Clinical trial NCT03356977
Conditions: Atopic Dermatitis
Sponsor: Pfizer
Start date: 2018-01-16; Completion date: 2019-04-12
Enrollment: 137 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This 4-week study will evaluate the safety, pharmacokinetics (PK), and efficacy of crisaborole ointment 2%, applied twice daily (BID) in subjects who are 3 months to less than 24 months of age with mild-to-moderate AD.

Detailed description:
Approximately 125 subjects will be enrolled. Subjects must have mild-to-moderate AD involving at least 5% treatable %BSA assessed on Baseline/Day 1. Treatable %BSA will be defined as the percent of a subject's total body surface area that is AD-involved, excluding the scalp.

In addition, a cohort of at least 16 of the 125 subjects will be included in a subgroup for PK assessment. These subjects must have moderate AD and a minimum of 35% treatable %BSA, excluding the scalp, and must complete all PK assessments to be included in the PK analysis. Of these subjects, at least 3 subjects who are less than 9 months of age will be enrolled. Subjects discontinuing for reasons other than treatment emergent adverse event ( TEAE) may be replaced at the discretion of the sponsor to ensure 16 subjects complete the PK assessments. Only selected study sites will participate in the PK assessment.

Scheduled study visits/telephone contacts for all subjects will occur at Screening (up to 28 days prior to Baseline/Day 1), Baseline/Day 1, Day 8, Day 15, Day 22, Day 29 (end of treatment/early termination), Day 36, and Day 57 (end of study).

Arms: arm 1: Subjects will be dosed for 28 days. A thin layer of ointment will be applied to all areas designated for treatment.
Interventions: intervention 1: Crisaborole ointment 2%
Intervention descriptions: intervention 1: Applied BID

Protocol documents:
Prot_000.pdf: 
Crisaborole (PF-06930164 [AN2728])
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Final Protocol Amendment 1, 01 May 2018
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A PHASE 4, MULTICENTER, OPEN-LABEL SAFETY STUDY OF CRISABOROLE
OINTMENT 2% IN CHILDREN AGED 3 MONTHS TO LESS THAN 24 MONTHS
WITH MILD TO MODERATE ATOPIC DERMATITIS 
Investigational Product Number:
PF-06930164
Investigational Product Name:
Crisaborole
United States (US) Investigational New 
Drug (IND) Number:
European Clinical Trials Database 
(EudraCT) Number:
Not Applicable
Protocol Number
C3291002
Phase:
4
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Document History
Document
Version Date
Summary of Changes and Rationale
Amendment 1
01 May 2018
To address the recommendations made by the Food 
and Drug Administration (FDA) following review of 
the protocol (ordered as they first appear in the 
protocol):
 
Sections 6.4; 6.5; 6.6; 6.7; 6.8; 6.10.1; 6.10.2; 
6.11.1; 6.11.2 and 6.11.3: Added text instructing 
investigators to monitor for potential 
hypersensitivity reactions at all visits;  
Section 6.10.2: Added that any subject with a new 
or ongoing adverse event at the time of the Day 57 
(end of study) follow-up contact, should be seen in 
the clinic for evaluation of that adverse event;
Section 6.12: Provided more specific withdrawal 
criteria relative to known and potential toxicities 
associated with systemic PDE4 inhibition 
Section 7.1.2: Added guidance to standardize the 
method for measuring both height (length) and 
weight, including that three reproducible 
measurements should be recorded and the average 
of the 3 recordings be entered onto the eCRF.
In addition, protocol inconsistencies and 
clarifications have been corrected as follows (ordered
as they first appear in the protocol):
SoA: Added subject height/length and weight at 
screening. Added ECG at screening. Added that 
treatable Atopic Dermatitis (AD) areas and the 
body map should be updated at clinic visits Day 8 
and Day 15. Corrected one spelling mistake.
Clarified the 
 days;
 
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Section 4.2: Exclusion criteria 3 corrected so 
subjects with creatinine clearance based on the 
age-appropriate calculation below the lower limit 
of normal (LLN), or serum creatinine that is 
greater than the upper limit of normal (ULN) are 
excluded;
Section 4.4: Updated lifestyle guidelines 
pertaining to nursing women or women of 
childbearing potential;
Section 5.2: Corrected the number of doses that 
must be applied for subjects to be considered 
compliant with the dosing regimen;
Section 5.5: Clarified that large areas that need to 
be treated can have the ointment applied slowly 
and segmentally to minimize pain associated with 
application;
Section 6.3: Added that subject weight and 
height/length will be measured at Screening;
Section 6.3; 6.4 and 7.1.3: Updated to reflect that 
an ECG may be taken at screening and that a 
6-lead ECG may be taken in the event a 12-lead 
ECG is not possible to obtain;
Section 6.4: Added that subjects will be 
randomized;
Sections 6.5 and 6.6: Added that updated 
documentation for treatable AD areas may be 
provided to parent(s)/legal guardian, if required;
Section 6.10.1: Removed reference to prohibited 
concomitant treatments;  
Section 6.12: Clarified that follow-up contacts 
must be completed for all withdrawn subjects;


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Section 7.2.3: Table 5 corrected;
Sections 7.3.1 and 7.3.2: Clarified that the 
‘168 hours’
may be described 
as ‘Day 8 (0 hours)’;  
Section 9.1: Corrected spelling error.
Original Protocol
06 July 2017
Not applicable (N/A)
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TABLE OF CONTENTS
LIST OF TABLES.....................................................................................................................9
APPENDICES ...........................................................................................................................9
PROTOCOL SUMMARY.......................................................................................................10
SCHEDULE OF ACTIVITIES................................................................................................14
1. INTRODUCTION ...............................................................................................................19
1.1. Mechanism of Action/Indication.............................................................................19
1.2. Background .............................................................................................................19
1.2.1. Anticipated Benefits and Risks...................................................................21
1.3. Drug Development ..................................................................................................21
1.3.1. Nonclinical Studies.....................................................................................22
1.3.3. Cutaneous Sensitization, Irritancy Potential and Tolerability....................23
1.3.3.1. Local Tolerability in Sensitive Skin Areas ...............................23
1.3.3.2. Sensitizing and Cumulative Irritation Potential ........................24
1.3.4. Clinical Experience.....................................................................................24
1.4. Rationale..................................................................................................................25
1.4.1. Study and Dose Rationale...........................................................................25
1.4.2. Single Reference Safety Document............................................................26
2. STUDY OBJECTIVES AND ENDPOINTS.......................................................................26
3. STUDY DESIGN.................................................................................................................27
3.1. Study Overview.......................................................................................................27
3.2. Number of Sites.......................................................................................................28
3.3. Duration of Study....................................................................................................28
4. SUBJECT ELIGIBILITY CRITERIA.................................................................................29
4.1. Inclusion Criteria.....................................................................................................29
4.2. Exclusion Criteria....................................................................................................30
4.3. Randomization Criteria ...........................................................................................32
4.4. Lifestyle Requirements ...........................................................................................32
4.5. Sponsor’s Qualified Medical Personnel..................................................................33
5. STUDY TREATMENTS.....................................................................................................33
5.1. Allocation to Treatment ..........................................................................................34
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5.2. Subject Compliance.................................................................................................34
5.3. Investigational Product Supplies.............................................................................34
5.3.1. Dosage Form(s) and Packaging..................................................................34
5.4. Investigational Product Storage ..............................................................................35
5.5. Administration.........................................................................................................36
5.6. Preparation and Dispensing of Investigational Product ..........................................36
5.7. Investigational Product Application........................................................................36
5.7.1. Non-PK Cohort Subjects ............................................................................36
5.8. Study Treatment Regimen.......................................................................................38
5.8.1. Non-PK Cohort Subjects ............................................................................38
5.9. Dosing Modifications..............................................................................................39
5.10. Investigational Product Accountability.................................................................40
5.10.1. Destruction of Investigational Product Supplies ......................................40
5.11. Concomitant Treatment(s).....................................................................................40
5.11.1. Medications/Therapies Prohibited During the Study ...............................41
5.11.2. Medications/Therapies Allowed During the Study ..................................42
6. STUDY PROCEDURES .....................................................................................................42
6.1. Study Visits .............................................................................................................42
6.2. Time Windows for Study Procedures .....................................................................42
6.3. Screening Period .....................................................................................................43
6.3.1. Investigational Product Application Period................................................45
6.4. Baseline/Day 1 ........................................................................................................45
6.5. Day 8 (1 day) Study Visit .....................................................................................48
6.6. Day 15 (3 days) Study Visit..................................................................................49
6.7. Day 22 (3 days) Telephone Contact......................................................................50
6.8. Day 29/End of Treatment (3 days) Study Visit.....................................................50
6.9. Unscheduled Visit ...................................................................................................51
6.10. Post-treatment Follow-up Period ..........................................................................52
6.10.1. Day 36 (3 days) Telephone Contact .......................................................52
6.10.2. Follow-up Contact (Day 57 (+3 days) End of Study) ..............................52
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6.12. Subject Withdrawal/Early Termination ................................................................56
7. ASSESSMENTS..................................................................................................................58
7.1. Safety.......................................................................................................................58
7.1.1. Clinical Laboratory Evaluations.................................................................58
7.1.2. Physical Examination, including Height/Length, and Weight ...................60
7.1.3. Electrocardiogram.......................................................................................61
7.1.4. Vital Signs (temperature, respiratory rate, pulse rate, and BP....................61
8. ADVERSE EVENT REPORTING......................................................................................66
8.1. Requirements...........................................................................................................66
8.1.1. Additional Details on Recording Adverse Events on the CRF...................68
8.1.2. Eliciting Adverse Event Information..........................................................68
8.1.3. Withdrawal From the Study Due to Adverse Events (see also the 
Subject Withdrawal/Early Termination section) .............................................68
8.1.4. Time Period for Collecting AE/SAE Information......................................68
8.1.4.1. Reporting SAEs to Pfizer Safety...............................................68
8.1.4.2. Recording Non-serious AEs and SAEs on the CRF .................69
8.1.5. Causality Assessment .................................................................................69
8.1.6. Sponsor’s Reporting Requirements to Regulatory Authorities ..................69
8.2. Definitions...............................................................................................................69
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8.2.1. Adverse Events...........................................................................................69
8.2.2. Abnormal Test Findings .............................................................................70
8.2.3. Serious Adverse Events ..............................................................................71
8.2.4. Hospitalization............................................................................................71
8.3. Severity Assessment................................................................................................72
8.4. Special Situations ....................................................................................................73
8.4.1. Protocol-Specified Serious Adverse Events...............................................73
8.4.2. Potential Cases of Drug-Induced Liver Injury............................................73
8.4.3. Exposure to the Investigational Product During Pregnancy or 
Breastfeeding, and Occupational Exposure.....................................................74
8.4.3.1. Exposure During Pregnancy......................................................75
8.4.3.2. Exposure During Breastfeeding ................................................76
8.4.3.3. Occupational Exposure .............................................................76
8.4.4. Medication Errors .......................................................................................76
8.4.4.1. Medication Errors......................................................................77
9. DATA ANALYSIS/STATISTICAL METHODS...............................................................77
9.1. Sample Size Determination.....................................................................................77
9.2. Analysis of the Primary Endpoint ...........................................................................79
9.2.1. Safety..........................................................................................................79
9.4. Extent of Exposure..................................................................................................81
9.5. Interim Analysis ......................................................................................................81
9.6. Data Monitoring Committee ...................................................................................81
10. QUALITY CONTROL AND QUALITY ASSURANCE.................................................81
11. DATA HANDLING AND RECORD KEEPING .............................................................82
11.1. Case Report Forms/Electronic Data Record .........................................................82
11.2. Record Retention...................................................................................................82
12. ETHICS..............................................................................................................................83
12.1. Institutional Review Board/Ethics Committee......................................................83
12.2. Ethical Conduct of the Study ................................................................................83
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12.3. Subject Information and Consent..........................................................................83
12.4. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH 
GCP ...........................................................................................................................85
13. DEFINITION OF END OF TRIAL...................................................................................85
13.1. End of Trial in All Participating Countries ...........................................................85
14. SPONSOR DISCONTINUATION CRITERIA ................................................................85
15. PUBLICATION OF STUDY RESULTS..........................................................................85
15.1. Communication of Results by Pfizer ....................................................................85
15.2. Publications by Investigators ................................................................................86
16. REFERENCES ..................................................................................................................88
LIST OF TABLES
Table 2.
Clinical Laboratory Test Parameters ....................................................................59
Table 3.
Investigator’s Static Global Assessment ..............................................................62
 
Table 7.
Calculated Safety Margins for Crisaborole ..........................................................79
Table 8.
Hanifin and Rajka’s Diagnostic Criteria for Atopic Dermatitis...........................94
APPENDICES
Appendix 1. Abbreviations......................................................................................................92
Appendix 2. Diagnostic Criteria for Atopic Dermatitis...........................................................94
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PROTOCOL SUMMARY
Background and Rationale:
Crisaborole, also referred to as PF-06930164 and AN2728, is a low molecular weight 
benzoxaborole anti-inflammatory phosphodiesterase-4 (PDE-4) inhibitor that penetrates into 
the skin to the sites of inflammation.  PDE-4 inhibition results in increased intracellular 
cyclic adenosine monophosphate (cAMP) levels.  While the specific mechanism(s) by
which crisaborole exerts its therapeutic action is not well defined, it is thought that 
crisaborole reduces the production of several inflammatory cytokines implicated in the 
pathophysiology of atopic dermatitis (AD).
Supporting evidence of the safety and efficacy of this product in patients 2 years and older 
represent a major advancement in the treatment of AD given the challenges of managing this 
common, chronic dermatologic condition and the treatment-limiting effects of currently 
available therapies.  All primary and secondary efficacy endpoints were statistically 
significant in favor of crisaborole ointment 2% BID versus vehicle ointment BID in the two 
Phase 3 pivotal studies.  Across the development program, crisaborole demonstrated an 
acceptable safety profile, with no crisaborole treatment-related serious adverse events (SAEs) 
(except 1 case of drug eruption in a Phase 2 study which was classified as possibly related), 
and the majority of adverse events (AEs) were mild and deemed unlikely or not related to 
investigational product.  Safety and efficacy have not yet been established in patients 
younger than 2 years of age.
This 4-week study will evaluate the safety, 
, and efficacy of 
crisaborole ointment 2%, applied twice daily (BID) in subjects who are 3 months to less than 
24 months of age with mild-to-moderate AD.  The dose selected for this study has been 
shown to be safe, well tolerated and efficacious in patients and healthy volunteers 2 years of 
age and older who participated in previously conducted studies.  Based on these results and 
the observed 
 profile of crisaborole, it is anticipated that crisaborole ointment 2% will 
demonstrate similar efficacy and satisfactory safety and local tolerability in the pediatric 
population to be enrolled in this study.
Objectives and Endpoints:
Primary Objective
Primary Endpoint(s)
To study the safety of crisaborole ointment 2% 
applied twice daily (BID) in children aged 3 months 
to less than 24 months with mild to moderate AD
Incidence of treatment emergent AEs (including 
application site reactions), SAEs, and clinically 
significant changes in height, weight, vital signs, 
ECG and clinical laboratory parameters
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Abbreviations: AD=atopic dermatitis; AE=adverse event; BID=twice a day; 
 
; ECG=electrocardiogram; EOT=end of treatment; 
; SAE=serious adverse event;
 
t; 
 Cmax =maximum observed plasma concentration; AUC(0–12)=area under 
the plasma concentration-time curve from 0 to 12 hours post dosing; Tmax= time to reach maximum observed 
plasma concentration
Study Design:
This is a Phase 4, multicenter, open-label safety study to evaluate the safety of crisaborole 
ointment 2% in approximately 125 subjects who are 3 months to less than 24 months of age, 
with mild-to-moderate AD involving at least 5% treatable 
  In 
addition, a cohort of at least 16 of the 125 subjects enrolled will be included in a subgroup 
for 
 assessment.  These subjects must have moderate AD with a minimum of 
, excluding the scalp, and must complete all 
 assessments to be 
included in the 
 analysis. Of these subjects, at least 3 subjects who are less than 9 months 
of age will be enrolled.  
Approximately 30 investigational sites will participate in this study. Only selected study 
sites will participate in the 
 assessment.
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Scheduled study visits/telephone contacts for all subjects will occur at Screening (up to 
28 days prior to Baseline/Day 1), Baseline/Day 1, Day 8, Day 15, Day 22, Day 29 (end of 
treatment/early termination), Day 36, and Day 57 (end of study).  Days 22 and 36 will be 
conducted through a telephone contact with the subject’s parent(s)/legal guardian.  A 
follow-up telephone call (end of study) will be made by site staff to the subject’s 
parent(s)/legal guardian on Day 57 (approximately 28 days after the last dose application) to 
assess AEs (nonserious and serious).  Subjects in the 
 cohort will also have twice daily
clinic visits on Days 2 through 7 for application of investigational product and a minimum of 
1 clinic visit on Day 8 for 
 sample collection and additional study procedures. Following 
the Baseline/Day 1 AM investigational product application, some or all of the remaining 
applications through Day 8 AM as well as 2 of the 3 scheduled Day 8 
 sample collections 
may be performed by a qualified health care professional in the subjects’ home at the 
discretion of the Investigator and subject’s parent(s)/legal guardian.  One on-site visit is 
required on Day 8 to perform the remaining visit assessments.
For the 16 subjects in the 
 Cohort 3 additional blood samples of approximately 1 mL each 
(approximately 3 mL total), will be collected for plasma 
 analysis, according to the 
following schedule:

Before the Day 8 AM dose (ie, 168 1 hour after recorded time of completion of the 
Day 1 dose application);

3 hours ±20 min after recorded time of completion of the Day 8 AM dose application;

12 hours ±1 hour after recorded time of completion of the Day 8 AM dose 
application.
Refer to the Schedule of Activities for a complete list of assessments to be performed during 
the study.
Statistical Methods:
Safety
Treatment emergent adverse events (TEAEs) will be summarized by the number of subjects 
reporting any TEAE, system organ class (SOC), preferred term (PT), 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.
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Efficacy
All efficacy data will be summarized using descriptive statistics.  No imputation will be 
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SCHEDULE OF ACTIVITIES
The schedule of activities table provides an overview of the protocol visits and procedures.  Refer to the STUDY PROCEDURES and 
ASSESSMENTS sections of the protocol for detailed information on each procedure and assessment required for compliance with the 
protocol. 
The investigator may schedule visits (unplanned visits) in addition to those listed in the schedule of activities table, in order to conduct 
evaluations or assessments required to protect the well-being of the subject.
All Subjects (Including non-PK and 
 Cohorts)
Day 
1
8
15
22
29
36
57
Window
-28 to -2 
day(s)
1 day
3 days
3 days
3 days
3 days
+3 days
Visit
Screening
Baseline
Telephone 
Contact
End of 
Treatment/Early 
Termination
Telephone 
Contact
Follow-up 
Contacta
(End of 
Study)
Informed Consent
X
Demographics
X
Review Inclusion/Exclusion Criteria
X
X
Medical History
X
X
Confirmation of Diagnosis of AD
X
X
Height/Length and Weight
X
X
X
Vital Signsb
X
X
X
X
X
Full Physical Examination
Xc
X
12-Lead Electrocardiogram (ECG)
       X          or       X
X
X
Limited Physical Examination
Xd
 
Body Site checklist of AD lesions
X
X 
X
 
 
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Day 
1
8
15
22
29
36
57
Window
-28 to -2 
day(s)
1 day
3 days
3 days
3 days
3 days
+3 days
Visit
Screening
Baseline
Telephone 
Contact
End of 
Treatment/Early 
Termination
Telephone 
Contact
Follow-up 
Contacta
(End of 
Study)
Blood collection for serum chemistry 
and hematology
Xg
X
 
 
Record treatable AD areas (excluding
scalp) in source and provide 
parent(s)/legal guardian with 
documentation of the designated 
treatment areas
X
Dispense dosing diary and instruct 
the subject’s parent(s)/legal guardian 
on use
X
X
X
Dispense and weigh the 
investigational product tube(s) and 
apply first dose. First dose applied in 
office by study staff
X
Dispense and weigh new 
investigational product tube(s) and 
provide for at-home dosing 
Xi
X
X
At-home dosing, applied by 
parent(s)/legal guardiani,j
2nd dose (PM) on Day 1, then BID up to PM 
dose prior to Day 29 visit
Review dosing diary; assess 
compliance; re-train parent(s)/legal 
guardian if doses missed
X
X
X
X
Collect and weigh empty, partially 
used and unused investigational 
product tubes
Xi
X
X
Review and record prior and 
concomitant medications
Xk
X
X
X
X
X
X
X
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Day 
1
8
15
22
29
36
57
Window
-28 to -2 
day(s)
1 day
3 days
3 days
3 days
3 days
+3 days
Visit
Screening
Baseline
Telephone 
Contact
End of 
Treatment/Early 
Termination
Telephone 
Contact
Follow-up 
Contacta
(End of 
Study)
Assess for AEs (including application 
site reactions) and SAEs
X
Xl
X
X
X
X
X
X
Review lifestyle requirements
X
X
X
X
X
X
Schedule/reconfirm next study 
visit/contact
X
X
X
X
X
X
X
Remind parent(s)/legal guardian to 
bring all investigational product tubes 
(empty, partially used and unused) 
and the dosing diary to the next visit
X
X
X
X
Abbreviations: AD=atopic dermatitis; BP=blood pressure; 
 PR=pulse rate; 
RR=respiratory rate; AE=adverse event; SAE=serious adverse event;
; BID=twice a day
a.
Follow-up contact will be completed 28 +3 calendar days after the last administration of the investigational product to capture any adverse events.
b.
Vital signs (temperature, respiratory rate, pulse rate, and BP) taken in seated or supine position after subject has been seated or lying face up for 5 minutes.
c.
A full physical examination will be performed at the Screening visit.  If the full examination cannot be completed during screening, an unscheduled visit 
may be performed prior to Baseline/Day 1 to complete the full assessment.
d.
A limited physical examination will be performed at Baseline/Day 1.
g.
Blood draw for clinical labs may be completed any time during the screening period, (Day -28 to Day -2) however the results must be available and 
reviewed by the PI prior to the Baseline/Day 1 visit and investigational product application.  If the laboratory sample cannot be obtained due to an upset 
child, parent or other collections issues, the subject will not be enrolled into the study. Serum chemistry laboratory assessments include lactate and 
parameters needed to perform calculation of osmolal gap and anion gap.
 
. 
i.
Not applicable to subjects in 
 cohort through Day 8.
j.
In the event the scheduled Day 29 visit does not fall exactly on Day 29, instruct parent(s)/legal guardian to keep dosing BID until the evening dose prior to 
the Day 29 visit.
k.
All medications and non-medication therapies used within 30 days prior to Screening. 
l.
Assess for AEs (including application site reactions) /SAEs before and after in clinic dose at Baseline/Day 1.
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 Cohort Subjects Only
Day 
1a
2-7
8b Prior to AM 
dose
(168 hours 
1 hour post time 
of AM application 
on Day 1)
8
3 hours 
20 minutes
after 
completion of 
AM dose
8
12 hours 1 hour 
after completion 
of AM dose
Non-PK 
Study 
Schedule
(see above)c
Visit
 
 
Blood collection for serum chemistryd,f
X
Review lifestyle requirements
X
X
X
Assess and record any pre- and/or post-dose AEs (including 
application site reactions) and SAEs
X
X
X
Assess and record any changes in concomitant medications
X
X
X
Weigh amount of investigational product to be applied before 
each dose application
X
X
Xh
Dispense dosing diary and train parent(s)/legal guardian on use
X
Dispense and weigh investigational product tube(s) and provide
for at-home dosing 
X
Review the schedule of upcoming study visits with the 
parent(s)/legal guardian
X
X
X
Remind parent(s)/legal guardian to bring all investigational 
product tubes and the dosing diary to the next visit
X
Abbreviations: 
 
a.
Perform Day 1 assessments prior to dosing procedures, as applicable (See All Subjects (Including non-
 and 
 Cohorts)).
b.
Aside from AM dose application, first 
sample collection, serum chemistry 
 sample collection which must all be performed at the first 
 
collection time point, all other Day 8 procedures may be performed at any of the 3 PK collection time points. 
c.
Subject to resume regular study schedule following completion of Day 8/PK 8 final PK sample collection.  
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f.
Serum chemistry laboratory assessments include lactate and parameters needed to perform calculation of osmolal gap and anion gap.
 
h.
Weighing of investigational product on Day 8 applies to the AM dose only.
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1. INTRODUCTION
1.1. Mechanism of Action/Indication
Crisaborole, also referred to as PF-06930164 and AN2728, is a low molecular weight 
benzoxaborole anti-inflammatory phosphodiesterase-4 (PDE-4) inhibitor that penetrates into 
the skin to the sites of inflammation.  PDE-4 inhibition results in increased intracellular 
cyclic adenosine monophosphate (cAMP) levels.  While the specific mechanism(s) by
which crisaborole exerts its therapeutic action is not well defined, it is thought that 
crisaborole reduces the production of several inflammatory cytokines implicated in the 
pathophysiology of atopic dermatitis (AD).  
On 14th December 2016, EUCRISA(Crisaborole) Ointment 2% was approved by the US 
Food and Drug Administration (FDA) for the treatment of mild to moderate AD in patients 
2 years of age and older.
1.2. Background 
AD, also referred to as eczema, is a chronic and relapsing disease affecting an increasing 
number of patients.  Although AD affects patients of all ages, it is one of the most common, 
chronic, relapsing childhood dermatoses, impacting 15-30% of all children in the United 
States (US) with 85% of affected individuals showing signs of the disease before 5 years of 
age.1,2  Over the past 50 years, AD has become more prevalent, especially in industrialized, 
temperate countries such as the US.3,4
AD is a distinctive inflammatory, highly pruritic, chronic eczematous condition that usually 
occurs in people who have a personal or family history of other atopic conditions such as 
asthma or allergic rhinitis.1, 4  The majority of patients (up to 90%) with AD present with 
mild to moderate disease.5 Manifestation of the disease includes intense pruritus, 
erythematous papules, excoriation, exudation, lichenification, and bacterial colonization.6
Continuous scratching during exacerbations can lead to lichenification, excoriations, and 
serious skin infections. AD is often associated with other conditions including asthma, 
allergic rhinitis, and food allergy. AD has been cited as a major risk factor for the 
development of asthma in a number of longitudinal studies, and children with AD are at 
increased odds of developing asthma compared to children without AD.7,8 The burden of the 
clinical symptoms of AD coupled with the stigma associated with highly visible skin lesions 
correlates with significant morbidity and extensive impairments on health related quality of 
life measures (HRQL) for patients, especially in children, and caregivers.1,9,10,11  
Psychosocial problems, depression, and anxiety are associated with AD in both adults and 
children.12
The negative impact on HRQoL caused by childhood AD exceeds that in asthma, epilepsy, 
and diabetes, is comparable to that in renal disease or cystic fibrosis, and is equal (child) or 
exceeds (parents) that in psoriasis.2,10,13  The hallmark symptom of itching causes scratching 
which is associated with sleep disturbance in greater than 60% of patients. Sleep deprivation 
leads to physical and mental exhaustion in patients and other family members resulting in 
loss of concentration and impaired performance at school or work.14,15 AD is often 
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including depression, attention deficit hyperactivity disorder, anxiety, stress, and autism.16  
Pre-school children with AD show a significant increase in behavioral symptoms compared 
with matched controls.17  Absolon et al18 reported that the rate of psychological disturbance 
in school-age children with AD doubled compared with matched controls. For older children 
with AD, in addition to problems associated with itching and sleep disturbance, their social 
and school life may be substantially affected. Social embarrassment, due to visible signs of 
the disease (crusted, excoriated, oozing, bleeding lesions), teasing, and bullying, often results 
in social isolation leading to depression.2
AD has a significant impact on day to day functioning, as evidenced by its impact on the 
overall well-being of the patient and their family on multiple levels; medical management 
and treatment, HRQoL, and psycho-social implications. In summary, AD is a disease with 
multiple comorbidities and significant impact on the health, day to day functioning, and 
HRQoL of AD patients, their caregivers, and family members.
AD may also be a source of significant economic burden19 as this relapsing disease is often 
misdiagnosed, misunderstood, and ineffectively treated.4
AD is a condition associated with significant morbidity. Currently, there is no cure for AD. 
AD is a chronic disease with treatment focused on the management of flares and maintenance 
of remissions. Due to the chronic, relapsing nature of the disease, treatment may be needed 
for many years. 
Crisaborole is a novel, non-steroidal, topical anti-inflammatory PDE-4 inhibitor that will 
serve an unmet need in the treatment of AD. Supporting evidence of the safety and efficacy 
of this product in patients 2 years and older represent a major advancement in the treatment 
of AD given the challenges of managing this common, chronic dermatologic condition and 
the treatment-limiting effects of currently available therapies. All primary and secondary 
efficacy endpoints were statistically significant in favor of crisaborole ointment 2% BID 
versus vehicle ointment BID in the two Phase 3 pivotal studies. Across the development 
program, crisaborole demonstrated an acceptable safety profile, with no crisaborole 
treatment-related SAEs (except 1 case of drug eruption in a Phase 2 study which was 
classified as possibly related), and the majority of AEs were mild and deemed unlikely or not 
related to investigational product.  Safety and efficacy have not yet been established in 
patients younger than 2 years of age.
 
 
 
  
 
 
 
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1.2.1. 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;

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 of treatment 
with crisaborole during the study. Based on the favorable clinical safety profile as well as 
the limited systemic exposure of crisaborole, the risk to subjects treated with crisaborole is 
deemed to be minimal and appropriately monitored. 
1.3. Drug Development
Crisaborole ointment 2% is an oxaborole compound developed as a topical 
anti-inflammatory agent. It demonstrates in vitro inhibition of a wide range of 
pro-inflammatory cytokines implicated in the pathogenesis of AD and other inflammatory 
skin diseases. Crisaborole has been formulated as a topical ointment. The formulation 
ingredients for crisaborole ointment 2% are listed in Section 5.
Crisaborole inhibits a range of cytokines implicated in the pathogenesis of inflammatory skin 
diseases, including TNF-, IFN-y, IL-2, IL-5, IL-6, IL-10, IL-12, and IL-23.22 The level of 
inhibitory activity, ie, the concentrations needed to produce 50% inhibition, ranges from the 
high nanomolar to the low micromolar concentrations. Crisaborole also inhibits the release 
of chemokines that are important inflammatory mediators. One mechanism of the 
anti-inflammatory effect of crisaborole is through inhibition PDE-4. Crisaborole proved 
efficacious against an inflammatory challenge in vivo, in a mouse model of ear edema 
induced by phorbol 12-myristate 13-acetate (PMA). Crisaborole formulated as ointment and 
cream formulations for topical use has demonstrated clinical benefit in nine psoriasis clinical 
studies and seven AD clinical studies. Safety has been evaluated in a total of 23 completed 
clinical studies.
The Investigator’s Brochure (IB) contains summaries of nonclinical and clinical studies 
performed with crisaborole.22  A brief summary as background to this study protocol is 
presented here.
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1.3.1. Nonclinical Studies
Crisaborole demonstrated inhibitory capacity against human leukocyte cytokine release with 
half maximal effective concentration (EC50) values ranging from high nanomolar to low 
micromolar concentrations.23-29  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 PDE4,30 which causes elevation of cAMP in 
leukocytes and subsequent protein kinase A(PKA)-mediated phosphorylation of transcription 
factors that are important for cytokine-, chemokine-, or prostaglandin-forming enzyme 
synthesis and release from cells.31  Crisaborole proved efficacious against an inflammatory 
challenge in vivo in a mouse PMA-induced ear edema model.32,33  AN8323, a metabolite of 
crisaborole, lacks anti-inflammatory activities against PDE434 and a panel of cytokines.35
In support of the current clinical study to evaluate crisaborole ointment 2% in children 
(aged 3 to less than 24 months), a juvenile toxicity study in rats was conducted.  Juvenile rats 
were administered crisaborole by oral gavage once daily for 4 weeks (from postnatal 
Days 7 to 35) at 0, 15, 50, and 100 mg/kg/day followed by a 2-week recovery period.  
Exposures at the No-Observed-Adverse-Effect Level (NOAEL, 100 mg/kg/day) in this study 
were approximately 9× higher than those observed in the AD Maximal Use Systemic 
Exposure (MUSE) clinical study.
Based on the nonclinical safety studies conducted to date, crisaborole ointment 2% has an 
acceptable safety profile.  Refer to the IB for further information on the nonclinical 
experience with crisaborole ointment 2%.
 
 
 
 
 
 
 
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In a TQT study (Study AN2728-TQT-108) in which healthy subjects were treated 
with crisaborole ointment 2% at a therapeutic dose (15 g,
 
 a supratherapeutic dose (45 g, representing
, mean 
Cmax values of 36.9 ng/mL and 87.4 ng/mL were observed in therapeutic and 
supratherapeutic dose groups, respectively, at Day 9. At both therapeutic and 
supratherapeutic doses had no effect on cardiac repolarization based on results from 
the primary assessment and the 
-pharmacodynamic analysis.
1.3.3. Cutaneous Sensitization, Irritancy Potential and Tolerability
1.3.3.1. Local Tolerability in Sensitive Skin Areas
In a study of healthy subjects (16 men and 16 women) who applied crisaborole ointment 
2% or vehicle for 21 days to sensitive area application sites (including extensor areas,
intertriginous areas, genitals, and face/hairline), 99% of assessments of local tolerability 
were graded as 0 (none), with an overall maximum grade of 2 (moderate) and only 0.1% of 
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assessments graded higher than 1 (mild) (Study AN2728-PSR-107). There were no marked 
differences in burning/stinging, erythema, or pruritus at any of the application sites over the 
course of the study between subjects who received crisaborole ointment 2% or Vehicle.
Overall, crisaborole ointment 2% was well tolerated over 21 days of dosing in sensitive skin
areas of healthy subjects.
1.3.3.2. Sensitizing and Cumulative Irritation Potential
In a repeat-insult patch test and cumulative irritation study in healthy subjects 
(Study AN2728-RIPT-101), the potential for inducing cutaneous sensitization was assessed 
in 238 subjects randomized in Cohort 1.  None of the subjects demonstrated cutaneous 
evidence of sensitization potential (a reaction of at least Grade 4 [definite edema] or a pattern 
suggestive of contact sensitization in the opinion of the Investigator) to the investigational 
products, crisaborole ointment 2% or vehicle.  The potential for causing cutaneous irritation 
was evaluated among 40 subjects randomized in Cohort 2.  There were no statistically 
significant differences in irritation between the crisaborole ointment 2% and vehicle.  
Crisaborole ointment 2% and vehicle showed no evidence of sensitization and only very 
minimal irritation.
1.3.4. Clinical Experience
Seven (7) clinical trials of topical formulations of crisaborole have been completed to date in 
subjects with AD.  Key study information is summarized below.

In a multicenter, maximal use, systemic exposure (MUSE) study in 34 pediatric 
subjects ranging in age from 2 to 17 years with mild-to-moderate AD who applied 
crisaborole ointment 2% BID,36 subjects had overall blood levels of crisaborole that 
were low and similar to those previously observed in adults after adjusting for 
 
  Absorption across the skin was rapid, with a median Tmax of 3.0 hours on 
both Day 1 and Day 8. 

In a 4-week, single arm, open-label safety, tolerability and 
 trial in adolescents 
with mild-to-moderate AD involving 
,37 disease severity improved over 
the 28-day treatment period. 

In a 6-week bilateral comparison trial of subjects with mild-to-moderate AD,38
68% of AD lesions treated with crisaborole ointment 2% 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).

In a 4-week bilateral comparison trial of 86 adolescent subjects with 
mild-to-moderate AD,39 crisaborole ointment 2% BID showed greater improvement 
than the lower concentration of crisaborole ointment, 0.5% applied BID for 29 days, 
and was more efficacious than either concentration applied once daily (QD). 
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
In two Phase 3 multicenter, randomized, double-blind, vehicle controlled studies in 
subjects 2 years of age and older with AD, crisaborole ointment 2% outperformed 
the vehicle in the primary efficacy analysis, proportion of subjects achieving success 
in 
 at Day 29.  
 
 
 
 

An additional Phase 3 multicenter, open-label, long-term extension study 
(AN2728-AD-303) of crisaborole ointment 2% for the treatment of mild to moderate 
AD in adults and children as young as 2 years of age evaluated the long-term safety 
of topical crisaborole. No clinically important safety signals were identified by this 
study.42
Crisaborole has been well tolerated across completed clinical studies.  No clinically 
important safety signals have been identified, including during a Phase 3 multicenter, 
open-label, long-term extension study of crisaborole ointment 2% for mild to moderate AD 
in adults and children as young as 2 years of age.  Most AEs have been mild, and most 
considered unrelated or unlikely to be related to investigational product.  The most common 
drug-related AEs have been application site reactions. 
Refer to the IB for further information on the clinical experience with crisaborole ointment 
2%.22
1.4. Rationale 
1.4.1. Study and Dose Rationale 
This 4-week safety study will evaluate the safety profile of crisaborole ointment 2% BID in 
subjects who are 3 months to less than 24 months of age with mild-to-moderate AD. In 
addition,
 will be assessed in a subgroup of at least 16 subjects under maximal use 
conditions, defined as systemic exposure conditions related to a high percent of body surface 
area involvement which would maximize the potential for drug absorption with anticipated
clinical use of crisaborole. While crisaborole has been studied extensively in patients and 
healthy volunteers 24 months of age and older, it has not been tested in patients less than 
2 years of age.  As such, the current study is being conducted as a post-approval commitment 
to FDA as part of the pediatric study plan.
The dose strength and regimen selected for this study has been shown to be safe, well 
tolerated and efficacious in patients and healthy volunteers 2 years of age and older who 
participated in previously conducted studies of crisaborole.  Crisaborole ointment 2% applied 
BID was studied in two Phase 3, randomized, double-blind, vehicle-controlled studies, and a 
Phase 3 open-label long-term safety study. Data from the two controlled studies showed a 
statistically significant therapeutic effect compared to vehicle with no safety concerns in 
patients 2 years and older.  In the open-label study, crisaborole ointment 2% applied BID, 
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demonstrated that the long-term use was well tolerated and not associated with any systemic 
safety signals.  The Phase 1 maximal use absorption study in children and adolescents aged
2 to 17 years old,36 showed that subjects who were administered crisaborole ointment 
2% BID (single dose on Days 1 and 8) to 
had overall 
blood levels of crisaborole that were similar to those previously observed in adults after 
.  An analysis of variance (ANOVA) showed no statistically 
significant differences in 
 parameters between the age cohorts represented in the study 
(Cohort 1, ages 12–17 years; Cohort 2, ages 6–11 years; and Cohort 3, ages 2–5 years). 
Based on the results of clinical studies conducted with crisaborole ointment 2% to date, it is 
anticipated that crisaborole ointment 2% will demonstrate similar efficacy and satisfactory 
safety and local tolerability in the pediatric population to be enrolled in this study.
1.4.2. Single Reference Safety Document
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.
2. STUDY OBJECTIVES AND ENDPOINTS
Primary Objective
Primary Endpoint(s)
To study the safety of crisaborole ointment
2% applied twice daily (BID) in children aged
3 months to less than 24 months with mild to 
moderate AD
Incidence of treatment emergent AEs (including 
application site reactions), SAEs, and clinically 
significant changes in height, weight, vital signs, 
ECG and clinical laboratory parameters
 
 
 
 
 
 
 
 
 
 
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Abbreviations: AD=atopic dermatitis; AE=adverse event; BID=twice a day; SAE=serious adverse event; 
 
; ECG=electrocardiogram; EOT=end of treatment; 
  
 Cmax =maximum observed plasma concentration; Tmax = time to maximum 
observed plasma concentration; AUC(0–12)=area under the plasma concentration-time curve from 
0 to 12 hours post dosing.
3. STUDY DESIGN
3.1. Study Overview
This is a Phase 4, multicenter, open label, safety study to evaluate the safety of crisaborole 
ointment 2% in children aged 3 months to less than 24 months with AD.
 
Approximately 125 subjects will be enrolled. Subjects will be between 3 months (at the time 
of the Screening visit) to less than 24 months of age at the time of Baseline/Day 1 with 
mild-to-moderate AD involving 
 assessed on Baseline/Day 1.  
 
 
In addition, a cohort of at least 16 of the 125 subjects will be included in a subgroup for 
 
assessment. These subjects must have moderate AD and a minimum of 35% treatable 
%BSA, excluding the scalp, and must complete all 
 assessments to be included in the 
 
analysis.  Of these subjects, at least 3 subjects who are less than 9 months of age will be 
enrolled.  Subjects discontinuing for reasons other than TEAE may be replaced at the 
discretion of the sponsor to ensure 16 subjects complete the 
 assessments.  Only selected 
study sites will participate in the 
 assessment.
Written informed consent will be obtained from the parent(s)/legal guardian prior to any 
study procedures.
Scheduled study visits/telephone contacts for all subjects will occur at Screening (up to 
28 days prior to Baseline/Day 1), Baseline/Day 1, Day 8, Day 15, Day 22, Day 29 (end of 
treatment/early termination), Day 36, and Day 57 (end of study).  
Days 22 and 36 will be conducted through a telephone contact with the subject’s 
parent(s)/legal guardian to assess the subject’s condition, and whether any AEs, including 
application site reactions, have occurred since the last visit.  Investigational product 
compliance, lifestyle requirements (Day 22 only) and concomitant medications will also be 
reviewed.  The parent(s)/legal guardian will be contacted by site staff on Day 57
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(approximately 28 days after the last dose application) for a follow-up telephone 
conversation (end of study) during which site staff will assess the subject’s condition and 
whether any AEs, including application site reactions, have occurred since the last visit. 
In addition, subjects in the 
 cohort will have twice daily visits on Days 2 through 7 for 
application of investigational product at the site, as well as 3
 sample collections from 
prior to AM dose until 12 hours post dose on Day 8. If desired, the protocol allows for a 
visiting health care professional to assist with twice daily dosing in the subject’s home for 
some or all of the dose applications during the 
 portion of the study and any 2 of the 3
 
sample collections.  Further information on home-based dose application and 
 sample 
collection for the 
 cohort is provided in Sections 5.8.2 and Section 7.3.1, respectively.  
For the approximately 16 subjects in the 
 cohort, 3 additional blood samples of 
approximately 1 mL each (approximately 3 mL total) will be collected for plasma crisaborole 
and metabolites PK analysis, according to the following schedule:

Before the Day 8 AM dose (ie, 168 hours 1 hour after recorded time of completion 
of the Day 1 dose application);

3 hours 20 minutes after recorded time of completion of the Day 8 AM dose 
application;

12 hours ±1 hour after recorded time of completion of the Day 8 AM dose 
application.
Selection criteria for the study population are described in Section 4.  Detailed information 
about the investigational product treatment regimen is provided in Section 5.8.  Detailed 
information about study procedures and assessments is provided in Section 6 and Section 7.
3.2. Number of Sites
Approximately 30 investigational sites will participate in this study.  Only selected study 
sites will participate in the 
 assessment.
3.3. Duration of Study
Subjects will be screened for the study no more than 28 days before the initial day of dosing 
(Baseline/Day 1), and will receive investigational product for approximately 28 days.  The 
study will comprise the following study periods:

Screening Period: maximum duration of 28 days;

Investigational Product Application Period: approximately 28 days (until Day 29 
visit);
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
Post-Treatment Follow-up Period: approximately 28 days. The follow-up period 
includes a telephone contact 7 days after the last application of investigational 
product and a telephone contact 28 (+3 days) days after the last application of 
investigational product.
The total duration of a subject’s participation in the study will range from a minimum of 
59 days to a maximum of 88 days, depending on the length of a given subject’s screening 
period.
4. SUBJECT ELIGIBILITY CRITERIA
This study can fulfill its objectives only if appropriate subjects are enrolled.  The following 
eligibility criteria are designed to select subjects for whom participation in the study is 
considered appropriate.  All relevant medical and nonmedical conditions should be taken into 
consideration when deciding whether a particular subject is suitable for this protocol.
4.1. Inclusion Criteria
Subjects must meet all of the following inclusion criteria to be eligible for enrollment into the 
study:
1. Is male or female aged at least 3 months at the Screening visit to less than 24 months 
on Baseline/Day 1.
2. Has a clinical diagnosis of AD according to the criteria of Hanifin and Rajka (1980)
(See Appendix 2).
 
 
b.
 
 
5. Evidence of a personally signed and dated informed consent document indicating 
that the subject’s parent(s)/legal guardian has been informed of all pertinent aspects 
of the study.  
6. Parent(s)/legal guardian who is/are willing and able to comply with all scheduled 
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4.2. Exclusion Criteria
Subjects with any of the following characteristics/conditions will not be included in the 
study:
1. Has any clinically significant dermatological condition or disease (including active 
or potentially recurrent non-AD dermatological conditions and/or known genetic 
dermatological conditions that overlap with AD such as Netherton Syndrome).
2. Was premature at birth, defined as less than 37 gestational weeks.
3. Has estimated creatinine clearance based on the age appropriate calculation that is 
below the lower limit of normal (LLN), or serum creatinine greater than the upper 
limit of normal (ULN).
4. Has aspartate aminotransferase (AST) or alanine aminotransferase (ALT) values 
greater than the ULN.
5. Has received any of the following AD treatment regimens without the required 
minimum washout: 
28 days prior to Baseline/Day 1

Systemic corticosteroids (use of intranasal/inhaled, and ophthalmic corticosteroids 
allowed);

Systemic immunosuppressive agents (eg, methotrexate, ciclosporin, azathioprine, 
hydroxychloroquine, mycophenolate mofetil).
7 days prior to Baseline/Day 1

Use of high-or-mid-potency topical corticosteroids or calcineurin inhibitors 
anywhere on the body;

Topical antibiotics on treatable AD lesions;

Light therapy (ultraviolet light therapy);

Use of antibacterial soaps (for bathing), bleach baths, or topical sodium 
hypochlorite-based products on treatable AD lesions.
3 days prior to Baseline/Day 1

Systemic antihistamines;

Use of low potency topical corticosteriod (eg hydrocortisone 1%) on treatable AD 
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8 hours prior to Baseline/Day 1

Use of emollients on treatable AD lesions;

Use of topical antihistamines on treatable AD lesions;

Use of topical hydrocortisone <1% on treatable AD lesions.
6. Has unstable AD or a consistent requirement for high-potency topical corticosteroids 
to manage AD signs and symptoms (see “Prohibited Therapies” for washout 
periods), or the mother requires treatment with high-potency topical corticosteroids 
due to potential for topical corticosteroids to transfer to the child. 
7. Child is nursing and the child’s mother requires high dose systemic steroids or 
systemic immunotherapy or other medications that might be transmitted in the breast 
milk and that might alter the course of the child’s AD. 
8. Has a history of hyperactive airway disease requiring systemic corticosteroid 
therapy. 
9. Has a significant active systemic or localized infection, including known actively 
infected AD, within two weeks prior to Baseline/Day 1. 
10. Has a history of use of biologic therapy including intravenous immunoglobulin 
(IVIG) at any time prior to study. 
11. Has recent or anticipated concomitant use of topical or systemic therapies that might 
alter the course of AD, as specified in protocol (see Concomitant Treatment(s)).
12. Participation in other studies involving investigational drug(s) within 30 days of 
Baseline/Day 1 and/or during study participation.
13. Has any planned surgical or medical procedure that would overlap with study 
participation from Screening through the final study visit on Day 57.
14. 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). 
15. Has a history of angioedema or anaphylaxis to topical products or a known 
sensitivity to any of the components of crisaborole ointment 2% (listed in Section 5).
16. Had previous treatment with crisaborole ointment 2%.
 
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18. Subjects who have parent(s)/legal guardian who is/are investigator site staff 
members directly involved in the conduct of the study and their family members, site 
staff members otherwise supervised by the investigator, or parent(s)/legal guardian
who is/are Pfizer employees, including their family members, directly involved in 
the conduct of the study.
19. Other acute or chronic medical or psychiatric condition 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.
4.3. Randomization Criteria
This open-label study will enroll subjects sequentially; no randomization will be performed.
4.4. Lifestyle Requirements

Routine preventative immunizations are permitted during the study; however, it is 
preferred that immunizations be administered at least 28 days before the start or 
following the completion of the subject’s participation.

The parent(s)/legal guardian will be instructed to dress the subject in loose-fitting 
clothing and avoid occluding the treated areas (with dry wraps, for example). Wet 
wraps are not permitted.

Subjects should not swim, be bathed or have treatment areas washed for at least 
4 hours after application.

Use of sunscreen is permitted, but only on skin areas without AD involvement. 

If there are treated lesions on the hands or feet, subjects should be encouraged, as 
much as possible, not to put these areas in the mouth to avoid ingestion of 
investigational product.

The parent(s)/legal guardian should avoid wiping the investigational product off the 
skin and investigational product should not be reapplied to wiped areas until the next 
scheduled dose.  

If there are AD lesions in the diaper area, they should be treated with investigational 
product; however, following diaper change, any investigational product inadvertently 
wiped off soiled skin should not be reapplied until the next scheduled dose.  Diaper
rash creams, lotions, ointments, powders, etc are not permitted where AD lesions are 
present. In the case of rash in the diaper area without AD involvement, standard 
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
When applying investigational product at home, the parent(s)/legal guardian will not 
be required to wear gloves.  However, they must be instructed to wash their hands 
with mild soap and water before and after each application.

Caregivers who are pregnant, or women of childbearing potential who are trying to 
become pregnant, should avoid accidental exposure by either avoiding applying 
investigational product or wearing gloves during its application. Care should also be 
taken when handling the child after investigational product has been applied.

 
 
 
4.5. Sponsor’s Qualified Medical Personnel
The contact information for the sponsor's appropriately qualified medical personnel for the 
study is documented in the study contact list located in the team SharePoint site.
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’s parent(s)/legal guardian directly, and if a 
subject’s parent(s)/legal guardian 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).  
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For this study, the investigational product is crisaborole ointment 2%.  Crisaborole ointment 
2% is formulated to contain PF-06930164 (2% wt/wt), white petrolatum,
 
mono- and diglycerides, paraffin wax, butylated hydroxytoluene, and edetate calcium 
disodium.
5.1. Allocation to Treatment
The investigator’s knowledge of the treatment should not influence the decision to enroll a 
particular subject or affect the order in which subjects are enrolled.
All subjects will receive crisaborole ointment 2% during their participation in this study.  
Subjects will be enrolled through the use of an interactive response technology (IRT) system 
(interactive Web-based response [IWR]).  The IRT system will provide a confirmation report 
containing the subject number and dispensable unit (DU) or container number(s) assigned.  
The confirmation report must be stored in the site’s files. 
The study-specific IRT reference manual will provide the contact information and further 
details on the use of the IRT system. 
5.2. Subject Compliance
For subjects in the 
 cohort, a subject will be considered compliant with the dosing regimen 
if they receive at least 12 investigational product doses (no more than 2 missed doses 
between Day 1 and Day 6) administered in accordance with the protocol.  Thereafter, 
 
cohort subjects will be considered compliant with the dosing regimen if they receive at least 
33 but no more than 49 investigational product doses (ie, 80–120%, inclusive, of the 
expected number of doses) administered in accordance with the protocol.
For Non-PK subjects, 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.
Following the Baseline/Day 1 visit, a parent/legal guardian will apply crisaborole ointment 
2% to the subject at home for subjects in the nonPK cohort The 
 cohort will have 
investigational product applied either at the site or at home by a visiting healthcare 
professional during the PK portion of the study, and the remaining doses applied at home.  
Compliance with all at-home dosing will be recorded by the parent(s)/legal guardian using a 
dosing diary provided by the site.  
5.3. Investigational Product Supplies
5.3.1. Dosage Form(s) and Packaging
Crisaborole ointment 2% investigational product will be supplied in 60 g tubes.  The tubes 
will be labeled according to local regulatory requirements. 
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5.4. Investigational Product Storage
The investigator or an approved representative, eg, pharmacist, will ensure that all 
investigational products are stored in a secured area with controlled access under required 
storage conditions and in accordance with applicable regulatory requirements.
Investigational products should be stored in their original containers and in accordance with 
the labels.
Any storage conditions stated in the SRSD will be superseded by the storage conditions 
stated on the product label.
Site systems must be capable of measuring and documenting (for example, via a log), at a 
minimum, daily minimum and maximum temperatures for all site storage locations (as 
applicable, including frozen, refrigerated, and/or room-temperature products).  This should 
be captured from the time of investigational product receipt throughout the study.  Even for 
continuous-monitoring systems, a log or site procedure that ensures active evaluation for 
excursions should be available.  The intent is to ensure that the minimum and maximum 
temperature is checked each business day to confirm that no excursion occurred since the last 
evaluation and to provide the site with the capability to store or view the minimum/maximum 
temperature for all non-working days upon return to normal operations.  The operation of the 
temperature monitoring device and storage unit (for example, refrigerator), as applicable, 
should be regularly inspected to ensure they are maintained in working order.  
Any excursions from the product label storage conditions should be reported to Pfizer upon 
discovery.  The site should actively pursue options for returning the product to the storage 
conditions described in the labeling, as soon as possible.  Deviations from the storage
requirements, including any actions taken, must be documented and reported to Pfizer.  
Once an excursion is identified, the investigational product must be quarantined and not used 
until Pfizer provides permission to use the investigational product.  It will not be considered a 
protocol deviation if Pfizer approves the use of the investigational product after the 
temperature excursion. Use of the investigational product prior to Pfizer approval will be 
considered a protocol deviation. Specific details regarding information the site should report 
for each excursion will be provided to the site.
Please see the Investigational Product Manual for additional details on storage conditions and 
actions to be taken when conditions are outside of the specified range.
Site staff will instruct the subject’s parent(s)/legal guardian on the proper storage 
requirements for take home investigational products.  For crisaborole ointment 2%, subject’s 
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5.5. Administration
Crisaborole ointment 2% is for external use on the skin only.  Large areas that need to be 
treated can have the ointment applied slowly and segmentally to minimize pain associated 
with application. Subjects should avoid contact with mucous membranes (ie, inside of 
nostrils, mouth, vagina, urethra, and rectum), and the eyes.  Additionally, for subjects in the 
 cohort, though AD lesions in the perioral area (within 2 cm of the mouth) or on the 
extremities (below wrists and below ankles) are exclusionary at baseline, if they occur 
following enrollment, crisaborole ointment 2% should not be applied to those areas during 
the 
 phase (Day 1 AM dose through Day 8 final 
 sample collection) in order to reduce 
the possibility of accidental ingestion that could adversely affect 
 results.
5.6. Preparation and Dispensing of Investigational Product
Within this protocol, preparation refers to the investigator site activities performed to make 
the investigational product ready for administration or dispensing to the subject/caregiver by 
qualified staff.  Dispensing is defined as the provision of investigational product, 
concomitant treatments, and accompanying information by qualified staff member(s) to a
healthcare provider, subject, or caregiver in accordance with this protocol.  Local health 
authority regulations or investigator site guidelines may use alternative terms for these 
activities. 
The investigational product will be dispensed using an IRT drug management system from 
Baseline/Day 1 to the Day 15 visit.  A qualified staff member will dispense the 
investigational product via unique container numbers in the cartons provided, in quantities 
appropriate for the study visit schedule.  
For doses to be administered at home, the caregiver (parent(s)/legal guardian) or the visiting 
health care professional, where applicable, should be instructed to maintain the product in the 
package provided throughout the course of dosing and return all used and unused product and 
cartons to the site at the next study visit.
5.7. Investigational Product Application
5.7.1. Non-PK Cohort Subjects
Before the Day 1 initial investigational product application is performed, the designated areas 
for treatment will be identified at the Baseline/Day 1 visit and documented in the subject’s 
study records. The subject’s parent(s)/legal guardian will be provided with a body map 
documenting the designated treatment areas and a paper dosing diary for recording all 
investigational product applications applied at home.
Wearing gloves, study staff will apply a thin layer of crisaborole ointment 2% to all treatable 
AD lesions identified at Baseline/Day 1 for the purpose of instructing the parent(s)/legal 
guardian how to dispense and apply the ointment. All subsequent doses, including second 
dose on Day 1, will be applied at home.  See Section 5.8 for details regarding study treatment 
regimen.  
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The parent(s)/legal guardian will not be expected to wear gloves when applying 
investigational product at home but will be instructed to wash their hands with mild soap and 
water before and after each application.  The investigational product will be applied to all 
treatable AD lesions as instructed by study staff.
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
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5.8. Study Treatment Regimen
5.8.1. Non-PK Cohort Subjects
The initial dose application on Baseline/Day 1 will be applied in the clinic, and all 
subsequent doses will be applied at home by the subject’s parent(s)/legal guardian.  The 
subject’s parent(s)/legal guardian will be instructed to apply evening (PM) doses 
approximately 8–12 hours after the morning (AM) doses (eg, if an AM dose is completed at 
8:00 AM, the PM dose can be applied anytime between 4:00 PM and 8:00 PM).
A thin layer of crisaborole ointment 2% will be applied BID to all treatable AD-involved 
areas identified at Baseline/Day 1.  Investigational product will continue to be applied to all 
treatable AD-involved areas (excluding scalp) identified at Baseline/Day 1 regardless of
whether they become clinically clear prior to Day 29. Investigational product may also be 
applied to any new treatable AD-involved areas that appear following Baseline/Day 1 after 
consultation with the Investigator at the next visit.
For each study visit, subjects will arrive at the clinic having had the morning dose applied at 
home, with the exception of Day 29/Early Termination visit.  Dosing should continue up 
until the PM dose before that visit but no morning dose should be applied on Day 29.  The 
parent(s)/legal guardian will be instructed regarding the preferred AM and PM time windows 
for dosing as well as the amount of crisaborole ointment 2% to be applied.  The 
parent(s)/legal guardian will be provided with dosing instructions and a dosing diary to be 
completed and brought to all study visits after Day 8.
 
 
 
 
 
 
 
 
  
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However, if desired, the protocol allows for a visiting health care professional to assist with 
twice daily doses in the subject’s home for some or all of the dose applications during the 
 
portion of the study. This service may be utilized after the Baseline/Day 1 AM dose, based 
on site and parent(s)/legal guardian agreement. Day 8 AM dosing application and with any 
2 of the 3 scheduled 
 sample collections may also be performed by the visiting health care 
professional if preferred, however the subject must visit the site for one of the scheduled 
 
sample collections in order to perform the remainder of the Day 8 assessments and 
procedures.
After the AM dose application on Day 8, the remainder of the doses following the last 
 
sample collection (Day 8 PM dose through the AM dose on the Day 29 visit) will be applied 
at home by the subject’s parent(s)/legal guardian.  If preferred, the Day 8 PM dose may be 
applied at the site. The weighed per application dose is no longer a requirement; rather the 
parent(s)/legal guardian will be instructed to apply a thin layer of crisaborole ointment 
2% BID to all treatable AD-involved areas identified at Baseline/Day 1.  Investigational 
product will continue to be applied to all treatable AD-involved areas (excluding scalp) 
identified at Baseline/Day 1 regardless of whether they become clinically clear prior to 
Day 29. 
Investigational product may also be applied to any new treatable AD-involved areas that 
appear following Baseline/Day 1 after consultation with the Investigator at the next 
scheduled visit.  While lesions on the extremities (below wrists and below ankles) or within 
2 cm of the mouth are exclusionary at the time of the Baseline/Day 1 visit for subjects in the 
 cohort visit, new lesions developing in these areas may be treated as appropriate 
following completion of the Day 8 
 sample collections. 
For all remaining visits post-Day 8, subjects will arrive at the clinic having had the morning 
dose applied at home, with the exception of Day 29/Early Termination visit.  Dosing should 
continue up until the PM dose before that visit but no morning dose should be applied on 
Day 29/ET.  The subject’s parent(s)/legal guardian will be instructed to apply evening (PM) 
doses approximately 8–12 hours after the morning (AM) doses (eg, if an AM dose is 
completed at 8:00 AM, the PM dose can be applied anytime between 4:00 PM and 8:00 PM.  
In addition, the parent(s)/legal guardian will be provided with a dosing diary to be completed 
and brought to all study visits after Day 8.
5.9. Dosing Modifications
In the event a scheduled application is missed, the parent(s)/legal guardian will be instructed 
to apply it when they remember if it is at least 8 hours before the next scheduled application.  
Otherwise, they will be instructed to skip the missed application, perform the next 
application at the normally-scheduled time, indicate the missed dose in the dosing diary, and 
report the missed application to the Investigator at the next visit.
If one or more doses are withheld or missed due to a safety concern, then the AE or other 
reason must be documented, noted as having led to a dosing interruption.
Criteria for study drug discontinuation are outlined in Section 6.12.
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5.10. Investigational Product Accountability
The investigator site must maintain adequate records documenting the receipt, use, loss, or 
other disposition of the investigational product supplies.  All investigational products will be 
accounted for using a drug accountability form/record.
Throughout the study, detailed investigational product accountability records, including tube 
weights for all dispensed tubes as well as all returned empty, partially used and unused tubes, 
will be maintained for each subject by study staff.  For PK cohort subjects during the 
Phase, study staff will record the weight (in g) of all applied doses, along with the weight 
of any amount(s) dispensed in error and discarded as waste. 
The subject’s parent(s)/legal guardian will be asked to bring all dispensed investigational 
product (including empty, partially used and unused tubes) and the dosing diary to the clinic 
at every visit.  Detailed drug accountability records, including weekly tube weights measured 
in the clinic, will be maintained by study staff for each subject.
The original investigational product accountability log, or equivalent document, must be 
accurately completed, signed by the Investigator, and retained at the study site (with a copy 
supplied to the Sponsor) when the study is complete.
5.10.1. 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.
For all investigational product returned to the investigator by the parent(s)/legal guardian, the 
investigator will maintain the returned supply until destruction is authorized.  The sponsor or 
designee will provide instructions as to the disposition of any unused investigational product.
5.11. Concomitant Treatment(s)
All treatments (including medications and non-medication therapies) used for the treatment 
of AD and all other medications and topical products (including bland emollients, diaper 
creams and wipes, sunscreen, over-the-counter drugs, vitamins, and antacids) used within
30 days prior to Screening will be recorded as a concomitant treatment at the Screening visit.  
Any changes in concomitant medications or dosage will be recorded at Baseline/Day 1 and at 
each subsequent visit. 
Medication entries should provide the correctly spelled drug or therapy name and the dose, 
units, frequency, route of administration, start and stop date, and reason for use.  The use of 
any concomitant medication must relate to the subject's medical history or to an AE, except 
for vitamins/nutritional supplements and routine immunizations.
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Classes of medications and non-medication therapies that might alter the course of AD and 
that require washout prior to Baseline/Day 1 are summarized below.  If a subject requires a 
medication washout, the Investigator will provide instructions on discontinuing the 
prohibited medication(s) at the Screening Visit.
5.11.1. Medications/Therapies Prohibited During the Study
During the Study (Day 1 through Day 29 Visit)

Systemic corticosteroids.

Systemic immunosuppressive agents (eg, methotrexate, ciclosporin, azathioprine, 
hydroxychloroquine, mycophenolate mofetil).

Use of high-or-mid-potency topical corticosteroids or calcineurin inhibitors anywhere 
on the body.

Systemic antihistamines.

Light therapy (ultraviolet light therapy).

Systemic antibiotics for the treatment of new onset infections that require use longer 
than 14 days.

Systemic leukotriene receptor antagonist agents (eg, montelukast).

Wet wrap therapy.

Use of topical medications or products on AD lesions, including, but not limited to: 

Antibacterial soaps (for bathing); 

Bleach baths;

Topical sodium hypochlorite-based products;

Topical antihistamines;

Topical antibiotics (unless required for AE treatment);

Emollients;

Topical low potency corticosteroids (including hydrocortisone 1%);

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5.11.2. Medications/Therapies Allowed During the Study
During the Study (Day 1 through Day 29 Visit):

Use of intranasal, ophthalmic and inhaled corticosteroids.

Use of bland emollient(s) of choice to manage dry skin in areas surrounding, but not 
on or overlapping with treatable AD-involved areas.

Use of bland emollient(s) of choice (not containing urea) in AD skin areas where 
crisaborole is not applied (eg, scalp).

Use of sunscreen, but not on or overlapping with treatable AD-involved areas.
All topical products and treatments applied during the study (including emollients, diaper 
creams, diaper wipes, sunscreen, etc.), whether over-the-counter or prescription, should be 
recorded as a concomitant treatment. 
 
6. STUDY PROCEDURES
6.1. Study Visits
Subjects will be required to visit the clinic for all scheduled visits.  The timing of each study 
day is relative to the day of initial dosing (Baseline/Day 1).
6.2. Time Windows for Study Procedures
When multiple assessments are scheduled at the same nominal time, they are to be performed 
in the following order: vital signs, followed by 
 sampling, followed by clinical laboratory 
tests.  Sampling for 
 should occur as close as possible to the scheduled nominal time.
Allowable time windows for other visits/contacts are as follows:

Day 8 1 day;

Day 15 3 days;

Day 22 3 days; 

Day 29 3 days;

Day 36 3 days;

Day 57 +3 days.
 
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
Before AM dose on Day 8 (ie, 168 hours 1 hour after recorded time of completion 
of the Day 1 AM dose application);

3 hours 20 minutes after recorded time of completion of the Day 8 AM dose 
application;

12 hours 1 hour after recorded time of completion of the Day 8 AM dose 
application.
Any 
 sample collections and/or investigational product applications that occur outside of 
the specified windows will be reported as protocol deviations.
6.3. Screening Period
Screening procedures must be completed between 2 and 28 days (inclusive) prior to the 
Baseline/Day 1 Visit.  The investigator (or an appropriate delegate at the investigator site) 
will obtain informed consent from the subject’s parent(s)/legal guardian in accordance with 
the procedures described in the Subject Information and Consent section.  If the time 
between Screening and dosing exceeds 28 days as a result of delays outside of the control of 
the study team (eg, delayed drug shipment), then subjects do not require re-screening if the 
laboratory results meet the eligibility criteria.
If necessary, the screening procedures may be completed over several days.
The following procedures will be performed at the Screening Visit:

Obtain written informed consent before any study-specific evaluations or procedures 
are done;

Collect demographic information;

Review and record medical history (including immunizations, childhood illnesses,
history of febrile convulsions);

Confirm clinical diagnosis of AD including the date of onset (date of diagnosis, as 
specifically as known);

Measure weight and height/length (see Section 7.1.2).

Obtain vital signs (temperature, respiratory rate, pulse rate, and blood pressure [BP]) 
in the seated or supine position, preferably after the subject has been sitting or lying 
face up for a minimum of 5 minutes;

Obtain a 12-lead ECG after the subject has been resting quietly (may be performed at 
Baseline/Day 1).
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
Perform a full physical examination. If the full examination cannot be completed 
during screening, an unscheduled visit may be performed prior to Baseline/Day 1 to 
complete the full assessment. 
 
 

 
;
 

Review Inclusion Criteria and Exclusion Criteria.

Draw blood for clinical laboratory tests (may be completed any time during the 
screening period Day -28 to Day -2), however the chemistry and hematology results 
must be available and reviewed by the PI prior to the Baseline/Day 1 visit and 
investigational product application.  If the laboratory sample cannot be obtained due 
to an upset child, parent or other collections issues the subject cannot be enrolled into 
the study. Assessment of vital signs should precede blood draw for clinical 
laboratory tests whenever possible. Laboratory testing includes: (see Section 7.1.1).

Serum chemistry and hematology (see Section 7.1.1). 
 
 
 
 
 

Note: The skin at the venous access area must be thoroughly cleansed prior to 
blood sample collection.

Note: Upon receipt of the Screening serum chemistry, and hematology results, 
if there are any clinically significant abnormalities that the PI or designee feels 
prohibit initiation of investigational product treatment, the PI or designee may 
contact the sponsor medical monitor to discuss the appropriate course of 
action.
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
Review and record prior and concomitant medications.  This includes all medications 
and non-medication therapies used for the treatment of AD, including bland 
emollients, and all other medications (over-the-counter drugs, vitamins, antacids, etc.) 
used within 30 days of Screening.

If a subject is using a prohibited medication (or non-medication therapy) at the 
time of Screening, the Investigator will provide instructions on discontinuing the 
prohibited medication or therapy (ie, a “washout” period) at the Screening Visit.

Record any AEs and SAEs that have occurred since the time the consent was signed.

Review the Lifestyle Requirements with the parent(s)/legal guardian.

Note: The results of all screening evaluations, including laboratory results, must be
reviewed for clinical significance by the PI or designee prior to enrollment on
Baseline/Day 1.  Only subjects with no clinically significant screening evaluation
findings (with the exception of AD) may be enrolled in the study.

Schedule the Baseline/Day 1 Visit and all future study visits for the subject’s study
visit calendar, and review the calendar with the parent(s)/legal guardian.
6.3.1. Investigational Product Application Period
For the study period described below, when multiple procedures are scheduled at the same 
time point(s) relative to dosing, the following chronology of events should be adhered to, 
where possible.

Blood pressure/pulse rate should be obtained prior to blood specimen collection
whenever possible;

 procedures: all other procedures may be obtained before or after blood 
specimen collection.
When an intravenous catheter is utilized for blood sample collections, vital signs (pulse rate 
[PR], respiration rate [RR], BP and Temperature) should be collected prior to the insertion of 
the catheter whenever possible.
6.4. Baseline/Day 1
Subjects may return for the Baseline/Day 1 visit as soon as all Screening procedures are 
performed, prohibited medications have been discontinued for the required washout period, 
and the safety laboratory results have been reviewed by the PI and deemed acceptable.
The following procedures will be performed at the Baseline/Day 1 visit.
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
Assess and record any changes in the subject’s medical history since the Screening 
visit.

Reconfirm diagnosis of AD and document in source.
 

Measure height/length and weight (see Section 7.1.2).

Obtain vital signs (temperature, respiratory rate, pulse rate, and BP) in the seated or 
supine position, preferably after the subject has been sitting or lying face up for a 
minimum of 5 minutes; assessment of vital signs should precede blood draw for 
clinical laboratory tests whenever possible. 

Perform a limited physical examination.

Obtain a 12-lead ECG after the subject has been resting quietly, if not performed at 
the Screening visit.
 
 
 
 
 

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
Mark the subject’s source documents to record the treatable AD areas, excluding 
the scalp, as identified by the PI or designee at Baseline/Day 1 and provide 
parent(s)/legal guardian with documentation of the designated treatment areas.

Confirm subject’s eligibility based on the Inclusion Criteria and Exclusion Criteria.

Assess and record any changes in concomitant medications, including confirming that 
subject is not taking any prohibited medications, as detailed in Section 5.11.

Assess and record any predose AEs and SAEs. 

Review the Lifestyle Requirements with the parent(s)/legal guardian.

After PI’s or designee’s documented confirmation of eligibility, access IRT system to 
receive randomization number.
 

Dispense and weigh investigational product tube(s) before applying first dose; record 
tube weight(s) in subject’s source documents. 

Wearing gloves, study staff will apply a layer of investigational product to all 
treatable AD lesions identified at Baseline/Day 1. 
The following procedures will be performed at the Baseline/Day 1 Visit AFTER 
dosing with investigational product:

Assess and record any post-dose AEs, including potential hypersensitivity and/or 
application site reactions, and SAEs.

Provide to parent(s)/legal guardian a sufficient number of tubes of investigational 
product to allow for dosing until the next scheduled visit.

Instruct the parent(s)/legal guardian regarding investigational product application (see 
Section 5.7) to begin with the evening (PM) dose on Day 1 followed by BID dosing 
up to the PM dose prior to the Day 29 visit. 

Dispense dosing diary and instruct the subject’s parent(s)/legal guardian on use
(ie, each time study drug is applied). 

Review the schedule of upcoming study visits with parent(s)/legal guardian, and 
instruct them to return at the scheduled time for the Day 8 Visit.

Remind the parent(s)/legal guardian to bring all investigational product tubes (empty, 
partially used and unused) and the dosing diary to their next visit. 
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6.5. Day 8 (1 day) Study Visit

Obtain vital signs (temperature, respiratory rate, pulse rate, and BP) in the seated or 
supine position, preferably after the subject has been sitting or lying face up for a 
minimum of 5 minutes.

Obtain a 12-lead ECG after the subject has been resting quietly.
. 

Assess and record any changes in concomitant medications, including confirming that 
subject is not taking any prohibited medications, as detailed in Section 5.11.

Assess and record any AEs, including potential hypersensitivity and/or application 
site reactions, and SAEs. 

Collect and weigh empty, partially used and unused investigational product tubes; 
record tube weight in subject’s source documents.  (Not applicable to subjects in 
 
cohort through Day 8).

Mark the subject’s source documents to record the treatable AD areas (including new 
areas to be treated), excluding the scalp, as identified by the PI or designee and 
provide parent(s)/legal guardian with documentation of the designated treatment 
areas.

Dispense, and weigh new investigational product tube(s) for at-home dosing by 
parent(s)/legal guardian and record tube weight in source documents. Provide a 
sufficient number of tubes of investigational product to allow for dosing until the next 
scheduled visit.

Review dosing diary; assess compliance; re-train parent(s)/legal guardian if doses 
missed.

Dispense dosing diary and instruct the subject’s parent(s)/legal guardian on use.

Review the Lifestyle Requirements with the parent(s)/legal guardian. 

Instruct the parent(s)/legal guardian regarding all procedures for at-home dosing BID 
dosing through Day 29 visit, including how to complete the dosing diary, which 
started at the Baseline/Day 1 visit and will continue BID through Day 29 visit 
(ie, each time investigational product is applied). 

Review the schedule of upcoming study visits with the parent(s)/legal guardian, and 
instruct them to return at the scheduled time for the Day 15 Visit.
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
Remind the parent(s)/legal guardian to bring all investigational product tubes (empty, 
partially used and unused) and the dosing diary to the next visit.
6.6. Day 15 (3 days) Study Visit

Obtain vital signs (temperature, respiratory rate, pulse rate, and BP) in the seated or 
supine position, preferably after the subject has been sitting or lying face up for a 
minimum of 5 minutes.
 
 

Assess and record any changes in concomitant medications, including confirming that 
subject is not taking any prohibited medications, as detailed in Section 5.11.

Assess and record any AEs, including potential hypersensitivity and/or application 
site reactions, and SAEs. 

Collect and weigh empty, partially used and unused investigational product tubes; 
record tube weight in subject’s source documents.

Mark the subject’s source documents to record the treatable AD areas (including new 
areas to be treated), excluding the scalp, as identified by the PI or designee and 
provide parent(s)/legal guardian with documentation of the designated treatment 
areas.

Review dosing diary; assess compliance; re-train parent(s)/legal guardian if doses 
missed.

Dispense and weigh new investigational product tube(s) for at-home dosing by 
parent(s)/legal guardian and record tube weight in source documents.  Provide a 
sufficient number of tubes of investigational product to allow for dosing until the next 
scheduled visit.

Dispense dosing diary and instruct the subject’s parent(s)/legal guardian on use.

Review the Lifestyle Requirements with parent(s)/legal guardian.

Instruct the parent(s)/legal guardian regarding all procedures for at-home dosing BID 
dosing through Day 29 visit, including how to complete the dosing diary, which 
started at the Baseline/Day 1 visit and will continue BID through Day 29 visit 
(ie, each time investigational product is applied).


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
Review the schedule of upcoming study visits with the parent(s)/legal guardian, and 
schedule a time for the Day 22 telephone contact.

Remind the parent(s)/legal guardian to bring all investigational product tubes (empty, 
partially used and unused) and the dosing diary to their next visit.
6.7. Day 22 (3 days) Telephone Contact

Assess and record any changes in concomitant medications, including confirming that 
subject is not taking any prohibited medications, as detailed in Section 5.11.

Assess and record any AEs, including potential hypersensitivity and/or application 
site reactions, and SAEs. 

If concerns are identified, the investigator may request the subject be brought to 
the site for an unscheduled visit for further assessment of AEs/SAEs.

Review dosing diary by phone; assess compliance; re-train parent(s)/legal guardian if 
doses missed.

Review the Lifestyle Requirements with the parent(s)/legal guardian. 

Review the schedule of upcoming study visits with the parent(s)/legal guardian, and 
instruct them to return at the scheduled time for the Day 29 visit.

Remind the parent(s)/legal guardian to bring all investigational product tubes (empty, 
partially used and unused) and the dosing diary to their next visit. Site staff should 
instruct the parent(s)/legal guardian that subject dosing should continue up until the 
PM dose prior to the Day 29 visit. No dose should be applied the morning of the 
Day 29 visit.
6.8. Day 29/End of Treatment (3 days) Study Visit
In the event that the scheduled Day 29 visit does not fall exactly on Day 29, instruct the 
parent(s)/legal guardian to keep dosing BID until the evening dose prior to the Day 29 visit.  
No dose should be applied at home the morning of the Day 29 visit.  Day 29 requires early 
morning scheduling as sample collection for assessment of 
 systemic levels 
and lactate should be collected within 12 3 hours of the final Day 28 evening application.  

Measure height/length and weight. 

Obtain vital signs (temperature, respiratory rate, pulse rate, and BP) in the seated or 
supine position, preferably after the subject has been sitting or lying face up for a 
minimum of 5 minutes.
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
Obtain a 12-lead ECG after the subject has been resting quietly.

Perform a full physical examination. 
 
 

Assess and record any changes in concomitant medications, including confirming that 
subject is not taking any prohibited medications, as detailed in Section 5.11.

Assess and record any AEs, including potential hypersensitivity and/or application 
site reactions, and SAEs. 

Draw blood for clinical laboratory tests; assessment of vital signs should precede 
blood draw for clinical laboratory tests whenever possible.  Laboratory testing 
includes: 

Serum chemistry and hematology (see Section 7.1.1).
 
 
 
 

Note: The skin at the venous access area must be thoroughly cleansed prior to 
blood sample collection.

Collect and weigh empty, partially used and unused investigational product tubes; 
record tube weight in subject’s source documents. 

Collect the dosing diary and assess compliance.

Review the Lifestyle Requirements with the parent(s)/legal guardian. 

Review the schedule of upcoming study visits with the parent(s)/legal guardian, and 
schedule a time for the Day 36 telephone contact. 
6.9. Unscheduled Visit
The procedures performed at an Unscheduled Visit will depend on the reason for the visit 
(some procedures may not apply). 
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
Assess and record any changes in concomitant medications, including confirming that 
subject is not taking any prohibited medications, as detailed in Section 5.11.

Obtain vital signs (temperature, respiratory rate, pulse rate, and BP) in the seated or 
supine position, preferably after the subject has been sitting or lying face up for a 
minimum of 5 minutes.

Ensure that the subject has adequate investigational product to support dosing until 
the next scheduled visit.  If additional investigational product is needed, provide to 
parent(s)/legal guardian a sufficient number of tubes of investigational product to 
allow for dosing until the next scheduled visit. Ensure that all dispensed tubes are 
weighed and weight is recorded in subject’s source documents.

Assess and record any AEs, including potential hypersensitivity and/or application 
site reactions, and SAEs. 

Review the schedule of upcoming study visits with the parent(s)/legal guardian, and 
instruct them to return at the scheduled time.
6.10. Post-treatment Follow-up Period
6.10.1. Day 36 (3 days) Telephone Contact

Assess and record any changes in concomitant medications, (see the Time Period for 
Collecting AE/SAE Information section).  Assess and record any AEs, including 
potential hypersensitivity and/or application site reactions, and SAEs. 

If concerns are identified, the investigator may request the subject be brought to 
the site for an unscheduled visit for further assessment of AEs/SAEs.

Schedule the Day 57 follow up phone contact.
6.10.2. Follow-up Contact (Day 57 (+3 days) End of Study)
Follow-up contact will be completed 28 +3 calendar days after the last administration of the 
investigational product to capture any adverse events including ongoing potential  
hypersensitivity and/or application site reactions and to review and record concomitant 
medications (see the Time Period for Collecting AE/SAE Information section).  Contact with 
the subject may be done via a phone call. Any subject with a new or ongoing adverse event 
at the time of the Day 57 visit should however be seen in the clinic for evaluation of that 
adverse event. 


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6.12. Subject Withdrawal/Early Termination
The following criteria will be considered for the subjects’ discontinuation or withdrawal from 
the study:

The occurrence of adverse events that require the subject to stop participation in the 
study, due to availability for, or intolerance to, the study procedures.

Adverse effects of the study active ingredient that are considered to be clinically 
significant by the physician in charge, and/or might be harmful to the subjects’ health.

Abnormal laboratory tests considered to be clinically relevant.

Concurrent diseases that require use of a prohibited medication.

 
 
  

Clinically significant hypersensitivity reactions.
Subjects may be withdrawn from the study at any time at their parent(s)/legal guardian’s 
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’s parent(s)/legal guardian to comply with 
the protocol required schedule of study visits or procedures at a given investigator site.  The 
early termination visit applies only to subjects who are enrolled and then are prematurely 
withdrawn from the study.
Subjects should return to the clinic for the early termination visit as early as practically 
feasible following the decision to withdraw from the study.  Subject’s parent(s)/legal 
guardian should be questioned regarding their reason for withdrawal.  Every effort must be 
made to complete the assessments outlined in the Day 29/End of Treatment visit 
(Section 6.8). Subjects will in addition be requested to be available for the follow-up 
contacts at 1 week and 4 weeks after last dose of study treatment.
Lack of completion of all or any of the withdrawal/early termination procedures will not be 
viewed as protocol deviations so long as the subject’s safety was preserved.
Withdrawal of consent:
Subjects for whom it has been requested to discontinue receipt of study treatment by the 
parent(s)/legal guardian must continue to be followed for protocol specified follow-up 
procedures.  The only exception to this is when a subject’s parent(s)/legal guardian 
specifically withdraws consent for the subject for any further contact with him or her or 
persons previously authorized to provide this information. The subject’s parent(s)/legal 
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guardian 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 case report form (CRF) page.  In the event 
that vital status (whether the subject is alive or dead) is being measured, publicly available 
information should be used to determine vital status only as appropriately directed in 
accordance with local law.
Subjects who are withdrawn from the study may be replaced at the discretion of the 
investigator upon consultation with the sponsor. In the 
 cohort, subjects discontinuing for 
reasons other than TEAE may be replaced at the discretion of the sponsor to ensure 16 
subjects complete the 
 assessments.
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’s parent(s)/legal 
guardian as noted above.  Lost to follow-up is defined by the inability to reach the subject’s 
parent(s)/legal guardian 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 
parent(s)/legal guardian 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, 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.
If a subject is not brought back for a scheduled visit, every effort should be made to contact 
the subject’s parent(s)/legal guardian.  The Investigator or site staff should attempt to contact 
the subject’s parent(s)/legal guardian twice.  After 2 attempts, CRU staff may send a 
registered letter.  If no response is received from the subject’s parent(s)/legal guardian, the 
subject will be considered lost to follow up.  All attempts to contact the subject’s 
parent(s)/legal guardian 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 the subject to return for a final visit, if applicable, and 
follow-up with the subject’s parent(s)/legal guardian regarding any unresolved adverse 
events (AEs).
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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. Clinical Laboratory Evaluations
The following safety laboratory tests will be performed at times defined in the STUDY 
PROCEDURES section of this protocol.  Additional laboratory results may be reported on 
these samples as a result of the method of analysis or the type of analyzer used by the clinical 
laboratory; or as derived from calculated values.  These additional tests would not require 
additional collection of blood.  Unscheduled clinical laboratory assessments may be obtained 
at any time during the study to assess any perceived safety concerns.
The clinical laboratory test parameters that will be reviewed for safety evaluation are 
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Table 2.
Clinical Laboratory Test Parameters
Hematology
Chemistry
Other Bioanalytical 
Laboratory Assessment
Hemoglobin
Hematocrit
Red blood cell count
Platelet count
White blood cell count 
(% and absolute)

Neutrophils

Eosinophils

Monocytes

Basophils

Lymphocytes
Blood urea nitrogen
Glucose (non-fasting)
Creatinine
Sodium
Potassium
Chloride
Bicarbonate
Alanine aminotransferase 
Aspartate aminotransferase 
Total bilirubin
Alkaline phosphatase
Albumin
Total protein
Lactate
Calculation of osmolal gap
Calculation of anion gap
 
Baseline clinical laboratory tests will be drawn during the Screening visit, after assessment of 
vital signs and prior to the first investigational product application.
At the discretion of the Investigator, a lidocaine-based topical anesthetic 
(eg, lidocaine 4% cream) may be used prior to clinical laboratory sample collection to 
decrease potential discomfort to the subject provided the anesthetic 
 
  The skin must be thoroughly cleansed prior to blood sample collection.
The Investigator will review all clinical laboratory test results for safety evaluation upon 
receipt.  After reviewing the laboratory reports and evaluating the results for clinical 
significance, the Investigator or designee must sign and date the laboratory report. Clinically 
significant laboratory abnormalities are defined as abnormal values that have clinical 
manifestations or require medical intervention.  Clinically significant laboratory 
abnormalities noted from the Screening Visit will be recorded in the medical history.  Note: 
Upon receipt of the Screening serum chemistry, and hematology results, if there are any 
clinically significant abnormalities that the PI or designee considers prohibit initiation of 
investigational product treatment, the PI or designee may contact the sponsor medical 
monitor to discuss the appropriate course of action. 
A clinically significant laboratory abnormality detected after the Screening Visit may reflect 
the development of an AE.  Whenever possible, Investigators should report the clinical 
diagnosis suggested by the laboratory abnormality rather than listing individual abnormal test 
results as AEs.  If no diagnosis has been found to explain the abnormal laboratory result, the 
clinically significant lab result should be recorded as an AE, reflecting the lack of a diagnosis
(see Section 8.2.2).
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7.1.2. Physical Examination, including Height/Length, and Weight
Physical examinations, including height/length, and weight will be performed at times 
specified in the STUDY PROCEDURES section of this protocol.
Physical examinations may be conducted by a physician, trained physician's assistant, or 
nurse practitioner as acceptable according to local regulation.  A full physical examination 
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), cardiovascular, and neurological systems.  In addition, an 
assessment will be made of the condition of all AD-involved skin.  
The limited or abbreviated physical examination will be focused on general appearance, the 
respiratory, cardiovascular, and neurological systems, as well as towards symptoms reported 
by the subject’s parent(s)/legal guardian. In addition, symptoms and signs of diarrhea and 
vomiting should be assessed to monitor for evidence of dehydration.
The neurological examination component of all physical examinations should include 
evaluation of clinical signs that have been associated, in published reports, with 
 toxicity21
including central nervous system depression, seizure activity, ataxia, as well as somnolence, 
poor feeding and irritability which are considered newly emergent and independent of the 
subject’s AD related signs.  
Results from blood pressure and prior ECG assessments should be referred to when 
performing the cardiovascular component of all physical examinations in order to actively 
monitor for clinical signs that have been associated, in published reports, with 
 toxicity
including hypotension and cardiac arrhythmia.
For both weight and height/length measurements, the investigator or examiner should be 
trained in measuring height/length and weight as well as in calibration procedures. Ideally, 
the same person should measure the subject at every visit. Attempts should be made to 
schedule visits, so that measurements can be taken at approximately the same time 
throughout the study. The parent / caregiver is needed to help with measurement and to 
soothe and comfort the child. Explain to the parent/ caregiver the steps in the procedures and 
that it is important to keep the child still and calm to obtain good measurements. 
For measuring weight, a scale with appropriate range and resolution is used and must be 
placed on a stable, flat surface.  Subjects must remove shoes, bulky layers of clothing, and 
jackets so that only light clothing remains.  They must also remove the contents of their 
pockets and remain still during measurement of weight.
For measuring length, a length board (infantometer) must be used and be placed on a flat, 
stable surface, such as a table.
For both weight and height/length, three reproducible measurements of both the child’s 
weight and height/length should be recorded and the average of the 3 recordings will be 
entered onto the eCRF.
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7.1.3. Electrocardiogram
A single standard supine 12-lead ECG will be performed at times defined in the STUDY 
PROCEDURES section of this protocol. In the event of a 12-lead ECG cannot be obtained 
due to technical reasons (eg, pediatric patient with small chest), a 6-lead ECG should be 
obtained instead. Assessment should be performed after the subject has been resting quietly
and precede measurement of vital signs and blood draws whenever possible.  An ECG 
collection device will be provided by a central vendor and ECG data will be submitted to the 
central laboratory for measurement.  ECG interpretation will be provided directly to the site 
indicating central reader assessed relevance of abnormal findings.  It is the responsibility of 
the investigator to assess the findings based on the subject’s clinical presentation and 
determine clinical significance for a given subject. Any clinically significant changes from 
the Baseline/Day 1 ECG should be recorded as AEs and evaluated further as clinically 
warranted.
7.1.4. Vital Signs (temperature, respiratory rate, pulse rate, and BP
Vital signs will be measured at times specified in the STUDY PROCEDURES section of this 
protocol. Vital sign measurements (temperature, respiratory rate, pulse rate, and BP) should 
be performed with the subject in the seated or supine position and after the subject has been 
sitting or lying face up for a minimum of 5 minutes.  Eating or drinking should be avoided
for 15 minutes prior to the measurements.
On study day visits when clinical laboratory tests are performed, assessment of vital signs 
should precede blood draw whenever possible.
7.2. Efficacy
 
 
 
 
 
 
 
 
 
 


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
25 to 28 = Very severe eczema.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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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.  
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Safety Event
Recorded on the CRF
Reported on the CT SAE 
Report Form to Pfizer 
Safety Within 24 Hours of 
Awareness
SAE
All
All
Non-serious AE
All
None
Exposure to the 
investigational product 
under study during 
pregnancy or 
breastfeeding, and 
occupational exposure
All (regardless of whether 
associated with an AE), 
except occupational 
exposure
Exposure during pregnancy, 
exposure via breastfeeding, 
occupational exposure 
(regardless of whether 
associated with an AE)
Abbreviations: CRF=case report form; CT=clinical trial; SAE=serious adverse event; AE=adverse event.
All observed or volunteered events regardless of treatment group or suspected causal 
relationship to the investigational product(s) will be reported as described in the following 
paragraphs.
Events listed in the table above that require reporting to Pfizer Safety on the CT SAE Report 
Form within 24 hours of awareness of the event by the investigator are to be reported 
regardless of whether the event is determined by the investigator to be related to an 
investigational product under study.  In particular, if the SAE is fatal or life-threatening, 
notification to Pfizer Safety must be made immediately, irrespective of the extent of available 
event information.  This time frame also applies to additional new (follow-up) information on 
previously forwarded reports.  In the rare situation that the investigator does not become 
immediately aware of the occurrence of an event, the investigator must report the event 
within 24 hours after learning of it and document the time of his/her first awareness of the 
event.
For each event, the investigator must pursue and obtain adequate information both to 
determine the outcome and to assess whether it meets the criteria for classification as an SAE 
(see the Serious Adverse Events section below).  In addition, the investigator may be 
requested by Pfizer Safety to obtain specific follow-up information in an expedited fashion.  
This information is more detailed than that recorded on the CRF.  In general, this will include 
a description of the event in sufficient detail to allow for a complete medical assessment of 
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.


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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’s parent(s)/legal guardian.  In addition, each study subject’s 
parent(s)/legal guardian 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.
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.


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


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
Clinically significant signs and symptoms;

Changes in physical examination findings;

Hypersensitivity;

Progression/worsening of underlying disease;

Drug abuse;

Drug dependency.
Additionally, AEs may include signs and symptoms resulting from:

Drug overdose;

Drug withdrawal;

Drug misuse; 

Drug interactions;

Extravasation;

Exposure during pregnancy (EDP);

Exposure via breastfeeding;

Medication error;

Occupational exposure.
8.2.2. Abnormal Test Findings
Abnormal objective test findings should be recorded as AEs when any of the following 
conditions are met: 

Test result is associated with accompanying symptoms; and/or

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.


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


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


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Note the distinction between the severity and the seriousness of an AE.  A severe event is not 
necessarily an SAE.  For example, a headache may be severe (interferes significantly with 
the subject's usual function) but would not be classified as serious unless it met one of the 
criteria for Serious Adverse Events, listed above.
8.4. Special Situations
8.4.1. Protocol-Specified Serious Adverse Events
There are no protocol-specified SAEs in this study.  All SAEs will be reported to Pfizer 
Safety by the investigator as described in previous sections, and will be handled as SAEs in 
the safety database. 
8.4.2. Potential Cases of Drug-Induced Liver Injury
Humans exposed to a drug who show no sign of liver injury (as determined by elevations in 
transaminases) are termed “tolerators,” while those who show transient liver injury, but adapt 
are termed “adaptors.”  In some subjects, transaminase elevations are a harbinger of a more 
serious potential outcome.  These subjects fail to adapt and therefore are "susceptible" to 
progressive and serious liver injury, commonly referred to as drug-induced liver injury 
(DILI).  Subjects who experience a transaminase elevation above 3 times the upper limit of 
normal (× ULN) should be monitored more frequently to determine if they are an “adaptor” 
or are “susceptible.” 
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 
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:


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
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. 
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.
8.4.3. Exposure to the Investigational Product During Pregnancy or Breastfeeding, and 
Occupational Exposure
Exposure to the investigational product under study during pregnancy or breastfeeding and 
occupational exposure are reportable to Pfizer Safety within 24 hours of investigator 
awareness.


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8.4.3.1. Exposure During Pregnancy
For both unapproved/unlicensed products and for marketed products, an exposure during 
pregnancy (EDP) occurs if:

A female becomes, or is found to be, pregnant either while receiving or having been 
exposed (eg, because of treatment or environmental exposure) to the investigational 
product; or the female becomes or is found to be pregnant after discontinuing and/or 
being exposed to the investigational product;

An example of environmental exposure would be a case involving direct contact 
with a Pfizer product in a pregnant woman (eg, a nurse reports that she is pregnant 
and has been exposed to chemotherapeutic products).

A male has been exposed (eg, because of treatment or environmental exposure) to the 
investigational product prior to or around the time of conception and/or is exposed 
during his partner’s pregnancy. 
In this protocol, in which the 3 month to less than 24 month old subjects are receiving 
investigational product via topical application by the parent/legal guardian, an EDP may 
occur to the parent/legal guardian via environmental exposure.  
If a subject’s parent/legal guardian 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 
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.


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Additional information about pregnancy outcomes that are reported to Pfizer Safety as SAEs 
follows: 

Spontaneous abortion includes miscarriage and missed abortion;

Neonatal deaths that occur within 1 month of birth should be reported, without regard 
to causality, as SAEs.  In addition, infant deaths after 1 month should be reported as 
SAEs when the investigator assesses the infant death as related or possibly related to 
exposure to the investigational product.
Additional information regarding the EDP may be requested by the sponsor.  Further 
follow-up of birth outcomes will be handled on a case-by-case basis (eg, follow-up on 
preterm infants to identify developmental delays).  In the case of paternal exposure, the 
investigator will provide the subject with the Pregnant Partner Release of Information Form 
to deliver to his partner.  The investigator must document in the source documents that the 
subject was given the Pregnant Partner Release of Information Form to provide to his 
partner.
8.4.3.2. Exposure During Breastfeeding
Scenarios of exposure during breastfeeding must be reported, irrespective of the presence of 
an associated SAE, to Pfizer Safety within 24 hours of the investigator’s awareness, using the 
CT SAE Report Form.  An exposure during breastfeeding report is not created when a Pfizer 
drug specifically approved for use in breastfeeding women (eg, vitamins) is administered in 
accord with authorized use.  However, if the infant experiences an SAE associated with such 
a drug’s administration, the SAE is reported together with the exposure during breastfeeding.
8.4.3.3. Occupational Exposure
An occupational exposure occurs when, during the performance of job duties, a person 
(whether a healthcare professional or otherwise) gets in unplanned direct contact with the 
product, which may or may not lead to the occurrence of an AE.
An occupational exposure is reported to Pfizer Safety within 24 hours of the investigator’s 
awareness, using the CT SAE Report Form, regardless of whether there is an associated 
SAE.  Since the information does not pertain to a subject enrolled in the study, the 
information is not recorded on a CRF; however, a copy of the completed CT SAE Report 
Form is maintained in the investigator site file.
8.4.4. Medication Errors 
Other exposures to the investigational product under study may occur in clinical trial settings, 
such as medication errors.


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Safety Event
Recorded on the CRF
Reported on the CT SAE 
Report Form to Pfizer 
Safety Within 24 Hours of 
Awareness
Medication errors
All (regardless of whether 
associated with an AE)
Only if associated with an 
SAE
8.4.4.1. Medication Errors
Medication errors may result from the administration or consumption of the investigational 
product by the wrong subject, or at the wrong time, or at the wrong dosage strength.
Medication errors include:

Medication errors involving subject exposure to the investigational product;

Potential medication errors or uses outside of what is foreseen in the protocol that do 
or do not involve the participating subject.
Such medication errors occurring to a study participant are to be captured on the medication 
error page of the CRF, which is a specific version of the AE page.
In the event of a medication dosing error, the sponsor should be notified immediately.
Whether or not the medication error is accompanied by an AE, as determined by the 
investigator, the medication error is recorded on the medication error page of the CRF and, if 
applicable, any associated AE(s), serious and non-serious, are recorded on an AE page of the 
CRF.
Medication errors should be reported to Pfizer Safety within 24 hours on a CT SAE Report 
Form only when associated with an SAE.
9. DATA ANALYSIS/STATISTICAL METHODS
Detailed methodology for summary and statistical analyses of the data collected in this study 
is outlined here and further detailed in a statistical analysis plan (SAP), which will be 
maintained by the sponsor.  The SAP may modify what is outlined in the protocol where 
appropriate; however, any major modifications of the primary endpoint definitions or their 
analyses will also be reflected in a protocol amendment.
9.1. Sample Size Determination
This is a multi-center, open-label, safety study of subjects with AD.  To ensure 
100 completers, 125 subjects will be enrolled assuming a 20% drop out rate.  Of the 
125 subjects enrolled, at least 16 subjects with moderate AD and 
 
 excluding scalp, who have completed all 
 assessments will be included in a 
subgroup for 
 assessment. The sample size was determined by clinical judgment based on 
CC
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Sponsor experience with other clinical studies with the investigational product and was not 
based on statistical power.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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.
9.2. Analysis of the Primary Endpoint 
Any subject receiving 1 dose of investigational product will be included in safety analysis 
set. 
9.2.1. Safety
Safety data will be descriptively summarized (including extent of exposure), and will be 
presented in tabular and/or graphical format. No imputation will be made for missing safety 
data.
All AE(s) that occur after signing of the informed consent through the final study visit will be 
recorded, classified and listed on the basis of Medical Dictionary for Regulatory Activities
(MedDRA) terminology. Treatment-emergent AE(s) (TEAEs) are defined as, 1) AEs where 
the onset is on or after the first investigational product administration or, 2) there is a 
worsening of a pre-existing condition 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, SOC, PT, severity, relationship to investigational treatment, and seriousness.  When 
summarizing TEAEs by relationship and severity, each subject will be counted only once 
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within a SOC or a preferred term by using the event with the greatest relationship and highest 
severity within each classification. 
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.
Clinically significant changes in height, weight, vital signs, ECG and safety laboratory 
parameters will be summarized. 
 
 
 
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9.4. Extent of Exposure
The extent of exposure to investigational product will be summarized by the total number of 
days of dosing, total number of applications, total amount of investigational product applied, 
and number and percentage of subjects who are compliant with the dosing regimen. 
9.5. Interim Analysis
No formal interim analysis will be conducted for this study. However, as this is an open 
label study, the sponsor may conduct unblinded reviews of the data during the course of the 
study for the purpose of safety assessment facilitating 
 
pharmacodynamic (PD) modeling, and/or to support clinical development.
9.6. Data Monitoring Committee 
This study will use an external data monitoring committee (E-DMC). 
The E-DMC will be responsible for ongoing monitoring of the safety of subjects in the study 
according to the charter.  The recommendations made by the E-DMC to alter the conduct of 
the study will be forwarded to Pfizer for a final decision.  Pfizer will forward such decisions, 
which may include summaries of aggregate analyses of endpoint events and of safety data 
that are not endpoints, to regulatory authorities, as appropriate.
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 independent review board/ethics committee (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 
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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 
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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.
If the study includes minor subjects who reach the age of majority during the study, as 
recognized under local law, they must re-consent as adults to remain in the study.  If the 
enrollment of emancipated minors is permitted by the study age criteria, the IRB/EC, and 
local law, they must provide documentation of legal status to give consent without the 
permission of a parent or legal guardian.
All subjects enrolled in this study will be 3 months to less than 24 months of age at the time 
of their enrollment in this study. The maximum duration of this study is 88 days and 
therefore no subjects will reach an age where they are able to provide informed 
consent/assent during their participation. As such, informed consent must be obtained from 
their parent(s)/legal guardian.
The investigator must ensure that each study subject’s parent(s)/legal guardian is fully 
informed about the nature and objectives of the study and possible risks associated with 
participation. 
Whenever consent is obtained from a subject’s parent(s)/legal guardian, the subject’s assent 
(affirmative agreement) must subsequently be obtained when the subject has the capacity to 
provide assent, as determined by the IRB/EC.  If the investigator determines that a subject’s 
decisional capacity is so limited he/she cannot reasonably be consulted, then, as permitted by 
the IRB/EC and consistent with local regulatory and legal requirements, the subject’s assent 
may be waived with source documentation of the reason assent was not obtained.  If the 
study subject does not provide his or her own consent, the source documents must record 
why the subject did not provide consent (eg, minor, decisionally impaired adult), how the 
investigator determined that the person signing the consent was the subject’s legally 
acceptable representative, the consent signer’s relationship to the study subject (eg, parent, 
spouse), and that the subject’s assent was obtained or waived.  If assent is obtained verbally, 
it must be documented in the source documents.
The investigator, or a person designated by the investigator, will obtain written informed 
consent from the subject's parent(s)/legal guardian before any study-specific activity is 
performed. The investigator will retain the original of each subject's signed consent 
document.


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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 at any time.
If a study is prematurely terminated, Pfizer will promptly notify the investigator.  After 
notification, the investigator must contact all participating subjects and the hospital pharmacy 
(if applicable) within 7 days.  As directed by Pfizer, all study materials must be collected and 
all CRFs completed to the greatest extent possible.
15. PUBLICATION OF STUDY RESULTS
15.1. Communication of Results by Pfizer
Pfizer fulfills its commitment to publicly disclose clinical trial results through posting the 
results of studies on www.clinicaltrials.gov (ClinicalTrials.gov), the European Clinical Trials 
Database (EudraCT), and/or www.pfizer.com, and other public registries in accordance with 
applicable local laws/regulations. 
In all cases, study results are reported by Pfizer in an objective, accurate, balanced, and 
complete manner and are reported regardless of the outcome of the study or the country in 
which the study was conducted.
www.clinicaltrials.gov
Pfizer posts clinical trial US Basic Results on www.clinicaltrials.gov for Pfizer-sponsored 
interventional studies (conducted in patients) that evaluate the safety and/or efficacy of a 
Pfizer product, regardless of the geographical location in which the study is conducted.  US 
Basic Results are submitted for posting within 1 year of the primary completion date (PCD) 
for studies in adult populations or within 6 months of the PCD for studies in pediatric 
populations.


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PCD is defined as the date that the final subject was examined or received an intervention for 
the purposes of final collection of data for the primary outcome, whether the clinical study 
concluded according to the prespecified protocol or was terminated.
EudraCT
Pfizer posts European Union (EU) Basic Results on EudraCT for all Pfizer-sponsored 
interventional studies that are in scope of EU requirements.  EU Basic Results are submitted 
for posting within 1 year of the PCD for studies in adult populations or within 6 months of 
the PCD for studies in pediatric populations.
www.pfizer.com
Pfizer posts Public Disclosure Synopses (clinical study report synopses in which any data 
that could be used to identify individual patients 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.
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.


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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.
Eichenfield LF, Ellis CN, Mancini AJ, et al. Atopic dermatitis: epidemiology and 
pathogenesis update. Semin Cutan Med Surg 2012;31(3 Suppl):S3-5. 
4.
Leicht S, Hanggi M. Atopic dermatitis. How to incorporate advances in management. 
Postgrad Med 2001;109(6):119–27. 
5.
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. 
6.
Leung DY. New insights into atopic dermatitis: role of skin barrier and immune 
dysregulation. Allergol Int. 2013 Jun;62(2):151-61. 
7.
Bantz SK, Zhu Z, Zheng T. The atopic march: progression from atopic dermatitis to 
allergic rhinitis and asthma. J Clin Cell Immunol. 2014 Apr;5(2). 
8.
Saunes M, Oien T, Dotterud C, et al. Early eczema and the risk of childhood asthma: a 
prospective, population-based study. BMC Pediatr. 2012 Oct 24;12:168. 
9.
Garg N, Silverberg J. Epidemiology of childhood atopic dermatitis. Clin Dermatol. 
2015 May-Jun;33(3):281-8.
10.
Beatti PE, Lewis-Jones MS. A comparative study of impairment of quality of life in 
children with skin disease and children with other chronic childhood diseases. Br J 
Dermatol. 2006 Jul;155(1):145-51.
11.
Carroll CL, Balkrishnan R, Feldman S, et al. The burden of atopic dermatitis: impact on 
the patient, family, and society. Pediatr Dermatol. 2005 May-Jun;22(3):192-9.
12.
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.
13.
Su JC, Kemp AS, Varigos GA, et al. Atopic eczema: its impact on the family and 
financial cost. Arch Dis Child. 1997 Feb;76(2):159-62.
14.
Lawson V, Lewis-Jones MS, Finlay AY, et al. The family impact of childhood atopic 
dermatitis: the Dermatitis Family Impact Questionnaire. Br J Dermatol. 1998 
Jan;138(1):107-13.
15.
Dahl RE, Bernhisel-Broadbent J, Scanlon-Holdford S, et al. Sleep disturbances in 
children with atopic dermatitis. Arch Pediatr Adolesc Med. 1995 Aug;149(8):856-60.


Crisaborole (PF-06930164 [AN2728])
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Final Protocol Amendment 1, 01 May 2018
Page 89
16.
Kim S, Hur J, Jang J, et al. Psychological Distress in Young Adult Males with Atopic 
Dermatitis: A Cross-Sectional Study. Medicine (Baltimore). 2015 Jun;94(23):e949.
17.
Daud LR, Garralda ME, David TJ. Psychosocial adjustment in preschool children with 
atopic eczema. Arch Dis Child. 1993 Dec;69(6):670-6.
18.
Absolon CM, Cottrell D, Eldridge SM, et al. Psychological disturbance in atopic 
eczema: the extent of the problem in school-aged children. Br J Dermatol. 1997 
Aug;137(2):241-5.
19.
Watson W, Kapur S. Atopic dermatitis. Allergy Asthma Clin Immunol. 2011 Nov 10;7 
Suppl 1:S4.
 
 
22.
Pfizer Investigator Brochure for Crisaborole, February 2017.
23.
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.
24.
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-
and Lipopolysaccharide.
25.
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-and 
Lipopolysaccharide.
26.
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.
27.
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.
28.
Anacor Pharmaceuticals Report No. 003-NCL PP-008-01, Effect of AN2728 in 
Inhibition of IL-1β, IL-4, TNFα, and IFNγ from PBMCs Challenged with PHA for 
24 or 48 h.
29.
Anacor Pharmaceuticals Report No. 003-NCL PP-006-01, Effect of AN2728 on 
Inhibition of IL-2 and IL-5 Cytokine Release from PBMCs.
CCI
CCI


Crisaborole (PF-06930164 [AN2728])
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Final Protocol Amendment 1, 01 May 2018
Page 90
30.
Anacor Pharmaceuticals Report No. 003-NCL PP-013-01, PDE Isoform Profiling 
(Percent Inhibition).
31.
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.
32.
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.
33.
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.
34.
Anacor Pharmaceuticals Report No. 003-NCL PP-024-01, Pharmacology Data report: 
AN7602 and AN8323 IC50 Against PDE4.
35.
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.
36.
An Open-Label, Maximal Use, Systemic Exposure Study to Assess the Safety and 
Pharmacokinetic Profile of AN2728 Topical Ointment, 2% in Children and Adolescents 
with Atopic Dermatitis (Protocol AN2728-AD-102).
37.
Anacor Pharmaceuticals Report No. 003-CLN CL-013-01, An Open-Label Study to 
Determine the Safety, Tolerability, and Pharmacokinetic Profile of AN2728 Ointment 
in Adolescents with Atopic Dermatitis (Protocol AN2728-AD-203).
38.
Anacor Pharmaceuticals Report No. 003-CLN CL-012-01, A Multi-Center, 
Randomized, Double-Blind, Vehicle-Controlled, Bilateral Study of the Safety and 
Efficacy of AN2898 and AN2728 in the Treatment of Patients with Mild-to-Moderate 
Atopic Dermatitis (Protocol AN2898-AD-202).
39.
Anacor Pharmaceuticals Report No. 003-CLN CL-014-01A Multicenter, Randomized, 
Double-Blind, Four-Week, Bilateral Study of the Safety and Efficacy of Two 
Concentrations of AN2728 Ointment Administered Once or Twice a Day in 
Adolescents With Atopic Dermatitis (Protocol AN2728-AD-204). 
40.
A Multicenter, Randomized, Double-Blind, Vehicle-Controlled Study of the Safety and 
Efficacy of AN2728 Topical Ointment, 2% in Children, Adolescents, and Adults 
(Ages 2 Years and Older) With Atopic Dermatitis (Protocol AN2728-AD-301).
41.
A Multicenter, Randomized, Double-Blind, Vehicle-Controlled Study of the Safety and 
Efficacy of AN2728 Topical Ointment, 2% in Children, Adolescents, and Adults 
(Ages 2 Years and Older) With Atopic Dermatitis (Protocol AN2728-AD-302).


Crisaborole (PF-06930164 [AN2728])
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Final Protocol Amendment 1, 01 May 2018
Page 91
42.
A Multicenter, Open-Label Study of the Long-Term Safety of AN2728 Topical 
Ointment, 2% in the Treatment of Children, Adolescents, and Adults (Ages 2 Years and 
Older) With Atopic Dermatitis (Protocol AN2728-AD-303).
43.
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 
Nov;175(5):902-911. doi: 10.1111/bjd.14871.  Topical tofacitinib for atopic dermatitis: 
a phase IIa randomized trial.  
44.
Charman CR, Venn AJ, Williams HC. The Patient-Oriented Eczema Measure: 
Development and Initial Validation of a New Tool for Measuring Atopic Eczema 
Severity From the Patients' Perspective. Arch Dermatol. 2004;140;1513-1519.
45.
Hanifin JM and Rajka G. Diagnostic features of atopic dermatitis. Acta Derm Venereol 
(Stockh) 1980;92(suppl):44-7.


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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
ANOVA
analysis of variance
AST
aspartate aminotransferase
AUC
area under the curve
BID
twice daily
BP
blood pressure
cAMP
cyclic adenosine monophosphate
CI
confidence interval
CK
creatine kinase
Cmax
maximum observed plasma concentration
CRF
case report form
CRU
clinical research unit
CSA
clinical study agreement
CSR
clinical study report
CT
clinical trial
CTA
clinical trial application
DILI
drug-induced liver injury
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
GCP
Good Clinical Practice
GGT
Gamma-glutamyl transferase
GRAS
generally recognized as safe
HRQL
health-related quality of life
IB
Investigator’s Brochure
ICH
International Conference on Harmonisation
IND
investigational new drug application
INR
international normalized ratio


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Abbreviation
Term
IP
investigational product
IRB
institutional review board
IRT
interactive response technology
IVIG
intravenous immunoglobulin
IWR
interactive web response
LFT
liver function test
LSLV
last subject last visit 
MedDRA
Medical Dictionary for Regulatory Activities
MUSE
maximal use, systemic exposure
N/A
not applicable
NOAEL
no observed-adverse-effect level
NOEL
no observed-effect level
PCD
primary completion date
PD
pharmacodynamics(s)
PDE4
phosphodiesterase-4
PI
principal investigator
PKA
protein kinase a
PMA
phorbol 12-myristate 13-acetate
PT
prothrombin time
QD
once daily
SAE
serious adverse event
SAP
statistical analysis plan
SOC
system organ class
SOP
standard operating procedure
SRSD
single reference safety document
SUSAR
suspected unexpected serious adverse reaction
t½
apparent terminal phase half-life
TEAE
treatment emergent adverse event
TBili
total bilirubin
Tmax
time to reach maximum observed plasma concentration
ULN
upper limit of normal
US
United States
CC
I
CC
I


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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 Rajka.45
Table 8.
Hanifin and Rajka’s Diagnostic Criteria for Atopic Dermatitis
Major Criteria (must have at least three)
Pruritus
Typical morphology and distribution:
Adults: flexural lichenification or linearity
Children and infants: facial and extensor involvement
Chronic or chronically-relapsing dermatitis
Personal or family history of atopy (asthma, allergic rhinitis, atopic dermatitis)
Minor Criteria (must have at least three)
Xerosis
Ichthyosis/keratosis pilaris/palmar hyperlinearity
Immediate (type 1) skin test reactivity
Elevated serum IgE
Early age of onset
Tendency toward cutaneous infections (esp. staphylococcus aureus and herpes simplex),
impaired cell-mediated immunity
Tendency toward non-specific hand or foot dermatitis
Nipple eczema
Cheilitis
Recurrent conjunctivitis
Dennie-Morgan infraorbital fold
Keratoconus
Anterior subcapsular cataracts
Orbital darkening
Facial pallor, facial erythema
Pityriasis alba
Anterior neck folds
Itch when sweating
Intolerance to wool and lipid solvents
Periofollicular accentuation
Food intolerance
Course influenced by environmental and emotional factors
White demographism, delayed blanch


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SAP_001.pdf: 
Protocol C3291002 (PF-06930164) Statistical Analysis Plan
Page 1
Protocol C3291002
A PHASE 4, MULTICENTER, OPEN-LABEL SAFETY STUDY OF CRISABOROLE
OINTMENT 2% IN CHILDREN AGED 3 MONTHS TO LESS THAN 24 MONTHS
WITH MILD TO MODERATE ATOPIC DERMATITIS
Statistical Analysis Plan 
(SAP)
Author:
Version:
2 
Date:
10 Apr-2019
PPD


Protocol C3291002 (PF-06930164) Statistical Analysis Plan
Page 2
TABLE OF CONTENTS 
LIST OF TABLES.....................................................................................................................3
1. VERSION HISTORY............................................................................................................4
2. INTRODUCTION .................................................................................................................4
2.1. Study Objectives .......................................................................................................5
2.1.1. Primary Objectives .......................................................................................5
2.2. Study Design .............................................................................................................5
3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS ..................................................................................................................6
3.1. Primary Endpoint(s) ..................................................................................................6
3.3. Baseline Variables.....................................................................................................7
4. ANALYSIS SETS .................................................................................................................7
4.1. Full Analysis Set .......................................................................................................7
4.2. Per Protocol Analysis Set..........................................................................................7
4.3. Safety Analysis Set....................................................................................................7
4.5. Other Analysis Sets ...................................................................................................8
5. GENERAL METHODOLOGY AND CONVENTIONS......................................................8
5.1. Hypotheses and Decision Rules ................................................................................8
5.2. General Methods .......................................................................................................8
5.2.1. Analyses for Binary Data..............................................................................8
5.2.2. Analyses for Continuous Efficacy Data .......................................................8
5.2.3. Analyses for Categorical Data......................................................................8
5.3. Methods to Manage Missing Data ............................................................................8
6. ANALYSES AND SUMMARIES ........................................................................................8
6.1. Primary Endpoint(s) ..................................................................................................8
6.1.1. Adverse Events.............................................................................................8
6.1.2. Laboratory Data............................................................................................9
6.1.3. Vital Signs ....................................................................................................9
6.1.4. ECG ..............................................................................................................9
6.1.5. Height/Length and Weight ...........................................................................9
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6.1.6. Physical Examination ...................................................................................9
 
6.3. Subset Analyses.......................................................................................................12
6.4. Baseline and Other Summaries and Analyses.........................................................12
6.4.1. Baseline Summaries....................................................................................12
6.4.2. Study Conduct and Subject Disposition .....................................................12
6.4.3. Study Treatment Exposure and Compliance ..............................................12
6.4.4. Concomitant Medications and Non-Drug Treatments................................12
7. INTERIM ANALYSES.......................................................................................................12
8. REFERENCES ....................................................................................................................13
LIST OF TABLES
Table 1.
Summary of Major Changes in SAP Amendments ....................................4
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Protocol C3291002 (PF-06930164) Statistical Analysis Plan
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1. VERSION HISTORY
This  Statistical Analysis Plan (SAP) for study C3291002 is based on the protocol dated 
06Jul2017.  
Table 1.
Summary of Major Changes in SAP Amendments
SAP 
Version
Change
Rationale
1
Not Applicable
Not Applicable
2
a.
New TEAE definition was added
a.
Pfizer released new 
TEAE definition
2. INTRODUCTION
Crisaborole, also referred to as PF-06930164 and AN2728, is a low molecular weight
benzoxaborole anti-inflammatory phosphodiesterase-4 (PDE-4) inhibitor that penetrates into
the skin to the sites of inflammation. PDE-4 inhibition results in increased intracellular 
cyclic adenosine monophosphate (cAMP) levels. While the specific mechanism(s) by which 
crisaborole exerts its therapeutic action is not well defined, it is thought that crisaborole 
reduces the production of several inflammatory cytokines implicated in the pathophysiology 
of atopic dermatitis (AD).
Across the development program, crisaborole demonstrated an acceptable safety profile, 
with no crisaborole treatment-related serious adverse events (SAEs) (except 1 case of drug 
eruption in a Phase 2 study which was classified as possibly related), and the majority of 
adverse events (AEs) were mild and deemed unlikely or not related to investigational 
product. Safety and efficacy have not yet been established in patients younger than 2 years 
of age.
This 4-week study will evaluate the safety, 
 of 
crisaborole ointment 2%, applied twice daily (BID) in subjects who are 3 months to less than
24 months of age with mild-to-moderate AD. The dose selected for this study has been 
shown to be safe, well tolerated and efficacious in patients and healthy volunteers 2 years of 
age and older who participated in previously conducted studies. Based on these results and 
 
 satisfactory safety and local tolerability in the pediatric
population to be enrolled in this study.


Protocol C3291002 (PF-06930164) Statistical Analysis Plan
Page 5
This SAP provides the detailed methodology for summary and statistical analyses of the data 
collected in study C3291002.  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 study the safety of crisaborole ointment 2% applied twice daily (BID) in children 
aged 3 months to less than 24 months with mild to moderate AD.
 
2.2. Study Design
This is a Phase 4, multicenter, open label, safety study to evaluate the safety of crisaborole 
ointment 2% in children aged 3 months to less than 24 months with AD. 
 
 
Approximately 125 subjects will be enrolled. Subjects will be between 3 months (at the time 
of the Screening visit) to less than 24 months of age at the time of Baseline/Day 1 with 
mild-to-moderate AD involving at least 
 assessed on Baseline/Day 1. 
 
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3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS
3.1. Primary Endpoint(s)

Incidence of treatment emergent AEs (including application site reactions), SAEs, 
and clinically significant changes in height, weight, vital signs, ECG and clinical 
laboratory parameters.
An adverse event is considered TEAE if the event start date is on or after the treatment 
period start date and prior to the treatment end date plus lag or within the Active Treatment 
Phase.
 
  
 
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Protocol C3291002 (PF-06930164) Statistical Analysis Plan
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3.3. Baseline Variables
Demographic and baseline characteristics include: 

Age (in months);

Sex;

Race;

Ethnicity;

Height (in cms);

Weight (in kg);

Body Mass Index;

Duration of disease (in months);
For endpoints based on scheduled visits, baseline will be defined as the last evaluation taken 
before the time of the first dose of investigational product.
4. ANALYSIS SETS
4.1. Full Analysis Set
Any subject receiving ≥1 dose of investigational product will be included in full analysis set 
(FAS).
4.2. Per Protocol Analysis Set 
None.
4.3. Safety Analysis Set
Any subject receiving ≥1 dose of investigational product will be included in safety analysis 
set.  


Protocol C3291002 (PF-06930164) Statistical Analysis Plan
Page 8
 
4.5. Other Analysis Sets
N/A.
5. GENERAL METHODOLOGY AND CONVENTIONS
5.1. Hypotheses and Decision Rules
This is an open label safety study. There is no hypotheses and decision rules.
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
Binary endpoints will be summarized using number, percentage and 95% CI of percentage.
5.2.2. Analyses for Continuous Efficacy Data
Continuous endpoints will be descriptively summarized using number, mean, standard 
deviation (standard error of the mean), minimum, 1st, 2nd and 3rd quartiles and maximum.
5.2.3. Analyses for Categorical Data
Categorical endpoints will be summarized using number and percentage. 
5.3. Methods to Manage Missing Data
Missing values will not be imputed for safety, 
6. ANALYSES AND SUMMARIES
6.1. Primary Endpoint(s)
6.1.1. Adverse Events
Adverse events will be summarized according to Pfizer reporting standards for 

TEAEs;

SAEs.
Overall TEAEs as well as treatment area TEAEs will be summarized by the number of 
subjects reporting any TEAE, system organ class (SOC), preferred term (PT), severity, 
relationship to investigational product, and seriousness.
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Overall SAEs as well as treatment area 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.
6.1.2. Laboratory Data
Clinical laboratory values and change from screening at Day 29/Early Termination and 
clinical significant change will be summarized according to Pfizer standards.
6.1.3. Vital Signs
Vital signs and change from baeline and clinical significant change will be summarized 
according to Pfizer standards.
6.1.4. ECG
ECG and change from baeline and clinical significant change wil be summarized according 
to Pfizer standards.
6.1.5. Height/Length and Weight
Height/length and weight values and change from baseline at Day 29/Early Termination and 
clinical significant change will be summarized according to Pfizer standards.
6.1.6. Physical Examination
Descriptive summary tables will be provided in accordance with Pfizer reporting standards.
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6.3. Subset Analyses 
N/A.
6.4. Baseline and Other Summaries and Analyses
6.4.1. Baseline Summaries
Demographic and baseline characteristics will be summarized according to Pfizer reporting 
standards
 and overall safety analysis set.
6.4.2. Study Conduct and Subject Disposition
Subjects evaluation, disposition, discontinuation will be summarized for safety analysis set 
according to Pfizer reporting standards.
6.4.3. Study Treatment Exposure and Compliance
The exposure to study drug 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 will be summarized 
 
 
 
 
 
 
 
For 
 subjects, 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.
6.4.4. Concomitant Medications and Non-Drug Treatments
Prior drug and non-drug treatment, concomitant drug and non-drug treatment will be 
summarized according to Pfizer reporting standards. 
7. INTERIM ANALYSES
No formal interim analysis will be conducted for this study. However, as this is an open 
label study, the sponsor may conduct unblinded reviews of the data during the course of the 
study for the purpose of safety assessment facilitating 
 
 and/or to support clinical development.
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This study will use an external data monitoring committee (E-DMC). The E-DMC will be 
responsible for ongoing monitoring of the safety of subjects in the study according to the 
charter. The recommendations made by the E-DMC to alter the conduct of the study will be 
forwarded to Pfizer for a final decision. Pfizer will forward such decisions, which may 
include summaries of aggregate analyses of endpoint events and of safety data that are not 
endpoints, to regulatory authorities, as appropriate.
8. REFERENCES 
1.
Pfizer Protocol C3291002.


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