Clinical trial NCT03233529
Conditions: Dermatitis, Atopic
Keywords: atopic dermatitis atopic eczema eczema topical treatment skin diseases phosphodiesterase-4 inhibitor PDE-4 inhibitor crisaborole
Sponsor: Pfizer
Start date: 2017-07-31; Completion date: 2018-05-04
Enrollment: 40 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study is being conducted to characterize the mechanism of action of crisaborole ointment 2%, by evaluation of efficacy and changes in key skin biomarkers in atopic dermatitis (AD) lesions treated with crisaborole ointment 2% over vehicle, in subjects with mild to moderate AD. Two identified AD skin lesions for each subject will be treated for the first 15 days, one with crisaborole ointment 2% and one with vehicle, in a blinded manner, and biopsies for biomarker analysis will be performed on the lesions. Following completion of the blinded treatment period, subjects will start the 28 day open label period during which all AD affected skin lesions will be treated with crisaborole ointment 2% twice daily.

Detailed description:

Arms: arm 1: None arm 2: None
Interventions: intervention 1: Crisaborole ointment 2% BID intervention 2: Placebo ointment (vehicle)
Intervention descriptions: intervention 1: Crisaborole ointment 2% BID for 15 days (double blind); additional 28 days (open label) intervention 2: Placebo ointment (vehicle) BID for 15 days (double blind)

Protocol documents:
Prot_000.pdf: 
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A PHASE 2A, RANDOMIZED, DOUBLE-BLIND, VEHICLE-CONTROLLED 
STUDY, TO CHARACTERIZE THE MECHANISM OF ACTION OF 
CRISABOROLE OINTMENT 2%, BY EVALUATION OF EFFICACY AND 
CHANGES IN SKIN BIOMARKERS, IN ADULT SUBJECTS WITH MILD TO 
MODERATE ATOPIC DERMATITIS, WITH A 4 WEEK OPEN-LABEL 
EXTENSION
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:
C3291001
Phase:
2a


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Document History
Document
Version Date
Summary of Changes and Rationale
Original protocol
02 May 2017
N/A


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TABLE OF CONTENTS
LIST OF TABLES.....................................................................................................................6
LIST OF FIGURES ...................................................................................................................6
APPENDICES ...........................................................................................................................6
PROTOCOL SUMMARY.........................................................................................................7
SCHEDULE OF ACTIVITIES................................................................................................10
1. INTRODUCTION ...............................................................................................................13
1.1. Background and Rationale ......................................................................................13
1.2. Study and Dose Rationale .......................................................................................16
1.3. Anticipated Benefits and Risks ...............................................................................16
2. STUDY OBJECTIVES AND ENDPOINTS.......................................................................17
3. STUDY DESIGN.................................................................................................................18
4. SUBJECT ELIGIBILITY CRITERIA.................................................................................20
4.1. Inclusion Criteria.....................................................................................................20
4.2. Exclusion Criteria....................................................................................................22
4.3. Lifestyle Requirements ...........................................................................................23
4.3.1. General Care ...............................................................................................23
4.3.2. Contraception..............................................................................................24
4.4. Sponsor’s Qualified Medical Personnel..................................................................25
5. STUDY TREATMENTS.....................................................................................................25
5.1. Randomization ........................................................................................................26
5.2. Blinding and Maintenance of the Blind ..................................................................26
5.3. Subject Compliance.................................................................................................27
5.4. Investigational Product Supplies.............................................................................27
5.4.1. Dosage Form(s) and Packaging..................................................................27
5.4.2. Preparation and Dispensing........................................................................27
5.5. Administration.........................................................................................................28
5.6. Investigational Product Storage ..............................................................................29
5.7. Investigational Product Accountability...................................................................30
5.7.1. Destruction of Investigational Product Supplies ........................................30
5.8. Concomitant Treatment(s).......................................................................................30


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5.8.1. Permitted Concomitant Treatments - Day 1 through Day 43 (end of 
treatment/early termination).............................................................................30
5.8.2. Prohibited Concomitant Treatments - Day 1 through Day 43 (end of 
treatment/early termination).............................................................................31
6. STUDY PROCEDURES .....................................................................................................32
6.1. Screening.................................................................................................................32
6.2. Study Period ............................................................................................................33
6.3. Day 1 (Baseline)......................................................................................................33
6.4. Days 2 through 14 ...................................................................................................34
6.5. Day 15 (+1 day).......................................................................................................35
6.6. Double-Blind Early Termination ............................................................................36
6.7. Days 16 to 42 Outpatient/Home based Dosing .......................................................36
6.8. Day 43 (3 days) - End of treatment/Open-label Early Termination......................36
6.9. Day 71 (+3 days) - Follow-up Contact....................................................................37
6.10. Subject Withdrawal/Early Termination ................................................................37
7. ASSESSMENTS..................................................................................................................38
7.1. Safety.......................................................................................................................38
7.1.1. Laboratory Tests .........................................................................................38
7.1.2. Pregnancy Testing ......................................................................................39
7.1.3. Physical Examinations................................................................................39
7.1.4. Vital Signs ..................................................................................................40
7.2. Skin Biopsy Samples...............................................................................................40
7.3. Investigator Static Global Assessment (ISGA).......................................................41
7.4. Lesion ISGA............................................................................................................41
7.5. Lesion Total Sign Score (TSS)................................................................................42
7.6. Pruritus Numerical Rating Scale (NRS)..................................................................43
7.8. %BSA with Atopic Dermatitis................................................................................45
8. ADVERSE EVENT REPORTING......................................................................................46
8.1. Requirements...........................................................................................................46
8.1.1. Additional Details on Recording Adverse Events on the CRF...................47
8.1.2. Eliciting Adverse Event Information..........................................................47
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8.1.3. Withdrawal from the Study Due to Adverse Events (see also the 
Subject Withdrawal/Early Termination section) .............................................47
8.1.4. Time Period for Collecting AE/SAE Information......................................48
8.1.4.1. Reporting SAEs to Pfizer Safety...............................................48
8.1.4.2. Recording Non-serious AEs and SAEs on the CRF .................48
8.1.5. Causality Assessment .................................................................................48
8.1.6. Sponsor’s Reporting Requirements to Regulatory Authorities ..................49
8.2. Definitions...............................................................................................................49
8.2.1. Adverse Events...........................................................................................49
8.2.2. Abnormal Test Findings .............................................................................50
8.2.3. Serious Adverse Events ..............................................................................50
8.2.4. Hospitalization............................................................................................51
8.3. Severity Assessment................................................................................................52
8.3.1. Protocol-Specified Serious Adverse Events...............................................52
8.3.2. Potential Cases of Drug-Induced Liver Injury............................................52
8.3.3. Exposure to the Investigational Product during Pregnancy or 
Breastfeeding, and Occupational Exposure.....................................................54
8.3.3.1. Exposure During Pregnancy......................................................54
8.3.3.2. Exposure during Breastfeeding .................................................55
8.3.3.3. Occupational Exposure .............................................................55
8.3.4. Medication Errors .......................................................................................56
8.3.4.1. Medication Errors......................................................................56
9. DATA ANALYSIS/STATISTICAL METHODS...............................................................56
9.1. Sample Size Determination.....................................................................................57
9.2. Analysis of Primary Efficacy Endpoints.................................................................57
9.3. Analysis of Biomarker Endpoints ...........................................................................57
9.4. Analysis of Other Efficacy Endpoints.....................................................................58
9.5. Safety Analysis........................................................................................................59
9.6. Interim Analysis ......................................................................................................59
9.7. Data Monitoring Committee ...................................................................................59
10. QUALITY CONTROL AND QUALITY ASSURANCE.................................................59
11. DATA HANDLING AND RECORD KEEPING .............................................................60
11.1. Case Report Forms/Electronic Data Record .........................................................60


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11.2. Record Retention...................................................................................................60
12. ETHICS..............................................................................................................................61
12.1. Institutional Review Board/Ethics Committee......................................................61
12.2. Ethical Conduct of the Study ................................................................................61
12.3. Subject Information and Consent..........................................................................61
12.4. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH 
GCP ...........................................................................................................................62
13. DEFINITION OF END OF TRIAL...................................................................................62
13.1. End of Trial in All Participating Countries ...........................................................62
14. SPONSOR DISCONTINUATION CRITERIA ................................................................62
15. PUBLICATION OF STUDY RESULTS..........................................................................63
15.1. Communication of Results by Pfizer ....................................................................63
15.2. Publications by Investigators ................................................................................63
16. REFERENCES ..................................................................................................................65
LIST OF TABLES
Table 1.
Laboratory Tests ...................................................................................................39
Table 2.
Investigator’s Static Global Assessment (ISGA) .................................................41
Table 3.
Lesion Total Sign Score........................................................................................42
 
LIST OF FIGURES
Figure 1.
Pruritus Numerical Rating Scale ..........................................................................43
APPENDICES
Appendix 1. Abbreviations......................................................................................................68
Appendix 2. Diagnostic Criteria for Atopic Dermatitis...........................................................71
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PROTOCOL SUMMARY 
Background and Rationale:
Atopic Dermatitis (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.1,6  The majority of patients (up to 90%) with AD present 
with mild to moderate disease7  Manifestation of the disease includes intense pruritus, 
erythematous papules, excoriation, exudation, and lichenification.8  Continuous scratching 
during exacerbations can lead to lichenification, excoriations, and serious skin infections.  
AD is often associated with significant morbidity, including asthma, allergic rhinitis, and 
food allergy.  Currently, there is no cure for AD.  AD is a chronic disease with treatment 
focused on the management of flares and maintenance of remissions. 
Crisaborole, also referred to as PF-06930164 and AN2728, is a low molecular weight 
benzoxaborole anti-inflammatory phosphodiesterase-4 (PDE-4) inhibitor that is expected to
penetrate into the skin to the sites of inflammation.  PDE-4 inhibition results in increased
intracellular cyclic adenosine monophosphate (cAMP) levels.  The specific mechanism(s)
by which crisaborole exerts its therapeutic action is not well defined, but it is thought that 
crisaborole reduces the production of several pro-inflammatory cytokines implicated in the 
pathophysiology of atopic dermatitis (AD).
Supporting evidence of the safety and efficacy of crisaborole in subjects 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 the two Phase 3 registration studies.  Across the Phase 3 development program, 
crisaborole demonstrated an acceptable safety profile, with no crisaborole treatment-related 
Serious Adverse Events (SAEs) and with the majority of Adverse Events (AEs) being mild 
and deemed unlikely or not related to investigational product.
Objectives and Endpoints
Primary Objective(s):

To evaluate the efficacy of crisaborole ointment 2% vs vehicle in subjects with mild 
to moderate AD.

To evaluate change in key skin biomarkers of AD in target lesions treated with 
crisaborole ointment 2% or vehicle.
Secondary Objective(s):

To evaluate change in other skin biomarkers of atopic dermatitis in target lesions 
treated with crisaborole ointment 2% or vehicle.


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
To evaluate normalization of biomarker and gene expression levels in lesional skin 
treated with crisaborole ointment 2% or vehicle.

To evaluate changes in AD clinical sign and symptom severity in target lesions 
treated with crisaborole ointment 2% or vehicle.

To assess the safety and local tolerability of crisaborole ointment 2% in subjects with 
mild to moderate AD.
 
Primary Endpoint(s):

Change from baseline in Total Sign Score (TSS) in target lesions treated with 
crisaborole ointment 2% or vehicle on Day 15.

Change from baseline in key skin biomarkers of AD (S100A12, CCL17, CCL18, 
CCL22, K16, elafin/PI3 and IL-13 expression level) in target lesions treated with 
crisaborole ointment 2% or vehicle at Day 15.
Secondary Endpoint(s):

Change from baseline in other skin biomarkers in target lesions treated with 
crisaborole ointment 2% or vehicle at Day 15.

Biomarker and gene expression level in lesional skin treated with crisaborole 
ointment 2% or vehicle at Day 15 and levels in non-lesional skin at Baseline.

Change from baseline in lesion severity as measured by TSS, Investigator Static 
Global Assessment (ISGA) and Pruritus Numerical Rating Scale at each visit up to 
Day 15.

The incidence of treatment emergent AEs and SAEs.
 
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Study Design
This is a Phase 2a randomized, double-blind, vehicle-controlled study to characterize the 
mechanism of action, by evaluation of efficacy and changes in key skin biomarkers, of 
crisaborole ointment 2% in subjects with mild to moderate atopic dermatitis.  After 
completing screening activities, including meeting eligibility criteria, approximately
40 subjects will be treated.  In the double-blind treatment period, each subject will be 
randomly assigned to be treated with crisaborole ointment 2% for one target lesion.  The 
other target lesion will receive vehicle. 
The double-blind treatment period will last from Baseline/Day 1 to Day 15 skin biopsy 
collection and will include twice daily visits to the site for IP application and study 
assessments, where applicable.  The open-label treatment period will start from the Day 15 
skin biopsy collection and last until Day 43 (end of treatment/early termination); during this 
time, subjects will be able to treat all AD skin areas (except scalp), at home, with crisaborole 
ointment 2%. 
In this study, skin biopsies will be collected to characterize the mechanism of action, by 
evaluation of efficacy and changes in skin biomarkers, of crisaborole ointment 2% over 
vehicle, applied twice a day in adult subjects with AD with maximum treatable BSA of 10%.  
The skin biopsy samples will be analyzed using immunohistochemistry (IHC) and gene 
expression, which will be done using Taqman Low Density Array (TLDA) polymerase chain 
reaction (PCR) for 48 genes including housekeeping genes as well as single gene PCR for a 
few genes that are below detection level on TLDA.
Statistical Method
Detailed methodology for summary and statistical analyses of the data collected in this study
will be documented in a Statistical Analysis Plan (SAP).  The following is the statistical 
methods for the primary endpoints. 
For the lesion TSS, the linear mixed model will be used to model the intra-subject change 
from baseline in TSS between crisaborole ointment 2% treated lesion and vehicle treated 
lesion. The model includes the fixed effect of visit as factor, and an unstructured variance 
and covariance matrix will be used to model the dependence among the same subjects across 
different visits. 
Comparison of pre and post treatment of biomarker expression levels in skin treated with 
crisaborole ointment 2% or vehicle will be performed. A mixed effect model will be used to 
analyze the change from baseline in biomarkers from the target lesion treated with 
crisaborole ointment 2% or vehicle.
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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 on the schedule of activities table, in order to 
conduct evaluations or assessments required to protect the well-being of the subject. 
Double-Blind Period
Open-Label Period
Study Day(s)/Visit Identifier/Visit Window
-30 to -1
Screen
1
Baseline
2 to 7
8
9 to 14 Double-Blind 
Early 
Termination
15+1 16-42
433 
End of Treatment/
Open-Label Early 
Termination 
71+3
Follow-up
Contacta
CRU Visit
X
X
X X
X
X X
X
X
X
Informed consent
X
Demographics
X
Medical/surgical history
X
X
Review prior/concomitant treatment
X




X


X
Vital signs
X
Height and Weight
X
Full physical examination
Xb
Limited physical examination
Xb
X
X
Safety Laboratory Tests
X
X
X
Pregnancy testc
X
X
X
X
X
FSHh
X
Inclusion/exclusion criteria
X
X
Randomization
X
Investigational product application (BID) and record 
dosingd
X
X
X
X
X
X
Train and Dispense investigational product for 
outpatient application
X
Subject diary training & distributione
X
Subject diary completion
Xi
XX
Subject diary collection & reviewe
X


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Double-Blind Period
Open-Label Period
Study Day(s)/Visit Identifier/Visit Window
-30 to -1
Screen
1
Baseline
2 to 7
8
9 to 14 Double-Blind 
Early 
Termination
15+1 16-42
433 
End of Treatment/
Open-Label Early 
Termination 
71+3
Follow-up
Contacta
Collect investigational product from outpatient 
administration
X
% BSA for eligibility (excluding face, scalp, axilla, 
genitals, groin area, palms, back of the hands, and 
soles)
X
X
ISGA
X
X
X
Xk
X
Lesion ISGA (for each target lesion)
X
X
X 
X
Xk
Lesion TSS (for each target lesion)
X
X 
X
Xk
Skin biopsyf
X
Xf
X
Xk
Pruritus numerical rating scale (for each target lesion)
X
XX
X
XX
X
Xk
Pruritus numerical rating scale (global)
X
X
Xk
X
X
Contraception Checkg
X
X
X
X
X
X
X
X
X
Serious and non-serious adverse event monitoring
X




X



X
Abbreviations: = ongoing/continuous event; AD = atopic dermatitis; BID = twice a day; % BSA = percent of body surface area; CRU = Clinical Research Unit; 
 
; ET = Early termination visit; FSH = follicle-stimulating hormone; ISGA = investigator’s static global assessment; 
 
TSS = Total Sign Score.
a.
Follow-up contact will be completed at least 28 calendar days after the last administration of the investigational product to capture any potential adverse events and to confirm 
appropriate contraception usage.  Visit is planned to occur as a telephone contact. 
b.
The Screening physical examination (full) may be performed at Baseline/Day 1 visit at the discretion of the Investigator.  If full exam is completed at Screening, a limited 
exam should be collected at baseline.  Target treatment areas must be identified at Screening and confirmed at Baseline.
c.
Women of childbearing potential only.  Serum pregnancy test at Screening and urine pregnancy tests at all other visits.
d.
From Day 1 to Day 15 study treatment will be applied at the site (CRU), at regular intervals twice a day, approximately every 8 to 12 hours.  From Day 15 through the end of 
treatment, subjects will apply open-label investigational product at home twice a day, approximately every 8-12 hours.  During the open-label period, subjects will be required 
to complete the diary which will include dosing, adverse events and pruritus numerical rating scale information.
e.
On Day 15 study visit, a diary will be distributed to the subject.  There will be a requirement to bring the subject diary to the subsequent visit(s) for collection and review. 
f.
One 4.5 mm skin biopsy will be collected from each target treatment area prior to IP application on Day 1, Day 8 (optional for subjects) and Day 15.  The biopsies on Day 8 
and Day 15 will be collected in the vicinity, but at least 1 cm distant from where the biopsies were collected at Day 1, even if the target treatment area has cleared.  One 
additional 4.5 mm skin biopsy will be collected from nonlesional skin on Day 1.  If a subject has an early termination visit during the double-blind treatment period, every 
attempt should be made for the skin biopsy to be collected at this visit.
g.
The investigator or his/her designee will discuss with the subject the need to use contraception consistently and correctly according to contraception guidelines. 
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h.
Serum FSH concentration will be determined for all females who are amenorrheic for at least 12 consecutive months.
i.
Completion of initial subject diary entry of the open-label period IP with oversight and training by the study site.
j.
k.
Assessment part of the double-blind period.
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1. INTRODUCTION
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.  PDE-4 inhibition 
results in increased intracellular cyclic adenosine monophosphate (cAMP) levels.  The 
specific mechanism(s) by which crisaborole exerts its therapeutic action is not well defined, 
but it is thought that crisaborole reduces the production of several pro-inflammatory
cytokines implicated in the pathophysiology of atopic dermatitis (AD).
On 14 December 2016, EUCRISA(crisaborole) topical ointment, 2% was approved by the 
United States (US) Food and Drug Administration (FDA) for the treatment of mild to 
moderate AD in patients 2 years of age and older.
1.1. Background and Rationale
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 and is of similar 
pathophysiology in adults and children of all ages.  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 United States (US) with 85% of affected individuals showing signs of the 
disease before 5 years of age.1,2 Adult-onset AD has been reported.3,4 However, reliable 
estimates of the incidence of AD in adults are unavailable.  Prevalence estimates among 
adults vary, but the condition may affect over 10% of adults in some regions.  Over the past 
50 years, AD has become more prevalent, especially in industrialized, temperate countries 
such as the US and Canada.5,6
The pathophysiology of AD is the product of a complex interaction between various 
susceptibility genes, host environments, infectious agents, defects in skin barrier function and 
immunologic responses.  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.1,6  The majority of patients (up to 90%) with 
AD present with mild to moderate disease.7  Manifestation of the disease includes intense 
pruritus, erythematous papules, excoriation, exudation, and lichenification.8  Continuous 
scratching during exacerbations can lead to lichenification, excoriations, and serious skin 
infections. 
AD is often associated with significant morbidity, including asthma, allergic rhinitis, and 
food allergy.  Psychosocial problems, depression, and anxiety are associated with AD in both 
adults and children.9
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, health-related quality of life (HRQoL), and psycho-social implications. 
AD may also be a source of significant economic burden10 as this relapsing disease is often 
misdiagnosed, misunderstood, and ineffectively treated.6


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Currently, there is no cure for AD.  AD is a chronic disease with treatment focused on the 
management of flares and maintenance of remissions.  Due to the chronic, relapsing nature of 
the disease, treatment may be needed for many years and may extend into adulthood.  In 
summary, AD is a disease with multiple comorbidities and significant impact on the health, 
day to day functioning, and HRQoL of patients, their caregivers, and family members.
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 the two Phase 3 registration studies.  
Across the development program, crisaborole demonstrated an acceptable safety profile, with 
no crisaborole treatment-related SAEs and with the majority of AEs being mild and deemed 
unlikely or not related to investigational product. 
The Investigator’s Brochure (IB) contains summaries of nonclinical and clinical studies 
performed with crisaborole.14 A brief summary as background to this study protocol is 
presented here.
Nonclinical 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.15-21  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 PDE4,22 which causes elevation of cyclic adenosine 
monophosphate (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.23 Crisaborole proved 
efficacious against an inflammatory challenge in vivo in a mouse phorbol 12-myristate 
13-acetate phorbol 12-myristate 13-acetate (PMA)-induced ear edema model.24,25 AN7602 
and AN8323, major metabolites of crisaborole lack anti-inflammatory activities against 
PDE426 and a panel of cytokines.27
Based on the nonclinical safety studies conducted to date, crisaborole topical ointment, 
2% has an acceptable safety profile.  Refer to the investigator’s brochure (IB) for further 
information on the nonclinical experience with crisaborole ointment, 2%.
Effects in Humans
Twenty-three (23) clinical trials of topical formulations of crisaborole have been completed 
to date, with a total of 2157 subjects exposed to one or more crisaborole formulations.  Key 
study information is summarized below.


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Clinical pharmacology studies

The pharmacokinetics (PK) of EUCRISA were investigated in 33 subjects 2 to 17 
years of age with mild to moderate atopic dermatitis and a mean standard deviation 
(SD) BSA involvement of 49 20% (range 27% to 92%).  In this study, subjects 
applied approximately 3 mg/cm2 of EUCRISA ointment (dose range was 
approximately 6 g to 30 g per application) twice daily for 8 days.  The mean SD 
maximum plasma concentration (Cmax) and area under the concentration time curve 
from 0 to 12 hours post dose (AUC0-12) for crisaborole on Day 8 were 127 
196 ng/mL and 949 1240 ng*h/mL, respectively.  Systemic concentrations of 
crisaborole were at steady state by Day 8.  Based on the ratios of AUC0-12 between 
Day 8 and Day 1, the mean accumulation factor for crisaborole was 1.9.

Healthy men who applied a single topical dose (9.5 g [approximately 100 Ci]) of 
14C-crisaborole ointment 2% had maximum mean blood and plasma radioactivity at 
6 hours postdose; no radioactivity was observed in any subject by 96 hours postdose 
in blood and 144 hours postdose in plasma (AN2728-PSR-105).  The major route of 
radioactive elimination was renal.

In a thorough QT (TQT) study conducted in healthy adult subjects 
(AN2728-TQT-108), crisaborole ointment, 2%, at both therapeutic and 
supratherapeutic doses had no effect on cardiac repolarization based on results from 
the primary assessment and the pharmacokinetic-pharmacodynamic analysis.

A drug drug interaction (DDI) study evaluated the effect of multiple topical 
administrations of crisaborole ointment, 2% at a supratherapeutic dose (covering 
approximately 60% BSA), on the single-dose pharmacokinetics of R- and S-warfarin, 
a CYP2C9 substrate, in healthy adult subjects.  The study concluded that there was no 
drug-drug interaction when warfarin is co-administered with crisaborole ointment 
(AN2728-PK-101).

In a randomized, single-center, controlled, within-subject comparison study of 
healthy volunteers, crisaborole ointment, 2% and crisaborole topical ointment, 
Vehicle showed no evidence of sensitization and only very minimal irritation 
(AN2728-RIPT-101).
Clinical studies

In a 6-week bilateral comparison trial of subjects with mild-to-moderate AD 
(AN2898-AD-202), 68% of AD lesions treated with crisaborole ointment E, 2% twice 
a day (BID) showed greater improvement in atopic dermatitis 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).


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
In a 4-week bilateral comparison dose selection trial of 86 adolescent subjects with 
mild-to-moderate AD (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 a day (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% BID 
outperformed the vehicle in the primary efficacy analysis and the difference between 
the treatment groups was statistically significant (AN2728-AD-301, 
AN2728-AD-302).

An additional Phase 3 multicenter, open-label, long-term extension study (48 weeks 
duration) of crisaborole ointment, 2% BID for the treatment of mild to moderate AD 
in adults and children as young as 2 years of age affirmed the long-term safety of 
topical crisaborole (AN2728-AD-303).  No clinically important safety signals were 
identified by this study.
Additional information for crisaborole may be found in the Single Reference Safety 
Document (SRSD), which for this study is the current version of the crisaborole 
Investigator’s Brochure.
1.2. Study and Dose Rationale
The specific mechanism(s) by which crisaborole exerts its therapeutic action is not well 
defined.  In this study, skin biopsies will be collected to characterize the mechanism of 
action, by evaluation of efficacy and changes in key skin biomarkers, of crisaborole ointment 
2% over vehicle, applied twice a day in adult subjects with AD with maximum treatable BSA
of 10%.  The skin biopsy samples will be analyzed using immunohistochemistry (IHC) and 
gene expression, which will be done using TLDA PCR for 48 genes including housekeeping 
genes as well as single gene PCR for a few genes that are below detection level on TLDA.
The safety and efficacy of crisaborole has been demonstrated in two phase 3 studies 
(AN2728-AD-301 and AN2728-AD-302) and one long term open-label study 
(AN2728-AD-303).  The 2% dose strength of crisaborole ointment is approved in the US for 
the treatment of mild-moderate atopic dermatitis for subjects 2 years. 
1.3. Anticipated Benefits and Risks
The benefit/risk balance of crisaborole ointment 2% application in this study is considered 
favorable and supported by the following:

The expected efficacy of crisaborole ointment 2% for the treatment of atopic 
dermatitis based on the results of clinical studies conducted to date.

The expected limited crisaborole systemic exposure when applied topically based on 
the results of clinical studies conducted with crisaborole ointment 2% to date.


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
The satisfactory safety and local tolerability demonstrated in non-clinical and clinical 
studies conducted with crisaborole ointment 2% to date.
The main benefit for subjects participating in this study is based on access to regular clinical 
assessments and active atopic disease management as well as expected efficacy for those 
subjects treated with crisaborole during the double-blind and/or open-label treatment period.  
Based on the favorable clinical safety profile as well as the projected low systemic 
availability of crisaborole, the risk to subjects treated with crisaborole is deemed to be 
minimal. 
2. STUDY OBJECTIVES AND ENDPOINTS
Primary Objective(s):
Primary Endpoint(s):

To evaluate the efficacy of 
crisaborole ointment 2% vs vehicle in 
subjects with mild to moderate AD.

To evaluate change in key skin 
biomarkers of AD in target lesions 
treated with crisaborole ointment 
2% or vehicle.

Change from baseline in TSS in target 
lesions treated with crisaborole ointment 
2% or vehicle on Day 15.

Change from baseline in key skin biomarkers 
of AD (S100A12, CCL17, CCL18, CCL22, 
K16, elafin/PI3 and IL-13 expression level) 
in target lesions treated with crisaborole 
ointment 2% or vehicle at Day 15.
Secondary Objective(s):
Secondary Endpoint(s):

To evaluate change in other skin 
biomarkers of atopic dermatitis in 
target lesions treated with crisaborole 
ointment 2% or vehicle.

To evaluate normalization of 
biomarker and gene expression levels 
in lesional skin treated with 
crisaborole ointment 2% or vehicle.

To evaluate changes in AD clinical 
sign and symptom severity in target 
lesions treated with crisaborole 
ointment 2% or vehicle.

To assess the safety and local 
tolerability of crisaborole ointment 
2% in subjects with mild to moderate 
AD.

Change from baseline in other skin 
biomarkers in target lesions treated with 
crisaborole ointment 2% or vehicle at 
Day 15.

Biomarker and gene expression level in 
lesional skin treated with crisaborole 
ointment 2% or vehicle at Day 15 and levels 
in non-lesional skin at Baseline.

Change from baseline in lesion severity as 
measured by TSS, ISGA, and Pruritus 
Numerical Rating Scale at each visit up to 
Day 15.

The incidence of treatment emergent AEs 
and SAEs.


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Abbreviations: AD = atopic dermatitis; AE = adverse event; 
 
 ISGA = Investigator’s static global assessment; SAE = serious adverse event; 
TSS = total sign score.
3. STUDY DESIGN
Overview
This is a Phase 2a randomized, double-blind, vehicle-controlled study to characterize the 
mechanism of action, by evaluation of efficacy and changes in key skin biomarkers, of 
crisaborole ointment 2% in subjects with mild to moderate atopic dermatitis.  After 
completing screening activities, including meeting eligibility criteria, approximately
40 subjects will be treated.  In the double-blind treatment period, each subject will be 
randomly assigned to be treated with crisaborole ointment 2% for one target lesion.  The 
other target lesion will receive vehicle. 
The double-blind treatment period will last from Baseline/Day 1 to Day 15 skin biopsy 
collection and will include twice daily visits to the site for IP application and study 
assessments, where applicable.  The open-label treatment period will start from the Day 15 
skin biopsy collection and last until Day 43 (end of treatment/early termination); during this 
time, subjects will be able to treat all AD skin areas (except scalp), at home, with crisaborole 
ointment 2%. 
Scheduled (outpatient) study visits for all subjects will occur at Screening (up to 30 days 
prior to Day 1/Baseline), Days 1 to 14 (twice daily), Day 15, and Day 43 (end of 
treatment/early termination).  On Day 71 (end of study), a follow-up telephone call will be 
made by site staff to assess for AEs that may have occurred since the last visit. 
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Skin biopsy and biomarkers
For all subjects, one 4.5 mm skin biopsy will be collected from each target treatment area on 
Day 1, and Day 15.  In addition, on Day 8, subjects will be offered one optional 4.5 mm skin 
biopsy collected from each target treatment area, to provide additional samples for analysis.  
The biopsies on Day 8 and Day 15 will be collected in the vicinity, but at least 1 cm distant 
from where the biopsies were collected at Day 1, even if the target treatment area has cleared.  
One additional 4.5 mm biopsy will be collected from nonlesional skin on Day 1.  Each 
biopsy will be cut in half.  One half will be used to perform reverse transcriptase (RT) PCR 
and gene arrays and the other half will be used for immunohistochemistry analysis and 
hematoxylin and eosin (H&E) staining.
Parameters studied using IHC will include epidermal thickness (performed on H&E 
sections), Ki-67+ cells, Keratin 16 (K16), CD3+ T-cells, CD11C+ dendritic cells (DCs), Fc 
Epsilon+ dendritic cells (DCs), langerin+ cells (for langerhans cells), filaggrin.
Gene expression by RT PCR panel (skin ribonucleic acid [RNA]) will include levels of the 
following established cytokines associated with AD: IL-13, IL-19, IL-22, IL-17A, IL-23 
(p19), IL-12/23 p40.
Gene expression by TLDA RT PCR will include the levels of the following established 
cytokines associated with AD: IL- 1B , IL-2, IL-2RA, IL-5, IL-6, IL-8, IL-9, IL-10, 
IL-12p35, IL-12/23p40, IL-13, IL-15, IL-15RA, IL-17A, IL-17F, IL-19, IL-22, IL-23 (p19), 
IL-31,  IL-32, K16, PDE4A, PDE4B, PDE4D, filaggrin, loricrin, periplakin, S100A7, 
S100A9, S100A12, MMP12, IFN-gamma,  CXCL1, CXCL2, CXCL9, CXCL10, CCL20, 
elafin/PI3, hBD2, CCL13,CCL17, CCL18, CCL22, CCL26, FOXP3 and TSLP receptor, of 
which the following are considered the key biomarkers associated with AD pathways:
S100A12 (general inflammation); Keratin 16 (epidermal hyperplasia; proliferation marker 
(barrier function)); Elafin/PI3 (Th17);CCL17 (Th2); CCL18 (Th2); CCL22
(Th2);IL13(Th2).  PDE4 expression will be quantified in the tissue by TLDA.
Gene arrays using Affymetrix UPlus 2 arrays will also be performed to allow for more global 
analyses of genomic changes and normalization of lesional samples towards non-lesional 
samples with treatment. 
Efficacy outcomes:
Severity of AD will be characterized at baseline and throughout the study with the lesion 
ISGA, lesion TSS, percent of BSA with AD (%BSA), ISGA, 
 and pruritus numerical
rating scale (NRS).  Lesion ISGA and lesion TSS will be used to evaluate any correlation 
between change from baseline in biomarkers and AD severity.
Safety Outcomes:
Safety will be assessed by physical exams, standard laboratory testing and collection of AEs.
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Refer to the Schedule of Activities for a complete list of assessments to be performed during 
the study.
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.
Subject eligibility should be reviewed and documented by an appropriate member of the 
investigator’s study team before subjects are included in the study. 
4.1. Inclusion Criteria
Subjects must meet all of the following inclusion criteria to be eligible for enrollment into the 
study:
1. Subject is a male or female aged at least 18 years old at the time of consent.
2. Subject has confirmed clinical diagnosis of active atopic dermatitis (AD) according to 
Hanifin and Rajka criteria (see Appendix 2) with at least 6 month history prior to 
Screening visit and that has been clinically stable for 1 month. 
3. Subject has a global ISGA of 2 or 3 at Baseline/Day 1 visit.
4. Subject has a BSA covered with atopic dermatitis of at least 0.5% and no more than 
10% at Baseline/Day 1, excluding face, scalp, axilla, genitals, groin area, palms, back 
of the hands, and soles.  The presence of AD on these areas (face, scalp, axilla, 
genitals, groin area, palms, back of the hands and soles) is not exclusionary, but will 
not be included in the calculation for coverage of BSA with AD.
5. Subject has two lesions of atopic dermatitis at least 3 cm x 3 cm with identical Lesion 
ISGA of 3.  These atopic dermatitis lesions must be at least 5 cm apart.  The target 
lesions must not be on the face, scalp, axilla, genitals, groin area, palms, back of the 
hands, and soles.
6. Subjects who received any of the following AD treatment regimens are eligible if the 
following minimum washout criteria are observed: 
Must be discontinued for at least 12 Weeks or 5 half-lives (whichever is longer):

Biological drugs.
Must be discontinued for at least 28 days prior to Baseline:

Systemic (oral/injectable) corticosteroids (Note: use of intranasal/inhaled or 
ophthalmic corticosteroids for stable medical conditions are allowed).


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
Systemic immunosuppressive agents (eg, retinoids, calcineurin inhibitors, 
methotrexate, ciclosporin, hydroxycarbamide (hydroxyurea), azathioprine, 
hydroxychloroquine, mycophenolate mofetil).

Nonbiological investigational product or device.

Excessive sun exposure, light therapy (eg, ultraviolet light therapy) including 
phototherapy.
Must be discontinued for at least 14 days prior to Baseline:

Topical products containing urea.

Topical medicated treatments for atopic dermatitis (eg, tars, bleach, 
antimicrobials, medical devices (eg, Atopiclair), and bleach/bath oil.

Topical corticosteroids (all potencies) and calcineurin inhibitors.

Prescription skin barrier repair products.

Systemic antibiotics.

Doxepin.
Must be discontinued for at least 7 days prior to Baseline:

Topical antibiotics.

Use of antibacterial soaps (for bathing), or topical sodium hypochlorite-based 
products.

Topical or oral antihistamines (eg, hydroxyzine or diphenhydramine or other 
sedating antihistamines).
Must be discontinued at least 8 hours prior to Baseline: 

Use of emollients.
7. 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; status must be confirmed with a serum follicle-stimulating 
hormone (FSH) level confirming the postmenopausal state;
b. Have undergone a documented hysterectomy and/or bilateral oophorectomy; 


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c.
Have medically confirmed ovarian failure. 
All other female subjects (including female subjects with tubal ligations) are 
considered to be of childbearing potential. 
8. Female subjects of childbearing potential who have a negative serum pregnancy test 
at the screening visit and negative urine pregnancy test at the baseline visit.
9. Evidence of a personally signed and dated informed consent document indicating that 
the subject has been informed of all pertinent aspects of the study.
10. Subjects who are willing and able to comply with scheduled visits, treatment plan, 
laboratory tests and other study procedures.
4.2. Exclusion Criteria
Subjects with any of the following characteristics/conditions will not be included in the 
study:
1. 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 at least 28 days prior to Day 1 and for 
the duration of the study and for at least 28 days after the last dose of investigational 
product.
2. Subject has clinically infected atopic dermatitis or subjects requiring high-potency 
topical corticosteroids (eg, clobetasol propionate 0.05% cream or ointment or 
bathamethasone dipropionate 0.05% cream or ointment) or systemic (oral/injectable) 
corticosteroids to manage AD.
3. History of angioedema or anaphylaxis to topical products or known sensitivity to any 
of the components of crisaborole ointment 2% (listed in Section 5).
4. Subject had previous treatment with any topical or systemic PDE4 inhibitor, 
including apremilast unless stopped for the reason of lack of efficacy (in which case it 
is not exclusionary).
5. Subject is not willing to minimize or avoid natural and artificial sunlight exposure 
during the study. 
6. Subject requires treatment with prohibited concomitant medication(s) as listed in 
Section 5.8.2.
7. Subject who has undergone treatment for any type of cancer (except squamous cell 
carcinoma, basal cell carcinoma or carcinoma in situ of the skin, curatively treated 
with cryosurgery or surgical excision only).


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8. Subject has a history of an allergic reaction or significant sensitivity to lidocaine or 
other local anesthetics.
9. Subject has a history of hypertrophic scarring or keloid formation in scars or suture 
sites.
10. Subject is taking anticoagulant medication, such as heparin, low molecular weight 
(LMW)-heparin, warfarin, antiplatelets, novel oral anticoagulants (eg apixaban), 
antiplatelet medication (eg clopidogrel), or has a contraindication to skin biopsies.  
Nonsteroidal anti-inflammatory drugs [NSAIDs] and low-dose aspirin 81 mg will 
not be considered antiplatelet therapy.
11. Subject with any planned surgical or medical procedure that would overlap with study 
participation from Screening through Day 71/end of study.
12. 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.
13. 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.
14. Participation in other studies involving investigational drug(s) within 30 days prior to 
study entry and/or during study participation.
4.3. Lifestyle Requirements
4.3.1. General Care
Subjects should avoid occluding the treated areas (with wraps, for example).  Subjects must 
avoid exposing the target treatment areas to water (eg swimming, bathing or washing) and 
refrain from any activities that will induce sweating, for at least 4 hours after investigational 
product (IP) application during the double-blind treatment period and at least 4 hours after IP 
application during the open-label treatment period.
Subjects should avoid wiping the IP off the skin. In the case of any IP inadvertently being 
wiped off, it should not be reapplied until the next scheduled dose.
Subjects are recommended to use sunscreen products and protective apparel during the study, 
when sun exposure cannot be avoided.  However these products must not be used on target 
treated areas during double-blind treatment period.


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When applying IP at home, there is no expectation to wear gloves.  However, subjects must 
be instructed to wash their hands with mild soap and water before and after each IP 
application.  Those subjects applying IP at home and having difficulty reaching 
treatment-eligible atopic dermatitis areas (eg, back) may be assisted by another person who 
will need to apply the investigational product to the subject according to the above IP 
application instructions.
4.3.2. Contraception
All fertile 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 at least 28 days prior to Day 1 and 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 from the permitted list of contraception methods (see below) and will confirm that the 
subject has been instructed in its consistent and correct use. 
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 
needs 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 or the partner. 
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:

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. 

Correctly placed copper-containing intrauterine device (IUD). 

Male condom or female condom used WITH a separate 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.

Male sterilization with absence of sperm in the postvasectomy ejaculate.


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
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.
4.4. 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 
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.  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 placebo 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, investigational products are the following:

Crisaborole ointment 2%, also referred to as active.

Crisaborole placebo vehicle ointment, referred to as 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.


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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. Randomization
All subjects will receive active and vehicle investigational products during the double-blind 
treatment period.
Each target treatment area (1 and 2) will be assigned per the randomization schedule to one 
of the following:  

Crisaborole ointment 2%.

Crisaborole placebo vehicle ointment.
All subjects will receive crisaborole ointment, 2% for the open-label treatment period 
(following the skin biopsy on Day 15).
5.2. Blinding and Maintenance of the Blind
In an effort to ensure unbiased evaluation of the treatment groups, a randomization schedule 
will be created by the study statistician.  The randomization schedule will be known only to 
the unblinded individual(s) at the site responsible for preparing the investigational product 
for the blinded doses for Days 1 through 14. 
Two target treatment areas, meeting the inclusion criteria, will be identified on each subject 
by the Investigator.  Upon randomization, the IP for that subject (for the double-blind 
treatment period) will be assigned to the respective target treatment area by the unblinded 
personnel at the site according to the randomization schedule.  Blinded tubes (differentiated 
by label color), will be used to dispense treatment for the corresponding target treatment area 
throughout the double-blind period.  The assessor and the subject will remain blind to 
treatment during this period.  Only the unblinded staff members(s) dispensing the IP will be 
unblinded with respect to which target treatment area is receiving crisaborole and which is 
receiving vehicle.  The unblinded dispenser(s) will not conduct any efficacy or safety 
assessments.  The open-labeled investigational product will be under the control of the 
unblinded dispenser(s) and stored in a secure area that is not accessible to other blinded staff 
until dispensed.
In the event the Investigator and medical monitor agree that the blind should be broken for an 
individual subject during the double-blind period, the investigator will unseal the envelope 
and break the blind for that subject only.  Since all subjects will receive both crisaborole and 
vehicle, the blinding is at the level of individual target treatment areas and not individual 
subjects. 
At the initiation of the study, the investigator site will be instructed on the method for 
breaking the blind.  The method will be a manual process.  Blinding codes should be broken 
only in exceptional circumstances when knowledge of the actual treatment code is absolutely 


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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 in the case report form (CRF).
5.3. Subject Compliance 
During the double-blind treatment period, subjects should not miss more than 6 IP 
applications in total, and have no missed IP applications the 2 days before Day 15 biopsy 
collection.  If the above requirement is not met, the subject will be discontinued from the 
study. Similarly, subjects should not miss more than 3 IP applications in total, and have no 
missed IP applications the 2 days before Day 8 biopsy collection (if collected). If the subject 
missed a dose in those 2 days, the biopsy should not be performed at Day 8, but the subject 
should not be discontinued.
Compliance for the double-blind treatment period is expected to be at least 80%.  This will 
be verified by the dosing records and visit schedule noted for each subject.  Subjects having 
missed doses of IP will be re-educated on the importance of compliance.  The Sponsor 
should be notified of any noncompliant subjects that are fulfilling above criteria for 
discontinuation.  At discretion of the Sponsor, those subjects may be replaced, as discussed 
in Section 9.
To facilitate compliance assessment during the open-label treatment period, subjects will be 
supplied with the subject diary and instructed to record the time for each daily dose of 
investigational product. Compliance for the open-blind treatment period will be collected 
and reviewed by the study site personnel at return to clinical research unit (CRU) visit(s).  
Subjects will be instructed to return this diary to the study staff at the scheduled visit, along 
with the investigational product carton(s) and tubes containing unused/partial/empty 
investigational product.
5.4. Investigational Product Supplies
5.4.1. Dosage Form(s) and Packaging
Open-labeled crisaborole ointment 2% and vehicle ointment will be provided in 60 gram 
tubes for topical administration.  The tubes will be provided in cartons and labeled in an 
open-label fashion according to local regulatory requirements.  Crisaborole ointment 
2% tubes/cartons and vehicle tubes/cartons will have different colored labels for clear 
differentiation of the products, as described in the IP manual.
5.4.2. Preparation and Dispensing
Investigational product should be prepared and dispensed by an appropriately qualified and 
experienced unblinded member of the study staff (eg, study coordinator, physician, nurse, 
physician’s assistant, nurse practitioner, pharmacy assistant/technician, or pharmacist) as 
allowed by local, state, and institutional guidance. 
For IP application during the double-blind treatment period, one tube of crisaborole and one 
tube of vehicle will be dispensed for each subject and assigned, as per Section 5.2, to the 
target treatment areas.  Upon assignment, the unblinded staff will indicate subject number on 


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the product label(s) in the designated area.  Each dose will be prepared by qualified 
unblinded site personnel.  Each dose will be prepared by weighing the investigational 
products to ensure accurate application rate of 3 mg/cm2 to an area of 10 cm x10 cm.  The 
investigational product will be administered in blinded fashion to the subject by blinded site 
staff. 
Refer to the Investigational Product Manual (IP manual) for instructions on how to prepare 
the investigational product for administration. 
Open-label crisaborole 2% ointment tubes and cartons will be dispensed at the Day 15 visit 
for self-application by the subject.  A qualified staff member will dispense the investigational 
product in the cartons provided, in quantities appropriate for the study visit schedule and 
subjects’ requirements.  On Day 15, the site should dispense an adequate amount of 
investigational product used until the subject returns for the Day 43 visit (end of 
treatment/early termination). 
The first dose of the open-label treatment period should be performed at the CRU after the 
Day 15 biopsy sample collection.  The subject should be instructed how to apply the product, 
and maintain the subject diary.  The subject should also be instructed to maintain the product 
in the tubes and cartons until dosing and return all dispensed supplies (unused/partial/empty) 
at the next study visit. 
5.5. Administration
Crisaborole ointment 2% is for external use on the skin only.  Contact with mucous 
membranes (ie, inside of nostrils, mouth, vagina, urethra, and rectum), and the eyes should be 
avoided.  Subjects should avoid ingestion of IP.
During the double-blind treatment period, the investigational product will be administered in 
blinded fashion, at the CRU, to the subject in the morning and evening (approximately 
8-12 hours apart).  To standardize the application, the investigational products (3 mg/cm2) 
will be applied on an area of 10 cm x10 cm for each of the two target treatment areas 
(designated ‘1’ and ‘2’) and applied at least 5 cm apart.  The treatment areas will be mapped 
on a transparency using natural skin landmark to ensure they remain the same throughout the 
double-blind treatment period.  If the target treatment area is smaller than 100 cm2, the 
application area will also include surrounding non-lesional skin.  If the target treatment area 
is larger than 100 cm2, only a 100 cm2 area will be treated.
During the double-blind treatment period, subjects will be permitted to use emollient on the 
remaining AD areas that are outside of targeted treatment areas.
Prior to initiation of the open-label treatment period, subjects will be provided appropriate 
training for IP application and will be instructed to apply a thin layer of crisaborole to all 
areas of the body with atopic dermatitis (except scalp), twice daily, from the Day 15 skin 
biopsy collection though Day 43 (end of treatment/early termination).  The first IP 
application will occur in the CRU, with all subsequent applications occurring at home, 
approximately every 8-12 hours.


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After Day 15 subjects will continue to apply the IP even if a lesion clears.  Any new atopic 
dermatitis on treatment-eligible areas occurring following Day 15 may be also treated with 
investigational product.
During the open-label treatment period (home-based), if a subject misses a scheduled 
morning dose, that day’s dose should be applied as soon as possible, but not later than 
6 hours beyond the scheduled time of applications.  If it is greater than 6 hours beyond the 
scheduled dose, the subject should be instructed to skip that dose and resume dosing the next 
regularly scheduled time.  Missed doses and reasons for missed doses should be noted on the 
subject diary. 
5.6. Investigational Product Storage 
The investigator or an approved representative, eg, unblinded dispenser, 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 single reference safety document (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 IP 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 in the IP Manual.
Temperature deviations outside of the labeled storage conditions for less than 20 minutes are 
not considered a temperature excursion, unless the recorded temperature is below 0C.


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Site staff will instruct subjects on the proper storage requirements for investigational 
products during the open-label treatment period. 
5.7. 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.  When IP is taken home by the 
subject, all used and unused products must be returned to the investigator by the subject at 
subsequent visit(s). 
5.7.1. 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.
5.8. Concomitant Treatment(s) 
Treatments taken before the first application of IP will be documented as a prior treatment.  
Treatments taken after the first application of IP will be documented as concomitant 
treatments.
All concomitant treatments taken during the study must be recorded with indication, daily 
dose, and start and stop dates of administration.  All subjects will be questioned about 
concomitant treatment at each CRU visit.
All treatments (including medications and non-medication therapies) used for the treatment 
of AD within 2 months prior to screening and all other treatments (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 at Baseline/Day 1 and at 
each subsequent visit.  All concomitant treatments taken during the study must be recorded 
with indication, daily dose, and start and stop dates of administration.  Classes of medications 
and non-medication treatments that might alter the course of AD and that require washout 
prior to Baseline/Day 1 are described in the Inclusion criteria.  If a subject requires a 
treatment washout, the Investigator will provide instructions on discontinuing the prohibited 
medication(s) at the Screening Visit. 
5.8.1. Permitted Concomitant Treatments - Day 1 through Day 43 (end of 
treatment/early termination)

Stable use of intranasal, inhaled, and ophthalmic corticosteroids.


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
Bland emollient(s) of choice (not containing urea) in skin areas where crisaborole is 
not applied (therefore not on or overlapping with target lesions) during double-blind 
treatment period.

Stable dose of non-sedating antihistamines (eg, fexofenadine, loratadine, 
desloratadine, cetirizine and levocetirizine).
5.8.2. Prohibited Concomitant Treatments - Day 1 through Day 43 (end of 
treatment/early termination)

Systemic (oral/injectable) corticosteroids.

Biological drugs.

Systemic immunosuppressive agents that could affect atopic dermatitis (eg, retinoids, 
calcineurin inhibitors, methotrexate, ciclosporin, hydroxycarbamide (hydroxyurea), 
azathioprine, hydroxychloroquine, mycophenolate mofetil).

Use of any potency topical corticosteroids or calcineurin inhibitors anywhere on the 
body.

Investigational product(s).

Systemic antibiotics for the treatment of new onset infections that require use longer 
than 14 days.

Doxepine.

Hydroxyzine and diphenhydramine.

Use of topical medications or products including, but not limited to: 

Topical products containing urea;

Prescription skin barrier repair products;

PDE4 products;

Antibacterial soaps (for bathing);

Bleach baths and bath oils;

Tars;

Antimicrobials;

Medical devices;


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
Topical sodium hypochlorite-based products;

Topical antihistamines;

Emollients (use of emollients on non-target lesions is permitted).
6. STUDY PROCEDURES 
6.1. Screening
Subjects will be screened within 30 days prior to Day 1 to confirm that they meet the subject 
eligibility 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 Section 12.3. 
The following procedures will be completed:

Obtain written informed consent.

Review Inclusion and Exclusion criteria.

Obtain medical and surgical history.

Obtain complete history of all treatments (including medications and non-medication 
therapies) used for the treatment of AD within 2 months prior to Screening and all 
other treatments (including over-the-counter drugs, vitamins, and antacids) used 
within 28 days prior to Screening. 

Conduct a full physical examination (may be performed at Baseline/Day 1 visit at the 
discretion of the investigator). Target treatment areas must be identified at Screening.

Obtain demography information.

Measure height and weight.

Conduct vital signs (single sitting blood pressure [BP], pulse rate and respiratory 
rate).

Collect blood specimens for the following:

Safety laboratory tests (as described in Section 7.1.1, Table 1);

Serum FSH concentration for any female who has been amenorrheic for at least 
12 consecutive months;

Serum pregnancy test for any woman of childbearing potential.

%BSA.


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
ISGA.

Lesion ISGA.

Contraception verification.

Begin AE collection with the signing of informed consent.
Rescreening may be permissible at investigator discretion and consultation with Sponsor. 
6.2. Study Period
For the study period described below, when multiple procedures are scheduled at the same 
time point(s) relative to dose application, the following chronology of events should be 
adhered to, where possible.

AD assessment scales.

Laboratory collection.

Biopsy collection (nonlesional skin and each target lesion).

Obtain all other procedures as close as possible to the scheduled time, but may be 
obtained before or after blood specimen collection.
When procedures are scheduled in addition to morning or evening dosing, the assessments 
are to be completed prior to the dose application.
During double-blind treatment period, any procedures not collected in the morning visit may 
be obtained during the evening CRU visit. 
6.3. Day 1 (Baseline)
Subjects will come to the CRU on Day 1 as scheduled by the site.  The following procedures 
will be completed:

Conduct limited physical examination (unless the full Screening PE was deferred to 
Day 1 visit).  Target treatment areas must be confirmed at Baseline.

Urine pregnancy test for women of childbearing potential.

Review inclusion and exclusion criteria.

Confirm and document that appropriate contraception is in place for the subject and 
their partner.

Assess symptoms by spontaneous reporting of AEs.


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
Review changes in the subject’s medical history including medication history since 
Screening.

Review prior and concomitant treatments.

Confirmation of the target treatment areas.

% BSA for eligibility.


ISGA.

Lesion ISGA.

Lesion TSS.


Pruritus numerical rating scale (global and for each target lesion).

Randomization number assigned after verification of eligibility.

Skin biopsy collection.

Application of the investigational product to target treatment areas ‘1’ and ‘2’ per the 
randomized assignment.
After morning dosing, the following procedures will be completed:

Assess symptoms by spontaneous reporting of AEs/AE monitoring.

Subject is to return to the CRU approximately 8-12 hours after morning dose 
application for a second dose application of investigational product to target treatment 
areas ‘1’ and ‘2’.

Subjects will be asked about concomitant treatment.
6.4. Days 2 through 14
Subjects will come to the CRU as scheduled by the site.  The following procedures will be 
completed:

Confirm and document that proper contraception is being used for the subject and 
their partner as appropriate.

Assess symptoms by spontaneous reporting of AEs.
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
Review concomitant treatments.


Lesion ISGA (Day 8 only).

Lesion TSS (Day 8 only).

Pruritus Numerical Rating Scale (for each target lesion).

Optional skin biopsy collection (Day 8 only).

Application of the investigational product to target treatment areas ‘1’ and ‘2’.
After morning dosing, the following procedures will be completed:

Assess symptoms by spontaneous reporting of AEs/AE monitoring.

Subject is to return to the CRU approximately 8-12 hours after morning dose 
application for a second dose application.  Any procedures not collected in the 
morning visit may be obtained during the evening CRU visit.  The subject may be 
discharged from CRU immediately post-dose application.

Subjects will be asked about concomitant treatment. 
6.5. Day 15 (+1 day)
Subjects will return to CRU on Day 15 and the following procedures will be completed:

Review concomitant treatments.

Assess symptoms by spontaneous reporting of AEs.

Confirm and document that proper contraception is being used for the subject and 
their partner, as appropriate.

Collect Urine pregnancy test.

ISGA.

Lesion ISGA.


Lesion TSS.

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
Pruritus Numerical rating scale (global and for each target lesion).

Skin biopsy collection.

Dispense open-label investigational product for outpatient administration.

Train subject on correct application of IP.

Subject diary training & distribution.

Subject application of the open-label IP to all AD lesions with oversight of the study 
site.

Completion of initial subject diary entry of the open-label IP with oversight and 
training by the study site.
After Day 15 dosing, the following procedures will be completed:

AE collection.

The subject may be discharged from CRU immediately post-dose application.
6.6. Double-Blind Early Termination 
If a subject has an early termination during the double-blind treatment period, every attempt 
should be made for the skin biopsy to be collected. 
All study procedures are identical as for Day 43 (end of treatment/early termination)
Section 6.8.  In addition lesion ISGA, lesion TSS, skin biopsy, 
, and pruritus for target 
lesion should be collected.
6.7. Days 16 to 42 Outpatient/Home based Dosing
Approximately every 8-12 hours until Day 43 (end of treatment/early termination) visit, the 
subjects will apply open-label IP at home to all AD lesions (excluding scalp), complete the 
subject diary and maintain all IP supplies. The subjects will be instructed how to complete 
the diary, which will include dosing, AEs and pruritus numerical rating scale information.
6.8. Day 43 (3 days) - End of treatment/Open-label Early Termination 
Subjects will return to the CRU on Day 43 (end of treatment/early termination) for an 
outpatient visit and the following procedures will be completed:

Collection and review of subject diary.

Confirm and document that proper contraception is being used for the subject and 
their partner as appropriate.

Perform a limited physical examination.
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
Collect urine pregnancy test.

Collect all IP tubes and cartons (full/partial/empty) returned by the subject.

Collect safety laboratory tests.

ISGA.


Pruritus Numerical Rating Scale (global only).

Review concomitant treatments.

AE collection.
6.9. Day 71 (+3 days) - Follow-up Contact
The subject is to have the follow-up contact at least 28 days after the last administration of 
the IP to capture any potential AEs (see the Time Period for Collecting AE/SAE Information
section), confirm appropriate contraception usage (see the Contraception section), and review 
concomitant treatments.  This visit is planned to occur as a telephone contact. 
6.10. Subject Withdrawal/Early Termination
Withdrawal of consent: Subjects who request to discontinue receipt of investigational 
product 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 post treatment study follow-up, and entered on the appropriate CRF page. 
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.  Lost to follow-up is defined by the inability to reach the subject after a 
minimum of 2 documented phone calls, faxes, or e-mails as well as lack of response by the 
subject to 1 registered mail letter.  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 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 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, 
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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 
procedures at a given study site. 
If a subject does not return for a scheduled visit, every effort should be made to contact the 
subject.  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 all unused investigational 
product, request that the subject return for a final visit, if applicable, and follow up with the 
subject regarding any unresolved AEs.
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.
7. ASSESSMENTS
Every effort should be made to ensure that the protocol-required tests and procedures are 
completed as described.  However, it is anticipated that from time to time there may be 
circumstances outside of the control of the investigator that may make it unfeasible to 
perform the test.  In these cases the investigator will 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 this and any corrective and preventive actions that 
he or she has taken to ensure that normal processes are adhered to as soon as possible.  The 
study team will 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 in Table 1 will be performed at times defined in the 
Schedule of Activities 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 laboratories may be obtained at 
any time during the study to assess any perceived safety concerns.


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Table 1.
Laboratory Tests
Hematology
Chemistry
Other
Hemoglobin
Hematocrit
RBC count
Platelet count
WBC count
Total neutrophils (abs)
Eosinophils (abs)
Monocytes (abs)
Basophils (abs)
Lymphocytes (abs)
Blood urea nitrogen
Glucose (random)
Creatinine
Sodium
Potassium
Aspartate aminotransferase
Alanine aminotransferase
Total bilirubin
Alkaline phosphatase
Albumin
Total protein
FSHa
Pregnancy test in all females of 
childbearing potential as defined by the 
protocolb
Abbreviations: abs=absolute, FSH=follicle-stimulating hormone, RBC=red blood cell, WBC=white blood 
cell.
a
At Screening only, in females who are amenorrheic for at least 12 consecutive months.
b
Serum pregnancy test at Screening and urine pregnancy test at Day 1, 15 and 43 or at Final Visit/Early 
Withdrawal/Termination.
7.1.2. Pregnancy Testing
For female subjects of childbearing potential, a serum pregnancy test with sensitivity of at 
least 25 mIU/mL will be performed at Screening, and urine pregnancy test on Day 1, 15 and 
Day 43 to confirm the subject has not become pregnant during the study, and at the 
early-termination visit, if applicable. 
A negative pregnancy test result is required before the subject may receive the investigational 
product application.  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)/ethics committees (ECs) or if required by local regulations. 
Urine pregnancy tests will be conducted with the test kit approved by the sponsor in 
accordance with instructions provided in its package insert.  Subjects who have missed a 
menstrual period or who show an indeterminate or positive result on the urine test may not 
further progress in the study until pregnancy is ruled out using further diagnostic testing 
(eg, a negative quantitative serum pregnancy test conducted at a certified laboratory).
In the case of a positive confirmed pregnancy, the subject will be withdrawn from 
administration of investigational product and from the study.
7.1.3. Physical Examinations
Physical examinations (PE) will be performed at times specified in the Schedule of Activities
of this protocol.


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PEs may be conducted by a physician, trained physician's assistant, or nurse practitioner as 
acceptable according to local regulation.  A full PE will include, but is not limited to the 
following organ or body systems: head, ears, eyes, nose, mouth, skin, heart and lung 
examinations, lymph nodes, gastrointestinal, musculoskeletal, abdomen (liver, spleen), and 
neurological systems.  The limited PE will be focused on general appearance, skin, the 
respiratory and cardiovascular systems, as well as towards subject reported symptoms.
Any changes to or worsening of existing physical examination findings, or new abnormal 
physical examination findings after dosing will be recorded as AEs, per the investigator’s 
judgment.
Identification of the target treatment areas will be included with the Screening PE with 
confirmation at Baseline.
7.1.4. Vital Signs
Vital signs (single sitting blood pressure, pulse rate and respiratory rate) will be assessed, at 
Screening only, prior to blood sample collection.
Additional collection times, or changes to collection times of vital signs will be permitted, as 
necessary, to ensure appropriate collection of safety data.
Vital signs will be measured in subjects in a sitting position with feet flat on the floor after 
5 minutes of rest. 
Blood pressure: For blood pressure, the subject’s arm is to be supported at the level of the 
heart, with the same arm (preferably the dominant arm, unless contraindicated) used 
throughout the study.  Subjects should be instructed not to speak during measurements. 
Pulse rate: The use of an automated device for measuring BP and pulse rate is acceptable, 
although, when done manually, pulse rate will be measured in the brachial/radial artery for at 
least 30 seconds. 
Respiratory rate: Measure the respiratory rate after at least 5 minutes at rest and accurately 
document.
7.2. Skin Biopsy Samples 
One 4.5 mm skin biopsy (punch biopsy) will be collected from each target treatment area on 
Day 1 and Day 15.  In addition, on Day 8, subjects will be offered to have one optional 
4.5 mm skin biopsy collected from each target treatment area.  Subjects should not miss more 
than 3 IP applications in total, and have no missed IP applications the 2 days before Day 8 or 
Day 15 biopsy collection. 
The biopsies on Day 8 and Day 15 will be collected in the vicinity, but at least 1 cm distant 
from where the biopsies were collected at Day 1, even if the target treatment area has cleared.  
One additional 4.5 mm biopsy will be collected from nonlesional skin on Day 1.  Each 


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biopsy will be cut in half.  One half will be used to perform RT PCR and gene array and the 
other half will be used for immunohistochemistry analysis.
Details of the biopsies sampling and handling will be described in a separate manual.
Tissue and derived material left over from the biopsy already being performed in this study 
may be used for potential further testing (eg, RNA-Seq analysis) provided material is 
available.  Each sample will be labeled with a code so that the laboratory personnel 
(including biomarker laboratory personnel) testing the samples will not know the subject’s 
identity.  Any tissue or derived material left over may be stored long term for further research 
purposes at a Sponsor-designated facility.  The samples will be used for the purposes 
described in the protocol and in the informed consent document; any other uses require 
additional ethical approval.  Unless a time limitation is required by local regulations or 
ethical requirements, the samples may be stored for up to 15 years after the end of the study 
and then destroyed. 
7.3. Investigator Static Global Assessment (ISGA)
The clinical evaluator of atopic dermatitis will perform an assessment of the overall severity 
of atopic dermatitis and assign ISGA score and category as described in Table 2.  The 
assessment will be a static evaluation without regard to the score at a previous visit. 
Table 2.
Investigator’s Static Global Assessment (ISGA)
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
7.4. Lesion ISGA
The clinical evaluator of atopic dermatitis will perform an assessment of each target lesion 
severity of atopic dermatitis and assign a lesion ISGA score and category as described in 
Table 2.


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7.5. Lesion Total Sign Score (TSS)
The Lesion TSS is an assessment of the severity of each of the following: erythema, 
edema/papulation, excoriation, and lichenification.  Each of these are rated using the 4-point 
severity scale described in Table 3.  These ratings are then added to create a total score 
(12-point scale; ranging from 0 to 12 points). 
Table 3.
Lesion Total Sign Score
Signs of Atopic Dermatitis
Erythema (Redness)
Score
Grade
Description
0
None
No redness
1
Mild
Mildly detectable erythema; pink
2
Moderate Dull red; clearly distinguishable
3
Severe
Deep, dark red; marked and extensive
Induration/Papulation
Score
Grade
Description
0
None
None
1
Mild
Slightly perceptible elevation
2
Moderate Clearly perceptible elevation but not extensive
3
Severe
Marked and extensive elevation
Excoriation (Evidence of Scratching)
Score
Grade
Description
0
None
No evidence of excoriation
1
Mild
Mild excoriation present
2
Moderate Definite excoriation present
3
Severe
Marked, deep, or extensive excoriation present
Lichenification (Epidermal Thickening)
Score
Grade
Description
0
None
No epidermal thickening
1
Mild
Minor epidermal thickening
2
Moderate Moderate epidermal thickening; accentuated skin lines
3
Severe
Severe epidermal thickening; deeply accentuated skin lines


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7.6. Pruritus Numerical Rating Scale (NRS) 
The intensity of pruritus will be assessed by a numerical rating scale (NRS),12,10 an 
eleven-point numeric rating scale from 0 to 10, to be completed for each target lesion and 
global, before IP morning dose is applied, at the time noted in the Schedule of Activities.
During the open-label treatment period, the pruritus NRS scale should be recorded 
consistently, once daily, before IP application.
This will be evaluated by asking subjects to assign a numerical score representing the current 
intensity/intensity over the last 24 hours of their pruritus on a scale from 0 to 10, with 
0 indicating no symptoms and 10 indicating the worst imaginable symptoms. The NRS of 
pruritus is presented in Figure 1.14
Figure 1.
Pruritus Numerical Rating Scale
Numeric Rating Scale (NRS)
0
1
2
3
4
5
6
7
8
9
10
No itch
Worst imaginable itch
CCI


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CCI
CCI
CCI


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7.8. %BSA with Atopic Dermatitis 
The overall BSA affected by AD will be evaluated (from 0% to 100%) at the visits specified 
in Schedule of Activities.  The Investigator may use the “handprint method” by which the 
area represented by the palmar (ie, outstretched) surface of the subject’s hand with all five 
digits adducted together is approximately 1% of the subject’s BSA, In addition, at the 
Screening and Baseline visit, the BSA will be evaluated to verify each subject’s eligibility 
using the same method as previously described, but excluding face, scalp, axilla, genitals, 
groin area, palms, back of the hands, and soles.
Percent BSA with Atopic Dermatitis (BSA Efficacy): The number of handprints of atopic 
dermatitis skin in a body region can be used to determine the extent (%) to which a body 
region is involved with atopic dermatitis (Table 6). 
Table 6.
Handprint Determination of Body Region Surface Area
Body Region
Total Number of Handprints 
in Body Region*
Surface Area of Body 
Region Equivalent of One 
Handprint
Head and Neck
10
10%
Upper Limbs
20
5%
Trunk (including axillae)
30
3.33%
Lower Limbs (including buttocks)
40
2.5%
*
The number of handprints are for the entire body region; these values are not adjusted for exclusion of 
scalp, palms, soles, groin, and genitals from the BSA Efficacy assessment 
The extent (%) to which each of the four body regions is involved with atopic dermatitis is 
categorized to a numerical Area Score using a non-linear scaling method according to the 
following BSA scoring criteria (Table 7).
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 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)
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 
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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 
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/Early Termination 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.


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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.
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. 


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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.
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.


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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

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 (SAE) 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.


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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 
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.


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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.
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 SAEs, listed above.
8.3.1. 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. 
8.3.2. 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.”
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 
are considered potential DILI (assessed per Hy’s law criteria) cases and should always be 


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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 
collected.  Further testing for acute hepatitis A, B, C, D, and E infection and liver imaging 
(eg, biliary tract) may be warranted. 


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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 liver function test (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.
8.3.3. 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.
8.3.3.1. 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).
If a subject 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).
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 


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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.
8.3.3.2. 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.
8.3.3.3. 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.
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.


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8.3.4. 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
8.3.4.1. 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.
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.


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9.1. Sample Size Determination
The sample size of this study is based on the objective to demonstrate crisaborole ointment 
2% is more efficacious than vehicle in the target lesion in subjects with mild to moderate AD 
as measured by the change from baseline in target lesion severity score (TSS) between 
crisaborole treated lesion and vehicle treated lesion. 
Approximately 40 subjects will be enrolled in the study to ensure approximately 30 subjects 
who will have skin biopsy done at Day 15 during the double-blind treatment period to have 
the precision described below (considering the non-compliance during the double-blind 
treatment period is ~20%). 
A sample size of 40 will have 90% power to establish the superiority of crisaborole to vehicle 
as measured by the change from baseline in TSS between crisaborole treated lesion and 
vehicle treated lesion at Day 15 using paired t-test at 0.05 (one-sided) significance level, 
assuming the difference is 1.4 and standard deviation 3.  With sample size of 30, the power 
becomes 80%.
A sample size of 30 also provides the following precision to estimate the change in the key 
skin biomarkers S100A12, CCL17, CCL18, CCL22, elafin/PI3, K16, or IL-13 in the target 
lesion treated with crisaborole 2% ointment or vehicle.  The expression level of biomarkers 
at Baseline or Day 15 will be expressed as log 2 transformed fold change (FCH) relative to 
house-keeping gene human acidic ribosomal protein gene (hARP), ie, the ratio between 
expression level of each biomarker and the expression level of hARP for each RT PCR 
sample.  The margin of error for the estimates, ie, the half width of the 95% confidence 
intervals (CIs) for the change from baseline in FCH, is less than 1.1 under the assumption 
that the maximal standard deviations for the change in FCH is 3 based on unpublished data. 
9.2. Analysis of Primary Efficacy Endpoints
The population for the analysis is the full analysis set (FAS), which includes any subject 
randomized and receiving 1 dose of investigational product.
For the lesion TSS, the linear mixed model will be used to model the intra-subject change 
from baseline in TSS between the crisaborole ointment 2% treated lesion and vehicle treated 
lesion.  The model includes the fixed effect of visit as factor, and an unstructured variance 
and covariance matrix will be used to model the dependence among the same subjects across 
different visits. 
9.3. Analysis of Biomarker Endpoints
In addition to the key biomarkers, the other biomarkers endpoints in this study include (but 
may not be limited to) the following:  
Parameters studied using immunohistochemistry (IHC) will include epidermal thickness 
(H&E staining), Ki-67+ cells, CD3+ T-cells, CD11c+ dendritic cells (DCs), FcEpsilonRI+ 
DCs, langerin+ cells, and FLG+ (filaggrin) cells.  Gene expression endpoints from RT PCR or 
Gene array will include MMP12, IL-1B, IL-2, IL-2RA, IL-5, IL-6, IL-8, IL-9, IL-10, 


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IL-12p35, IL-15, IL-15RA, IL-17A, IL-17F, IL-19, IL-22, IL-31, IL-32, IL-23p19, 
IL-12/23p40, INF-, CXCL1, CXCL2, CXCL9, CXCL10, CCL13, CCL20, CCL26, S100A7, 
S100A9, hBD2 (human Defensive 2), FLG (filaggrin), LOR (loricrin), periplakin, FOXP3, 
and thymic stromal lymphopoietin (TSLP) receptor.  PDE4A, PDE4B, and PDE4D 
expression will also be quantified. 
The population for the analysis of the biomarkers will be ‘per protocol’ (PP) population, 
which includes any subject receiving 1 dose of investigational product, with both Day 1 and 
Day 15 biopsies done, and without protocol violations that were thought to impact the 
biomarker expression during the vehicle controlled period.  All protocol deviations will be 
reviewed and assessed by the study team prior to database release.  In general, all data will be 
summarized using descriptive statistics.  No imputation will be made for missing data. 
Comparison of pre- and post- treatment of skin treated with crisaborole ointment 2% or 
vehicle will be performed.  Expression levels from RT PCR will be normalized to the 
housekeeping gene hARP (validated in other studies31) and log2-transformed prior to 
analysis (reporting unit: Expression/hARP).  Microarray data will be preprocessed using 
standard pipeline and log-2 transformed expressions.  Adjustments by batch effect and 
clinical variables will be carried out using ComBat, if needed.  Mixed effect model will be 
used and p-values will be adjusted by Benjamini-Hochberg procedure. 
Additionally, extensive bioinformatics tools will be employed to gain insights into the 
mechanism of action of crisaborole. 
Correlation analysis will be performed to assess if change from baseline in biomarkers 
correlates with change in the lesion TSS.
9.4. Analysis of Other Efficacy Endpoints
The lesion TSS, lesion ISGA, and lesion Pruritus Numerical Rating Scale will be 
summarized descriptively by visit and treatment during the vehicle-controlled period.  The 
difference of the improvement from baseline between crisaborole treated target treatment 
area and vehicle treated target treatment area will be derived. 
 
 
The overall (global) efficacy of treatment with crisaborole ointment 2% during the open 
label-period will include 
 Pruritus Numerical 
Rating Scale and ISGA response of clear or almost clear and at least a 2 grade improvement 
from baseline, which will be summarized descriptively by visit. 
No imputation will be made for missing data.
CCI
CCI


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9.5. Safety Analysis
The Safety population will include any subject receiving 1 dose of investigational product.  
All safety data will be summarized using descriptive statistics.  No imputation will be made 
for missing safety data.
All AE(s) that occur during the study after signing the informed consent through the final 
study visit will be recorded, classified on the basis of Medical Dictionary for Regulatory 
Activities (MedDRA) terminology and listed.  Treatment emergent adverse events (TEAEs)
are defined as 1) AEs where the onset is on or after the first administration or, 2) AEs that 
occur prior to the first investigational product administration and there is an increase of 
severity on or after the time of the first dose of investigational product administration.  
TEAEs will be summarized by the number of subjects reporting any TEAE, system organ 
class (SOC), preferred term, severity, relationship to investigational product, and seriousness. 
Serious adverse events (SAEs) will be summarized by severity and relationship to 
investigational product, and individual SAEs will be listed by subject.  A list of subjects who 
prematurely discontinue from the study due to an AE will be provided.
9.6. Interim Analysis 
No formal interim analysis will be conducted for this study.
9.7. Data Monitoring Committee 
This study will not use a Data Monitoring Committee.
10. QUALITY CONTROL AND QUALITY ASSURANCE
Pfizer or its agent will conduct periodic monitoring visits during study conduct 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 


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authorities, the investigator will provide Pfizer or its agents with an opportunity to review 
and comment on responses to any such findings.
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.
11. DATA HANDLING AND RECORD KEEPING
11.1. Case Report Forms/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 subject chart.  In these 
cases, data collected on the CRFs must match the data in 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, 
and 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.


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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 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.
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 law. 
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.


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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. 
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
13.1. End of Trial in All Participating Countries 
End of trial in all participating countries is defined as last subject last visit (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 (PF-06930164) 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.


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15. PUBLICATION OF STUDY RESULTS
15.1. Communication of Results by Pfizer
Pfizer fulfills its commitment to publicly disclose clinical trial results through posting the 
results of studies on www.clinicaltrials.gov (ClinicalTrials.gov), 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.
www.clinicaltrials.gov
Pfizer posts clinical trial US Basic Results on www.clinicaltrials.gov for Pfizer-sponsored 
interventional studies (conducted in subjects) 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.
www.pfizer.com
Pfizer posts Public Disclosure Synopses (clinical study report synopses in which any data 
that could be used to identify individual subjects has 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.


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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.
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;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.
Ozkaya E. Adult-onset atopic dermatitis. J Am Acad Dermatol 2005; 52(4):579-82.
4.
Bannister MJ, Freeman S. Adult-onset atopic dermatitis. Australas J Dermatol 2000; 
41(4):225–8.
5.
Eichenfield LF, Ellis CN, Mancini AJ, et al. Atopic dermatitis: epidemiology and 
pathogenesis update. Semin Cutan Med Surg 2012;31(3 Suppl):S3-5. 
6.
Leicht S, Hanggi M. Atopic dermatitis. How to incorporate advances in management. 
Postgrad Med 2001;109(6):119–27. 
7.
Arkwright PD, Motala C, Subramanian H, et al. Management of difficult-to-treat atopic 
dermatitis, 2013. J Allergy Clin Immunol Pract. 2013 Mar;1(2):142-51. 
8.
Leung DY. New insights into atopic dermatitis: role of skin barrier and immune 
dysregulation. Allergol Int. 2013 Jun;62(2):151-61. 
9.
Halvorsen J, 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. 
10.
Watson W, Kapur S. Atopic dermatitis. Allergy Asthma Clin Immunol. 2011 Nov 10;7 
Suppl 1:S4.
11.
Simpson EL, Bieber T, Guttman-Yussky E, et al. Two Phase 3 Trials of Dupilumab 
versus Placebo in Atopic Dermatitis N Engl J Med 2016; 375:2335-2348.
12.
Phan NQ, Blome C, Fritz F, Gerss J, Reich A, Ebata T, et al. Assessment of pruritus 
intensity: prospective study on validity and reliability of the visual analogue scale, 
numerical rating scale and verbal rating scale in 471 subjects with chronic pruritus. Acta 
dermato-venereologica. 2012;92(5):502-7.
13.
Hamilton JD, Suarez-Farinas M, Nikhil D, et al. Dupilumab improves the molecular 
signature in skin of patients with moderate-to-severe atopic dermatitis. JACI 2014;134 
(6): 1293–1300.
14.
Pfizer Crisaborole IB February 2017.
15.
Anacor Pharmaceuticals Report No. 003-NCL PP-002-01, Effect of AN2728 on the 
Inhibition of Cytokine Release from THP-1 Cells Stimulated with LPS.


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16.
Anacor Pharmaceuticals Report No. 003-NCL PP-010-01, Effect of AN2728 on 
Inhibition of IL-12 and IL-23 Production in THP-1 Cells Stimulated with Interferon-γ 
and Lipopolysaccharide.
17.
Anacor Pharmaceuticals Report No. 003-NCL PP-017-01, Effect of AN2728 on 
Inhibition of IL-23 Production in THP-1 Cells Stimulated with Interferon-γ and 
Lipopolysaccharide.
18.
Anacor Pharmaceuticals Report No. 003-NCL PP-001-01, Effect of AN2728 on the 
Inhibition of Cytokine Release from Human Peripheral Blood Mononuclear Cells 
Challenged with LPS or PHA.
19.
Anacor Pharmaceuticals Report No. 003-NCL PP-007-01, Effect of AN2728 in 
Inhibition of IL-1β, IL-4, TNFα, and IFNγ from PBMCs Challenged with PHA for 24 h.
20.
Anacor Pharmaceuticals Report No. 003-NCL PP-008-01, Effect of AN2728 in 
Inhibition of IL-1, IL-4, TNF, and IFNfrom PBMCs Challenged with PHA for 
24 or 48 h.
21.
Anacor Pharmaceuticals Report No. 003-NCL PP-006-01, Effect of AN2728 on 
Inhibition of IL-2 and IL-5 Cytokine Release from PBMCs.
22.
Anacor Pharmaceuticals Report No. 003-NCL PP-013-01, PDE Isoform Profiling 
(Percent Inhibition).
23.
Houslay MD, Adams DR. PDE4 cAMP phosphodiesterases: modular enzymes that 
orchestrate signalling cross-talk, desensitization and compartmentalization. Biochem J. 
2003;370(Pt 1):1-18.
24.
Anacor Pharmaceuticals Report No. 003-NCL PP-022-01, Pharmacology Data Report: 
Evaluation of Anti-Inflammatory Activity of AN2728 in the Topical Inflammation, 
Phorbol Ester Assay.
25.
Anacor Pharmaceuticals Report No. 003-NCL PP-023-01, Pharmacology Data Report: 
Evaluation of Anti-Inflammatory Activity of AN2728 in the Topical Inflammation, 
Phorbol Ester Assay.
26.
Anacor Pharmaceuticals Report No. 003-NCL PP-024-01, Pharmacology Data report: 
AN7602 and AN8323 IC50 Against PDE4.
27.
Anacor Pharmaceuticals Report No. 003-NCL PP-025-01, Effect of AN7602 and 
AN8323 on Cytokine Release from Human Peripheral Blood Mononuclear Cells 
Stimulated with Lipopolysaccharide or Phytohemagglutinin-L.
28.
Bissonnette R, Papp KA, Poulin Y, Gooderham M, Raman M, Mallbris L, Wang C, 
Purohit V, Mamolo C, Papacharalambous J, Ports WC.  Br J Dermatol. 2016 


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Nov;175(5):902-911. doi: 10.1111/bjd.14871.  Topical tofacitinib for atopic dermatitis: 
a phase IIa randomized trial.  
29.
Hanifin JM and Rajka G. Diagnostic features of atopic dermatitis. Acta Derm Venereol 
(Stockh) 1980;92(suppl):44-7.
30.
E Guttman-Yassky et al. A model to evaluate intra-patient differential effects of topical 
agents in atopic dermatitis. Icahn School of Medicine Mount Sinai 2016; Abstract.
31.
Imhof et al. TEWL, Closed-Chamber Methods: AquaFlux and VapoMeter 
(Springer 2013).


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Appendix 1. Abbreviations 
This 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 concentration time curve
BBS
biospecimen banking system
BP
blood pressure
BID
twice a day
BSA
body surface area
cAMP
cyclic adenosine monophosphate
CI
confidence interval
CK
creatine kinase
Cmax
maximum plasma concentration
CRF
case report form
CRU
Clinical Research Unit
CSA
clinical study agreement
CSF
cerebrospinal fluid
CSR
clinical study report
CT
Clinical Trial
CTA
clinical trial application
CTCAE
Common Terminology Criteria for Adverse Events
DCs
dendritic cells
DDI
drug drug interaction
DILI
drug-induced liver injury
DMC
data monitoring committee
DNA
deoxyribonucleic acid
DU
dispensable unit
EC
ethics committee
EC50
half maximal effective concentration
ECG
Electrocardiogram
E-DMC
external data monitoring committee 
EDP
exposure during pregnancy
EU
European Union
EudraCT
European Clinical Trials Database
FDA
Food and Drug Administration
FLG
filaggrin
GCP
Good Clinical Practice
GGT
Gamma-glutamyl transferase
CCI


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Abbreviation
Term
GSVA
Gene Set Variation Analysis
H&E
hematoxylin and eosin
hARP
human acidic ribosomal protein gene
HIV
human immunodeficiency virus
HRQL
health-related quality of life
HRQoL
health-related quality of life
IB
investigator’s brochure
ICH
International Conference on Harmonisation
ID
identification
IGA
Investigator’s global assessment
IgE
immunogloblin E
IHC
immunohistochemistry
IND
investigational new drug application
INR
international normalized ratio
IP
investigational product
IRB
institutional review board
IRC
internal review committee
IRT
interactive response technology
ISGA
investigator static global assessment
IUD
intrauterine device
IWR
interactive web response
K2EDTA
dipotassium ethylenediaminetetraacetic acid
LFT
liver function test
LMW
low molecular weight
LOR
loricrin
LSLV
last subject last visit 
MedDRA
Medical Dictionary for Regulatory Activities
MnB
meningitidis serogroup B
N/A
not applicable
NRS
numeric rating scale
NSAID
nonsteroidal anti-inflammatory drug
PCD
primary completion date
PCR
polymerase chain reaction
PD
Pharmacodynamics(s)
PDE-4
phosphodiesterase-4
PE
physical examination
PFS
prefilled syringe
PGx
Pharmacogenomics(s)
PI
principal investigator
PK
pharmacokinetic
PKA
protein kinase A
PMA
phorbol 12-myristate 13-acetate
PT
prothrombin time


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Abbreviation
Term
QD
once a day
RNA
ribonucleic acid
RT
reverse transcriptase
SAE
serious adverse event
SAP
statistical analysis plan
SC
subcutaneous
SD
standard deviation
SOC
system organ class
SOP
standard operating procedure
SRSD
single reference safety document
SUSAR
suspected unexpected serious adverse reaction
TBili
total bilirubin
TEAE
treatment emergent adverse events
TLDA
Taqman Low Density Array
TQT
thorough QT
TSLP
thymic stromal lymphopoietin
TSS
total sign score
ULN
upper limit of normal
US
United States
UV
ultraviolet
CCI


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Appendix 2. Diagnostic Criteria for Atopic Dermatitis
Per Inclusion Criterion 2, a subject is to have a clinical diagnosis of atopic dermatitis 
according to the criteria of Hanifin and Rajka19 or at least 6 months prior to Screening visit 
and that has been clinically stable for 1 month.
Table 4: 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: involvement of facial and extensor surfaces
Chronic or relapsing dermatitis
Personal or family history of atopy
Minor Criteria (must have at least three)
Xerosis
Icthyosis/keratosis pilaris/palmer hyperlinearity
Immediate (type 1) skin test reactivity
Elevated serum immunogloblin E (IgE)
Early age at onset
Tendency to skin infections (Staphylococcus aureus, herpes simplex)/impaired cellular 
immunity
Hand/foot dermatitis
Nipple eczema
Conjunctivitis
Dennie-Morgan fold
Keratoconus
Anterior subcapsular cataracts
Orbital darkening
Facial pallor/erythema
Pityriasis alba
Anterior neck folds
Itch when sweating
Intolerance to wool and lipid solvents
Perifollicular accentuation
Food intolerance
Course influenced by environmental/emotional factors
White demographic/delayed blanch

SAP_001.pdf: 
Protocol C3291001 (PF-06930164) Statistical Analysis Plan
Page 1
Protocol C3291001
A PHASE 2A, RANDOMIZED, DOUBLE-BLIND, VEHICLE-CONTROLLED 
STUDY, TO CHARACTERIZE THE MECHANISM OF ACTION OF 
CRISABOROLE OINTMENT 2%, BY EVALUATION OF EFFICACY AND 
CHANGES IN SKIN BIOMARKERS, IN ADULT SUBJECTS WITH MILD TO 
MODERATE ATOPIC DERMATITIS, WITH A 4 WEEK OPEN-LABEL 
EXTENSION
Statistical Analysis Plan 
(SAP)
Author:
Version:
2
Date:
1-Jun-2018
PPD


Protocol C3291001 (PF-06930164) Statistical Analysis Plan
Page 2
TABLE OF CONTENTS 
TABLE OF CONTENTS...........................................................................................................2
LIST OF TABLES.....................................................................................................................4
1. VERSION HISTORY............................................................................................................5
2. INTRODUCTION .................................................................................................................6
2.1. Study Objectives .......................................................................................................6
2.1.1. Primary Objectives .......................................................................................6
2.1.2. Secondary Objectives ...................................................................................6
2.2. Study Design .............................................................................................................7
3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS ..................................................................................................................7
3.1. Primary Endpoint(s) ..................................................................................................7
3.2. Secondary Endpoint(s) ..............................................................................................7
3.4. Baseline Variables.....................................................................................................8
3.5. Safety Endpoints .......................................................................................................9
3.5.1. Adverse Events.............................................................................................9
3.5.2. Laboratory Data............................................................................................9
4. ANALYSIS SETS .................................................................................................................9
4.1. Full Analysis Set .......................................................................................................9
4.2. Per Protocol Analysis Set..........................................................................................9
4.3. Safety Analysis Set....................................................................................................9
4.4. Other Analysis Sets ...................................................................................................9
5. GENERAL METHODOLOGY AND CONVENTIONS....................................................10
5.1. Hypotheses and Decision Rules ..............................................................................10
5.2. General Methods .....................................................................................................10
5.2.1. Analyses for Binary Data............................................................................10
5.2.2. Analyses for Continuous Efficacy Data .....................................................10
5.2.3. Analyses for Biomarkers ............................................................................11
5.2.4. Analyses for Categorical Data....................................................................12
5.3. Methods to Manage Missing Data ..........................................................................12
6. ANALYSES AND SUMMARIES ......................................................................................12
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6.1. Primary Endpoint(s) ................................................................................................12
6.1.1. Change In Lesion TSS From Baseline To Day 15 .....................................12
6.1.2. Change in Key Skin Biomarkers (S100A12, CCL17, CCL18, 
CCL22, K16, elafin/PI3 and IL-13 expression level) From Baseline to 
Day 15..............................................................................................................14
6.2. Secondary Endpoint(s) ............................................................................................14
6.2.1. Change in The Lesion TSS From Baseline to Day 8..................................14
6.2.2. Changes in Key Skin Biomarkers From Baseline to Day 8........................14
6.2.3. Correlation Between Biomarkers Change And Lesion TSS Change .........14
6.2.4. Change From Baseline to Day 8 and Day 15 in ISGA...............................15
6.2.5. Change From Baseline To Visits Up To Day 15 In Pruritus 
Numerical Scale...............................................................................................15
 
 
6.4. Subset Analyses.......................................................................................................18
6.5. Baseline and Other Summaries and Analyses.........................................................19
6.5.1. Baseline Summaries....................................................................................19
6.5.2. Study Conduct and Subject Disposition .....................................................19
6.5.3. Study Treatment Exposure and Compliance ..............................................19
6.5.4. Concomitant Medications and Non-Drug Treatments................................19
6.6. Safety Summaries and Analyses .............................................................................19
6.6.1. Adverse Events...........................................................................................19
6.6.2. Laboratory Data..........................................................................................20
6.6.3. Vital Signs ..................................................................................................20
6.6.4. Physical Examination .................................................................................20
7. INTERIM ANALYSES.......................................................................................................20
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8. REFERENCES ....................................................................................................................21
9. APPENDICES .....................................................................................................................22
9.1. Definition and Use of Visit Windows in Reporting................................................22
LIST OF TABLES
Table 1. Summary of Major Changes in SAP Amendments .....................................................5
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1. VERSION HISTORY
This Statistical Analysis Plan (SAP) for study C32910011 is based on the protocol dated 
02May2017.  
Table 1. Summary of Major Changes in SAP Amendments
SAP 
Version
Change
Rationale
1
Not Applicable
Not Applicable
2
Additional Day 15 visit window for 
ISGA (global), 
 and 
pruritus NRS (global) was added
No Day 8 assessments for these 
endpoints
AR(1) variance-covariance matrix was 
added to Section 5.2.2 for mixed model.
In case there is convergence issue 
for unstructured 
variance-covariance matrix.
Summary of pruritus NRS change from 
Day 15 to Day 43 was updated as 
change from Day 15 to Day 16 through 
Day 43.
Pruritus NRS was collected daily.
TEAE definition was updated
Per Pfizer Standard
 
Line plots for mean change (SE)  
from baseline up to Day 15, and mean 
change (SE) from Day15 to Day 16 
through Day 43 in pruritus NRS were 
added.
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2. INTRODUCTION
Crisaborole, also referred to as PF-06930164 and AN2728, is a low molecular weight 
benzoxaborole anti-inflammatory phosphodiesterase-4 (PDE-4) inhibitor.  The safety and 
efficacy of crisaborole has been demonstrated in two phase 3 studies (AN2728-AD-301 and 
AN2728-AD-302) and one long term open-label study (AN2728-AD-303).  The 2% dose 
strength of crisaborole ointment is approved in the US for the treatment of mild-moderate 
atopic dermatitis (AD) for subjects 2 years.
The specific mechanism(s) by which crisaborole exerts its therapeutic action is not well 
defined.  In this study, skin biopsies will be collected to characterize the mechanism of 
action, by evaluation of efficacy and changes in key skin biomarkers, of crisaborole ointment 
2% over vehicle, applied twice a day in adult subjects with AD with maximum treatable BSA 
of 10%.  The skin biopsy samples will be analyzed using immunohistochemistry (IHC) and 
gene expression, which will be done using TLDA PCR for 48 genes including housekeeping 
genes as well as single gene PCR for a few genes that are below detection level on TLDA.
This SAP provides the detailed methodology for summary and statistical analyses of the data 
collected in study C3291001.1  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
2.1.1. Primary Objectives

To evaluate the efficacy of crisaborole ointment 2% vs vehicle in subjects with mild to 
moderate AD.

To evaluate change in key skin biomarkers of AD in target lesions treated with 
crisaborole ointment 2% or vehicle.
2.1.2. Secondary Objectives

To evaluate change in other skin biomarkers of atopic dermatitis in target lesions 
treated with crisaborole ointment 2% or vehicle.

To evaluate normalization of biomarker and gene expression levels in lesional skin 
treated with crisaborole ointment 2% or vehicle.

To evaluate changes in AD clinical sign and symptom severity in target lesions 
treated with crisaborole ointment 2% or vehicle.

To assess the safety and local tolerability of crisaborole ointment 2% in subjects with 
mild to moderate AD.
 
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
2.2. Study Design
This is a Phase 2a randomized, double-blind, vehicle-controlled study to characterize the 
mechanism of action, by evaluation of efficacy and changes in key skin biomarkers, of 
crisaborole ointment 2% in subjects with mild to moderate atopic dermatitis.  After 
completing screening activities, including meeting eligibility criteria, approximately
40 subjects will be treated.  In the double-blind treatment period, each subject will be 
randomly assigned to be treated with crisaborole ointment 2% for one target lesion.  The 
other target lesion will receive vehicle. 
The double-blind treatment period will last from Baseline/Day 1 to Day 15 skin biopsy 
collection and will include twice daily visits to the site for IP application and study 
assessments, where applicable.  The open-label treatment period will start from the Day 15 
skin biopsy collection and last until Day 43 (end of treatment/early termination); during this 
time, subjects will be able to treat all AD skin areas (except scalp), at home, with crisaborole 
ointment 2%.
Scheduled (outpatient) study visits for all subjects will occur at Screening (up to 30 days 
prior to Day 1/Baseline), Days 1 to 14 (twice daily), Day 15, and Day 43 (end of 
treatment/early termination).  On Day 71 (end of study), a follow-up telephone call will be 
made by site staff to assess for AEs that may have occurred since the last visit.
3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS
3.1. Primary Endpoint(s)

Change from baseline in TSS in target lesions treated with crisaborole ointment 
2% or vehicle on Day 15.

Change from baseline in key skin biomarkers of AD (S100A12, CCL17, CCL18, 
CCL22, K16, elafin/PI3 and IL-13 expression level) in target lesions treated with 
crisaborole ointment 2% or vehicle at Day 15.
3.2. Secondary Endpoint(s)

Change from baseline in other skin biomarkers in target lesions treated with 
crisaborole ointment 2% or vehicle at Day 15.

Biomarker and gene expression level in lesional skin treated with crisaborole 
ointment 2% or vehicle at Day 15 and levels in non-lesional skin at Baseline.

Change from baseline in lesion severity as measured by TSS, ISGA, and Pruritus 
Numerical Rating Scale at each visit up to Day 15.

The incidence of treatment emergent AEs and SAEs.
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3.4. Baseline Variables
Demographic and baseline characteristics include: 

Age (in years);

Sex;

Race;

Ethnicity;

Height (in cms);

Weight (in kg);

Body Mass Index;

Duration of disease (in years);

ISGA (global and target lesions);



TSS (target lesions);


Pruritus numerical scale (global and target lesions).
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3.5. Safety Endpoints
3.5.1. Adverse Events

All adverse events (AEs), including serious adverse events (SAEs).
An AE 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 (eg, during the screening period), or

The event was seen prior to the start of treatment but increased in severity during 
treatment, or

The event was seen and was resolved prior to the start of treatment but reported again 
during treatment.
3.5.2. Laboratory Data

Clinically significant abnormal laboratory parameters.

Clinical laboratory values and change from screening at Day 43/Early Termination.
4. ANALYSIS SETS
4.1. Full Analysis Set
The full analysis set (FAS) includes all subjects who are randomized and receive at least one 
dose of investigational product. 
4.2. Per Protocol Analysis Set 
The Per Protocol Analysis Set (PPAS) will be a subset of subjects from FAS. PPAS includes 
any subject randomized and receiving 1 dose of investigational product, with both Day 1 
and Day 15 biopsies done, and without protocol violations that were thought to impact the 
biomarker expression during the vehicle controlled period.  All protocol deviations will be 
reviewed and assessed by the study team prior to database release.  In general, all data will 
be summarized using descriptive statistics.  No imputation will be made for missing data.
4.3. Safety Analysis Set
The Safety Analysis Set will include any subject receiving 1 dose of investigational 
product.  
4.4. Other Analysis Sets
N/A.


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5. GENERAL METHODOLOGY AND CONVENTIONS
5.1. Hypotheses and Decision Rules
One of the primary analyses will be a superiority test to demonstrate crisaborole ointment 2% 
is more efficacious than vehicle in the target lesion in subjects with mild to moderate AD as 
measured by the change from baseline in target lesion severity score (TSS) between 
crisaborole treated lesion and vehicle treated lesion. The null hypothesis is that there is no 
difference between crisaborole ointment 2% and vehicle, and the alternative hypothesis is 
that crisaborole ointment 2% is superior to vehicle as measured by change from baseline in 
TSS at Day 15. The difference between crisaborole and vehicle in TSS change from baseline 
at Day 15 is significant if p-value<0.05.  
Another primary analysis is for the change in the key skin biomarkers S100A12, 
CCL17, .CCL18, CCL22, elafin/PI3, K16, or IL-13 in the target lesion treated with 
crisaborole 2% ointment or vehicle.  The null hypothesis is that there is no difference 
between crisaborole ointment 2% and vehicle in the change from baseline to Day 15 in these 
biomarkers, and the alternative hypothesis is that there is a difference between crisaborole 
ointment 2% and vehicle in the expression level of biomarkers. Mixed effect model will be 
used and p-values will be adjusted by Benjamini-Hochberg procedure.
5.2. General Methods 
In general, number and percent will be presented for categorical variables. Number, mean, 
standard deviation, minimum, 1st, 2nd and 3rd quartiles and maximum will be presented for 
continuous variables.
5.2.1. Analyses for Binary Data
Lesion ISGA response of clear or almost clear and at least a 2 grade improvement from 
Baseline to Day 8 and Day 15 will be descriptively summarized using number, percentage 
and 95% confidence interval (CI) of percentage, and compared using McNemar’s test for the 
comparison of crisaborole vs vehicle at each time point.
 
 
5.2.2. Analyses for Continuous Efficacy Data
For the lesion TSS, the linear mixed model will be used to model the intra-subject change 
from baseline in TSS between the crisaborole ointment 2% treated lesion and vehicle treated 
lesion.  The model includes the fixed effect of visit as factor, and an unstructured variance 
and covariance matrix will be used to model the dependence among the same subjects across 
different visits up to Day 15. If there is convergence issue for unstructured
variance-covariance matrix, first order autoregressive (AR(1)) variance-covariance matrix
will be used. The least square (LS) mean of difference and the associated 95% CI will be 
presented.
Continuous secondary endpoints in the double blind period:
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
Change from baseline in lesion ISGA up to day 15;

Change from baseline in lesion pruritus numerical rating scale up to Day 15.
will be analyzed using similar methods as lesion TSS.
will be descriptively summarized using number, mean, standard deviation, minimum, 1st, 
2nd and 3rd quartiles and maximum. 
5.2.3. Analyses for Biomarkers
The skin biopsy samples will be analyzed using immunohistochemistry (IHC), gene arrays 
and gene expression of specific genes to elucidate the mechanism of action of Crisaborole, 
which will be done using Taqman Low Denstity Array (TLDA) PCR for 48 genes including 
housekeeping genes as well as single gene PCR for few genes that are below detection level 
on TLDA. TLDA PCR expression values are estimated by -∆Ct that is computed relative to 
RPLPO housekeeping gene. Measurements under the limit of detections are imputed as 20% 
of the minimum value observed for that gene.
The gene expression data is modeled using a mixed effect model with Time, Tissue, and 
Treatment as a fixed effect and a random intercept for each patient. This formulation 
intrinsically models the patient correlation structure as in the case of a paired t-test, having 
the advantage that estimation of the main effects is possible even in the presence of missing 
values. This allows to use all available data at each time point rather than using only 
complete observations. This approach introduces less bias than restricting the analysis for 
those patients who completed the study. Contrasts are used to estimate the fold changes with 
treatment within each treatment group and conduct hypothesis testing. Changes with 
treatment will be estimated and per gene improvement will be defined 
as -100*(XW12,LS-XW0,LS)/(XW0,LS-XW0,NL), XW12,LS-XW0,LS represents the least 
square means for the treatment change and XW0,LS-XW0,NL represents the least square 
means for the baseline differences. 
The microarray data is processed using standard QC metrics and R packages. Expression 
measures are obtained using GCRMA algorithm. Adjustments by batch effect and clinical 
variables are carried out using ComBat. Probe-sets with at least 15 samples with expression 
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values larger than 3 are kept for further analysis. Expression values are modeled using 
mixed-effect models with fixed factors Time, Tissue and Treatment and a random effect for 
each patient. Fold changes for the comparisons of interest are estimated and hypothesis 
testing was conducted on such comparisons using contrasts under the general framework for 
linear models. P-values from the moderated (paired) t-test were adjusted for multiple 
hypotheses using the Benjamini–Hochberg procedure which controls the False Discovery 
Rate (FDR). 
Additionally, extensive bioinformatics tools will be employed to gain insights into the 
mechanism of action of crisaborole. 
Correlation analysis will be performed to assess if change from baseline in biomarkers 
correlates with change in the lesion TSS. Pearson correlation coefficient will be provided.
5.2.4. Analyses for Categorical Data
Categorical endpoints will be summarized using number and percentage. Shift table from 
baseline to Day 8 and Day 15 will be provided for lesion ISGA. 
5.3. Methods to Manage Missing Data
Missing will not be imputed for efficacy descriptive summary.  For continuous endpoints 
analyzed using mixed model in the double blinded period, the missing values 
post-randomization will be handled in a linear mixed-effect model with repeated measures 
for this continuous variable, where the values are assumed to be missing at random.  
Non responder imputation (NRI) will be used for missing values of lesion ISGA response of 
clear or almost clear and at least a 2 grade improvement from baseline at Day 8 and Day 15. 
No imputation for missing values of ISGA response of clear or almost clear and at least a 
2 grade improvement from Day 15 to Day 43.
In addition, missing values for safety endpoints will not be imputed.
6. ANALYSES AND SUMMARIES
6.1. Primary Endpoint(s)
6.1.1. Change In Lesion TSS From Baseline To Day 15
6.1.1.1. Primary Analysis

Analysis time points: Day 15.

Analysis population: FAS.

Analysis methodology: the intra-subject difference of change from baseline in lesion 
TSS between crisaborole and vehicle up to Day 15 will be analyzed using the model 
specified in Section 5.2.2.  


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
Imputation for missing values: observed data will be included in the model, the 
missing values will be handled in the model, where the values are assumed to be 
missing at random.

Supporting objective and Decision rule: Primary Objective, the lesion TSS change is 
superior for crisaborole treated area if pvalue<0.05.
Reporting results:

Raw data: The sample size, mean, standard deviation, median, Q1, Q3, minimum and 
maximum at baseline and post-baseline visits will be presented for each treatment.

Change from baseline: The sample size, mean, standard deviation, median, Q1, Q3, 
minimum and maximum will be presented for each treatment. The LS means of 
difference and the corresponding standard error, 95% CI, p-value will be presented.  
Figures

Line plots of the means change from baseline at Day 15 and 8 for two treatments.
6.1.1.2. Sensitivity/Robustness Analyses
To support the interpretation of the primary analysis the following analyses will be 
performed: 
6.1.1.2.1. Analysis for PPAS

Analysis time points: up to Day 15.

Analysis population: PPAS.

Analysis methodology: the intra-subject difference of change from baseline in lesion 
TSS between crisaborole and vehicle will be analyzed using the model  specified in 
Section 5.2.2.  

Imputation for missing values: observed data will be included in the model, the 
missing values will be handled in the model, where the values are assumed to be 
missing at random. 

Supporting objective and Decision rule: Primary Objective, the lesion TSS change is 
superior for crisaborole treated area if pvalue<0.05.
Reporting results:

Raw data: The sample size, mean, standard deviation, median, Q1, Q3, minimum and 
maximum at baseline and post-baseline visits will be presented for each treatment.


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
Change from baseline: The sample size, mean, standard deviation, median, Q1, Q3, 
minimum and maximum will be presented for each treatment. The  LS means of 
difference and the corresponding standard error, 95% CI, p-value will be presented.  
6.1.2. Change in Key Skin Biomarkers (S100A12, CCL17, CCL18, CCL22, K16, 
elafin/PI3 and IL-13 expression level) From Baseline to Day 15
6.1.2.1. Primary Analysis

Analysis time points: Day 15.

Analysis population: PPAS.

Analysis methodology: the change from baseline in lesion biomarkers will be 
analyzed using the model  specified in Section 5.2.3.  

Imputation for missing values: observed data will be included in the model, the 
missing values will be handled in the model, where the values are assumed to be 
missing at random. 

Supporting objective and Decision rule: Primary Objective, the lesion biomarker
change is superior for crisaborole treated area if adjusted pvalue<0.05.
Reporting results:

Raw data: The sample size, mean, standard deviation, median, Q1, Q3, minimum and 
maximum at baseline and post-baseline visits will be presented for each treatment.

Change from baseline: The sample size, mean, standard deviation, median, Q1, Q3, 
minimum and maximum will be presented for each treatment. The  LS means of 
difference and the corresponding standard error, 95% CI, p-value will be presented. 
6.2. Secondary Endpoint(s)
6.2.1. Change in The Lesion TSS From Baseline to Day 8
Day 8 is a time point in the mixed model for the primary analysis for lesion TSS change from 
baseline at Day 15. The analysis for lesion TSS change at Day 8 is from the same model, 
and data reporting is same as for Day 15. See Section 6.1.1.
6.2.2. Changes in Key Skin Biomarkers From Baseline to Day 8
Day 8 is a time point in the mixed model for the primary analysis for miomarkers change 
from baseline at Day 15. The analysis for biomarkers change at Day 8 is from the same 
model, and data reporting is same as for Day 15. See Section 6.1.2.
6.2.3. Correlation Between Biomarkers Change And Lesion TSS Change
The analysis for correlation between change from baseline to Day 15 in key biomarkers and 
change from baseline to day 15 in lesion TSS will be performed by treatment. Pearson 
correlation coefficient will be presented.


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6.2.4. Change From Baseline to Day 8 and Day 15 in ISGA
6.2.4.1. Primary Analysis

Analysis time points: Day 8 and Day 15.

Analysis population: FAS.

Analysis methodology: the intra-subject difference of change from baseline in lesion 
ISGA between crisaborole and vehicle will be analyzed using the model specified in 
Section 5.2.2.  

Imputation for missing values: observed data will be included in the model, the 
missing values will be handled in the model, where the values are assumed to be 
missing at random. 
Reporting results:

Raw data: The sample size, number and percentage for each category at baseline and 
post-baseline visits will be presented for each treatment.

Change from baseline: The sample size, mean, standard deviation, median, Q1, Q3, 
minimum and maximum will be presented for each treatment. The  LS means of 
difference and the corresponding standard error, 95% CI, p-value will be presented.

Shift table: number and percentage from each category at baseline to each category at 
Day 8 and Day 15 will be presented. 
6.2.5. Change From Baseline To Visits Up To Day 15 In Pruritus Numerical Scale 

Analysis time points: Day 2 to Day 15

Analysis population: FAS 

Analysis methodology: the intra-subject difference of change from baseline in lesion 
pruritus between crisaborole and vehicle will be analyzed using the model  specified 
in Section 5.2.2.  

Imputation for missing values: observed data will be included in the model, the 
missing values will be handled in the model, where the values are assumed to be 
missing at random. 
Reporting results:

Raw data: The sample size, mean, standard deviation, median, Q1, Q3, minimum and 
maximum at baseline and post-baseline visits will be presented for each treatment.


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
Change from baseline: The sample size, mean, standard deviation, median, Q1, Q3, 
minimum and maximum will be presented for each treatment. The  LS means of 
difference and the corresponding standard error, 95% CI, p-value will be presented. 

Plot: Line plot will be provided for mean change (SE) from baseline. 
  
 
 
  
 
 
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6.4. Subset Analyses 
N/A
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6.5. Baseline and Other Summaries and Analyses
6.5.1. Baseline Summaries
Demographic and baseline characteristics will be summarized for safety analysis set
according to Pfizer data standards. Lesion baseline data will be summarized by treatment. 
6.5.2. Study Conduct and Subject Disposition
Subjects evaluation, disposition, discontinuation will be summarized for safety analysis set 
according to Pfizer data standards.
6.5.3. Study Treatment Exposure and Compliance
The exposure to study drug in each treatment group in double blind period will be 
summarized by total number of applications, the total number of days of dosing, and number 
and percentage of subjects who are compliant with the dosing regimen. The exposure to 
crisaborole in open label period will be summarized as well.
For double blind period, a subject is considered compliant with the dosing regimen if the
subjects:

not miss more than 6 IP applications during the double-blind treatment period;

and have no missed IP applications the 2 days before Day 15 biopsy collection;

and not miss more than 3 IP applications in total before Day 8;, 

and have no missed IP applications the 2 days before Day 8 biopsy collection (if 
collected).  
For open label period, a total of 56 doses are expected to be applied. A subject will be 
considered compliant with the dosing regimen if they receive at least 45 but no more than 67 
investigational product doses (ie, 80–120%, inclusive, of the expected number of doses) 
administered in accordance with the protocol.
6.5.4. Concomitant Medications and Non-Drug Treatments
Prior drug and non-drug treatment, concomitant drug and non-drug treatment will be 
summarized according to Pfizer data standards.
6.6. Safety Summaries and Analyses
6.6.1. Adverse Events
Adverse events will be summarized according to Pfizer data standards for each phase. 

TEAEs.

Serious AEs.


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AEs will not be double counted across phases.  Counting of AEs will be based on start date 
of AE.  If the start date of an AE is in the double blind period, the end date of the AE in the 
open label period and severity of AE remained the same in both phases or became lower, 
then the AE will be counted in double blind period, not in the open label period. However, if 
the same AE started in the double blind period, and get worse in severity in the open label 
period, then the AE will be counted in both phases. 
Lesion TEAEs and SAEs in double blind phase will be summarized by treatment. General 
TEAEs and SAEs will be summarized for overall safety analysis set.
TEAEs will be summarized by the number of subjects reporting any TEAE, system organ 
class (SOC), preferred term, severity, relationship to investigational product, and 
seriousness.
Serious adverse events (SAEs) will be summarized by SOC and PT, and individual SAEs will 
be listed by subject. A list of subjects who prematurely discontinue from the study due to an 
AE will be provided. (If no SAE or few SAEs, SAE summary table may not be needed. 
Listing would be enough).
6.6.2. Laboratory Data
Safety laboratory data will be summarized according to Pfizer standards.
6.6.3. Vital Signs
Descriptive summary tables for vital signs at screening will be provided.
6.6.4. Physical Examination
Descriptive summary tables will be provided in accordance with Pfizer reporting standards.
7. INTERIM ANALYSES
N/A.  


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8. REFERENCES 
1.
Pfizer Protocol C3291001.


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9. APPENDICES 
9.1. Definition and Use of Visit Windows in Reporting
Visit windows will be used for efficacy biomarker variables. 
If more than one observation from the same subject falls into the same visit window, the 
value closest to the targeted day will be used as the observation for that week. All 
observations will, however, be included in the listings.
Double Blind Phase
Visit Label
Targeted Day
Analysis window for data sets
Baseline (Screening (Day -30) 
to up to first dosing date)
Day 1
Last observation up to and 
including first dosing date
Day 8
Day 8
Day 2 – Day 11
Day 15
Day 15
Day 12 – First day of open label 
phase/day of early terminate (early 
one)
Day 15*
Day 15
Day 2 – First day of open label 
phase/day of early terminate (early 
one)
Open Label Phase
Day 15
Day 15
Last observation up to and 
including first dosing date of open 
label phase  
Day 43
Day 43
Second day of first dosing date of 
open label phase - end of study
* For ISGA (global), 
 and pruritus NRS (global). There is no Day 8 assessment for these 
endpoints.
CCI


Protocol C3291001 (PF-06930164) Statistical Analysis Plan
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CCI