Clinical trial NCT04360187
Conditions: Atopic Dermatitis
Sponsor: Pfizer
Start date: 2020-07-27; Completion date: 2021-09-08
Enrollment: 391 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study is a phase 3, randomized, double blind and vehicle study to evaluate the efficacy and safety of Crisaborole ointment, 2% in Chinese and Japanese subjects with mild to moderate atopic dermatitis involving at least 5% treatable BSA. Eligible subjects will be randomized in a 2:1 ratio to one of 2 treatment groups (Crisaborole BID, Vehicle BID, respectively).

Detailed description:

Arms: arm 1: Crisaborole ointment application twice daily for 28 days arm 2: Vehicle Ointment application twice daily for 28 days
Interventions: intervention 1: Crisaborole Ointment intervention 2: Crisaborole Placebo Vehicle
Intervention descriptions: intervention 1: Crisaborole ointment 2% intervention 2: Placebo for crisaborole ointment

Protocol documents:
Prot_000.pdf: 
Crisaborole (PF-06930164 [AN2728])
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A PHASE 3, MULTICENTER, RANDOMIZED, DOUBLE BLIND, VEHICLE 
CONTROLLED STUDY OF THE EFFICACY AND SAFETY OF CRISABOROLE 
OINTMENT, 2% IN CHINESE AND JAPANESE PEDIATRIC AND ADULT
SUBJECTS (AGES 2 YEARS AND OLDER) WITH MILD TO MODERATE ATOPIC 
DERMATITIS
Investigational Product Number:
PF-06930164
Investigational Product Name:
Crisaborole
United States (US) Investigational New 
Drug (IND) Number:
Not applicable
European Clinical Trials Database 
(EudraCT) Number:
Not applicable
Protocol Number
C3291032
Phase:
3
This document and accompanying materials contain confidential information belonging to Pfizer.  Except as 
otherwise agreed to in writing, by accepting or reviewing these documents, you agree to hold this information in 
confidence and not copy or disclose it to others (except where required by applicable law) or use it for 
unauthorized purposes.  In the event of any actual or suspected breach of this obligation, Pfizer must be 
promptly notified.


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Document History
Document
Version Date
Summary of Changes and Rationale
Original protocol
17 October 2017
Not applicable (N/A)
Amendment 1
15 November 2019
Section 1: Update of additional study 
information of studies completed after the 
original protocol of 17 October 2017
Rationale: To reflect updated Crisaborole 
knowledge. 
Section 2: Update of the primary and key 
secondary efficacy endpoints to align with 
global clinical development program, 
including: 
•
Change primary endpoint from ISGA 
(Investigator’s Static Global 
Assessment) to EASI (Eczema Area and 
Severity Index).
•
Addition of ISGA as a key secondary 
endpoint.
•
Addition of age specification for Pruritus 
assessments.  
•
 
Section 4.2 and Section 7.2.4: Addition of 
C-SSRS assessment at screening visit to 
exclude the subject with suicidal ideation. 
Rationale: To align with global development 
program.
Section 5.8.1: Addition of requirement that 
prior dupilumab use is exclusionary. 
Rationale: To minimize confounding factors 
on efficacy and safety assessment.
Section 5.8.1, 5.8.2 and 5.8.3: Unified 
requirements on the washout periods of non-
sedating and sedating systemic 
antihistamines as 7 days prior to 
Baseline/Day 1; clarified a stable systemic 
CCI


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antihistamine regimen with at least 7 days of
consistent use prior to Baseline/Day 1 is 
permitted to continue but must not alter or 
stop their regimen during the study.
Section 7.1.4: addition of table Handprint 
Determination of Body Region Surface Area 
to provide more instruction about EASI.
Section 7.1.6: Modify instructions for PROs 
(Patient Reported Outcomes) and remove all 
questionnaires in text.
Rationale: For the purpose of compliance 
with legal requirements for use of 
copyrighted questionnaires while required 
processes are carried out for obtaining 
licenses for their use according to this 
Amendment and current study timelines. 
This will also provide for more simple and 
clear instructions in protocol.
Section 7.2.1: Extend the longest acceptable 
interval period between Screening visit and 
Day 1 for serum chemistry & hematology 
tests from 7 days to 14 days.
Section 9: Update of sample size justification 
and statistical analyses after the change in 
primary efficacy endpoint specified in 
Section 2.
Amendment 2
28 August 2020

Only for Japan: Japan participants who 
complete the study intervention period in 
Study C3291032 will be offered 
participation in the long-term safety 
extension study C3291027 if eligibility 
criteria are met. The participants who 
roll over into study C3291027 without a 
Post Treatment Follow Up period will be 
considered completers in this study.
Rationale: This change is made to allow 
Japan subjects who complete the study 
intervention period in Study C3291032 
and roll over into the long-term safety 
extension study C3291027 to be 


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considered completers in C3291032.
The following sections of the protocol 
are affected: Protocol Summary, 
Schedule of Activities, Section 3, and 
Section 6.4.3.

All female subjects who are of 
childbearing potential as applicable to 
the study who are, in the opinion of the 
investigator, sexually active and at risk 
for pregnancy with their partner(s) must 
agree to use an appropriate method of 
contraception consistently and correctly 
for the screening period, the duration of 
the active treatment period and for at
least 28 days after the last dose of 
investigational product. 
Male condom or female condom used 
with or without a spermicide product (ie, 
foam, gel, film, cream, or suppository) is 
viewed as an appropriate contraceptive 
method.
Rationale: As the crisaborole label does 
not require contraceptive precautions 
and there is no suspicion of human 
teratogenicity based on the intended 
pharmacology, male condom or female 
condom used without a spermicide 
product will be acceptable in this study.
The following sections of the protocol 
are affected: Section 4.2, and Section 
4.4.1.

Subjects who had previous treatment 
with Crisaborole ointment, 2%, or other 
topical or oral PDE-4 inhibitor will be 
excluded.  
Rationale: To enroll PDE-4 inhibitor 
treatment naïve subjects to avoid 
inclusion of participant who has a 
potential lack of efficacy to PDE-4 


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inhibitor. 
The following section of the protocol is 
affected: Section 4.2.

Medications Prohibited 28 Days Prior to 
Baseline/Day 1: Use of systemic JAK 
inhibitor, within 28 days prior to 
Baseline/Day 1.
Rationale: To avoid potential impact of 
systemic JAK inhibitor on AD lesions, 
which may interfere with crisaborole 
efficacy and safety evaluation. 
The following section of the protocol is 
affected: Schedule of Activities and 
Section 5.8.1.

As the documentation of treatable areas 
will be updated for any new AD lesions 
that appear after the Baseline/Day 1 
Visit. The subject and parent/legal 
guardian (if applicable) will be provided 
with documentation of the designated 
treatment areas after the Baseline/Day 1 
Visit, to ensure that previously treated 
areas which have resolved continue to be 
treated as required.  
The following sections of the protocol 
are affected: Schedule of Activities and 
Section 6.4.2. 

If the screening serum chemistry and 
hematology tests are performed within 
14 days 15 days prior to Day 1, whether 
the Day 1 serum chemistry and 
hematology tests are to be performed 
will be at the discretion of the 
investigator or his/her designee. 
Rationale: 14 days is revised to 15 days 
as if a subject happens to take a 
medication that needs to be washed-out 
for 14 days at Day 1, the next possible 
date to start Day 1 is 15 days later. In 


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such case, clinical laboratory tests need 
to be repeated as per the current 
description.
The following section of the protocol is 
affected: Schedule of Activities note l. 

Use of emollients, not only non-
medicated but also medicated emollients 
should also be prohibited within 1 day 
prior to Baseline/Day 1.
Rationale: medicated emollients should 
also be prohibited as it has clear effect 
on AD and may interfere with the 
efficacy and safety evaluation of study 
drug.
The following section of the protocol is 
affected: Section 5.8.1.

Further clarify the definition of 
medication error. 
Rationale: Explain clearly to avoid 
misunderstanding. 
The following section of the protocol is 
affected: Section 8.4.4.1. 

Rationale: Age could differ at screening 
visit vs. inform consent. Age at time of 
inform consent is chosen for the cutoff 
consistently in the protocol.
The following sections of the protocol is 
affected: Schedule of Activities note j,  
Section 4.1, Section 7.1.4, and Section 
7.1.6.

Delete “BL” in the Appendix 1. 
Abbreviations. 
Rationale: The wording “BL” is not used 
in the protocol. 
The following section of the protocol is 


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affected: Appendix 1. Abbreviations. 

The protocol changes specified in 
Protocol Administrative Change Letter 
(29 May 2020) have been incorporated 
in Section 4.4.1, Section 5.8.1, Section 
5.8.2, Section 6.3, Schedule of Activities 
endnote (q), Section 6.4.2, Section 6.4.3, 
Section 6.4.5, Schedule of Activities 
endnote (r), Section 7.1.4, and Section 
7.1.6.1. 
Amendment 3
18 Dec 2020

Change wording “Asia regional/Asia” to 
“China and Japan” and Change wording
“Asian” related to C3291032 study to 
Chinese and Japanese”
Rationale: To make the study description
more precise as only China and Japan 
will participate the study.
The following sections of the protocol 
are affected: Protocol title, Protocol 
summary, Section 1.4, Section 3.

In this China and Japan study, a similar 
study design to the two global pivotal 
studies (AN2728-AD-301 and 
AN2728-AD-302) will be used to 
investigate the efficacy and safety of 
Crisaborole Ointment, 2% twice daily 
(BID) in Chinese and Japanese pediatric 
and adult subjects (ages 2 years and 
older) with mild to moderate AD, to 
support the registration of Crisaborole in 
China and Japan.
Rationale: According to current 
decision, only China and Japan will 
participate the study.
The following sections of the protocol 
are affected: Protocol summary and 
Section 1.4.1.

Delete the content: Only for Japan: 
Japan participants who complete the 


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study intervention period in Study 
C3291032 will be offered participation 
in the long-term safety extension study 
C3291027 if eligibility criteria are met. 
z
Replacement for the deleted content: 
The participants who rolled over into 
study C3291027 without a Post 
Treatment Follow Up period prior to 21 
Oct 2020 are considered completers in 
this study.
Rationale: This change is made based on 
current termination decision on 
C3291027 study for Japan. After 21 Oct 
2020, participants who complete study 
C3291032 will no longer participate in 
C3291027 study.
The following sections of the protocol are 
affected: Protocol Summary, Schedule of 
Activities note t, Section 3, Section 6.4.3 and 
Study Design Schematic
z
Update the sample size and power: The 
total sample size of 384 subjects in this 
study with a 2:1 randomization ratio 
(256:128) will provide approximately 
90% power to detect a 12% difference of 
percent change from baseline in EASI 
total score at Day 29 between 
crisaborole arm and vehicle arm at the 
0.05 (2-sided) significance level  
 
Rationale: Sample size is being reduced 
from 510 to 384 to ensure adequate 
recruitment time within the new country 
footprint while maintaining adequate 
statistical power which will still have a
~90% power to detect the 12%
difference of primary endpoint between 
CCI


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2 arms.
The following sections of the protocol 
are affected: Protocol Summary, Study 
Design Schematic, Section 3 and Section 
9.1.

Other secondary efficacy endpoints 
including change from Baseline in % 
BSA, percent change from baseline in 
EASI total score at all time points other 
than Day 29, change from baseline in 
weekly average of peak pruritus NRS of 
weeks other than Week 4, change from 
baseline in weekly average of Patient 
Reported Itch Severity Scale, and 
change from baseline in weekly average
of Observer Reported Itch Severity Scale 
will be analyzed similarly as the primary 
efficacy endpoints using a linear mixed 
effect model for repeated measures.  
DLQI, CDLQI, IDQOL, DFI, POEM, 
PGIS/OGIS, PGIC/OGIC will be 
summarized descriptively, missing 
values will be handled following 
instrument specific procedures when 
available and as per the SAP.
Rationale: The analysis of other 
secondary endpoints is updated to
include Patient Reported Itch Severity 
Scale and Observer Reported Itch
Severity Scale, and to make the wording 
more precise.

The following section of the protocol is
affected: Section 9.2.3.After the 
Baseline/Day 1 Visit, use of 
emollient(s), moisturizer or sunscreen is 
permitted during the study to manage 
dry skin in areas surrounding but not on 
or overlapping the treatable AD involved 
areas until Day 29.

Use of emollient(s), moisturizer or 


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sunscreen is permitted in the skin of 
whole body after Day 29 telephone 
contact.
Rationale: To clarify that emollient(s), 
moisturizer or sunscreen could not be 
used on treatable area until Day 29. 
After Day 29 telephone visit completed,
emollient(s), moisturizer or sunscreen 
could be used on treatable area.
The following section of the protocol is
affected: Section 5.8.1

Calculate subject’s Treatable %BSA.

Update the documentation of treatable 
areas for any new AD lesions that appear 
after the Baseline/Day 1 Visit. The
subject and parent/legal guardian (if
applicable) will be provided with 
documentation of the designated 
treatment areas, to ensure that previously 
treated areas which have resolved 
continue to be treated as required.
Rationale: Divide above content into 2
paragraphs as to clearly explain the 
separate actions.
The following section of the protocol is 
affected: Section 6.4.2

Calculate subject’s Treatable %BSA 
based on all AD lesions present at 
Day 29, excluding the scalp.
Rationale: Adjust the wording to make it
more concise
The following section of the protocol is 
affected: Section 6.4.3
All nonserious AEs and SAEs occurring 
in a participant during the active 
collection period, which begins after 
obtaining informed consent/assent as 


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described in Section 8.1.4, will be 
recorded on the AE section of the CRF
Rationale: Explain clearly the approach 
of AE recording after informed
consent/assent obtained while 
investigational invention has not been 
initiated. 
The following section of the protocol is 
affected: Section 8.1.4.

Typos correction in below sections: 
Section 1.3.2, Section 3, Section 6.3, 
Section 6.4.1, Section 7.1.1,Section 
7.2.1, Section 8.1.1 and Section 8.1.3.
This amendment incorporates all revisions to date, including amendments made at the
request of country health authorities and institutional review boards (IRBs)/ethics committees
(ECs). 


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TABLE OF CONTENTS
LIST OF TABLES...................................................................................................................15
LIST OF FIGURES .................................................................................................................15
APPENDICES .........................................................................................................................15
PROTOCOL SUMMARY.......................................................................................................17
SCHEDULE OF ACTIVITIES................................................................................................21
1. INTRODUCTION ...............................................................................................................25
1.1. Mechanism of Action/Indication.............................................................................25
1.2. Background .............................................................................................................25
1.3. Drug Development ..................................................................................................27
1.3.1. Nonclinical Studies.....................................................................................28
1.3.3. Cutaneous Sensitization, Irritancy Potential and Tolerability....................29
1.3.4. Clinical Experience.....................................................................................30
1.4. Rationale..................................................................................................................32
1.4.1. Study and Dose Rationale...........................................................................32
1.4.2. Single Reference Safety Document............................................................33
1.5. Anticipated Benefits and Risks ...............................................................................33
2. STUDY OBJECTIVES AND ENDPOINTS.......................................................................35
3. STUDY DESIGN.................................................................................................................36
4. SUBJECT ELIGIBILITY CRITERIA.................................................................................38
4.1. Inclusion Criteria.....................................................................................................39
4.2. Exclusion Criteria....................................................................................................40
4.3. Randomization Criteria ...........................................................................................42
4.4. Lifestyle Requirements ...........................................................................................42
4.4.1. Contraception..............................................................................................42
4.4.2. Other Lifestyle Requirements.....................................................................43
4.5. Sponsor’s Qualified Medical Personnel..................................................................44
5. STUDY TREATMENTS.....................................................................................................44
5.1. Allocation to Treatment ..........................................................................................46
5.2. Breaking the Blind ..................................................................................................46
5.3. Subject Compliance.................................................................................................46
CCI


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5.4. Investigational Product Supplies.............................................................................47
5.4.1. Dosage Form(s) and Packaging..................................................................47
5.4.2. Preparation and Dispensing ........................................................................47
5.5. Administration.........................................................................................................47
5.6. Investigational Product Storage ..............................................................................50
5.7. Investigational Product Accountability...................................................................51
5.7.1. Destruction of Investigational Product Supplies ........................................51
5.8. Prior and Concomitant Treatment(s).......................................................................51
5.8.1. Medications Prohibited Prior to Baseline/Day 1 ........................................52
5.8.2. Medications Prohibited During the Study (Days 1–36) .............................54
5.8.3. Medications Allowed During the Study (Days 1–29) ................................55
6. STUDY PROCEDURES .....................................................................................................56
6.1. Study Visits .............................................................................................................56
6.2. Time Windows for Study Procedures .....................................................................56
6.3. Screening period......................................................................................................56
6.4. Study Period/Treatment Period ...............................................................................60
6.4.1. Baseline/Day 1 Visit...................................................................................60
6.4.2. Day 8 (±1 day), Day 15 (±3 days) and Day 22 (±3 days) Study Visit .......63
6.4.3. Day 29 (±3 days) (End-of-Treatment)/Early termination Study Visit........64
6.4.4. Unscheduled Visit.......................................................................................66
6.4.5. Follow-up Contact/Follow Up Period ........................................................67
6.5. Subject Withdrawal/Early Termination ..................................................................67
7. ASSESSMENTS..................................................................................................................68
7.1. Efficacy Assessments..............................................................................................68
7.1.1. Calculation of Subject’s Treatable %Body Surface Area (BSA) ...............69
7.1.2. Investigator’s Static Global Assessment ....................................................69
7.1.4. Eczema Area and Severity Index (EASI) ...................................................70
7.1.5. Body Site Checklist for Atopic Dermatitis.................................................73
7.1.6. Patient/Observer Reported Outcomes.........................................................73
7.2. Safety Assessments .................................................................................................75
7.2.1. Clinical Laboratory Evaluations.................................................................75
CCI


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7.2.2. Physical Examination, including Height, and Weight................................76
7.2.3. Vital Signs ..................................................................................................77
7.2.4. Columbia Suicide Severity Rating Scale (C-SSRS)...................................77
7.3. Pregnancy Testing...................................................................................................77
8. ADVERSE EVENT REPORTING......................................................................................78
8.1. Requirements...........................................................................................................78
8.1.1. Additional Details on Recording Adverse Events on the CRF...................80
8.1.2. Eliciting Adverse Event Information..........................................................80
8.1.3. Withdrawal from the Study Due to Adverse Events (see also the 
Subject Withdrawal/Early Termination section) ............................................80
8.1.4. Time Period for Collecting AE/SAE Information......................................80
8.2. Definitions...............................................................................................................82
8.2.1. Adverse Events...........................................................................................82
8.2.2. Abnormal Test Findings .............................................................................83
8.2.3. Serious Adverse Events ..............................................................................83
8.2.4. Hospitalization............................................................................................84
8.3. Severity Assessment................................................................................................85
8.4. Special Situations ....................................................................................................86
8.4.1. Protocol-Specified Serious Adverse Events...............................................86
8.4.2. Potential Cases of Drug-Induced Liver Injury............................................86
8.4.3. Exposure to the Investigational Product During Pregnancy or 
Breastfeeding, and Occupational Exposure.....................................................88
8.4.4. Medication Errors .......................................................................................91
9. DATA ANALYSIS/STATISTICAL METHODS...............................................................92
9.1. Sample Size Determination.....................................................................................92
9.2. Efficacy Analysis ....................................................................................................93
9.2.1. Analysis of the Primary Endpoint...............................................................93
9.2.2. Analysis of Key Secondary Endpoints .......................................................93
9.2.3. Analysis of Other Secondary Endpoints.....................................................93
9.3. Safety Analysis........................................................................................................94
9.4. Interim Analysis ......................................................................................................94
9.5. Data Monitoring Committee ...................................................................................95
10. QUALITY CONTROL AND QUALITY ASSURANCE.................................................95


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11. DATA HANDLING AND RECORD KEEPING .............................................................96
11.1. Case Report Forms/Electronic Data Record .........................................................96
11.2. Record Retention...................................................................................................96
12. ETHICS..............................................................................................................................97
12.1. Institutional Review Board/Ethics Committee......................................................97
12.2. Ethical Conduct of the Study ................................................................................97
12.3. Subject Information and Consent..........................................................................97
12.4. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH 
GCP ...........................................................................................................................99
13. DEFINITION OF END OF TRIAL...................................................................................99
13.1. End of Trial in All Participating Countries ...........................................................99
14. SPONSOR DISCONTINUATION CRITERIA ................................................................99
15. PUBLICATION OF STUDY RESULTS..........................................................................99
15.1. Communication of Results by Pfizer ....................................................................99
15.2. Publications by Investigators ..............................................................................100
16. REFERENCES ................................................................................................................102
LIST OF TABLES
Table 1.
Investigator’s Static Global Assessment ..............................................................69
Table 2
Handprint Determination of Body Region Surface Area .....................................70
Table 3.
Eczema Area and Severity Index (EASI) Area Score Criteria.............................71
Table 4.
Clinical Sign Severity Scoring Criteria for the Eczema Area and Severity 
Index (EASI).........................................................................................................72
Table 5.
Clinical Laboratory Test Parameters ....................................................................75
Table 6.
Hanifin and Rajka’s Diagnostic Criteria for Atopic Dermatitis .........................108
LIST OF FIGURES
Figure 1.
Study Design Schematic.......................................................................................38
APPENDICES
Appendix 1. Abbreviations....................................................................................................105
Appendix 2. Diagnostic Criteria for Atopic Dermatitis.........................................................108


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PROTOCOL SUMMARY 
Background and Rationale:
Crisaborole, also referred as PF-06930164 and AN2728, is a low molecular weight 
benzoxaborole antiinflammatory phosphodiesterase4 (PDE4) inhibitor that penetrates into the 
skin to the sites of inflammation.  The primary mechanism of the anti-inflammatory effect of 
crisaborole is through inhibition of PDE-4.  Crisaborole has demonstrated in vitro inhibition 
of a range of cytokines implicated in the pathogenesis of atopic dermatitis (AD).  Crisaborole 
inhibits the release of chemokines that are also important inflammatory mediators.  
Crisaborole applied to human skin ex vivo or on AD lesions on a subject reduces expression 
of key drivers of atopic inflammation including T-cell derived cytokines IL-13, IL-31, and 
interferon gamma (IFN) as well as innate markers of inflammation such as matrix 
metalloproteinase (MMP)12.
Supporting evidence of the safety and efficacy of this product in patients 2 years and older 
represent a major advancement in the treatment of AD given the challenges of managing this 
common, chronic dermatologic condition and the treatment limiting effects of currently 
available therapies. All primary and secondary efficacy endpoints were statistically 
significant in the two Phase 3 registration studies.  Across the development program, 
crisaborole demonstrated an acceptable safety profile, with no crisaborole treatment related 
Serious Adverse Events (SAEs) and with the majority of Adverse Events (AEs) being mild 
and deemed unlikely or not related to investigational product.  
In this China and Japan study, a similar study design to the two global pivotal studies 
(AN2728-AD-301 and AN2728-AD-302) will be used to investigate the efficacy and safety 
of crisaborole ointment, 2% twice daily (BID) in Chinese and Japanese pediatric and adult 
subjects (ages 2 years and older) with mild to moderate AD, to support the registration of
crisaborole in China and Japan.
Objectives and Endpoints:
Primary Objectives
Primary Endpoint(s)

To evaluate the efficacy of 
crisaborole ointment, 2% applied 
BID versus Vehicle in Chinese and 
Japanese pediatric and adult subjects 
(ages 2 years and older) with mild to 
moderate AD.

To evaluate the safety and 
tolerability of crisaborole ointment, 
2% applied BID versus Vehicle in 
Chinese and Japanese pediatric and 
adult subjects (ages 2 years and 
older) with mild to moderate AD.

Efficacy endpoint: Percent Change from Baseline (BL) in 
Eczema Area and Severity Index (EASI) total score at 
Day 29.

Safety endpoint: TEAEs (including application site
reactions) & SAEs, and clinically significant changes in 
vital signs and clinical laboratory parameters.


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Secondary Objectives
Secondary Endpoints
•
To evaluate the effect of crisaborole 
ointment, 2% applied BID versus 
Vehicle on additional efficacy 
endpoints over time in Chinese and 
Japanese pediatric and adults subjects 
(Ages 2 years and older) with mild to 
moderate AD. 
•
To evaluate the effect of crisaborole 
ointment, 2% applied BID versus 
Vehicle on patient/observer reported 
outcomes over time in Chinese and 
Japanese pediatric and adults subjects 
(Ages 2 years and older) with mild to
moderate AD.
•
Efficacy endpoints
•
Key secondary efficacy endpoints:
•
Achievement of Improvement in Investigator’s 
Static Global Assessment (ISGA) (defined as 
ISGA score of clear (0) or almost clear (1)) at 
Day 29.
•
Achievement of Success in ISGA (defined as an 
ISGA score of Clear (0) or Almost Clear (1) with 
at least a 2 grade improvement from Baseline) at 
Day 29
•
Change from Baseline in Peak Pruritus Numeric 
Rating Scale (NRS) at Week 4 - for subjects 
≥12 years.
•
Other secondary efficacy endpoints:
•
Success in ISGA over time.
•
Improvement in ISGA over time.
•
Percent Change from BL in EASI total score over 
time.
•
Change from Baseline in % body surface area
(BSA) over time.
•
Achievement of EASI-50 (≥50% improvement 
from baseline) over time.
•
Achievement of EASI-75 (≥75% improvement 
from baseline) over time.
•
Change from baseline in Peak Pruritus NRS over 
time - for subjects ≥12 years.
•
Change from baseline in Patient Reported Itch 
Severity Scale over time - for subjects ≥6 years 
and <12 years.
•
Change from baseline in Observer Reported Itch 
Severity Scale over time - for subjects <6 years. 
•
DLQI, CDLQI, IDQOL, DFI, POEM, PGIS/OGIS, 
PGIC/OGIC over time. 
 
 
 
 
 
 
 
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Study Design:
This is a Phase 3, multicenter, randomized, double blind, vehicle controlled study to evaluate 
the efficacy and safety of crisaborole ointment, 2% in Chinese and Japanese pediatric and 
adult subjects (ages 2 years and older) with mild to moderate atopic dermatitis involving at 
least 5% treatable BSA.
A total of approximately 384 subjects (approximately 50% for age ≥12 years old and 
approximately 50% for age <12 years old) will be enrolled in the study from multiple sites in 
China and Japan.  Following the screening period (up to 35 days prior to Baseline/Day 1), 
eligible subjects will be randomized at the Baseline/Day 1 visit in a 2:1 ratio to one of 
2 treatment groups (crisaborole ointment, 2% BID; vehicle BID, respectively), the 
investigational product will be applied BID for 28 days to the Treatable BSA identified at 
Baseline/Day 1. Primary efficacy endpoint percent change from baseline in EASI total score 
will be assessed at Day 29.
Scheduled study visits for all subjects will occur at Screening, Baseline/Day 1, Day 8, 
Day 15, Day 22, Day 29 (End of treatment/Early termination).  A follow up telephone call 
will be made by site staff to the subjects/subjects’ legally acceptable guardians on Day 36 
and Day 60 (see Section 6.4.5).
The participants who rolled over into study C3291027 without a Post Treatment Follow Up 
period prior to 21 Oct 2020  are considered completers in this study.
Refer to the Schedule of Activities for a complete list of assessments to be performed during 
the study.
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Statistical Methods:
Sample Size Determination
The total sample size of 384 subjects in this study with a 2:1 randomization ratio (256:128) 
will provide approximately 90% power to detect a 12% difference of percent change from 
baseline in EASI total score at Day 29 between crisaborole arm and vehicle arm at the 
0.05 (2-sided) significance level
 
Analysis of the Primary Endpoint
The primary efficacy endpoint, percent change from baseline in EASI total score at Day 29, 
will be analyzed using a linear mixed-effect model for repeated measures that includes 
treatment group, visit, and treatment group by visit interaction as factors and baseline value 
as a covariate.  Within-subject variability will be accounted for using a random effect with 
the first order autoregressive (AR(1)) covariance matrix.
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SCHEDULE OF ACTIVITIES
The schedule of activities table provides an overview of the protocol visits and procedures.  Refer to the STUDY PROCEDURES and 
ASSESSMENTS sections of the protocol for detailed information on each procedure and assessment required for compliance with the 
protocol. 
The investigator may schedule visits (unplanned visits) in addition to those listed on the schedule of activities table, in order to 
conduct evaluations or assessments required to protect the well-being of the subject. 
Day
[relative to start of study treatment (Day 1)]
Within 35 days 
prior to 
Day 1
Day 1
Day 8
Day 15
Day 22
Day 29t
Day 36
Day 60
Window
±1 d
±3 d
±3 d
±3 d
±3 d
±3 d
Visit
Screeningq
Baseline
End of Treatment/
Early Termination
Follow up 
telephone
Contactr
Follow up 
telephone 
contactr
Informed consent, including assent 
X
Demographics
X
Height and weight
X
x
Review of Inclusion and Exclusion Criteria 
X
x
Medical history
X
x
Prior and concomitant medications
xa
x
X
x
x
X
x
x
Vital signsb
X
x
x
X
Physical examination 
xc
xd
xc
Calculate Treatable %BSA 
X
x
X
x
x
x
Serious and non-serious adverse event monitoring
X
x
X
x
x
x
x
X
ISGAe
X
x
X
x
x
x
EASIe
x
X
x
x
x
Record treatable AD areas (excluding scalp) in source 
and provide subjects and/or parent(s)/legal guardian 
with documentation of the designated treatment areasu
x
X
X
X
X
Body Site checklist of AD lesions
x
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Day
[relative to start of study treatment (Day 1)]
Within 35 days 
prior to 
Day 1
Day 1
Day 8
Day 15
Day 22
Day 29t
Day 36
Day 60
Window
±1 d
±3 d
±3 d
±3 d
±3 d
±3 d
Visit
Screeningq
Baseline
End of Treatment/
Early Termination
Follow up 
telephone
Contactr
Follow up 
telephone 
contactr
Peak Pruritus Numerical Rating Scale (NRS), Patient
Reported Itch Severity Scale OR Observer Reported 
Itch Severity Scaleg
Daily During 
Screening
To be captured daily from Day 1 to Day 29
Patient Global Impression of Severity (PGIS) OR 
Observer Reported Global Impression of Severity 
(OGIS)h
Daily During 
Screening
To be captured daily from Day 1 to Day 29
Patient Global Impression of Change (PGIC) OR 
Observer Reported Global Impression of Change 
(OGIC)i
x
x
x
x
CDLQI/DLQI/IDQOL, DFIj
X
x
x
x
Patient Oriented Eczema Measure (POEM)s
X
x
x
x
Columbia Suicide Severity Rating Scale (C-SSRS)k
X
Serum chemistry and hematology
X
xl
x
Urine pregnancy test (in female subjects of 
childbearing potential only)m
X
x
x
FSH (to confirm postmenopausal status in females 
who are amenorrheic for at least 12 consecutive 
months)
X
Randomization
x
In-clinic dosing instruction
x
x
x
x
In-clinic dose application by study staff (1st dose 
[preferred AM]n)
x
At-home dosing, applied by subject or 
parent/legal guardian, as appropriateo
2nd dose (PM) on Day 1, then BID through 
Day 28n
Dispense Dosing Diary 
x
x
x
x
Obtain and review Dosing Diary data and assess 
compliance
x
x
x
x
Weigh investigational product tube(s) and dispense for
at-home dosing
x
x
x
x


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Day
[relative to start of study treatment (Day 1)]
Within 35 days 
prior to 
Day 1
Day 1
Day 8
Day 15
Day 22
Day 29t
Day 36
Day 60
Window
±1 d
±3 d
±3 d
±3 d
±3 d
±3 d
Visit
Screeningq
Baseline
End of Treatment/
Early Termination
Follow up 
telephone
Contactr
Follow up 
telephone 
contactr
Collect and weigh returned investigational product 
tube(s)
x
x
x
x
Contraception Check
X
x
x
x
x
x
x
X
a.
Record all treatments (including medications and non-medication therapies) used for AD 90 days prior to screening and all other medications (including bland [non-
medicated] emollients, over-the-counter drugs, vitamins, and antacids) used within 30 days prior to Screening. 
b.
Temperature, respiratory rate, pulse rate, and blood pressure taken in the seated or supine position, after the subject has been sitting or lying calmly for a minimum of 
5 minutes.  Position of recording must be consistent within subject through-out the study.  At Baseline/Day 1 and Day 29, assessment of vital signs should precede blood draw 
for clinical laboratory tests.
c.
Full physical examination including, but is not limited to the following organ or body systems: head, ears, eyes, nose, mouth, skin, heart and lung examinations, lymph nodes, 
musculoskeletal, abdomen (liver, spleen), and neurological systems.  In addition, an assessment will be made of the condition of all AD involved skin.
d.
Disease focused physical examination of all AD involved skin (in treatable and non-treatable areas) and evaluate any current or reported symptoms for clinically significant
changes.
  
 
g.
Peak Pruritus NRS will be completed by subject (≥12 years), Patient Reported Itch Severity Scale will be completed by the subject (≥6 years and <12 years.), and Observer 
Reported Itch Severity Scale will be completed by observer [parent/legal guardian/other caregiver] when applicable) for patients <6 years in screening once daily prior to 
Day 1, and once daily from Day 1 to Day 29 before IP morning dose application preferably at the same time of each day if applicable. 
h.
PGIS will be completed by the subject (≥12 years) or OGIS will be completed by observer (for subjects 2-11 years) once daily preferably at the same time as the Pruritus NRS.
i.
PGIC will be completed by the subject (≥12 years) or OGIC will be completed by observer (for subjects 2-11 years) at the same day when ISGA was assessed post baseline. 
j.
The CDLQI will be completed by subject or observer for subjects aged 4–15 years, based on the age at time of informed consent/assent.  The DLQI will be completed by all 
subjects aged 16 years and older, based on the age at time of informed consent/assent.  IDQOL will be completed by observer for subjects aged 2-3 years based on age at time 
of informed consent/assent.  The DFI will be completed by observer for subjects aged 2–17 years, based on the age at time of informed consent/assent.
k.
Investigator completed C-SSRS for subjects ≥7 years old.
l.
Blood draw for clinical laboratory tests (serum chemistry and hematology) on Day 1 will be performed before the in-clinic investigational product application. If the screening 
serum chemistry and hematology tests are performed within 15 days prior to Day 1, whether the Day 1 serum chemistry and hematology tests are to be performed will be at 
the discretion of the investigator or his/her designee.
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m.
Urine pregnancy testing (-hCG) is required only for women of childbearing potential: test may be repeated as per request of IRB/IECs, if required by local regulations, if a 
menstrual cycle is missed, or if potential pregnancy is otherwise suspected or at the discretion of the investigator or his/her designee.  Urine pregnancy testing will be 
performed at the site.  Pediatric female subject who has not experienced menarche is not required to perform pregnancy testing. If the Pediatric female subject starts menarche 
during the study, pregnancy testing will be performed.
n.
In special situation if the subject come to the clinic in the afternoon, two doses (8-16 hours apart) or single dose could be administered on Day 1, if single dose is administered 
on Day 1, a morning dose will be applied at Day 29 for these special subjects.
o.
In the event the scheduled Day 29 (End of Treatment) Visit does not occur on Day 29, eg, due to an unavoidable scheduling conflict, the subject and/or parent/legal guardian 
will be instructed to continue investigational product application BID through the evening before the day that the rescheduled End of Treatment Visit is to occur.
p.
During study visits at Day 8, Day 15, and Day 22, re-educate subject and/or parent/legal guardian if any investigational product doses were missed during the interval since 
the previous study visit.
q.
Peak Pruritus NRS/Patient Reported Itch Severity Scale/Observer Reported Itch Severity Scale, PGIS/OGIS, DLQI, CDLQI, IDQOL, DFI, POEM and ISGA will be collected 
at screening for all subjects including screen failure subjects. If a subject is screen failed before above procedures are completed, then related data will not be collected.
r.
The follow up telephone contact will be performed 7 (±3) days and 31 (±3) days after the End of treatment/Early Termination visit.
s.
POEM will be completed by subject (POEM for self-completion for subjects ≥12 years) or observer (POEM for proxy completion for subjects 2-11 years).
t.
The participants who rolled over into study C3291027 without a Post Treatment Follow Up period prior to 21 Oct 2020 are considered completers in this study.
u.
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 source document study records.  The subject and parent/legal guardian (if applicable) will be provided with documentation of the designated treatment areas, to 
ensure that previously treated areas which have resolved continue to be treated as required.  The documentation of treatable areas will be updated for any new AD lesions that 
appear after the Baseline/Day 1 Visit.          


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1. INTRODUCTION
1.1. Mechanism of Action/Indication
Crisaborole, also referred to as PF-06930164 and AN2728, is a low molecular weight 
benzoxaborole anti-inflammatory phosphodiesterase 4(PDE 4) inhibitor that penetrates into 
the skin to the sites of inflammation and is currently being investigated for topical treatment 
in patients with mild to moderate atopic dermatitis.  The primary mechanism of the anti-
inflammatory effect of crisaborole is through inhibition of PDE-4.  Crisaborole has 
demonstrated in vitro inhibition of a range of cytokines implicated in the pathogenesis of 
AD.  Crisaborole inhibits the release of chemokines that are also important inflammatory 
mediators.  Crisaborole applied to human skin ex vivo or on AD lesions on a subject reduces 
expression of key drivers of atopic inflammation including T-cell derived cytokines IL-13, 
IL-31, and IFNas well as innate markers of inflammation such as MMP-12.
Crisaborole ointment, 2% (weight by weight) (20 mg/g) (referred to as crisaborole hereafter), 
is an approved therapy in the United States (US) and Canada (EUCRISA®), and Israel and 
Australia (STAQUIS®) as a topical treatment therapy in patients 2 years of age and older 
with mild-to-moderate AD.  It is currently being developed worldwide as a topical therapy 
for patients with mild to moderate AD.
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 and Japan.3,4  The prevalence rate of atopic dermatitis is 
gradually increasing in recent 20 years in China and the total prevalence rate in the school 
age population 6-20 years old was 0.69% in 19985 and the prevalence rate in the preschool 
age children (1-7 years) in 10 cities was 2.78% in 2002,6 however, the epidemiological 
survey in Shanghai district in 2012 revealed that the prevalence rate was up to 8.3% in the 
3-6 years old children,7 a recent national survey revealed that the prevalence of AD was 
12.94% in the 1-7 years old children by clinical diagnosis of dermatologists.8
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.9  Manifestation of the disease includes intense pruritus, erythematous 
papules, excoriation, exudation, lichenification, and bacterial colonization.10  Continuous 


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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.11,12  The burden of the clinical symptoms of AD coupled with the stigma 
associated with highly visible skin lesions correlates with significant morbidity and extensive 
impairments on health related quality of life measures (HRQOL) for patients, especially in 
children, and caregivers.1,13,14,15  Psychosocial problems, depression, and anxiety are 
associated with AD in both adults and children.16
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.2,14,17  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.18,19  AD is often 
associated with significant childhood behavioral problems and psychological disorders 
including depression, attention deficit hyperactivity disorder, anxiety, stress, and autism.16  
Preschool children with AD show a significant increase in behavioral symptoms compared 
with matched controls.21  Absolon et al22 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 wellbeing 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 burden23 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 
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Crisaborole Ointment, 2% was developed by Anacor Pharmaceuticals, Inc. (Anacor), Palo 
Alto, California, USA, which became a wholly owned subsidiary of Pfizer Inc. on 
24 June 2016. 
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.24  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. 
1.3. Drug Development 
Crisaborole ointment, 2% is an oxaborole compound developed as a topical 
antiinflammatory- agent.  It demonstrates in vitro inhibition of a wide range of 
proinflammatory 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-23.25  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.25  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.  Crisaborole also inhibits the release of chemokines that are 
important inflammatory mediators.  The primary mechanism of the antiinflammatory effect 
of crisaborole is through inhibition of PDE4, which causes elevation of cAMP in leukocytes 
and subsequent protein kinase A (PKA)mediated phosphorylation of transcription factors that 
are important for cytokine, chemokine, or prostaglandin forming enzyme synthesis and 
release from cells.  Crisaborole proved efficacious against an inflammatory challenge in vivo 
in a mouse PMA induced ear edema model.  AN8323, a metabolite of crisaborole, lacks 
antiinflammatory activities against PDE4 and a panel of cytokines. 
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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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 
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 
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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.  
In addition, the similar results were observed from Japan study C3291029 Cohort 1.  In this 
study, crisaborole ointment 2% and vehicle were applied topically to 1-side of the 
intrascapular area of the back once on Day 1 and remained under occlusion for 48 hours 
(Cohort 1 in Study C3291029) to Japanese healthy participants.  The skin irritancy was to be 
evaluated approximately 30 minutes after removal of the patches on Day 3 and 24 hours after 
removal of the patches on Day 4.  The degree of erythema, edema and other signs of skin 
irritation at the application site was evaluated using the visual scale.  All participants for the 
crisaborole ointment 2% patch had a maximum irritation score of 0 (No reaction) or 
0.5 (Mild erythema) except for the 3 participants with a maximum irritation score of 
2 (Erythema + edema, papule).
Overall, Crisaborole ointment, 2% and vehicle showed no evidence of sensitization and only 
very minimal irritation.
1.3.4. Clinical Experience
Eight (8) clinical trials of topical formulations of crisaborole have been completed to date in 
subjects 2 years of age and older with mild to moderate AD.  Key study information is 
summarized below.
 
 
 
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•
In a 6-week bilateral comparison trial of subjects with mild to moderate AD, 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 6-week, randomized, vehicle-controlled intra-subject efficacy and biomarker 
study of adult subjects with mild to moderate AD (C3291001), crisaborole ointment, 
2% applied BID statistically significantly improved lesion Target Sign Scores (TSS) 
more than vehicle at Day 15 (primary efficacy endpoint).  Crisaborole significantly 
reduced 7 key skin biomarkers of AD from Baseline to Day 15 (primary biomarker 
endpoint).
•
In a 4-week bilateral comparison trial of 86 adolescent subjects with mild to moderate 
AD, crisaborole ointment, 2% BID showed greater improvement than the lower 
concentration of crisaborole ointment, 0.5% applied BID for 29 days, and was more 
efficacious than either concentration applied once daily (QD). 
•
In two Phase 3 multicenter, randomized, doubleblind, 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 ISGA at Day 29.  Success was defined as an Investigator’s Static Global 
Assessment (ISGA) score of Clear (0) or Almost Clear (1) with at least a 2 grade 
improvement over baseline.  Proportion of success was 32.8% and 25.4% for 
crisaborole ointment, 2% and vehicle, respectively in AN2728-AD-301 and 
31.4% and 18.0%, respectively in AN2728-AD-302.  Differences from vehicle were 
statistically significant in both studies. 
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
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. 
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 
drugrelated AEs was application site pain (eg, cutaneous stinging and or burning). 
Refer to the Investigator Brochure for further information on the clinical experience with 
crisaborole ointment, 2%.25
1.4. Rationale
1.4.1. Study and Dose Rationale 
In this China and Japan study, a similar study design to the two global pivotal studies 
(AN2728-AD-301 and AN2728-AD-302) will be used to investigate the efficacy and safety 
of Crisaborole Ointment, 2% twice daily (BID) in Chinese and Japanese pediatric and adult 
subjects (ages 2 years and older) with mild to moderate AD, to support the registration of 
Crisaborole in China and Japan.
Dose selection for the global pivotal clinical studies was based on safety and efficacy results 
from Phase 2 studies, and the dose selected was later confirmed to be safe and effective for 
commercialization by the results of the Phase 3 studies.
Phase 2 Study AN2728-AD-204 compared two concentrations of crisaborole (2% and 0.5%) 
applied QD or BID in adolescents with mild to moderate AD.  The largest dose-related 
response and the greatest improvement in all 5 component signs and symptoms of AD 
occurred in the crisaborole 2% BID group, with a notable reduction from baseline in the 
pruritus score.
The 2% dosage strength of the crisaborole ointment formulation administered BID was 
selected for study in Phase 3 as the highest well-tolerated dose to maximize the potential for 
efficacy with minimal safety risk.  Results from the Phase 3 trials in which subjects aged 
2 years and older with mild to moderate AD were dosed BID for 28 days with Crisaborole 


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Ointment, 2% confirm the safety and efficacy of this formulation strength and dosing 
regimen in subjects with mild to moderate AD (AN2728-AD-301, AN2728-AD-302).  
Long-term (up to 12 months) intermittent use in this patient population was shown to be safe 
in a 48-week long -term safety study (AN2728-AD-303).
The safety of the 2% dosage strength was confirmed in additional studies, including maximal 
use systemic exposure (MUSE) studies (pediatric subjects with AD and adult subjects with 
psoriasis) and with supra-therapeutic dosing in a TQT study (healthy adult subjects).  In the 
pooled Phase 3 registration studies, higher rates of success in ISGA at Day 29 were observed 
in the crisaborole group than in the vehicle group for the subgroups of sex, age, race, and 
ethnicity.  The proportion of Asian subjects is around 5%, similar trend was observed in the 
Asian subgroup of the pooled global pivotal studies, with a success in ISGA of 17.3% in the 
crisaborole group and 11.1% in the vehicle group.  The safety profile of crisaborole was not 
affected by age, sex, ethnicity, or race.  
 
 
 
  
This China and Japan Phase 3 study will evaluate the same dosing regimen which was 
investigated in the global pivotal Phase 3 studies.
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 crisaborole Investigator’s Brochure.
1.5. 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.
CCI


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
The satisfactory safety and local tolerability demonstrated in non-clinical and clinical 
studies conducted with crisaborole ointment, 2% to date.
The main benefit for subjects participating in this study is based on access to regular clinical 
assessments and active atopic disease management as well as expected efficacy of treatment 
with crisaborole during the study, in which the safety will be monitored appropriately.  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.


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2. STUDY OBJECTIVES AND ENDPOINTS
Primary Objectives
Primary Endpoint(s)

To evaluate the efficacy of 
crisaborole ointment, 2% applied 
BID versus Vehicle in Chinese and 
Japanese pediatric and adult subjects 
(ages 2 years and older) with mild to 
moderate AD.

To evaluate the safety and 
tolerability of crisaborole ointment, 
2% applied BID versus Vehicle in 
Chinese and Japanese pediatric and 
adult subjects (ages 2 years and 
older) with mild to moderate AD.

Efficacy endpoint: Percent Change from Baseline in 
Eczema Area and Severity Index (EASI) total score at 
Day 29.

Safety endpoint: TEAEs (including application site 
reactions) & SAEs and clinically significant changes in 
vital signs and clinical laboratory parameters.
Secondary Objectives
Secondary Endpoints

To evaluate the effect of crisaborole 
ointment, 2% applied BID versus 
Vehicle on additional efficacy 
endpoints in Chinese and Japanese
pediatric and adults subjects 
(Ages 2 years and older) with mild 
to moderate AD. 

To evaluate the effect of crisaborole 
ointment, 2% applied BID versus 
Vehicle on patient/observer reported 
outcomes over time in Chinese and 
Japanese pediatric and adults 
subjects (Ages 2 years and older) 
with mild to moderate AD.

Efficacy endpoints.

Key secondary efficacy endpoints.

Achievement of improvement in ISGA (defined as 
ISGA score of clear (0) or almost clear (1)) at 
Day 29.

Achievement of Success in ISGA (defined as an 
ISGA score of Clear (0) or Almost Clear (1) with 
at least a 2 grade improvement from Baseline) at 
Day 29.

Change from Baseline in Peak Pruritus Numeric 
Rating Scale (NRS) at Week 4 - for subjects 
≥12 years.

Other secondary efficacy endpoints.

Success in ISGA (defined as an ISGA score of 
Clear (0) or Almost Clear (1) with at least a 
2 grade improvement from Baseline) over time.

Improvement in ISGA (defined as ISGA score of 
clear (0) or almost clear (1)) over time.

Percent Change from BL in EASI total score over 
time.

Change from Baseline in % BSA over time.

Achievement of EASI-50 (≥50% improvement 
from baseline) over time.


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•
Achievement of EASI-75 (≥75% improvement 
from baseline) over time.
•
Change from baseline in Peak Pruritus NRS over 
time - for subjects ≥12 years.
•
Changes from baseline in Patient Reported Itch 
Severity Scale over time - for subjects ≥6 years 
and <12 years.
•
Change from baseline in Observer Reported Itch 
Severity Scale over time - for subjects <6 years.
•
DLQI, CDLQI, IDQOL, DFI, POEM, PGIS/OGIS, 
PGIC/OGIC over time.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
3. STUDY DESIGN
This is a Phase 3, multicenter, randomized, double-blind, vehicle-controlled study to evaluate 
the efficacy and safety of crisaborole ointment, 2% in Chinese and Japanese pediatric and 
CCI


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adult subjects (ages 2 years and older) with mild to moderate atopic dermatitis involving at 
least 5% treatable BSA.
A total of approximately 384 subjects (approximately 50% for age ≥12 years old and 
approximately 50% for age <12 years old) will be enrolled in the study from multiple sites in 
China and Japan.  Following the screening period (up to 35 days prior to Baseline/Day 1), 
eligible subjects will be randomized at the Baseline/Day 1 visit in a 2:1 ratio to one of 
2 treatment groups (crisaborole ointment, 2% BID; vehicle BID, respectively), the 
investigational product will be applied BID for 28 days to the Treatable BSA identified at 
Baseline/Day 1 and new AD lesions that appear after the Baseline/Day 1.  The primary 
efficacy endpoint, percent change from baseline in EASI total score, will be assessed at 
Day 29.


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Scheduled study visits for all subjects will occur at Screening, Baseline/Day 1, Day 8, 
Day 15, Day 22, Day 29 (End of treatment/Early termination).  A follow up telephone call 
will be made by site staff to the subjects and/or parents/legal guardians on Day 36 and 
Day 60 (See Section 6.4.5). 
Japan participants who rolled over into study C3291027 without a Post Treatment Follow Up 
period prior to 21 Oct 2020 are considered completers in this study.A schematic of the study 
design is shown in Figure 1.
Figure 1.
Study Design Schematic 
4. SUBJECT ELIGIBILITY CRITERIA
This study can fulfill its objectives only if appropriate subjects are enrolled.  The following 
eligibility criteria are designed to select subjects for whom participation in the study is 
considered appropriate.  All relevant medical and nonmedical conditions should be taken into 
consideration when deciding whether a particular subject is suitable for this protocol. 
Subject eligibility should be reviewed and documented by an appropriate member of the 
investigator’s study team before subjects are included in the study. 
n ≈128
n ≈256
Japan participants who rolled over into study 
C3291027 without a Post Treatment Follow Up period
prior to 21 Oct 2020 are considered completers in this 
study.


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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 and the appropriate age in years (2 years and older) at time of 
informed consent/assent.
2. Has a clinical diagnosis of AD according to the criteria of Hanifin and Rajka (See 
Appendix 2).
3. Has AD involvement of ≥5% Treatable BSA (excluding the scalp) at Baseline/Day 1.
4. Has an ISGA score of Mild (2) or Moderate (3) (excluding the scalp) at 
Baseline/Day 1.
5. Has adequate venous access to permit venipuncture for clinical safety laboratory 
sampling.
6. Female subjects of childbearing potential who have a negative urine pregnancy test at 
the screening visit and negative urine pregnancy test at the baseline visit prior to 
randomization.  A female is of childbearing potential if, in the opinion of the 
investigator, she is biologically capable of having Children (includes any female who 
has experienced menarche and does not meet the criteria for females not of 
childbearing potential.  Female subjects of non-childbearing potential must meet at 
least 1 of the following criteria:
a.
Achieved postmenopausal status, defined as follows: cessation of regular menses 
for at least 12 consecutive months with no alternative pathological or 
physiological cause; have a serum follicle stimulating hormone (FSH) level 
confirming the postmenopausal state;
b. Have undergone a documented hysterectomy and/or bilateral oophorectomy; 
c.
Have medically confirmed ovarian failure. 
7. Evidence of a personally signed and dated informed consent/assent document 
indicating that the subject [or parent(s)/legal guardian] has been informed of all 
pertinent aspects of the study. 
8. Willing and able to comply with scheduled visits, treatment plan, laboratory tests and 
other study procedures.


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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 medical disorder, condition, or disease (including active 
or potentially recurrent non-AD dermatological conditions and known genetic 
dermatological conditions that overlap with AD, such as Netherton syndrome) or 
clinically significant physical examination finding at Screening that in the PI’s or 
designee’s opinion may interfere with study objectives (eg, expose subject to 
unacceptable risk by study participation, confound evaluation of treatment response 
or AEs, or interfere with subject’s ability to complete the study).
2. Has unstable AD or any consistent requirement for high/strong potency or very 
high/very strong potency topical corticosteroids to manage AD signs and symptoms. 
3. Has a history of angioedema or anaphylaxis.
4. Has a significant active systemic or localized infection, including known actively 
infected AD.
5. Has received any of the prohibited medications/therapies that may alter the course of 
AD without the required minimum washout (see Section 5.8.1) or anticipated 
concomitant use of the any of the prohibited medications/therapy (see Section 5.8.2).
6. Has any planned surgical or medical procedure that would overlap with study 
participation, from Screening through the end of study.
7. Has history of cancer within 5 years or 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).
8. Has a known sensitivity to any of the components of the investigational product.
9. Has participated in a previous crisaborole clinical study or had previous treatment 
with Crisaborole ointment, 2%, or other topical or oral PDE-4 inhibitors.
10. Investigator site staff members directly involved in the conduct of the study and their 
family members, site staff members otherwise supervised by the investigator, or 
subjects who are Pfizer employees, including their family members, directly involved 
in the conduct of the study.


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11. Participation in other studies involving investigational drug(s) within 30 days prior to 
study entry and/or during study participation.
12. Other acute or chronic medical or psychiatric condition including history of or active 
suicidal ideation or behavior or laboratory abnormality that may increase the risk 
associated with study participation or investigational product administration or may 
interfere with the interpretation of study results and, in the judgment of the 
investigator, would make the subject inappropriate for entry into this study including 
the following:

For subjects 7-11 years of age, suicidal ideation associated with actual intent and 
a method or plan in the past 6 months: “Yes” answers on items 4 or 5  of the 
Columbia suicide severity rating scale (C-SSRS) or a previous history of suicidal 
behaviors in their lifetime: “Yes” answer to any of the suicidal behavior items of 
the C-SSRS.  


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
For subjects ≥12 years of age, suicidal ideation associated with actual intent and a 
method or plan in the past year: “Yes” answers on items 4 or 5 of the C-SSRS or a 
previous history of suicidal behaviors in the past 5 years: “Yes” answer (for 
events that occurred in the past 5 years) to any of the suicidal behavior items of 
the C-SSRS

For younger subjects under 7 years of age, subject has suicidal ideation and 
behavior risks assessed clinically and in consultation with their parents/caregivers
13. Pregnant female subjects; breastfeeding female subjects; and female subjects of 
childbearing potential who are unwilling or unable to use an appropriate method of 
contraception as outlined in this protocol for the duration of the study and for at least 
28 days after the last dose of investigational product.
4.3. Randomization Criteria 
Subject will be randomized into the study provided that the subject [or parent(s)/legal 
guardian] has signed an informed consent (or assent, if applicable) document to participate in 
the study, and the subject has undergone all screening procedures, and meets all inclusion 
and exclusion criteria for participation in the study at the baseline visit.  A centralized 
computer generated randomization schedule will be used to assign subjects to the treatment 
groups.  Subjects will be randomized in a 2:1 ratio to one of the 2 parallel treatment groups 
(Crisaborole ointment, 2% BID or Crisaborole placebo vehicle ointment BID).
Subjects will be assigned a subject identification number in the order of their screening for 
the study.  The identifying number will be retained throughout the study.
4.4. Lifestyle Requirements 
4.4.1. Contraception
All female subjects who are of childbearing potential as applicable to the study who are, in 
the opinion of the investigator, sexually active and at risk for pregnancy with their partner(s) 
must agree to use an appropriate method of contraception consistently and correctly for the 
screening period, the duration of the active treatment period and for at least 28 days after the 
last dose of investigational product.  The investigator or his or her designee, in consultation 
with the subject, will confirm that the subject has selected an appropriate method of 
contraception for the individual subject from the permitted list of contraception methods (see 
below) and will confirm that the subject has been instructed in its consistent and correct use.  
At time points indicated in the Schedule of Activities, the investigator or his/her designee 
will inform the subject of the need to use an appropriate contraceptive method consistently 
and correctly and document the conversation and the subject’s affirmation in the subject’s 


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chart (subjects needs to affirm their consistent and correct use of at least 1 of the selected 
methods of contraception).  In addition, the investigator or his/her designee will instruct the 
subject to call immediately if the selected contraception method is discontinued or if 
pregnancy is known or suspected in the subject or the partner. 
Contraceptives allowed during the study include:
1. Established use of hormonal methods of contraception associated with inhibition of 
ovulation (eg, oral, inserted, injected, implanted, transdermal) provided the subject 
plans to remain on the same treatment throughout the entire study and has been using 
that hormonal contraceptive for an adequate period of time to ensure effectiveness. 
2. Correctly placed copper containing intrauterine device (IUD). 
3. Male condom or female condom used with or without a spermicide product (ie, foam, 
gel, film, cream, or suppository).  
4. Male sterilization with absence of sperm in the post vasectomy ejaculate.
5. Bilateral tubal ligation/bilateral salpingectomy or bilateral tubal occlusive procedure 
(provided that occlusion has been confirmed in accordance with the device’s label).
NOTE: Sexual abstinence, defined as completely and persistently refraining from all 
heterosexual intercourse (including during the entire period of risk associated with the study 
treatments) may obviate the need for contraception ONLY if this is the preferred and usual 
lifestyle of the subject.
4.4.2. Other 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.

Subjects should not swim, be bathed or have treatment areas washed for at least 
4 hours after application of investigational product.

Use of sunscreen is permitted, but only on areas without AD involvement.


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
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. 

When applying investigational product, the parent(s)/legal guardian will not be 
required to wear gloves when applying investigational product at home.  However, 
they must be instructed to wash their hands with mild soap and water before and after 
each application.
4.5. Sponsor’s Qualified Medical Personnel
The contact information for the sponsor's appropriately qualified medical personnel for the 
study is documented in the study contact list located in the supporting study documentation. 
To facilitate access to appropriately qualified medical personnel on study related medical 
questions or problems, subjects are provided with a contact card.  The contact card contains, 
at a minimum, protocol and investigational product identifiers, subject study numbers, 
contact information for the investigator site, and contact details for a contact center in the 
event that the investigator site staff cannot be reached to provide advice on a medical 
question or problem originating from another healthcare professional not involved in the 
subject’s participation in the study.  The contact number can also be used by investigator 
staff if they are seeking advice on medical questions or problems; however, it should be used 
only in the event that the established communication pathways between the investigator site 
and the study team are not available.  It is therefore intended to augment, but not replace, the 
established communication pathways between the investigator site and the study team for 
advice on medical questions or problems that may arise during the study.  The contact 
number is not intended for use by the subject directly, and if a subject calls that number, he 
or she will be directed back to the investigator site.
5. STUDY TREATMENTS
For the purposes of this study, and per International Conference on Harmonisation (ICH) 
guidelines, investigational product is defined as a pharmaceutical form of an active 
ingredient or placebo being tested or used as a reference/comparator in a clinical trial, 
including a product with a marketing authorization when used or assembled (formulated or 
packaged) in a way different from the approved form, or when used for an unapproved 
indication, or when used to gain further information about an approved use (ICH E6 1.33). 
For this study, investigational products are the following:

Crisaborole ointment, 2%, also referred to as active.


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
Crisaborole placebo vehicle ointment, referred to as vehicle.
Crisaborole ointment, 2%, is formulated to contain PF-06930164 (2% wt/wt), white 
petrolatum, propylene glycol, mono and diglycerides, paraffin wax, butylated 
hydroxytoluene, and edetate calcium disodium. 
Vehicle (no active drug in the formulation) contains white petrolatum, propylene glycol, 
mono- and diglycerides, paraffin wax, butylated hydroxytoluene, and edetate calcium 
disodium.


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5.1. Allocation to Treatment
Allocation of subjects to treatment groups will proceed through the use of an interactive 
response technology (IRT) system (interactive Web-based response [IWR]).  The site 
personnel (study coordinator or specified designee) will be required to enter or select 
information including but not limited to the user’s identification (ID) and password, the 
protocol number, and the subject number.  The site personnel will then be provided with a 
treatment assignment, randomization number, and dispensable unit (DU) or container number 
when investigational product is being supplied via the IRT system.  The IRT system will 
provide a confirmation report containing the subject number, randomization number, and DU 
or container number 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. Breaking the Blind

The study will be subject, and investigator blinded.

At the initiation of the study, the investigator site will be instructed on the method for 
breaking the blind.  The method will be an electronic process.  Blinding codes should 
be broken only in exceptional circumstances when knowledge of the actual treatment 
code is absolutely essential for further management of the subject.  Investigators are 
encouraged to discuss with a member of the study team if they believe that unblinding 
is necessary.  When the blinding code is broken, the reason must be fully documented 
and entered on the case report form (CRF).
5.3. Subject Compliance
Subject/a parent/legal guardian will apply crisaborole ointment, 2% or Vehicle to the subject 
at home; compliance will be captured and completed by the subject/parent/legal 
guardian/legally acceptable representative using a dosing diary provided by the site.  The 
subject and parent/legal guardian (if applicable) will be instructed to complete the Dosing 
Diary starting with the first dose applied in the clinic on Day 1, then BID through Day 28 
(ie, each time investigational product is applied) for the investigational product doses applied 
at home.  In special situation if the subject come to the clinic in the afternoon, two doses 
(8-16 hours apart) or single dose could be administered on Day 1, if single dose is 
administered on Day 1, a morning dose will be applied at Day 29 for these special subjects in 
order to keep 56 doses.  Subjects and parents/legal guardians (if applicable) will be instructed 
to bring the Dosing Diary and all dispensed investigational product supplies to the clinic at 
Days 8, 15, 22, and 29.


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A subject will be considered compliant with the dosing regimen if the subject applies at least 
80% but no more than 120% of the expected applications during the investigational product 
application period and has not missed 6 or more consecutive doses.  This will be verified by 
the dosing records.  Subjects having missed doses of IP will be re-educated on the 
importance of compliance.
5.4. Investigational Product Supplies
5.4.1. Dosage Form(s) and Packaging
Crisaborole Ointment, 2% and vehicle ointment will be supplied in 60 g tubes for topical 
administration.  The tubes will be provided in cartons and labeled in a blinded fashion 
according to local regulatory requirements.
5.4.2. Preparation and Dispensing
Within this protocol, preparation refers to the investigator site activities performed to make 
the investigational product ready for administration or dispensing to the subject/caregiver by 
qualified staff.  Dispensing is defined as the provision of investigational product, 
concomitant treatments, and accompanying information by qualified staff member(s) to a 
healthcare provider, subject, or caregiver in accordance with this protocol.  Local health 
authority regulations or investigator site guidelines may use alternative terms for these 
activities.
The investigational product will be dispensed in a blinded fashion using an IRT system at 
each visit from Baseline/Day 1 to the Day 22 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 (parents/legal guardians) should be 
instructed to maintain the product in the package provided throughout the course of dosing 
and return the product (including empty, partial used and unused tubes) to the site at the next 
study visit.
5.5. Administration
Ointment should be applied as an even layer of approximately 3 mg/cm2.
The tool to standardize the calculation of the amount of ointment required for each 
participant will be provided by the sponsor to the study sites, which is based on each 
participant’s own AD %BSA adjusted by height and weight.


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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 
source document study records.  The subject and parent/legal guardian (if applicable) will be 
provided with documentation of the designated treatment areas.  The documentation of 
treatable areas will be updated for any new AD lesions that appear after the 
Baseline/Day 1 Visit.
Crisaborole Ointment, 2% is for external use on the skin only.  Avoid contact with mucous 
membranes (ie, inside of nostrils, mouth, vagina, urethra, and rectum), and the eyes. 


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Wearing gloves, study staff will apply a layer of investigational product ointment to all 
treatable AD lesions identified at Baseline/Day 1.  Subjects and parents/legal guardians (if 
applicable) will be encouraged to observe and participate in the initial investigational product 
application on Day 1.  All subsequent doses, including the second dose on Day 1, will be 
applied at home.  Those subjects applying IP at home and having difficulty reaching 
treatment eligible atopic dermatitis areas (eg, back) may be assisted by another person who 
will need to apply the investigational product to the subject according to the above IP 
application instructions.
Subjects and/or parents/guardian/legal guardians will be instructed to not wipe 
investigational product off the skin, avoid occluding the treated areas, and refrain from 
swimming or bathing/washing the treated areas within 4 hours after application.
Regimen: Investigational product will be applied BID to all treatable AD involved areas 
(excluding the scalp) identified at Baseline/Day 1 through Day 28.  The initial dose 
application on Baseline/Day 1 will be applied in the clinic, and all subsequent doses will be 
applied at home.  Subjects and/or parents/legal guardians will be instructed to apply enough 
investigational product to cover each lesion with a layer of ointment.  A total of 56 doses are 
expected to be applied between Baseline/Day 1 and Day 29, inclusive.  In the event the 
scheduled Day 29 (End of Treatment) Visit does not occur on Day 29, eg, due to an 
unavoidable scheduling conflict, the subject and parent/legal guardian (if applicable) will be 
instructed to continue investigational product application BID through the evening before the 
day that the rescheduled End of Treatment Visit is to occur. 
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 will also be applied to any new treatable AD 
involved areas that appear following Baseline/Day 1.
Subjects and parents/legal guardians (if applicable) will be instructed to apply evening (PM) 
doses approximately 8–16 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 
12:00 AM).  Caregivers or partners may also be ones to apply investigational product, 
especially for areas that a subject cannot reach, even in adults.  The first dose is preferred to 
be administered in the morning on Day 1 if applicable.  In special situation if the subject 
come to the clinic in the afternoon, two doses (8-16 hours apart) or single dose could be 
administered fine to only administer the PM dose on Day 1, if single dose is administered on 
Day 1, a morning dose will be applied at Day 29 for these special subjects.


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5.6. 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 nonworking 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.
Receipt of materials, door opening and closing, and other routine handling operations where 
the products are briefly out of the temperature range described in the labeling are not 
considered excursions.  Site staff will instruct subjects and/or parents/legal guardians on the 
proper storage requirements for take home investigational products. 


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The Investigational Product Manual should be referenced for any additional guidance on 
storage conditions and actions to be taken when conditions are outside the specified range.
5.7. Investigational Product Accountability 
The investigator site must maintain adequate records documenting the receipt, use, loss, or 
other disposition of the investigational product supplies.  All investigational products will be 
accounted for using a drug accountability form/record. 
Throughout the study, detailed investigational product accountability records, including tube 
weights, will be maintained for each subject by study staff. 
The subjects and/or subject’s parents/legal guardians will be asked to bring all dispensed 
investigational product (including empty, partial 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.
5.7.1. Destruction of Investigational Product Supplies
The sponsor or designee will provide guidance on the destruction of unused investigational 
product (eg, at the site).  If destruction is authorized to take place at the investigator site, the 
investigator must ensure that the materials are destroyed in compliance with applicable 
environmental regulations, institutional policy, and any special instructions provided by 
Pfizer, and all destruction must be adequately documented.
For all investigational product returned to the investigator by subjects and/or the parents/legal 
guardians, 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.
5.8. Prior and Concomitant Treatment(s)

All prior medications, including all medications and non-medication therapies used 
for AD within 90 days prior to Screening and all other treatments, including bland 
(non-medicated) emollients, over the counter drugs, vitamins, and antacids, used
within 30 days prior to Screening will be recorded at the screening visit.  Any 
changes in concomitant medications or dosage will be recorded at Baseline/Day 1 and 
at each subsequent visit.  Medication entries should provide the correctly spelled drug 


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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.
5.8.1. Medications Prohibited Prior to Baseline/Day 1

Classes of medications and non-medication therapies that may alter the course of AD 
and for which washout is required prior to Baseline/Day 1 are listed below.  If a 
subject requires a washout, the investigator or his/her designee will provide 
instructions on discontinuing the prohibited medication(s) or non-medication therapy 
(ies) at the Screening Visit. 

Medications Prohibited 12 weeks or 5 half-lives (whichever is longer) Prior to 
Baseline/Day 1

Biological drugs.  (Note: prior dupilumab use is exclusionary).
Medications Prohibited 28 Days Prior to Baseline/Day 1

Use of systemic (oral, parenteral) corticosteroids, within 28 days prior to 
Baseline/Day 1.
Subjects with stable use (regular regimen) of intranasal/inhaled/ophthalmic 
corticosteroids with ≥14 days of consistent use prior to Baseline/Day 1 are permitted 
to continue use of intranasal/inhaled/ophthalmic corticosteroids but must not alter or 
stop their regimen during the study.

Use of systemic immunosuppressive agents, including but not limited to, 
methotrexate, cyclosporine, azathioprine, hydroxychloroquine, and mycophenolate 
mofetil (MMF), within 28 days prior to Baseline/Day 1.

Use of systemic JAK inhibitor, within 28 days prior to Baseline/Day 1.

Use of sunbathing, tanning bed use, or light therapy (UV, UV-B, psoralen–UV-A 
[PUVA]), within 28 days prior to Baseline/Day 1.

Escalating, decreasing, or as needed (PRN) use of topical retinoids or benzoyl 
peroxide (BPO) on treatable AD lesions, within 28 days prior to Baseline/Day 1.


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Subjects on a stable regimen of topical retinoids and/or BPO regimen with ≥14 days 
of consistent use prior to Baseline/Day 1 are permitted to continue the topical 
retinoids or BPO regimen (not on the AD lesions) but must not alter or stop their 
regimen during the study. 

Systemic Traditional Chinese Medicine/herbal preparation that might alter the course 
of atopic dermatitis, for example Lei Gong Teng.
Medications Prohibited 14 Days Prior to Baseline/Day 1

Use of systemic antibiotics, within 14 days prior to Baseline/Day 1.

Use of topical corticosteroids, or topical calcineurin inhibitors, anywhere on the body, 
within 14 days prior to Baseline/Day 1.

Use of a topical JAK inhibitor, anywhere on the body within 14 days prior to 
Baseline/Day1.

Use of topical antihistamines anywhere on the body, within 14 days prior to 
Baseline/Day 1.

Topical traditional Chinese medicine/herbal preparation that might alter the course of 
atopic dermatitis, within 14 days prior to Baseline/Day 1 
Medications Prohibited 7 Days Prior to Baseline/Day 1

Use of topical antibacterial medications or products, including soaps, bleach baths, or 
topical sodium hypochlorite-based products anywhere on the body, within 7 days 
prior to Baseline/Day 1.

Escalating, decreasing, or PRN use of systemic antihistamines. 
Subjects on a stable systemic antihistamine regimen with ≥7 days of consistent use 
prior to Baseline/Day 1 are permitted to continue but must not alter or stop their 
regimen during the study.
Medications Prohibited 1 Day Prior to Baseline/Day 1

Use of emollients (medicated and non-medicated), moisturizer or sunscreen on 
treatable AD lesions, within 1 day prior to Baseline/Day 1 (ie, during the 24-hour 
period before the Baseline/Day 1 Visit).


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After the Baseline/Day 1 Visit, use of emollient(s), moisturizer or sunscreen is 
permitted during the study to manage dry skin in areas surrounding but not on or 
overlapping the treatable AD involved areas until Day 29. Use of emollient(s), 
moisturizer or sunscreen in the skin of whole body is permitted after Day 29
telephone contact. 
5.8.2. Medications Prohibited During the Study (Days 1–36)
Classes of medications and non-medication therapies that may alter the course of AD and 
that are prohibited during the study (from Baseline/Day 1 through the post-treatment 
follow-up visit on Day 36) are listed below.

Use of systemic (oral, parenteral) corticosteroids.

Subjects with stable regimen of intranasal/inhaled/ophthalmic corticosteroids with 
≥14 days of consistent use prior to Baseline/Day 1 are permitted to continue use of 
intranasal/inhaled corticosteroids but must not alter or stop their regimen during the 
study.

Use of topical corticosteroids, or topical calcineurin inhibitors, or topical JAK 
inhibitors, anywhere on the body.

Use of systemic immunosuppressive agents, including but not limited to 
methotrexate, cyclosporine, azathioprine, hydroxychloroquine, or MMF.

Escalating, decreasing, or PRN use of topical retinoids or BPO on treatable AD 
lesions.
Subjects on a stable topical retinoid and/or BPO regimen with ≥14 days of consistent 
use prior to Baseline/Day 1 are permitted to continue the topical retinoid or BPO 
regimen (not on AD lesions) but must not alter or stop their regimen during the study.

Use of systemic antihistamines, unless on stable ≥regimen (see note in Section 5.8.1). 

Use of systemic or topical traditional Chinese medicine/herbal preparation that might 
alter the course of atopic dermatitis

Use of systemic antibiotics for more than 14 consecutive days.
Short courses (≤14 days) of systemic antibiotics may be given during the study if 
clinically necessary for the treatment of new onset infections.


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
Use of topical antibacterial medications or products, including soaps, bleach baths, or 
topical sodium hypochlorite-based products anywhere on the body.

Use of sunbathing, tanning bed use, light therapy (UV, UV-B, PUVA) anywhere on 
the body.

Use of topical antihistamines anywhere on the body.

Participation in another drug or device research study.
5.8.3. Medications Allowed During the Study (Days 1–29)
Classes of medications that are allowed during the study (from Baseline/Day 1 through the 
end of treatment visit on Day 29) are summarized below:

After the Baseline/Day 1 Visit, use of bland emollient(s) is permitted during the study 
to manage dry skin in areas surrounding but not on or overlapping the treatable 
AD-involved areas. 

Subjects on a stable regimen of inhaled, intranasal, or ocular corticosteroids, with 
≥14 days of consistent use prior to Baseline/Day 1, are permitted to continue but must 
not alter or stop their regimen during the study 

Short courses (≤14 days) of systemic antibiotics may be given during the course of 
the study, if clinically necessary for the treatment of new onset infections.

Subjects on a stable systemic antihistamine regimen, with at least 7 days of consistent 
use prior to Baseline/Day 1, are permitted to continue but must not alter or stop their 
regimen during the study.

Subjects on a stable topical retinoid and/or BPO regimen, with ≥14 days of consistent 
use prior to Baseline/Day 1, are permitted to continue (not on AD lesions) but must 
not alter or stop their regimen during the study.

Nonsteroidal anti-inflammatory drugs are allowed throughout the study.

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 in study.


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
Oral, transdermal, intrauterine, injected, or implanted hormonal methods of 
contraception are permitted during the study, for female subjects of childbearing 
potential.

Concomitant medications for other chronic medical conditions are permitted during 
the study unless the medication/therapy is specifically prohibited by the protocol.
6. STUDY PROCEDURES 
6.1. Study Visits
Subjects will be required to visit the clinic for all scheduled visits (Screening, Day 1, Day 8, 
Day 15, Day 22, Day 29/Early termination visit).  The timing of each study day is relative to 
the day of initial dosing (Baseline/Day 1).
6.2. Time Windows for Study Procedures
Allowable time windows for visits/contacts are as follows:

Screening visit: up to 35 Days prior to Day 1/baseline;

Day 1 Visit: Day 1;

Day 8 Visit: Day 8 ±1 day;

Day 15 Visit: Day 15 ±3 day;

Day 22 Visit: Day 22 ±3 day;

Day 29 End of Treatment Visit: Day 29 ±3 day;

Follow up telephone contact 1: Day 36 ±3 day;

Follow up telephone contact 2: Day 60 ±3 day.
Refer to the Schedule of Activities for a complete list of assessments to be performed during 
the study.
6.3. Screening period
Screening procedures must be completed within 35 days (inclusive) before the 
baseline/Day 1 Visit.  If necessary, the screening procedures may be completed over several 
days, with the exception of the Peak Pruritus NRS and Patient Reported Itch Severity 


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Scale/Observer Reported Itch Severity Scale that would be completed once daily during 
screening period.
The following procedures will be performed at the Screening Visit:

Obtain written informed consent (from adult subject or parent/legal guardian of 
pediatric subjects) and assent (from pediatric subjects, as applicable) before any study 
procedures are performed.

Register subjects with IRT.  The IRT must be contacted before screening assessments 
begin in order to obtain a subject screening identification number (SSID).

Peak pruritus NRS/Patient Reported Itch Severity Scale/Observer Reported Itch 
Severity Scale and Patient Global Impression of Severity (PGIS)/Observer Global 
Impression of Severity (OGIS) will be completed by subject or observer when 
applicable once daily during screening prior to Day 1 regardless of whether the 
subject continues to randomization. If a subject is screen failed before above 
procedures are completed, then related data will not be collected.

Complete the Patient Oriented Eczema Measure (POEM) (completed by subject or 
observer), Dermatology Life Quality Index (DLQI) (for subject >= 16 years old, 
completed by subject) Children’s Dermatology Life Quality Index (CDLQI) (for 
subject 4-15 years old, completed by subject or observer), Infants’ Dermatitis Quality 
of Life Index (IDQOL) (for subject 2-3 years old, completed by observer) and 
Dermatitis Family Impact Questionnaire (DFI) (for subject 2-17 years old, completed 
by observer).
Note: DLQI, CDLQI, IDQOL, DFI, POEM will be collected at screening for all 
subjects including screen failure subjects. If a subject is screen failed before above 
procedures are completed, then related data will not be collected.

Ask C-SSRS questions for subjects ≥7 years of age. Subjects meeting any of the 
criteria specified in Exclusion Criterion 12 will be ineligible for participation (See 
Section 4.2).

Collect demographic information (sex, date of birth, race, ethnicity).

Obtain vital signs (temperature, respiratory rate, pulse rate, and blood pressure [BP]) 
in the seated position or supine position, after the subject has been sitting or lying 
calmly for a minimum of 5 minutes.


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
Collect complete medical history, including onset of AD (date of diagnosis, as 
specifically as known).

Measure height and weight.

Perform a complete physical examination and confirm clinical diagnosis of AD per 
Hanifin and Rajka criteria (Appendix 2).

Record all prior and concomitant medications (including all medications and non-
medication therapies) used for AD used within 90 days prior to screening and all 
other treatments, including bland emollients, over-the-counter- drugs, vitamins, and 
antacids, used within 30 days prior to Screening.


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
If a subject is using a prohibited medication (or non-medication therapy) at the time 
of Screening, the investigator or his/her designee will provide instructions on 
discontinuing the prohibited medication or therapy (ie, a washout period) at 
Screening.

If a subject will be undergoing washout of a prohibited medication as directed by the 
investigator or his/her designee, the subject’s tentative eligibility will be confirmed 
pending successful completion of the washout (to be confirmed at Baseline/Day 1 
Visit).

Assess for AEs/SAEs, starting from the time of informed consent and assent, as 
applicable.

Urine pregnancy test (female subjects of childbearing potential only).

Serum chemistry and hematology. 

FSH (to confirm postmenopausal status in females who are amenorrheic for at least 
12 consecutive months).

Complete the ISGA (will be completed at screening for all subjects including screen 
failure subjects, if a subject is screen failed before above procedures are completed, 
then related data will not be collected). 

Calculate subject’s Treatable %BSA.

Review subject’s tentative eligibility according to the Inclusion and Exclusion 
Criteria.
Note: The results of all screening evaluations must be reviewed for clinical 
significance by the investigator or his/her designee prior to randomization of the 
subject on Baseline/Day 1.

Contraception check: Confirm and document in source documents that proper 
contraception has been reviewed for the female subject of child bearing potential and 
their partner as appropriate, and the subject’s agreement to use appropriate 
contraception methods throughout 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 subject and/or parent/legal guardian.


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6.4. Study Period/Treatment Period
6.4.1. Baseline/Day 1 Visit
a.
The following procedures will be performed at the Baseline/Day 1 Visit BEFORE dosing 
with investigational product:
•
Ask the subject or observer (parent/legal guardian/other caregiver) when applicable to 
complete the Peak Pruritus NRS/Patient Reported Itch Severity Scale/Observer 
Reported Itch Severity Scale and PGIS/OGIS QD (preferably same time of day each 
day if applicable) before IP morning dose applied starting at Baseline/Day 1 and 
continuing through Day 28 and at Day 29.
•
Ask the subject or observer when applicable to complete the POEM, DLQI, CDLQI, 
IDQOL, and DFI.
•
Assess and record any changes in the subject’s prior and concomitant medications 
since the Screening Visit (if Screening and Baseline are 2 visits); see Section 5.8 for 
medications prohibited prior to Baseline/Day 1 and during the study.
•
Obtain and record medical history.
•
Obtain vital signs (temperature, respiratory rate, pulse rate, and BP) in the seated or 
supine position, after the subject has been sitting or lying calmly for a minimum of 
5 minutes; assessment of vital signs should precede blood draw for clinical laboratory 
tests.
•
Measure height and weight.
•
Perform a disease focused physical examination of all AD involved skin (in treatable 
and non-treatable areas) and evaluate any current or reported symptoms for clinically 
significant changes.
•
Complete the ISGA. ISGA must be completed prior to 
 
the EASI assessment (Note: The ISGA score must be 2 or 3 at Baseline/Day 1 for 
subject to be eligible for the study).
•
Complete the EASI assessment, after completing the ISGA
 
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
Calculate subject’s Treatable %BSA.

Confirm subject’s eligibility based on the Inclusion Criteria and Exclusion Criteria, 
including confirming acceptable methods of birth control for female subjects of 
childbearing potential.

Assess and record any AEs/SAEs.

Draw blood for clinical laboratory tests on Day 1 prior to initial dosing; assessment of 
vital signs should precede blood draw for clinical laboratory tests; testing includes
serum chemistry and hematology. 
Note: If the screening serum chemistry and hematology tests are performed within 
15 days prior to Day 1, whether the Day 1 serum chemistry and hematology tests are 
to be performed will be at the discretion of Principle Investigator (PI) or designee.
At the discretion of the investigator or his/her designee, a topical lidocaine-based 
anesthetic (eg, lidocaine 4% cream) may be used prior to clinical laboratory sample 
collection to decrease potential discomfort to the subject.  However, the skin must be 
thoroughly cleansed prior to blood sample collection.  Use of a topical 
lidocaine-based anesthetic must be recorded in the Concomitant Medication eCRF.

Perform a urine pregnancy test (female subjects of childbearing potential only) and 
confirm the subject has a negative urine pregnancy test result prior to randomization.

Mark the subject’s source documents to record the treatable AD areas (excluding the 
scalp) as identified by the investigator or his/her designee at Baseline/Day 1 and 
provide subject and/or parent/legal guardian with documentation of the designated 
treatment areas.

A checklist of body areas currently affected by AD will be completed at the 
baseline/Day 1 visit.  Location of skin lesions will be selected from a prepopulated 
listing of body locations. 

After PI’s or designee’s documented confirmation of eligibility, access IRT system to 
randomize subject to investigational product treatment. 

Access into IRT system to dispense the investigational products based on IRT 
randomization code.


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
Weigh investigational product tube(s) before applying first dose; record 
investigational product tube(s) weight in subject’s source documents.

Wearing gloves, study staff will apply a layer of investigational product ointment 
(first dose) 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 AEs (including application site reactions) and SAEs.

Provide to subject and/or parent/legal guardian a sufficient number of tubes of 
investigational product for 1 week of dosing; ensure that all dispensed tubes are 
weighed, and weight is recorded in subject’s source documents.

Instruct the subject and/or the parent/legal guardian that subject should not wipe 
investigational product off the skin, avoid occluding the treated areas, and refrain 
from swimming or bathing/washing the treated areas within 4 hours after application.

Dispense dosing diary and instruct the subject’s parent(s)/legal guardian on use 
(ie, each time investigational product is applied). Instruct the subject and/or 
parent/legal guardian regarding all procedures for at home dosing beginning with the 
evening (PM) dose on Day 1 followed by BID dosing through Day 28, including how 
to complete the Dosing Diary, which will start at the Baseline/Day 1 Visit and 
continue BID through Day 28 (ie, each time investigational product is applied). 

Contraception check: Confirm and document that proper contraception is being used 
for the female subject of childbearing potential and their partner as appropriate.

Review the schedule of upcoming study visits with the subject and/or parent/legal 
guardian and instruct them to return at the scheduled time for the Day 8 Visit. 

Remind the subject and/or parent/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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6.4.2. Day 8 (±1 day), Day 15 (±3 days) and Day 22 (±3 days) Study Visit
The following procedures will be performed:
•
Remind the subject or observer when applicable to complete the Peak Pruritus 
NRS/Patient Reported Itch Severity Scale/Observer Reported Itch Severity Scale (QD
before investigational product is applied).
•
Remind the subject or observer when applicable to complete the PGIS/OGIS, Patient 
Global Impression of Change (PGIC)/Observer Global Impression of Change 
(OGIC).
•
Remind the subject or observer when applicable to complete the POEM, DLQI, 
CDLQI, IDQOL, DFI (these questionnaires will only be completed for Day 15 visit, 
not for Day 8 and Day 22 visit).
•
Assess and record any changes in concomitant medications, including confirming that 
subject is not taking any prohibited medications.
•
Assess and record any AEs (including application site reactions) and SAEs. For any 
AE occurring in the treated area, a body site check list will be used to report the AE 
locations.
•
Obtain vital signs (temperature, respiratory rate, pulse rate, and blood pressure) (only 
for Day 15 visit, not scheduled for Day 8 and Day 22 visit) in the seated or supine 
position, after the subject has been sitting or lying calmly for a minimum of 
5 minutes.
•
Complete the ISGA.  ISGA must be completed prior to 
 
EASI assessment.
•
Complete the EASI assessment, after completing the ISGA
 
•
Calculate subject’s Treatable %BSA. 
•
Update the documentation of treatable areas for any new AD lesions that appear after 
the Baseline/Day 1 Visit. The subject and parent/legal guardian (if applicable) will be 
CCI
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provided with documentation of the designated treatment areas, to ensure that 
previously treated areas which have resolved continue to be treated as required.

Review Dosing Diary and assess compliance; re-educate the subject and/or 
parent/legal guardian if any missed doses have occurred.

Collect returned tube(s) of investigational product from the subject and/or 
parent/legal guardian and weigh them. Weights will be recorded in subject’s source 
documents.

Access into IRT system to assign new tube(s) of investigational product (enough for 
1 week of dosing) and weigh them prior to dispensing the tube(s) to subject and/or 
parent/legal guardian.

Remind the subject and/or parent/legal guardian that investigational product must 
continue to be applied at home twice each day (am and pm), as instructed.

Dispense dosing diary.

Instruct the subject and/or parent/legal guardian that subject should not wipe 
investigational product off the skin, avoid occluding the treated areas, and refrain 
from swimming or bathing/washing the treated areas within 4 hours after application.

Contraception check: Confirm and document that proper contraception is being used
for the female subject of child bearing potential and their partner as appropriate.

Review the schedule of upcoming study visits with the subject and/or parent/legal 
guardian, and instruct them to return at the scheduled time for the next visit.

Remind subject and/or parent/legal guardian to bring all investigational product tubes 
(empty, partially used and unused) and the Dosing Diary to their next visit.
6.4.3. Day 29 (±3 days) (End-of-Treatment)/Early termination Study Visit
In the event the Day 29 Visit must be delayed, eg, due to an unavoidable scheduling conflict, 
subject and/or parent/legal guardian will be instructed to continue blinded investigational 
product application BID through the evening before the day on which the rescheduled 
End-of-Treatment Visit is to occur.  The following procedures will be performed at the 
Day 29/Early Termination Visit:


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•
Ask the subject or observer when applicable to complete Day 29 Peak Pruritus 
NRS/Patient Reported Itch Severity Scale/Observer Reported Itch Severity Scale, 
PGIS/OGIS scale if not already completed.
•
Ask the subject or observer when applicable to complete the PGIC/OGIC, POEM, 
DLQI, CDLQI, IDQOL, DFI.
•
Assess and record any changes in concomitant medications, including confirming that 
subject is not taking any prohibited medications.
•
Assess and record any AEs (including application site reactions) and SAEs. For any 
AE occurring in the treated area, a body site check list will be used to report the AE 
locations.
•
Urine pregnancy test (female subjects of childbearing potential only).
•
Obtain vital signs (temperature, respiratory rate, pulse rate, and BP) in the seated or 
supine position, after the subject has been sitting calmly for a minimum of 5 minutes; 
assessment of vital signs should precede blood draw for clinical laboratory tests.
•
Draw blood for clinical laboratory tests including chemistry and hematology (after 
having assessed vital signs).
Note: At the discretion of the investigator or his/her designee, a topical lidocaine-
based anesthetic (eg, lidocaine 4% cream) may be used prior to clinical laboratory 
sample collection to decrease potential discomfort to the subject.  However, the skin 
must be thoroughly cleansed prior to blood sample collection.  Use of a topical 
lidocaine-based anesthetic must be recorded in the Concomitant Medication eCRF.
•
Perform a full physical examination, evaluate any current or reported symptoms for 
clinically significant changes and report relevant AE if applicable.
•
Complete the ISGA. ISGA must be completed prior to
 
the EASI assessment.
•
Complete the EASI assessment, after completing the ISGA
 
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
Calculate subject’s Treatable %BSA based on all AD lesions present at Day 29,
excluding the scalp.

Review Dosing Diary and assess compliance.

Collect Dosing Diary.

Collect returned tube(s) of investigational product from the subject and/or 
parent/legal guardian and weigh them.

Contraception check: Confirm and document that proper contraception is being used 
for the female subject of childbearing potential and their partner as appropriate.

The participants who rolled over into study C3291027 without a Post Treatment 
Follow Up period prior to 21 Oct 2020 are considered completers in this study.
6.4.4. Unscheduled Visit 
The procedures performed at an Unscheduled Visit will depend on the reason for the visit 
(some procedures may not apply). 

Assess and record any changes in concomitant medications, including confirming that 
subject is not taking any prohibited medications, as detailed in Section 5.8.3.

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.

Weigh investigational product tubes; record investigational product tubes weight in 
subject’s source documents.

Instruct the parent(s)/legal guardian regarding all procedures for at home dosing 
beginning BID dosing through Day 29 visit, including how to complete the dosing 
diary. 

Assess and record any AEs, including 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.


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6.4.5. Follow-up Contact/Follow Up Period
Follow-up contact will be done via a phone call on 7 (±3) days and 31 (±3) days after the
End of Treatment/Early Termination Visit to capture any potential adverse events and to 
review (see the Time Period for Collecting AE/SAE Information section) and record 
concomitant medications and to confirm appropriate contraception usage (see the 
Contraception section).
6.5. Subject Withdrawal/Early Termination
Withdrawal of consent:
Subjects and/or parent(s)/legal guardian/legally acceptable representative who request to 
discontinue receipt of study treatment will remain in the study and must continue to be 
followed for protocol specified follow-up procedures.  The only exception to this is when a 
subject specifically withdraws consent for any further contact with him or her or persons 
previously authorized by the subject to provide this information.  Subjects should notify the 
investigator in writing of the decision to withdraw consent from future follow-up, whenever 
possible.  The withdrawal of consent should be explained in detail in the medical records by 
the investigator, as to whether the withdrawal is only from further receipt of investigational 
product or also from study procedures and/or posttreatment study follow-up, and entered on 
the appropriate CRF page. 
Lost to follow-up: 
All reasonable efforts must be made to locate subjects to determine and report their ongoing 
status.  This includes follow-up with persons authorized by the subject as noted above.  Lost 
to follow-up is defined by the inability to reach the subject after a minimum of 2 documented 
phone calls, faxes, or e-mails as well as lack of response by the subject to 1 registered mail 
letter.  All attempts should be documented in the subject’s medical records.  If it is 
determined that the subject has died, the site will use locally permissible methods to obtain 
the date and cause of death.  If the investigator’s use of a third-party representative to assist 
in the follow-up portion of the study has been included in the subject’s informed consent, 
then the investigator may use a sponsor-retained third-party representative to assist site staff 
with obtaining the subject’s contact information or other public vital status data necessary to 
complete the follow-up portion of the study.  The site staff and representative will consult 
publicly available sources, such as public health registries and databases, in order to obtain 
updated contact information.  If, after all attempts, the subject remains lost to follow-up, then 
the last-known-alive date as determined by the investigator should be reported and 
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Subjects may withdraw from the study at any time at their own request, or they may be 
withdrawn at any time at the discretion of the investigator or sponsor for safety (see also the 
Withdrawal From the Study Due to Adverse Events section) or behavioral reasons, or the 
inability of the subject to comply with the protocol-required schedule of study visits or 
procedures at a given study site. 
If a subject does not return for a scheduled visit, every effort should be made to contact the 
subject.  All attempts to contact the subject and information received during contact attempts 
must be documented in the subject’s medical record. In any circumstance, every effort 
should be made to document subject outcome, if possible.  The investigator should inquire 
about the reason for withdrawal, request that the subject return all unused investigational, 
request that the subject return for a final visit, if applicable, and follow up with the subject 
regarding any unresolved adverse events (AEs).
If the subject withdraws from the study, and also withdraws consent for disclosure of future 
information, no further evaluations should be performed, and no additional data should be 
collected.  The sponsor may retain and continue to use any data collected before such 
withdrawal of consent.
7. ASSESSMENTS
Every effort should be made to ensure that the protocol required tests and procedures are 
completed as described.  However, it is anticipated that from time to time there may be 
circumstances outside of the control of the investigator that may make it unfeasible to 
perform the test.  In these cases, the investigator will take all steps necessary to ensure the 
safety and wellbeing 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. Efficacy Assessments
Clinical evaluations of atopic dermatitis will be performed by an experienced and certified 
physician, dermatologist, or medical professional.  The evaluator must have received 
documented training to conduct the protocol AD specific clinical evaluations prior to 
performing these evaluations.  To assure consistency and reduce variability, the same 
evaluator must assess all clinical evaluation of atopic dermatitis for any individual subject 


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throughout the study; a backup experienced and qualified, protocol trained evaluator will 
only be allowed and documented in case of emergency or special situation when the 
designated evaluator is unable to perform the evaluation.  Identity (eg, initials) of the 
evaluator will be captured on the source documentation (eg, scale worksheet).
7.1.1. Calculation of Subject’s Treatable %Body Surface Area (BSA)
The Treatable %BSA will be calculated for each subject at Screening, Baseline/Day 1, 
Days 8, 15, 22 and Day 29. The Treatable %BSA should be evaluated based on all AD 
lesions present on the day of the visit, excluding the scalp. Score 0 in the ISGA definition 
will not be evaluated as BSA while Score 1-4 will be.
Treatable %BSA is defined as the percentage of the subject’s total BSA that is AD involved, 
excluding the scalp.  To estimate the subject’s Treatable %BSA, the investigator or his/her 
designee will use “handprint method”, by which the area represented by the palmar (ie, 
outstretched) surface of the subject’s hand with all five digits adducted together is 
approximately 1% of the subject’s BSA, regardless of the subjects age.
7.1.2. Investigator’s Static Global Assessment
The Investigator’s Static Global Assessment (ISGA), a five point global static assessment of 
AD severity (Table 1), will be assessed at times specified in the STUDY PROCEDURES
section of this protocol to characterize subjects’ overall disease severity across all treatable 
AD lesions. 
The assessment will be a static evaluation without regard to the score at a previous visit.
ISGA assessment during the study must be done by the investigator or his/her designee.  
Every effort should be made to ensure that all ISGA assessments for a given subject are done 
by the same qualified individual throughout the study. 
Table 1.
Investigator’s Static Global Assessment
Score Grade
Definition
0
Clear
Minor residual hypo/hyperpigmentation; no erythema or induration/papulation; no 
oozing/crusting
1
Almost 
Clear
Trace faint pink erythema, with barely perceptible induration/papulation and no 
oozing/crusting
2
Mild
Faint pink erythema with mild induration/papulation and no oozing/crusting 
3
Moderate Pink-red erythema with moderate induration/papulation with or without oozing/crusting
4
Severe
Deep or bright red erythema with severe induration/papulation and with oozing/crusting


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7.1.4. Eczema Area and Severity Index (EASI)
The EASI26 quantifies the severity of a subject’s atopic dermatitis based on both severity of 
lesion clinical signs and the percent of BSA affected.  EASI is a composite scoring of the 
degree of erythema, induration/papulation, excoriation, and lichenification (each scored 
separately) for each of four body regions, with adjustment for the percent of BSA involved 
for each body region and for the proportion of the body region to the whole body.  
Percent BSA with Treatable AD: The number of handprints of AD skin in a body region
can be used to determine the extent (%) to which a body region is involved with atopic 
dermatitis (Table 2).
Table 2
Handprint Determination of Body Region Surface Area 
Body Region
Total Number 
of Handprints 
in Body 
Region*
Surface Area of 
Body Region 
Equivalent of One 
Handprint
Total Number of 
Handprints in 
Body Region*
Surface Area of
Body Region 
Equivalent of One 
Handprint
≥8 years of age
2-7 years of age
Head and Neck
10
10%
20
5%
Upper Limbs
20
5%
20
5%
Trunk (including 
axillae)
30
3.33%
30
3.33%
Lower Limbs (including 
buttocks)
40
2.5%
30
3.33%
*The number of handprints will be for the entire body region; these values will not be adjusted for exclusion of 
scalp from the BSA assessment.
Note: The age of cut-off is based on the age at time of informed consent.
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The extent (%) to which each of the four body regions is involved with AD is categorized 
using a non-linear scaling method to a numerical area score according to the following BSA 
scoring criteria.  See Table 3 on EASI Area Score Criteria.
Table 3.
Eczema Area and Severity Index (EASI) Area Score Criteria
Percent BSA with Atopic Dermatitis in a Body Region
Area Score
0%
0
<10%
1
10% to <30%
2
30% to <50%
3
50% to <70%
4
70% to <90%
5
90% to 100%
6
Lesion Severity by Clinical Signs: The basic characteristics of atopic dermatitis lesions 
erythema, induration/papulation, excoriation, and lichenification provide a means for 
assessing the severity of lesions.  Assessment of these four main clinical signs is performed 
separately for four body regions: head and neck, upper limbs, trunk (including axillae and 
groin) and lower limbs (including buttocks).  Average erythema, induration/papulation, 
excoriation, and lichenification are scored for each body region according to a 4 point scale: 
0 = absent; 1 = mild; 2 = moderate; 3 = severe.  Morphologic descriptors for each clinical 
sign severity score are shown in Table 4.


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Table 4.
Clinical Sign Severity Scoring Criteria for the Eczema Area and Severity 
Index (EASI)
Score
Description
Erythema (E)
0
Absent
None; may have residual discoloration (post-inflammatory hyperpigmentation 
and/or hypopigmentation).
1
Mild
Light pink to light red
2
Moderate
Red
3
Severe
Deep, dark red
Induration/Papulation (I)
0
Absent
None
1
Mild
Barely palpable to slight, but definite hard thickened skin and/or papules
2
Moderate
Easily palpable moderate hard thickened skin and/or papules
3
Severe
Severe hard thickened skin and/or papules
Excoriation (Ex)
0
Absent
None
1
Mild
Slight, but definite linear or picked scratch marks or penetrating surface injury
2
Moderate
Moderate linear or picked scratch marks or penetrating surface injury
3
Severe
Severe linear or picked scratch marks or penetrating surface injury
Lichenification (L)
0
Absent
None
1
Mild
Barely perceptible to slight, but definite thickened skin, fine skin markings, 
and lichenoid scale
2
Moderate
Moderate thickened skin, coarse skin markings, and coarse lichenoid scale
3
Severe
Severe thickened skin with very coarse skin markings and lichenoid scale
The EASI will exclude scalp from the assessment/scoring 
In each body region, the sum of the Clinical Signs Severity Scores for erythema, 
induration/papulation, excoriation, and lichenification is multiplied by the Area Score and by 
the Body Region Weighting to provide a body region value, which is then summed across all 
four body regions resulting in an EASI score as described in Equation 1 and Equation 2: 
Equation 1 (subjects aged ≥8 years old): EASI =0.1Ah(Eh+Ih+Exh+Lh) + 
0.2Au(Eu+Iu+Exu+Lu) + 0.3At(Et+It+Ext+Lt) + 0.4Al(El+Il+Exl+Ll)
Equation 2 (subjects aged 2-<8 years old):  EASI =0.2Ah(Eh+Ih+Exh+Lh) + 
0.2Au(Eu+Iu+Exu+Lu) + 0.3At(Et+It+Ext+Lt) + 0.3Al(El+Il+Exl+Ll)
A = Area Score; E = erythema; I = induration/papulation; Ex = excoriation; L = lichenification; h = head and 
neck; u = upper limbs; t = trunk; l = lower limbs.
The EASI score can vary in increments of range from 0.0 to 72.0, with higher scores 
representing greater severity of atopic dermatitis.  Considering the scalp will be excluded 


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from the EASI assessment in the present study, the maximum possible score will be less than 
72.0 (modified EASI score).
7.1.5. Body Site Checklist for Atopic Dermatitis
A checklist of body areas currently affected by AD will be completed at the baseline visit.  
Location of skin lesions will be selected from a prepopulated listing of body locations.
7.1.6. Patient/Observer Reported Outcomes 
The Patient/Observer Reported Outcomes questionnaires in this study include: Peak pruritus 
NRS/Patient Reported Itch Severity Scale/Observer Reported Itch Severity Scale, 
PGIS/OGIS, PGIC/OGIC, POEM, DLQI, CDLQI, IDQOL, DFI.  They will be performed at 
the time points defined in the Schedule of Activities.  The age cut-offs are based on the age at 
informed consent.
On study visit days, subjects or observer (ie, the one who provides the information to 
complete the questionnaires other than subject, eg, parent/legal guardian/other caregiver) 
should complete the patient reported outcomes at the clinic prior to any procedures being 
performed.  The one who completed the questionnaires should be captured and stored in 
database and available for analysis.  It’s preferred that all observer reported outcomes for a 
given subject are completed by same individual throughout the study.
7.1.6.1. Pruritus and Itch Assessment
Participants will be asked to assess their worst itch or scratching due to AD over the past 
24 hours. Participants ı6 years and <12 years will be asked to assess their worst itch or 
scratching due to AD for today.
•
Peak Pruritus Numerical Rating Scale (NRS)27 is an 11-point scale and must be 
completed by participants ≥12 years of age. 
•
Patient reported Itch Severity Scale is a 5-point scale must be completed by 
participants ≥6 years and <12 years. 
•
Observer reported Itch Severity Scale is an 11-point scale and must be completed by 
the observers (caregivers of participants) for participants <6 years of age.
7.1.6.2. Patient Global Impression of Severity (PGIS) and Observer Reported Global 
Impression of Severity (OGIS)
The PGIS and OGIS is a single item patient- or observer-rated measure of the subject’s AD 
condition severity at a given point in time. 


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This single item instrument uses a 7-point rating scale.  The PGIS/OGIS will be used as an 
anchor for defining a ‘clinical important difference’ on the pruritus and itch assessments and 
can also be used to create severity categorization for pruritus and itch assessments to enhance 
interpretation.

The PGIS will be completed by all participants ≥12 years of age.

The OGIS will be completed by the observer for participants 2-11 years of age.
7.1.6.3. Patient Global Impression of Change (PGIC) and Observer Reported Global 
Impression of Change (OGIC)
The PGIC and OGIC are an one item- question to rate change in a patient's overall status.  
This single item instrument is a 7-point rating scale and will be used to determine global 
improvement.  It will be used as an anchor to define a responder definition for the pruritus 
and itch assessments for ‘clinically important responder’ and as a sensitivity analysis for 
defining a ‘clinical important difference’ for pruritus and itch assessments.

The PGIC will be completed by participants ≥12 years of age.

The OGIC will be completed by the observer for participants 2-11 years of age.
7.1.6.4. Patient Oriented Eczema Measure (POEM)
The POEM28,29,30 is a validated 7-item measure used to assess the impact of AD over the past 
week.

The POEM will be completed by participants ≥12 years of age.

The proxy POEM will be completed by observers for participants 2-11 years of age.
7.1.6.5. Dermatology related Quality of Life Questionnaires
Dermatology related quality of life (QoL) scores will be descriptively summarized by 
treatment group for each collection time point defined in the Schedule of Activities.

The Dermatology Life Quality Index (DLQI) will be completed by all subjects aged 
16 years and older, based on the age at time of informed consent/assent.

The Children’s Dermatology Life Quality Index (CDLQI) will be completed by the 
subject or observer for subjects aged 4–15 years, based on the age at time of informed 
consent/assent.

The Infants’ Dermatitis Quality of Life Index (IDQOL) will be completed by 
observer for subjects aged 2–3 years, based on the age at time of informed 
consent/assent.


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
The Dermatitis Family Impact Questionnaire (DFI) will be completed by all observer 
for subjects aged 2–17 years, based on the age at time of informed consent/assent.
7.2. Safety Assessments
7.2.1. Clinical Laboratory Evaluations
The following safety laboratory tests will be performed at times defined in the Schedule of 
Activity 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 labs may be obtained at any time during 
the study to assess any perceived safety concerns.
The clinical laboratory test parameters that will be reviewed for safety evaluation are 
presented in Table 5.  Hematology, Chemistry and FSH will be done at a central laboratory.
Table 5.
Clinical Laboratory Test Parameters
Hematology
Chemistry
Pregnancy
FSHa
Hemoglobin
Hematocrit
Red blood cell count
Platelet count
White blood cell count 
(% and absolute)

Neutrophils;

Eosinophils;

Monocytes;

Basophils;

Lymphocytes.
Blood urea nitrogen/Urea
Glucose 
Creatinine
Sodium
Potassium
Chloride
Bicarbonate or Total CO2
Alanine aminotransferase 
Aspartate aminotransferase 
Total bilirubin
Alkaline phosphatase
Albumin
Total protein
At Screening, 
Baseline/Day 1, and 
Day 29 (End of 
treatment)/Early 
termination visit: Urine 
pregnancy testb (female 
subjects of childbearing 
potential only).
At Screening
a.
At Screening only, to confirm postmenopausal status in females who are amenorrheic for at least 
12 consecutive months.
b.
Subjects who have missed a menstrual period or who show an indeterminate or positive result on the urine 
test may not further progress in the study until pregnancy is ruled out using further diagnostic testing (eg, a 
negative quantitative serum pregnancy test conducted at a certified laboratory).  In the case of a positive 
urine -hCG test during the treatment period, the subject will have study drug interrupted and a serum 
sample submitted to the central laboratory for -hCG testing. In the case of a positive confirmed 
pregnancy, the subject will be withdrawn from administration of investigational product and from the 
study; if the serum -hCG test is negative and investigator judged that the subject is not pregnant, the 
subject may resume investigational product.


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Baseline clinical laboratory tests will be drawn during the Baseline/Day1 visit, after 
assessment of vital signs and prior to the first investigational product application.
If the screening serum chemistry and hematology tests are performed within 15 days prior to 
Baseline/Day 1, whether the Day 1 serum chemistry and hematology tests are to be 
performed will be at the discretion of the investigator or his/her designee.
At the discretion of the investigator or his/her designee, 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 does not contain 
propylene glycol.  However, 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 his/her 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. 
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).
7.2.2. Physical Examination, including Height, and Weight
Physical examinations, including height, and weight will be performed at times specified in 
the Schedules of Activities 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 be performed at Screening and Day 29 (End of 
treatment)/Early termination visit which 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, musculoskeletal, abdomen (liver, spleen), and neurological systems.  In 
addition, an assessment will be made of the condition of all AD involved skin. 


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A disease focused physical examination of all AD involved skin (in treatable and 
non-treatable areas) will be performed at Baseline/Day 1.
For measuring weight, a scale with appropriate range and resolution is used and must be 
placed on a stable, flat surface.  Subjects must remove shoes, bulky layers of clothing, and 
jackets so that only light clothing remains.  They must also remove the contents of their 
pockets and remain still during measurement of weight.
7.2.3. Vital Signs
Vital sign measurements (temperature, respiratory rate, pulse rate, and BP) will be performed 
at Screening, Baseline/Day 1, Day15 and Day 29.  Vital sign measurements should be 
performed with the subject in the seated or lying position and after the subject has been 
sitting or lying calmly for a minimum of 5 minutes.  The position of recording must be 
consistent within subject through-out the study. On study day visits when clinical laboratory 
tests are performed, assessment of vital signs should precede blood draw.
7.2.4. Columbia Suicide Severity Rating Scale (C-SSRS)
The Columbia Suicide Severity Rating Scale (C-SSRS) is a validated tool for investigative 
staff to use to evaluate suicidal ideation and behavior and will be completed at the Screening 
for subjects ≥7 years of age.  This is investigator completed.  For younger participants under 
7 years of age, the investigator/designee should assess the suicidal ideation and behavior 
risks clinically in consultation with their parents/caregivers.
7.3. Pregnancy Testing 
For female subjects of childbearing potential, a urine pregnancy test (beta-human chorionic 
gonadotropin (-hCG), with sensitivity of at least 25 mIU/mL, will be performed at 
screening, prior to dosing with investigational product on Day 1 and at the end-of-treatment 
(Day 29) visit, to confirm the subject has not become pregnant during the study.  
A negative pregnancy test result is required before the subject may receive the Crisaborole.  
Pregnancy tests will also be done whenever 1 menstrual cycle is missed during the active 
treatment period (or when potential pregnancy is otherwise suspected).  Pregnancy tests may 
also be repeated if requested by institutional review boards (IRBs)/ethics committees (ECs) 
or if required by local regulations or at the discretion of the investigator or his/her designee. 
Pediatric female subject who has not experienced menarche is not required to perform 
pregnancy testing.  If the pediatric female subject starts menarche during the study, 
pregnancy testing will be performed.


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Urine pregnancy tests must be sensitive to at least 25 mIU/mL and will be conducted at site 
with the test kit provided by the central laboratory in accordance with instructions provided 
in its package insert.  Subjects who have missed a menstrual period or who show an 
indeterminate or positive result on the urine test may not further progress in the study until 
pregnancy is ruled out using further diagnostic testing (eg, a negative quantitative serum 
pregnancy test conducted at a certified laboratory). In the case of a positive urine -hCG test
during the treatment period, the subject will have study drug interrupted and a serum sample 
submitted to the central laboratory for -hCG testing.  In the case of a positive confirmed 
pregnancy, the subject will be withdrawn from administration of investigational product and 
from the study; if the serum -hCG test is negative and investigator judges that the subject is 
not pregnant, the subject may resume investigational product.
8. ADVERSE EVENT REPORTING
8.1. Requirements
The table below summarizes the requirements for recording safety events on the CRF and for 
reporting safety events on the Clinical Trial (CT) Serious Adverse Event (SAE) Report Form
to Pfizer Safety.  These requirements are delineated for 3 types of events: (1) SAEs; 
(2) non-serious adverse events (AEs); and (3) exposure to the investigational product under 
study during pregnancy or breastfeeding, and occupational exposure. 
Safety Event
Recorded on the CRF
Reported on the CT SAE 
Report Form to Pfizer 
Safety Within 24 Hours of 
Awareness
SAE
All
All
Non-serious AE
All
None
Exposure to the 
investigational product 
under study during 
pregnancy or 
breastfeeding, and 
occupational exposure
All (regardless of whether 
associated with an AE), 
except occupational 
exposure
Exposure during pregnancy, 
exposure via breastfeeding, 
occupational exposure 
(regardless of whether 
associated with an AE)
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.


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


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All nonserious AEs and SAEs occurring in a participant during the active collection period, 
which begins after obtaining informed consent/assent as described in Section 8.1.4, will be 
recorded on the AE section of the CRF.
8.1.4.1. Reporting SAEs to Pfizer Safety
All SAEs occurring in a subject during the active collection period are reported to Pfizer 
Safety on the CT SAE Report Form.
SAEs occurring in a subject after the active collection period has ended are reported to Pfizer 
Safety if the investigator becomes aware of them; at a minimum, all SAEs that the 
investigator believes have at least a reasonable possibility of being related to investigational 
product must be reported to Pfizer Safety.
Follow up by the investigator continues throughout and after the active collection period and 
until the event or its sequelae resolve or stabilize at a level acceptable to the investigator, and 
Pfizer concurs with that assessment.
8.1.4.2. Recording Non-serious AEs and SAEs on the CRF
During the active collection period, both non-serious AEs and SAEs are recorded on the 
CRF.
Follow-up by the investigator may be required until the event or its sequelae resolve or 
stabilize at a level acceptable to the investigator, and Pfizer concurs with that assessment.
8.1.4.3. 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.


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8.1.4.4. Sponsor’s Reporting Requirements to Regulatory Authorities
AE reporting, including suspected unexpected serious adverse reactions, will be carried out 
in accordance with applicable local regulations.
8.2. Definitions
8.2.1. Adverse Events
An AE is any untoward medical occurrence in a study subject administered a product or 
medical device; the event need not necessarily have a causal relationship with the treatment 
or usage.  Examples of AEs include, but are not limited to: 

Abnormal test findings;

Clinically significant signs and symptoms;

Changes in physical examination findings;

Hypersensitivity;

Progression/worsening of underlying disease;

Drug abuse;

Drug dependency.
Additionally, AEs may include signs and symptoms resulting from:

Drug overdose;

Drug withdrawal;

Drug misuse; 

Drug interactions;

Extravasation;

Exposure during pregnancy (EDP);

Exposure via breastfeeding;


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
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.
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.


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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;

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);


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
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.
Note the distinction between the severity and the seriousness of an AE.  A severe event is not 
necessarily an SAE.  For example, a headache may be severe (interferes significantly with
the subject's usual function) but would not be classified as serious unless it met one of the 
criteria for SAEs, listed above.


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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;


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
For subjects with baseline AST OR ALT OR TBili values above the ULN, the 
following threshold values are used in the definition mentioned above, as needed, 
depending on which values are above the ULN at baseline:

Preexisting AST or ALT baseline values above the normal range: AST or ALT
values >2 times the baseline values AND >3 × ULN; or >8 × ULN (whichever is 
smaller).

Preexisting values of TBili above the normal range: TBili level increased from 
baseline value by an amount of at least 1 × ULN or if the value reaches >3 × ULN 
(whichever is smaller).
Rises in AST/ALT and TBili separated by more than a few weeks should be assessed 
individually based on clinical judgment; any case where uncertainty remains as to whether it 
represents a potential Hy’s law case should be reviewed with the sponsor. 
The subject should return to the investigator site and be evaluated as soon as possible, 
preferably within 48 hours from awareness of the abnormal results.  This evaluation should 
include laboratory tests, detailed history, and physical assessment.
In addition to repeating measurements of AST and ALT and TBili, laboratory tests should 
include albumin, creatine kinase (CK), direct and indirect bilirubin, gamma-glutamyl 
transferase (GGT), prothrombin time (PT)/international normalized ratio (INR), total bile
acids, alkaline phosphatase and acetaminophen drug and/or protein adduct levels.  
Consideration should also be given to drawing a separate tube of clotted blood and an 
anticoagulated tube of blood for further testing, as needed, for further contemporaneous 
analyses at the time of the recognized initial abnormalities to determine etiology.  A detailed 
history, including relevant information, such as review of ethanol, acetaminophen (either by 
itself or as a coformulated product in prescription or over-the-counter medications), 
recreational drug, supplement (herbal) use and consumption, family history, sexual history, 
travel history, history of contact with a jaundiced person, surgery, blood transfusion, history 
of liver or allergic disease, and potential occupational exposure to chemicals, should be 
collected.  Further testing for acute hepatitis A, B, C, D, and E infection and liver imaging 
(eg, biliary tract) may be warranted. 
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 


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of all the results of the investigations performed to determine etiology of the LFT 
abnormalities.
A potential DILI (Hy’s law) case becomes a confirmed case only after all results of 
reasonable investigations have been received and have excluded an alternative etiology.
8.4.3. Exposure to the Investigational Product During Pregnancy or Breastfeeding, and 
Occupational Exposure
Exposure to the investigational product under study during pregnancy or breastfeeding and 
occupational exposure are reportable to Pfizer Safety within 24 hours of investigator 
awareness.
8.4.3.1. Exposure During Pregnancy
For both unapproved/unlicensed products and for marketed products, an exposure during 
pregnancy (EDP) occurs if:

A female becomes, or is found to be, pregnant either while receiving or having been 
exposed (eg, because of treatment or environmental exposure) to the investigational 
product; or the female becomes or is found to be pregnant after discontinuing and/or 
being exposed to the investigational product.

An example of environmental exposure would be a case involving direct contact 
with a Pfizer product in a pregnant woman (eg, a nurse reports that she is pregnant 
and has been exposed to chemotherapeutic products).

A male has been exposed (eg, because of treatment or environmental exposure) to the 
investigational product prior to or around the time of conception and/or is exposed 
during his partner’s pregnancy. 

If a subject or subject’s partner becomes or is found to be pregnant during the 
subject’s treatment with the investigational product, the investigator must report this 
information to Pfizer Safety on the CT SAE Report Form and an EDP supplemental 
form, regardless of whether an SAE has occurred.  In addition, the investigator must 
submit information regarding environmental exposure to a Pfizer product in a 
pregnant woman (eg, a subject reports that she is pregnant and has been exposed to a 
cytotoxic product by inhalation or spillage) to Pfizer Safety using the EDP 
supplemental form.  This must be done irrespective of whether an AE has occurred 
and within 24 hours of awareness of the exposure.  The information submitted should 


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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.


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8.4.4. Medication Errors 
Other exposures to the investigational product under study may occur in clinical trial settings, 
such as medication errors.
Safety Event
Recorded on the CRF
Reported on the CT SAE 
Report Form to Pfizer 
Safety Within 24 Hours of 
Awareness
Medication errors 
All (regardless of whether 
associated with an AE)
Only if associated with an 
SAE
8.4.4.1. Medication Errors
Medication errors may result from the administration or consumption of the investigational 
product by the wrong subject, or at the wrong time, or at the wrong dosage strength.  
Medication errors include:

Medication errors involving participant exposure to the study intervention;

Potential medication errors or uses outside of what is foreseen in the protocol that do 
or do not involve the study participant.
For further clarification, a medication error is:

Any scenarios leading to inappropriate medication use or participant harm;

When participant misunderstood, could not read prescription, was not aware of, or not 
given appropriate dosing instructions.
A medication error is any unintentional error. Intentionally missing a dose or use of extra 
dose of study medication by a participant, who understands dosing instructions, is a 
compliance issue.
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 


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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.
Efficacy analyses will be performed on the Full Analysis Set (FAS) which includes all 
subjects who are randomized and dispensed investigational product.  Analyses based on the 
Per Protocol Analysis Set (PPAS) will be considered supportive.  The PPAS includes all 
subjects in the FAS who complete the Day 29 evaluation without any major protocol 
deviations.  Safety analyses will be performed on the Safety Analysis Set (SAFETY) which 
includes all subjects who are randomized and received at least one confirmed dose of 
investigational product. 
Major protocol deviations will be summarized.  Noncompliance with investigational product 
administration requirement will be summarized in terms of number of applications, number 
of days dosing, amount of drug used, and compliant status.  A subject will be considered 
compliant with the dosing regimen if the subject applies at least 80% but no more than 
120% of the expected applications during the investigational product application period, and 
has not missed 6 or more consecutive doses.
9.1. Sample Size Determination
The total sample size of 384 subjects in this study with a 2:1 randomization ratio (256:128) 
will provide approximately 90% power to detect a 12% difference of percent change from 
baseline in EASI total score at Day 29 between crisaborole arm and vehicle arm at the 
0.05 (2-sided) significance level,
 
Comparative EASI data relative to vehicle was not collected in previous crisaborole studies. 
The 12% treatment effect in EASI percent improvement was converted from the ISGA 
response in the Phase 3 studies using a linear regression equation that evaluated the 
relationship between ISGA response rate and EASI percent improvement from historical trial 
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data of other topical products (data on file).  From the crisaborole Phase 3 pooled data, the 
ISGA response rate is 32.1 % for crisaborole and 21.8% for vehicle.  The converted EASI 
percent improvement is 38.9% and 26.8% respectively.  The difference of EASI percent 
improvement between crisaborole and vehicle is approximately 12%.
9.2. Efficacy Analysis
9.2.1. Analysis of the Primary Endpoint
The primary efficacy endpoint, percent change from baseline in EASI total score at Day 29, 
will be analyzed using a linear mixed-effect model for repeated measures that includes 
treatment group, visit, and treatment group by visit interaction as factors and baseline value 
as a covariate.  Within-subject variability will be accounted for using a random effect with 
the first order autoregressive (AR(1)) covariance matrix.
9.2.2. Analysis of Key Secondary Endpoints
Type I error rate will be strictly controlled for the analyses of the key secondary efficacy 
endpoints with sequential testing in the following order: Improvement in ISGA (defined as 
ISGA score of Clear (0) or Almost Clear (1)) at Day 29, Success in ISGA (defined as an 
ISGA score of Clear (0) or Almost Clear (1) with at least a 2 grade improvement from 
Baseline) at Day 29, and change from baseline to Week 4 in weekly average of peak pruritus 
Numeric Rating Scale (NRS).  The percentage of subjects with Improvement in ISGA at 
Day 29 will be compared between crisaborole arm and vehicle arm and the difference will be 
tested based on normal approximation to response rates. Missing Day 29 ISGA scores will 
be derived for the analysis using the method of multiple imputations (MI) based on Markov 
Chain Monte Carlo (MCMC). 
The percentage of subjects with Success in ISGA at Day 29 will be analyzed in the same way
as Improvement in ISGA.  The same sets of imputed ISGA scores will be used for both 
Success in ISGA and Improvement in ISGA.
The change from baseline to Week 4 in weekly average of peak pruritus NRS will be 
analyzed using a linear mixed-effect model for repeated measures that includes treatment 
group, visit, and treatment -group by visit interaction as factors and baseline value as a 
covariate. Within-subject variability will be accounted for using a random effect with the first 
order autoregressive (AR(1)) covariance matrix.
9.2.3. Analysis of Other Secondary Endpoints
Other secondary efficacy endpoints including change from Baseline in % BSA, percent 
change from baseline in EASI total score at all time points other than Day 29, change from 


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baseline in weekly average of peak pruritus NRS of weeks other than Week 4, change from 
baseline in weekly average of Patient Reported Itch Severity Scale, and change from baseline 
in weekly average of Observer Reported Itch Severity Scale will be analyzed similarly as the 
primary efficacy endpoints using a linear mixed effect model for repeated measures.  
Other secondary efficacy endpoints including EASI50 and EASI75 at all time points, as well
as Success in ISGA and Improvement in ISGA at all time points other than Day 29, will be 
analyzed using normal approximation to response rates.
DLQI, CDLQI, IDQOL, DFI, POEM, PGIS/OGIS, PGIC/OGIC will be summarized 
descriptively, missing values will be handled following instrument-specific procedures when 
available and as per the SAP.
9.3. Safety Analysis
Safety data will be descriptively summarized and will be presented in tabular and/or 
graphical format.  No imputation will be made for missing safety data.  The following safety 
data will be summarized:

TEAEs, including SAEs;

Clinically significant changes in vital signs;

Clinically significant changes in laboratory parameters. 
9.4. Interim Analysis
No formal interim analysis will be conducted for this study.


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9.5. 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 IRB/EC, and/or to quality assurance audits performed by Pfizer, or companies 
working with or on behalf of Pfizer, and/or to inspection by appropriate regulatory 
authorities.
The investigator(s) will notify Pfizer or its agents immediately of any regulatory inspection 
notification in relation to the study.  Furthermore, the investigator will cooperate with Pfizer 
or its agents to prepare the investigator site for the inspection and will allow Pfizer or its 
agent, whenever feasible, to be present during the inspection.  The investigator site and 
investigator will promptly resolve any discrepancies that are identified between the study 
data and the subject's medical records.  The investigator will promptly provide copies of the 
inspection findings to Pfizer or its agent.  Before response submission to the regulatory 
authorities, the investigator will provide Pfizer or its agents with an opportunity to review 
and comment on responses to any such findings.
It is important that the investigator(s) and their relevant personnel are available during the 
monitoring visits and possible audits or inspections and that sufficient time is devoted to the 
process.


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11. DATA HANDLING AND RECORD KEEPING
11.1. Case Report Forms/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[/assent] documents, copies of all CRFs, safety reporting forms, source 
documents, and detailed records of treatment disposition, and adequate documentation of 
relevant correspondence (eg, letters, meeting minutes, and telephone call reports).  The 
records should be retained by the investigator according to the ICH guidelines, according to 
local regulations, or as specified in the clinical study agreement (CSA), whichever is longer.
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 


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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[/assent] 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 


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maintain high standards of confidentiality and protection of subjects’ personal data consistent 
with applicable privacy laws.
The informed consent[/assent] 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[/assent] documents used during the informed consent process and any 
subject recruitment materials must be reviewed and approved by Pfizer, approved by the 
IRB/EC before use, and available for inspection.
The investigator must ensure that each study subject, or parent(s) or legal guardian if a minor 
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) or 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), 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), and that the 
subject’s assent was obtained or waived.  If assent is obtained verbally, it must be 
documented in the source documents.
If the study includes minor subjects who reach the age of majority during the study, as 
recognized under local law, they must reconsent 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. 
The investigator, or a person designated by the investigator, will obtain written informed 
consent from each subject [or the subject's parent(s) or legal guardian and the subject’s 
assent, when applicable,] before any study-specific activity is performed [unless a waiver of 
informed consent has been granted by an IRB/EC].  The investigator will retain the original 
of each subject's signed consent[/assent] document.


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Crisaborole will not be provided to subjects after the study is over. 
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.


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


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


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16. REFERENCES
1.
Bieber T. Atopic dermatitis. N Engl J Med 2008;358(14):1483–94. 
2.
Lewis Jones S. Quality of life and childhood atopic dermatitis: the misery of living with 
childhood eczema. Int J Clin Pract. 2006 Aug;60(8):984 92.
3.
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.
Gu Heng, YAN Yan, CHEN Kun, et al. Survey on Atopic Dermatitis in China. Chin J 
Dermatol. 2000 Dec 33 (6):379-382. 
6.
GU Heng, You Li-ping, LIU Yong-sheng, et al. Survey on the Prevalence of Childhood 
Atopic Dermatitis in Ten Cities of China. Chin J Dermatol.2004 Jan 37 (1):29-31.
7.
Feng Xu, Shuxian Yan, Fei Li, et al. Prevalence of Childhood Atopic Dermatitis: An 
Urban and Rural Community-Based Study in Shanghai, China. PLoS  ONE. 2012 May 
7(5 ): e36174.
8.
Guo Y, Li P, Tang J, et al. Prevalence of Atopic Dermatitis in Chinese Children aged 
1-7 ys. Sci Rep. 2016 Jul 19;6:29751.
9.
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. 
10.
Leung DY. New insights into atopic dermatitis: role of skin barrier and immune 
dysregulation. Allergol Int. 2013 Jun;62(2):151 61. 
11.
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). 
12.
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. 
13.
Garg N, Silverberg J. Epidemiology of childhood atopic dermatitis. Clin Dermatol. 
2015 May Jun;33(3):281 8.


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14.
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.
15.
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.
16.
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.
17.
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.
18.
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.
19.
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.
20.
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.
21.
Daud LR, Garralda ME, David TJ. Psychosocial adjustment in preschool children with
atopic eczema. Arch Dis Child. 1993 Dec;69(6):670 6.
22.
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.
23.
Watson W, Kapur S. Atopic dermatitis. Allergy Asthma Clin Immunol. 2011 Nov 10;7 
Suppl 1:S4.
24.
Paller AS, Tom WL, Lebwohl MG, et al. Efficacy and safety of crisaborole ointment, a 
novel, nonsteroidal phosphodiesterase 4 (PDE4) inhibitor for the topical treatment of 
atopic dermatitis (AD) in children and adults. J Am Acad Dermatol. 2016 
Sep;75(3):494-503.
25.
Pfizer Investigator Brochure for Crisaborole, February 2017.


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26.
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. 
27.
Yosipovitch G, Reaney M, Mastey V, et al. Peak Pruritus Numerical Rating Scale: 
Psychometric Validation and Responder Definition for Assessing Itch in Moderate-To-
Severe Atopic Dermatitis. Br J Dermatol. 2019.
28.
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.
29.
Ersser SJ, Cowdell F, Latter S, et al. Psychological and educational interventions for 
atopic eczema in children. Cochrane Database Syst Rev. 2014(1):CD004054.
30.
Schmitt J, Langan S, Williams HC, et al. What are the best outcome measurements for 
atopic eczema? A systematic review. J Allergy Clin Immunol. 2007;120(6):1389-98.
31.
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
AM
Morning
AR
Autoregressive
AST
Aspartate Aminotransferase
BBS
Biospecimen Banking System
BID
Twice Daily
BP
Blood Pressure
BPO
Benzoyl Peroxide
%BSA
Percent Body Surface Area
cAMP
Cyclic Adenosine Monophosphate
CI
Confidence Interval
CK
Creatine Kinase
Cmax
Maximum Observed Plasma Concentration
CDLQI
Children’S Dermatology Life Quality Index
CRF
Case Report Form
CSA
Clinical Study Agreement
CSR
Clinical Study Report
C-SSRS
Columbia Suicide Severity Rating Scale
CT
Clinical Trial
CTA
Clinical Trial Application
DFI
Dermatitis Family Impact Questionnaire
DILI
Drug-Induced Liver Injury
DLQI
Dermatology Life Quality Index
DNA
Deoxyribonucleic Acid
DU
Dispensable Unit
EASI
Eczema Area And Severity Index
EC
Ethics Committee
EC50
Half Maximal Effective Concentration
E-DMC
External Data Monitoring Committee 
EDP
Exposure During Pregnancy
EU
European Union


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Abbreviation
Term
EudraCT
European Clinical Trials Database
FAS
Full Analysis Set
FDA
Food And Drug Administration
FSH
Follicle Stimulating Hormone
GCP
Good Clinical Practice
GGT
Gamma-Glutamyl Transferase
HRQOL
Health-Related Quality Of Life
IB
Investigator’S Brochure
ID
Identification
ICH
International Conference On Harmonisation
IDQOL
Infants’ Dermatitis Quality Of Life Index
IND
Investigational New Drug Application
INR
International Normalized Ratio
IP
Investigational Product
IRB
Institutional Review Board
IRT
Interactive Response Technology
ISGA
Investigator’S Static Global Assessment
IUD
Intrauterine Devicem
IWR
Interactive Web Response
JAK
Janus Kinase
LFT
Liver Function Test
LOCF
Last Observation Carried Forward
LSLV
Last Subject Last Visit 
MI
Multiple Imputations
MCMC
Markov Chain Monte Carlo
MMF
Mycophenolate Mofetil
MMP
matrix metalloproteinase
MUSE
Maximal Use Systemic Exposure
N/A
Not Applicable
NRI
Non Responder Imputation
NRS
Numeric Rating Scale
OGIC
Observer Global Impression of Change
OGIS
Observer Global Impression of Severity
PCD
Primary Completion Date
PD
Pharmacodynamics(S)
PDE4
Phosphodiesterase-4
PGIC
Patient Global Impression of Change


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Abbreviation
Term
PGIS
Patient Global Impression of Severity
PI
Principal Investigator
PK
Pharmacokinetic
PM
Evening
PMA
Phorbol 12-myristate 13-acetate
POEM
Patient-Oriented Eczema Measure
PKA
Protein Kinase A
PPAS
Per Protocol Analysis Set
PRN
As Needed
PT
Prothrombin Time
PUVA
Psoralen–UV-A
QD
Once Daily
QoL
Quality of Life
RNA
Ribonucleic Acid
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SOP
Standard Operating Procedure
SRSD
Single Reference Safety Document
SSIN
Subject Screening Identification Number
SUSAR
Suspected Unexpected Serious Adverse Reaction
TEAE
Treatment Emergent Adverse Event
TBili
Total Bilirubin
Tmax
Time to Reach Maximum Observed Plasma Concentration
TQT
Thorough QT/QTc
TSS
Target Sign Scores
ULN
Upper Limit of Normal
US
United States


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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.31
Table 6.
Hanifin and Rajka’s Diagnostic Criteria for Atopic Dermatitis
Major Criteria (must have at least three)
Pruritus
Typical morphology and distribution:
Adults: flexural lichenification or linearity
Children and infants: facial and extensor involvement
Chronic or chronically-relapsing dermatitis
Personal or family history of atopy (asthma, allergic rhinitis, atopic dermatitis)
Minor Criteria (must have at least three)
Xerosis
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


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Food intolerance
Course influenced by environmental and emotional factors
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SAP_001.pdf: 
Protocol C3291032 (PF-06930164) Statistical Analysis Plan
PFIZER CONFIDENTIAL 
Page 1
Protocol C3291032
A PHASE 3, MULTICENTER, RANDOMIZED, DOUBLE-BLIND, 
VEHICLE-CONTROLLED STUDY OF THE EFFICACY AND SAFETY OF 
CRISABOROLE OINTMENT, 2% IN CHINESE AND JAPANESE PEDIATRIC AND 
ADULT SUBJECTS (AGES 2 YEARS AND OLDER) WITH MILD TO MODERATE 
ATOPIC DERMATITIS
Statistical Analysis Plan 
(SAP)
Version:
3
Date:
18-Sep-2021


Protocol C3291032 (PF-06930164) Statistical Analysis Plan
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TABLE OF CONTENTS
LIST OF TABLES.....................................................................................................................4
LIST OF FIGURES ...................................................................................................................4
APPENDICES ...........................................................................................................................5
1. VERSION HISTORY............................................................................................................6
2. INTRODUCTION .................................................................................................................7
2.1. Study Objectives, Endpoints, and Estimands............................................................8
2.2. Study Design ...........................................................................................................13
3. ENDPOINTS AND BASELINE VARIABLES:  DEFINITIONS AND 
CONVENTIONS ................................................................................................................14
3.1. Primary Endpoints...................................................................................................14
3.2. Secondary Endpoints...............................................................................................14
3.3. Other Endpoint(s)....................................................................................................15
3.4. Baseline Variables...................................................................................................16
3.5. Safety Endpoints .....................................................................................................17
3.5.1. Adverse Events...........................................................................................17
3.5.2. Laboratory Data..........................................................................................17
3.5.3. Physical Examinations................................................................................18
3.5.4. Vital Signs ..................................................................................................18
4. ANALYSIS SETS ...............................................................................................................18
5. GENERAL METHODOLOGY AND CONVENTIONS....................................................19
5.1. Hypotheses and Decision Rules ..............................................................................19
5.2. General Methods .....................................................................................................19
5.2.1. Analyses for Binary Endpoints...................................................................19
5.2.2. Analyses for Continuous Endpoints ...........................................................20
5.2.3. Analyses for Time-to-Event Endpoints ......................................................20
5.3. Methods to Manage Missing Data ..........................................................................20
6. ANALYSES AND SUMMARIES ......................................................................................21
6.1. Primary Endpoints...................................................................................................21
6.1.1. Percent Change from Baseline in EASI total score at Day 29 ...................21
6.1.1.1. Main Analysis ...........................................................................21
6.1.1.2. Supplementary Analyses...........................................................21


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6.1.2. TEAEs  (including application site reactions) & SAEs and clinically 
significant changes in vital signs and clinical laboratory parameters..............22
6.2. Secondary Endpoints...............................................................................................22
6.2.1. Achievement of Improvement in ISGA at Day 29 .....................................22
6.2.1.1. Main Analysis ...........................................................................22
6.2.1.2. Supportive/Supplementary Analysis.........................................22
6.2.2. Achievement of Success in ISGA at Day 29..............................................23
6.2.2.1. Main Analysis ...........................................................................23
6.2.2.2. Supportive/Supplementary Analysis.........................................23
6.2.3. Change from Baseline in Peak Pruritus NRS at Week 4 – for subjects 
൒12 years .........................................................................................................23
6.2.3.1. Main Analysis ...........................................................................23
6.2.3.2. Supplementary Analyses...........................................................24
6.2.4. Success in ISGA and Improvement in ISGA over time .............................24
6.2.5. Percent Change from baseline in EASI total score over time ....................25
6.2.6. Change from baseline in %BSA over time.................................................25
6.2.7. Achivevment of EASI-50, EASI-75 over time...........................................25
6.2.8. Change from Baseline in Peak Pruritus NRS over time - for 
subjects൒12 years ............................................................................................26
6.2.9. Change from Baseline in Patient Reported Itch Severity Scale over 
time - for subjects ൒6 years and <12 years......................................................26
6.2.10. Change from Baseline in Observer Reported Itch Severity Scale 
over time - for subjects <6 years......................................................................27
6.2.11. DLQI, CDLQI, IDQOL, DFI, POEM, PGIS/OGIS, PGIC/OGIC 
over time ..........................................................................................................27
6.4. Subset Analyses.......................................................................................................31
6.5. Baseline and Other Summaries and Analyses.........................................................31
6.5.1. Baseline Summaries....................................................................................31
6.5.2. Study Conduct and Participant Disposition................................................31
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6.5.3. Study Treatment Exposure .........................................................................31
6.5.4. Concomitant Medications and Nondrug Treatments..................................31
6.6. Safety Summaries and Analyses .............................................................................31
6.7. Additional Analyses to Address COVID-19 Pandemic Impacts.............................32
7. INTERIM ANALYSES.......................................................................................................32
7.1. Introduction .............................................................................................................32
7.2. Interim Analyses and Summaries............................................................................32
8. REFERENCES ....................................................................................................................32
9. APPENDICES .....................................................................................................................33
LIST OF TABLES
Table 1.
Summary of Changes..................................................................................6
LIST OF FIGURES
Figure 1.
Study Design Schematic...........................................................................14


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APPENDICES
Appendix 1. Summary of Efficacy Analysis ...........................................................................34
Appendix 2. DATA DERIVATION DETAILS ......................................................................37
Appendix 2.1. Definition and Use of Visit Windows in Reporting.........................................37
Appendix 3. Details of Efficacy Assessments .........................................................................38
Appendix 3.1. Investigator's Static Global Assessment (ISGA) .............................................38
Appendix 3.2. Eczema Area and Severity Index (EASI).........................................................39
Appendix 3.3. Peak Pruritus Numerical Rating Scale (NRS) for subjects ൒12 years, 
Patient Reported Itch Severity Scale - for subjects age 6-11 years, 
and Observer Reported Itch Severity Scale - for subjects <6 years. ........43
Appendix 3.4. Dermatology Life Quality Index (DLQI).........................................................45
Appendix 3.5. Children’s Dermatology Life Quality Index (CDLQI)....................................49
Appendix 3.6. Dermatitis Family Impact Questionnaire (DFI)...............................................52
Appendix 3.7. The Infant’s Dermatitis Quality of Life Index (IDQOL).................................54
Appendix 3.8. Patient Oriented Eczema Measure (POEM) ....................................................57
Appendix 3.9. Patient Global Impression of Change (PGIC) and Observer Reported 
Global Impression of Change (OGIC)......................................................60
Appendix 3.10. Patient Global Impression of Severity (PGIS) and Observer Reported 
Global Impression of Severity (OGIS).....................................................60
Appendix 4. List of Abbreviations...........................................................................................62


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1. VERSION HISTORY
Table 1.
Summary of Changes
Version/
Date
Associated
Protocol 
Amendment
Rationale
Specific Changes
1
20 Oct 2017
Original 
17 Oct 2017
N/A
N/A
2
13 Apr 2020
Protocol 
Amendment 
1  
15 Nov 2019
Issuance of a 
protocol 
amendment, 
template 
change, TLF 
bold moves
Update endpoints to align with global 
clinical development program, including: 
•
Update the primary and key secondary 
estimands.
•
Change primary endpoint from
Investigator’s Static Global Assessment 
(ISGA) to Eczema Area and Severity 
Index (EASI).
•
Addition of ISGA as a key secondary 
endpoint.
•
Update the analysis for Patient Reported 
Outcomes (PROs).  
•
Update the analysis for Dermatology 
Life Quality Index (DLQI), Children’s 
Dermatology Life Quality Index
(CDLQI), Infant’s Dermatitis Quality of 
Life Index (IDQOL), Dermatitis Family 
Impact Questionnaire (DFI), Patient 
Oriented Eczema Measure (POEM), 
Patient Global Impression of Change
(PGIC)/ Observer Reported Global 
Impression of Change (OGIC).
 
3
18 Sep 2021
Protocol 
Amendment 
3
18 Dec 2020
To align with 
the current 
protocol, 
specify PPAS 
criteria, provide 
further 
clarification on 
•
Updated Section 2 to align with the 
current protocol.
•
Updated the detailed list of PPAS 
criteria.
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Table 1.
Summary of Changes
Version/
Date
Associated
Protocol 
Amendment
Rationale
Specific Changes
analysis and 
reporting 
details, add 
additional 
analyses to 
address 
COVID-19 
pandemic 
impacts.

Added detailed descriptive summary 
statistics for binary and continuous 
variables.

Deleted supportive analysis for 
Section 6.1.1 and Section 6.2.3.

Missing data handlings in Section 6.2.4,
Section 6.2.5 and Section 6.2.8 are 
updated to align with the analysis of 
primary and key secondary estimands.

Updated the analysis set in 
Section 6.2.2, Section 6.2.4, 
Section 6.3.1, Section 6.3.2 and 
Section 6.3.3 to exclude participants
who do not have the chance to achieve 
the event.

Added additional analyses to address 
COVID-19 pandemic impacts in 
Section 6.7.

Added by country safety summaries in 
Section 6.4.
2. INTRODUCTION
Crisaborole, also referred 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. The primary mechanism of the anti-inflammatory effect 
of crisaborole is through inhibition of PDE 4.  Crisaborole has demonstrated in vitro 
inhibition of a range of cytokines implicated in the pathogenesis of atopic dermatitis (AD).  
Crisaborole inhibits the release of chemokines that are also important inflammatory 
mediators.  Crisaborole applied to human skin ex vivo or on AD lesions on a subject reduces 
expression of key drivers of atopic inflammation including T-cell derived cytokines IL-13, IL-
31, and interferon gamma (IFNγ) as well as innate markers of inflammation such as matrix 
metalloproteinase (MMP)12.
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 


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common, chronic dermatologic condition and the treatment limiting effects of currently 
available therapies.  All primary and secondary efficacy endpoints were statistically 
significant in the two Phase 3 registration studies.  Across the development program, 
Crisaborole demonstrated an acceptable safety profile, with no crisaborole treatment related 
Serious Adverse Events (SAEs) and with the majority of Adverse Events (AEs) being mild and 
deemed unlikely or not related to investigational product.  
In this China and Japan study, a similar study design to the two global pivotal studies 
(AN2728-AD-301 and AN2728-AD-302) will be used to investigate the efficacy and safety of 
crisaborole ointment, 2% twice daily (BID) in Chinese and Japanese pediatric and adult 
subjects (ages 2 years and older) with mild to moderate AD, to support the registration of 
crisaborole in China and Japan.
This SAP provides the detailed methodology for summary and statistical analyses of the data 
collected in study C3291032.  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, Endpoints, and Estimands
Estimands will be defined for the primary and key secondary efficacy objectives.
Objectives
Endpoints
Estimands
Primary:
Primary:
Primary:

To evaluate the 
efficacy of 
crisaborole 
ointment, 2% 
applied BID versus 
Vehicle in Chinese 
and Japanese
pediatric and adult 
subjects (ages 2 
years and older) 
with mild to 
moderate AD.

Percent Change from Baseline 
in EASI total score at Day 29.
The estimand is the hypothetical 
estimand, which estimates the effect if 
all participants maintain their 
randomized treatment and adhere to 
the protocol.  It includes the following 
5 attributes:

Treatment: Crisaborole Ointment 
2% BID vs Vehicle Ointment 
BID.

Population: Chinese and 
Japanese pediatric and adult 
subjects (ages 2 years and older) 
with mild to moderate AD as 
defined by the inclusion and 
exclusion criteria.

Variable: % change from 
baseline in EASI total score at 
Day 29. 


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Objectives
Endpoints
Estimands

Intercurrent events: Had patient 
not discontinued from treatment
prior to Day 29.

Population-level summary:
Difference in means between 
crisaborole ointment 2% BID vs
corresponding vehicle.

To evaluate the 
safety and 
tolerability of 
crisaborole
ointment, 2% 
applied BID versus 
Vehicle in Chinese 
and Japanese
pediatric and adult 
subjects (ages 2 
years and older) 
with mild to 
moderate AD.

Treatment emergent adverse 
events (TEAEs)  (including 
application site reactions) & 
SAEs, and clinically 
significant changes in vital 
signs and clinical laboratory 
parameters.
No estimands will be defined.
Key Secondary:
Key Secondary:
Key Secondary:

To evaluate the 
effect of 
crisaborole
ointment, 2% 
applied BID versus 
Vehicle on 
additional efficacy 
endpoints in 
Chinese and 
Japanese pediatric 
and adult subjects 
(Ages 2 years and 
older) with mild to 
moderate AD. 

Achievement of Improvement 
in ISGA (defined as ISGA 
score of clear (0) or almost 
clear (1)) at Day 29.
The estimand is the hypothetical 
estimand, which estimates the effect if 
all participants maintain their 
randomized treatment and adhere to 
the protocol.  It includes the following 
5 attributes

Treatment: Crisaborole Ointment 
2% BID vs Vehicle Ointment 
BID.

Population: Chinese and 
Japanese pediatric and adult 
subjects (ages 2 years and older) 
with mild to moderate AD as 
defined by the inclusion and 
exclusion criteria

Variable: Improvement in ISGA 
at Day 29.

Intercurrent events: Had patient 
not discontinued from treatment
prior to Day 29.


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Objectives
Endpoints
Estimands
•
Population-level summary:
Difference in percentage of 
subjects with Improvement in 
ISGA between crisaborole 
ointment 2% BID vs
corresponding vehicle.
Secondary:
Secondary:
Secondary:
•
To evaluate the 
effect of 
crisaborole 
ointment, 2% 
applied BID versus 
Vehicle on 
additional efficacy 
endpoints in 
Chinese and 
Japanese pediatric 
and adult subjects 
(Ages 2 years and 
older) with mild to 
moderate AD.
•
Achievement of Success in 
ISGA (defined as an ISGA 
score of Clear (0) or Almost 
Clear (1) with at least a 2 
grade improvement from 
Baseline) at Day 29.
The estimand is the hypothetical 
estimand, which estimates the effect if 
all participants maintain their 
randomized treatment and adhere to 
the protocol.  It includes the following 
5 attributes
•
Treatment: Crisaborole Ointment 
2% BID vs Vehicle Ointment 
BID.
•
Population: Chinese and 
Japanese pediatric and adult 
subjects (ages 2 years and older) 
with mild to moderate AD as 
defined by the inclusion and 
exclusion criteria.
•
Variable: Success in ISGA at 
Day 29.
•
Intercurrent events: Had patient 
not discontinued from treatment 
prior to Day 29.
•
Population-level summary:
Difference in percentage of 
subjects with Success in ISGA
between crisaborole ointment 2%
BID vs corresponding vehicle.
•
To evaluate the 
effect of 
crisaborole
ointment, 2% 
applied BID versus 
Vehicle on 
patient/observer 
reported outcomes 
over time in 
Chinese and 
•
Change from Baseline in Peak 
Pruritus Numeric Rating Scale 
(NRS) at Week 4 - for subjects 
൒12 years.
The estimand is the hypothetical 
estimand, which estimates the effect if 
all participants maintain their 
randomized treatment and adhere to 
the protocol.  It includes the following 
5 attributes:


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Objectives
Endpoints
Estimands
Japanese pediatric 
and adult subjects 
(Ages 2 years and 
older) with mild to 
moderate AD.
•
Treatment: Crisaborole Ointment 
2% BID vs Vehicle Ointment 
BID.
•
Population: Chinese and 
Japanese pediatric and adult 
subjects (ages 2 years and older) 
with mild to moderate AD as 
defined by the inclusion and 
exclusion criteria.
•
Variable: Change from Baseline 
in Peak Pruritus NRS at Week 4 
for subjects ൒12 years.
•
Intercurrent events: Had patient 
not discontinued from treatment 
prior to Day 29.
•
Population-level summary:
Difference in means between 
crisaborole ointment 2% BID vs 
corresponding vehicle.
Other Secondary:
Other Secondary:
Other Secondary:
•
To evaluate the 
effect of 
crisaborole 
ointment, 2% 
applied BID versus 
Vehicle on 
additional efficacy 
endpoints in 
Chinese and 
Japanese pediatric 
and adult subjects 
(Ages 2 years and 
older) with mild to 
moderate AD.
•
To evaluate the 
effect of 
crisaborole 
ointment, 2% 
applied BID versus 
Vehicle on 
patient/observer 
reported outcomes 
over time in 
•
Success in ISGA (defined as 
an ISGA score of Clear (0) or 
Almost Clear (1) with at least 
a 2 grade improvement from 
Baseline) over time.
•
Improvement in ISGA 
(defined as ISGA score of 
clear (0) or almost clear (1))
over time.
•
Percent change from Baseline 
in EASI total score over time. 
•
Change from Baseline in %
body surface area (BSA) over 
time.
•
Achievement of EASI-50 
(൒50% improvement from 
baseline) over time.
•
Achievement of EASI-75 
(൒75% improvement from 
baseline) over time.
•
Change from baseline in Peak 
Pruritus NRS over time - for
subjects൒12 years.
No estimands will be defined. 


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Objectives
Endpoints
Estimands
Chinese and 
Japanese pediatric 
and adult subjects 
(Ages 2 years and 
older) with mild to 
moderate AD.
•
Changes from baseline in 
Patient Reported Itch Severity 
Scale over time - for subjects
൒6 years and <12 years.
•
Change from baseline in 
Observer Reported Itch 
Severity Scale over time - for 
subjects <6 years.
•
DLQI, CDLQI, IDQOL, DFI, 
POEM, PGIS/OGIS, 
PGIC/OGIC over time.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Objectives
Endpoints
Estimands
 
 
 
 
2.2. Study Design
This is a Phase 3, multicenter, randomized, double blind, vehicle controlled study to evaluate 
the efficacy and safety of crisaborole ointment 2% in Chinese and Japanese pediatric and 
adult subjects (ages 2 years and older) with mild to moderate atopic dermatitis involving at 
least 5% treatable BSA.
A total of approximately 384 subjects (approximately 50% for age ൒12 years old and 
approximately 50% for age <12 years old) will be enrolled in the study from multiple sites in 
China and Japan.  Following the screening period (up to 35 days prior to Baseline/Day 1), 
eligible subjects will be randomized at the Baseline/Day 1 visit in a 2:1 ratio to one of 2 
treatment groups (crisaborole ointment, 2% BID; vehicle BID, respectively), the 
investigational product will be applied BID for 28 days to the Treatable BSA identified at 
Baseline/Day 1 and new AD lesions that appear after the Baseline/Day 1. The primary 
efficacy endpoint, percent change from baseline in EASI total score, will be assessed at Day 
29.  
Scheduled study visits for all subjects will occur at Screening, Baseline/Day 1, Day 8, Day 
15, Day 22, Day 29 (End of treatment/Early termination).  A follow up telephone call will be 
made by site staff to the subjects and/or parents/legal guardians on Day 36 and Day 60. 
Japan participants who rolled over into study C3291027 without a Post Treatment Follow 
Up period prior to 21 Oct 2020  are considered completers in this study. A schematic of the 
study design is shown in Figure 1.
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Figure 1.
Study Design Schematic
3. ENDPOINTS AND BASELINE VARIABLES:  DEFINITIONS AND 
CONVENTIONS
3.1. Primary Endpoints
Efficacy endpoint: Percent Change from Baseline in EASI total score at Day 29.
Safety endpoint: TEAEs  (including application site reactions) & SAEs and clinically 
significant changes in vital signs and clinical laboratory parameters.
3.2. Secondary Endpoints
Efficacy endpoints:

Key secondary efficacy endpoints

Achievement of Improvement in ISGA (defined as ISGA score of clear (0) or 
almost clear (1)) at Day 29.
n ≈256
n ≈128
Japan participants who rolled over into study 
C3291027 without a Post Treatment Follow Up period
prior to 21 Oct 2020 are considered completers in this 
study.


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•
Achievement of Success in ISGA (defined as an ISGA score of Clear (0) or 
Almost Clear (1) with at least a 2 grade improvement from Baseline) at Day 
29.
•
Change from Baseline in Peak Pruritus Numeric Rating Scale (NRS) at Week 
4 - for subjects ൒12 years.
•
Other secondary efficacy endpoints
•
Success in ISGA (defined as an ISGA score of Clear (0) or Almost Clear (1) 
with at least a 2 grade improvement from Baseline) over time.
•
Improvement in ISGA (defined as ISGA score of clear (0) or almost clear (1))
over time.
•
Percent change from Baseline in EASI total score over time. 
•
Change from Baseline in %BSA over time.
•
Achievement of EASI-50 (≥50% improvement from baseline) over time.
•
Achievement of EASI-75 (≥75% improvement from baseline) over time.
•
Change from baseline in Peak Pruritus NRS over time - for subjects ൒12 
years.
•
Changes from baseline in Patient Reported Itch Severity Scale over time - for 
subjects ൒6 years and <12 years.
•
Change from baseline in Observer Reported Itch Severity Scale over time - for 
subjects <6 years.
•
DLQI, CDLQI, IDQOL, DFI, POEM, PGIS/OGIS, PGIC/OGIC over time.
 
 
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3.4. Baseline Variables
For Peak Pruritus NRS, Patient/Observer Reported Itch Severity Scale and PGIS/OGIS, the 
average of the latest available 7-day scores immediately prior to Day 1 (including Day 1) will 
be used as the baseline. The baseline is considered missing if the daily scores are only 
available for less than four days. If the daily scores are available for more than three days, 
then the baseline is calculated as the average of the available scores. 
Day 1 is defined as the first dosing date.
The baseline values of all other endpoints are defined as the last values collected prior to the 
first dose of study drug.
Baseline variables include
•
Demographics;  
•
Height and weight;
•
ISGA score;
•
EASI total score;
•
Peak Pruritus NRS, Patient/Observer Reported Itch Severity Scale;
•
Treatable %BSA;
•
DLQI/CDLQI/IDQOL;
•
DFI;
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•
POEM;
•
PGIS/OGIS;
These data will be summarized as part of the demographic characteristics and baseline 
characteristics.
3.5. Safety Endpoints
Safety will be assessed by the spontaneous reporting of AEs, SAEs, physical examinations, 
vital signs, and clinical laboratory results in all subjects who receive at least one dose of the 
investigational product.  Unscheduled safety assessments may be performed at any time 
during the study to assess any perceived safety concerns.
Safety data will be descriptively summarized and will be presented in tabular. No imputation 
will be made for missing safety data.  The following safety data will be summarized:
•
TEAEs, including SAEs;
•
Clinically significant changes in vital signs;
•
Clinically significant changes in laboratory parameters.  
3.5.1. Adverse Events
An adverse event will be considered as a TEAE if the event started after the first dose of 
treatment regardless of whether a similar event of equal or greater severity existed in the 
baseline period.
Adverse events will be assessed by the spontaneous reporting of:
•
Incidence of TEAEs;
•
Incidence of SAEs;
•
Incidence of AEs leading to discontinuation.
3.5.2. Laboratory Data
Below is a list of clinical laboratory test parameters.
•
Hematology: hemoglobin, hematocrit, red blood cell count, platelet count, white 
blood cell count (% and absolute), neutrophils, eosinophils, monocytes, basophils and 
lymphocytes.
•
Chemistry: blood urea nitrogen/Urea, glucose, creatinine, sodium, potassium, 
chloride, Bicarbonate or Total CO2, alanine aminotransferase, aspartate 
aminotransferase, total bilirubin, alkaline phosphatase, albumin, and total protein.
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3.5.3. Physical Examinations
A physical examination includes, but not limited to the following organ or body systems; 
head, ears, eyes, nose, mouth, skin, heart and lung examinations, lymph nodes,
musculoskeletal, abdomen (liver, spleen), and neurological systems. In addition, an 
assessment will be made of the condition of all AD-involved skin.
3.5.4. Vital Signs
Vital sign measurements are temperature, respiratory rate, pulse rate, and blood pressures.
4. ANALYSIS SETS
Population
Description
Full Analysis Set (FAS)
All subjects randomized and dispensed study drug, subjects are 
assigned to the randomized treatment regardless of what 
treatment was received.
Per Protocol Analysis Set 
(PPAS)
All subjects in the FAS who complete the Day 29 evaluation
without any major protocol deviations.
Safety Analysis Set
All subjects who are randomized and received at least one 
confirmed dose of investigational product. The subject will be 
assigned to the randomized treatment group if he received at 
least one dose of the randomized treatment. The subject will be 
assigned to the other treatment group if he does not receive any 
of the randomized treatment.
Specifically, PPAS will include subjects in the FAS who meet all of the following criteria:
•
Met all of the Inclusion Criteria and none of the Exclusion Criteria;
•
Have not taken any prohibited concomitant medications during the treatment period;
•
Completed the Day 29 Visit, including the Day 29 efficacy evaluation of EASI and 
ISGA, subjects ൒12 years who have missing Week 4 Peak Pruritus NRS evaluation 
will be excluded;
•
Have applied 80%–120% of the total number of expected doses (56 doses) during the 
treatment period;
•
Have not missed 6 or more consecutive doses during the treatment period;
•
Were in the visit window (±3 days) for the Day 29 Visit.
Subjects who prematurely discontinue from the study due to lack of efficacy or a treatment 
related TEAE will be placed back into PPAS.


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Data for all participants will be assessed to determine if participants meet the criteria for 
inclusion in PPAS prior to unblinding and releasing the database and classifications will be 
documented per standard operating procedures.
5. GENERAL METHODOLOGY AND CONVENTIONS
The final analysis will be performed based on the final released data set after last subject last
visit (LSLV).
5.1. Hypotheses and Decision Rules
The study will be declared a success with crisaborole shown to be superior to vehicle with 
respect to the primary efficacy endpoint, percent change from baseline in EASI total score at 
Day 29, if the mean percent change in the Crisaborole arm is lower than that in the vehicle 
arm and the difference is statistically significant at the two-sided level of 0.05.
After crisaborole is shown to be superior to vehicle with respect to the primary efficacy 
endpoint, it will be compared with vehicle with respect to the key secondary efficacy 
endpoints using gate-keeping method. 
After and only after crisaborole is shown to be superior to vehicle with respect to the percent 
change from baseline in EASI total score at Day 29, crisaborole will be declared superior to 
vehicle with respect to the improvement rate in ISGA at Day 29, i.e., the percentage of 
patients with ISGA score of Clear (0) or Almost Clear (1), at Day 29, if the rate in the 
crisaborole arm is higher than that in the vehicle arm and the difference is statistically 
significant at the two-sided level of 0.05.
After and only after crisaborole is shown to be superior to vehicle with respect to the 
improvement rate in ISGA at Day 29, crisaborole will be declared superior to vehicle with 
respect to the success rate in ISGA at Day 29, i. e, the percentage of patients with ISGA 
score of Clear (0) or Almost Clear (1) with at least a 2 grade improvement from Baseline, at 
Day 29, if the rate in the crisaborole arms is higher than that in the vehicle arm and the 
difference is statistically significant at the two-sided level of 0.05.
After and only after crisaborole is shown to be superior to vehicle with respect to the success 
rate in ISGA at Day 29, crisaborole will be declared superior to vehicle with respect to the 
change from baseline in Peak Pruritus NRS at Week 4 - for subjects ൒12 years, if the mean 
change of the crisaborole arm is lower (i.e., larger reduction) than that in the vehicle arm and 
the difference is statistically significant at the two-sided level of 0.05.
5.2. General Methods  
5.2.1. Analyses for Binary Endpoints
The binary endpoints will be descriptively summarized using sample size, number, 
percentage and 95% confidence interval (CI) of percentage at each time point.
Binary data will be analyzed by comparing response rates between treatment groups. Normal 
approximation to the difference in response rates will be used to obtain p-values and 95% CI.


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5.2.2. Analyses for Continuous Endpoints
Continuous endpoints will be descriptively summarized using sample size, mean, standard
deviation, median and range.
For the analysis in which missing values are not explicitly imputed, continuous endpoints 
will be analyzed using a linear Mixed effect Model for Repeated Measures (MMRM, 
Mallinckrodt et al. 2001) with treatment group, visit, and treatment group-by-visit interaction 
as factors and baseline value as a covariate. Within-subject variability will be accounted for 
using a random effect with the first-order autoregressive (AR(1)) covariance matrix if there 
are no convergence issues, otherwise other structures will be considered.
5.2.3. Analyses for Time-to-Event Endpoints
Time-to-event analysis will be used to analyze time-to-event data.
Kaplan-Meier (product limit) method will be used for estimation of proportion of participants
with event, time-to-event curve, median (95% CI) time-to-event.
5.3. Methods to Manage Missing Data
Multiple Imputation based on Markov Chain Monte Carlo (MI-MCMC)
Missing ISGA scores will be derived for the analysis using the method of MCMC multiple 
imputation. Multiple imputation and subsequent analysis will involve the following four 
principal tasks:
1. Calculate the number of missing values to be imputed by MCMC (nmiss) for the Day 
29 value.
2. Create a data set, one for each treatment group, of subjects with observed values and 
those needing imputation by MCMC. The missing ISGA values in each data set will 
be filled in using the MCMC method “10× nmiss” times to generate “10 × nmiss” 
data sets. The resulting data sets for each treatment group will be combined into one 
complete data set by imputation. The imputed values will be rounded to the nearest  
value of 0, 1, 2, 3, or 4.
3. For each complete data set, derive dichotomous variables Success in ISGA (Clear [0] 
or Almost Clear [1] with a 2-point change from Baseline) and Improvement in ISGA 
(Clear [0] or Almost Clear [1]). The estimated treatment effect and its standard error 
for each complete data set will be calculated with the method specified in
Section 5.2.1.
4. Combine the estimated treatment effects and standard errors from the above into a 
single inference using Rubin’s formulae as implemented in SAS PROC 
MIANALYZE.
Success in ISGA and Improvement in ISGA will be derived from the imputed complete 
ISGA data sets.


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For EASI-50 and EASI-75, missing EASI total scores will be imputed in the same way as 
missing ISGA scores except no rounding will be done to the imputed values. Missing EASI-
50 and EASI-75 values will be derived from the imputed complete EASI data sets.
Non-Responder Imputation (NRI) Non-Responder Imputation (NRI) as another alternative 
way of handling missing data will also be used in Supportive analyses. If a subject has 
missing data for a binary endpoint at a scheduled visit, this subject will be defined as a non-
responder for that endpoint at that visit.
Repeated measure modeling with no explicit imputation For continuous endpoints, missing 
values are assumed missing at random (MAR) and will be handled by MMRM.
In general, for descriptive statistics and time to event analysis, missing values will not be 
imputed.
6. ANALYSES AND SUMMARIES
6.1. Primary Endpoints
6.1.1. Percent Change from Baseline in EASI total score at Day 29
6.1.1.1. Main Analysis

Estimand strategy:  Hypothetical.

Analysis set: FAS.

Analysis methodology: percent change from baseline in EASI total score at Day 29, will 
be analyzed using MMRM that includes treatment group, visit, and treatment group-by-
visit interaction as factors and baseline value as a covariate.  Within-subject variability 
will be accounted for using a random effect with the first-order autoregressive (AR(1)) 
covariance matrix.

Intercurrent events and missing data: data after treatment discontinuation prior to Day 29
will not be considered. Missing values will not be explicitly imputed and will be 
assumed to be MAR.

Reporting results:
Tables: The sample size, least-squares (LS) mean of percent change from baseline and
95% CI for each treatment, LS mean of difference and the corresponding  95% CI,
and p-value will be presented at Day 29.
6.1.1.2. Supplementary Analyses
An analysis using PPAS will be performed.  It will use the same methodology and handling 
of intercurrent events as the main analysis.


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6.1.2. TEAEs  (including application site reactions) & SAEs and clinically significant 
changes in vital signs and clinical laboratory parameters
All safety analyses will be conducted on the Safety Analysis Set.
Pfizer standard will be utilized in reporting routine safety variables (Pfizer Safety Rulebook).
6.2. Secondary Endpoints
6.2.1. Achievement of Improvement in ISGA at Day 29
6.2.1.1. Main Analysis

Estimand strategy:  Hypothetical.

Analysis set: FAS.

Analysis methodology: The percentage of subjects achieving Improvement in ISGA at 
Day 29 will be compared between crisaborole arm and vehicle arm and the difference 
will be tested based on normal approximation to response rates.

Intercurrent events and missing data: Data after treatment discontinuation prior to Day 29
will not be considered. Missing ISGA scores will be derived for the analysis using MI-
MCMC.

Reporting results:

Tables: The sample size, number, percentage and 95% CI of percentage of subjects 
achieving Improvement in ISGA at Day 29 will be presented for each treatment. Risk 
difference and the corresponding  95% CI and p-value for the test of difference based 
on normal approximation to response rates will also be presented at Day 29.
6.2.1.2. Supportive/Supplementary Analysis
Supportive Analyses
Missing Improvement in ISGA (binary variable) will be handled by using NRI in supportive
analyses. Reporting results are the same as tables above for the main analysis.
Supplementary Analysis
An analysis using PPAS will be performed.  It will use the same methodology and handling 
of intercurrent events as the main analysis.


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6.2.2. Achievement of Success in ISGA at Day 29
6.2.2.1. Main Analysis
•
Estimand strategy:  Hypothetical.
•
Analysis set: FAS. Participants with baseline ISGA score of Clear (0) or Almost Clear (1)
will be excluded.
•
Analysis methodology: The percentage of subjects achieving Success in ISGA at Day 29 
will be compared between crisaborole arm and vehicle arm and the difference will be 
tested based on normal approximation to response rates.
•
Intercurrent events and missing data: Data after treatment discontinuation prior to Day 29 
will not be considered. Missing ISGA scores will be derived for the analysis using MI-
MCMC.
•
Reporting results: 
•
Tables: The sample size, number, percentage and 95% CI of percentage of subjects 
achieving Success in ISGA at Day 29 will be presented for each treatment. Risk 
difference and the corresponding  95% CI and p-value for the test of difference based 
on normal approximation to response rates will also be presented at Day 29.
6.2.2.2. Supportive/Supplementary Analysis
Supportive Analyses
Missing Success in ISGA (binary variable) will be handled by using NRI in supportive 
analyses. Reporting results are the same as tables above for the main analysis.
Supplementary Analysis
An analysis using PPAS will be performed.  It will use the same methodology and handling 
of intercurrent events as the main analysis.
6.2.3. Change from Baseline in Peak Pruritus NRS at Week 4 – for subjects ൒12 years
6.2.3.1. Main Analysis
•
Estimand strategy:  Hypothetical.
•
Analysis set: FAS.
•
Analysis methodology: change from baseline to Week 4 (Days 23-29) in weekly average 
of Peak Pruritus NRS for subjects ൒12 years, will be analyzed using a MMRM that 
includes treatment group, visit, and treatment group-by-visit interaction as factors and


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baseline value as a covariate.  Within-subject variability will be accounted for using a 
random effect with the first-order autoregressive (AR(1)) covariance matrix.

Intercurrent events and missing data: Data after treatment discontinuation prior to Day 29 
will not be considered. The weekly average is considered missing if Peak Pruritus NRS 
scores are missing for more than three days. If the scores are missing for less than four 
days, then the weekly average is computed as the mean of the scores for the non-missing 
days. Missing weekly average values will not be explicitly imputed and will be assumed 
to be MAR.

Reporting results: 

Tables: The sample size, LS mean of change from baseline and 95% CI for each
treatment, LS mean of difference and the corresponding  95% CI, and p-value will be 
presented at Week 4.
6.2.3.2. Supplementary Analyses
An analysis using PPAS will be performed.  It will use the same methodology and handling 
of intercurrent events as the main analysis.
6.2.4. Success in ISGA and Improvement in ISGA over time

Analysis set: FAS. Participants with baseline ISGA score of Clear (0) or Almost Clear (1)
will be excluded for Success in ISGA.

Analysis methodology: At Day 8, Day 15, Day 22 and Day 29, the percentage of subjects 
achieving Success or Improvement in ISGA will be compared between crisaborole arm 
and vehicle arm and the difference will be tested based on normal approximation to 
response rates.

Missing data: Data after treatment discontinuation prior to Day 29 will not be considered. 
Missing data handling will be the same as in Section 6.2.1.1.

Reporting results: 

Tables: The sample size, number, percentage and 95% CI of percentage of subjects 
achieving Success or Improvement in ISGA at Day 8, Day 15, Day 22 and Day 29
will be presented for each treatment. Risk difference and the corresponding  95% CI
and p-values for the test of difference based on normal approximation to response 
rates will be presented.

Figures: For two treatments, line plots of the percentage of subjects achieving 
Success or Improvement in ISGA and 95% CIs at each post-baseline visit will be 
displayed graphically


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6.2.5. Percent Change from baseline in EASI total score over time

Analysis set: FAS.

Analysis methodology: At Day 8, Day 15, Day 22 and Day 29, percent change from 
baseline in EASI total score will be analyzed using a MMRM that includes treatment 
group, visit, and treatment group-by-visit interaction as factors and baseline value as a 
covariate.  Within-subject variability will be accounted for using a random effect with the 
first-order autoregressive (AR(1)) covariance matrix.

Missing data: data after treatment discontinuation prior to Day 29 will not be considered.
Missing data handling will be the same as in Section 6.1.1.1.

Reporting results: 

Tables: The sample size, LS mean of percent change from baseline and 95% CI for 
each treatment, LS mean of difference and the corresponding 95% CI, and p-value 
will be presented for all post-baseline visits.

Figures: For two treatments, line plots of the LS means and 95% CIs at each post-
baseline visit will be displayed graphically.
6.2.6. Change from baseline in %BSA over time

Analysis set: FAS.

Analysis methodology: At Day 8, Day 15, Day 22 and Day 29, change from baseline 
in %BSA with AD will be analyzed using a MMRM that includes treatment group, visit, 
and treatment group-by-visit interaction as factors and baseline value as a covariate.  
Within-subject variability will be accounted for using a random effect with the first-order 
autoregressive (AR(1)) covariance matrix.

Missing values will not be explicitly imputed and will be assumed to be MAR.

Reporting results:

Tables: The sample size, LS mean of change from baseline and 95% CI for each 
treatment, LS mean of difference and the corresponding 95% CI, and p-value will be 
presented for all post-baseline visits.
6.2.7. Achivevment of EASI-50, EASI-75 over time

Analysis set: FAS.

Analysis methodology: At Day 8, Day 15, Day 22 and Day 29, the percentage of subjects 
achieving EASI-50 or EASI-75 will be compared between crisaborole arm and vehicle 
arm and the difference will be tested based on normal approximation to response rates. 


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•
Missing data: Missing EASI scores will be derived for the analysis using MI-MCMC.
•
Reporting results:
•
Tables: The sample size, number, percentage and 95% CI of percentage of subjects 
achieving EASI-50 or EASI-75 at Day 8, Day 15, Day 22 and Day 29 will be 
presented for each treatment. Risk difference and the corresponding  95% CI and p-
values for the test of difference based on normal approximation to response rates will 
be presented.
6.2.8. Change from Baseline in Peak Pruritus NRS over time - for subjects൒12 years
•
Analysis set: FAS.
•
Analysis methodology: change from baseline in weekly average of Peak Pruritus NRS at 
Week 1 (Days 2-8 ), Week 2 (Days 9-15), Week 3 (Days 16-22) and Week 4 (Days 23-
29) for subjects ൒12 years, will be analyzed using a MMRM that includes treatment 
group, visit, and treatment group-by-visit interaction as factors and baseline value as a 
covariate.  Within-subject variability will be accounted for using a random effect with the 
first-order autoregressive (AR(1)) covariance matrix.
•
Missing data: Data after treatment discontinuation prior to Day 29 will not be considered. 
Missing data handling will be the same as in Section 6.2.3.1.
•
Reporting results:
•
Tables: The sample size, LS mean of change from baseline and 95% CI for each
treatment, LS mean of difference and the corresponding  95% CI, and p-value will be 
presented at Week 1, Week 2, Week 3 and Week 4.
•
Figures: For two treatments, line plots of the LS means and 95% CIs at each week 
will be displayed graphically.
6.2.9. Change from Baseline in Patient Reported Itch Severity Scale over time - for 
subjects ൒6 years and <12 years
•
Analysis set: FAS.
•
Analysis methodology: change from baseline in weekly average of Patient Reported Itch 
Severity Scale at Week 1, Week 2, Week 3 and Week 4, for subjects ൒6 years and <12 
years, will be analyzed using a MMRM that includes treatment group, visit, and treatment 
group-by-visit interaction as factors and baseline value as a covariate.  Within-subject 
variability will be accounted for using a random effect with the first-order autoregressive 
(AR(1)) covariance matrix.
•
Missing data: The weekly average is considered missing if Patient Reported Itch Severity 
Scales are missing for more than three days. If the scores are missing for less than four 


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days, then the weekly average is computed as the mean of the scores for the non-missing 
days. Missing weekly average values will not be explicitly imputed and will be assumed 
to be MAR.

Reporting results: 

Tables: The sample size, LS mean of change from baseline and 95% CI for each
treatment, LS mean of difference and the corresponding 95% CI, and p-value will be 
presented for each week.
6.2.10. Change from Baseline in Observer Reported Itch Severity Scale over time - for 
subjects <6 years

Analysis set: FAS.

Analysis methodology: change from baseline in weekly average of Observer Reported 
Itch Severity Scale at Week 1, Week 2, Week 3 and Week 4, for subjects<6 years, will be 
analyzed using a MMRM that includes treatment group, visit, and treatment group-by-
visit interaction as factors and baseline value as a covariate.  Within-subject variability 
will be accounted for using a random effect with the first-order autoregressive (AR(1)) 
covariance matrix.

Missing data: The weekly average is considered missing if Observer Reported Itch 
Severity Scales are missing for more than three days. If the scores are missing for less 
than four days, then the weekly average is computed as the mean of the scores for the 
non-missing days. Missing weekly average values will not be explicitly imputed and will 
be assumed to be MAR.

Reporting results: 

Tables: The sample size, LS mean of change from baseline and 95% CI for each
treatment, LS mean of difference and the corresponding 95% CI, and p-value will be 
presented for each week.
6.2.11. DLQI, CDLQI, IDQOL, DFI, POEM, PGIS/OGIS, PGIC/OGIC over time
Endpoints:

Change from baseline in DLQI total score for subjects aged 16 years and older at Day 15
and Day 29.

Change from baseline in CDLQI total score for subjects aged 4-15 years at Day 15 and 
Day 29.

Change from baseline in IDQOL total score for subjects aged 2-3 years at Day 15 and 
Day 29.


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•
Change from baseline in DFI total score for subjects aged 2-17 years at Day 15 and Day 
29.
•
Change from baseline in POEM total score for self-report subjects aged 12 years or older 
at Day 15 and Day 29.
•
Change from baseline in POEM total score for proxy-report subjects ൒2 and <12 years at 
Day 15 and Day 29.
•
Change from baseline in weekly average of PGIS for subjects aged 12 years and older at 
Week 1, Week 2, Week 3 and Week 4.
•
Change from baseline in weekly average of OGIS for subjects ൒2 and <12 years at Week 
1, Week 2, Week 3 and Week 4.
•
Observed PGIC for subjects aged 12 years and older at Day 8, Day 15, Day 22 and Day 
29.
•
Observed OGIC for subjects ൒2 and <12 years at Day 8, Day 15, Day 22 and Day 29.
Analysis:
•
Analysis set: FAS
•
Analysis methodology: Descriptive statistics will be summarized for the above endpoints.
•
Missing data: 
If two or more response options are checked, the response option with the highest score 
should be recorded. If there is a response between two boxes, the lower of the two score 
options should be recorded.
For DLQI, CDLQI, IDQOL, DFI and POEM, the total score is considered missing if more 
than one item is missing. If one item is missing then total score is computed as the simple 
algebraic sum of the final item scores for nine non-missing items.
For PGIS/OGIS, missing data for any day will not be imputed. The weekly average is 
considered missing if PGIS/OGIS scores are missing for more than three days. If the scores 
are missing for less than four days, then the weekly average is computed as the mean of the
scores for the non-missing days. 
For PGIC/OGIC, missing data will not be imputed.
•
Reporting results: 
•
Tables: For change from baseline in DLQI, CDLQI, IDQOL, DFI and POEM, the 
sample size, mean, standard deviation, median and range, will be presented for each 


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treatment at Day 15 and Day 29. For change from baseline in weekly average of PGIS
and OGIS, the sample size, mean, standard deviation, median and range, will be 
presented for each treatment at Week 1, Week 2, Week 3 and Week 4. For observed 
PGIC and OGIC, the sample size, mean, standard deviation, median and range, will 
be presented for each treatment at Day 8, Day 15, Day 22 and Day 29. 
 
 
 
 
 
 
 
 
CCI
CCI
CCI


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CCI
CCI
CCI


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6.4. Subset Analyses
The main analysis of primary efficacy endpoint and key secondary efficacy endpoints will be 
repeated by subgroups defined through geographical regions, age groups (ages 2–11 years, 
ages 12–17 years, and ages 18 years and older), and baseline ISGA score (ISGA score 2, 
ISGA score 3). Subset analyses of these endpoints aim to evaluate the consistency of 
treatment effect across various subsets. P-values will not be reported here.
Summary of TEAEs and participant discontinuations due to AE will be reported by 
subgroups defined through geographical regions.
6.5. Baseline and Other Summaries and Analyses
6.5.1. Baseline Summaries
Baseline variables will be summarized. Demographics and baseline characteristics will be 
summarized according to Pfizer standards.
6.5.2. Study Conduct and Participant Disposition
Subjects evaluation, disposition, discontinuation will be summarized according to Pfizer 
standards.
6.5.3. Study Treatment Exposure
The extent of exposure to study drug in each treatment group will be summarized by the total 
number of days of dosing, total number of applications, total amount of study drug applied, 
and number and percentage of subjects who are compliant with the dosing regimen.
During Days 1–29, a subject will be considered compliant with the dosing regimen if they 
receive at least 45 but no more than 67 (ie, 80%–120%, inclusive) of the expected 56 total 
doses to be administered between Baseline/Day 1 and Day 29, and has not missed 6 or more 
consecutive doses during the treatment period.
6.5.4. Concomitant Medications and Nondrug Treatments
Prior drug and non-drug treatment, concomitant drug and non-drug treatment will be 
summarized according to Pfizer standards.
6.6. Safety Summaries and Analyses
All safety analyses will be conducted on the Safety Analysis Sset.
Pfizer standard will be utilized in reporting routine safety variables (Pfizer Safety Rulebook). 
CCI


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6.7. Additional Analyses to Address COVID-19 Pandemic Impacts

Protocol deviations related to COVID-19 pandemic will be summarized and listed 
separately. Both important and non-important PDs related to COVID-19 pandemic 
will be reported.

A separate summary table solely for subject discontinuations related to COVID-19
pandemic, if any, will be provided.

COVID-19 related AEs, if any, will be reported.
7. INTERIM ANALYSES
7.1. Introduction
This study uses an External Data Monitoring Committee (E-DMC).
The E-DMC is 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 final decision.  Pfizer will forward such decisions, 
which may include summaries of aggregate analyses of safety data, to regulatory authorities, 
as appropriate.
7.2. Interim Analyses and Summaries
No interim analyses of the study data is planned for use outside the E-DMC.  
8. REFERENCES
Mallinckrodt, C.H., Clark, W.S. and David, S.R., 2001. Accounting for dropout bias using 
mixed-effects models. Journal of biopharmaceutical statistics, 11(1-2), pp.9-21.


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9. APPENDICES


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Appendix 1. Summary of Efficacy Analysis
Table1.
List of primary and secondary efficacy analyses
Efficacy Endpoints
Analysis Set
Analysis Method
Missing Data Imputation
Primary
Analysis 
Endpoints
Percent change from baseline in EASI total score at 
Day 29
FAS
MMRM (model 
includes Days 8, 15, 22, 
29)
Data after treatment discontinuation will not be 
included, MMRM handles missing data. 
Yes
Percent change from baseline in EASI total score at 
Day 29 (Supplementary)
PPAS
MMRM (model 
includes Days 8, 15, 22, 
29)
Data after treatment discontinuation will not be 
included, MMRM handles missing data.
Yes
Achievement of Improvement in ISGA at Days 29
FAS
normal approximation 
to response rates
MI-MCMC
No
Achievement of Improvement in ISGA at Days 29
(Supportive)
FAS
normal approximation 
to response rates
NRI
No
Achievement of Improvement in ISGA at Days 29
(Supplementary)
PPAS
normal approximation 
to response rates
MI-MCMC
NO
Achievement of Success in ISGA at Day 29
FAS
Normal approximation 
to response rates
MI-MCMC
No
Achievement of Success in ISGA at Day 29 
(Supportive)
FAS
Normal approximation 
to response rates
NRI
No
Achievement of Success in ISGA at Day 29 
(Supplementary)
PPAS
Normal approximation 
to response rates
MI-MCMC
No


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Table1.
List of primary and secondary efficacy analyses
Efficacy Endpoints
Analysis Set
Analysis Method
Missing Data Imputation
Primary
Analysis 
Endpoints
Change from Baseline in Peak Pruritus NRS at Week 4 
– for subjects ≥12 years
FAS
MMRM (model 
includes Week 1, 2, 3, 4)
Data after treatment discontinuation will not be 
included, MMRM handles missing data.
No
Change from Baseline in Peak Pruritus NRS at Week 4 
– for subjects ≥12 years (Supplementary)
PPAS
MMRM (model 
includes Week 1, 2, 3, 4)
Data after treatment discontinuation will not be 
included, MMRM handles missing data.
No
Success in ISGA over time
FAS
normal approximation 
to response rates
MI-MCMC
No
Improvement in ISGA over time
FAS
normal approximation 
to response rates
MI-MCMC
No
Percent Change from baseline in EASI total score 
over time
FAS
MMRM (model 
includes Days 8, 15, 22, 
29)
MMRM handles missing data
No
Change from baseline in %BSA over time
FAS
MMRM (model 
includes Days 8, 15, 22, 
29)
MMRM handles missing data
No
Achievement of EASI-50 over time
FAS
normal approximation 
to response rates
MI-MCMC
No
Achievement of EASI-75 over time
FAS
normal approximation 
to response rates
MI-MCMC
No
Change from Baseline in Peak Pruritus NRS over 
time - for subjects ≥12 years
FAS
MMRM (model 
includes Week 1, 2, 3, 4)
MMRM handles missing data
No


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Table1.
List of primary and secondary efficacy analyses
Efficacy Endpoints
Analysis Set
Analysis Method
Missing Data Imputation
Primary
Analysis 
Endpoints
Change from Baseline in Patient Reported Itch 
Severity Scale over time - for subjects ≥6 years and 
<12 years
FAS
MMRM (model 
includes Week 1, 2, 3, 4)
MMRM handles missing data
No
Change from Baseline in Observer Reported Itch 
Severity Scale over time - for subjects <6 years
FAS
MMRM (model 
includes Week 1, 2, 3, 4)
MMRM handles missing data
No
DLQI, CDLQI, IDQOL, DFI, POEM, PGIS/OGIS, 
PGIC/OGIC over time
FAS
Descriptive statistics
Specified in Section 6.2.11
No
MMRM= Mixed Effect Model for Repeated Measures; FAS=Full Analysis Set; NRI= Non-responder imputation; MI-MCMC=Multiple Imputation based on 
Markov Chain Monte Carlo.


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Appendix 2. DATA DERIVATION DETAILS
Appendix 2.1. Definition and Use of Visit Windows in Reporting
Visit windows will be used for efficacy summaries, and for any safety summaries that 
display by visit.
Table 2.
Definition of Visit Windows
Visit Label
Target Day
Definition [Day window]
Baseline
Day 1, 
൑Day 1
Day 8
Day 8
Days 2-11
Dat 15
Day 15
Days 12-18
Day 22
Day 22
Days 19-25
Day 29
Day 29
Days 26-last dose+7
Table 3.
Visit window of Vital Signs/POEM/CDLQI/DLQI/IDLQI/DFI:
Visit Label
Target Day
Definition
Baseline
Day 1
<=Day 1
Day 15
Day 15
Days 2-21
Day 29
Day 29
Days 22 – last dosing date+7
Table 4.
Visit window of Lab and limited physical exam:
Visit Label
Target Day
Definition
Baseline
Day 1
<=Day 1
Day 29
Day 29
Days 2 - last dosing date+7
Table 5.
Visit window of weekly average of NRS/PGIS/OGIS: 
Visit Label
Definition
Baseline
Days -6 - 1
Week 1
Days 2 - 8
Week 2
Days 9 - 15
Week 3
Days 16 - 22
Week 4
Days 23 - 29
If two or more visits fall into the same window, keep the one closest to the Target Day.  If 
two visits are of equal distance from the Target Day in absolute value, the later visit should 
be used. But if two visits both fall on Day 1, then the first visit will be selected.
(Safety analysis to follow Pfizer standard.  See Pfizer Safety Rulebook.)


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Appendix 3. Details of Efficacy Assessments
Appendix 3.1. Investigator's Static Global Assessment (ISGA)
The Investigator’s Static Global Assessment (ISGA), a five point global static assessment of 
AD severity (Table 6), will be assessed at times specified in the Schedule of Activities of the 
protocol to characterize subjects’ overall disease severity across all treatable AD lesions. 
The assessment will be a static evaluation without regard to the score at a previous visit.
ISGA assessment during the study must be done by the investigator or his/her designee.  
Every effort should be made to ensure that all ISGA assessments for a given subject are done 
by the same qualified individual throughout the study.
Table 6.
Investigator’s Static Global Assessment
Score
Grade
Definition
0
Clear
Minor residual hypo/hyperpigmentation; no erythema or 
induration/papulation; no oozing/crusting
1
Almost 
Clear
Trace faint pink erythema, with barely perceptible 
induration/papulation and no oozing/crusting
2
Mild
Faint pink erythema  with mild induration/papulation and no 
oozing/crusting
3
Moderate
Pink-red erythema with moderate induration/population with or 
without oozing/crusting
4
Severe
Deep or bright red erythema with severe induration/population
and with oozing/crusting


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Appendix 3.2. Eczema Area and Severity Index (EASI)
The EASI quantifies the severity of a subject’s atopic dermatitis based on both severity of 
lesion clinical signs and the percent of BSA affected.  EASI is a composite scoring of the 
degree of erythema, induration/papulation, excoriation, and lichenification (each scored 
separately) for each of four body regions, with adjustment for the percent of BSA involved 
for each body region and for the proportion of the body region to the whole body.  
Percent BSA with Treatable AD: The number of handprints of AD skin in a body region 
can be used to determine the extent (%) to which a body region is involved with atopic 
dermatitis (Table 7).
Table 7.
Handprint Determination of Body Region Surface Area
Body Region
Total Number 
of Handprints 
in Body 
Region*
Surface Area of 
Body Region 
Equivalent of 
One Handprint
Total Number of 
Handprints in 
Body Region*
Surface Area of 
Body Region 
Equivalent of 
One Handprint
≥8 years of age
2-7 years of age
Head and Neck
10
10%
20
5%
Upper Limbs
20
5%
20
5%
Trunk (including 
axillae)
30
3.33%
30
3.33%
Lower Limbs 
(including buttocks)
40
2.5%
30
3.33%
*The number of handprints will be for the entire body region; these values will not be adjusted for exclusion of 
scalp, palms, and soles from the BSA assessment.
The extent (%) to which each of the four body regions is involved with AD is categorized 
using a non-linear scaling method to a numerical area score according to the following BSA 
scoring criteria. See Table 8 on EASI Area Score Criteria.
Table 8.
EASI Area Score Criteria
Treatable Percent Body Surface Area (BSA) with Atopic 
Dermatitis in a Body Region
Area Score
0%
0
>0-<10%
1
10-<30%
2
30-<50%
3
50-<70%
4
70-<90%
5
90-<100%
6


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Lesion Severity by Clinical Signs: The basic characteristics of atopic dermatitis lesions 
erythema, induration/papulation, excoriation, and lichenification provide a means for 
assessing the severity of lesions.  Assessment of these four main clinical signs is performed 
separately for four body regions: head and neck, upper limbs, trunk (including axillae and 
groin) and lower limbs (including buttocks).  Average erythema, induration/papulation, 
excoriation, and lichenification are scored for each body region according to a 4 point scale: 
0 = absent; 1 = mild; 2 = moderate; 3 = severe.  Morphologic descriptors for each clinical 
sign severity score are shown in Table 9.


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Table 9.
Clinical Sign Severity Scoring Criteria for the EASI
Score
Description
Erythema (E)
0
Absent
None; may have residual discoloration (post-inflammatory 
hyperpigmentation and/or hypopigmentation).
1
Mild
Light pink to light red
2
Moderate
Red
3
Severe
Deep, dark red
Induration/Papulation (I)
0
Absent
None
1
Mild
Barely palpable to slight, but definite hard thickened skin and/or 
papules
2
Moderate
Easily palpable moderate hard thickened skin and/or papules
3
Severe
Severe hard thickened skin and/or papules
Excoriation (Ex)
0
Absent
None
1
Mild
Slight, but definite linear or picked scratch marks or penetrating 
surface injury
2
Moderate
Moderate linear or picked scratch marks or penetrating surface 
injury
3
Severe
Severe linear or picked scratch marks or penetrating surface 
injury
Lichenification (L)
0
Absent
None
1
Mild
Barely perceptible to slight, but definite thickened skin, fine 
skin markings, and lichenoid scale
2
Moderate
Moderate thickened skin, coarse skin markings, and coarse 
lichenoid scale
3
Severe
Severe thickened skin with very coarse skin markings and 
lichenoid scale
* The EASI will exclude scalp from the assessment/scoring 


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In each body region, the sum of the Clinical Signs Severity Scores for erythema, 
induration/papulation, excoriation, and lichenification is multiplied by the Area Score and by 
the Body Region Weighting to provide a body region value, which is then summed across all 
four body regions resulting in an EASI score as described in Equation 1 and Equation 2: 
Equation 1 (subject aged 2-7 years old):  EASI =0.2Ah(Eh+Ih+Exh+Lh) + 
0.2Au(Eu+Iu+Exu+Lu) + 0.3At(Et+It+Ext+Lt) + 0.3Al(El+Il+Exl+Ll)
Equation 2 (subject aged > 7 years old):  EASI =0.1Ah(Eh+Ih+Exh+Lh) + 
0.2Au(Eu+Iu+Exu+Lu) + 0.3At(Et+It+Ext+Lt) + 0.4Al(El+Il+Exl+Ll)
A = Area Score; E = erythema; I = induration/papulation; Ex = excoriation; 
L = lichenification; h = head and neck; u = upper limbs; t = trunk; l = lower limbs
The EASI score can vary in increments of range from 0.0 to 72.0, with higher scores 
representing greater severity of AD. Considering the scalp will be excluded from EASI 
assessment in the study, the maximum possible score will be less than 72.0 (modified EASI 
score).
Reference:
Bissonnette R, Papp KA, Poulin Y, et al. Topical tofacitinib for atopic dermatitis: a phase IIa 
randomized trial. Bit J Dermatol 2016; 175(5):902-911.


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Appendix 3.3. Peak Pruritus Numerical Rating Scale (NRS) for subjects ൒12 years,
Patient Reported Itch Severity Scale - for subjects age 6-11 years, and Observer 
Reported Itch Severity Scale - for subjects <6 years.
The severity of itch (pruritus) due to atopic dermatitis will be assessed using the Peak
Pruritus Numerical Rating Scale (NRS) for subjects ൒12 years, an 11-category numeric 
rating scale from 0 to 10, which is subject (12 years and older) reported. A five-category
Patient Reported Itch Severity Scale - for subjects age 6-11 years has been developed for
subjects ൒6 and <12 years of age. The Observer Reported Itch Severity Scale - for subjects
<6 years will be completed by a caregiver for subjects <6 years old. It is preferred that all
observer reported outcomes for a given subject are completed by same individual throughout
the study.
Subjects will be asked to assess their worst itching due to atopic dermatitis over the past 24 
hours on an NRS anchored by the terms “no itch” (0) and “worst itch imaginable” (10). The 
Peak Pruritus NRS for subjects ൒12 years is presented in Figure 1. The Patient Reported Itch 
Severity Scale - for subjects age 6-11 years is presented in Figure 2. The Observer Reported 
Itch Severity Scale - for subjects <6 years is presented in Figure 3. These scales are designed 
to capture a similar concept.
Figure 1.
Peak Pruritus NRS [©Regeneron Pharmaceuticals, Inc. and Sanofi (2017)] 
for subjects ≥12 years
On a scale of 0 to 10, with 0 being “no itch” and 10 being “worst itch imaginable”, how would you rate 
your itch at the worst moment during the previous 24 hours?
0
1
2
3
4
5
6
7
8
9
10
                           No itch
                              
Worst imaginable itch
Figure 2.
Patient Reported Itch Severity Scale - for subjects age 6-11 years
Circle the face that shows how itchy your skin has been today:
Not Itchy
Very Itchy


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Figure 3.
Observer Reported Itch Severity Scale - for subjects <6 years
On a scale of 0 to 10, with 0 being “no itch” and 10 being “worst itch imaginable”, how would you rate 
your observation of your child’s itch (scratching, rubbing) at the worst moment during the previous 24 
hours?
0
1
2
3
4
5
6
7
8
9
10
                          No itch
                             
Worst imaginable itch
References:
Yosipovitch G, Reaney M, Mastey V, et al. Validation of the peak pruritus numerical rating scale: Results from 
clinical studies of dupilumab in adult patients with moderate-to-severe atopic dermatitis. J Am Acad of 
Dermatol 2017; 76:AB278.
Simpson E, Beck L, Abhijit G, et al. Defining a responder on the Peak Pruritus Numerical Rating Scale (NRS) 
in patients with moderate-to-severe atopic dermatitis: Detailed analysis from randomized trials of dupilumab J 
Am Acad of Dermatol 2017; 76:AB93.


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Appendix 3.4. Dermatology Life Quality Index (DLQI)
http://sites.cardiff.ac.uk/dermatology/quality-of-life/dermatology-quality-of-life-index-
dlqi/dlqi-instructions-for-use-and-scoring/
The Dermatology Life Quality Index questionnaire is designed for use in adults, ie, patients 
aged 16 years and over.  It is self explanatory and can be simply handed to the patient who is 
asked to fill it in without the need for detailed explanation.  It is usually completed in one to 
two minutes.
The aim of this questionnaire is to measure how much your skin problem has affected your life 
OVER THE LAST WEEK.  Please tick one box for each question.
1.
Over the last week, how itchy, sore, 
Very much

painful or stinging has your skin 
A lot

been? 
A little

Not at all

2.
Over the last week, how embarrassed
Very much

or self conscious have you been because 
A lot

of your skin?
A little

Not at all

3.
Over the last week, how much has your 
Very much

skin interfered with you going
A lot

shopping or looking after your home or 
A little

garden?       
Not at all

Not relevant 
4.
Over the last week, how much has your 
Very much

skin influenced the clothes
A lot

you wear?
A little

Not at all

Not relevant 
5.
Over the last week, how much has your 
Very much

skin affected any social or 
A lot

leisure activities?
A little

Not at all

Not relevant 
6.
Over the last week, how much has your 
Very much

skin made it difficult for 
A lot

you to do any sport?
A little

Not at all

Not relevant 
7.
Over the last week, has your skin prevented
Yes

you from working or studying?
No

Not relevant 
If "No", over the last week how much has 
A lot

your skin been a problem at 
A little

work or studying?
Not at all

8.
Over the last week, how much has your 
Very much



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skin created problems with your 
A lot

partner or any of your close friends
A little

or relatives? 
Not at all

Not relevant 
9.
Over the last week, how much has your 
Very much

skin caused any sexual
A lot

difficulties?
A little

Not at all

Not relevant 
10.
Over the last week, how much of a 
Very much

problem has the treatment for your
A lot

skin been, for example by making
A little

your home messy, or by taking up time? 
Not at all

Not relevant 
Scoring
The scoring of each question is as follows:
Response
Score
Very much
scored 3
A lot
scored 2
A little
scored 1
Not at all
scored 0
Not relevant
scored 0
Question unanswered
scored 0
Question 7: “prevented work or studying”
scored 3
The DLQI is calculated by summing the score of each question resulting in a maximum of 
30 and a minimum of 0. The higher the score, the more quality of life is impaired. The 
DLQI can also be expressed as a percentage of the maximum possible score of 30.
**Please Note: That the scores associated with the different answers should not be printed 
on the DLQI itself, as this might cause bias**
Meaning of DLQI Scores
0-1 = no effect at all on patient’s life
2-5 = small effect on patient’s life
6-10 = moderate effect on patient’s life
11-20 = very large effect on patient’s life
21-30 = extremely large effect on patient’s life


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Detailed analysis of the DLQI
The DLQI can be analysed under six headings as follows:
Section
Questions
Score
Symptoms and feelings
Questions 1 and 2
Score maximum 6
Daily activities
Questions 3 and 4
Score maximum 6
Leisure
Questions 5 and 6
Score maximum 6
Work and School
Question 7
Score maximum 3
Personal relationships
Questions 8 and 9
Score maximum 6
Treatment
Question 10
Score maximum 3
The scores for each of these sections can also be expressed as a percentage of either 6 or 3.
Interpretation of incorrectly completed questionnaires
There is a very high success rate of accurate completion of the DLQI. However, sometimes 
subjects do make mistakes.
1. If one question is left unanswered this is scored 0 and the scores are summed and 
expressed as usual out of a maximum of 30.
2. If two or more questions are left unanswered the questionnaire is not scored.
3. If question 7 is answered ‘yes’ this is scored 3. If question 7 is answered ‘no’ but 
then either ‘a lot’ or ‘a little’ is ticked this is then scored 2 or 1. If “Not relevant” is 
ticked, the score for Question 7 is 0. If it is answered ‘no’, but the second half is left 
incomplete, the score will remain 0.
4. If two or more response options are ticked, the response option with the highest score 
should be recorded.
5. If there is a response between two tick boxes, the lower of the two score options 
should be recorded.
6. The DLQI can be analysed by calculating the score for each of its six sub-scales (see 
above). When using sub-scales, if the answer to one question in a sub-scale is 
missing, that sub-scale should not be scored.
Minimal Clinically Important Difference of the DLQI
For general inflammatory skin conditions a change in DLQI score of at least 4 points is 
considered clinically important (Basra et al, 2015, see below). This means that a patient’s 
DLQI score has to either increase or decrease by at least 4 points in order to suggest that 


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there has actually been a meaningful change in that patient’s quality of life since the previous 
measurement of his/her DLQI scores.
Key References
Original Reference
Finlay AY, Khan GK. Dermatology Life Quality Index (DLQI): a simple practical 
measure for routine clinical use. Clin Exp Dermatol, 1994; 19: 210-216.


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Appendix 3.5. Children’s Dermatology Life Quality Index (CDLQI)
http://sites.cardiff.ac.uk/dermatology/quality-of-life/childrens-dermatology-life-quality-
index-cdlqi/cdlqi-information-and-instructions/
The Children’s Dermatology Life Quality Index questionnaire is designed for use in children, 
ie, patients from age 4 to age 16. It is self explanatory and can be simply handed to the 
patient who is asked to fill it in with the help of the child’s parent or guardian. It is usually 
completed in one to two minutes.
The aim of this questionnaire is to measure how much your skin problem has
affected you OVER THE LAST WEEK.  Please tick one box for each question.
1.
Over the last week, how itchy, "scratchy",
          
  
Very much
□
sore or painful has your skin been?
      
Quite a lot
□
Only a little
□
Not at all
□
2.
Over the last week, how embarrassed
          
Very much
□
or self conscious, upset or sad have you 
            
Quite a lot
□
been because of your skin?
Only a little
□
Not at all
□
3.
Over the last week, how much has your 
            
Very much
□
skin affected your friendships?
            
Quite a lot
□
Only a little
□
Not at all
□
4.
Over the last week, how much have you changed
           
  Very much
□
or worn different or special clothes/shoes
         
    Quite a lot
□
because of your skin?
           
  Only a little
□
Not at all
□
5.
Over the last week, how much has your 
           
Very much
□
skin trouble affected going out, playing,
          
Quite a lot
□
or doing hobbies?
Only a little
□
Not at all
□
6.
Over the last week, how much have you
       
Very much
□
avoided swimming or other sports because                          
Quite a lot
□
of your skin trouble?
Only a little
□
Not at all
□
7.
Last week,
If school time: Over the
       
Prevented school
□    
was it
last week, how much did
Very much
□
school time?  
            your skin problem affect your           Quite a lot
□




school work?
Only a little
□
   OR
Not at all
□


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was it
  
If holiday time: How much
Very much

□
holiday time?
  
              over the last week, has your
Quite a lot

□
skin problem interfered with
Only a little

□
your enjoyment of the holiday?
Not at all

□
8.
Over the last week, how much trouble 
     
Very much
□
have you had because of your skin with
Quite a lot
□
other people calling you names, teasing,
         
Only a little
□
bullying, asking questions or avoiding you?
           
Not at all
□
9.
Over the last week, how much has your sleep
            Very much
□
been affected by your skin problem?
             Quite a lot
□
Only a little
□
Not at all
□
10.
Over the last week, how much of a 
             Very much
□
problem has the treatment for your 
             Quite a lot
□
skin been?
Only a little
□
Not at all
□
Scoring
The scoring of each question is as follows:
Very much
scored 3
Quite a lot
scored 2
Only a little
scored 1
Not at all
scored 0
Question unanswered
scored 0
Question 7: “Prevented school”
scored 3
The CDLQI is calculated by summing the score of each question resulting in a maximum of 
30 and a minimum of 0. The higher the score, the more quality of life is impaired. The 
CDLQI can also be expressed as a percentage of the maximum possible score of 30.
Detailed analysis of the CDLQI
The CDLQI can be analysed under six headings as follows:
Symptoms and feelings
Questions 1 and 2
Score maximum 6
Leisure
Questions 4, 5 and 6
Score maximum 9
School or holidays
Questions 7
Score maximum 3
Personal relationships
Question 3 and 8
Score maximum 6
Sleep
Questions 9
Score maximum 3


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Treatment
Question 10
Score maximum 3
The scores for each of these sections can also be expressed as a percentage of 9, 6 or 3.
The severity banding for CDLQI scores:
0-1 = no effect on child’s life
2-6 = small effect
7-12 = moderate effect
13-18 = very large effect
19-30 = extremely large effect
Ref: Waters A, Sandhu D, Beattie P, Ezughah F, Lewis-Jones S. Severity stratification of 
Children’s Dermatology Life Quality Index (CDLQI) scores. Br J Dermatol 2010; 163 
(Suppl 1): 121.
Interpretation of incorrectly completed questionnaires
There is a very high success rate of accurate completion of the CDLQI. However, sometimes 
subjects do make mistakes.
1. If one question is left unanswered this is scored 0 and the scores are summed and 
expressed as usual out of a maximum of 30.
2. If two or more questions are left unanswered the questionnaire is not scored.
3. If both parts of question 7 are completed the higher of the two scores should be 
counted
References
Lewis-Jones MS, Finlay AY. The Children’s Dermatology Life Quality Index (CDLQI): 
Initial validation and practical use. British Journal of Dermatology, 1995; 132: 942-949.


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Appendix 3.6. Dermatitis Family Impact Questionnaire (DFI)
http://sites.cardiff.ac.uk/dermatology/quality-of-life/dermatitis-family-impact-questionnaire-
dfi/dfi-information-and-instructions/
The aim of this questionnaire is to measure how much your child’s skin problem has affected 
you and your family OVER THE LAST WEEK.  Please tick one box for each question.
1.
Over the last week, how much effect
Very much

has your child having eczema had on 
A lot

housework, eg, washing, cleaning.
A little










Not at all

2.
Over the last week, how much effect
Very much

has your child having eczema had on
A lot

food preparation and feeding.
A little

Not at all

3.
Over the last week, how much effect has
Very much

your child having eczema had on the sleep
A lot

of others in family.
A little

Not at all

4.
Over the last week, how much effect has
Very much

your child having eczema had on 
A lot

family leisure activities, eg swimming.
A little

Not at all

5.
Over the last week, how much effect has
Very much

your child having eczema had on time spent
A lot

on shopping for the family.
A little

Not at all

6.
Over the last week, how much effect has your
Very much

child having eczema had on your expenditure,
A lot

eg costs related to treatment, clothes, etc.
A little

Not at all

7.
Over the last week, how much effect has your
Very much

child having eczema had on causing tiredness
A lot

or exhaustion in your child’s parents/carers.
A little

Not at all

8.
Over the last week, how much effect has your
Very much

child having eczema had on causing emotional
A lot

distress such as depression, frustration or
A little

guilt in your child’s parents/carers.
Not at all

9.
Over the last week, how much effect has your
Very much

child having eczema had on relationships
A lot

between the main carer and partner or
A little



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between the main carer and other children
Not at all

in the family.
10.
Over the last week, how much effect has helping
Very much

with your child’s treatment had on the
A lot

main carer’s life.
A little

Not at all

Instructions for Use and Scoring
The scoring system for the DFI is as follows:
Each question is scored from 0-3.
Not at all = 0
A little = 1
A lot = 2
Very much = 3
The score of each of the 10 questions is summed.
The minimum DFI score is 0 (= no impact on life of family)
The maximum DFI score is 30 (= maximum effect on life of family)
There are no validated score banding descriptors yet published.
Key References
For details of the Dermatitis Family Impact Questionnaire please see the following 
references:
Lawson V, Lewis-Jones MS, Finlay AY, Reid P, Owens RG. The family impact of childhood 
atopic dermatitis: the Dermatitis Family Impact.


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Appendix 3.7. The Infant’s Dermatitis Quality of Life Index (IDQOL)
http://sites.cardiff.ac.uk/dermatology/quality-of-life/the-infants-dermatitis-quality-of-life-
index-idqol/idqol-information-and-instructions/
Instructions for Use and Scoring
The Infant’s Dermatitis Quality of Life Index questionnaire is designed for use in infants 
with atopic dermatitis below the age of 4 years. It is self-explanatory and should be 
completed by the child’s parent (s) or regular carer. It can usually be completed within 2 or 3 
minutes.
The aim of this chart is to record how your child’s dermatitis has been.  Each question 
concerns THE LAST WEEK ONLY.  Please could you answer every question.
Dermatitis Severity
Over the last week, how severe do you
Extremely severe

think your child’s dermatitis has been?;
Severe

ie, how red, scaly, inflamed or widespread.
Average

Fairly good

None

Life Quality Index
1.
Over the last week, how much has your
All the time

child been itching and scratching?
A lot

A little

None

2.
Over the last week, what has your child’s
Always crying,
mood been?
extremely difficult

Very fretful

Slightly fretful

Happy

3.
Over the last week approximately how
More than 2 hrs

much time on average has it taken to
1 - 2 hrs

get your child off to sleep each night?
15mins - 1 hr

0-15mins

4.
Over the last week, what was the total
5 hrs or more

time that your child’s sleep was disturbed
3 - 4 hrs

on average each night?
1 - 2 hrs

Less than 1 hour

5.
Over the last week, has your child’s eczema
Very much

interfered with playing or swimming?
A lot

A little

Not at all

6.
Over the last week, has your child’s eczema
Very much

interfered with your child taking part in or
A lot

enjoying other family activities?
A little

Not at all

7.
Over the last week, have there been
Very much

problems with your child at mealtimes
A lot

because of the eczema?
A little



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None

8.
Over the last week, have there been problems
Very much

with your child caused by the treatment?
A lot

A little

None

9.
Over the last week, has your child’s eczema
Very much

meant that dressing and undressing the
A lot

child has been uncomfortable?
A little

None

10.
Over the last week how much has your child
Very much

having eczema been a problem at bathtime?
A lot

A little

None

Scoring
The scoring of each question is as follows:
Dermatitis Severity (this is scored separately from the Life Quality Index)
Extremely severe
scored 4
Severe
scored 3
Average
scored 2
Fairly good
scored 1
None
scored 0
Maximum score is 4
Life Quality Index Questions 1 and 5-10
All the time
scored 3
A lot
scored 2
A little
scored 1
None
scored 0


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Question 2
Always crying etc.
scored 3
Very fretful
scored 2
Slightly fretful
scored 1
Happy
scored 0
Question 3
More than 2 hrs
scored 3
1-2 hrs
scored 2
15 mins-1hr
scored 1
0-15 mins
scored 0
Question 4
5hrs or more
scored 3
3-4 hours
scored 2
1-2 hours
scored 1
Less than 1 hour
scored 0
Question 5-10
Very much
scored 3
A lot
scored 2
A little
scored 1
Not at all/none
scored 0
The IDQOL is calculated by summing the score of each question resulting in a maximum of 
30 and a minimum of 0. The higher the score the more quality of life is impaired. The 
severity of eczema is scored separately and can be correlated with the IDQOL.


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POEM for self-completion and/or proxy completion
Appendix 3.8. Patient Oriented Eczema Measure (POEM)
The POEM is a tool used for monitoring atopic eczema severity and is to be completed by the subject (POEM for self-completion, by 
subjects 12 years and older) or by the caregiver (POEM for proxy completion, for subjects <12 years).  It is preferred that all observer 
reported outcomes for a given subject are completed by same individual throughout the study.  The POEM contains 7 symptom based 
questions with responses rating number of days each symptom is experienced over the past week, from 0 (no days) to 4 (every day), 
with a maximum score of 28.  A higher score indicates a worse outcome.
Please circle one response for each of the seven questions below about your/your child’s eczema. If your child is old enough to 
understand the questions then please fill in the questionnaire together. Please leave blank any questions you feel unable to answer. 
1. Over the last week, on how many days has your/your child’s skin been itchy because of the eczema? 
No days 
1-2 days 
3-4 days 
5-6 days 
Every day 
2. Over the last week, on how many nights has your/your child’s sleep been disturbed because of the eczema? 
No days 
1-2 days 
3-4 days 
5-6 days 
Every day 
3. Over the last week, on how many days has your/your child’s skin been bleeding because of the eczema? 
No days 
1-2 days 
3-4 days 
5-6 days 
Every day 
4. Over the last week, on how many days has your/your child’s skin been weeping or oozing clear fluid because of the eczema? 
No days 
1-2 days 
3-4 days 
5-6 days 
Every day 


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5. Over the last week, on how many days has your/your child’s skin been cracked because of the eczema? 
No days 
1-2 days 
3-4 days 
5-6 days 
Every day 
6. Over the last week, on how many days has your /your child’s skin been flaking off because of the eczema? 
No days 
1-2 days 
3-4 days 
5-6 days 
Every day 
7. Over the last week, on how many days has your/your child’s skin felt dry or rough because of the eczema?
No days 
1-2 days 
3-4 days 
5-6 days 
Every day 
Scoring
Each of the seven questions carries equal weight and is scored from 0 to 4 as follows:
No days
= 0
1-2 days
= 1
3-4 days
= 2
5-6 days
= 3
Every day
= 4
Total scores are associated with the following disease severities:

0 to 2 = Clear or almost clear;

3 to 7 = Mild eczema;

8 to 16 = Moderate eczema;


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
17 to 24 = Severe eczema;

25 to 28 = Very severe eczema.
Reference:
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(12);1513-19.


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Appendix 3.9. Patient Global Impression of Change (PGIC) and Observer Reported 
Global Impression of Change (OGIC)
The scale will be completed by the subject (PGIC, by subjects 12 years and older) or 
observer (OGIC, for subjects <12 years).  It is preferred that all observer reported outcomes
for a given subject are completed by same individual throughout the study.  The PGIC and 
OGIC are single-item questions to rate change (retrospectively) in a subjects overall status 
since the start of the study.
This single item instrument uses a 7-point rating scale, anchored by (1) ‘very much 
improved’ to (7) ‘very much worse’.  The PGIC and OGIC will be used to determine global 
improvement as assessed by the subject or caregiver.  It will be used as an anchor to define a 
responder definition for the peak pruritus scales for ‘clinically important responder’ and as a 
sensitivity analysis for defining a ‘clinical important difference’ on the peak pruritus scales.
Place an X in the box you feel most closely describes any change which you have 
experienced.  Take into account all change, whether or not you believe it is entirely due 
to drug treatment.  Select only ONE response.
Since starting the study medication, my atopic dermatitis is:
Very much improved
Much improved
Minimally improved
No change
Minimally worse
Much worse
Very much worse
When an observer assesses the state of the atopic dermatitis, the question will be stated as 
follows:
Since starting the study medication, the child’s atopic dermatitis is (select only ONE 
response).
PGIC or OGIC will be completed at the same day as the ISGA will be assessed post baseline.
Appendix 3.10. Patient Global Impression of Severity (PGIS) and Observer Reported 
Global Impression of Severity (OGIS)
The scale will be completed by the subject (PGIS, by subjects 12 years and older) or observer 
(OGIS, for subjects <12 years) every day and preferably at the same time as the peak pruritus 
NRS/peak pruritus scale or Observer Reported peak pruritus NRS.  It is preferred that all 


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observer reported outcomes for a given subject are completed by same individual throughout 
the study.
The PGIS and OGIS is a single-item patient or observer-rated measure of the subject’s atopic 
dermatitis condition severity at a given point in time.
This single item instrument uses a 7-point rating scale. The PGIS and OGIS will be used as 
an anchor for defining a ‘clinical important difference’ on the peak pruritus scales and can 
also be used to create severity categorization for peak pruritus scales to enhance 
interpretation.
Please rate the severity of your atopic dermatitis right now (select only ONE response):
Not present
Very mild
Mild
Moderate
Moderately Severe
Severe
Extremely Severe
The OGIS is similarly structured:
Please rate the severity of the child’s atopic dermatitis right now (select only ONE 
response):
Not present
Very mild
Mild
Moderate
Moderately Severe
Severe
Extremely Severe


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Appendix 4. List of Abbreviations
Abbreviation
Term
AD
atopic dermatitis
AE
adverse event
BID
twice daily
BSA
Body Surface Area
CDLQI
Children’s Dermatology Life Quality Index
CI
confidence interval
DFI
Dermatitis Family Impact Questionnaire
DLQI
Dermatology Life Quality Index
EASI
Eczema Area and Severity Index
E-DMC
external data monitoring committee 
FAS
full analysis set
IDQOL
Infant’s Dermatitis Quality of Life Index
IFN
interferon gamma
ISGA
Investigator's Static Global Assessment
LS
least-squares
LSLV
last subject last visit
MAR
missing at random
MCMC
Markov Chain Monte Carlo
MI
Multiple Imputation
MMP
matrix metalloproteinase
MMRM
Mixed effect model for repeated measures
NRI
Non-Responder Imputation
NRS
Numeric Rating Scale
OGIC
Observer Reported Global Impression of Change
OGIS
Observer Reported Global Impression of Severity
PDE 4
phosphodiesterase 4
PGIC
Patient Global Impression of Change
PGIS
Patient Global Impression of Severity
POEM
Patient Oriented Eczema Measure
PPAS
Per Protocol Analysis Set
PRO
Patient Reported Outcome
SAE
serious adverse event
SAP
statistical analysis plan
TEAE
treatment emergent adverse event