidence of sensitization and only very minimal irritation (minimal erythema, barely 
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1.3.4. Clinical Experience
Seven (7) clinical trials of topical formulations of crisaborole have been completed to date in 
subjects with AD.  Key study information is summarized below.

In a 4-week, multicenter, MUSE study in 34 children and adolescents aged 2-17 years 
with mild-to-moderate AD (Study AN2728-AD-102) who applied crisaborole 
ointment 2% twice daily (BID), subjects had overall blood levels of crisaborole that 
were low and similar to those previously observed in adults psoriasis patients (Study 
AN2728-PSR-106) after adjusting for %BSA treated. 

A total of 63 AEs were reported in 23/34 subjects (67.6%): 40 were mild, 20 were 
moderate, and 3 were severe. No treatment-emergent adverse event (TEAE) was 
considered serious, and no deaths occurred.  The most common TEAEs were 
application site reactions that were generally mild or moderate in severity and 
resolved spontaneously without sequelae.  The TEAEs reported for more than 
1 subject were application site pain (12/34, 35.3%), worsening of atopic dermatitis 
(7/34, 20.6%), upper respiratory tract infection (3/34, 8.8%), and application site 
paresthesia (2/34, 5.9%).  About half (36/63, 57.1%) of the TEAEs were considered 
related to study drug, two of which (application site pain) were severe and occurred in 
a 2-year-old female subject who experienced intermittent application site burning on 
Study Days 6, 7, 10, 11, and 12 (nonserious, mild to severe, possibly to definitely 
related).  On Study Day 13, this subject was withdrawn from the study at her father’s 
request.  The events resolved following the final application of study drug on Study 
Day 12.  Overall, no clinically important safety signals were observed in a review of 
TEAEs, topical TEAEs (application site reactions), and laboratory test, vital sign, and 
physical examination results.

In a 4-week, open-label, safety, tolerability and PK trial in adolescents with 
mild-to-moderate AD involving 10%-35% BSA, crisaborole ointment 2% BID 
improved disease severity over the 28-day treatment period (Study 
AN2728-AD-203). A total of 19 TEAEs were reported in 43.5% (10/23) subjects.
All TEAEs were either mild (57.9% [11/19]) or moderate (42.1% [8/19]).  The 
majority of TEAEs (68.4% [13/19]) were unrelated or unlikely to be related to study 
drug.  All drug-related AEs were application site reactions. The most commonly 
reported TEAEs, application site pain and nasopharyngitis, were each reported by 
3 subjects.  No other TEAE was reported by more than 1 subject.  No SAEs or deaths 
were reported.  No clear correlation was observed between plasma exposure levels 
and the incidence of AEs.  Overall, no safety signals were observed in a review of 
local tolerability, AEs, TEAEs, clinical laboratory results, and vital sign results.


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
In a 6-week bilateral comparison trial of subjects with mild-to-moderate AD (Study 
AN2898-AD-202), 68% of AD lesions treated with crisaborole ointment 2% BID 
showed greater improvement in AD severity index (ADSI) than vehicle-treated 
lesions (20%) at 4 weeks (primary endpoint).  These response rates were similar at 
Day 14 and Day 42 (end of treatment). In a 4-week bilateral comparison trial of 
86 adolescent subjects with mild-to-moderate AD (Study AN2728-AD-204),
crisaborole ointment 2% BID showed greater improvement than the lower 
concentration of crisaborole ointment 0.5% applied BID for 29 days, and was more 
efficacious than either concentration applied once daily (QD). 

In two Phase 3, multicenter, randomized, double-blind, vehicle controlled studies in 
subjects ≥ 2 years of age and older with AD, crisaborole ointment 2% outperformed 
the vehicle in the primary efficacy analysis (success in investigator’s static global 
assessment [ISGA] defined as an ISGA score of clear or almost clear with at least a 
2-grade improvement from Baseline) and the difference between the treatment groups 
was statistically significant (Study AN2728-AD-301 and Study AN2728-AD-302).

An additional Phase 3, multicenter, open-label, long-term extension study of 
crisaborole ointment 2% for the treatment of mild to moderate AD in adults and 
children as young as 2 years of age evaluated the long-term safety of topical 
crisaborole (Study AN2728-AD-303). Crisaborole showed an acceptable safety 
profile for long-term topical treatment of mild to moderate AD in adults and children 
as young as 2 years of age.
Crisaborole has been well tolerated across completed clinical studies.  No clinically 
important safety signals have been identified, including during a Phase 3 multicenter, 
open-label, long-term extension study of crisaborole ointment 2% for mild to moderate 
AD in adults and children as young as 2 years of age.  Most AEs have been mild, and most 
considered unrelated or unlikely to be related to investigational product.  The most common 
drug-related AEs have been application site reactions. 
In a thorough QT (TQT) study (Study AN2728TQT108) in which healthy subjects were 
treated with crisaborole ointment 2% at a therapeutic dose (15 g, representing 30% BSA 
treatment) or a supratherapeutic dose (45 g, representing 60% BSA treatment), mean Cmax
values of 36.9 ng/mL and 87.4 ng/mL were observed in therapeutic and supratherapeutic 
dose groups, respectively, at Day 9. At both therapeutic and supratherapeutic doses had no 
effect on cardiac repolarization based on results from the primary assessment and the 
pharmacokinetic-pharmacodynamic analysis.
Additional information for this compound may be found in the single reference safety 
document (SRSD), which for this study is current version of the crisaborole IB.


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1.4. Rationale 
1.4.1. Study Rationale 
This Phase 1 study is planned to evaluate the skin irritation potential of crisaborole ointment 
2% and vehicle in healthy adult male Japanese subjects in Cohort 1, and safety and PK of 
crisaborole ointment 2% in adult Japanese subjects with AD in Cohort 2. 
There have been reports about racial difference in skin pathophysiology,15,16 and conflicting 
literatures about the racial difference in irritant response with topical therapy.17,18,19  Even 
though there was no evidence of cutaneous sensitization in the RIPT study, and the cutaneous
irritation was very minimal in Western subjects (Section 1.3.3), it is considered useful to 
evaluate the irritant response in Japanese subjects. All subjects in Cohort 1 will be treated 
topically under occlusive patch conditions with 2 study products (crisaborole ointment 
2% and vehicle) on the infrascapular area of the back for 48-hour duration before irritant 
response assessment. The assessment will be based on the Japan standard evaluation 
methods.20,21,23 The cohort will be conducted as an observer-blinded design to minimize
evaluation bias for skin irritation.
Cohort 2 will be conducted in adult Japanese subjects with mild to moderate AD with
Treatable %BSA >25%. This cohort will investigate the safety and PK of crisaborole 
ointment 2% in Japanese subjects with AD under MUSE condition. The Cohort 2 can 
provide useful information to evaluate the safety and possible maximum systemic exposure
of crisaborole ointment 2% in Japanese subjects under the maximal use condition to enable
further development in Japan. The cohort will be conducted as a double-blind design to 
minimize evaluation bias for safety. Considering the well acceptable safety results in 
previous MUSE study, the two Phase 3 and one long-term safety studies, and the securement
of safety by confinement, the Cohort 2 can be conducted in parallel with Cohort 1 study.
 
 
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1.4.2. Dose Rationale
Crisaborole ointment 2% BID was selected as the recommended clinical dose based on the 
superior efficacy to vehicle, lower concentration of 0.5% applied BID, 0.5% and 
2% concentration applied QD (Study AN2898-AD-202 and Study AN2728-AD-204). The 
efficacy and safety of this dose has also been confirmed in two Phase 3 studies and one 
long-term safety study in AD patients 2 years of age and older (Studies AN2728-AD-301, 
302 and 303). Crisaborole ointment 2% BID was approved by the FDA as the clinical dose 
in US.24 Considering the current available highest dose strength is crisaborole ointment 
2%, the efficacy and well tolerated safety profile of this dose strength obtained in Western 
subjects, crisaborole ointment 2% will be used in the Cohort 1 of this study to assess its skin 
irritant potential in Japanese healthy subjects. Crisaborole ointment 2% BID will be used in 
Cohort 2 to investigate the safety and PK of crisaborole in Japanese AD subjects. 
2. STUDY OBJECTIVES AND ENDPOINTS
Primary Objective for Cohort 1
Primary Endpoint for Cohort 1

To investigate the skin irritation potential of a 
single topical dose of crisaborole ointment 2%
and vehicle in adult Japanese healthy subjects

Skin irritation indexa
Secondary Objective for Cohort 1
Secondary Endpoint for Cohort 1

To investigate the safety and tolerability of a 
single topical dose of crisaborole ointment 2%
and vehicle in adult Japanese healthy subjects

Assessment of adverse events (AEs)
Primary Objective for Cohort 2
Primary Endpoint for Cohort 2

To investigate the safety and tolerability of 
multiple topical doses of crisaborole ointment 
2% BID in adult Japanese subjects with mild to 
moderate AD

Assessment of AEs, clinical laboratory tests, 
vital signs, and 12 lead electrocardiogram 
(ECG)
Secondary Objective for Cohort 2
Secondary Endpoint for Cohort 2

To characterize plasma PK of crisaborole and its 
identified main oxidative metabolites (AN7602 
and AN8323) following multiple topical doses 
of crisaborole ointment 2% BID in adult 
Japanese subjects with mild to moderate AD

PK parameters: Cmax, Tmax, AUClast, AUC24, 
AUCτ on Day 1 and Day 8, and Rac (Cmax) and 
Rac (AUCτ) on Day 8


Abbreviations: AD=atopic dermatitis; AE=adverse event; Cmax=maximum observed plasma concentration; 
AUCτ= area under the plasma concentration-time profile from time zero to time tau (τ), the dosing interval,
where τ = 12 hours for BID dosing; BID=twice daily; AUClast= area under the plasma concentration-time 
curve from zero time until the last measurable concentration (Clast); AUC24= area under the plasma
concentration-time curve from time zero to the 24 hours postdose; Tmax=time to reach maximum observed 
plasma concentration; ECG=electrocardiogram; PK=pharmacokinetics.
a: Skin irritation index is calculated as the sum of the individual maximum irritation scores divided by the 
number of subjects and multiplied by 100, which ranges from 0 to 400.
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3. STUDY DESIGN
3.1. Study Overview
This is a Phase 1, single-center, randomized, vehicle-controlled, parallel-cohort study of 
crisaborole ointment 2% to evaluate the skin irritation potential in adult Japanese healthy 
subjects in Cohort 1, and to evaluate the safety, tolerability and PK in adult Japanese subjects 
with mild to moderate AD in Cohort 2.  Both cohorts will be run in parallel and completion
of Cohort 1 is not required to make a decision to proceed with Cohort 2. 
Cohort
N
Investigational products
Cohort 1
Skin irritation cohort in 
healthy subjects
20
Crisaborole ointment 2% and vehicle
Cohort 2
Safety, tolerability and PK 
cohort in subjects with mild 
to moderate AD
12
Crisaborole ointment 2% (n=10)
Vehicle (n=2)
Cohort 1
This is a randomized, observer and subject-blind, vehicle-controlled cohort, of the
investigational products (crisaborole ointment 2% and vehicle) under occlusive patch 
conditions to evaluate the skin irritation potential and safety in Japanese healthy male 
subjects aged 20 to 55 years, inclusive. Approximately 20 subjects will be enrolled into the 
cohort.  All subjects will have skin area fields designated for the investigational products 
patches at two randomly assigned, adjacent sites, for the purpose of determining irritation 
potential.  
The investigational products will be applied to one side of the infrascapular area of the back. 
Evaluation of dermal reactions at the application sites will be assessed clinically using a 
visual scale that rates the degree of erythema, edema, and other signs of skin irritation (see
Section 7.1.6).
The investigational products will be applied topically once on Day 1 and remain under 
occlusion for 48 hours.  The skin irritancy will be evaluated approximately 30 minutes after 
removal of the patches (Day 3, around 48 hours after the investigational products patches
application) and 24 hours after removal of the patches (Day 4, approximately 72 hours after 
the investigational products patches application). A follow-up telephone call (end of study) 
will be made by study site staff to the subjects on Day 29 (+7 days) to assess AEs.
All applications of the investigational product will be conducted by the study site staff.
The observer and subjects will be blinded to minimize evaluation bias for skin irritation.


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Cohort 2
This is a randomized, double-blind cohort of crisaborole ointment 2% BID to evaluate the 
safety, tolerability and PK in adult Japanese subjects with mild to moderate AD. The cohort
will enroll male and female subjects with AD aged 20 years to 55 years, inclusive, at the time 
of screening. Approximately 12 subjects having at least 25% Treatable %BSA, defined as 
the percent of a subject’s total body surface area (BSA) that is AD-involved and is not on the 
scalp or in designated venous access areas, will be enrolled into the study.  The 
Treatable %BSA will be calculated at Screening and Day 1. The investigational product will 
be applied BID to the Treatable %BSA areas identified on Day 1 for 8 days, except on Days 
1 and 8, when investigational product will be administered QD in the AM.  All 
investigational product doses will be dispensed and applied by study site staff.
Subjects will be screened within 28 days prior to application of investigational product on
Day 1 to confirm that they meet the subject eligibility criteria for the study. Subjects will be
admitted to the Clinical Research Unit (CRU) on Day –1 and will remain confined in the
CRU until completion of all assessments on Day 9.  A follow-up telephone call (end of 
study) will be made by study site staff to the subjects on Day 36 (+7 days) to assess AEs.  
Refer to the SCHEDULE OF ACTIVITIES for a complete list of assessments to be 
performed during the study.
Eligibility criteria for the study population are described in Section 4.  Detailed information 
about the investigational product treatment regimen is provided in Section 5.  Detailed 
information about study procedures and assessments is provided in Section 6 and Section 7.
3.2. Number of Sites
Both cohorts will be conducted in one study site.  
3.3. Duration of Study
Cohort 1
Subjects will be screened for the study no more than 28 days before the initial day of dosing 
(Day 1). Investigational products will be applied topically once on Day 1 and remain under a 
patch occlusion for 48 hours.  The study will comprise the following study periods:

Screening Period: maximum duration of 28 days;

Investigational product patch Application Period: 48 hours;

Patch Sites Observation Period: Day 3 and 4;

Post-Treatment Follow-up Period: a telephone call on Day 29 (28 +7 days after the 
application of investigational product patch on Day 1).


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Cohort 2
Subjects will be screened for the study no more than 28 days before the initial day of dosing 
(Day 1), and will receive investigational products topically BID for 8 days, except on Days 1 
and 8, when investigational product will be administered QD in the AM.  The study will 
comprise of the following study periods:

Screening Period: maximum duration of 28 days;

Investigational product Application Period: 8 days;

Post-Treatment Follow-up Period: a telephone call on Day 36 (28 +7 days after the 
last application of investigational product).
4. SUBJECT ELIGIBILITY CRITERIA
This study can fulfill its objectives only if appropriate subjects are enrolled.  The following 
eligibility criteria are designed to select subjects for whom participation in the study is 
considered appropriate.  All relevant medical and nonmedical conditions should be taken into 
consideration when deciding whether a particular subject is suitable for this protocol.
4.1. Inclusion Criteria
Subjects must meet all of the following inclusion criteria to be eligible for enrollment in the 
study:
Cohort 1
1. Healthy male Japanese subjects who, at the time of screening, are between the ages of 
20 and 55 years, inclusive. Healthy is defined as no clinically relevant abnormalities 
identified by a detailed medical history, physical examination, including blood 
pressure (BP) and pulse rate (PR) measurement, 12-lead electrocardiogram (ECG),
and clinical laboratory tests. 
2. Body mass index (BMI) of 17.5 to 30.5 kg/m2; and a total body weight >50 kg 
(110 lb).
3. Evidence of a personally signed and dated informed consent document indicating that 
the subject has been informed of all pertinent aspects of the study.  
4. Subjects who are willing and able to comply with all scheduled visits, treatment plan, 
laboratory tests, and other study procedures.
5. Healthy skin on which reddening can be easily recognized in the area of the test fields.


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Cohort 2
1. Male or female Japanese subjects aged 20 years to 55 years (inclusive) at the time of 
screening, and in generally good health except for AD.  Good health is defined as no 
clinically relevant abnormalities identified by a detailed medical history, physical 
examination, including BP and PR measurement, 12 lead ECG, and clinical 
laboratory tests.
Female subjects of nonchildbearing potential must meet at least 1 of the following 
criteria:
a.
Achieved postmenopausal status, defined as follows: cessation of regular menses 
for at least 12 consecutive months with no alternative pathological or 
physiological cause; and have a serum follicle-stimulating hormone (FSH) level 
confirming the postmenopausal state;  
b. Have undergone a documented hysterectomy and/or bilateral oophorectomy;
c.
Have medically confirmed ovarian failure.
All other female subjects (including female subjects with tubal ligations) are 
considered to be of childbearing potential.
2. Diagnosis of AD based on the criteria of Hanifin and Rajka (1980) (see Appendix 2).
3. Has at least 25% Treatable %BSA on Day 1 (excluding the scalp and designated 
venous access areas).
4. Has an Investigator’s static global assessment (ISGA) score of Mild (2) or Moderate 
(3) on Day 1 (see Appendix 3).
5. BMI of 17.5 to 35.0 kg/m2; and a total body weight >50 kg (110 lb).
6. Evidence of a personally signed and dated informed consent document indicating that 
the subject has been informed of all pertinent aspects of the study.  
7. Subjects who are willing and able to comply with scheduled visits, treatment plan, 
laboratory tests and other study procedures.
8. Has adequate venous access to permit repeated PK sampling on Days 1–9 through 
uninfected skin to which investigational product will not be applied (Each designated 
venous access area must have an untreated margin of at least 5 cm radius around the 
venipuncture site).


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4.2. Exclusion Criteria
Subjects with any of the following characteristics/conditions will not be included in the 
study:
Cohort 1
1. Subjects who have any visible skin disease at the application site which, in the 
opinion of the investigative personnel, will interfere with the evaluation of the test 
site reaction.
2. Subjects who have psoriasis and/or active AD/eczema.
3. Subjects who have a history of AD.
4. Subjects who have damaged skin in or around the test sites, including sunburn, 
excessively deep tans, uneven skin tones, tattoos, scars, excessive hair, numerous 
freckles, or other disfigurations of the test site.
5. Evidence or history of clinically significant hematological, renal, endocrine, 
pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, neurological, or 
allergic disease (including drug allergies, but excluding untreated, asymptomatic, 
seasonal allergies at the time of dosing).
6. A positive urine drug test.
7. History of regular alcohol consumption exceeding 14 drinks/week for male subjects 
(1 drink = 5 ounces [150 mL] of wine or 12 ounces [360 mL] of beer or 1.5 ounces 
[45 mL] of hard liquor) within 6 months before screening.
8. Treatment with an investigational drug within 30 days or 5 half-lives preceding the 
first dose of investigational product (whichever is longer). 
9. Subjects with ANY of the following abnormalities in clinical laboratory tests at 
screening, as assessed by the study-specific laboratory and confirmed by a single 
repeat test, if deemed necessary: 

Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) level 
1.5 × upper limit of normal (ULN);

Total bilirubin level 1.5 × ULN; subjects with a history of Gilbert’s syndrome 
may have direct bilirubin measured and would be eligible for this study provided 
the direct bilirubin level is ULN.
10. Blood donation (excluding plasma and platelet donations) of approximately 400 mL 
within 3 months or 200 mL within a month prior to dosing. 
11. History of sensitivity to heparin or heparin-induced thrombocytopenia. 


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12. Known sensitivity to any of the components of the investigational products (see 
Section 5).
13. History of the rash to the adhesive plaster, contact dermatitis to metal, or cosmetic 
and household articles.
14. History of human immunodeficiency virus (HIV), hepatitis B, hepatitis C or syphilis; 
positive testing for HIV, hepatitis B surface antigen (HepBsAg), hepatitis B core 
antibody (HepBcAb), hepatitis C antibody (HCVAb) or syphilis.
15. Unwilling or unable to comply with the criteria in the Lifestyle Requirements section 
of this protocol.
16. Subjects who are investigator site staff members directly involved in the conduct of 
the study and their family members, site staff members otherwise supervised by the 
investigator, or subjects who are Pfizer employees, including their family members, 
directly involved in the conduct of the study. 
17. Other acute or chronic medical or psychiatric condition including recent (within the 
past year) or active suicidal ideation or behavior or laboratory abnormality that may 
increase the risk associated with study participation or investigational product 
administration or may interfere with the interpretation of study results and, in the 
judgment of the investigator, would make the subject inappropriate for entry into this 
study.
Cohort 2
1. Has any clinically significant medical disorder, condition, disease (including active or 
potentially recurrent dermatological conditions other than AD), significant physical 
examination or laboratory findings that may interfere with study objectives, in the 
Investigator’s opinion (eg, conditions or findings that may expose a subject to 
unacceptable risk by study participation, confound the evaluation of treatment 
response or adverse events, or otherwise interfere with a subject’s ability to complete 
the study).
2. Has unstable AD or a consistent requirement for strong to strongest potency topical 
corticosteroids to manage AD signs and symptoms (see Concomitant Treatment(s) for 
washout periods).
3. Has a significant active systemic or localized infection, including known 
actively-infected AD.


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4. Has a history or evidence of clinically significant or severe allergies (eg, seasonal, pet 
dander, environmental, food) requiring acute or chronic treatment (Subjects with 
allergic rhinitis that does not require treatment, or for whom an ongoing allergy 
treatment meets the definition of a stable regimen under Concomitant Treatment(s)
section, may be eligible to participate in the study).
5. Has recent or anticipated concomitant use of topical or systemic therapies that might 
alter the course of AD, as specified in protocol (see Concomitant Treatment(s)).
6. Has a history of recent (within 4 weeks of Day 1) sunbathing, tanning bed use, or 
ultraviolet (UV) light B therapy (UVB) or psoralen plus UVA [PUVA]) (Sunbathing, 
tanning bed use, and UV light therapy are prohibited during the study).
7. Has any planned surgical or medical procedure that would overlap with study 
participation from Screening through the end of study.
8. Has any cancer or have a history of cancers within the last 5 years (except curatively 
treated with surgical excised squamous cell carcinoma, basal cell carcinoma, or 
carcinoma in situ of the skin).
9. Has a known sensitivity to any of the components of crisaborole ointment 2%.
10. A positive urine drug test.
11. History of regular alcohol consumption exceeding 7 drinks/week for female subjects 
or 14 drinks/week for male subjects (1 drink = 5 ounces [150 mL] of wine or 
12 ounces [360 mL] of beer or 1.5 ounces [45 mL] of hard liquor) within 6 months 
before screening.
12. Treatment with an investigational drug within 30 days or 5 half-lives preceding the 
first dose of investigational product (whichever is longer).
13. Screening supine BP 140 mm Hg (systolic) or 90 mm Hg (diastolic), following at 
least 5 minutes of supine rest.  If BP is 140 mm Hg (systolic) or 90 mm Hg 
(diastolic), the BP should be repeated 2 more times and the average of the 3 BP 
values should be used to determine the subject’s eligibility.
14. Screening supine 12-lead ECG demonstrating a QTc interval >450 msec or a QRS 
interval >120 msec.  If QTc exceeds 450 msec, or QRS exceeds 120 msec, the ECG 
should be repeated 2 more times and the average of the 3 QTc or QRS values should 
be used to determine the subject’s eligibility. 
15. Subjects with ANY of the following abnormalities in clinical laboratory tests at 
screening, as assessed by the study-specific laboratory and confirmed by a single 
repeat test, if deemed necessary: 


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
Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) level 
1.5 × upper limit of normal (ULN);

Total bilirubin level 1.5 × ULN; subjects with a history of Gilbert’s syndrome 
may have direct bilirubin measured and would be eligible for this study provided 
the direct bilirubin level is ULN.
16. Use of prescription or nonprescription drugs, vitaminic and dietary supplements 
within 14 days or 5 half-lives (whichever is longer) prior to the first dose of 
investigational product (refer to Section 5.10.1 for drugs or therapies with different 
requirement for washout period).  As an exception, acetaminophen/paracetamol may 
be used at doses of 1 g/day.  Limited use of nonprescription medications that are not 
believed to affect subject safety or the overall results of the study may be permitted 
on a case-by-case basis following approval by the sponsor. 
Herbal supplements (including St. John’s Wort) must have been discontinued at least 
28 days prior to the first dose of investigational product.
17. Pregnant female subjects; breastfeeding female subjects; female subjects of 
childbearing potential who are unwilling or unable to use a highly effective method of 
contraception as outlined in this protocol for the duration of the study and for at least 
28 days after the last dose of investigational product.
18. Blood donation (excluding plasma donations and platelet donations) of approximately 
400 mL within 3 months or 200 mL within a month prior to dosing. 
19. History of sensitivity to heparin or heparin-induced thrombocytopenia.
20. History of HIV, hepatitis B, hepatitis C or syphilis; positive testing for HIV, 
HepBsAg, HepBcAb, HCVAb or syphilis.
21. Unwilling or unable to comply with the criteria in the Lifestyle Requirements section 
of this protocol.
22. Subjects who are investigator site staff members directly involved in the conduct of 
the study and their family members, site staff members otherwise supervised by the 
investigator, or subjects who are Pfizer employees, including their family members, 
directly involved in the conduct of the study. 
23. Other acute or chronic medical or psychiatric condition including recent (within the 
past year) or active suicidal ideation or behavior or laboratory abnormality that may 
increase the risk associated with study participation or investigational product 
administration or may interfere with the interpretation of study results and, in the 
judgment of the investigator, would make the subject inappropriate for entry into this 
study.


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4.3. Randomization Criteria
Subjects will be randomized into the study provided they have satisfied all subject eligibility 
criteria. 
4.4. Lifestyle Requirements
The following guidelines are provided:
4.4.1. Alcohol

Subjects will abstain from alcohol for 24 hours prior to admission to the CRU and 
continue abstaining from alcohol during confinement in the CRU.  Subjects may 
undergo an alcohol breath, blood or urine alcohol test at the discretion of the 
investigator.
4.4.2. Activity
Cohort 1

Bathing, sauna or sunbathing are not allowed during confinement in the CRU.

Activities which would lead to excessive sweating or any type of sun exposure are 
prohibited during confinement in the CRU.

The use of any products in the patch area is prohibited during confinement in the 
CRU.
Cohort 2

Occluding the treated areas (with wraps, for example) should be avoided.

Subjects should refrain from swimming, bathing, sauna or washing the treated areas 
for at least 4 hours after application.

Subjects should be encouraged not to put hands in the mouth to avoid ingestion of 
investigational product.

Subjects should avoid wiping the investigational product off the skin.  
4.4.3. Contraception (Cohort 2)
All female subjects who are of childbearing potential, as applicable to the study who are, in 
the opinion of the investigator, sexually active and at risk for pregnancy with their partner(s) 
must agree to use a highly effective method of contraception consistently and correctly for 
the duration of the active treatment period and for at least 28 days after the last dose of 
investigational product.  The investigator or his or her designee, in consultation with the 
subject, will confirm that the subject has selected an appropriate method of contraception for 
the individual subject and her partner(s) from the permitted list of contraception methods (see 
below) and will confirm that the subject has been instructed in its consistent and correct use.  


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At time points indicated in the Schedule of Activities, the investigator or designee will 
inform the subject of the need to use highly effective contraception consistently and correctly 
and document the conversation and the subject’s affirmation in the subject’s chart (subjects 
need to affirm their consistent and correct use of at least 1 of the selected methods of 
contraception).  In addition, the investigator or designee will instruct the subject to call 
immediately if the selected contraception method is discontinued or if pregnancy is known or 
suspected in the subject. 
Highly effective methods of contraception are those that, alone or in combination, result in a 
failure rate of less than 1% per year when used consistently and correctly (ie, perfect use) and 
include the following:
1. Established use of hormonal methods of contraception associated with inhibition of 
ovulation (eg, oral, inserted, injected, implanted, transdermal), provided the subject 
plans to remain on the same treatment throughout the entire study and has been using 
that hormonal contraceptive for an adequate period of time to ensure effectiveness. 
2. Correctly placed copper-containing intrauterine device (IUD). 
3. Male condom or female condom used WITH a spermicide product (ie, foam, gel, 
film, cream, or suppository).  For countries where spermicide is not available or 
condom plus spermicide is not accepted as highly effective contraception, this option 
is not appropriate.
4. Male sterilization with absence of sperm in the postvasectomy ejaculate.
5. Bilateral tubal ligation/bilateral salpingectomy or bilateral tubal occlusive procedure 
(provided that occlusion has been confirmed in accordance with the device’s label).
NOTE: Sexual abstinence, defined as completely and persistently refraining from all 
heterosexual intercourse (including during the entire period of risk associated with the study 
treatments) may obviate the need for contraception ONLY if this is the preferred and usual 
lifestyle of the subject.
4.5. Sponsor’s Qualified Medical Personnel
The contact information for the sponsor’s appropriately qualified medical personnel for the 
study is documented in the study contact list located in the supporting study documentation. 
To facilitate access to appropriately qualified medical personnel on study-related medical 
questions or problems, subjects are provided with a contact card. The contact card contains, 
at a minimum, protocol and investigational product identifiers, subject study numbers, 
contact information for the investigator site, and contact details for a contact center in the 
event that the investigator site staff cannot be reached to provide advice on a medical 
question or problem originating from another healthcare professional not involved in the 
subject’s participation in the study. The contact number can also be used by investigator
staff if they are seeking advice on medical questions or problems; however, it should be used 


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only in the event that the established communication pathways between the investigator site 
and the study team are not available. It is therefore intended to augment, but not replace, the 
established communication pathways between the investigator site and the study team for 
advice on medical questions or problems that may arise during the study. For sites other than 
a Pfizer CRU, the contact number is not intended for use by the subject directly, and if a 
subject calls that number, he or she will be directed back to the investigator site.
5. STUDY TREATMENTS
For the purposes of this study, and per International Conference on Harmonisation (ICH) 
guidelines, investigational product is defined as a pharmaceutical form of an active 
ingredient or vehicle being tested or used as a reference/comparator in a clinical trial, 
including a product with a marketing authorization when used or assembled (formulated or 
packaged) in a way different from the approved form, or when used for an unapproved 
indication, or when used to gain further information about an approved use (ICH E6 1.33).
For this study, the investigational products are crisaborole ointment 2% and matching 
vehicle.
Crisaborole ointment 2%, is formulated to contain PF-06930164 (2% wt/wt), white 
petrolatum, propylene glycol, mono- and diglycerides, paraffin wax, butylated 
hydroxytoluene, and edetate calcium disodium. 
Vehicle (no active drug in the formulation) contains white petrolatum, propylene glycol, 
mono- and diglycerides, paraffin wax, butylated hydroxytoluene, and edetate calcium 
disodium.
5.1. Allocation to Treatment
The investigator’s knowledge of the treatment should not influence the decision to enroll a 
particular subject or affect the order in which subjects are enrolled.
The investigator will assign subject numbers to the subjects as they are screened for the study
by each cohort.  Each subject enrolled in either Cohort 1 or Cohort 2 will sign the informed 
consent for the appropriate cohort and successfully complete the screening procedures. 
Pfizer will provide a randomization schedule to the personnel who will conduct the subject
allocation and, in accordance with the randomization numbers, the subject will receive the 
study treatment regimen assigned to the corresponding randomization number. 
All subjects enrolled in Cohort 1 will receive both products (crisaborole ointment 2%, and 
vehicle). The randomization schedule of Cohort 1 indicates the randomized sequence of 
application placement of the investigational product.  According to the randomization 
sequence (Table 2), each subject will receive 2 patches, one is crisaborole ointment 2% and 
the other is vehicle.


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For Cohort 1, subjects will be randomly assigned in a 1:1 ratio to either Randomization 
sequence 1 [Application placement 1 (Upper): Crisaborole ointment 2%, Application 
placement 2 (Lower): Vehicle] or Randomization sequence 2 [Application placement
1 (Upper): Vehicle, Application placement 2 (Lower): Crisaborole ointment 2%].
Table 2.
Randomization sequence for Cohort 1
Randomization sequence
Application placement 1 (Upper)
Application placement 2 (Lower)
1
Crisaborole ointment 2%
Vehicle
2
Vehicle
Crisaborole ointment 2%
For Cohort 2, subjects will be randomly assigned in a 5:1 ratio to either crisaborole ointment 
2% or vehicle.
5.2. Blinding of Site Personnel
Cohort 1
In this observer-blinded cohort, the observer and subject will be blinded, but all other study 
site staff, including the principal investigator and the study site staff who are involved in the 
preparation/application and removal of the patches, will be unblinded. However, the access 
to the unblinded information of any site staff other than the study site staff who are involved 
in the preparation/application and removal of the patches should be kept to a minimum.
The principal investigator will assign the responsibility to a blinded observer of the 
evaluation of skin irritation potential. A blinded observer should fulfill this role. The 
blinded observer must not be allowed to know the randomization sequence.
Cohort 2
In this double blind cohort, the personal who will conduct the subject allocation to the 
investigational products will be unblinded, but all other site study personnel will be blinded.
The principal investigator will assign the unblinded staff. The unblinded staff will assign 
randomization number to the investigational product according to the randomization schedule 
provided by the sponsor, and will not participate in the evaluation of any study subject. One 
or two unblinded staff who will conduct the subject allocation to the investigational products 
will be assigned.  The member(s) of the study site staff should fulfill this role. 
Contact between the unblinded staff and study subjects should be kept to a minimum. The 
investigator, study coordinator, the study staff who are involved in the 
preparation/application of the investigational product and any site staff other than the 
unblinded staff who assign randomization number to the investigational product must not be 
allowed to know the investigational product assigned to any study subject.


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5.3. Blinding of the Sponsor
Cohort 1
All study team members may be unblinded in order to evaluate safety and skin irritation (see 
Section 9.6).
Cohort 2
All study team members will remain blinded to the investigational product assigned/received 
throughout the study.
5.4. Breaking the Blind
At the initiation of the study, the investigator site will be instructed on the method for 
breaking the blind.  The method will be either a manual or an electronic process.  Blinding 
codes should be broken only in exceptional circumstances when knowledge of the actual 
treatment code is absolutely essential for further management of the subject.  Investigators 
are encouraged to discuss with a member of the study team if they believe that unblinding is 
necessary.  When the blinding code is broken, the reason must be fully documented and 
entered on the case report form (CRF).
5.5. Subject Compliance
For Cohort 1, all patches will be prepared, applied and removed by study site staff.  For 
Cohort 2, the dispensing and application of investigational product will be performed by
study site staff. Treatment compliance for each subject will be ensured and documented 
during treatment period.
5.6. Investigational Product Supplies
5.6.1. Dosage Form and Packaging
Crisaborole ointment 2% and vehicle will be provided in 60 g tubes by Pfizer.  The tubes will 
be labeled according to local regulatory requirements.
5.6.2. Preparation and Dispensing 
Within this protocol, preparation refers to the investigator site activities performed to make 
the investigational product ready for administration or dispensing to the subject/caregiver by 
qualified staff.  Dispensing is defined as the provision of investigational product, 
concomitant treatments, and accompanying information by qualified staff member(s) to a 
healthcare provider, subject, or caregiver in accordance with this protocol.  Local health 
authority regulations or investigator site guidelines may use alternative terms for these 
activities. 
The investigational products will be prepared by study site staff according to the 
Investigational Product (IP) manual.


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5.7. Administration
5.7.1. Administration for Cohort 1
Subjects will receive the investigational products once on Day 1 to the designated areas of 
the back according to the randomization sequence and remain under occlusion for 48 hours in 
accordance with a skin irritation manual.
All applications of the investigational product will be conducted by the study site staff.
5.7.2. Administration for Cohort 2
Crisaborole ointment 2% is for external use on the skin only.  Avoid contact with mucous 
membranes (ie, inside of nostrils, mouth, vagina, urethra, and rectum), and the eyes.  
Additionally, Crisaborole ointment 2% should not be administrated to the perioral area in 
order to reduce the possibility of accidental ingestion that could adversely affect PK results.  
Care must be taken to avoid study drug contamination of designated venous access areas 
used for PK sampling, by leaving an untreated margin of at least 5 cm radius around each 
venipuncture site.
5.7.2.1. Study Treatment Regimen
From Day 1 AM through the Day 8 AM dose, all applications of the investigational product 
will be dispensed and applied by study site staff. The subject-specific per application dose
will be applied BID to all treatable AD-involved areas identified on Day 1 except on Days 1
and 8, when investigational product will be administered QD in the AM. Every effort must 
be made for the AM dose applications on Days 2–8 to be completed at 24 ±1 hour intervals 
from the recorded time of completion of the Day 1 dose application, for each subject. The 
PM dose applications on Days 2–7 will be applied at 12 ±1 hour after the recorded time of
completion of the each AM dose application, for each subject.
The per application dose will be calculated using the formula provided below in Section 
5.7.2.4, based on each subject’s total BSA in square meters (Section 5.7.2.2) and
Treatable %BSA (Section 5.7.2.3) on Day 1. The intended dose of the investigational 
product application to the treatable AD-involved areas is approximately 3 mg/cm2. The 
investigational product should be applied evenly to all treatable areas. The per application 
dose will be expressed as the weight of ointment in grams.  The per application dose will 
remain fixed and the investigational product will be applied to all treatable AD-involved 
areas identified on Day 1, regardless of whether they become clinically clear. Any 
AD-involved venous access areas and/or new AD lesions that appear after Baseline may be 
treated only with bland emollients until discharge from CRU on Day 9.
5.7.2.2. Calculation of Subject’s Total BSA
The subject’s total BSA (in m2) will be calculated using the Mosteller formula:
BSA (m²) = ඨܪ݁݅݃ℎݐ(ܿ݉) × ܹ݁݅݃ℎݐ(݇݃)
3600


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5.7.2.3. Calculation of Treatable %BSA
Treatable %BSA is defined as the percent of the subject’s total BSA that is AD-involved and
is not on the scalp or in venous access areas, by leaving an untreated margin of at least 5 cm 
radius around each venipuncture site. The Treatable %BSA will be calculated for each 
subject at Screening and Day 1, and all calculations should exclude the scalp and venous 
access areas. To estimate the Treatable %BSA, the investigator may use one of two methods 
of approximation.

The “Rule of Nines” provides a general estimation of total BSA for several anatomic 
areas (each arm = 9%, each leg = 18%, back = 18%, chest and abdomen = 18%, head 
= 9%, groin = 1%). The investigator may then visually estimate the proportion of the 
involved skin within each anatomic area and calculate the total percentage of BSA 
affected with AD;

Alternatively, the investigator may use the “handprint method”, wherein the area 
represented by the subject’s outstretched hand (including all five digits adducted 
together) equals approximately 1% of the subject’s BSA.25
The Treatable %BSA calculated on Day 1 will be used for calculation of the per application 
dose as defined in Section 5.7.2.4.
5.7.2.4. Calculation of Per Application Dose
The per application dose (expressed in g) will be calculated by study site staff once on Day 1, 
for each subject, using the formula below:
ܶ݋ݐ݈ܽܤܵܣܽݐܤܽݏ݈݁݅݊݁(݉ଶ) × ܶݎ݁ܽݐܾ݈ܽ݁%ܤܵܣ× 0.003 ቀ݃
ܿ݉ଶቁ× 100 ቆܿ݉ଶ
݉ଶቇ
= Weight of investigational product (in g) per application
5.7.2.5. Dispensing of Investigational Product
Prior to application, the per application dose will be carefully weighed out by study site staff
on a calibrated scale capable of readouts to 0.1 g. Investigational product must be applied 
within 2 hours of dispensing from the tube. If excess study drug is accidentally dispensed, 
the excess amount is to be weighed and documented in the drug accountability log as 
wastage from the specified tube of study drug, and then discarded.
5.7.2.6. Application of Investigational Product
Before the Day 1 AM dose is applied for each subject, the designated areas for treatment will
be identified on Day 1 and documented in the subject’s study records. For each subsequent
investigational product application, study site staff will refer to the documented locations of 
treatable AD lesions as determined on Day 1. 


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Wearing gloves, study site staff will apply the per application dose to all treatable AD lesions
determined on Day 1. If possible, the same study site staff should administer study drug to 
the subject at each dosing. Study drug will be applied as a thin layer of subject’s skin. Care 
must be taken to avoid study drug contamination of designated venous access areas used for 
PK sampling, by leaving an untreated margin of at least 5 cm radius around each 
venipuncture site. Following investigational product application, subjects will be instructed 
to wear loose-fitting clothing, to not wipe investigational product off the skin, to avoid 
occluding the treated areas, and to refrain from swimming, bathing, sauna or washing the 
treated areas within 4 hours after application. 
5.8. Investigational Product Storage 
The investigator or an approved representative, eg, pharmacist, will ensure that all 
investigational products are stored in a secured area with controlled access under required 
storage conditions and in accordance with applicable regulatory requirements.
Investigational products should be stored in their original containers and in accordance with 
the labels. 
Any storage conditions stated in the SRSD will be superseded by the storage conditions 
stated on the product label. 
Site systems must be capable of measuring and documenting (for example, via a log), at a 
minimum, daily minimum and maximum temperatures for all site storage locations (as 
applicable, including frozen, refrigerated, and/or room-temperature products).  This should 
be captured from the time of investigational product receipt throughout the study.  Even for 
continuous-monitoring systems, a log or site procedure that ensures active evaluation for 
excursions should be available.  The intent is to ensure that the minimum and maximum 
temperature is checked each business day to confirm that no excursion occurred since the last 
evaluation and to provide the site with the capability to store or view the minimum/maximum 
temperature for all non-working days upon return to normal operations.  The operation of the 
temperature-monitoring device and storage unit (for example, refrigerator), as applicable, 
should be regularly inspected to ensure they are maintained in working order. 
Any excursions from the product-label storage conditions should be reported to Pfizer upon 
discovery.  The site should actively pursue options for returning the product to the storage 
conditions described in the labeling, as soon as possible.  Deviations from the storage 
requirements, including any actions taken, must be documented and reported to Pfizer. 
Once an excursion is identified, the investigational product must be quarantined and not used 
until Pfizer provides permission to use the investigational product.  It will not be considered a 
protocol deviation if Pfizer approves the use of the investigational product after the 
temperature excursion.  Use of the investigational product prior to Pfizer approval will be 
considered a protocol deviation.  Specific details regarding information the site should report 
for each excursion will be provided to the site. 


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Please see the Investigational Product Manual for additional details on storage conditions and 
actions to be taken when conditions are outside of the specified range.
5.9. Investigational Product Accountability 
The investigator site must maintain adequate records documenting the receipt, use, loss, or 
other disposition of the investigational product supplies.  All investigational products will be 
accounted for using a drug accountability form/record. 
Throughout the study, detailed investigational product accountability records, including tube 
weights, will be maintained for each subject by study site staff.  Study site staff will record 
the weight (in g) of all applied doses, along with the weight of any amount(s) dispensed in 
error and discarded as waste. 
The original study drug accountability log, or equivalent document, must be accurately 
completed, signed by the investigator, and retained at the CRU (with a copy supplied to the 
sponsor) when the study is complete. 
5.9.1. Destruction of Investigational Product Supplies 
The sponsor or designee will provide guidance on the destruction of unused investigational 
product (eg, at the site).  If destruction is authorized to take place at the investigator site, the 
investigator must ensure that the materials are destroyed in compliance with applicable 
environmental regulations, institutional policy, and any special instructions provided by 
Pfizer, and all destruction must be adequately documented.
5.10. Concomitant Treatment(s)
Medication entries should provide the correctly spelled drug or therapy name and the dose, 
units, frequency, route of administration, start and stop date, and reason for use.  The use of 
any concomitant medication must relate to the subject’s medical history or to an AE, except 
for vitamins/nutritional supplements and routine immunizations.
Cohort 1
Subjects will abstain from all concomitant treatments, except for the treatment of 
AEs. Limited use of nonprescription medications that are not believed to affect subject 
safety or the overall results of the study may be permitted on a case-by-case basis following 
approval by the sponsor.
Treatments taken within 28 days before the first application of investigational product will be 
documented as a prior treatment.  Treatments taken after the first application of 
investigational product will be documented as concomitant treatments.


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Cohort 2
All treatments (including medications and non-medication therapies) used for the treatment 
of AD and all other medications (including over-the-counter drugs, vitamins, and antacids) 
used within 28 days prior to Screening will be recorded at the Screening visit.  Any changes 
in concomitant medications or dosage will be recorded on Day 1 and at each subsequent visit. 
Treatments taken after the first application of investigational product will be documented as 
concomitant treatments.
5.10.1. Washout Periods for Medications/Therapies Prior to Day 1 (Cohort 2)
Classes of medications and non-medication therapies that might alter the course of AD and
that require washout prior to Day 1 are summarized below with necessary washout periods:
28 Days Prior to Day 1

Systemic (oral/injectable) corticosteroids (excluding intranasal, inhaled or 
ophthalmic);

Systemic immunosuppressive agents (eg, methotrexate, ciclosporin, azathioprine, 
hydroxychloroquine);

Topical retinoids or benzoyl peroxide (BPO);

Sunbathing, tanning bed use, or UV light therapy (UVB or PUVA).
14 Days Prior to Day 1 

Systemic anti-inflammatory or immunomodulatory drugs (including biologics, but
excluding systemic antihistamines and nonsteroidal anti-inflammatory drugs
[NSAIDs]);

Escalating, decreasing, or as needed (PRN) use of systemic antihistamine(s)
(Subjects on a stable systemic antihistamine regimen [eg, QD, BID, three times a 
week], with at least 2 weeks consistent use prior to Day 1, are permitted to continue 
but should not alter or stop their regimen during the study);

Systemic antibiotics;

Strong potency topical corticosteroids or calcineurin inhibitors, on any skin (treatable 
AD lesions and skin not to be treated with study drug).
7 Days Prior to Day 1 

Topical antihistamines on any skin (treatable AD lesions and skin not to be treated 
with study drug) or systemic sedating antihistamines (eg, hydroxyzine or 
diphenhydramine or other sedating antihistamines);


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
Topical antimicrobial medications on treatable AD lesions only;

Medium potency topical corticosteroids on any skin (treatable AD lesions and skin 
not to be treated with study drug).
3 Days Prior to Day 1 

Weak potency topical corticosteroids on any skin (treatable AD lesions and skin not 
to be treated with study drug) (Subjects who require step down therapy during a 
medication washout period are permitted to use weak potency topical corticosteroids
until 3 days prior to Baseline).
At least 8 hours Prior to Application of Day 1 

Emollients on treatable AD lesions only.
If a subject requires a medication washout, the investigator will provide instructions on
discontinuing the prohibited medication(s) at the Screening Visit. All screening examinations
and tests/labs should be performed by the end of the washout period, if applicable.
5.10.2. Medications/Therapies Prohibited During the Study (Cohort 2)
Classes of medications and non-medication therapies that might alter the course of AD and
that are prohibited during the study (from Day 1 through Day 9) are summarized below:
During the Study (Day 1 through Day 9 Visit):

Systemic therapies that might alter the course of AD, including but not limited to:

Systemic (oral/injectable) corticosteroids (excluding intranasal, inhaled or 
ophthalmic);

Systemic immunosuppressive agents (eg, methotrexate, ciclosporin, azathioprine, 
hydroxychloroquine);

Systemic anti-inflammatory or immunomodulatory drugs (including biologics but
excluding systemic antihistamines and NSAIDs);

Escalating, decreasing, or PRN use of systemic antihistamine(s) and stable
systemic sedating antihistamines (eg, hydroxyzine or diphenhydramine or other).

Topical therapies that might alter the course of AD, used on any skin (treatable AD
lesions and skin not to be treated with study drug), including but not limited to:

Topical corticosteroids or calcineurin inhibitors;

Topical antihistamines;


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
Topical therapies that might alter the course of AD, used on treatable AD lesions,
including but not limited to:

Topical antimicrobial medications;

Topical retinoids or BPO.

Emollients.

Sunbathing, tanning bed use, or UV light therapy (UVB or PUVA);

Participation in another drug or device research study;

Treatment with medications known to be potent CYP3A4 and strong CYP1A2 
inhibitors.
5.10.3. Medications/Therapies Allowed During the Study (Cohort 2)
Classes of medications that are allowed during the study (from Day 1 through Day 9) are 
summarized below:
During the Study (Day 1 through Day 9 Visit):

Inhaled, intranasal or ophthalmic corticosteroids are allowed throughout the study;

Short courses of systemic antibiotics may be given during the course of the study, if 
clinically necessary for the treatment of new-onset infections;

Stable dose of systemic non-sedating antihistamines (eg, fexofenadine, loratadine,
desloratadine, cetirizine and levocetirizine) [eg, QD, BID, three times a week];

NSAIDs are allowed throughout the study;

Oral, transdermal, intrauterine, injected, or implanted hormonal methods of 
contraception are permitted during the study, for female subjects;

Concomitant medications for other chronic medical conditions are permitted during 
the study unless the medication/therapy is prohibited by the protocol.
6. STUDY PROCEDURES
6.1. Screening (Days –28 to –2)
Subjects will be screened within 28 days prior to administration of the investigational 
product to confirm that they meet the subject selection criteria for the study.  The investigator 
(or an appropriate delegate at the investigator site) will obtain informed consent from each 
subject in accordance with the procedures described in the Subject Information and Consent
section.  If the time between screening and dosing exceeds 28 days as a result of unexpected 
delays (eg, delayed drug shipment), then subjects do not require rescreening if the Day –1
laboratory results meet the eligibility criteria.


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6.1.1. Cohort 1
The following procedures will be completed:

Obtain written informed consent;

Confirm and document that the subject meets the inclusion/exclusion criteria;

Collect demography;

Collect height and weight;

Obtain medical history, including history of illegal drug, alcohol, and tobacco use;

Obtain complete medication history of all prescription or nonprescription drugs, and 
herbal supplements taken within 28 days prior to the planned first dose;

Obtain supine BP and PR;

Conduct physical examination;

Collect 12-lead ECG.

Collect blood and urine specimens for the following:

Safety laboratory tests: The results must have no clinically significant findings, as 
judged by the investigator, in order for a subject to be given investigational 
product on Day 1;

Urine drug test;

HIV, HepBsAg, HepBcAb, HCVAb and syphilis testing.

Assess the application field.

Assess for AEs and SAEs.
To prepare for study participation, subjects will be instructed on the information in the 
Lifestyle Requirements and Concomitant Treatment(s) sections of the protocol.
6.1.2. Cohort 2
The following procedures will be completed:

Obtain written informed consent;

Confirm and document that the subject meets the inclusion/exclusion criteria;


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
Collect demography;

Collect height and weight;

Confirm clinical diagnosis of AD;

Complete the ISGA (the ISGA score must be 2 or 3 on Day 1 for subject to be 
eligible);

Calculate and record Treatable %BSA;

Obtain medical history, including history of illegal drug, alcohol, and tobacco use;

Obtain complete medication history of all prescription or nonprescription drugs, and 
dietary, vitamic and herbal supplements taken within 28 days prior to Screening;

Obtain supine BP and PR;

Conduct physical examination;  

Collect 12-lead ECG.

Collect blood and urine specimens for the following:

Safety laboratory tests: The results must have no clinically significant findings, as 
judged by the investigator, in order for a subject to be given investigational 
product on Day 1;

Urine drug test;

Serum FSH concentration for any female subject who has been amenorrheic for at 
least 12 consecutive months; 

HIV, HepBsAg, HepBcAb, HCVAb and syphilis testing;

Urine beta-human chorionic gonadotropin (β-hCG) level for all female subjects of 
childbearing potential.

Assess for AEs and SAEs.

Instruct highly effective contraception for all female subjects of childbearing potential.
To prepare for study participation, subjects will be instructed on the information in the 
Lifestyle Requirements and Concomitant Treatment(s) sections of the protocol.


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6.2. Study Period
For the study period described below, when multiple procedures are scheduled at the same 
time point(s) relative to dosing, the following chronology of events should be adhered to, 
where possible.

ECGs: obtain prior to vital sign measurements, but prior to blood specimen 
collection;

BP/PR: obtain prior to blood specimen collection;

PK blood specimens: obtain at the scheduled time;

Other procedures: may be obtained before or after blood specimen collection.
When an IV catheter is utilized for blood sample collections, ECGs and vital sign 
assessments (PR, BP) should be collected prior to the insertion of the catheter.
6.2.1. Cohort 1
6.2.1.1. Day –1
Subjects will be admitted to the CRU at least the day prior to Day 1 dosing.  The following 
procedures will be completed following admission to the CRU:

Review inclusion and exclusion criteria;

Obtain blood and urine samples for safety laboratory tests.  The results must have no 
clinically significant findings, as judged by the investigator, in order for a subject to 
be given investigational product on Day 1.  Do not have to be repeated if clinical labs 
are completed within 7 days prior to Day –1;

Collect urine for drug testing. Do not have to be repeated if urine drug testing is 
completed within 7 days prior to Day –1;

Assess baseline symptoms/AEs;

Review changes in the subject’s medical history, including medication history since 
screening;

Conduct physical examination.
6.2.1.2. Day 1
Prior to dosing, the following procedures will be completed:

Review inclusion and exclusion criteria;

Assess baseline symptoms /AEs;


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
Review and record prior medications;

Assess the application field;

After all predose procedures have been completed, apply the investigational product 
patches (see the Administration section). 
After application of the investigational product patches, the following procedures will be 
completed:

Assess symptoms by spontaneous reporting of AEs and by asking the subjects to 
respond to a nonleading question such as “How do you feel?”  If AEs/SAEs occur at a 
patch site, the patch site location must be recorded.
6.2.1.3. Day 2
The following procedures will be completed: 

Review and record concomitant medications;

Assess symptoms by spontaneous reporting of AEs and by asking the subjects to 
respond to a nonleading question such as “How do you feel?”  If AEs/SAEs occur at a 
patch site, the patch site location must be recorded;

Confirm patches remain in place appropriately.
6.2.1.4. Day 3
The following procedures will be completed:

Review and record concomitant medications;

Remove the investigational product patches (48 hours post application on Day 1);

Assess the skin irritation response of the patch sites by a blinded observer 
approximately 30 minutes after removal of the patches;

Assess symptoms by spontaneous reporting of AEs and by asking the subjects to 
respond to a nonleading question such as “How do you feel?”  If AEs/SAEs occur at a 
patch site, the patch site location must be recorded.
6.2.1.5. Day 4
The following procedures will be completed:

Review and record concomitant medications;

Assess the skin irritation response of the patch sites by a blinded observer
approximately 24 hours after removal of the patches;


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
Assess symptoms by spontaneous reporting of AEs and by asking the subjects to 
respond to a nonleading question such as “How do you feel?” If AEs/SAEs occur at a 
patch site, the patch site location must be recorded;

Conduct physical examination;

Discharge from CRU confinement. 
If a subject has any clinically significant, study-related abnormalities at the conclusion of a 
scheduled inpatient portion of the study, the Pfizer medical monitor (or designated 
representative) should be notified and the subject may be asked to remain in the CRU until 
such abnormalities are deemed not clinically significant, or it is safe for outpatient follow-up.  
If the subject is unable or unwilling to remain in the CRU and/or when outpatient follow-up 
is deemed appropriate, the Pfizer medical monitor (or designated representative) should be so 
notified, and the investigator should make every effort to arrange follow-up evaluations at 
appropriate intervals to document the course of the abnormalities.
6.2.2. Cohort 2
6.2.2.1. Day –1
Subjects will be admitted to the CRU at least the day prior to Day 1 dosing.  The following 
procedures will be completed following admission to the CRU:

Review inclusion and exclusion criteria;

Obtain blood and urine samples for safety laboratory tests.  The results must have no 
clinically significant findings, as judged by the investigator, in order for a subject to 
be given investigational product on Day 1;

Collect urine for drug testing. Do not have to be repeated if urine drug testing is 
completed within 7 days prior to Day –1;

Collect urine pregnancy test for female subjects of childbearing potential;

Confirm highly effective contraception is being used for female subjects of 
childbearing potential;


Assess baseline symptoms/AEs;

Review changes in the subject’s medical history, including medication history since 
screening;

Conduct physical examination except skin examination.
CCI


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6.2.2.2. Day 1
Prior to dosing, the following procedures will be completed:

Review inclusion and exclusion criteria;

Conduct physical examination for skin examination;

Complete the ISGA (the ISGA score must be 2 or 3 on Day 1 for subject to be 
eligible);

Record treatable AD areas;

Calculate and record Treatable %BSA;

Assess baseline symptoms/AEs;

Collect weight;

Collect 12-lead ECG measurements prior to insertion of the IV catheter;

Collect supine BP and PR prior to insertion of the IV catheter;

Collect a blood sample for PK analysis at predose;

Review and record prior medications;

After all predose procedures have been completed, apply the investigational product 
(see the Administration section);

AM application: wearing gloves, study site staff will apply the calculated amount of 
study drug (per application dose) to all treatable AD lesions identified on Day 1;

Collect blood samples for PK analysis at 3 and 12 hours following application on 
Day 1;

Assess symptoms by spontaneous reporting of AEs and by asking the subjects to 
respond to a nonleading question such as “How do you feel?”
6.2.2.3. Day 2
The following procedures will be completed: 

Collect blood samples for PK analysis at 24 hours following application on Day 1;

Review and record concomitant medications;


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
AM application: wearing gloves, study site staff will apply the calculated amount of 
study drug (per application dose) to all treatable AD lesions identified on Day 1;

PM application: wearing gloves, study site staff will apply the calculated amount of 
study drug (per application dose) to all treatable AD lesions identified on Day 1;

Assess symptoms by spontaneous reporting of AEs and by asking the subjects to 
respond to a nonleading question such as “How do you feel?”
6.2.2.4. Day 3 to 6
The following procedures will be completed: 

Review and record concomitant medications;

AM application: wearing gloves, study site staff will apply the calculated amount of 
study drug (per application dose) to all treatable AD lesions identified on Day 1;

PM application: wearing gloves, study site staff will apply the calculated amount of 
study drug (per application dose) to all treatable AD lesions identified on Day 1;

Assess symptoms by spontaneous reporting of AEs and by asking the subjects to 
respond to a nonleading question such as “How do you feel?”
6.2.2.5. Day 7
The following procedures will be completed: 

Collect blood samples for PK analysis at 24 hours following application on Day 6 
AM;

Review and record concomitant medications;

AM application: wearing gloves, study site staff will apply the calculated amount of 
study drug (per application dose) to all treatable AD lesions identified on Day 1;

PM application: wearing gloves, study site staff will apply the calculated amount of 
study drug (per application dose) to all treatable AD lesions identified on Day 1;

Assess symptoms by spontaneous reporting of AEs and by asking the subjects to 
respond to a nonleading question such as “How do you feel?”
6.2.2.6. Day 8

Review and record concomitant medications.

Collect single 12-lead ECG measurements prior to insertion of the IV catheter. 


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
Collect supine BP and PR prior to insertion of the IV catheter.

Obtain blood and urine samples for safety laboratory tests.

Collect a blood sample for PK analysis at predose.

AM application: wearing gloves, study site staff will apply the calculated amount of 
study drug (per application dose) to all treatable AD lesions identified on Day 1.

Collect blood samples for PK analysis at 3 and 12 hours following application on 
Day 8.

Assess symptoms by spontaneous reporting of AEs and by asking the subjects to 
respond to a nonleading question such as “How do you feel?”
6.2.2.7. Day 9

Review and record concomitant medications.

Collect blood samples for PK analysis at 24 hours following application on Day 8.

Assess symptoms by spontaneous reporting of AEs and by asking the subjects to 
respond to a nonleading question such as “How do you feel?”

Conduct physical examination.

Confirm highly effective contraception is being used for all female subjects of 
childbearing potential.

Discharge from CRU confinement. 
If a subject has any clinically significant, study-related abnormalities at the conclusion of a 
scheduled inpatient portion of the study, the Pfizer medical monitor (or designated 
representative) should be notified and the subject may be asked to remain in the CRU until 
such abnormalities are deemed not clinically significant, or it is safe for outpatient follow-up.  
If the subject is unable or unwilling to remain in the CRU and/or when outpatient follow-up 
is deemed appropriate, the Pfizer medical monitor (or designated representative) should be so 
notified, and the investigator should make every effort to arrange follow-up evaluations at 
appropriate intervals to document the course of the abnormalities.


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6.3. Follow-up 
6.3.1. Follow-up Contact
Follow-up contact will be completed at least 28 calendar days and up to 35 calendar days 
after the last administration of the investigational product to capture any potential adverse 
events (see the Time Period for Collecting AE/SAE Information section) and to confirm 
appropriate contraception usage (Cohort 2 only, see the Contraception section).  Contact with 
the subject may be done via a phone call.
6.4. Subject Withdrawal/Early Termination
Withdrawal of consent: 
Subjects who request to discontinue receipt of study treatment will remain in the study and 
must continue to be followed for protocol-specified follow-up procedures.  The only 
exception to this is when a subject specifically withdraws consent for any further contact 
with him or her or persons previously authorized by the subject to provide this information.  
Subjects should notify the investigator in writing of the decision to withdraw consent from 
future follow-up, whenever possible.  The withdrawal of consent should be explained in 
detail in the medical records by the investigator, as to whether the withdrawal is only from 
further receipt of investigational product or also from study procedures and/or posttreatment 
study follow-up, and entered on the appropriate CRF page.  In the event that vital status 
(whether the subject is alive or dead) is being measured, publicly available information 
should be used to determine vital status only as appropriately directed in accordance with 
local law.
Lost to follow-up: 
All reasonable efforts must be made to locate subjects to determine and report their ongoing 
status.  This includes follow-up with persons authorized by the subject as noted above.  All 
attempts should be documented in the subject’s medical records.  If it is determined that the 
subject has died, the site will use locally permissible methods to obtain the date and cause of 
death.  If the investigator’s use of a third-party representative to assist in the follow-up 
portion of the study has been included in the subject’s informed consent, then the investigator 
may use a sponsor-retained third-party representative to assist study site staff with obtaining 
the subject’s contact information or other public vital status data necessary to complete the 
follow-up portion of the study.  The study site staff and representative will consult publicly 
available sources, such as public health registries and databases, in order to obtain updated 
contact information.  If, after all attempts, the subject remains lost to follow-up, then the 
last-known-alive date as determined by the investigator should be reported and documented 
in the subject’s medical records.
Subjects may withdraw from the study at any time at their own request, or they may be 
withdrawn at any time at the discretion of the investigator or sponsor for safety (see also the 
Withdrawal From the Study Due to Adverse Events section) or behavioral reasons, or the 
inability of the subject to comply with the protocol-required schedule of study visits or 


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procedures at a given investigator site.  The early termination visit applies only to subjects 
who are randomized and then are prematurely withdrawn from the study.
If a subject does not return for a scheduled visit, every effort should be made to contact the 
subject.  The investigator or site staff should attempt to contact the subject twice.  After 
2 attempts, CRU staff may send a registered letter.  If no response is received from the 
subject, the subject will be considered lost to follow-up.  All attempts to contact the subject 
and information received during contact attempts must be documented in the subject’s 
medical record.  In any circumstance, every effort should be made to document subject 
outcome, if possible.  The investigator should inquire about the reason for withdrawal, 
request that the subject return for a final visit, if applicable, and follow-up with the subject 
regarding any unresolved AEs.
It may be appropriate for the subject to return to the clinic for final safety assessments to be 
scheduled as early as practically feasible following the decision to withdraw from the study.  
Subjects should be questioned regarding their reason for withdrawal.  At the 
early-withdrawal visit, every effort must be made to complete the following assessments:
Cohort 1

Review and record concomitant medications.

Assess the skin irritation response of the patch sites.

Conduct physical examination

Assess symptoms by spontaneous reporting of AEs and by asking the subjects to 
respond to a nonleading question such as “How do you feel?”  If AEs/SAEs occur at a 
patch site, the patch site location must be recorded.
Cohort 2

Review and record concomitant medications.

Collect 12-lead ECG measurements prior to insertion of the IV catheter. 

Collect supine BP and PR prior to insertion of the IV catheter.

Obtain blood and urine samples for safety laboratory tests.

Collect a blood sample for PK analysis.

Conduct physical examination

Assess symptoms by spontaneous reporting of AEs and by asking the subjects to 
respond to a nonleading question such as “How do you feel?”


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Lack of completion of all or any of the withdrawal/early termination procedures will not be 
viewed as protocol deviations so long as the subject’s safety was preserved.
If the subject withdraws from the study and also withdraws consent for disclosure of future 
information, no further evaluations should be performed and no additional data should be 
collected.  The sponsor may retain and continue to use any data collected before such 
withdrawal of consent.
Subjects who withdraw from the study may be replaced at the discretion of the investigator 
upon consultation with the sponsor. 
7. ASSESSMENTS
Every effort should be made to ensure that protocol-required tests and procedures are 
completed as described.  However, it is anticipated that from time to time there may be 
circumstances outside the control of the investigator that may make it unfeasible to perform 
the test.  In these cases, the investigator must take all steps necessary to ensure the safety and 
well-being of the subject.  When a protocol-required test cannot be performed, the 
investigator will document the reason for the missed test and any corrective and preventive 
actions that he or she has taken to ensure that required processes are adhered to as soon as 
possible.  The study team must be informed of these incidents in a timely manner.
For samples being collected and shipped, detailed collection, processing, storage, and 
shipment instructions and contact information will be provided to the investigator site prior 
to initiation of the study.
7.1. Safety
7.1.1. Laboratory Tests
The following safety laboratory tests will be performed at times defined in the STUDY 
PROCEDURES section of this protocol.  Additional laboratory results may be reported on 
these samples as a result of the method of analysis or the type of analyzer used by the clinical 
laboratory; or as derived from calculated values.  These additional tests would not require 
additional collection of blood.  Unscheduled clinical laboratory measurements may be 
obtained at any time during the study to assess any perceived safety concerns.
The clinical laboratory test parameters that will be reviewed for safety evaluation are 
presented in Table 3.


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Table 3.
Safety Laboratory Tests
Hematology
Chemistry
Urinalysis
Other
Hemoglobin
Hematocrit
RBC count
MCV
MCH
MCHC
Platelet count
WBC count
Total neutrophils (%)
Eosinophils (%)
Monocytes (%)
Basophils (%)
Lymphocytes (%)
BUN/urea and creatinine
Glucose (fasting)
Calcium
Sodium
Potassium
Chloride
AST, ALT
Total bilirubin
Alkaline phosphatase
Uric acid
Albumin
Total protein
pH
Glucose (qual)
Protein (qual)
Blood (qual)
Ketones
Nitrites
Leukocyte esterase
Urobilinogen
Urine bilirubin
Microscopya
FSHb
Urine drug screening
β-hCGc
HIV
HepBsAg
HepBcAb
HCVAb,
Syphilis
Additional Tests, as 
applicable (Needed for 
Hy’s Law)
AST, ALT (repeat)
Total bilirubin (repeat)
Albumin (repeat)
Alkaline phosphatase 
(repeat)
Direct bilirubin
Indirect bilirubin
Creatine kinase
GGT
PT/INR
Total bile acids
Acetaminophen drug 
and/or protein adduct 
levels
Abbreviations:  ALT=alanine transaminase; AST=aspartate transaminase; β-hCG=beta human chorionic 
gonadotropin; BUN= blood urea nitrogen; FSH=follicle-stimulating hormone; GGT=gamma-glutamyl
transferase; HIV=human immunodeficiency virus; HepBsAg=hepatitis B surface antigen; 
HepBcAb=hepatitis B core antibody; HCVAb=hepatitis C antibody; INR= international normalized ratio;
MCH=mean corpuscular hemoglobin; MCHC=mean corpuscular hemoglobin concentration; MCV=mean 
corpuscular volume; PT=prothrombin time; RBC=red blood cell; WBC = white blood Cell.
a Only if urine dipstick is positive for blood, protein, nitrites or leukocyte esterase.
b Any female subject who has been amenorrheic for at least 12 consecutive months.
c Urine -hCG for female subjects of childbearing potential.

The minimum requirement for drug screening includes cocaine, tetrahydrocannabinol
(THC), opiates/opioids, benzodiazepines, and amphetamines.

Subjects may undergo random urine drug testing at the discretion of the investigator.  
Drug testing conducted prior to dosing must be negative for subjects to receive 
investigational product. 


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7.1.2. Pregnancy Testing (Cohort 2)
For female subjects of childbearing potential, a urine pregnancy test, with sensitivity of at 
least 25 mIU/mL, will be performed at screening, and at admission on Day -1, if applicable. 
A negative pregnancy test result is required before the subject may receive the investigational 
product.  Pregnancy tests will also be done whenever 1 menstrual cycle is missed during the 
active treatment period (or when potential pregnancy is otherwise suspected). Pregnancy 
tests may also be repeated if requested by institutional review boards (IRBs)/ECs or if 
required by local regulations.
In the case of a positive confirmed pregnancy, the subject will be withdrawn from application 
of investigational product and from the study.
7.1.3. Physical Examinations
Physical examinations may be conducted by a physician, and especially skin examination 
may be conducted by a dermatologist.  A physical examination will include head, ears, eyes, 
nose, mouth, skin, heart and lung examinations, lymph nodes, gastrointestinal, 
musculoskeletal, neurological systems, general appearance, the respiratory and 
cardiovascular systems, and subject-reported symptoms.
For measuring weight, a scale with appropriate range and resolution is used and must be 
placed on a stable, flat surface. Subjects must remove shoes, bulky layers of clothing, and 
jackets so that only light clothing remains.  They must also remove the contents of their 
pockets and remain still during measurement of weight. 
7.1.4. Blood Pressure and Pulse Rate
BP and PR will be measured at times specified in the STUDY PROCEDURES section of this
protocol.  Additional collection times, or changes to collection times, of BP and PR will be 
permitted, as necessary, to ensure appropriate collection of safety data.
Supine BP will be measured with the subject’s arm supported at the level of the heart, and 
recorded to the nearest mm Hg after approximately 5 minutes of rest.  The same arm 
(preferably the dominant arm) will be used throughout the study. Subjects should be 
instructed not to speak during measurements.
The same properly sized and calibrated BP cuff will be used to measure BP each time.  The 
use of an automated device for measuring BP and PR is acceptable; however, when done 
manually, PR will be measured in the brachial/radial artery for at least 30 seconds.  When the 
timing of these measurements coincides with a blood collection, BP and PR should be 
obtained prior to the nominal time of the blood collection.
7.1.5. Electrocardiogram 
A single 12-lead ECGs should be collected at times specified in the STUDY PROCEDURES
section of this protocol.


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All scheduled ECGs should be performed after the subject has rested quietly for at least 
5 minutes in a supine position. 
For Cohort 2, to ensure safety of the subjects, a qualified individual at the investigator site 
will make comparisons to baseline measurements.  If the QTc interval is increased by 
45 msec from the baseline, or an absolute QTc value is 500 msec for any scheduled ECG, 
then 2 additional ECGs will be collected, approximately 2 to 4 minutes apart, to confirm the 
original measurement.  If either of the QTc values from these repeated ECGs remains above 
the threshold value (ie, is 45 msec from the baseline, or is 500 msec), then a single ECG 
must be repeated at least hourly until QTc values from 2 successive ECGs fall below the 
threshold value that triggered the repeat measurement.
If QTc values remain 500 msec (or 45 msec from the baseline) for greater than 4 hours (or 
sooner, at the discretion of the investigator), or QTc intervals get progressively longer, the 
subject should undergo continuous ECG monitoring.  A cardiologist should be consulted if 
QTc intervals do not return to less than 500 msec (or to <45 msec above the baseline) after 
8 hours of monitoring (or sooner, at the discretion of the investigator).
In some cases, it may be appropriate to repeat abnormal ECGs to rule out improper lead 
placement as contributing to the ECG abnormality.  It is important that leads are placed in the 
same positions each time in order to achieve precise ECG recordings.  If a machine-read QTc 
value is prolonged, as defined above, repeat measurements may not be necessary if a 
qualified medical provider’s interpretation determines that the QTc values are in the 
acceptable range.
7.1.6. Skin Irritation Assessment (Cohort 1)
Skin irritation assessment of the patch sites will be conducted on Day 3 (approximately 
30 minutes after removal of the patches) and Day 4 (approximately 24 hours after removal of 
the patches) by a blinded observer who is a dermatologist. The following grade and score
will be used to evaluate the response observed at the time of examination20,21,22:
Table 4.
Skin Irritation Assessment Grades and Scores
Definition
Grade
Score
No reaction
-
0
Mild erythema

0.5
Erythema
+
1
Erythema + edema, papula
++
2
Erythema + edema + papula + small water blister
+++
3
Large water blister
++++
4
Expected reactions in the patch area (ie, irritation reactions outlined in Table 4 above) will 
not be recorded as AEs during the study. Unexpected reactions (eg, rash, hives) will be
recorded as AEs.


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7.2. Pharmacokinetics
7.2.1. Plasma for Analysis of crisaborole and main metabolites (Cohort 2)
During all study periods, blood samples (2 mL) to provide a minimum of 0.4 mL plasma for 
PK analysis will be collected into appropriately labeled tubes containing dipotassium 
ethylenediaminetetraacetic acid (K2EDTA) at times specified in the SCHEDULE OF 
ACTIVITIES section of the protocol.
The actual times may change, but the number of samples will remain the same.  All efforts 
will be made to obtain the PK samples at the exact nominal time relative to dosing.  
However, samples obtained within 10% of the nominal time (eg, within 6 minutes of a 
60-minute sample) from dosing will not be captured as a protocol deviation, as long as the 
exact time of the sample collection is noted on the source document and data collection tool 
(eg, CRF).
Samples will be analyzed using a validated analytical method in compliance with Pfizer 
standard operating procedures (SOPs).
The PK samples must be processed and shipped as indicated in the instructions provided to 
the investigator site to maintain sample integrity. Any deviations from the PK sample 
handling procedure (eg, sample collection and processing steps, interim storage or shipping 
conditions), including any actions taken, must be documented and reported to the sponsor.
On a case-by-case basis, the sponsor may make a determination as to whether sample 
integrity has been compromised.  Any deviation from the specified sample handling 
procedure resulting in compromised sample integrity will be considered a protocol deviation.
As part of understanding the PK of the investigational product, samples may be used for 
metabolite identification and/or evaluation of the bioanalytical method, as well as for other 
internal exploratory purposes.  These data will not be included in the clinical study report 
(CSR).
CCI


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7.4. Blood Volume
The total blood sampling volume for individual subjects in this study is approximately 20 mL
for Cohort 1 or 53 mL for Cohort 2, respectively.  The actual collection times of blood 
sampling may change.  Additional blood samples may be taken for safety assessments at 
times specified by Pfizer, provided the total volume taken during the study does not exceed 
550 mL during any period of 60 consecutive days.
CCI
CCI
CCI


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8. ADVERSE EVENT REPORTING
8.1. Requirements
The table below summarizes the requirements for recording safety events on the CRF and for 
reporting safety events on the Clinical Trial (CT) Serious Adverse Event (SAE) Report Form 
to Pfizer Safety.  These requirements are delineated for 3 types of events: (1) SAEs; 
(2) non-serious adverse events (AEs); and (3) exposure to the investigational product under 
study during pregnancy or breastfeeding, and occupational exposure. 
Safety Event
Recorded on the CRF
Reported on the CT SAE 
Report Form to Pfizer 
Safety Within 24 Hours of 
Awareness
SAE
All
All
Non-serious AE
All
None
Exposure to the 
investigational product under 
study during pregnancy or 
breastfeeding, and 
occupational exposure
All (regardless of whether 
associated with an AE), 
except occupational 
exposure
Exposure during pregnancy, 
exposure via breastfeeding, 
occupational exposure 
(regardless of whether 
associated with an AE)
Abbreviations: CRF=case report form; CT=clinical trial; SAE=serious adverse event; AE=adverse event.
All observed or volunteered events regardless of treatment group or suspected causal 
relationship to the investigational product(s) will be reported as described in the following 
paragraphs.
Events listed in the table above that require reporting to Pfizer Safety on the CT SAE Report 
Form within 24 hours of awareness of the event by the investigator are to be reported 
regardless of whether the event is determined by the investigator to be related to an 
investigational product under study.  In particular, if the SAE is fatal or life-threatening, 
notification to Pfizer Safety must be made immediately, irrespective of the extent of available 
event information.  This time frame also applies to additional new (follow-up) information on 
previously forwarded reports.  In the rare situation that the investigator does not become 
immediately aware of the occurrence of an event, the investigator must report the event 
within 24 hours after learning of it and document the time of his/her first awareness of the 
event.
For each event, the investigator must pursue and obtain adequate information both to 
determine the outcome and to assess whether it meets the criteria for classification as an SAE 
(see the Serious Adverse Events section below).  In addition, the investigator may be 
requested by Pfizer Safety to obtain specific follow-up information in an expedited fashion.  
This information is more detailed than that recorded on the CRF.  In general, this will include 
a description of the event in sufficient detail to allow for a complete medical assessment of 


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the case and independent determination of possible causality.  Any information relevant to 
the event, such as concomitant medications and illnesses, must be provided.  In the case of a 
subject death, a summary of available autopsy findings must be submitted as soon as possible 
to Pfizer Safety.  Any pertinent additional information must be reported on the CT SAE 
Report Form; additional source documents (eg, medical records, CRF, laboratory data) are to 
be sent to Pfizer Safety ONLY upon request.
As part of ongoing safety reviews conducted by the sponsor, any non-serious AE that is 
determined by the sponsor to be serious will be reported by the sponsor as an SAE.  To assist 
in the determination of case seriousness, further information may be requested from the 
investigator to provide clarity and understanding of the event in the context of the clinical 
study.
8.1.1. Additional Details on Recording Adverse Events on the CRF
All events detailed in the table above will be recorded on the AE page(s) of the CRF.  It 
should be noted that the CT SAE Report Form for reporting of SAE information is not the 
same as the AE page of the CRF.  When the same data are collected, the forms must be 
completed in a consistent manner.  AEs should be recorded using concise medical 
terminology and the same AE term should be used on both the CRF and the CT SAE Report 
Form for reporting of SAE information.
8.1.2. Eliciting Adverse Event Information
The investigator is to record on the CRF all directly observed AEs and all AEs spontaneously 
reported by the study subject.  In addition, each study subject will be questioned about the 
occurrence of AEs in a non-leading manner.
8.1.3. Withdrawal From the Study Due to Adverse Events (see also the Subject 
Withdrawal section)
Withdrawal due to AEs should be distinguished from withdrawal due to other causes, 
according to the definition of AE noted below, and recorded on the CRF. 
When a subject withdraws from the study because of an SAE, the SAE must be recorded on 
the CRF and reported, as appropriate, on the CT SAE Report Form, in accordance with the 
Requirements section above.
8.1.4. Time Period for Collecting AE/SAE Information
The time period for actively eliciting and collecting AEs and SAEs (“active collection 
period”) for each subject begins from the time the subject provides informed consent, which 
is obtained before the subject’s participation in the study (ie, before undergoing any 
study-related procedure and/or receiving investigational product), through and including a 
minimum of 28 calendar days after the last administration of the investigational product.
For subjects who are screen failures, the active collection period ends when screen failure 
status is determined.


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8.1.4.1. Reporting SAEs to Pfizer Safety
All SAEs occurring in a subject during the active collection period are reported to Pfizer 
Safety on the CT SAE Report Form.
SAEs occurring in a subject after the active collection period has ended are reported to Pfizer 
Safety if the investigator becomes aware of them; at a minimum, all SAEs that the 
investigator believes have at least a reasonable possibility of being related to investigational 
product must be reported to Pfizer Safety.
Follow up by the investigator continues throughout and after the active collection period and 
until the event or its sequelae resolve or stabilize at a level acceptable to the investigator, and 
Pfizer concurs with that assessment.
8.1.4.2. Recording Non-serious AEs and SAEs on the CRF
During the active collection period, both non-serious AEs and SAEs are recorded on the 
CRF.
Follow-up by the investigator may be required until the event or its sequelae resolve or 
stabilize at a level acceptable to the investigator, and Pfizer concurs with that assessment.
8.1.5. Causality Assessment
The investigator’s assessment of causality must be provided for all AEs (serious and 
non-serious); the investigator must record the causal relationship on the CRF, and report such 
an assessment in accordance with the SAE reporting requirements, if applicable.  An 
investigator’s causality assessment is the determination of whether there exists a reasonable 
possibility that the investigational product caused or contributed to an AE; generally the facts 
(evidence) or arguments to suggest a causal relationship should be provided.  If the 
investigator does not know whether or not the investigational product caused the event, then 
the event will be handled as “related to investigational product” for reporting purposes, as 
defined by the sponsor.  If the investigator's causality assessment is “unknown but not 
related” to investigational product, this should be clearly documented on study records. 
In addition, if the investigator determines that an SAE is associated with study procedures, 
the investigator must record this causal relationship in the source documents and CRF, and 
report such an assessment in the dedicated section of the CT SAE Report Form and in 
accordance with the SAE reporting requirements.
8.1.6. Sponsor’s Reporting Requirements to Regulatory Authorities
AE reporting, including suspected unexpected serious adverse reactions, will be carried out 
in accordance with applicable local regulations.


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8.2. Definitions
8.2.1. Adverse Events
An AE is any untoward medical occurrence in a study subject administered a product or 
medical device; the event need not necessarily have a causal relationship with the treatment 
or usage.  Examples of AEs include, but are not limited to: 

Abnormal test findings;

Clinically significant signs and symptoms;

Changes in physical examination findings;

Hypersensitivity;

Progression/worsening of underlying disease;

Drug abuse;

Drug dependency.
Additionally, AEs may include signs and symptoms resulting from:

Drug overdose;

Drug withdrawal;

Drug misuse; 

Drug interactions;

Extravasation;

Exposure during pregnancy (EDP);

Exposure via breastfeeding;

Medication error;

Occupational exposure.
8.2.2. Abnormal Test Findings
Abnormal objective test findings should be recorded as AEs when any of the following 
conditions are met: 

Test result is associated with accompanying symptoms; and/or


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
Test result requires additional diagnostic testing or medical/surgical intervention; 
and/or

Test result leads to a change in study dosing (outside of any protocol-specified dose 
adjustments) or discontinuation from the study, significant additional concomitant 
drug treatment, or other therapy; and/or

Test result is considered to be an AE by the investigator or sponsor.
Merely repeating an abnormal test, in the absence of any of the above conditions, does not 
constitute an AE.  Any abnormal test result that is determined to be an error does not require 
recording as an AE.
8.2.3. Serious Adverse Events
A serious adverse event is any untoward medical occurrence at any dose that:

Results in death;

Is life-threatening (immediate risk of death);

Requires inpatient hospitalization or prolongation of existing hospitalization;

Results in persistent or significant disability/incapacity (substantial disruption of the 
ability to conduct normal life functions);

Results in congenital anomaly/birth defect.
Or that is considered to be:

An important medical event.
Medical and scientific judgment is exercised in determining whether an event is an important 
medical event.  An important medical event may not be immediately life-threatening and/or 
result in death or hospitalization.  However, if it is determined that the event may jeopardize 
the subject or may require intervention to prevent one of the other AE outcomes, the
important medical event should be reported as serious.
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization; 
or development of drug dependency or drug abuse.
8.2.4. Hospitalization
Hospitalization is defined as any initial admission (even less than 24 hours) in a hospital or 
equivalent healthcare facility, or any prolongation of an existing admission.  Admission also 
includes transfer within the hospital to an acute/intensive care unit (eg, from the psychiatric 
wing to a medical floor, medical floor to a coronary care unit, or neurological floor to a 


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tuberculosis unit).  An emergency room visit does not necessarily constitute a hospitalization; 
however, the event leading to the emergency room visit is assessed for medical importance.
Hospitalization does not include the following:

Rehabilitation facilities;

Hospice facilities;

Respite care (eg, caregiver relief);

Skilled nursing facilities;

Nursing homes;

Same-day surgeries (as outpatient/same-day/ambulatory procedures).
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 not associated with the 
development of a new AE or with a worsening of the preexisting condition (eg, for 
workup of a persistent pretreatment laboratory abnormality);

Social admission (eg, subject has no place to sleep);

Administrative admission (eg, for yearly physical examination);

Protocol-specified admission during a study (eg, for a procedure required by the study 
protocol);

Optional admission not associated with a precipitating clinical AE (eg, for elective 
cosmetic surgery);

Hospitalization for observation without a medical AE;

Preplanned treatments or surgical procedures.  These should be noted in the baseline 
documentation for the entire protocol and/or for the individual subject.
Diagnostic and therapeutic noninvasive and invasive procedures, such as surgery, should not 
be reported as SAEs.  However, the medical condition for which the procedure was 
performed should be reported if it meets the definition of an SAE.  For example, an acute 
appendicitis that begins during the reporting period should be reported if the SAE 
requirements are met, and the resulting appendectomy should be recorded as treatment of the 
AE.


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8.3. Severity Assessment
If required on the AE page of the CRF, the investigator will use the adjectives MILD, 
MODERATE, or SEVERE to describe the maximum intensity of the AE.  For purposes of 
consistency, these intensity grades are defined as follows:
MILD
Does not interfere with subject's usual function.
MODERATE
Interferes to some extent with subject's usual function.
SEVERE
Interferes significantly with subject's usual function.
Note the distinction between the severity and the seriousness of an AE.  A severe event is not 
necessarily an SAE.  For example, a headache may be severe (interferes significantly with 
the subject's usual function) but would not be classified as serious unless it met one of the 
criteria for Serious Adverse Events, listed above.
8.4. Special Situations
8.4.1. Protocol-Specified Serious Adverse Events
There are no protocol-specified SAEs in this study.  All SAEs will be reported to Pfizer 
Safety by the investigator as described in previous sections, and will be handled as SAEs in 
the safety database. 
8.4.2. Potential Cases of Drug-Induced Liver Injury
Humans exposed to a drug who show no sign of liver injury (as determined by elevations in 
transaminases) are termed “tolerators,” while those who show transient liver injury, but adapt 
are termed “adaptors.”  In some subjects, transaminase elevations are a harbinger of a more 
serious potential outcome.  These subjects fail to adapt and therefore are "susceptible" to 
progressive and serious liver injury, commonly referred to as drug-induced liver injury 
(DILI).  Subjects who experience a transaminase elevation above 3 times the upper limit of 
normal (× ULN) should be monitored more frequently to determine if they are an “adaptor” 
or are “susceptible.”
Liver function tests (LFTs) are not required as a routine safety monitoring procedure in this 
study.  However, should an investigator deem it necessary to assess LFTs because a subject 
presents with clinical signs/symptoms, such LFT results should be managed and followed as 
described below.
In the majority of DILI cases, elevations in aspartate aminotransferase (AST) and/or alanine 
aminotransferase (ALT) precede total bilirubin (TBili) elevations (>2 × ULN) by several 
days or weeks.  The increase in TBili typically occurs while AST/ALT is/are still elevated 
above 3 × ULN (ie, AST/ALT and TBili values will be elevated within the same lab sample).  
In rare instances, by the time TBili elevations are detected, AST/ALT values might have 
decreased.  This occurrence is still regarded as a potential DILI.  Therefore, abnormal 
elevations in either AST OR ALT in addition to TBili that meet the criteria outlined below 


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are considered potential DILI (assessed per Hy’s law criteria) cases and should always be 
considered important medical events, even before all other possible causes of liver injury 
have been excluded.
The threshold of laboratory abnormalities for a potential DILI case depends on the subject’s 
individual baseline values and underlying conditions.  Subjects who present with the 
following laboratory abnormalities should be evaluated further as potential DILI (Hy’s law) 
cases to definitively determine the etiology of the abnormal laboratory values:

Subjects with AST/ALT and TBili baseline values within the normal range who 
subsequently present with AST OR ALT values >3 × ULN AND a TBili value 
>2 × ULN with no evidence of hemolysis and an alkaline phosphatase value 
<2 × ULN or not available.

For subjects with baseline AST OR ALT OR TBili values above the ULN, the 
following threshold values are used in the definition mentioned above, as needed, 
depending on which values are above the ULN at baseline:

Preexisting AST or ALT baseline values above the normal range: AST or ALT 
values >2 times the baseline values AND >3 × ULN; or >8 × ULN (whichever is 
smaller).

Preexisting values of TBili above the normal range: TBili level increased from 
baseline value by an amount of at least 1 × ULN or if the value reaches 
>3 × ULN (whichever is smaller).
Rises in AST/ALT and TBili separated by more than a few weeks should be assessed 
individually based on clinical judgment; any case where uncertainty remains as to whether it 
represents a potential Hy’s law case should be reviewed with the sponsor.  
The subject should return to the investigator site and be evaluated as soon as possible, 
preferably within 48 hours from awareness of the abnormal results.  This evaluation should 
include laboratory tests, detailed history, and physical assessment.   
In addition to repeating measurements of AST and ALT and TBili, laboratory tests should 
include albumin, creatine kinase (CK), direct and indirect bilirubin, gamma-glutamyl 
transferase (GGT), prothrombin time (PT)/international normalized ratio (INR), total bile 
acids, alkaline phosphatase and acetaminophen drug and/or protein adduct levels.  
Consideration should also be given to drawing a separate tube of clotted blood and an 
anticoagulated tube of blood for further testing, as needed, for further contemporaneous 
analyses at the time of the recognized initial abnormalities to determine etiology.  A detailed 
history, including relevant information, such as review of ethanol, acetaminophen (either by 
itself or as a coformulated product in prescription or over-the-counter medications), 
recreational drug, supplement (herbal) use and consumption, family history, sexual history, 
travel history, history of contact with a jaundiced person, surgery, blood transfusion, history 
of liver or allergic disease, and potential occupational exposure to chemicals, should be 


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collected.  Further testing for acute hepatitis A, B, C, D, and E infection and liver imaging 
(eg, biliary tract) may be warranted. 
All cases demonstrated on repeat testing as meeting the laboratory criteria of AST/ALT and 
TBili elevation defined above should be considered potential DILI (Hy’s law) cases if no 
other reason for the LFT abnormalities has yet been found.  Such potential DILI (Hy’s law) 
cases are to be reported as SAEs, irrespective of availability of all the results of the 
investigations performed to determine etiology of the LFT abnormalities.
A potential DILI (Hy’s law) case becomes a confirmed case only after all results of 
reasonable investigations have been received and have excluded an alternative etiology.
8.4.3. Exposure to the Investigational Product During Pregnancy or Breastfeeding, and 
Occupational Exposure
Exposure to the investigational product under study during pregnancy or breastfeeding and 
occupational exposure are reportable to Pfizer Safety within 24 hours of investigator 
awareness.
8.4.3.1. Exposure During Pregnancy
For both unapproved/unlicensed products and for marketed products, an exposure during 
pregnancy (EDP) occurs if:

A female becomes, or is found to be, pregnant either while receiving or having been 
exposed (eg, because of treatment or environmental exposure) to the investigational 
product; or the female becomes or is found to be pregnant after discontinuing and/or 
being exposed to the investigational product;

An example of environmental exposure would be a case involving direct contact 
with a Pfizer product in a pregnant woman (eg, a nurse reports that she is pregnant 
and has been exposed to chemotherapeutic products).

A male has been exposed (eg, because of treatment or environmental exposure) to the 
investigational product prior to or around the time of conception and/or is exposed 
during his partner’s pregnancy.
If a subject or subject’s partner becomes or is found to be pregnant during the subject’s 
treatment with the investigational product, the investigator must report this information to 
Pfizer Safety on the CT SAE Report Form and an EDP supplemental form, regardless of 
whether an SAE has occurred.  In addition, the investigator must submit information 
regarding environmental exposure to a Pfizer product in a pregnant woman (eg, a subject 
reports that she is pregnant and has been exposed to a cytotoxic product by inhalation or 
spillage) to Pfizer Safety using the EDP supplemental form.  This must be done irrespective 
of whether an AE has occurred and within 24 hours of awareness of the exposure.  The 
information submitted should include the anticipated date of delivery (see below for 
information related to termination of pregnancy).


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Follow-up is conducted to obtain general information on the pregnancy and its outcome for 
all EDP reports with an unknown outcome.  The investigator will follow the pregnancy until 
completion (or until pregnancy termination) and notify Pfizer Safety of the outcome as a 
follow-up to the initial EDP supplemental form.  In the case of a live birth, the structural 
integrity of the neonate can be assessed at the time of birth.  In the event of a termination, the 
reason(s) for termination should be specified and, if clinically possible, the structural 
integrity of the terminated fetus should be assessed by gross visual inspection (unless 
pre-procedure test findings are conclusive for a congenital anomaly and the findings are 
reported).
If the outcome of the pregnancy meets the criteria for an SAE (ie, ectopic pregnancy, 
spontaneous abortion, intrauterine fetal demise, neonatal death, or congenital anomaly [in a 
live-born baby, a terminated fetus, an intrauterine fetal demise, or a neonatal death]), the 
investigator should follow the procedures for reporting SAEs.
Additional information about pregnancy outcomes that are reported to Pfizer Safety as SAEs 
follows: 

Spontaneous abortion includes miscarriage and missed abortion;

Neonatal deaths that occur within 1 month of birth should be reported, without regard 
to causality, as SAEs.  In addition, infant deaths after 1 month should be reported as 
SAEs when the investigator assesses the infant death as related or possibly related to 
exposure to the investigational product. 
Additional information regarding the EDP may be requested by the sponsor.  Further 
follow-up of birth outcomes will be handled on a case-by-case basis (eg, follow-up on 
preterm infants to identify developmental delays).  In the case of paternal exposure, the 
investigator will provide the subject with the Pregnant Partner Release of Information Form 
to deliver to his partner.  The investigator must document in the source documents that the 
subject was given the Pregnant Partner Release of Information Form to provide to his 
partner.
8.4.3.2. Exposure During Breastfeeding
Scenarios of exposure during breastfeeding must be reported, irrespective of the presence of 
an associated SAE, to Pfizer Safety within 24 hours of the investigator’s awareness, using the 
CT SAE Report Form.  An exposure during breastfeeding report is not created when a Pfizer 
drug specifically approved for use in breastfeeding women (eg, vitamins) is administered in 
accord with authorized use.  However, if the infant experiences an SAE associated with such 
a drug’s administration, the SAE is reported together with the exposure during breastfeeding.
8.4.3.3. Occupational Exposure
An occupational exposure occurs when, during the performance of job duties, a person 
(whether a healthcare professional or otherwise) gets in unplanned direct contact with the 
product, which may or may not lead to the occurrence of an AE.


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An occupational exposure is reported to Pfizer Safety within 24 hours of the investigator’s 
awareness, using the CT SAE Report Form, regardless of whether there is an associated 
SAE.  Since the information does not pertain to a subject enrolled in the study, the 
information is not recorded on a CRF; however, a copy of the completed CT SAE Report 
Form is maintained in the investigator site file.
8.4.4. Medication Errors
Other exposures to the investigational product under study may occur in clinical trial settings, 
such as medication errors.
Safety Event
Recorded on the CRF 
Reported on the CT SAE 
Report Form to Pfizer 
Safety Within 24 Hours of 
Awareness
Medication errors 
All (regardless of whether 
associated with an AE) 
Only if associated with an 
SAE 
8.4.4.1. Medication Errors
Medication errors may result from the administration or consumption of the investigational 
product by the wrong subject, or at the wrong time, or at the wrong dosage strength. 
Medication errors include:

Medication errors involving subject exposure to the investigational product;

Potential medication errors or uses outside of what is foreseen in the protocol that do 
or do not involve the participating subject.
Such medication errors occurring to a study participant are to be captured on the medication 
error page of the CRF, which is a specific version of the AE page.
In the event of a medication dosing error, the sponsor should be notified immediately.
Whether or not the medication error is accompanied by an AE, as determined by the 
investigator, the medication error is recorded on the medication error page of the CRF and, if 
applicable, any associated AE(s), serious and non-serious, are recorded on an AE page of the 
CRF. 
Medication errors should be reported to Pfizer Safety within 24 hours on a CT SAE Report 
Form only when associated with an SAE.


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9. DATA ANALYSIS/STATISTICAL METHODS
Detailed methodology for summary and statistical analyses of the data collected in this study 
is outlined here and further detailed in a statistical analysis plan (SAP), which will be 
maintained by the sponsor.  The SAP may modify what is outlined in the protocol where 
appropriate; however, any major modifications of the primary endpoint definitions or their
analyses will also be reflected in a protocol amendment.
9.1. Sample Size Determination
The total sample size will be approximately 32 in this study.  This sample size has been 
determined by clinical judgment based on sponsor experience with other clinical studies with 
the investigational product and has not been based on statistical power.
For Cohort 1, a sample size of approximately 20 subjects has been selected empirically based 
upon the plan to confirm safety as for the skin irritation potential of crisaborole ointment 
2% in healthy Japanese subjects 20,21,23.
For Cohort 2, a sample size of approximately 12 subjects (10 subjects for crisaborole 
ointment 2% and 2 subjects for vehicle) with at least 25% Treatable %BSA, excluding scalp
and venous access area was selected empirically to minimize first exposure to Japanese 
subjects of a new drug. 
9.2. Efficacy Analysis
Efficacy analysis is not applicable to this study.
9.3. Pharmacokinetic Analysis (Cohort 2)
PK analysis sets are defined as follows:

The PK concentration population is defined as all subjects randomized and treated 
who have at least 1 concentration.

The PK parameter analysis population is defined as all subjects randomized and
treated who have at least 1 of the PK parameters of primary interest.
PK data will be descriptively summarized by study day for crisaborole and its metabolites 
respectively.  Comparison between study days will be performed by descriptive analysis of 
the within-subject ratio of Day 8/Day 1 PK parameters.  
Individual subject, mean and median profiles of the plasma concentration-time data will be 
plotted through Day 1 to Day 9, for crisaborole and its metabolites respectively.  Mean and 
median profiles will be presented on both linear and semi-log linear scales.
All plasma concentration values and plasma PK parameters will be listed by subject.


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For each subject, the following PK parameters will be calculated for crisaborole and its 
identified main oxidative metabolites (AN7602 and AN8323), whenever possible using 
noncompartmental analysis of concentration-time data.  Concentration values that are below 
the lower limit of quantification (BLQ) will be set to zero for this analysis.  Actual sample 
collection times will be used for this pharmacokinetic analysis:
Parameter
Day
Definition
Method of Determination
AUCτ
1, 8
Area under the plasma concentration-time 
curve from time zero to time tau (τ), the 
dosing interval, where τ = 12 hours for BID
dosing
Linear/Log trapezoidal 
method
AUClast
1, 8
Area under the plasma concentration-time 
curve from zero time until the last measurable 
concentration (Clast)
Linear/Log trapezoidal 
method
AUC24
1, 8
Area under the plasma concentration-time 
curve from time zero to the 24 hours postdose
Linear/Log trapezoidal 
method
Cmax
1, 8
Maximum observed plasma concentration 
over the dosing interval (12 hours) and over a 
24 hour time period (total daily dose)
Observed directly from data
Tmax
1, 8
Time to reach maximum observed plasma 
concentration
Observed directly from data as 
time of first occurrence
Rac (Cmax)
8
Accumulation ratio for Cmax
Cmax, Day 8/Cmax(first dose)
Rac (AUCτ)
8
Accumulation ratio for AUCτ
AUCτ, Day 8/AUCτ(first dose)
9.5. Safety Analysis
The safety analysis will be conducted for Cohort 1 and Cohort 2, separately.
The safety analysis population is defined as all subjects who receive at least one dose of 
study medication.
AEs, ECGs, BP, PR and safety laboratory data will be reviewed and summarized on an 
ongoing basis during the study to evaluate the safety of subjects.  Any clinical laboratory, 
ECG, BP, PR abnormalities of potential clinical concern will be described.  Safety data will 
be presented in tabular and/or graphical format and summarized descriptively, where 
appropriate.
Physical examination information collected during the course of the study will be considered 
source data and will not be required to be reported, unless otherwise noted.  However, any 
untoward findings identified on physical examinations conducted during the active collection 
period will be captured as AEs, if those findings meet the definition of an AE. Data collected 
at screening that are used for inclusion/exclusion criteria, such as laboratory data, ECGs, and 
vital signs, will be considered source data, and will not be required to be reported, unless 
otherwise noted.  Demographic data collected at screening will be reported.
CCI
CCI


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9.5.1. Electrocardiogram Analysis (Cohort 2)
Changes from baseline for the ECG parameters QT interval, heart rate, QTc interval, PR 
interval, and QRS interval will be summarized by treatment and time.
The number (%) of subjects with maximum postdose QTc values and maximum increases 
from baseline in the following categories will be tabulated by treatment: 
Safety QTc Assessment
Borderline (msec)
Prolonged (msec)
Absolute value
450 - <480
480
Absolute change
30 - <60
60
In addition, the number of subjects with corrected and uncorrected QT values 500 msec will 
be summarized.
9.5.2. Skin Irritation Analysis (Cohort 1)
For each subject, the maximum irritation score of the skin irritation assessment through all 
visits (ie, Day 3 and Day 4) will be calculated.
The primary endpoint for the skin irritation assessment will be the skin irritation index.  For
each investigational product, the skin irritation index will be calculated as the sum of the 
individual maximum irritation scores divided by the number of evaluable subjects who have 
the skin irritation assessment and multiplied by 100.23  The calculated skin irritation index 
will range from 0 to 400. As show in Table 5, for example, when the skin irritation index is 
equal to or smaller than 5, the investigational product will be categorized as ‘Safe’.  
Table 5.
Safety Criteria of Skin irritation index
Skin irritation indexa
Category
0- 5
Safe
5< - 15
Acceptable
15< - 30
Improvable
30< - 400
Risky
a: Skin irritation index = (Sum of higher scores in two assessments / number of evaluable subjects) × 100
For the maximum irritation score, the frequency (number and %) of individual maximum
irritation scores will be presented for each investigational product. The descriptive statistics 
[number, mean, standard deviation (SD), median, minimum and maximum] of the maximum 
irritation score will also be calculated for each investigational product.
For the irritation score, the frequency (number and %) of individual irritation scores will be 
presented for each investigational product at each visit. The descriptive statistics (number, 
mean, SD, median, minimum and maximum) of the irritation score will also be calculated for 
each investigational product at each visit.


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Individual irritation scores will be displayed in a data listing for all subjects.
9.6. Interim Analysis
No formal interim analysis will be conducted for this study.  However, for Cohort 1, as this is 
a sponsor open study, the sponsor may conduct unblinded reviews of the data during the 
course of the study for the purpose of safety assessment, facilitating dose escalation decisions, 
facilitating PK/pharmacodynamics (PD) modeling, skin irritation assessment, and/or 
supporting clinical development.
9.7. Data Monitoring Committee 
This study will not use a data monitoring committee (DMC).
10. QUALITY CONTROL AND QUALITY ASSURANCE
Pfizer or its agent will conduct periodic monitoring visits during study conduct for studies 
conducted at non-Pfizer investigator sites, to ensure that the protocol and Good Clinical 
Practices (GCPs) are being followed.  The monitors may review source documents to 
confirm that the data recorded on CRFs are accurate.  The investigator and institution will 
allow Pfizer monitors/auditors or its agents and appropriate regulatory authorities direct 
access to source documents to perform this verification.  This verification may also occur 
after study completion.
During study conduct and/or after study completion, the investigator site may be subject to 
review by the IRB/EC, and/or to quality assurance audits performed by Pfizer, or companies 
working with or on behalf of Pfizer, and/or to inspection by appropriate regulatory 
authorities.
The investigator(s) will notify Pfizer or its agents immediately of any regulatory inspection 
notification in relation to the study.  Furthermore, the investigator will cooperate with Pfizer 
or its agents to prepare the investigator site for the inspection and will allow Pfizer or its 
agent, whenever feasible, to be present during the inspection.  The investigator site and 
investigator will promptly resolve any discrepancies that are identified between the study 
data and the subject’s medical records.  The investigator will promptly provide copies of the 
inspection findings to Pfizer or its agent.  Before response submission to the regulatory 
authorities, the investigator will provide Pfizer or its agents with an opportunity to review 
and comment on responses to any such findings.
For studies conducted at non-Pfizer investigator sites, it is important that the investigator(s) 
and their relevant personnel are available during the monitoring visits and possible audits or 
inspections and that sufficient time is devoted to the process. 


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11. DATA HANDLING AND RECORD KEEPING
11.1. Case Report Forms/Data Collection Tools/Electronic Data Record
As used in this protocol, the term CRF should be understood to refer to either a paper form or 
an electronic data record or both, depending on the data collection method used in this study.
A CRF is required and should be completed for each included subject.  The completed 
original CRFs are the sole property of Pfizer and should not be made available in any form to 
third parties, except for authorized representatives of Pfizer or appropriate regulatory 
authorities, without written permission from Pfizer.
The investigator has ultimate responsibility for the collection and reporting of all clinical, 
safety, and laboratory data entered on the CRFs and any other data collection forms (source 
documents) and ensuring that they are accurate, authentic/original, attributable, complete, 
consistent, legible, timely (contemporaneous), enduring, and available when required.  The 
CRFs must be signed by the investigator or by an authorized staff member to attest that the 
data contained on the CRFs are true.  Any corrections to entries made in the CRFs or source 
documents must be dated, initialed, and explained (if necessary) and should not obscure the 
original entry.
In most cases the source documents are the hospital or the physician's chart.  In these cases, 
data collected on the CRFs must match those charts. 
In some cases, the CRF may also serve as the source document.  In these cases, a document 
should be available at the investigator site and at Pfizer that clearly identifies those data that 
will be recorded on the CRF, and for which the CRF will stand as the source document. 
11.2. Record Retention
To enable evaluations and/or inspections/audits from regulatory authorities or Pfizer, the 
investigator agrees to keep records, including the identity of all participating subjects 
(sufficient information to link records, eg, CRFs and hospital records), all original signed 
informed consent documents, copies of all CRFs, safety reporting forms, source documents, 
detailed records of treatment disposition, and adequate documentation of relevant 
correspondence (eg, letters, meeting minutes, and telephone call reports).  The records should 
be retained by the investigator according to the ICH guidelines, according to local 
regulations, or as specified in the clinical study agreement (CSA), whichever is longer.
If the investigator becomes unable for any reason to continue to retain study records for the 
required period (eg, retirement, relocation), Pfizer should be prospectively notified.  The 
study records must be transferred to a designee acceptable to Pfizer, such as another 
investigator, another institution, or to an independent third party arranged by Pfizer. 
Investigator records must be kept for a minimum of 15 years after completion or 
discontinuation of the study or for longer if required by applicable local regulations. 


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The investigator must obtain Pfizer's written permission before disposing of any records, 
even if retention requirements have been met.
12. ETHICS
12.1. Institutional Review Board/Ethics Committee
It is the responsibility of the investigator to have prospective approval of the study protocol, 
protocol amendments, informed consent documents, and other relevant documents, 
eg, recruitment advertisements, if applicable, from the IRB/EC.  All correspondence with the 
IRB/EC should be retained in the investigator file.  Copies of IRB/EC approvals should be 
forwarded to Pfizer.
The only circumstance in which an amendment may be initiated prior to IRB/EC approval is 
where the change is necessary to eliminate apparent immediate hazards to the subjects.  In 
that event, the investigator must notify the IRB/EC and Pfizer in writing immediately after 
the implementation.
12.2. Ethical Conduct of the Study
The study will be conducted in accordance with the protocol, legal and regulatory 
requirements, and the general principles set forth in the International Ethical Guidelines for 
Biomedical Research Involving Human Subjects (Council for International Organizations of 
Medical Sciences 2002), ICH Guideline for Good Clinical Practice, and the Declaration of 
Helsinki.
12.3. Subject Information and Consent
All parties will ensure protection of subject personal data and will not include subject names 
or other identifiable data in any reports, publications, or other disclosures, except where 
required by laws. 
When study data are compiled for transfer to Pfizer and other authorized parties, subject 
names, addresses, and other identifiable data will be replaced by numerical codes based on a 
numbering system provided by Pfizer in order to de-identify study subjects.  The investigator 
site will maintain a confidential list of subjects who participated in the study, linking each 
subject’s numerical code to his or her actual identity.  In case of data transfer, Pfizer will 
maintain high standards of confidentiality and protection of subjects’ personal data consistent 
with applicable privacy laws.
The informed consent documents and any subject recruitment materials must be in 
compliance with ICH GCP, local regulatory requirements, and legal requirements, including 
applicable privacy laws.
The informed consent documents used during the informed consent process and any subject 
recruitment materials must be reviewed and approved by Pfizer, approved by the IRB/EC 
before use, and available for inspection.


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The investigator must ensure that each study subject is fully informed about the nature and 
objectives of the study and possible risks associated with participation. 
The investigator, or a person designated by the investigator, will obtain written informed 
consent from each subject before any study-specific activity is performed.  The investigator 
will retain the original of each subject's signed consent document.
12.4. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP
In the event of any prohibition or restriction imposed (ie, clinical hold) by an applicable 
regulatory authority in any area of the world, or if the investigator is aware of any new 
information that might influence the evaluation of the benefits and risks of the investigational 
product, Pfizer should be informed immediately. 
In addition, the investigator will inform Pfizer immediately of any urgent safety measures 
taken by the investigator to protect the study subjects against any immediate hazard, and of 
any serious breaches of this protocol or of ICH GCP that the investigator becomes aware of.
13. DEFINITION OF END OF TRIAL
Last subject last visit (LSLV) is defined as the date the investigator reviews the last subject’s 
final safety data and determines that no further evaluation is required for the subject to 
complete the trial.  End of Trial in Japan is defined as LSLV.
14. SPONSOR DISCONTINUATION CRITERIA
Premature termination of this study may occur because of a regulatory authority decision, 
change in opinion of the IRB/EC, or investigational product safety problems, or at the 
discretion of Pfizer.  In addition, Pfizer retains the right to discontinue development of 
crisaborole at any time.
If a study is prematurely terminated, Pfizer will promptly notify the investigator.  After 
notification, the investigator must contact all participating subjects and the hospital pharmacy 
(if applicable) within 7 days.  As directed by Pfizer, all study materials must be collected and 
all CRFs completed to the greatest extent possible.
15. PUBLICATION OF STUDY RESULTS 
15.1. Communication of Results by Pfizer
Pfizer fulfills its commitment to publicly disclose clinical study results through posting the 
results of studies on www.clinicaltrials.gov (ClinicalTrials.gov), the European Clinical Trials 
Database (EudraCT), and/or www.pfizer.com, and other public registries in accordance with 
applicable local laws/regulations.
In all cases, study results are reported by Pfizer in an objective, accurate, balanced, and 
complete manner and are reported regardless of the outcome of the study or the country in 
which the study was conducted.


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www.clinicaltrials.gov 
Pfizer posts clinical trial US Basic Results on www.clinicaltrials.gov for Pfizer-sponsored 
interventional studies (conducted in patients) that evaluate the safety and/or efficacy of a 
Pfizer product, regardless of the geographical location in which the study is conducted.  US 
Basic Results are submitted for posting within 1 year of the primary completion date (PCD) 
for studies in adult populations or within 6 months of the PCD for studies in pediatric 
populations.
PCD is defined as the date that the final subject was examined or received an intervention for 
the purposes of final collection of data for the primary outcome, whether the clinical study 
concluded according to the prespecified protocol or was terminated.
EudraCT
Pfizer posts European Union (EU) Basic Results on EudraCT for all Pfizer-sponsored 
interventional studies that are in scope of EU requirements.  EU Basic Results are submitted 
for posting within 1 year of the PCD for studies in adult populations or within 6 months of 
the PCD for studies in pediatric populations.
www.pfizer.com
Pfizer posts public disclosure synopses (CSR synopses in which any data that could be used 
to identify individual patients have been removed) on www.pfizer.com for Pfizer-sponsored 
interventional studies at the same time the US Basic Results document is posted to 
www.clinicaltrials.gov.
15.2. Publications by Investigators 
Pfizer supports the exercise of academic freedom and has no objection to publication by the 
principal investigator (PI) of the results of the study based on information collected or 
generated by the PI, whether or not the results are favorable to the Pfizer product.  However, 
to ensure against inadvertent disclosure of confidential information or unprotected 
inventions, the investigator will provide Pfizer an opportunity to review any proposed 
publication or other type of disclosure of the results of the study (collectively, “publication”) 
before it is submitted or otherwise disclosed.
The investigator will provide any publication to Pfizer at least 30 days before it is submitted 
for publication or otherwise disclosed.  If any patent action is required to protect intellectual 
property rights, the investigator agrees to delay the disclosure for a period not to exceed an 
additional 60 days.
The investigator will, on request, remove any previously undisclosed confidential 
information before disclosure, except for any study- or Pfizer product-related information 
necessary to the appropriate scientific presentation or understanding of the study results.


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If the study is part of a multicenter study, the investigator agrees that the first publication is 
to be a joint publication covering all investigator sites, and that any subsequent publications 
by the PI will reference that primary publication.  However, if a joint manuscript has not 
been submitted for publication within 12 months of completion or termination of the study at 
all participating sites, the investigator is free to publish separately, subject to the other 
requirements of this section.
For all publications relating to the study, the institution will comply with recognized ethical 
standards concerning publications and authorship, including Section II - “Ethical 
Considerations in the Conduct and Reporting of Research” of the Uniform Requirements for 
Manuscripts Submitted to Biomedical Journals, http://www.icmje.org/index.html#authorship,
established by the International Committee of Medical Journal Editors.
Publication of study results is also provided for in the CSA between Pfizer and the 
institution.  In this section entitled Publications by Investigators, the defined terms shall have 
the meanings given to them in the CSA.
If there is any conflict between the CSA and any attachments to it, the terms of the CSA 
control.  If there is any conflict between this protocol and the CSA, this protocol will control 
as to any issue regarding treatment of study subjects, and the CSA will control as to all other 
issues.


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16. REFERENCES
1.
Bieber T. Atopic dermatitis. N Engl J Med. 2008 Apr;358(14):1483-94. 
2.
Lewis-Jones S. Quality of life and childhood atopic dermatitis: the misery of living with 
childhood eczema. Int J Clin Pract. 2006 Aug;60(8):984-92.
3.
Eichenfield LF, Ellis CN, Mancini AJ, et al. Atopic dermatitis: epidemiology and 
pathogenesis update. Semin Cutan Med Surg. 2012 Sep;31(3 Suppl):S3-5. 
4.
Leicht S, Hanggi M. Atopic dermatitis. How to incorporate advances in management. 
Postgrad Med. 2001 Jun;109(6):119–27. 
5.
Saeki H. Management of Atopic Dermatitis in Japan. J Nippon Med Sch. 
2017;84(1):2-11.
6.
Arkwright PD, Motala C, Subramanian H, et al. Management of difficult-to-treat atopic 
dermatitis. J Allergy Clin Immunol Pract. 2013 Mar;1(2):142-51. 
7.
Leung DY. New insights into atopic dermatitis: role of skin barrier and immune 
dysregulation. Allergol Int. 2013 Jun;62(2):151-61. 
8.
Bantz SK, Zhu Z, Zheng T. The atopic march: progression from atopic dermatitis to 
allergic rhinitis and asthma. J Clin Cell Immunol. 2014 Apr;5(2). 
9.
Saunes M, Oien T, Dotterud CK, et al. Early eczema and the risk of childhood asthma: a 
prospective, population-based study. BMC Pediatr. 2012 Oct 24;12:168. 
10.
Garg N, Silverberg JI. Epidemiology of childhood atopic dermatitis. Clin Dermatol. 
2015 May-Jun;33(3):281-8.
11.
Beatti PE, Lewis-Jones MS. A comparative study of impairment of quality of life in 
children with skin disease and children with other chronic childhood diseases. Br J 
Dermatol. 2006 Jul;155(1):145-51.
12.
Carroll CL, Balkrishnan R, Feldman SR, et al. The burden of atopic dermatitis: impact 
on the patient, family, and society. Pediatr Dermatol. 2005 May-Jun;22(3):192-9.
13.
Halvorsen JA, Lien L, Dalgard F, et al. Suicidal ideation, mental health problems, and 
social function in adolescents with eczema: a population-based study. J Invest 
Dermatol. 2014 Jul;134(7):1847-54.
14.
Watson W, Kapur S. Atopic dermatitis. Allergy Asthma Clin Immunol. 2011 Nov 10;7 
Suppl 1:S4.
15.
Berardesca E, Maibach H. Racial differences in skin pathophysiology. J Am Acad 
Dermatol. 1996 Apr;34(4):667-72.


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16.
Muizzuddin N, Hellemans L, Overloop LV. Structural and functional differences in 
barrier properties of African American, Caucasian and East Asian skin. J Dermatol Sci. 
2010 Aug;59(2):123-8.
17.
Rapaport MJ. Patch testing in Japanese subjects. Contact Dermatitis. 1984 
Aug;11(2):93-7.
18.
Aramaki J, Kawana S, Effendy I, et al. Differences of skin irritation between Japanese 
and European women. Br J Dermatol. 2002 Jun;146(6):1052-6.
19.
Robinson MK. Racial differences in acute and cumulative skin irritation responses 
between Caucasian and Asian populations. Contact Dermatitis. 2000 Mar;42(3):134-43.
20.
Kawamura T, Shoji S, Masuda T et al. Basic studies on the standardization of patch test. 
Jpn J Dermatol. 1970; 80: 301-14 (Japanese).
21.
Sugai T. Contact dermatitis and patch test. Skin Research. 1977; 19(2):210–22
(Japanese).
22.
Committee for Guideline for Diagnosis of Contact Dermatitis. Japanese Dermatological 
Association. Guideline for diagnosis of contact dermatitis. Jpn J Dermatol. 2009; 
119(9):1757-93 (Japanese).
23.
Sugai T. Safety Evaluation of Cosmetic Products. J. Jpn Cosmet Sci Soc. 1995;19:49-56
(Japanese) .
24.
EucrisaUSPI 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/207695s000lbl.pdf
25.
Thomas CL, Finlay AY. The 'handprint' approximates to 1% of the total body surface 
area whereas the 'palm minus the fingers' does not. Br J Dermatol. 2007 Nov; 157(5): 
1080-1.
26.
Hanifin JM, Rajka G. Diagnostic features of atopic dermatitis. Acta Derm Venereol 
(Stockh) 1980;92(suppl):44-7.


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Appendix 1. Abbreviations 
The following is a list of abbreviations that may be used in the protocol.
Abbreviation
Term
AD
atopic dermatitis
ADSI
atopic dermatitis severity index
AE
adverse event
ALT
alanine aminotransferase
AST
aspartate aminotransferase
AUC
area under the curve
AUC12
area under the plasma concentration-time curve from time zero to 
the 12 hours
AUC24
area under the plasma concentration-time curve from time zero to 
the 24 hours
AUClast
area under the plasma concentration-time curve from zero time until 
the last measurable concentration
AUCτ
area under the plasma concentration-time curve from time zero to 
time tau (τ)
BID
twice daily
BLQ
below the lower limit of quantification
-hCG
beta-human chorionic gonadotropin
BMI
body mass index
BP
blood pressure
BPO
benzoyl peroxide
BSA
body surface area
BUN
blood urea nitrogen
cAMP
cyclic adenosine monophosphate
CK
creatine kinase
CT
clinical trial
Cmax
maximum observed plasma concentration
CO2
carbon dioxide (bicarbonate)
CRF
case report form
CRU
clinical research unit
CSA
clinical study agreement
CSR
clinical study report
DILI
drug-induced liver injury
DMC
data monitoring committee
DNA
deoxyribonucleic acid
EC
ethics committee
EC50
half maximal effective concentration
ECG
electrocardiogram
EDP
exposure during pregnancy
CCI
CCI


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Abbreviation
Term
EU
European Union
EudraCT
European Clinical Trials Database
FDA
Food and Drug Administration
FSH
follicle-stimulating hormone
GCP
Good Clinical Practice
GGT
gamma-glutamyl transferase
HepBcAb
hepatitis B core antibody
HepBsAg 
hepatitis B surface antigen
HCVAb
hepatitis C antibody
HIV
human immunodeficiency virus
HRQoL
health related quality of life
IB
Investigator’s Brochure
ICH
International Conference on Harmonisation
ID
identification
IND
investigational new drug application
INR
international normalized ratio
IP manual
investigational product manual
IRB
institutional review board
ISGA
investigator’s static global assessment
IUD
intrauterine device
IV
intravenous
K2EDTA
dipotassium ethylenediaminetetraacetic acid
LFT
liver function test
LSLV
last subject last visit 
MCH
mean corpuscular hemoglobin
MCHC
mean corpuscular hemoglobin concentration
MCV
mean corpuscular volume
MUSE
maximal use systemic exposure
N/A
not applicable
NSAIDs
nonsteroidal anti-inflammatory drugs
PCD
primary completion date
PD
pharmacodynamic(s)
PDE-4
phosphodiesterase-4
pH
potential of hydrogen
PI
principal investigator
PK
pharmacokinetic(s)
PKA
protein kinase a
PMA
phorbol 12 myristate 13 acetate
PR
pulse rate
PRN
as needed
PT
prothrombin time
CCI
CCI


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Abbreviation
Term
PUVA
psoralen plus UVA
QD
once daily
QTc
corrected QT
qual
qualitative
RBC
red blood cell
RIPT
repeat-insult patch test
RNA
ribonucleic acid
SAE
serious adverse event
SAP
statistical analysis plan
SD
standard deviation
SOP
standard operating procedure
SRSD
single reference safety document
TBili
total bilirubin
TEAE
treatment-emergent adverse event
Tmax
time to reach maximum observed plasma concentration
THC
tetrahydrocannabinol
TQT
thorough QT
ULN
upper limit of normal
US
United States
UV
ultraviolet
UVA
ultraviolet A
UVB
ultraviolet B
WBC
white blood cell


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Appendix 2. Diagnostic Criteria for Atopic Dermatitis (Cohort 2)
Per Inclusion Criterion 2 for Cohort 2, a subject is to have a clinical diagnosis of atopic 
dermatitis according to the criteria of Hanifin and Rajka.26
Table 6.
Hanifin and Rajka’s Diagnostic Criteria for Atopic Dermatitis
Major Criteria (must have at least three)
Pruritus
Typical morphology and distribution:
   Adults: flexural lichenification or linearity
   Children and infants: facial and extensor involvement
Chronic or chronically-relapsing dermatitis
Personal or family history of atopy (asthma, allergic rhinitis, atopic dermatitis)
Minor Criteria (must have at least three)
Xerosis
Icthyosis/keratosis pilaris/palmar hyperlinearity
Immediate (type 1) skin test reactivity
Elevated serum immunogloblin E (IgE)
Early age of onset
Tendency toward cutaneous infections (esp. staphylococcus aureus and herpes simplex), 
impaired cell-mediated immunity
Tendency toward non-specific hand or foot dermatitis
Nipple eczema
Cheilitis
Recurrent conjunctivitis
Dennie-Morgan infraorbital fold
Keratoconus
Anterior subcapsular cataracts
Orbital darkening
Facial pallor, facial erythema
Pityriasis alba
Anterior neck folds
Itch when sweating
Intolerance to wool and lipid solvents
Perifollicular accentuation
Food intolerance
Course influenced by environmental and emotional factors
White demographism, delayed blanch


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Appendix 3. Investigator’s Static Global Assessment (Cohort 2)
The ISGA, a five-point global static assessment of AD severity (Table 7), will be assessed to 
characterize subjects’ overall disease severity across all treatable AD lesions. 
ISGA assessment must be done by the PI or designee. 
Table 7.
Investigator’s Static Global Assessment
Score
Grade
Definition
0
Clear
Minor residual hypo/hyperpigmentation; no erythema or 
induration/papulation; no oozing/crusting
1
Almost Clear
Trace faint pink erythema, with barely perceptible 
induration/papulation and no oozing/crusting
2
Mild
Faint pink erythema with mild induration/papulation and no 
oozing/crusting 
3
Moderate
Pink red erythema with moderate induration/papulation with or 
without oozing/crusting
4
Severe
Deep or bright red erythema with severe induration/papulation and 
with oozing/crusting

SAP_001.pdf: 
Protocol C3291029 (PF-06930164) Statistical Analysis Plan
Page 1
TMF Doc ID: 98.03
Protocol C3291029
A phase 1, single-center, randomized, vehicle-controlled, parallel-cohort study of crisaborole 
ointment 2% to evaluate the skin irritation potential in adult Japanese healthy subjects, and to 
evaluate the safety, tolerability and pharmacokinetics in adult Japanese subjects with mild to 
moderate atopic dermatitis
Statistical Analysis Plan 
(SAP)
Version:
2.0
Date:
30-Nov-2017


Protocol C3291029 (PF-06930164) Statistical Analysis Plan
Page 2
TMF Doc ID: 98.03
TABLE OF CONTENTS
LIST OF TABLES.....................................................................................................................3
APPENDICES ...........................................................................................................................4
1. VERSION HISTORY............................................................................................................5
2. INTRODUCTION .................................................................................................................5
2.1. Study Objectives .......................................................................................................5
2.2. Study Design .............................................................................................................6
3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS ..................................................................................................................7
3.1. Primary Endpoints.....................................................................................................7
3.2. Secondary Endpoints.................................................................................................7
3.3. Other Endpoints.........................................................................................................7
3.3.1. PK Endpoints................................................................................................7
..........................................................................................8
3.4. Baseline Variables.....................................................................................................8
3.5. Safety Endpoints .......................................................................................................8
3.5.1. Adverse Events.............................................................................................8
4. ANALYSIS SETS .................................................................................................................8
4.1. Full Analysis Set .......................................................................................................8
4.2. Per Protocol Analysis Set..........................................................................................8
4.3. Safety Analysis Set....................................................................................................8
4.4. Other Analysis Sets ...................................................................................................9
4.4.1. PK Analysis Sets...........................................................................................9
4.5. Protocol Deviations...................................................................................................9
5. GENERAL METHODOLOGY AND CONVENTIONS......................................................9
5.1. Hypotheses and Decision Rules ................................................................................9
5.2. General Methods .......................................................................................................9
5.2.1. Analyses for Binary Data..............................................................................9
5.2.2. Analyses for Continuous Data......................................................................9
5.3. Methods to Manage Missing Data ..........................................................................10
5.3.1. Safety Data..................................................................................................10
5.3.2. Skin Irritation Score....................................................................................10
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5.3.3. Concentrations Below the Limit of Quantification (BLQ).........................10
5.3.4. Deviations, Missing Concentrations and Anomalous Values for PK.........10
5.3.5. Pharmacokinetic Parameters.......................................................................10
6. ANALYSES AND SUMMARIES ......................................................................................11
6.1. Primary Endpoints...................................................................................................11
6.1.1. Skin Irritation Index....................................................................................11
6.1.2. Adverse Events...........................................................................................11
6.1.3. Laboratory Data..........................................................................................11
6.1.4. Vital Signs ..................................................................................................11
6.1.5. Electrocardiogram.......................................................................................12
6.2. Secondary Endpoints...............................................................................................12
6.2.1. Adverse Events...........................................................................................12
6.2.2. PK Parameters ............................................................................................12
6.3. Other Endpoints.......................................................................................................13
6.3.1. Skin Irritation Score....................................................................................13
...................................................................13
6.4. Subset Analyses.......................................................................................................13
6.5. Baseline and Other Summaries and Analyses.........................................................14
6.5.1. Baseline Summaries....................................................................................14
6.5.2. Study Conduct and Subject Disposition .....................................................14
6.5.3. Study Treatment Exposure .........................................................................14
6.5.4. Concomitant Medications and Non-Drug Treatments................................14
6.6. Safety Summaries and Analyses .............................................................................14
7. INTERIM ANALYSES.......................................................................................................15
7.1. Introduction .............................................................................................................15
7.2. Interim Analyses and Summaries............................................................................15
8. REFERENCES ....................................................................................................................15
9. APPENDICES .....................................................................................................................16
LIST OF TABLES
Table 1.
Summary of Major Changes in SAP Amendments................................................5
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APPENDICES
Appendix 1. DATA DERIVATION DETAILS ......................................................................16


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1. VERSION HISTORY
This Statistical Analysis Plan (SAP) for study C3291029 is based on the protocol 
amendment-1 dated 14July2017.  
Table 1.
Summary of Major Changes in SAP Amendments
SAP Version
Change
Rationale
1.0
Not Applicable
Not Applicable
2.0
6.1.4. Vital Signs, 6.1.5. Electrocardiogram, 
6.5.1. Baseline Summaries, 6.5.3. Study 
Treatment Exposure

Clarified the analysis plan.
9. APPENDICES

Defined the visit windows for safety 
parameters.
Blind table 
review before the 
final analysis
2. INTRODUCTION
This SAP provides the detailed methodology for summary and statistical analyses of the data 
collected in study C3291029.  This document may modify the plans outlined in the protocol; 
however, any major modifications of the primary endpoint definition or its analysis will also 
be reflected in a protocol amendment.
2.1. Study Objectives
Cohort 1
The primary objective is to investigate the skin irritation potential of a single topical dose of 
crisaborole ointment 2% and vehicle in adult Japanese healthy subjects.
The secondary objective is to investigate the safety and tolerability of a single topical dose of 
crisaborole ointment 2% and vehicle in adult Japanese healthy subjects.
Cohort 2
The primary objective is to investigate the safety and tolerability of multiple topical doses of 
crisaborole ointment 2% twice daily (BID) in adult Japanese subjects with mild to moderate 
atopic dermatitis (AD).


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The secondary objective is to characterize plasma pharmacokinetic (PK) of crisaborole and 
its identified main oxidative metabolites (AN7602 and AN8323) following multiple topical 
doses of crisaborole ointment 2% BID in adult Japanese subjects with mild to moderate AD.
2.2. Study Design
This is a Phase 1, single-center, randomized, vehicle-controlled, parallel-cohort study of 
crisaborole ointment 2% to evaluate the skin irritation potential in adult Japanese healthy 
subjects in Cohort 1, and to evaluate the safety, tolerability and PK in adult Japanese subjects
with mild to moderate AD in Cohort 2.  Both cohorts will be run in parallel and completion 
of Cohort 1 is not required to make a decision to proceed with Cohort 2. 
Cohort
N
Investigational products
Cohort 1
Skin irritation cohort in 
healthy subjects
20
Crisaborole ointment 2% and vehicle
Cohort 2
Safety, tolerability and PK 
cohort in subjects with mild 
to moderate AD
12
Crisaborole ointment 2% (n=10)
Vehicle (n=2)
Cohort 1
This is a randomized, observer and subject blind, vehicle controlled cohort, of the 
investigational products (crisaborole ointment 2% and vehicle) under occlusive patch 
conditions to evaluate the skin irritation potential and safety in Japanese healthy male 
subjects aged 20 to 55 years, inclusive.  Approximately 20 subjects will be enrolled into the 
cohort.  All subjects will have skin area fields designated for the investigational products 
patches at two randomly assigned, adjacent sites, for the purpose of determining irritation 
potential.  All subjects enrolled in Cohort 1 will receive both products (crisaborole ointment 
2%, and vehicle).  For Cohort 1, subjects will be randomly assigned in a 1:1 ratio to either
Randomization sequence 1 [Application placement 1 (Upper): Crisaborole ointment 2%, 
Application placement 2 (Lower): Vehicle] or Randomization sequence 2 [Application 
placement 1 (Upper): Vehicle, Application placement 2 (Lower): Crisaborole ointment 2%].
Cohort 2
This is a randomized, double blind cohort of crisaborole ointment 2% BID to evaluate the 
safety, tolerability and PK in adult Japanese subjects with mild to moderate AD.  The cohort 
will enroll male and female subjects with AD aged 20 years to 55 years, inclusive, at the time 
of screening.  Approximately 12 subjects having at least 25% Treatable %BSA, defined as 
the percent of a subject’s total body surface area (BSA) that is AD involved and is not on the 
scalp or in designated venous access areas, will be enrolled into the study.  For Cohort 2, 
subjects will be randomly assigned in a 5:1 ratio to either crisaborole ointment 2% or vehicle.
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3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS
3.1. Primary Endpoints
Cohort 1

Skin irritation index.
Cohort 2

Adverse events (AEs), clinical laboratory tests, vital signs, and 12 lead 
electrocardiogram (ECG).
3.2. Secondary Endpoints
Cohort 1

AEs.
Cohort 2

PK parameters: Cmax, Tmax, AUClast, AUC24, AUCτ on Day 1 and Day 8, and Rac
(Cmax) and Rac (AUCτ) on Day 8.
3.3. Other Endpoints
3.3.1. PK Endpoints
PK parameters are the secondary endpoints for Cohort 2.  For each subject, the following PK 
parameters will be calculated for crisaborole and its identified main oxidative metabolites 
(AN7602 and AN8323), as data allows using noncompartmental analysis of 
concentration-time data.
Parameter
Day
Definition
Method of Determination
AUCτ
1, 8
Area under the plasma concentration-time 
curve from time zero to time tau (τ), the 
dosing interval, where τ = 12 hours for BID 
dosing
Linear/Log trapezoidal 
method
AUClast
1, 8
Area under the plasma concentration-time 
curve from zero time until the last measurable 
concentration (Clast)
Linear/Log trapezoidal 
method
AUC24
1, 8
Area under the plasma concentration-time 
curve from time zero to the 24 hours postdose
Linear/Log trapezoidal 
method
Cmax
1, 8
Maximum observed plasma concentration 
over the dosing interval (12 hours) and over a 
24 hour time period (total daily dose)
Observed directly from data
Tmax
1, 8
Time to reach maximum observed plasma 
concentration
Observed directly from data as 
time of first occurrence
Rac (Cmax)
8
Accumulation ratio for Cmax
Cmax, Day 8/Cmax(first dose)
Rac (AUCτ)
8
Accumulation ratio for AUCτ
AUCτ, Day 8/AUCτ(first dose)


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3.4. Baseline Variables
There are no baseline variables used as covariates or stratification factors in analyses.
3.5. Safety Endpoints
3.5.1. Adverse Events
AEs will be captured and reported in accordance with Pfizer data standards.
An adverse event is considered treatment emergent relative to a given treatment if:

the event occurs for the first time during the effective duration of treatment and was 
not seen prior to the start of treatment (for example, during the baseline or run-in 
period), or

the event was seen prior to the start of treatment but increased in severity during 
treatment.
The effective duration of treatment is determined by the lag time.  Any event occurring 
within the lag time, whether this occurs during a break in treatment or at the end of treatment, 
is attributed to the corresponding treatment period.  An infinite lag will be used for this study.
4. ANALYSIS SETS
Data for all subjects will be assessed to determine if subjects meet the criteria for inclusion in 
each analysis population prior to unblinding and releasing the database and classifications 
will be documented per standard operating procedures.
4.1. Full Analysis Set
Not Applicable.
4.2. Per Protocol Analysis Set
Not Applicable.
4.3. Safety Analysis Set
The safety analysis population is defined as all subjects who receive at least one dose of 
study medication. All subjects who receive at least one dose of study medication are 
classified according actual study treatment received. The safety analysis set is the primary 
population for treatment administration/compliance and safety. A randomized but not treated 
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subject will be excluded from the safety analyses.  A treated but not randomized subject will 
be reported under the treatment actually received.
4.4. Other Analysis Sets
4.4.1. PK Analysis Sets

The PK concentration population is defined as all subjects randomized and treated 
who have at least 1 concentration.

The PK parameter analysis population is defined as all subjects randomized and
treated who have at least 1 of the PK parameters of primary interest.
4.5. Protocol Deviations
Subjects who experience events that may affect their PK profile may be excluded from the 
PK analysis. At the discretion of the pharmacokineticist a concentration value may also be 
excluded if the deviation in sampling time is of sufficient concern or if the concentration is 
anomalous for any other reason.
A full list of protocol deviations will be complied and reviewed to identify major and minor
deviation prior to database closure.
5. GENERAL METHODOLOGY AND CONVENTIONS

The final analysis will be performed at study subjects’ dataset release after last subject 
last visit.

All data will be analyzed separately for each cohort.
5.1. Hypotheses and Decision Rules
There are no statistical hypotheses to be tested.
5.2. General Methods 
5.2.1. Analyses for Binary Data
Unless otherwise explicitly stated, descriptive statistics for binary variables are the
percentage (%), and the numerator (n) and the denominator (N) used in the percentage 
calculation.
5.2.2. Analyses for Continuous Data
Unless otherwise explicitly stated, descriptive statistics for continuous variables are n, mean, 
median, standard deviation, minimum, and maximum.


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5.3. Methods to Manage Missing Data
5.3.1. Safety Data
Handling of missing information related to safety data, such as missing or partially missing 
data, will be in accordance with Pfizer data standards.
5.3.2. Skin Irritation Score
Missing values of the skin irritation score will not be imputed in any data analysis.
5.3.3. Concentrations Below the Limit of Quantification (BLQ)
In all data presentations (except listings), concentrations BLQ will be set to zero (In listings 
BLQ values will be reported as “<LLQ”, where LLQ will be replaced with value for the 
lower limit of qualntification).
5.3.4. Deviations, Missing Concentrations and Anomalous Values for PK
In summary tables and plots of mean and median profiles, statistics will be calculated having 
set concentrations to missing if one of the following cases is true:

A concentration has been collected as ND (ie, not done) or NS (ie, no sample);

A deviation in sampling time is of sufficient concern (ie, sampling time outside of 
20% of nominal time) or a concentration has been flagged anomalous by the 
pharmacokineticist.
Note that summary statistics will not be presented at a particular time point if more than 
50% of the data are missing.
5.3.5. Pharmacokinetic Parameters
Actual PK sampling times will be used in the derivation of PK parameters.
If a PK parameter cannot be derived from a subject’s concentration data, the parameter will 
be coded as NC (ie, not calculated).  (Note that NC values will not be generated beyond the 
day that a subject discontinues).
In summary tables, statistics will be calculated by setting NC values to missing; and statistics
will not be presented for a particular treatment if more than 50% of the data are NC.
If an individual subject has a known biased estimate of a PK parameter (for example, due to 
an unexpected event before all the drug is absorbed in the body), this will be footnoted in 
summary tables and will not be included in the calculation of summary statistics or statistical 
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6. ANALYSES AND SUMMARIES
6.1. Primary Endpoints
6.1.1. Skin Irritation Index
Skin irritation index is the primary endpoint for Cohort1.  For each investigational product
(ie, treatment), the skin irritation index will be calculated as the sum of the individual 
maximum irritation scores divided by the number of evaluable subjects who have the skin 
irritation assessment for the safety analysis population and multiplied by 100.  The calculated 
skin irritation index will range from 0 to 400.  As show in the following table, for example, 
when the skin irritation index is equal to or smaller than 5, the investigational product will be 
categorized as ‘Safe’.1,2,3
Safety Criteria of Skin Irritation Index
Skin irritation indexa
Category
0- 5
Safe
5< - 15
Acceptable
15< - 30
Improvable
30< - 400
Risky
a: Skin irritation index = (Sum of individual maximum irritation scores / number of evaluable subjects) × 
100
6.1.2. Adverse Events
AEs are one of the primary endpoints for Cohort 2.  The analysis of AEs will be based on the 
safety analysis population.  Descriptive summaries and listing of the AE/SAE data will be 
provided by treatment.  In addition, AEs occurred in the treatment area will be separately 
summarized by treatment.  AEs will be reported in accordance with the Pfizer data standards.
It should be recognized that most studies are not designed to reliably demonstrate a causal 
relationship between the use of a pharmaceutical product and an adverse event or a group of 
adverse events. Except for select events in unique situations, studies do not employ formal 
adjudication procedures for the purpose of event classification. As such, safety analysis is 
generally considered as an exploratory analysis and its purpose is to generate hypotheses for 
further investigation.
6.1.3. Laboratory Data
Laboratory data are one of the primary endpoints for Cohort 2.  The analysis of laboratory 
data will be based on the safety analysis population. Laboratory data will be descriptively
summarized and listed by treatment in accordance with the Pfizer data standards.  Baseline 
will be the last predose measurement.
6.1.4. Vital Signs
Vital signs data are one of the primary endpoints for Cohort 2.  The analysis of vital signs 
data will be based on the safety analysis population.  Absolute values and changes from 


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baseline in blood pressure and pulse rate will be summarized and listed by treatment and visit
in accordance with the Pfizer data standards.  Baseline will be the last predose measurement.
6.1.5. Electrocardiogram
ECG data are one of the primary endpoints for Cohort 2.  Absolute values and changes from 
baseline for the ECG parameters, QT interval, heart rate, QTc (ie, QTcF) interval, PR 
interval, QRS interval, and RR interval will be summarized descriptively by treatment and 
visit for the safety analysis population.
The number (%) of subjects with maximum postdose QTc values and maximum increases 
from baseline in the following categories will be tabulated by treatment: 
Safety QTc Assessment
Borderline (msec)
Prolonged (msec)
Absolute value
450 - <480
480
Absolute change
30 - <60
60
In addition, the number of subjects with corrected and uncorrected QT values 500 msec will 
be summarized.
6.2. Secondary Endpoints
6.2.1. Adverse Events
AEs are the sencondary endpoint for Cohort 1. The analysis of AEs will be based on the 
safety analysis population.  Descriptive summaries and listing of the AE/SAE data will be 
provided.  In addition, AEs occurred in the application area will be summarized by treatment 
separately.  AEs will be reported in accordance with the Pfizer data standards.
6.2.2. PK Parameters
PK parameters are the secondary endpoints for Cohort 2.  PK analysis will be based on the 
PK analysis set.
PK data will be descriptively summarized by day and analyte for crisaborole and its 
metabolites respectively.  Comparison between days will be performed by descriptive 
analysis of the within-subject ratio of Day 8/Day 1 PK parameters.  The set of summary 
statistics as specified in the table below:
Day
Parameter
Summary statistics
1, 8
AUCτ, AUClast, AUC24, Cmax
n, arithmetic mean, median, CV%, standard deviation, 
minimum, maximum, geometric mean, geometric CV%
1, 8
Tmax
n, median, minimum, maximum
8
Rac (Cmax), Rac (AUCτ)
n, arithmetic mean, median, CV%, standard deviation, 
minimum, maximum, geometric mean, geometric CV%


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A summary of concentrations by day and nominal time point, for crisaborole and its 
metabolites respectively, where the set of statistics will include n, mean, median, standard 
deviation, CV(%), minimum, maximum and the number of concentrations above the lower 
limit of quantification.
Mean and median profiles of the plasma concentration-time data will be plotted through Day 
1 to Day 9, for crisaborole and its metabolites respectively.  In addition, mean and median 
profile of trough concentration data on Day 7, Day 8 and Day 9 will be ploted against time
for crisaborole and its metabolites respectively. Mean and median profiles against nominal 
time point will be presented on both linear and semi-log linear scales.
Individual plasma concentration-time data will be plotted through Day 1 to Day 9, for 
crisaborole and its metabolites respectively.  In addition, the individual plasma 
concentration-time data for all subjects will be plotted through Day 1 to Day 9 on the same 
graph, for crisaborole and its metabolites respectively. Individual profiles against actual time 
point will be presented on both linear and semi-log linear scales.
All plasma concentration values and plasma PK parameters will be listed by subject.
6.3. Other Endpoints
6.3.1. Skin Irritation Score
For each subject, the maximum irritation score of the skin irritation assessment through all 
visits (ie, Day 3 and Day 4) will be calculated.
For the maximum irritation score, the frequency (number and %) of individual maximum
irritation scores will be presented for each investigational product. The descriptive statistics 
(n, number of missing, mean, standard deviation, median, minimum and maximum) of the 
maximum irritation score will also be calculated for each investigational product.
For the irritation score, the frequency (number and %) of individual irritation scores will be 
presented for each investigational product at each visit. The descriptive statistics (n, number 
of missing, mean, standard deviation, median, minimum and maximum) of the irritation 
score will also be calculated for each investigational product at each visit.
Individual irritation scores will be displayed in a data listing for all subjects.
6.4. Subset Analyses 
Not Applicable
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6.5. Baseline and Other Summaries and Analyses
6.5.1. Baseline Summaries
For Cohort 1, descriptive summary reports for demographic and baseline characteristics (age,
gender, ethnicity, race, weight, height and body mass index) will be provided for the safety
analysis population.  For cohort 2, descriptive summary reports for demographic and baseline 
characteristics (age, gender, ethnicity, race, weight, height, body mass index, investigator's
static global assessment score and treatable % BSA) will be provided by treatment for the
safety analysis population.
Medical history will be summarized for Cohort 1, and by treatment for Cohort 2, for the 
safety analysis population.
Data will be reported in accordance with the Pfizer data standards.
6.5.2. Study Conduct and Subject Disposition
Subject evaluation groups will show end of study subject disposition and will show which 
subjects were analyzed for pharmacokinetics (for Cohort 2 only) and safety.  Frequency 
counts will be supplied for subject discontinuation(s) for Cohort 1, and by treatment for 
Cohort 2.
Data will be reported in accordance with the Pfizer data standards.
6.5.3. Study Treatment Exposure
The administration schedule (duration of treatment, total number of applications) will be 
summarized descriptively by treatment, separately for each cohort for the safety analysis 
population.
Data will be reported in accordance with the Pfizer data standards.
6.5.4. Concomitant Medications and Non-Drug Treatments
All prior and concomitant medication(s) as well as non-drug treatment(s) will be summarized
for Cohort 1, and by treatment for Cohort 2, and provided in the listings.
6.6. Safety Summaries and Analyses
Physical examination information collected during the course of the study will be considered 
source data and will not be required to be reported.  However, any untoward findings 
identified on physical examinations conducted during the active collection period will be 
captured as AEs, if those findings meet the definition of an AE. Data collected at screening 
that are used for inclusion/exclusion criteria, such as laboratory data, ECGs, and vital signs,
will be considered source data, and will not be required to be reported.
The statistical analysis for adverse events, labolatory data, vital signs and ECG are described 
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7. INTERIM ANALYSES
7.1. Introduction
No formal interim analysis will be conducted for this study.  However, for Cohort 1, as this is 
a sponsor open study, the sponsor may conduct unblinded reviews of the data during the 
course of the study for the purpose of safety assessment, skin irritation assessment, and/or 
supporting clinical development.
7.2. Interim Analyses and Summaries
Not Applicable.
8. REFERENCES 
1.
Kawamura T, Shoji S, Masuda T et al. Basic studies on the standardization of patch test. 
Jpn J Dermatol. 1970; 80: 301–14 (Japanese).
2.
Sugai T. Contact dermatitis and patch test. Skin Research. 1977; 19(2): 210–22 
(Japanese).
3.
Sugai T. Safety Evaluation of Cosmetic Products. J. Jpn Cosmet Sci Soc. 1995; 19:
49-56 (Japanese) .


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9. APPENDICES
Appendix 1. DATA DERIVATION DETAILS
Definition and use of visit windows in reporting
For cohort 2, the visit windows below will be used for any safety summaries that display by 
visit.
Definition of Visit Windows
Visit Label
Target Day
Definition [Day window]
Day 1
Prior to Day 1, start of study 
treatment
Day 1
Day 8/ET
Day 8
Day 2 or later
If two or more visits fall into the same window, keep the one closest to the Target Day.  If 
two visits are of equal distance from the Target Day in absolute value, the later visit should 
be used.