Clinical trial NCT03539601
Conditions: Atopic Dermatitis
Keywords: Atopic Dermatitis, Crisaborole ointment 2%, TCS, TCI
Sponsor: Pfizer
Start date: 2018-04-27; Completion date: 2020-12-11
Enrollment: 237 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This 4-week study will evaluate the safety and efficacy of crisaborole ointment 2%; crisaborole vehicle; topical corticosteroid and topical calcineurin inhibitor, applied twice daily (BID) in subjects who are at least 2 years of age with mild-moderate AD.

A Sub-Study of Optical Coherence Tomography and Biomarkers in Subjects ages 2 to \<18 years old, with Mild to Moderate Atopic Dermatitis, treated with Crisaborole Ointment, 2% or Crisaborole Vehicle Ointment or Hydrocortisone Butyrate 0.1% Cream applied BID will also be conducted at select sites.

Detailed description:
Approximately 600 subjects will be enrolled in the study, of which at least 150 subjects aged 2-6; at least 140 subjects aged 7-11; at least 120 subjects aged 12-17 and up to 90 subjects will be adults. Subjects must have mild-moderate AD involving at least 5% treatable %BSA assessed on baseline/Day 1. Treatable %BSA will be defined as the percent of a subject's total body surface area that is AD involved, excluding the scalp.

Eligible subjects will be randomized at the Baseline/Day 1 visit. Randomization will be stratified by eligibility for TCS or TCI treatment as per national approved labels. Cohort 1 will be for subjects who are eligible for TCS therapy, and Cohort 2 will be for subjects who are not eligible for TCS therapy but eligible for TCI therapy. The investigational products will be applied BID for 28 days to the Treatable body surface area (BSA) identified at Baseline/Day 1.

The primary efficacy endpoint is the percent change from baseline in the Eczema Area and Severity Index (EASI) total score at Day 29.

For the efficacy comparison of crisaborole versus vehicle, subjects from both Cohort 1 and Cohort 2 are included in the analysis, adjusted for cohort effect. For the efficacy comparison of crisaborole versus TCS, only subjects from Cohort 1 are included in the analysis. For the comparison of crisaborole versus TCI, only subjects from Cohort 2 are included in the analysis.

Safety and efficacy assessments will be conducted at the investigator site by a clinical assessor blinded to treatment assignment.

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), Day 43 or 14 Days after last dose if subject is terminated early from treatment. A follow up telephone call will be made by site staff to the subjects/subject's legally acceptable guardian(s) on Day 60 or at least 28 days after last dose if subject is terminated early from treatment. The Day 60 visit will be completed in the clinic for subjects enrolled in the OCT sub-study.

To further explore the benefit/risk of crisaborole ointment, 2%, a sub-study to evaluate differences in atrophic skin changes across study treatment groups in Cohort 1 will be conducted at select sites.

The sub-study will include obtaining Optical coherence tomography (OCT) imaging to evaluate atrophic changes in epidermal thickness during and after treatment with study investigational product in Cohort 1. This sub-study also provides an opportunity to explore differences in Transepidermal Water Loss (TEWL) and cutaneous inflammatory and barrier biomarkers associated with AD within the stratum corneum (SC) across treatment groups in Cohort 1. The Aquaflux (an evaporimeter) will be used in this sub-study to evaluate TEWL during and after treatment at select sub-study centers. Tape-strips will also be used in this sub-study to evaluate SC biomarkers from AD lesional and non-lesional skin.

This sub-study will include approximately 60 subjects from Cohort 1 that are enrolled in the main study (C3291037). Subjects will follow the main study assessments and visits as per the schedule of activities for the main study but will also follow additional procedures as described in the protocol. The telephone call at Day 60 in the main study is replaced with an in-clinic visit for sub-study participants.

Arms: arm 1: This treatment arm will be administered both in Cohort 1 and Cohort 2. arm 2: This treatment arm will be administered in Cohort 1 only. arm 3: This treatment arm will be administered in Cohort 2 only. arm 4: This treatment arm will be administered both in Cohort 1 and Cohort 2.
Interventions: intervention 1: Crisaborole ointment, 2% intervention 2: Hydrocortisone butyrate cream, 0.1% intervention 3: Pimecrolimus cream, 1% intervention 4: Crisaborole Vehicle
Intervention descriptions: intervention 1: Applied twice a day (BID) intervention 2: Applied BID intervention 3: Applied BID intervention 4: Applied BID

Protocol documents:
Prot_000.pdf: 
Crisaborole (PF-06930164)
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A PHASE 3B/4, MULTICENTER, RANDOMIZED, ASSESSOR BLINDED, 
VEHICLE AND ACTIVE (TOPICAL CORTICOSTEROID AND CALCINEURIN 
INHIBITOR) CONTROLLED, PARALLEL GROUP STUDY OF THE EFFICACY,
SAFETY, AND LOCAL TOLERABILITY OF CRISABOROLE OINTMENT, 2% IN 
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:
77,537
European Clinical Trials Database 
(EudraCT) Number:
2018-001043-31
Protocol Number
C3291037
Phase:
3b/4
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
16 Mar 2018
Not applicable (N/A)
Amendment 1
18 Oct 2018
Administrative changes following Swedish
Medical Products Agency (MPA) review; a 
clearly defined benefit/risk assessment
section, clarification on the break-blind 
methods and up-dates with regard to 
Regulatory compliance and Investigator 
reporting responsibilities.
Amendment 2
23 Jan 2019
Addition of investigational product 
withdrawal criteria for signs and symptoms 
of hypersensitivity as requested by the 
German Federal Institute for Drugs and 
Medical Devices (BfArM).
Amendment 3
12 Aug 2019
Addition of Appendix 4 detailing the Optical 
Coherence Tomography and biomarker sub-
study; removal of telephone follow-up at 
Day 36; addition of a clinic visit at Day 43; 
addition of restrictions to concurrent 
medications during the follow-up phase; and 
changes to the pruritis scale descriptions, 
endpoints, and analysis.  
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
TABLE OF CONTENTS...........................................................................................................3
LIST OF TABLES.....................................................................................................................7
LIST OF FIGURES ...................................................................................................................7
APPENDICES ...........................................................................................................................7
PROTOCOL SUMMARY.........................................................................................................8
SCHEDULE OF ACTIVITIES................................................................................................14
1. INTRODUCTION ...............................................................................................................19
1.1. Mechanism of Action/Indication (Crisaborole) ......................................................19
1.2. Background .............................................................................................................19
1.3. Drug Development ..................................................................................................21
1.3.1. Nonclinical Studies.....................................................................................21
1.3.2. Pharmacokinetics........................................................................................21
1.3.3. Cutaneous Sensitization, Irritancy Potential and Tolerability....................22
1.3.4. Clinical Experience.....................................................................................23
1.4. Rationale..................................................................................................................24
1.4.1. Study and Dose Rationale...........................................................................24
1.4.2. Benefit/Risk Assessment ............................................................................25
1.4.3. Single Reference Safety Document............................................................27
2. STUDY OBJECTIVES AND ENDPOINTS.......................................................................28
3. STUDY DESIGN.................................................................................................................30
4. SUBJECT ELIGIBILITY CRITERIA.................................................................................32
4.1. Inclusion Criteria.....................................................................................................33
4.1.1. Inclusion Criteria – All Cohorts .................................................................33
4.1.2. Inclusion Criteria – Cohort 1......................................................................34
4.1.3. Inclusion Criteria – Cohort 2......................................................................34
4.2. Exclusion Criteria....................................................................................................34
4.2.1. Exclusion Criteria – All Cohorts ................................................................34
4.2.2. Exclusion Criteria – Cohort 1.....................................................................36
4.2.3. Exclusion Criteria – Cohort 2.....................................................................36
4.3. Randomization Criteria ...........................................................................................36


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4.4. Lifestyle Requirements ...........................................................................................36
4.4.1. Contraception..............................................................................................36
4.4.2. Other Lifestyle Requirements.....................................................................37
4.5. Sponsor’s Qualified Medical Personnel..................................................................38
5. STUDY TREATMENTS.....................................................................................................38
5.1. Allocation to Treatment ..........................................................................................39
5.2. Breaking the Blind ..................................................................................................39
5.3. Subject Compliance.................................................................................................40
5.4. Investigational Product Supplies.............................................................................40
5.4.1. Dosage Form(s) and Packaging..................................................................40
5.4.2. Preparation and Dispensing........................................................................40
5.5. Administration.........................................................................................................41
5.6. Investigational Product Storage ..............................................................................42
5.7. Investigational Product Accountability...................................................................43
5.7.1. Destruction of Investigational Product Supplies ........................................43
5.8. Prior and Concomitant Treatment(s).......................................................................44
5.8.1. Medications Prohibited Prior to Baseline/Day 1 ........................................44
5.8.2. Medications Prohibited During Treatment (Days 1–29) ............................45
5.8.3. Medications Allowed During Treatment (Days 1–29) ...............................47
5.8.4. Medications Allowed After the End of Treatment (Day 29 or after 
early termination from treatment until Day 43 visit).......................................47
6. STUDY PROCEDURES .....................................................................................................48
6.1. Study Visits .............................................................................................................48
6.2. Time Windows for Study Procedures .....................................................................48
6.3. Screening Period .....................................................................................................49
6.4. Study Period/Treatment Period ...............................................................................51
6.4.1. Baseline/Day 1 Visit...................................................................................51
6.4.2. Day 8 (1 day), Day 15 (3 days) and Day 22 (3 days) Study Visit .......54
6.4.3. Day 29 (3 days) (End-of-Treatment)/Early Termination Study Visit ......56
6.4.4. Day 43 (5 days), or 14 days (5 days) after Early Termination, Off 
Treatment Study Visit......................................................................................57
6.4.5. Unscheduled Visit.......................................................................................58


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6.4.6. Follow-up Contact ......................................................................................58
6.5. Subject Withdrawal/Early Termination ..................................................................59
7. ASSESSMENTS..................................................................................................................60
7.1. Efficacy Assessments..............................................................................................60
7.1.1. Investigator’s Static Global Assessment ....................................................60
7.1.2. Eczema Area and Severity Index (EASI) ...................................................61
7.1.3. Patient/Observer Reported Outcomes.........................................................64
7.2. Body Surface Area for Investigational Product ......................................................69
7.3. Body Site Checklist for Atopic Dermatitis .............................................................69
7.4. Photography of Representative AD Lesion (Selected Study Sites Only) ...............69
7.5. Columbia Suicide Severity Rating Scale (C-SSRS)................................................70
7.6. Safety Assessments .................................................................................................70
7.6.1. Clinical Laboratory Evaluations.................................................................70
7.6.2. Physical Examination, Height, and Weight................................................72
7.6.3. Vital Signs ..................................................................................................72
7.7. Pregnancy Testing...................................................................................................72
7.8. Rater Qualifications.................................................................................................73
8. ADVERSE EVENT REPORTING......................................................................................73
8.1. Requirements...........................................................................................................73
8.1.1. Additional Details On Recording Adverse Events on the CRF..................75
8.1.2. Eliciting Adverse Event Information..........................................................75
8.1.3. Withdrawal From the Study Due to Adverse Events (see also the 
Subject Withdrawal/Early Termination section) .............................................75
8.1.4. Time Period for Collecting AE/SAE Information......................................75
8.2. Definitions...............................................................................................................77
8.2.1. Adverse Events...........................................................................................77
8.2.2. 7Abnormal Test Findings ...........................................................................77
8.2.3. Serious Adverse Events ..............................................................................78
8.2.4. Hospitalization............................................................................................78
8.3. Severity Assessment................................................................................................80
8.4. Special Situations ....................................................................................................80
8.4.1. Protocol-Specified Serious Adverse Events...............................................80


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8.4.2. Potential Cases of Drug-Induced Liver Injury............................................80
8.4.3. Exposure to the Investigational Product During Pregnancy or 
Breastfeeding, and Occupational Exposure.....................................................82
8.4.4. Medication Errors .......................................................................................84
9. DATA ANALYSIS/STATISTICAL METHODS...............................................................84
9.1. Sample Size Determination.....................................................................................84
9.2. Efficacy Analysis ....................................................................................................85
9.2.1. Analysis Sets...............................................................................................85
9.2.2. Analysis of the Primary Endpoint...............................................................85
9.2.3. Analysis of the Secondary Endpoints.........................................................86
9.3. Safety Analysis........................................................................................................87
9.4. Interim Analysis ......................................................................................................87
9.5. Data Monitoring Committee ...................................................................................87
10. QUALITY CONTROL AND QUALITY ASSURANCE.................................................87
11. DATA HANDLING AND RECORD KEEPING .............................................................88
11.1. Case Report Forms/Electronic Data Record .........................................................88
11.2. Record Retention...................................................................................................88
12. ETHICS..............................................................................................................................90
12.1. Institutional Review Board/Ethics Committee......................................................90
12.2. Ethical Conduct of the Study ................................................................................90
12.3. Subject Information and Consent..........................................................................90
12.4. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH 
GCP ...........................................................................................................................93
13. DEFINITION OF END OF TRIAL...................................................................................93
13.1. End of Trial in All Participating Countries ...........................................................93
14. SPONSOR DISCONTINUATION CRITERIA ................................................................93
15. PUBLICATION OF STUDY RESULTS..........................................................................93
15.1. Communication of Results by Pfizer ....................................................................93
15.2. Publications by Investigators ................................................................................94
16. REFERENCES ..................................................................................................................96
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LIST OF TABLES
Table 1.
Investigator’s Static Global Assessment ..................................................61
Table 2.
Clinical Sign Severity Scoring Criteria for the Eczema Area and 
Severity Index (EASI) ..............................................................................62
Table 3.
Handprint Determination of Body Region Surface Area for Subjects 
aged 8 years old.....................................................................................62
Table 4.
Handprint Determination of Body Region Surface Area for Subjects 
aged < 8 years old.....................................................................................63
Table 5.
Eczema Area and Severity Index (EASI) Area Score Criteria.................63
Table 6.
Eczema Area and Severity Index (EASI) Body Region Weighting.........63
Table 7.
Clinical Laboratory Test Parameters ........................................................71
Table 8.
Hanifin and Rajka’s Diagnostic Criteria for Atopic Dermatitis.............102
LIST OF FIGURES
Figure 1.
Study Design Schematic...........................................................................32
Figure 2.
Peak Pruritus NRS [©Regeneron Pharmaceuticals, Inc. and Sanofi 
(2017)] for subjects >12 years ..................................................................65
Figure 3.
Patient Reported Itch Severity Scale - for subjects age 6-11 years ..........65
Figure 4.
Observer Reported Itch Severity Scale - for subjects <6 years ................65
APPENDICES
Appendix 1. Abbreviations......................................................................................................99
Appendix 2. Diagnostic Criteria for Atopic Dermatitis.........................................................102
Appendix 3. Very High/Very Strong and High/Strong Potency Topical Corticosteroids.....103
Appendix 4. Optical Coherence Tomography Sub-Study – A Study of Optical 
Coherence Tomography and Biomarkers in Subjects ages 2 to <18 
years old, with Mild to Moderate Atopic Dermatitis, treated with 
Crisaborole Ointment, 2% or Crisaborole Vehicle Ointment or 
Hydrocortisone Butyrate 0.1% Cream applied BID...............................104


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PROTOCOL SUMMARY
Background and Rationale:
Crisaborole, also referred to as PF-06930164 or AN2728, is a low molecular weight 
benzoxaborole anti-inflammatory phosphodiesterase-4 (PDE-4) inhibitor that penetrates into 
the skin to the sites of inflammation.  PDE-4 inhibition results in increased intracellular 
cyclic adenosine monophosphate (cAMP) levels.  While the specific mechanism(s) by which 
crisaborole exerts its therapeutic action is not well defined, crisaborole reduces the 
production of several inflammatory cytokines implicated in the pathophysiology of atopic 
dermatitis (AD).
Supporting evidence for the safety and efficacy of this product in patients 2 years and older 
represents a major advancement in the treatment of AD given the challenges of managing 
this common, chronic dermatologic condition and the limitations of currently available 
therapies.  All primary and secondary efficacy endpoints were statistically significant in the 
two previous Phase 3 vehicle-controlled studies, AN2728-AD-301 and AN2728-AD-302.  
Across the development program, crisaborole demonstrated an acceptable safety profile; the 
majority of adverse events (AEs) were mild and deemed unlikely or not related to 
investigational product, with no crisaborole treatment related serious adverse events (SAEs)
(except 1 case of drug eruption in a Phase 2 study which was classified as possibly related).
This 4-week, randomized, assessor blinded, crisaborole ointment, 2%, vehicle and active
(topical corticosteroid [TCS] and topical calcineurin inhibitor [TCI]) controlled study will 
determine the efficacy and safety of crisaborole ointment, 2% applied twice daily (BID)
compared with vehicle in subjects ages 2 years and older with mild to moderate AD.  The 
study will also evaluate the efficacy and safety of crisaborole ointment, 2% compared with 
the active controls; hydrocortisone butyrate cream, 0.1% [TCS] and pimecrolimus cream,
1% [TCI].  Hence, this study will, provide contextualization of the efficacy and safety of 
crisaborole ointment, 2% in the treatment of mild to moderate AD.
The crisaborole dose strength and regimen selected for this study has been demonstrated to 
be safe, well-tolerated and efficacious in subjects and healthy volunteers 2 years of age and 
older who participated in previous studies.
Hydrocortisone butyrate cream, 0.1% and pimecrolimus cream, 1% are approved products 
for the treatment of mild to moderate atopic dermatitis in subjects ages 2 years and older, and 
will be used as per their national approved label in this study.


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Objectives and Endpoints:
Primary Efficacy Objective
Primary Efficacy Endpoint

To compare the efficacy of 
crisaborole ointment, 2% applied 
BID versus vehicle in pediatric and 
adult subjects, aged 2 years and 
older, with mild to moderate AD.

Percent change from Baseline in the Eczema Area and 
Severity Index (EASI) total score at Day 29.
Primary Safety Objectives
Primary Safety Endpoints

To evaluate the safety and local 
tolerability of crisaborole ointment 
2% applied BID versus vehicle in 
pediatric and adult subjects (ages 2 
years and older) with mild to 
moderate AD.

To evaluate the safety and local 
tolerability of hydrocortisone 
butyrate cream 0.1% and 
pimecrolimus cream 1% applied BID 
in pediatric and adult subjects (ages 
2 years and older) with mild to 
moderate AD.

AEs, SAEs, local tolerability, discontinuations 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 over time in pediatric and 
adult subjects (ages 2 years and 
older) with mild to moderate AD.

To evaluate the efficacy of 
crisaborole ointment, 2% BID versus 
hydrocortisone butyrate cream 
0.1% and pimecrolimus cream 
1% applied BID in pediatric and 
adult subjects (ages 2 years and 
older) with mild to moderate AD.

Efficacy endpoints

Percent change from Baseline in EASI total score by
scheduled time points except Day 29.

Achievement of success in the Investigator’s Static 
Global Assessment (ISGA) (defined as an ISGA score 
of Clear (0) or Almost Clear (1) with at least a 2-grade 
improvement from Baseline) by scheduled time points.

Achievement of ISGA score of clear (0) or almost clear 
(1) by scheduled time points.

Achievement of EASI75 (75% improvement from 
Baseline) by scheduled time points.

Time to EASI75.

Change from Baseline in % BSA by scheduled time
points.

To evaluate the effect of crisaborole 
ointment, 2% applied BID versus 
vehicle, hydrocortisone butyrate 
cream 0.1% and pimecrolimus cream 
1% applied BID on patient/observer 

Patient/observer reported outcomes endpoints:

Change from Baseline in Peak Pruritus Numerical 
Rating Scale (NRS) – for subjects >12 years by
scheduled time points. Change from Baseline in Patient 


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reported outcomes over time in 
pediatric and adult subjects (ages 2 
years and older) with mild to 
moderate AD.
Reported Itch Severity Scale - for subjects age 6-11 
years Scale by scheduled time points.
•
Change from Baseline in Observer Reported Itch 
Severity Scale – for subjects <6 years by scheduled 
time points. Time to ≥2 point improvement from 
Baseline in Peak Pruritus NRS for subjects >12 years.
Time to ≥3 point improvement from Baseline in Peak 
Pruritus NRS for subjects >12 years. Time ≥2 point to 
improvement from Baseline in Observer Reported Itch 
Severity Scale - for subjects <6 years.
•
Time to ≥3 point improvement from Baseline in 
Observer Reported Itch Severity Scale - for subjects <6 
years.
•
Achievement of ≥2 point improvement from Baseline 
in Peak Pruritus NRS for subjects >12 years. 
Achievement of ≥3 point improvement from Baseline 
in Peak Pruritus NRS for subjects  >12 years.
•
Achievement of ≥2 point improvement from Baseline 
in Observer Reported Itch Severity Scale - for subjects 
<6 years.
•
Achievement of ≥3 point improvement from Baseline 
in Observer Reported Itch Severity Scale - for subjects 
<6 years. Change from Baseline in Dermatology Life 
Quality Index (DLQI) (for Subjects 16 years and 
older), Children’s Dermatology Life Quality Index 
(CDLQI) (for Subjects 4-15 years), and Dermatitis 
Family Impact Questionnaire (DFI) (Completed by 
parent/caregiver of Subjects 2-17 years) by scheduled 
time points.
 
 
 
 
 
 
 
 
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Study Design:
This is a Phase 3b/4, multicenter, randomized, assessor blinded, vehicle and active (TCS and 
TCI) controlled study of the efficacy, safety and local tolerability of crisaborole ointment,
2% in pediatric and adult subjects (ages 2 years and older) with mild to moderate AD
involving at least 5% treatable body surface area (%BSA).  Treatment will be clinical 
assessor-blinded for all treatment arms and double-blinded for crisaborole ointment, 2% and 
vehicle treatment arms.
A total of approximately 600 subjects will be enrolled in the study, of which at least 
150 subjects aged 2-6; at least 140 subjects aged 7-11; at least 120 subjects aged 12-17 and 
up to 90 subjects will be adults.  Following the screening period (up to 35 days prior to 
Baseline/Day 1), eligible subjects will be randomized at the Baseline/Day 1 visit.  
Randomization will be stratified by eligibility for TCS or TCI treatment as per national 
approved labels.  Cohort 1 will be for subjects who are eligible for TCS therapy, and Cohort 
2 will be for subjects who are not eligible for TCS therapy but eligible for TCI therapy.  The 
investigational products will be applied BID for 28 days to the Treatable body surface area 
(BSA) identified at Baseline/Day 1.
The primary efficacy endpoint is the percent change from baseline in the Eczema Area and 
Severity Index (EASI) total score at Day 29.
For the efficacy comparison of crisaborole versus vehicle, subjects from both Cohort 1 and 
Cohort 2 are included in the analysis, adjusted for cohort effect.  For the efficacy comparison 
of crisaborole versus TCS, only subjects from Cohort 1 are included in the analysis.  For the 
comparison of crisaborole versus TCI, only subjects from Cohort 2 are included in the 
analysis.
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Safety and efficacy assessments will be conducted at the investigator site by a clinical 
assessor blinded to treatment assignment.
A sub-study will be conducted at selected investigator sites to evaluate differences of 
changes in epidermal skin thickness as measured by Optical Coherence Tomography (OCT) 
between treatment groups in Cohort 1.  (see Appendix 4). 
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), Day 43 or 14 Days after last 
dose if subject is terminated early from treatment.  A follow up telephone call will be made 
by site staff to the subjects/subject’s legally acceptable guardian(s) on Day 60 or at least 28 
days after last dose if subject is terminated early from treatment.  The Day 60 visit will be 
completed in the clinic for subjects enrolled in the OCT sub-study. Refer to the Schedule of 
Activities for a complete list of assessments to be performed during the study.
Statistical Methods:
The primary endpoint, EASI % change from baseline, as well as other change from baseline
continuous endpoints, will be analyzed using a mixed-effect repeated measures model that 
includes the fixed effects of treatment, visit as class variable, treatment by visit interaction, 
and baseline value.  Within-subject variability will be accounted for using a random effect 
with the first order autoregressive (AR(1)) covariance matrix.
Binary endpoints will be analyzed using the Cochran-Mantel-Haenszel (CMH) test.
Time to event endpoints will be analyzed by log rank test and duration of time to event will 
be estimated by the product limit method. A Kaplan-Meier plot will be provided.
Safety data will be descriptively summarized, and will be presented in tabular and/or 
graphical format.
Sample Size Determination
A total of approximately 600 subjects will be enrolled into this study, of which 
approximately 300 subjects who are eligible to receive TCS therapy (Cohort 1) will be 
randomized to crisaborole ointment, 2%, the matching vehicle ointment for crisaborole, or 
TCS with a randomization ratio of 1:1:2. Approximately 300 subjects who are ineligible to 
receive TCS therapy and eligible to receive TCI therapy (Cohort 2) will be randomized to 
crisaborole ointment, 2%, the matching vehicle ointment for crisaborole, or pimecrolimus 
cream, 1% with randomization ratio 1:1:2.
A sample size of 150 subjects in the crisaborole treatment arm (combined from Cohort 1 and 
Cohort 2) and 150 subjects in vehicle treatment arm (combined from Cohort 1 and Cohort 2)
will provide 86% power to detect a 12% difference in EASI percent reduction from baseline 
at Day 29 between crisaborole and vehicle at the 0.05 (2-sided) significance level
(See Figure 1).
The sample size within each Cohort will also provide sufficient precision to enable 
contextualization of the efficacy of crisaborole in treating subjects with mild to moderate AD 


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relative to each active comparator. With a sample size of 75 subjects in the crisaborole group 
and 150 subjects in the TCS or TCI groups, the half width of the 95% confidence interval for 
the difference of EASI percent reduction from baseline at Day 29 between crisaborole and 
active comparator is 9.4%.


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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 29
Day 43b
Day 60b
Window
1 d
3 d
3 d
3 d
5 d
3 d
Visit
Screeninga
Baseline
End of 
Treatment/
Early 
Termination
Off 
Treatment 
Follow-up
Follow up 
telephone
Contactt
Informed consent, including assent 
X
Demographics
X
Height 
X
Weight
X
X
Review of Inclusion and Exclusion Criteria 
X
X
Medical history
X
X
Prior and concomitant medications
Xc
X
X
X
X
X
X
X
Vital signsd
X
X
X
Detailed Physical examination
Xe
Xe
Xe
C SSRSf
X
CLINICAL EVALUATION OF AD
Serious and non serious adverse event monitoringg
X
X
X
X
X
X
X
X
ISGAh
X
X
X
X
X
X
X
EASIh
X
X
X
X
X
X
Body Surface Area for Investigational Product
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 29
Day 43b
Day 60b
Window
±1 d
±3 d
±3 d
±3 d
±5 d
±3 d
Visit
Screeninga
Baseline
End of 
Treatment/
Early 
Termination
Off 
Treatment 
Follow-up
Follow up 
telephone
Contactt
Record treatable AD areas (excluding scalp) in source 
and provide subjects and/or parent(s)/legal guardian 
with documentation of the designated treatment areas
(body maps)
X
Body Site checklist of treatable AD lesionsh
X
Photography of Representative treatable AD lesion(s)i
X
X
X
PATIENT/OBSERVER REPORTED OUTCOMES
Peak Pruritus Numerical Rating Scale (NRS) for 
subjects  >12 years OR Patient Reported Itch Severity 
Scale - for subjects age 6-11 years OR Observer 
Reported Itch Severity Scale - for subjects <6 years
Xj
To be captured QD from Day 1 to Day 29
 
 
 
 
 CDLQI or DLQIm
X
X
X
X
X
DFIm
X
X
X
X
X
 
 
LABORATORY TESTING
Serum chemistry and hematology
X
Xo
X
Urine pregnancy test (in female subjects of 
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 29
Day 43b
Day 60b
Window
1 d
3 d
3 d
3 d
5 d
3 d
Visit
Screeninga
Baseline
End of 
Treatment/
Early 
Termination
Off 
Treatment 
Follow-up
Follow up 
telephone
Contactt
childbearing potential only)p
FSH (to confirm postmenopausal status in females who 
are amenorrheic for at least 12 consecutive months)
X
OTHER ACTIVITIES
Register Subject with IRT to obtain a SSIN
X
Randomization
X
In-clinic dosing instruction
X
X
X
X
In clinic dose application by study staff (1st dose 
[preferred AM])q
X
At home dosing, applied by subject or caregiver, as 
appropriater
2nd dose (PM) on Day 1, then BID through 
Day 28q,r
Dispense/Assess Dosing Diary and Instructions
X
X
X
X
Obtain and review Dosing Diary data and assess 
compliances
X
X
X
X
Weigh new investigational product tube(s) and 
dispense for at-home dosing
X
X
X
X
Collect and weigh returned investigational product 
tube(s)
X
X
X
X
Contraception Check (for female subjects of 
childbearing potential only)
X
X
X
X
X
X
X
X
Optical Coherence Tomography Sub-study (see 
Appendix 4) for participating sites and subjects 
only. 


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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 29
Day 43b
Day 60b
Window
±1 d
±3 d
±3 d
±3 d
±5 d
±3 d
Visit
Screeninga
Baseline
End of 
Treatment/
Early 
Termination
Off 
Treatment 
Follow-up
Follow up 
telephone
Contactt
AD=Atopic Dermatitis, CDLQI= Children’s Dermatology Life Quality Index, C-SSRS=Columbia Suicide Severity Rating Scale, DLQI= Dermatology Life 
Quality Index, DFI= Dermatitis Family Impact Questionnaire, FSH=Follicle Stimulating Hormone, 
 IRT= 
Interactive response technology, 
 SSIN= subject screening identification number, 
a.
Peak Pruritus NRS for subjects  >12 years or Patient Reported Itch Severity Scale - for subjects age 6-11 years or Observer Reported Itch Severity Scale -
for subjects <6 years and ISGA will be collected at screening for all subjects scheduled for a Baseline Visit, regardless of whether the subject continues to 
randomization.
b.
Day 43 (±5 days) or 14 days (±5 days) after Early Termination.  Day 60 (±3 d) or at least 28 days following the End of Treatment or Early Termination.
c.
Record all treatments (including medications and non-medication therapies) used for AD, as well as any biologic drugs used within 180 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. 
d.
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 (when possible for younger children).  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.
e.
Detailed physical examination includes, 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.  At screening confirm clinical diagnosis of AD per Hanifin and Rajka criteria.
f.
Investigator completed. Children’s C-SSRS for subjects 7-11 years old, C-SSRS for subjects ≥12 years old.
g.
Completed by a clinical assessor blinded for treatment arms for AEs and SAEs.  Other site personnel may also report and record AEs and SAEs reported to 
them spontaneously by the subject.
h.
Completed by a clinical assessor blinded for treatment arms.
i.
For subjects (optional) at a selected study site(s), photographs of treatable AD lesions will be obtained. Photographs will be utilized for illustrative purposes 
and not evaluated as an endpoint. (see Section 7.4).
j.
Peak Pruritus NRS for subjects  >12 years will be completed by the subject (12 years and older) or the Patient Reported Itch Severity Scale - for subjects age 
6-11 years will be completed by the subjects age 6-11 years or the Observer Reported Itch Severity Scale - for subjects <6 years will be completed by 
caregiver [parent/legal guardian/legally acceptable representative] during screening prior to Day 1, and once daily from Day 1 to Day 29 before IP morning 
dose application (as applicable) preferably at the same time of each day.
 
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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 29
Day 43b
Day 60b
Window
±1 d
±3 d
±3 d
±3 d
±5 d
±3 d
Visit
Screeninga
Baseline
End of 
Treatment/
Early 
Termination
Off 
Treatment 
Follow-up
Follow up 
telephone
Contactt
 
m. The CDLQI will be completed by all subjects aged 4–15 years, based on the age at Screening Visit/time of informed consent/assent.  The DLQI will be 
completed by all subjects aged 16 years and older, based on the age at Screening Visit/time of informed consent/assent.
 
  The DFI will be completed by the caregiver for
subjects aged 2–17 years, based on the age at Screening Visit/time of informed consent/assent.  
 
 
 
o.
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 14 days prior to Day 1, whether the Day 1 serum chemistry and 
hematology tests are to be performed will be at the medical judgment of the investigator or his/her designee.
p.
Urine pregnancy testing (β-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. For pediatric female subjects who have not experienced menarche, pregnancy testing is not required to be 
performed. If the pediatric female subject starts menarche during the study, pregnancy testing will be performed at the next visit and all visits according to 
the schedule of activities.
q.
If the subject comes to the clinic in the afternoon, two doses (12 ±4 hours apart) or single dose could be administered on Day 1.
r.
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 
caregiver 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.
s.
During study visits at Day 8, Day 15, and Day 22, re-educate subject and/or caregiver on the dosing instructions if any investigational product doses were 
missed during the interval since the previous study visit.
t.
A telephone call is not required for subjects enrolled in the OCT sub-study, as they are required to attend the clinic for this visit.
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1. INTRODUCTION
1.1. Mechanism of Action/Indication (Crisaborole)
Crisaborole, also referred to as PF-06930164 or AN2728, is a low molecular weight 
benzoxaborole anti-inflammatory phosphodiesterase-4 (PDE-4) inhibitor that penetrates into 
the skin to the sites of inflammation.  PDE-4 inhibition results in increased intracellular 
cyclic adenosine monophosphate (cAMP) levels.  While the specific mechanism(s) by which 
crisaborole exerts its therapeutic action is not well defined, crisaborole reduces the 
production of several inflammatory cytokines implicated in the pathophysiology of atopic 
dermatitis (AD).
Crisaborole ointment, 2% is being developed for the topical treatment of patients with mild 
to moderate AD.  On 14 December 2016, EUCRISA (crisaborole) ointment, 2% was 
approved by the United States (US) Food and Drug Administration (FDA) for the treatment 
of mild to moderate AD in patients 2 years of age and older.  
1.2. Background
AD, also referred to as atopic eczema or, simply as eczema, is a chronic and relapsing 
disease affecting an increasing number of persons.  Although AD affects patients of all ages, 
it is one of the most common, chronic, relapsing childhood dermatoses.  The lifetime 
prevalence of AD is estimated to be 15-30% in children and 2-10% in adults while the 
incidence of AD has increased by 2- to 3-fold during the past 3 decades in industrialized 
countries.1
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.2,3  The majority of patients (up to 90%) with AD present with mild 
to moderate disease.4  Manifestation of the disease includes intense pruritus, erythematous 
papules, excoriation, exudation, lichenification, and bacterial colonization.5  Continuous 
scratching during exacerbations can lead to lichenification, excoriations, and serious skin 
infections. AD is often associated with other conditions including asthma, allergic rhinitis, 
and food allergy.6,7
AD is a condition associated with significant morbitidty.  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.2,8,9,10  
Psychosocial problems, depression, and anxiety are associated with AD in both adults and 
children.11  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.9,12,13  The hallmark symptom of itching causes 
scratching which is associated with sleep disturbance in greater than 60% of patients.  Sleep 
deprivation leads to physical and mental exhaustion in patients and other family members 
resulting in loss of concentration and impaired performance at school or work.14,15  AD is 
often associated with significant childhood behavioral problems and psychological disorders 
including depression, attention deficit hyperactivity disorder, anxiety, stress, and autism.11  


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Preschool children with AD show a significant increase in behavioral symptoms compared 
with matched controls.16  Absolon et al17 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.12
AD has a significant impact on day to day functioning, as evidenced by its impact on the 
overall well-being of the patient and their family on multiple levels; medical management 
and treatment; HRQOL; and psychosocial 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 burden18 as this relapsing disease is often 
misdiagnosed, misunderstood, and ineffectively treated.3
Currently, there is no cure for AD.  AD is a chronic disease with treatment focused on the 
management of flares and maintenance of remissions.  Due to the chronic, relapsing nature of 
the disease, treatment may be needed for many years.
The objectives of AD management are to improve clinical signs and symptoms and quality of 
life, while minimizing potential medication side effects.  The main treatment options targeted 
at the underlying disease process of mild to moderate AD are topical emollients.  Topical 
corticosteroids (TCS) of varying potency, and the topical calcineurin inhibitor (TCI)
pimecrolimus cream, 1% as second line therapy.  Emollients, which are fundamental to basic 
skin care in AD, have limited efficacy.  TCSs are limited in the treatment duration and body
regions of treatment, due to risk of local and potentially irreversible skin toxicities such as 
atrophy, telangiectasia, and striae.  Given the potential for inhibition of tumor surveillance in 
the skin and reports of malignancy (eg, skin and lymphoma), TCIs are designated as second 
line therapy for the short-term and non-continuous treatment of AD in 
non-immunocompromised patients.
Crisaborole ointment, 2% was developed by Anacor Pharmaceuticals, Inc. (Anacor), Palo 
Alto, California, United States of America (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 being developed for the topical treatment of patients with 
mild to moderate 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 limitations on 
patient age, location, duration of use and line of therapy 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, 
AN2728-AD-301 and AN3728-302.19  Across the development program, crisaborole 
demonstrated an acceptable safety profile; the majority of AEs were mild and deemed 


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unlikely or not related to investigational product, with no crisaborole treatment related SAEs 
(except 1 case of drug eruption in a Phase 2 study which was classified as possibly related).
1.3. Drug Development
Crisaborole ointment, 2% is a benzooxaborole compound developed as a topical 
anti-inflammatory agent.  Crisaborole has been formulated as a topical ointment.  The 
formulation ingredients for crisaborole ointment, 2% are listed in Section 5.
Crisaborole demonstrates in vitro inhibition of a wide range of pro-inflammatory cytokines 
implicated in the pathogenesis of AD and other inflammatory skin diseases, including 
TNF-, IFN-y, IL-2, IL-5, IL-6, IL-10, IL-12, and IL-23.20  Crisaborole also inhibits the 
release of chemokines that are important inflammatory mediators.  Crisaborole inhibits the 
enzymatic activity of PDE-4 through binding to the PDE-4 catalytic site in a manner that is 
competitive with cyclic adenosine monophosphate.  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.
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 anti-inflammatory 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 phorbol 12-myristate 13-acetate (PMA)-induced ear edema model.  
Based on the nonclinical safety studies conducted to date, crisaborole ointment, 2% has an 
acceptable safety profile.  
1.3.2. Pharmacokinetics
The efficacy of crisaborole for the treatment of AD is not dependent on systemic exposure.  
The development program evaluated systemic exposure to crisaborole and its main 
metabolites relative to establishing the safety of topically applied crisaborole.  Systemic 
exposures to crisaborole following topical application were assessed in healthy volunteers 
and patients (atopic dermatitis and psoriasis). Based on a nonlinear regression analysis at a 
given ointment dose, patients will have 2.5 fold higher exposures compared to healthy 
volunteers.21 In pediatric and adolescent subjects (2-17 years) with AD, and in adults with 
psoriasis, crisaborole demonstrated similar pharmacokinetic profiles and systemic exposure, 
irrespective of age and established that following topical application, crisaborole penetrated 
through the stratum corneum, epidermis, and dermis of human skin, as evidenced by the 
presence of crisaborole and its main metabolites in plasma.


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Upon reaching the systemic circulation, biotransformation of crisaborole is rapid and 
extensive and primarily consists of oxidative deboronation/hydrolysis to produce AN7602 by 
CYP3A4 and CYP1A1/2, followed by subsequent downstream oxidation of this metabolite to 
form AN8323, without notable species-related qualitative differences.  These two main 
metabolites of crisaborole observed in plasma following topical application to several 
species, including humans, were found to be inactive against PDE-4.  Further, as a result of 
rapid biotransformation, systemic exposure of crisaborole is limited following topical 
application of crisaborole.

In a clinical pharmacokinetic (PK) study conducted under maximal use conditions 
(maximal use systemic exposure [MUSE] study) in children and adolescents aged 
2-17 years with extensive AD (mean treatable percent body surface area [Treatable % 
BSA] 48.7%; range 27%-92%), absorption across the skin was rapid, with a median time 
to reach maximum observed plasma concentration (Tmax) of 3.0 hours on both Day 1 and 
Day 8 (Study AN2728-AD-102).  Steady state was achieved within the first 8 days of 
dosing, with a mean crisaborole maximum observed plasma concentration (Cmax) of 
127 ng/mL. Minimal plasma accumulation of crisaborole and AN7602 was observed at 
steady state whereas AN8323 accumulated in plasma at a rate of 3-4 times that of 
crisaborole or AN7602, based on mean Cmax. 

In a Thorough QT/QTc (TQT) study (Study AN2728-TQT-108) in which healthy 
subjects were treated with crisaborole ointment, 2% at a therapeutic dose (15 g using an 
approximate 30% BSA treatment area) or a supratherapeutic dose (45 g, using an 
approximate 60% BSA treatment area), mean Cmax values of 36.9 ng/mL and 87.4 ng/mL 
were observed in therapeutic and supratherapeutic dose groups, respectively, at Day 9.  
Both therapeutic and supratherapeutic doses had no effect on cardiac repolarization based 
on results from the primary assessment and the pharmacokinetic-pharmacodynamic 
analysis. 
1.3.3. Cutaneous Sensitization, Irritancy Potential and Tolerability
1.3.3.1. Local Tolerability in Sensitive Skin Areas
In a study of healthy subjects (16 men and 16 women) who applied crisaborole ointment,
2% BID or vehicle BID 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 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.


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1.3.3.2. Sensitizing and Cumulative Irritation Potential
In a repeat-insult patch test and cumulative irritation study in healthy subjects 
(Study AN2728-RIPT-101), the potential for inducing cutaneous sensitization was assessed 
in 238 subjects randomized in Cohort 1.  None of the subjects demonstrated cutaneous 
evidence of sensitization potential (a reaction of at least Grade 4 [definite edema] or a pattern 
suggestive of contact sensitization in the opinion of the Investigator) to the investigational 
products, crisaborole ointment, 2% or vehicle.  The potential for causing cutaneous irritation 
was evaluated among 40 subjects randomized in Cohort 2.  There were no statistically 
significant differences in irritation between the crisaborole ointment, 2% and vehicle.  
Crisaborole ointment, 2% and vehicle showed no evidence of sensitization and only very 
minimal irritation.
1.3.4. Clinical Experience
Seven (7) clinical trials of topical formulations of crisaborole have been completed to date in 
subjects with AD.  Key study information is summarized below.

In a multicenter, maximal use, systemic exposure (MUSE) study in 34 pediatric subjects 
ranging in age from 2 to 17 years with mild-to-moderate AD who applied crisaborole 
ointment, 2% BID, subjects had overall blood levels of crisaborole that were low and 
similar to those previously observed in adults after adjusting for % BSA treated.  
Absorption across the skin was rapid, with a median Tmax of 3.0 hours on both Day 1 and 
Day 8. 

In a 4-week, single arm, open-label safety, tolerability and PK trial in adolescents with 
mild-to-moderate AD involving 10-35% BSA, disease severity improved over the 28-day 
treatment period. 

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 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). 


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
In two Phase 3 multicenter, randomized, double-blind, vehicle controlled studies in 
subjects 2 years of age and older with mild to moderate AD, crisaborole ointment,
2% outperformed the vehicle in the primary efficacy analysis, proportion of subjects 
achieving success in Investigator’s Static Global Assessment (ISGA) at Day 29.  Success 
was defined as an (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.  The primary efficacy endpoint was met; differences 
from vehicle were statistically significant in both studies. 

A 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.  
Crisaborole ointment, 2% was well-tolerated and no clinically important safety signals 
were identified by this study. 
In summary, crisaborole has been well-tolerated across completed clinical studies.  No 
clinically important safety signals have been identified in adults and children as young as 
2 years of age.  Most AEs have been mild, and most considered unrelated or unlikely to be 
related to investigational product.  The most common drug-related AEs was application site 
pain (eg, cutaneous stinging and or burning).
1.4. Rationale
1.4.1. Study and Dose Rationale
This 4-week, randomized, assessor blinded, vehicle and active (TCS and TCI) controlled 
study will determine the efficacy of crisaborole ointment, 2% applied BID compared with
vehicle and evaluate the efficacy of crisaborole ointment, 2% applied BID compared with a 
TCS or TCI, in subjects ages 2 years and older with mild to moderate AD.  The study will 
also evaluate the efficacy and safety of crisaborole ointment, 2% compared with the active 
controls; hydrocortisone butyrate cream, 0.1% [TCS] and pimecrolimus cream, 1% [TCI].  
Hence, this study will, provide contextualization of the efficacy and safety of crisaborole 
ointment, 2% in the treatment of mild to moderate AD.
In the current treatment paradigm of mild to moderate AD there are only two main topical 
treatment options – TCS and the TCI pimecrolimus cream 1% (Elidel). To fully inform the 
position of crisaborole ointment, 2% in relation to the available topical treatments for mild to 
moderate AD, both the TCS hydrocortisone butyrate cream 0.1% (a standard of care 
treatment) and pimecrolimus cream, 1% (a second line treatment) have been included as 
active comparators.  The study will therefore provide contextualization of the efficacy of 
crisaborole ointment, 2% in the treatment of mild to moderate AD compared with 
hydrocortisone butyrate cream, 0.1% and pimecrolimus cream, 1%.


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The dose strength and regimen of crisaborole for this study has been shown to be safe, 
well-tolerated and efficacious in subjects and healthy volunteers 2 years of age and older who 
participated in previously conducted studies. Crisaborole ointment, 2% applied BID was 
studied in two Phase 3, randomized, double-blind, vehicle-controlled studies, and a Phase 3 
open-label long-term safety study. Data from the two controlled studies showed a 
statistically significant therapeutic effect compared to vehicle with no safety concerns in 
subjects 2 years and older.  In the subsequent Phase 3 open-label extension study, crisaborole 
ointment, 2% applied BID, demonstrated that long-term use was well-tolerated and not 
associated with any systemic safety signals.
Dose selection for the previous Phase 3 clinical studies was based on the safety and efficacy 
results from Phase 2 studies.  The Phase 2 Study AN2728-AD-204 compared two 
concentrations of crisaborole (2% and 0.5%) applied QD or BID in adolescents (12 to 
17.9 years of age) 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 
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).
This study will evaluate crisaborole ointment, 2% applied BID, a dose strength and regimen 
that has been demonstrated to be safe, well-tolerated and efficacious.
Hydrocortisone butyrate cream, 0.1% and pimecrolimus cream, 1% are approved products 
for the treatment of mild to moderate atopic dermatitis in subjects ages 2 years and older, and 
will be used as per national approved label in this study.
1.4.2. Benefit/Risk Assessment

This study will evaluate crisaborole at a dose strength and regimen that has been 
demonstrated to be well-tolerated and efficacious based on the completed Phase 3 
development program data.  Crisaborole ointment, 2% was applied BID in two Phase 3, 
randomized, double-blind, vehicle-controlled 4-week studies (AN2728-AD-301 and 
AN2728-AD-302) in subjects with mild to moderate AD aged 2 years and older.  The 
pediatric population comprised approximately 86% of the pooled study population.

This study also contains a vehicle arm that has important emollient properties and does 
not represent a true placebo.  It is known that some vehicle excipients have a more 
pronounced beneficial effect on the skin than previously considered and can improve 
clinical appearance and skin barrier function.  In particular, petrolatum the main excipient 
and base of crisaborole ointment, 2% was selected for its emollient properties and 
favorable tolerability profile.  The use of topical emollients is an essential element of the 
treatment of AD recommended by published clinical guidelines.

This study also contains two active comparator therapies, hydrocortisone butyrate cream 
0.1% and pimecrolimus cream 1%, that have been approved for the treatment of mild to 


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moderate AD in patients 2 years of age and older and will be used per the national 
approved labels in this study.

The crisaborole dose strength and regimen of crisaborole for this study has been shown to 
have a favorable safety profile and to be well tolerated in subjects and healthy volunteers 
(adults only) of 2 years of age and older who participated in previously conducted 
studies.  Crisaborole ointment, 2% applied BID was studied in two Phase 3, randomized, 
double-blind, vehicle-controlled studies (AN2728-AD-301 and AN2728-AD-302), and a 
Phase 3 open-label long-term safety study (AN2728-AD-303).  Data from the two 
controlled studies showed no systemic safety concerns in subjects aged 2 years and older.  
In the open-label study, crisaborole ointment, 2% applied BID, demonstrated that long-
term use was well tolerated and no clinically important systemic safety signals were 
identified in subjects aged 2 years and older.

The most common drug related adverse events (AEs) from the two controlled studies 
were application site reactions (5.6% and 3.6% for crisaborole and vehicle groups, 
respectively) and most were classified as mild.  Of these drug related application site 
reactions, application site pain (eg, burning or stinging) was the only treatment related 
AE that showed a clinically relevant difference in rates between the treatment groups 
(4.4% and 1.2% for crisaborole and vehicle groups, respectively).  Generally, application 
site pain was noted early in the treatment period and was transient in nature, resolving 
spontaneously.

The safety profile from the open label long term clinical study in which crisaborole was 
applied intermittently for up to 48 weeks was consistent with that of the two controlled 
pivotal clinical studies.

A review of the post-marketing safety data, to date, has shown that the type and 
occurrence of adverse event reports are consistent with the known safety profile of 
crisaborole.  No new safety signals or unusual trends have been identified.

Adequate and well-controlled clinical studies of pregnant women have not been 
performed for crisaborole and there is a limited amount of data from the use of 
crisaborole in pregnant women.  As per protocol, women who are pregnant or intending 
to become pregnant are excluded from the study and women of child-bearing potential 
must use a highly effective method of contraception.

Studies in renal or hepatic impaired patient populations have not been conducted.  Studies 
to date did not include sufficient numbers of subjects aged 65 years and over to determine 
whether they respond differently from younger subjects.

Hypersensitivity, including contact urticaria, has occurred in subjects treated with 
crisaborole.  As per protocol, subjects with a history of angioedema or anaphylaxis to 
topical products or known sensitivity to any of the components of the investigational 
products are excluded.


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
Hydrocortisone butyrate 0.1% cream is an approved treatment for AD and has a well-
documented and established safety profile that is clearly described in the product label.  
The most common side effects (these may affect up to 1 in 10 people, or up to 10%) are 
application site reactions including skin infections, eczema, and redness.

Pimecrolimus 1% cream is an approved treatment for mild to moderate AD and has a 
well-documented and established safety profile that is clearly described in the product 
label.  In this study, pimecrolimus is used as a second-line treatment as per label.  The 
most common side effects (these may affect up to 1 in 10 people, or up to 10%) are skin 
infections and application site reactions (irritation, redness, and itching).
In conclusion, the clinical experience obtained to date with crisaborole, support the continued 
development of crisaborole for the treatment of AD and support the initiation of this Phase 
3b/4 clinical Study C3291037.  Subjects will be monitored closely during the study for safety 
and local tolerability adverse events of the investigational products by the Investigators, 
Sponsor and External Data Monitoring Committee to ensure subject safety.
1.4.3. 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.  The 
SRSD for hydrocortisone butyrate cream, 0.1% is the United States Prescribing Information 
and for pimecrolimus cream, 1% is the Summary of Product Characteristics.  These SRSDs 
will serve to assess whether a serious adverse event related to the investigational products 
meets the criteria for a suspected unexpected serious adverse reaction (SUSAR).


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2. STUDY OBJECTIVES AND ENDPOINTS
Primary Efficacy Objective
Primary Efficacy Endpoint

To compare the efficacy of 
crisaborole ointment, 2% applied 
BID versus vehicle in pediatric and 
adult subjects, aged 2 years and 
older, with mild to moderate AD.

Percent change from Baseline in the Eczema Area and 
Severity Index (EASI) total score at Day 29.
Primary Safety Objectives
Primary Safety Endpoints

To evaluate the safety and local 
tolerability of crisaborole ointment 
2% applied BID versus vehicle in 
pediatric and adult subjects (ages 2 
years and older) with mild to 
moderate AD.

To evaluate the safety and local 
tolerability of hydrocortisone 
butyrate cream 0.1% and 
pimecrolimus cream 1% applied BID 
in pediatric and adult subjects (ages 
2 years and older) with mild to 
moderate AD.

AEs, SAEs, local tolerability, discontinuations 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 over time in pediatric and 
adult subjects (ages 2 years and 
older) with mild to moderate AD.

To evaluate the efficacy of 
crisaborole ointment, 2% BID versus 
hydrocortisone butyrate cream 0.1% 
and pimecrolimus cream 1% applied 
BID in pediatric and adult subjects 
(ages 2 years and older) with mild to 
moderate AD.

Efficacy endpoints:

Percent change from Baseline in EASI total score by 
scheduled time points except Day 29.

Achievement of success in the Investigator’s Static 
Global Assessment (ISGA) (defined as an ISGA score 
of Clear (0) or Almost Clear (1) with at least a 2-grade 
improvement from Baseline) by scheduled time points.

Achievement of ISGA score of clear (0) or almost clear 
(1) by scheduled time points.

Achievement of EASI75 (75% improvement from 
Baseline) by scheduled time points.

Time to EASI75.

Change from Baseline in % BSA by scheduled time 
points.

To evaluate the effect of crisaborole 
ointment, 2% applied BID versus 
vehicle, hydrocortisone butyrate 
cream 0.1% applied BID on 
patient/observer reported outcomes 

Patient/observer reported outcomes endpoints:

Change from Baseline in Peak Pruritus Numerical 
Rating Scale (NRS) for subjects >12 years by


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over time in pediatric and adult 
subjects (ages 2 years and older) with 
mild to moderate AD.
scheduled time points
•
Change from Baseline in Patient Reported Itch Severity 
Scale - for subjects age 6-11 years by scheduled time 
points. Change from Baseline in Observer Reported 
Itch Severity Scale - for subjects <6 years by 
scheduled time points.
•
Time to ≥2 point improvement from Baseline in Peak 
Pruritus NRS for subjects >12 years. Time to ≥3 point
improvement from Baseline in Peak Pruritus NRS for 
subjects >12 years. Time to ≥2 point improvement 
from Baseline in Observer Reported Itch Severity Scale
- for subjects <6 years.
•
Time to ≥3 point improvement from Baseline in 
Observer Reported Itch Severity Scale - for subjects <6 
years.
•
Achievement of ≥2 point improvement from Baseline 
in Peak Pruritus NRS for subjects >12 years.
•
Achievement of ≥3 point improvement from Baseline 
in Peak Pruritus NRS for subjects >12 years.
•
Achievement of ≥2 point improvement from Baseline 
in Observer Reported Itch Severity Scale - for subjects 
<6 years.
•
Achievement of ≥3 point improvement from Baseline 
in Observer Reported Itch Severity Scale - for subjects 
<6 years.
•
Change from Baseline in Dermatology Life Quality 
Index (DLQI) (for Subjects 16 years and older), 
Children’s Dermatology Life Quality Index (CDLQI) 
(for Subjects 4-15 years), and Dermatitis Family 
Impact Questionnaire (DFI) (Completed by 
parent/caregiver of Subjects 2-17 years) by scheduled 
time points.
 
 
 
 
 
 
 
 
 
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3. STUDY DESIGN
This is a Phase 3b/4, multicenter, randomized, assessor blinded, vehicle and active (TCS and 
TCI) controlled study of the efficacy, safety and local tolerability of crisaborole ointment,
2% in pediatric and adult subjects, ages 2 years and older, with mild to moderate AD 
involving at least 5% treatable %BSA.  Treatment will be clinical assessor-blinded for all 
treatment arms and double-blinded for crisaborole ointment, 2% and vehicle treatment arms.
A total of approximately 600 subjects will be enrolled in the study, of which at least 
150 subjects aged 2-6; at least 140 subjects aged 7-11; at least 120 subjects aged 12-17 and 
up to 90 subjects will be adults.  Following the screening period (up to 35 days prior to 
Baseline/Day 1), eligible subjects will be randomized at the Baseline/Day 1 visit.  
Randomization will be stratified by eligibility for TCS or TCI treatment as per national 
approved labels and eligibility provided in Section 4. Cohort 1 will be for subjects who are 
eligible for TCS therapy, and Cohort 2 will be for subjects who are not eligible for TCS 
therapy but eligible for TCI therapy.  The investigational product will be applied BID for 28 
days to the Treatable BSA identified at Baseline/Day 1. Any new AD on treatment-eligible 
locations occurring following Baseline/Day 1 should also be treated with the study drug after 
consultation with the Investigator at the next visit.
The primary efficacy endpoint is the percent change from baseline in the EASI total score at 
Day 29.
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For the efficacy comparison of crisaborole versus vehicle, subjects from both Cohort 1 and 
Cohort 2 are included in the analysis, adjusted for cohort effect.  For the efficacy comparison 
of crisaborole versus TCS, only subjects from Cohort 1 are included in the analysis.  For the 
comparison of crisaborole versus TCI, only subjects from Cohort 2 are included in the 
analysis.
Safety and efficacy assessments will be conducted at the investigator site by a clinical 
assessor blinded for treatment arms.
A sub-study will be conducted at selected investigator sites to evaluate differences of 
changes in epidermal skin thickness as measured by Optical Coherence Tomography (OCT) 
between treatment groups in Cohort 1.  (see Appendix 4).
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) and Day 43 or 14 Days after 
last dose if subject is terminated early from treatment. A follow up telephone call will be 
made by site staff to the subjects/caregivers on Day 60 or at least 28 days after last dose if 
subject is terminated early from treatment.  Subjects enrolled in the OCT sub-study will 
attend the clinic on Day 60 and do not require a telephone call on Day 60.
A schematic of the study design is shown in Figure 1.


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Figure 1.
Study Design Schematic
1
Crisaborole ointment, 2% BID (n = 75)
Crisaborole Vehicle ointment BID (n = 75)
Hydrocortisone butyrate cream 0.1% BID (n = 150)
Crisaborole Vehicle ointment BID (n = 75)
Pimecrolimus 1% cream BID (n = 150)
Crisaborole ointment, 2% BID (n = 75)
Double-blind treatment period
Follow-
up
Screening/
Washout
Randomization/
Start of Treatment
End of Treatment
Day
Cohort 1
Cohort 2
-35
15
29
60
8
1
22
43
Treatment will be clinical assessor-blinded for all treatment arms and double-blinded for 
crisaborole ointment, 2% and vehicle treatment arms.
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.
Subjects screening for the study prior to informed consent approval by IRB/EC for 
amendment 3 should complete the version of the study for which they consented.  Subjects 
screening for the study after IRB/EC approval of the amendment 3 version of the protocol 
and consent should complete the amendment 3 version of the study.     


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Subject eligibility for the sub-study will be reviewed and documented according to additional 
criteria specified in Appendix 4. The sub-study informed consent process will be separate 
and in addition to the informed consent process for the main study. 
4.1. Inclusion Criteria
4.1.1. Inclusion Criteria – All Cohorts
Subjects must meet all of the following inclusion criteria to be eligible for enrollment into the 
study:
1. Is male or female 2 years and older at the Screening visit/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. 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).
6. 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. 
All other female subjects (including female subjects with tubal ligations) are considered 
to be of childbearing potential.
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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4.1.2. Inclusion Criteria – Cohort 1
1. Subjects considered to be a candidate for hydrocortisone butyrate cream, 0.1% therapy 
according to the national approved labeling.
4.1.3. Inclusion Criteria – Cohort 2
1. Subjects who are not considered candidates for treatment with a topical corticosteroid
because it is either inadvisable or not appropriate according to the national approved 
labeling. This may include:

Intolerance to topical corticosteroids;

Lack of effect of topical corticosteroids;

Use on the body regions where treatment with topical corticosteroids may be 
inappropriate.
4.2. Exclusion Criteria
4.2.1. Exclusion Criteria – All Cohorts
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 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 a history of requirement for high/strong potency or very high/very 
strong potency topical corticosteroids to manage AD signs and symptoms (See 
Appendix 3).
3. Has a significant active systemic or localized infection, including known actively infected 
AD.
4. History of or active suicidal ideation or behavior, or chronic psychiatric 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:


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
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 Children’s 
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 
Children’s C-SSRS.

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.
5. Pregnant female subjects; breastfeeding female subjects; and female of childbearing 
potential who are unwilling or unable to use a highly effective method of contraception as 
outlined in this protocol for the duration of the study and for at least 28 days after the last 
dose of investigational product.
6. Has received any of the prohibited medications/therapies that may alter the course of AD 
without the required minimum washout period (see Section 5.8.1) or anticipated 
concomitant use of any of the prohibited medications/therapy (see Section 5.8.2).
7. Has any planned surgical or medical procedure that would overlap with study 
participation, from Screening through the end of study.
8. Has a 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).
9. Has a history of angioedema or anaphylaxis to topical products or known sensitivity to 
any of the components of the investigational products.
10. Has a known lack of efficacy to crisaborole.
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 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.
13. 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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4.2.2. Exclusion Criteria – Cohort 1
1. Has a contraindication for treatment with hydrocortisone butyrate cream 0.1% or meets
warnings and precautions for use specifications in accordance with the national approved 
label or treatment with hydrocortisone butyrate cream, 0.1% is otherwise medically 
inadvisable.
4.2.3. Exclusion Criteria – Cohort 2
1. Has a contraindication for treatment with pimecrolimus cream, 1%, or meets warnings 
and precautions for use specifications in accordance with the national approved label or 
treatment with pimecrolimus cream, 1% is otherwise medically inadvisable.
4.3. Randomization Criteria
Subjects will be randomized into the study provided that the subject or caregiver
[parent/legal guardian/legally acceptable representative] has signed an informed consent (or 
assent, if applicable) document to participate in the study, and the subject has undergone all 
screening procedures, and satisfies 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 assigned to one of two cohorts prior to randomization.  Subjects will be 
enrolled into Cohort 1 if eligible to receive TCS therapy; randomization will be 1:1:2 to 
crisaborole ointment, 2%, the matching vehicle ointment for crisaborole, or hydrocortisone 
butyrate cream, 0.1%, respectively.  Subjects will be enrolled into Cohort 2 if ineligible to 
receive TCS therapy and eligible to receive pimecrolimus cream, 1%; randomization will be 
1:1:2 to crisaborole ointment, 2%, the matching vehicle ointment for crisaborole, or 
pimecrolimus cream, 1%, respectively.
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 fertile female subjects who are of childbearing potential as applicable to the study who 
are, in the opinion of the investigator, sexually active and at risk for pregnancy with their 
partner(s) must agree to use a highly effective method of contraception consistently and 
correctly for 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 highly effective contraception 
consistently and correctly and document the conversation and the subject’s affirmation in the 
subject’s chart (subjects needs to affirm their consistent and correct use of at least 1 of the 


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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. 
Highly effective methods of contraception are those that, alone or in combination, result in a 
failure rate of less than 1% per year when used consistently and correctly (ie, perfect use) and 
include the following:
1. Established use of hormonal methods of contraception associated with inhibition of 
ovulation (eg, oral, inserted, injected, implanted, transdermal) provided the subject or 
male subject’s female partner plans to remain on the same treatment throughout the entire 
study and has been using that hormonal contraceptive for an adequate period of time to 
ensure effectiveness. 
2. Correctly placed copper-containing intrauterine device (IUD). 
3. Male condom or female condom used WITH a spermicide product (ie, foam, gel, film, 
cream, or suppository).  For countries where spermicide is not available or condom plus 
spermicide is not accepted as highly effective contraception, this option is not appropriate.
4. Male sterilization with absence of sperm in the 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.  The Pfizer Medical Monitor can be contacted for further guidance, if 
necessary.
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 avoid applying an occlusive dressing to the treated areas, not swim, bathe 
or 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.

Due to the potential to affect AD with ultraviolet light exposure, subjects must also avoid 
prolonged exposure to the sun and not use tanning booths, sun lamps or other ultraviolet 
light sources during the study.


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
The subject and/or caregiver should avoid wiping the investigational product off the skin 
and investigational product should not be reapplied to areas that were inadvertently wiped 
until the next scheduled dose.

When applying investigational product, the subject and/or caregiver will generally not be 
required to wear gloves.  However, they must be instructed to wash their hands with mild 
soap and water before and after each application.  Subjects with lesions on hands must 
take care not to wash off investigational product from the hands.

Caregivers who are pregnant or women of childbearing potential, who are trying to 
become pregnant, should avoid accidental exposure by either avoiding applying 
investigational product or wearing gloves during its application.  Care should also be 
taken when handling the child after investigational product has been applied.
4.5. Sponsor’s Qualified Medical Personnel
The contact information for the sponsor's appropriately qualified medical personnel for the 
study is documented in the study contact list located in the 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 Council for 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 vehicle ointment, also referred to as vehicle;

Hydrocortisone butyrate cream, 0.1% (eg. Locoid), also referred to as TCS;

Pimecrolimus cream, 1% (eg. Elidel), also referred to as TCI.
Crisaborole ointment, 2%, is formulated to contain crisaborole (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.
For hydrocortisone butyrate cream, 0.1% and pimecrolimus cream, 1% the national approved 
label insert will be provided to each site for content information.
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(s) 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(s) assigned.  The confirmation report must be stored in 
the site’s files. 
The study-specific IRT reference manual will provide the contact information and further 
details on the use of the IRT system.
5.2. Breaking the Blind

In this study treatment will be clinical assessor-blinded for all treatment arms and 
double-blinded for crisaborole ointment, 2% and vehicle treatment arms.  Unblinded 
personnel will be required to manage subject treatment allocation, handle investigational 
products, review the Dosing Diary and participate in the Baseline/Day 1 investigational 
product application training.  All study treatments will be masked by over-labeling with a 
tube label that will be applied over the entire body and crimp of the tube.

At the initiation of the study, the investigator site will be instructed on the method for 
breaking the blind.  The methods will be by an electronic or telephone 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 


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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
The subject and/or a caregiver will apply investigational product at home; compliance will be 
captured and completed by the subject/caregiver using a Dosing Diary and instructions 
provided by the site.  The subject and/or caregiver 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. If the subject comes to the clinic in the afternoon, two doses (12 4 hours apart) or 
single dose could be administered on Day 1.  Subjects and/or caregivers will be instructed to 
bring the Dosing Diary and all dispensed investigational product supplies in its original 
package (used as well as unused) to the clinic at Days 8, 15, 22, and 29.
A total of 56 doses are expected to be applied. A subject will be considered compliant with 
the dosing regimen if they receive at least 45 but no more than 67 investigational product 
doses (ie, 80–120%, inclusive, of the expected number of doses) administered in accordance 
with the protocol.  This will be verified by the dosing records.  Subjects and/or caregivers
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 gram tubes for topical 
administration.  The tubes will be provided in cartons and labeled in a blinded fashion.
Hydrocortisone butyrate cream, 0.1% will be supplied in either 30 gram or 45 gram tubes for 
topical administration.  The tubes will be masked by a label and provided in cartons.  The 
product will be labeled in a blinded fashion to mask contents.
Pimecrolimus cream, 1% will be supplied in either 30 gram or 60 gram tubes for topical 
administration.  The tubes will be masked by a label and provided in cartons.  The product 
will be labeled in a blinded fashion to mask contents.
The blinded labeling for all products will be according to local regulatory requirements.
The investigational products above are masked for appearance, and will be placed into 
identical cartons.  Once removed from the product cartons, the investigational products could
be discerned from each other based on commercial product tube shape/size and should only 
be handled by unblinded site personnel.
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 


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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.  An unblinded qualified staff member will 
dispense the investigational product via unique container numbers on the cartons provided, in 
quantities appropriate for the study visit schedule and the treatable %BSA.
For doses to be administered at home, the subject or caregiver should be instructed to 
maintain the product in its original package provided throughout the course of dosing and 
return the product and its original package (including empty, partial used and unused tubes) 
to the site at the next study visit.  All previously dispensed investigational product tubes will 
be retained by the site.  Investigational product tubes will be weighed individually or 
collectively by the study site before dispensing and after return and the weights will be 
recorded.  The sponsor will use the recorded weights to estimate usage (mg/cm2/day) by each 
subject. Note that the weight recorded on the investigational product label is a nominal 
weight and not an exact weight of the investigational product and tube.
5.5. Administration
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 (body maps).  The subject and/or caregiver will be provided 
with documentation of the designated treatment areas.
Regimen: Investigational product will be applied BID (12 4 hours apart) to all treatable AD
involved areas (excluding the scalp) identified at Baseline/Day 1 through Day 28.  Wearing 
gloves, unblinded personnel will apply a thin layer of investigational product to all treatable 
AD lesions identified at Baseline/Day 1.  Subjects and/or caregivers 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 (if applicable), 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 investigational product
application instructions.
Subjects and/or caregivers will be instructed to not wipe investigational product off the skin, 
avoid applying an occlusive dressing to the treated areas, and refrain from swimming or 
bathing/washing the treated areas within 4 hours after application.
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 caregiver 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 (see Subject Compliance Section 5.3).  
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 


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clear prior to Day 29.  Investigational product will also be applied to any new AD on 
treatment eligible locations occurring following Baseline/Day 1 after consultation with the 
Investigator at the next visit.  Therefore, the BSA for Investigational Product at subsequent 
visits should be equal to or greater than the value at Baseline/Day 1.
Subjects and/or caregivers 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 the subject comes to the clinic in the afternoon, two doses (12 4 hours apart) or single 
dose could be administered on Day 1.
5.6. Investigational Product Storage
The investigator or an approved unblinded representative, eg, pharmacist or other 
appropriately trained personnel, will ensure that all investigational products are stored in a 
secured area with controlled access under required storage conditions and in accordance with 
applicable regulatory requirements.
Investigational products should be stored in their original containers and in accordance with 
the labels.
Any storage conditions stated in the SRSD will be superseded by the storage conditions 
stated on the product label.
Site systems must be capable of measuring and documenting (for example, via a log), at a 
minimum, daily minimum and maximum temperatures for all site storage locations (as 
applicable, including frozen, refrigerated, and/or room-temperature products).  This should 
be captured from the time of investigational product receipt throughout the study.  Even for 
continuous-monitoring systems, a log or site procedure that ensures active evaluation for 
excursions should be available.  The intent is to ensure that the minimum and maximum 
temperature is checked each business day to confirm that no excursion occurred since the last 
evaluation and to provide the site with the capability to store or view the minimum/maximum 
temperature for all non-working days upon return to normal operations.  The operation of the 
temperature monitoring device and storage unit (for example, refrigerator), as applicable, 
should be regularly inspected to ensure they are maintained in working order.


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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. 
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 caregivers 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 unblinded personnel 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.  The accountability log will be an 
unblinded document until study completion and therefore should only be accessed by 
unblinded site personnel.
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.


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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.
Only unblinded personnel should have access or view any returned product. 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, non-medication therapies, as well as 
biologic drugs used for AD within 180 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 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 at the Screening Visit.
Medications Prohibited 12 weeks or 5 half-lives (whichever is longer) Prior to 
Baseline/Day 1

Biological drugs.
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, 
ciclosporin, azathioprine, hydroxychloroquine, and mycophenolate mofetil (MMF), 
within 28 days prior to Baseline/Day 1.

Use of sunbathing, tanning bed use, or light therapy Ultraviolet (UV), Ultraviolet B 
(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.
Medications Prohibited 14 Days Prior to Baseline/Day 1

Use of systemic antibiotics, within 14 days prior to Baseline/Day 1.

Use of TCS, or TCI, anywhere on the body, within 14 days prior to Baseline/Day 1.

Use of crisaborole ointment, 2%, anywhere on the body, within 14 days prior to 
Baseline/Day 1.

Use of topical antihistamines anywhere on the body, 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.

Systemic sedating antihistamines (eg, hydroxyzine or diphenhydramine or other sedating 
antihistamines). 

Use of systemic non-sedating antihistamines in a nonstable (eg, escalating, decreasing, or 
PRN) regimen, within 7 days prior to Baseline/Day 1.

Subjects on a stable non-sedating 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 bland (non-medicated) emollients on treatable AD lesions, within 1 day prior to 
Baseline/Day 1 (ie, during the 24-hour period before the Baseline/Day 1 Visit).
After the Baseline/Day 1 Visit, use of bland (non-medicated) emollient(s) is permitted 
during the study to manage dry skin in areas surrounding but not on or overlapping the 
treatable AD-involved areas (See Section 5.8.2 and Section 5.8.3).
5.8.2. Medications Prohibited During Treatment (Days 1–29)
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 to the end of treatment
visit on Day 29) are listed below.


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
Use of systemic (oral, parenteral) corticosteroids.

Subjects with a 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 TCS, or TCI, anywhere on the body other than allocated investigational product.

Use of systemic immunosuppressive agents, including but not limited to methotrexate, 
ciclosporin, 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 sedating antihistamines (eg, hydroxyzine or diphenhydramine or other 
sedating antihistamines).

Use of systemic non-sedating antihistamines in a nonstable (eg, escalating, decreasing, or 
PRN) regimen.
Subjects on a stable non-sedating systemic antihistamine regimen 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.

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.

Use of topical antibacterial medications or products, including soaps, bleach baths, or 
topical sodium hypochlorite-based products anywhere on the body.

Use of topical antihistamines anywhere on the body.

Use of sunbathing, tanning bed use, light therapy (UV, UV-B, PUVA) anywhere on the 
body.

Use of bland (non-medicated) emollients, moisturizers or sunscreen on AD lesions.

Participation in another drug or device research study.


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5.8.3. Medications Allowed During Treatment (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 (non-medicated) 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 non-sedating 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;

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;

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.
5.8.4. Medications Allowed After the End of Treatment (Day 29 or after early 
termination from treatment until Day 43 visit)

In addition to medications allowed during the treatment phase, if the EASI score at the 
End of Treatment/Early Termination Visit is the same or higher than the EASI score at 
the Baseline Visit (ie, no improvement or worsening of AD severity), there are no 
restrictions to medications used to treat AD during this period.  

If the EASI score at the End of Treatment/Early Termination Visit is lower than the EASI 
score at the Baseline Visit (ie, improvement in AD severity), then medications prohibited 


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during treatment period (Day 1 to 29; see Section 5.8.2) are prohibited until the 
completion of the Day 43 Visit.

After the end of treatment, and prior to the Day 43 visit, unscheduled clinic visits are 
available if subject’s condition worsens, so that an assessment can be conducted in-clinic, 
and nonstudy treatment intervention prescribed as necessary.  If the EASI score at this 
unscheduled visit is the same or higher than the EASI score at the Baseline Visit (ie no 
improvement or worsening of AD severity) there are no restrictions to medications used 
to treat AD.After the Day 43 visit, there are no restrictions to medications used to treat 
AD, except for subjects participating in the sub-study (Appendix 4). 
6. STUDY PROCEDURES
A number of tasks within the study procedures are completed by dedicated assigned roles at 
the site level; unblinded personnel and a clinical assessor blinded for treatment arms.  The 
clinical assessor blinded for treatment arms should not have knowledge or access to the 
assigned subject’s investigational product and should not participate in the Baseline/Day 1
investigational product application training and review of the Dosing Diary. The subject 
and/or caregiver must be instructed not to discuss any element of their study treatment 
(including study drug appearance) with the blinded clinical assessor.
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 days;

Day 22 Visit: Day 22 3 days;

Day 29 End of Treatment Visit: Day 29 3 days;

Day 43 Off Treatment Follow Up Visit: Day 43 5 days;

Follow up telephone contact: Day 60 3 days.  Subjects enrolled in the OCT sub-
study do not require a follow up telephone contact at Day 60 as this visit will occur in 
clinic.


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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.
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;

Only subjects that are enrolled after IRB/EC approval of an amendment should be 
consented to the study under that amendment.  If a subject consents to the study prior to 
local approval of an amendment, they will consent and complete the study according to 
the version of the study currently approved by the IRB/EC at the time of their enrollment. 

Collect demographic information (sex, date of birth, race, and ethnicity);

Measure height and weight;

Measure and calculate the Body Surface Area for Investigational Product (per 
Section 7.2);

Register subject with IRT in order to obtain a subject screening identification number 
(SSIN);

Perform a detailed physical examination and confirm clinical diagnosis of AD per 
Hanifin and Rajka criteria (Appendix 2);

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 (when possible for younger children);

Collect complete medical history, including onset of AD (date of diagnosis, as 
specifically as possible);

Record treatments (including all medications and non-medication therapies) used for AD, 
as well as any biologic drugs used within 180 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;


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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;
•
Urine pregnancy test (female subjects of childbearing potential only);
•
Contraception check: Confirm and document in source documents that proper 
contraception have been reviewed for a female subject of child bearing potential and their 
partner as appropriate, and the subject’s agreement to use appropriate contraception
methods throughout the study (see Section 4.4.1);
•
Serum chemistry and hematology;
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 electronic case report form 
(eCRF);
•
FSH (to confirm postmenopausal status in female subjects who have been amenorrheic 
for at least 12 months);
•
Dispense daily diary (electronic patient reported outcome (ePRO) device or paper);
•
Instruct subject and/or caregiver on the use of daily diary (ePRO device or paper);
•
Peak Pruritus Numeric Rating Scale (NRS) for subjects >12 years/Patient Reported Itch 
Severity Scale - for subjects age 6-11 years/Observer Reported Itch Severity Scale - for 
subjects <6 years
 
 will be completed by subject or caregiver when applicable during 
screening prior to Day 1 regardless of whether the subject continues to randomization;
 
•
Administer C-SSRS. Children’s C-SSRS for subjects 7-11 years old, C-SSRS for 
subjects ≥12 years old.  Subjects ≥7 years of age meeting any of the criteria specified in 
Exclusion Criterion 4 will be ineligible for participation (See Section 4.2.1);
•
Assess for AEs/SAEs, starting from the time of informed consent and assent, as 
applicable;
•
ISGA completed by a clinical assessor blinded for treatment arms;
•
Review subject’s tentative eligibility according to the Inclusion and Exclusion Criteria;
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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;
•
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.
6.4. Study Period/Treatment Period
6.4.1. Baseline/Day 1 Visit
The following procedures will be performed at the Baseline/Day 1 Visit BEFORE dosing 
with investigational product:
•
Administer
Dermatology Life Quality 
Index (DLQI) (completed by subjects ≥16 years old), Children’s Dermatology Life 
Quality Index (CDLQI) (completed by subjects 4-15 years old), 
 
Dermatitis Family Impact Questionnaire (DFI) (completed by caregivers of subject 
2-17 years old
 
 
•
Confirm subject and/or caregiver has been instructed on the use of the diary (ePRO 
device or paper);
•
Confirm subject and/or caregiver has completed Peak Pruritus NRS for subjects >12 
years/Patient Reported Itch Severity Scale - for subjects age 6-11 years/Observer 
Reported Itch Severity Scale - for subjects <6 years
during screening 
prior to Day 1 to demonstrate understanding and compliance;
•
If a subject was undergoing washout of a prohibited medication as directed by the 
investigator or his/her designee, confirm successful completion of the washout period;
•
Perform a detailed physical examination;
•
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 (when possible for younger children); assessment of vital signs should precede 
blood draw for clinical laboratory tests;
•
Obtain and record medical history;
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•
Assess and record any changes in the subject’s prior and concomitant medications since 
the Screening Visit; see Section 5.8 for medications prohibited prior to Baseline/Day 1 
and during the study;
•
Ask the subject or caregiver (when applicable) to complete the Peak Pruritus NRS for 
subjects >12 years/Patient Reported Itch Severity Scale - for subjects age 6-11 
years/Observer Reported Itch Severity Scale - for subjects <6 years
before investigational product (IP) morning dose applied starting at Baseline/Day 1 and 
continuing through Day 28 and at Day 29 (as applicable);
•
Contraception check: Confirm and document that proper contraception is being used for 
the female subject of child bearing potential and their partner as appropriate;
•
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;
•
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 
14 days prior to Day 1, whether the Day 1 serum chemistry and hematology tests are to 
be performed will be at the medical judgment 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 electronic case report form 
(eCRF);
•
ISGA completed by a clinical assessor blinded for treatment arms prior to the application 
of investigational product (Note: The ISGA score must be 2 or 3 at Baseline/Day 1 for 
subject to be eligible for the study);
•
EASI assessment completed by a clinical assessor blinded for treatment arms prior to the 
application of investigational product;
•
A checklist of body areas currently affected by AD will be completed at the 
Baseline/Day 1 visit by a clinical assessor blinded for treatment arms.  Location of skin 
lesions will be selected from a prepopulated listing of body locations on the eCRF;
•
Confirm subject’s eligibility based on the Inclusion and Exclusion Criteria, including 
confirming acceptable methods of birth control for female subjects of childbearing 
potential;
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
Assess and record any AEs/SAEs related to AD lesions by a clinical assessor blinded for
treatment arms.  Other site personnel may also report and record AE’s and SAE’s
reported to them spontaneously by the subject;

Mark the subject’s source documents to record the treatable AD areas (excluding the 
scalp) as identified by a clinical assessor blinded for treatment arms at Baseline/Day 1 
and provide subject and/or caregiver with documentation of the designated treatment 
areas (body maps);

Photography of AD lesions (at selected sites – see Section 7.4);

After PI’s or designee’s documented confirmation of eligibility and Cohort assignment, 
access IRT system to randomize subject to receive randomization number and 
investigational product treatment;

Dispense investigational product supply to subject and/or caregiver;

Unblinded personnel to provide to subject and/or caregiver 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;
Wearing gloves, unblinded study staff will apply a thin layer of investigational product (first 
dose) to all treatable AD lesions identified at Baseline/Day 1 (See Administration 
Section 5.5).

Assess and record any post-dose AEs/SAEs including application site reactions.
The following procedures will be performed at the Baseline/Day 1 Visit AFTER dosing with 
investigational product:

Unblinded personnel to instruct the subject and/or caregiver that investigational product 
should not be wiped off the skin, avoid applying an occlusive dressing to the treated 
areas, and refrain from swimming or bathing/washing the treated areas within 4 hours 
after application;

Dispense subject dosing instructions and Dosing Diary and instruct the subject and/or 
caregiver on use (ie, each time investigational product is applied). Instruct the subject 
and/or caregiver 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 
the evening before Day 28 or End of Treatment Visit (ie, each time investigational 
product is applied);

The subject or caregiver must be instructed to avoid discussing treatment details (eg,
ointment or cream) with the clinical assessor blinded for treatment arms;


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•
Review the schedule of upcoming study visits with the subject and/or caregiver, and 
instruct them to return at the scheduled time for the Day 8 Visit.  Advise subject and/or 
caregiver that the investigational product should be applied at least 4 hours prior to the 
clinic visit to ensure that there are no visible residues left on the lesions so as to not 
unblind the blinded clinical assessor;
•
Remind the subject and/or caregiver to bring all investigational product tubes (empty, 
partially used and unused) in their original packages and the Dosing Diary to their next 
visit.
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 caregiver (when applicable) to complete the Peak Pruritus NRS
for subjects >12 years/Patient Reported Itch Severity Scale - for subjects age 6-11 
years/Observer Reported Itch Severity Scale - for subjects <6 years
(QD
before investigational product is applied);
•
Administer
 
 DLQI (completed by subjects ≥16 years old), CDLQI (completed by 
subjects 4-15 years old), 
 
 
 
 
 
•
Assess and record any changes in concomitant medications, including confirming that 
subject is not taking any prohibited medications;
•
Contraception check: Confirm and document that proper contraception is being used for 
the female subject of child bearing potential and their partner as appropriate;
•
Unblinded personnel to review Dosing Diary and assess compliance; re-educate the 
subject and/or caregiver if any missed doses have occurred;
•
Unblinded personnel to weigh returned investigational product tubes (including empty, 
partial used and unused tubes); record investigational product tubes weight in subject’s 
source documents and eCRF;
•
Dispense 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 caregiver.  Weights will be recorded 
in the subject’s source documents;
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
Remind the subject and/or caregiver that investigational product must continue to be 
applied at home twice each day (am and pm), as instructed, 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 should also be applied to any 
new treatable AD involved areas that appear following Baseline/Day 1 after consultation 
with the Investigator;

Re-educate subject and/or caregiver on the dosing instructions if any investigational 
product doses were missed during the interval since the previous study visit;

Re-dispense dosing instructions and new Dosing Diary;

Unblinded personnel to instruct the subject and/or caregiver that investigational product
should not be wiped off the skin, avoid applying an occlusive dressing to the treated 
areas, and refrain from swimming or bathing/washing the treated areas within 4 hours 
after application;

Unblinded personnel must remind the subject and/or caregiver not to discuss any element 
of the Investigational product with the blinded assessor, including study drug appearance;

Unblinded personnel should check for any residue of investigational product.  If any 
investigational product is visible, it is permissible to gently remove it prior to the 
assessments performed by the clinical assessor blinded to treatment arms to avoid 
potential unblinding;.

Photography of AD lesions (at selected sites - see Section 7.4) (only Day 15 visit, not 
scheduled for Day 8 and Day 22 visit);

Review the schedule of upcoming study visits with the subject and/or caregiver, and 
instruct them to return at the scheduled time for the next visit;

Remind subject and/or caregiver to bring all investigational product tubes (empty, 
partially used and unused) in their original packages and the Dosing Diary to their next 
visit.  Advise subject and/or caregiver that the investigational product should be applied 
at least 4 hours prior to the clinic visit to ensure that there are no visible residues left on 
the lesions as to unblind the blinded assessor;

Assess and record any AEs and SAEs by a clinical assessor blinded for treatment arms.  
Other site personnel may also report and record AEs and SAEs reported to them 
spontaneously by the subject;

ISGA completed by a clinical assessor blinded for treatment arms;

EASI assessment, including treatable BSA, completed by a clinical assessor blinded for
treatment arms.


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6.4.3. Day 29 (±3 days) (End-of-Treatment)/Early Termination Study Visit
The following procedures will be performed at the Day 29/Early Termination Visit:
•
Ask the subject or caregiver (when applicable) to complete Day 29 Peak Pruritus NRS
for subjects >12 years/Patient Reported Itch Severity Scale - for subjects age 6-11 
years/Observer Reported Itch Severity Scale - for subjects <6 years
if 
not already completed;
•
Administer
 
DLQI (completed by subjects ≥16 years old), CDLQI (completed by 
subjects 4-15 years old), 
 DFI
(completed by caregivers of subject 2-17 years old
 
 
 
•
Perform a detailed physical examination, evaluate any current or reported symptoms for 
clinically significant changes and report relevant AE if applicable;
•
Measure weight;
•
Obtain vital signs (temperature, respiratory rate, pulse rate, and BP) in the seated 
position, after the subject has been sitting calmly for a minimum of 5 minutes (when 
possible for younger children); assessment of vital signs should precede blood draw for 
clinical laboratory tests;
•
Assess and record any changes in concomitant medications, including confirming that 
subject is not taking any prohibited medications;
•
Urine pregnancy test (female subjects of childbearing potential only);
•
Contraception check: Confirm and document that proper contraception is being used for 
the female subject of child bearing potential and their partner as appropriate;
•
Draw blood for clinical laboratory tests (testing includes serum 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;
•
Photography of AD lesions (at selected site(s) – see Section 7.4);
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
Unblinded personnel to collect and review Dosing Diary and assess compliance;

Unblinded personnel to weigh returned investigational product tubes (including empty, 
partial used and unused tubes); record investigational product tubes weight in subject’s 
source documents and eCRF;

Unblinded personnel must remind the subject not to discuss any element of the 
Investigational product with the blinded assessor, including study drug appearance;

Unblinded personnel should check for any residue of Investigational product.  If any 
Investigational product is visible, it is permissible to gently remove it prior to the 
assessments performed by the clinical assessor blinded to treatment arms to avoid 
potential unblinding;

Assess and record any AEs and SAEs by a clinical assessor blinded for treatment arms.  
Other site personnel may also report and record AEs and SAEs reported to them 
spontaneously by the subject;

ISGA completed by a clinical assessor blinded for treatment arms;

EASI assessment, including treatable BSA, completed by a clinical assessor blinded for
treatment arms.
6.4.4. Day 43 (5 days), or 14 days (5 days) after Early Termination, Off Treatment 
Study Visit
This visit will occur at Day 43 (5 days) or 14 days (5 days) after last dose if subject is 
terminated early from treatment.  The following procedures will be performed at the Day 43 
Study Visit:

Assess and record any changes in concomitant medications, including confirming that 
subject is not taking any prohibited medications (see Section 5.8.4);

Assess and record any AEs and SAEs by a clinical assessor blinded for treatment arms.  
Other site personnel may also report and record AEs and SAEs reported to them 
spontaneously by the subject;

ISGA completed by a clinical assessor blinded for treatment arms;

EASI assessment completed by a clinical assessor blinded for treatment arms including 
treatable BSA calculation.

Contraception check: Confirm and document that proper contraception is being used for 
the female subject of child bearing potential and their partner as appropriate.


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6.4.5. Unscheduled Visit
The procedures performed at an Unscheduled Visit will depend on the reason for the visit 
(some procedures may not apply). 

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 (when possible for younger children);

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;

Unblinded personnel to instruct the subject and/or caregiver regarding all procedures for 
at home dosing beginning BID dosing through Day 29 visit, including how to complete 
the dosing diary;

Unblinded personnel must remind the subject not to discuss any element of the 
Investigational product with the blinded assessor, including study drug appearance;

Unblinded personnel should check for any residue of Investigational product.  If any 
Investigational product is visible, it is permissible to gently remove it prior to the 
assessments performed by the clinical assessor blinded to treatment arms to avoid 
potential unblinding;

Review the schedule of upcoming study visits with the subject and/or caregiver, and 
instruct them to return at the scheduled time;

Assess and record any AEs and SAEs by a clinical assessor blinded for treatment arms.  
Other site personnel may also report and record AEs and SAEs reported to them 
spontaneously by the subject.

After the end of treatment, unscheduled clinic visits are available if subject’s condition 
worsens, so that an assessment can be conducted in-clinic, and nonstudy treatment for 
AD may be prescribed if the subject qualified for this treatment.  At this visit, an EASI
assessment completed by a clinical assessor blinded for treatment arms will be completed 
to determine if treatment is allowed per the protocol. If a subject is participating in the 
sub-study, all efforts should be made not to treat the sub-study target skin sites until after 
the end of the follow up phase (Day 60). 
6.4.6. Follow-up Contact
Follow-up contact will be done via a phone call on Day 60 (or at least 28 days after End of 
Treatment/Early Termination) to capture any potential adverse events (see the Time Period 
for Collecting AE/SAE Information section 8.1.4), to review and record concomitant 
medications and to confirm appropriate contraception usage (see the Contraception
section 4.4.1).  For subjects participating in the sub-study, this visit will occur in the clinic.  


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6.5. Subject Withdrawal/Early Termination
Withdrawal of Investigational Product:

If signs and symptoms of hypersensitivity are attributable to the investigational 
product, including contact urticaria, it must be discontinued immediately and 
appropriate therapy initiated.
The subject will remain in the study and continue to be followed for protocol specified 
follow-up procedures, unless they have withdrawn consent. If consent is withdrawn for the 
follow-up period, the procedures for withdrawal of consent will be followed. 
Withdrawal of consent:
Subjects and/or parent/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 
documented in the subject’s medical records.
Subjects may withdraw from the study at any time at their own request, or they may be 
withdrawn at any time at the discretion of the investigator or sponsor for safety (see also the 
Withdrawal From the Study Due to Adverse Events section) or behavioral reasons, or the 


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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 well-being of the subject.  When a protocol-required test cannot be performed, the 
investigator will document the reason for this and any corrective and preventive actions that 
he or she has taken to ensure that normal processes are adhered to as soon as possible.  The 
study team will be informed of these incidents in a timely manner.
For samples being collected and shipped, detailed collection, processing, storage, and 
shipment instructions and contact information will be provided to the investigator site prior 
to initiation of the study.
7.1. Efficacy Assessments
7.1.1. Investigator’s Static Global Assessment
The Investigator’s Static Global Assessment (ISGA), a five point global 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 (excluding the scalp).
The assessment will be a static evaluation without regard to the score at a previous visit.
ISGA assessment during the study must be completed by a clinical assessor blinded for
treatment arms.  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.


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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
The ISGA will exclude scalp from the assessment/scoring
7.1.2. Eczema Area and Severity Index (EASI)
The EASI22 quantifies the severity of a subject’s AD 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.
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 2.


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Table 2.
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 
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 3 and Table 4).
Table 3.
Handprint Determination of Body Region Surface Area for Subjects aged 
8 years old
Body Region
Total Number of 
Handprints in Body 
Region
Surface Area of Body 
Region Equivalent of 
One Handprint
Head and Neck
10
10%
Upper Limbs
20
5%
Trunk (including axillae)
30
3.33%
Lower Limbs (including buttocks)
40
2.5%


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Table 4.
Handprint Determination of Body Region Surface Area for Subjects aged 
< 8 years old
Body Region
Total Number of 
Handprints in Body 
Region*
Surface Area of Body 
Region Equivalent of 
One Handprint
Head and Neck
20
5%
Upper Limbs
20
5%
Trunk (including axillae)
30
3.33%
Lower Limbs (including buttocks)
30
3.33%
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 (Table 5).
Table 5.
Eczema Area and Severity Index (EASI) Area Score Criteria
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
Body Region Weighting: Each body region is weighted according to its approximate 
percentage of the whole body (Table 6).
Table 6.
Eczema Area and Severity Index (EASI) Body Region Weighting
Body Region
Body Region Weighting
for 8 years old subjects
Body Region Weighting
for <8 years old subjects
Head and Neck
0.1
0.2
Upper Limbs
0.2
0.2
Trunk (including axillae)
0.3
0.3
Lower Limbs (including 
buttocks)
0.4
0.3
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:


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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 0.1 and range from 0.0 to 72.0, with higher scores 
representing greater severity of AD.  Since the scalp will be excluded from the EASI 
assessment in this study, the maximum possible score will be less than 72.0.
7.1.3. Patient/Observer Reported Outcomes
The Patient/Observer Reported Outcomes questionnaires in this study include: Peak Pruritus 
NRS for subjects >12 years/Patient Reported Itch Severity Scale - for subjects age 6-11 
years/Observer Reported Itch Severity Scale - for subjects <6 years ,
 
 DLQI, CDLQI, 
DFI, 
 
.  They will be performed at the time points defined in the Schedule of 
Activities.
On study visit days, subjects or caregiver as instructed should complete the patient/observer
reported outcomes at the clinic prior to any procedures being performed. It is preferred that 
all observer reported outcomes for a given subject are completed by same individual 
throughout the study.  The one who completes the questionnaires should be captured and 
stored in database and available for analysis.
7.1.3.1. 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 10,23, 24 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.
The Peak Pruritus NRS for subjects >12 years/Patient Reported Itch Severity Scale - for 
subjects age 6-11 years/Observer Reported Itch Severity Scale - for subjects <6 years will be 
completed during screening prior to Day 1 and completed once daily every day from Day 1 
to Day 29 before IP morning dose is applied preferably at the same time of each day, as 
noted in the Schedule of Activities.
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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 2.  The Patient Reported 
Itch Severity Scale - for subjects age 6-11 years is presented in Figure 3.  The Observer 
Reported Itch Severity Scale - for subjects <6 years is presented in Figure 4.  These scales are 
designed to capture a similar concept.
Figure 2.
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 itch 
imaginable
Figure 3.
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
Figure 4.
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 itch 
imaginable
 
 
 
 
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.
7.1.3.5. 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.  It is 
preferred that all observer reported outcomes for a given subject are completed by same 
individual throughout the study.
•
The DLQI will be completed by all subjects aged 16 years and older, based on the age at 
Screening Visit/time of informed consent/assent.
•
The CDLQI will be completed by all subjects aged 4–15 years with the help of the 
caregiver as needed, based on the age at Screening Visit/time of informed consent/assent.
 
•
The DFI will be completed by the caregiver for subjects aged 2–17 years, based on the 
age at Screening Visit/time of informed consent/assent.
 
 
 
 
 
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7.2. Body Surface Area for Investigational Product
Evaluation of BSA for Investigational Product is the percent BSA across all body locations
being treated with the study drug.  Percent BSA for Investigational Product evaluation 
method will be the same as described in Section 7.1.2, except that it will exclude AD on the 
scalp.
Study drug should be applied at Baseline/Day 1 throughout the treatment period regardless of 
clearing or improvement of AD.  Any new AD on treatment-eligible locations occurring 
following Baseline/Day 1 should also be treated with the study drug after consultation with 
the Investigator at the next visit.  Therefore, the BSA for Investigational Product at 
subsequent visits should be equal to or greater than the value at Baseline/Day 1.
7.3. Body Site Checklist for Atopic Dermatitis
A checklist of body areas currently affected by AD will be completed at the Baseline/Day 1.  
Location of skin lesions will be selected from a prepopulated listing of body locations.
Treatable AD areas (excluding the scalp) as identified by a clinical assessor blinded for 
treatment arms will be recorded in the subject’s source documents at Baseline/Day 1 and will 
be provided to the subject and/or caregiver with documentation of the designated treatment 
areas (body maps).
7.4. Photography of Representative AD Lesion (Selected Study Sites Only)
For subjects (optional) at a selected study sites, photographs of treatable AD lesions will be 
obtained (according to the separately provided Photography Instructions) at Baseline/Day 1, 
Day 15 and Day 29.  Areas photographed should be recorded in study documents so that the 
same AD body region(s) will be photographed at Day 15 and Day 29.  Photographs will be 
utilized for illustrative purposes and not evaluated as an endpoint.
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Photographic services will be provided through a central photography laboratory selected by 
the sponsor.  Detailed procedures to assure consistency will be provided separately in a 
central photography laboratory instruction manual.
7.5. 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 behaviour and will be completed at the 
Screening for subjects 7 years of age.  The children’s C-SSRS will be administered for 
subjects 7-11 years old and the C-SSRS for subjects 12 years old.  This is investigator 
completed.
7.6. Safety Assessments
7.6.1. 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 7. Hematology, Chemistry and FSH will be done at a central laboratory.


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Table 7.
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 (non-fasting)
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.
rClinical laboratory tests will be drawn at the Screening visit and Baseline/Day 1, after 
assessment of vital signs and prior to the first investigational product application and on 
Day 29.
If the screening serum chemistry and hematology tests are performed within 14 days prior to 
Baseline/Day 1, whether the Baseline/Day 1 serum chemistry and hematology tests are to be 
performed will be at the medical judgment of the investigator.
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.  However, the skin must be thoroughly cleansed 
prior to blood sample collection.  This must be recorded in the eCRF.
The blinded clinical assessor 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 blinded clinical assessor must sign and date the laboratory report.  
Clinically significant laboratory abnormalities are defined as abnormal values that have 


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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).
7.6.2. Physical Examination, Height, and Weight
Physical examinations, 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 detailed physical examination will be performed at Screening, Baseline/ Day 1 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.
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.
7.6.3. Vital Signs
Vital sign measurements (temperature, respiratory rate, pulse rate, and BP) will be performed 
at Screening, Baseline/Day 1 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.
7.7. 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 can receive investigational 
product.  Pregnancy tests will also be done whenever 1 menstrual cycle is missed during the 
active treatment period (or when potential pregnancy is otherwise suspected).  Pregnancy 


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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. 
A 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 at the next visit and all visits according to the
Schedule of Activities.
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.
7.8. Rater Qualifications
Clinical evaluations of atopic dermatitis will be performed by an experienced and qualified
dermatologist (board certified or equivalent) who is treatment blinded. An experienced and 
qualified non-dermatologist physician or experienced medical professional with experience 
in the conduct of AD clinical trials who is treatment blinded may be permitted to perform 
the clinical evaluations of atopic dermatitis when designated by the primary site Investigator 
and with Sponsor approval.  The evaluator must receive and document protocol specific and 
applicable efficacy assessment scales training prior to performing these evaluations.  To 
assure consistency and reduce variability, the same evaluator must assess all 
dermatological clinical evaluations for any individual subject throughout the study 
whenever possible; a back-up experienced and qualified, protocol-trained evaluator will 
only be allowed and documented in case of emergency or special situations when the 
designated evaluator is unable to perform the evaluation.
Study personnel administering the C-SSRS must have completed the appropriate training and 
have valid certification.
8. ADVERSE EVENT REPORTING
8.1. Requirements
The table below summarizes the requirements for recording safety events on the CRF and for 
reporting safety events on the Clinical Trial (CT) Serious Adverse Event (SAE) Report Form 
to Pfizer Safety.  These requirements are delineated for 3 types of events: (1) SAEs; 
(2) non-serious adverse events (AEs); and (3) exposure to the investigational product under 
study during pregnancy or breastfeeding, and occupational exposure. 


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Safety Event
Recorded on the CRF
Reported on the CT SAE 
Report Form to Pfizer 
Safety Within 24 Hours of 
Awareness
SAE
All
All
Non-serious AE
All
None
Exposure to the 
investigational product 
under study during 
pregnancy or 
breastfeeding, and 
occupational exposure
All (regardless of whether 
associated with an AE), 
except occupational 
exposure
Exposure during pregnancy, 
exposure via breastfeeding, 
occupational exposure 
(regardless of whether 
associated with an AE)
All observed or volunteered events regardless of treatment group or suspected causal 
relationship to the investigational product(s) will be reported as described in the following 
paragraphs.
Events listed in the table above that require reporting to Pfizer Safety on the CT SAE Report 
Form within 24 hours of awareness of the event by the investigator are to be reported 
regardless of whether the event is determined by the investigator to be related to an 
investigational product under study.  In particular, if the SAE is fatal or life-threatening, 
notification to Pfizer Safety must be made immediately, irrespective of the extent of available 
event information.  This time frame also applies to additional new (follow-up) information on 
previously forwarded reports.  In the rare situation that the investigator does not become 
immediately aware of the occurrence of an event, the investigator must report the event 
within 24 hours after learning of it and document the time of his/her first awareness of the 
event.
For each event, the investigator must pursue and obtain adequate information both to 
determine the outcome and to assess whether it meets the criteria for classification as an SAE 
(see the Serious Adverse Events section below).  In addition, the investigator may be 
requested by Pfizer Safety to obtain specific follow-up information in an expedited fashion.  
This information is more detailed than that recorded on the CRF.  In general, this will include 
a description of the event in sufficient detail to allow for a complete medical assessment of 
the case and independent determination of possible causality.  Any information relevant to 
the event, such as concomitant medications and illnesses, must be provided.  In the case of a 
subject death, a summary of available autopsy findings must be submitted as soon as possible 
to Pfizer Safety.  Any pertinent additional information must be reported on the CT SAE 
Report Form; additional source documents (eg, medical records, CRF, laboratory data) are to 
be sent to Pfizer Safety ONLY upon request.


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As part of ongoing safety reviews conducted by the sponsor, any non-serious AE that is 
determined by the sponsor to be serious will be reported by the sponsor as an SAE.  To assist 
in the determination of case seriousness, further information may be requested from the 
investigator to provide clarity and understanding of the event in the context of the clinical 
study.
8.1.1. Additional Details On Recording Adverse Events on the CRF
All events detailed in the table above will be recorded on the AE page(s) of the CRF.  It 
should be noted that the CT SAE Report Form for reporting of SAE information is not the 
same as the AE page of the CRF.  When the same data are collected, the forms must be 
completed in a consistent manner.  AEs should be recorded using concise medical 
terminology and the same AE term should be used on both the CRF and the CT SAE Report 
Form for reporting of SAE information.
8.1.2. Eliciting Adverse Event Information
The investigator is to record on the CRF all directly observed AEs and all AEs spontaneously 
reported by the study subject/[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.
8.1.4.1. Reporting SAEs to Pfizer Safety
All SAEs occurring in a subject during the active collection period are reported to Pfizer 
Safety on the CT SAE Report Form.


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SAEs occurring in a subject after the active collection period has ended are reported to Pfizer 
Safety if the investigator becomes aware of them; at a minimum, all SAEs that the 
investigator believes have at least a reasonable possibility of being related to investigational 
product must be reported to Pfizer Safety.
Follow up by the investigator continues throughout and after the active collection period and 
until the event or its sequelae resolve or stabilize at a level acceptable to the investigator, and 
Pfizer concurs with that assessment.
8.1.4.2. Recording Non-serious AEs and SAEs on the CRF
During the active collection period, both non-serious AEs and SAEs are recorded on the 
CRF.
Follow-up by the investigator may be required until the event or its sequelae resolve or 
stabilize at a level acceptable to the investigator, and Pfizer concurs with that assessment.
8.1.4.3. 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.
8.1.4.4. Reporting Requirements Regarding SUSARs
AE reporting, including suspected unexpected serious adverse reactions (SUSARs), will be 
carried out in accordance with applicable local regulations.
Investigator safety reports must be prepared for SUSARs according to local regulatory 
requirements and sponsor policy and forwarded to investigators as necessary.
An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAEs) from the sponsor will review 
and then file it along with the investigator’s brochure and will notify the IRB/EC, if 
appropriate according to local requirements.


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


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
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.
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 


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


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


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


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integrity of the terminated fetus should be assessed by gross visual inspection (unless 
pre-procedure test findings are conclusive for a congenital anomaly and the findings are 
reported).
If the outcome of the pregnancy meets the criteria for an SAE (ie, ectopic pregnancy, 
spontaneous abortion, intrauterine fetal demise, neonatal death, or congenital anomaly [in a 
live-born baby, a terminated fetus, an intrauterine fetal demise, or a neonatal death]), the 
investigator should follow the procedures for reporting SAEs.
Additional information about pregnancy outcomes that are reported to Pfizer Safety as SAEs 
follows: 

Spontaneous abortion includes miscarriage and missed abortion.

Neonatal deaths that occur within 1 month of birth should be reported, without regard to 
causality, as SAEs.  In addition, infant deaths after 1 month should be reported as SAEs 
when the investigator assesses the infant death as related or possibly related to exposure 
to the investigational product.
Additional information regarding the EDP may be requested by the sponsor.  Further 
follow-up of birth outcomes will be handled on a case-by-case basis (eg, follow-up on 
preterm infants to identify developmental delays).  In the case of paternal exposure, the 
investigator will provide the subject with the Pregnant Partner Release of Information Form 
to deliver to his partner.  The investigator must document in the source documents that the 
subject was given the Pregnant Partner Release of Information Form to provide to his 
partner.
8.4.3.2. Exposure During Breastfeeding
Scenarios of exposure during breastfeeding must be reported, irrespective of the presence of 
an associated SAE, to Pfizer Safety within 24 hours of the investigator’s awareness, using the 
CT SAE Report Form.  An exposure during breastfeeding report is not created when a Pfizer 
drug specifically approved for use in breastfeeding women (eg, vitamins) is administered in 
accord with authorized use.  However, if the infant experiences an SAE associated with such 
a drug’s administration, the SAE is reported together with the exposure during breastfeeding.
8.4.3.3. Occupational Exposure
An occupational exposure occurs when, during the performance of job duties, a person 
(whether a healthcare professional or otherwise) gets in unplanned direct contact with the 
product, which may or may not lead to the occurrence of an AE.
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 subject exposure to the investigational product;

Potential medication errors or uses outside of what is foreseen in the protocol that do or 
do not involve the participating subject.
Such medication errors occurring to a study participant are to be captured on the medication 
error page of the CRF, which is a specific version of the AE page.
In the event of a medication dosing error, the sponsor should be notified immediately.
Whether or not the medication error is accompanied by an AE, as determined by the 
investigator, the medication error is recorded on the medication error page of the CRF and, if 
applicable, any associated AE(s), serious and non-serious, are recorded on an AE page of the 
CRF.
Medication errors should be reported to Pfizer Safety within 24 hours on a CT SAE Report 
Form only when associated with an SAE.
9. DATA ANALYSIS/STATISTICAL METHODS
Detailed methodology for summary and statistical analyses of the data collected in this study 
is outlined here and further detailed in a statistical analysis plan (SAP), which will be 
maintained by the sponsor.  The SAP may modify what is outlined in the protocol where 
appropriate; however, any major modifications of the primary endpoint definitions or their 
analyses will also be reflected in a protocol amendment.
9.1. Sample Size Determination
A total of approximately 600 subjects will be enrolled into this study. Approximately 
300 subjects who are eligible to receive TCS therapy (Cohort 1) will be randomized to 
crisaborole ointment, 2%, the matching vehicle ointment for crisaborole, or TCS with a 


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randomization ratio of 1:1:2. Approximately 300 subjects who are ineligible to receive TCS 
therapy and eligible to receive TCI therapy (Cohort 2) will be randomized to crisaborole 
ointment, 2%, the matching vehicle ointment for crisaborole, or pimecrolimus cream 
1% with randomization ratio 1:1:2.
A sample size of 150 subjects in the crisaborole group combined from Cohort 1 and Cohort 2 
and 150 subjects in vehicle group combined from Cohort 1 and Cohort 2 will provide 
86% power to detect a 12% difference of EASI percent reduction from baseline at Day 29 
between crisaborole and vehicle at the 0.05 (2-sided) significance level, assuming the 
common standard deviation of EASI percent reduction from baseline at Day 29 is 34%.
EASI 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 percentage improvement from historical trial data of other topical products. From the 
crisaborole Phase 3 pooled data, the ISGA response rate is 32.1 % for crisaborole ointment, 
2%, 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 
ointment, 2% and vehicle is approximately 12%.
With sample size of 75 subjects in the crisaborole group and 150 subjects in the TCS or TCI 
groups, the half width of the 95% confidence interval for the difference of EASI percent 
reduction from baseline at Day 29 between crisaborole and active comparator is 9.4%.  The 
sample size within each Cohort will also provide sufficient precision to enable 
contextualization of the efficacy of crisaborole in treating subjects with mild to moderate AD 
relative to each active comparator.
9.2. Efficacy Analysis
9.2.1. Analysis Sets
The primary analysis population for efficacy data will be the Full Analysis Set (FAS) defined 
as all randomized subjects receiving at least one dose of investigational product. The 
primary efficacy endpoint will also be analyzed for the Per-Protocol Analysis Set (PPAS) 
defined as a subset of FAS who had no protocol violations affecting the efficacy endpoints.  
The subjects excluded from the PPAS will be determined and documented before the study is 
unblinded.  For all analyses, baseline value will be based on observations collected pre-dose.
For the comparison of crisaborole versus vehicle, subjects from both Cohort 1 and Cohort 2 
are included in the analysis, and effect of Cohort will be adjusted. For the comparison of 
crisaborole versus TCS, only subjects from Cohort 1 are included in the analysis.  For the 
comparison of crisaborole versus TCI, only subjects from Cohort 2 are included in the 
analysis.
9.2.2. Analysis of the Primary Endpoint
The primary endpoint, EASI % change from baseline, will be analyzed using a mixed-effect 
repeated measures model that includes the fixed effects of treatment, visit as class variable, 


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treatment by visit interaction.  Within-subject variability will be accounted for using a 
random effect with the first order autoregressive (AR(1)) covariance matrix. For the 
comparison of crisaborole versus vehicle, the model will also include factor of Cohort.
9.2.3. Analysis of the Secondary Endpoints
Binary endpoints such as ISGA success (defined as an ISGA score of Clear ([0]) or Almost 
Clear ([1]) with at least a 2 grade improvement from baseline), ISGA score of clear ([0]) or 
almost clear ([1]), improvement in Peak Pruritus NRS for subjects >12 years and Observer 
Reported Itch Severity Scale - for subjects <6 years (defined as achieving ≥2 points reduction
in NRS from baseline), improvement in Peak Pruritus NRS for subjects >12 years and 
Observer Reported Itch Severity Scale - for subjects <6 years (defined as achieving ≥3 points 
reduction in NRS from baseline), and achievement of EASI75 at each time point will be 
analyzed using the CMH test. The comparison of crisaborole versus vehicle will be stratified 
by Cohort. The evaluation of efficacy of crisaborole versus active comparator (TCS, TCI) 
will be performed within each Cohort.
Continuous endpoints such as change from baseline in Peak Pruritus NRS for subjects >12 
years/Patient Reported Itch Severity Scale - for subjects age 6-11 years/Observer Reported 
Itch Severity Scale - for subjects <6 years, % BSA, DLQI, CDLQI, and DFI will be analyzed 
using the same method as proposed in Section 9.2.2. Baseline value will be used as an 
additional covariate when modeling the change from baseline.    
For peak pruritus 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,
weekly average score will be used in the analyses of binary endpoint improvement in peak 
pruritus/itch and continuous endpoint change from baseline in peak pruritus/itch.  There will 
be no pooling of data from the pruritus/itch scales from different age groups.  Data from each 
instrument will be analyzed separately.
Time to event endpoints such as time to EASI75 and time to improvement in peak 
pruritus/itch will be analyzed by log rank test and duration of time to event will be estimated 
by the product limit method. A Kaplan-Meier plot will be provided.  Log rank test will be 
stratified by cohort for comparison of crisaborole versus vehicle.  The evaluation of efficacy
of crisaborole versus active treatment will be performed within each cohort. For Peak 
Pruritus 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, daily peak 
pruritus/itch assessment value will be used for the analysis of time to improvement in peak 
pruritus/itch.
All secondary endpoints will be evaluated at the 5% level of significance, without 
adjustments for multiple comparisons.
 
 
CCI


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9.3. Safety Analysis
The safety data will be summarized in accordance with Pfizer Reporting Standards.  All 
subjects who receive investigational product (safety population) will be included in the safety 
analyses. 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:

AEs, including SAEs, local tolerability AEs/SAEs and discontinuations;

Clinically significant changes in vital signs;

Clinically significant changes in clinical laboratory parameters.
9.4. Interim Analysis
No formal interim analysis will be conducted for this study.
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 


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authorities, the investigator will provide Pfizer or its agents with an opportunity to review 
and comment on responses to any such findings.
It is important that the investigator(s) and their relevant personnel are available during the 
monitoring visits and possible audits or inspections and that sufficient time is devoted to the 
process.
11. DATA HANDLING AND RECORD KEEPING
11.1. Case Report Forms/Electronic Data Record
As used in this protocol, the term CRF should be understood to refer to either a paper form or 
an electronic data record or both, depending on the data collection method used in this study.
A CRF is required and should be completed for each included subject.  The completed 
original CRFs are the sole property of Pfizer and should not be made available in any form to 
third parties, except for authorized representatives of Pfizer or appropriate regulatory 
authorities, without written permission from Pfizer.  The investigator shall ensure that the 
CRFs/DCTs are securely stored at the study site in encrypted electronic and/or paper form 
and will be password protected or secured in a locked room to prevent access by 
unauthorized third parties.
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.  


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The investigator must ensure that the records continue to be stored securely for so long as 
they are retained.
If the investigator becomes unable for any reason to continue to retain study records for the 
required period (eg, retirement, relocation), Pfizer should be prospectively notified.  The 
study records must be transferred to a designee acceptable to Pfizer, such as another 
investigator, another institution, or an independent third party arranged by Pfizer. 
Investigator records must be kept for a minimum of 15 years after completion or 
discontinuation of the study or for longer if required by applicable local regulations. 
The investigator must obtain Pfizer's written permission before disposing of any records, 
even if retention requirements have been met.


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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).
In addition, this study will be conducted in accordance with the following:
•
Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical Sciences 
(CIOMS) International Ethical Guidelines;
•
Applicable International Council for Harmonisation (ICH) Good Clinical Practice 
(GCP) guidelines;
•
Applicable laws and regulations, including applicable privacy laws.
12.3. Subject Information and Consent
All parties will comply with all applicable laws, including laws regarding the implementation 
of organizational and technical measures to ensure protection of subject personal data. Such 
measures will include omitting subject names or other directly identifiable data in any 
reports, publications, or other disclosures, except where required by applicable law. 
The personal data will be stored at the study site in encrypted electronic and/or paper form 
and will be password protected or secured in a locked room to ensure that only authorized 
study staff have access.  The study site will implement appropriate technical and 
organizational measures to ensure that the personal data can be recovered in the event of 
disaster.  In the event of a potential personal data breach, the study site shall be responsible 
for determining whether a personal data breach has in fact occurred and, if so, providing 
breach notifications as required by law.


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To protect the rights and freedoms of natural persons with regard to the processing of 
personal data, when study data are compiled for transfer to Pfizer and other authorized 
parties, subject names will be removed and will be replaced by a single, specific, numerical 
code, based on a numbering system defined by Pfizer. All other identifiable data transferred 
to Pfizer or other authorized parties will be identified by this single, subject-specific code. 
The investigator site will maintain a confidential list of subjects who participated in the 
study, linking each subject’s numerical code to his or her actual identity.  In case of data 
transfer, Pfizer will maintain high standards of confidentiality and protection of subjects’ 
personal data consistent with the Clinical Study Agreement and 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, the sharing of data relating to 
the study and possible risks associated with participation, including the risks associated with 
the processing of the subject’s personal data.  The investigator further must ensure that each 
study subject, or his or her legally acceptable representative, or parent(s) or legal guardian if 
a minor, is fully informed about his or her right to access and correct his or her personal data 
and to withdraw consent for the processing of his or her personal data.
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. 


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


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12.4. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP
In the event of any prohibition or restriction imposed (ie, clinical hold) by an applicable 
regulatory authority in any area of the world, or if the investigator is aware of any new 
information that might influence the evaluation of the benefits and risks of the investigational 
product, Pfizer should be informed immediately. 
In addition, the investigator will inform Pfizer immediately of any urgent safety measures 
taken by the investigator to protect the study subjects against any immediate hazard, and of 
any serious breaches of this protocol or of ICH GCP that the investigator becomes aware of.
13. DEFINITION OF END OF TRIAL
13.1. End of Trial in All Participating Countries 
End of trial in all participating countries is defined as last subject last visit (LSLV).
14. SPONSOR DISCONTINUATION CRITERIA
Premature termination of this study may occur because of a regulatory authority decision, 
change in opinion of the IRB/EC, or investigational product safety problems, or at the 
discretion of Pfizer.  In addition, Pfizer retains the right to discontinue development of 
crisaborole at any time.
If a study is prematurely terminated, Pfizer will promptly notify the investigator.  After 
notification, the investigator must contact all participating subjects and the hospital pharmacy 
(if applicable) within 7 days.  As directed by Pfizer, all study materials must be collected and 
all CRFs completed to the greatest extent possible.
15. PUBLICATION OF STUDY RESULTS
15.1. Communication of Results by Pfizer
Pfizer fulfills its commitment to publicly disclose clinical trial results through posting the 
results of studies on www.clinicaltrials.gov (ClinicalTrials.gov), the European Clinical Trials 
Database (EudraCT), and/or www.pfizer.com, and other public registries in accordance with 
applicable local laws/regulations. 
In all cases, study results are reported by Pfizer in an objective, accurate, balanced, and 
complete manner and are reported regardless of the outcome of the study or the country in 
which the study was conducted.
www.clinicaltrials.gov
Pfizer posts clinical trial US Basic Results on www.clinicaltrials.gov for Pfizer-sponsored 
interventional studies (conducted in patients) that evaluate the safety and/or efficacy of a 
Pfizer product, regardless of the geographical location in which the study is conducted.  US 
Basic Results are submitted for posting within 1 year of the primary completion date (PCD) 
for studies in adult populations or within 6 months of the PCD for studies in pediatric 
populations.


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PCD is defined as the date that the final subject was examined or received an intervention for 
the purposes of final collection of data for the primary outcome, whether the clinical study 
concluded according to the prespecified protocol or was terminated.
EudraCT
Pfizer posts European Union (EU) Basic Results on EudraCT for all Pfizer-sponsored 
interventional studies that are in scope of EU requirements.  EU Basic Results are submitted 
for posting within 1 year of the PCD for studies in adult populations or within 6 months of 
the PCD for studies in pediatric populations.
www.pfizer.com
Pfizer posts Public Disclosure Synopses (clinical study report synopses in which any data 
that could be used to identify individual patients has been removed) on www.pfizer.com for 
Pfizer-sponsored interventional studies 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.
The investigator will, on request, remove any previously undisclosed confidential 
information before disclosure, except for any study- or Pfizer product-related information 
necessary to the appropriate scientific presentation or understanding of the study results.
If the study is part of a multicenter study, the investigator agrees that the first publication is 
to be a joint publication covering all investigator sites, and that any subsequent publications 
by the PI will reference that primary publication.  However, if a joint manuscript has not 
been submitted for publication within 12 months of completion or termination of the study at 
all participating sites, the investigator is free to publish separately, subject to the other 
requirements of this section.


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For all publications relating to the study, the institution will comply with recognized ethical 
standards concerning publications and authorship, including Section II - “Ethical 
Considerations in the Conduct and Reporting of Research” of the Uniform Requirements for 
Manuscripts Submitted to Biomedical Journals, http://www.icmje.org/index.html#authorship, 
established by the International Committee of Medical Journal Editors.
Publication of study results is also provided for in the CSA between Pfizer and the 
institution.  In this section entitled Publications by Investigators, the defined terms shall have 
the meanings given to them in the CSA.
If there is any conflict between the CSA and any attachments to it, the terms of the CSA 
control.  If there is any conflict between this protocol and the CSA, this protocol will control 
as to any issue regarding treatment of study subjects, and the CSA will control as to all other 
issues.


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16. REFERENCES
1.
Bieber T. Atopic dermatitis. Ann Dermatol 2010 May; 22(2):125-137.
2.
Bieber T. Atopic dermatitis. N Engl J Med 2008; 358(14):1483-94. 
3.
Leicht S, Hanggi M. Atopic dermatitis. How to incorporate advances in management. 
Postgrad Med 2001; 109(6):119-27. 
4.
Arkwright PD, Motala C, Subramanian H, et al. Management of difficult-to-treat atopic 
dermatitis, 2013. J Allergy Clin Immunol Pract 2013; 1(2):142-51. 
5.
Leung DY. New insights into atopic dermatitis: role of skin barrier and immune 
dysregulation. Allergol Int. 2013; 62(2):151-61. 
6.
Bantz SK, Zhu Z, Zheng T. The atopic march: progression from atopic dermatitis to 
allergic rhinitis and asthma. J Clin Cell Immunol. 2014; 5(2): 8 pages. 
7.
Saunes M, Oien T, Dotterud CK, et al. Early eczema and the risk of childhood asthma: a 
prospective, population based study. BMC Pediatr 2012; 12:168. 
8.
Garg N, Silverberg JI. Epidemiology of childhood atopic dermatitis. Clin Dermatol 
2015; 33(3):281-8.
9.
Beattie 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; 155(1):145-51.
10.
Carroll CL, Balkrishnan R, Feldman SR, et al. The burden of atopic dermatitis: impact 
on the patient, family, and society. Pediatr Dermatol 2005; 22(3):192-9.
11.
Halvorsen JA, Lien L, Dalgard F, et al. Suicidal ideation, mental health problems, and 
social function in adolescents with eczema: a population based study. J Invest Dermatol 
2014; 134(7):1847-54.
12.
Lewis-Jones S. Quality of life and childhood atopic dermatitis: the misery of living with 
childhood eczema. Int J Clin Pract 2006; 60(8):984-92.
13.
Su JC, Kemp AS, Varigos GA, et al. Atopic eczema: its impact on the family and 
financial cost. Arch Dis Child 1997; 76(2):159-62.
14.
Lawson V, Lewis-Jones MS, Finlay AY, et al. The family impact of childhood atopic 
dermatitis: the Dermatitis Family Impact Questionnaire. Br J Dermatol 1998;
138(1):107-13.
15.
Dahl RE, Bernhisel Broadbent J, Scanlon Holdford S, et al. Sleep disturbances in 
children with atopic dermatitis. Arch Pediatr Adolesc Med 1995; 149(8):856-60.


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16.
Daud LR, Garralda ME, David TJ. Psychosocial adjustment in preschool children with 
atopic eczema. Arch Dis Child 1993; 69(6):670-6.
17.
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;
137(2):241-5.
18.
Watson W, Kapur S. Atopic dermatitis. Allergy Asthma Clin Immunol 2011; 7 (Suppl 
1):S4.
19.
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;
75(3):494-503.e6.
20.
Pfizer Investigator Brochure for Crisaborole, February 2017.
21.
Vivek, PS.  Pfizer Population Modeling Analysis Report (PMAR): Non-linear 
regression analysis of crisaborole systemic exposures, September 2017.
22.
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.
23.
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.
24.
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.
 
 
 
 
 
 
 
CCI
CCI
CCI
CCI


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31.
Hanifin JM and Rajka G. Diagnostic features of atopic dermatitis. Acta Derm Venereol 
(Stockh) 1980; 92(suppl):44-7. 
CCI


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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 
AR
Autoregressive
ADSI
Atopic Dermatitis Severity Index
AE
Adverse Event
ALT
Alanine Aminotransferase
AM
Morning
AST
Aspartate Aminotransferase
BID
Twice Daily
-hCG
Beta Human Chorionic Gonadotrophin
BP
Blood Pressure
BPO
Benzoyl Peroxide
BSA
Body Surface Area
%BSA
Percent Body Surface Area
cAMP
Cyclic Adenosine Monophosphate
CI
Confidence Interval
CIOMS
Council for International Organizations of Medical Science
CK
Creatine Kinase
Cmax
Maximum Observed Plasma Concentration
CDLQI
Children’s Dermatology Life Quality Index
CMH
Cochran-Mantel-Haenszel test
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
DU
Dispensable Unit
EASI
Eczema Area And Severity Index
EASI75
Eczema Area And Severity Index 75% improvement from 
Baseline
EC
Ethics Committee
EC50
Half Maximal Effective Concentration
eCRF
Electronic Case Report Form
E-DMC
External Data Monitoring Committee 
EDP
Exposure During Pregnancy
ePRO
Electronic patient reported outcome


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Abbreviation
Term
EU
European Union
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
HTA
health technologies assessment
IB
Investigator’s Brochure
ID
Identification
ICH
International Council For Harmonisation
IND
Investigational New Drug Application
INR
International Normalized Ratio
IP
Investigational Product
IRB
Institutional Review Board
IRT
Interactive Response Technology
IWR
Interactive Web Response
ISGA
Investigator’S Static Global Assessment
IUD
Intrauterine Devicem
LFT
Liver Function Test
LSLV
Last Subject Last Visit 
MMF
Mycophenolate Mofetil
MMRM
mixed model repeated measure
MUSE
Maximal Use Systemic Exposure
N/A
Not Applicable
NRI
Non Responder Imputation
NRS
Numeric Rating Scale
OCT
Optical Coherence Tomography
PCD
Primary Completion Date
PD
Pharmacodynamics(S)
PDE-4
Phosphodiesterase-4
PI
Principal Investigator
PK
Pharmacokinetic
PKA
Protein Kinase A
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CCI
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Abbreviation
Term
PM
Evening
PMA
Phorbol 12-myristate 13-acetate
PKA
Protein Kinase A
PPAS
Per Protocol Analysis Set
PRO
Patient Reported Outcome
PRN
As Needed
PT
Prothrombin Time
PUVA
Psoralen–UV-A
QD
Once Daily
QoL
Quality of Life
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SC
stratum corneum
SRSD
Single Reference Safety Document
SSIN
Subject Screening Identification Number
SUSAR
Suspected Unexpected Serious Adverse Reaction
TEAE
Treatment Emergent Adverse Event
TBili
Total Bilirubin
TCI
topical calcineurin inhibitor
TCS
topical corticosteroid
TEWL
Transepidermal Water Loss
Tmax
Time to Reach Maximum Observed Plasma Concentration
TQT
Thorough QT/QTc
TSS
Total Severity Score
ULN
Upper Limit of Normal
US
United States
USA
United States of America
UV
Ultraviolet
UV-B
Ultraviolet B
VAS
Visual Analog Scale
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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 8.
Hanifin and Rajka’s Diagnostic Criteria for Atopic Dermatitis
Major Criteria (must have at least three)
Pruritus
Typical morphology and distribution:
Adults: flexural lichenification or linearity
Children and infants: facial and extensor involvement
Chronic or chronically-relapsing dermatitis
Personal or family history of atopy (asthma, allergic rhinitis, atopic dermatitis)
Minor Criteria (must have at least three)
Xerosis
Ichthyosis/keratosis pilaris/palmar hyperlinearity
Immediate (type 1) skin test reactivity
Elevated serum IgE
Early age of onset
Tendency toward cutaneous infections (esp. staphylococcus aureus and herpes simplex), 
impaired cell-mediated immunity
Tendency toward non-specific hand or foot dermatitis
Nipple eczema
Cheilitis
Recurrent conjunctivitis
Dennie-Morgan infraorbital fold
Keratoconus
Anterior subcapsular cataracts
Orbital darkening
Facial pallor, facial erythema
Pityriasis alba
Anterior neck folds
Itch when sweating
Intolerance to wool and lipid solvents
Periofollicular accentuation
Food intolerance
Course influenced by environmental and emotional factors
White demographism, delayed blanch


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Appendix 3. Very High/Very Strong and High/Strong Potency Topical Corticosteroids
Per Exclusion Criterion 2.  Based upon the World Health Organization classification where 
topical corticosteroids have been ranked in terms of potency into four groups consisting of 
seven classes.
Including but not limited to;
Very high potency topical corticosteroids
Group 1

Clobetasol propionate cream (0.05%);

Diflorasone diacetate ointment (0.05%).
High potency topical corticosteroids
Group II

Amcinonide ointment (0.1%);

Betamethasone dipropionate ointment (0.05%);

Desoximetasone (cream or ointment) (0.025%);

Fluocinonide (cream, ointment, or gel) (0.05%);

Halcinonide cream (0.1%).
Group III

Betamethasone dipropionate cream (0.05%);

Betamethasone valerate ointment (0.1%);

Diflorasone diacetate cream (0.05%);

Triamcinolone acetonide ointment (0.1%).


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Appendix 4. Optical Coherence Tomography Sub-Study – A Study of Optical 
Coherence Tomography and Biomarkers in Subjects ages 2 to <18 years old, with Mild 
to Moderate Atopic Dermatitis, treated with Crisaborole Ointment, 2% or Crisaborole 
Vehicle Ointment or Hydrocortisone Butyrate 0.1% Cream applied BID.
1.  Introduction
Skin atrophy, characterized by whole skin thinning and damage to the skin barrier, is a 
common problem in the treatment of AD with TCS.  Often, effective treatment with TCS 
must be limited because of the risk of skin atrophy.1  To further explore the benefit/risk of
crisaborole ointment, 2%, this sub-study aims to evaluate differences in atrophic skin 
changes across study treatment groups in Cohort 1.
Optical coherence tomography (OCT) is a non-invasive imaging modality conceptually 
similar to ultrasound but uses near-infrared radiation rather than sound.  It has a 2-10 micron 
depth resolution compared with 100-1,000 micron typical for clinical US; and 1-2 mm 
imaging depth vs. 10-100 mm for clinical US.  It is thus ideal for imaging the surface layers 
of accessible tissues such as the skin.2  OCT imaging will be obtained using the VivoSight 
OCT scanner, by Michelson Diagnostics, Ltd. in this sub-study to evaluate atrophic changes 
in epidermal thickness during and after treatment with study investigational product in 
Cohort 1.
This sub-study also provides an opportunity to explore differences in Transepidermal Water 
Loss (TEWL) and cutaneous inflammatory and barrier biomarkers associated with AD within 
the stratum corneum (SC) across treatment groups in Cohort 1.
The Aquaflux device is an evaporimeter that measures water exchange through human skin 
using the condenser-chamber method.  The condenser-chamber method uses a humidity 
gradient to determine the amount of water diffusing through the SC3.  This device will be 
used in this sub-study to evaluate TEWL during and after treatment at select sub-study 
centers.
Tape-strips are a minimally invasive method that captures cutaneous inflammatory and 
barrier biomarkers within the SC, circumventing the need for skin biopsies, especially in the 
pediatric population.  Studies have used proteomic immune assays and messenger ribonucleic 
acid analyses to evaluate SC biomarkers in tape-strips from AD lesional and non-lesional 
skin from patients with AD.  Expression of AD-associated biomarkers in AD tape-stripped 
skin have been significantly correlated with disease severity (EASI/pruritus) and the 
functional barrier measure TEWL.  Tape-strips will be used in this sub-study to evaluate SC 
biomarkers from AD lesional and non-lesional skin.
2.  Objectives and Endpoints
The primary objective of this sub-study is to evaluate the differences in atrophic changes in 
epidermal thickness by structural OCT after treatment with crisaborole ointment, 2% or 


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crisaborole vehicle ointment, or hydrocortisone butyrate 0.1% cream applied BID for 28 
days. 
The secondary objectives of this sub-study are to evaluate the differences in atrophic change 
in epidermal thickness, skin biomarkers of AD, and TEWL during the course of treatment 
and following treatment with crisaborole ointment, 2% or crisaborole vehicle ointment, or 
hydrocortisone butyrate 0.1% cream applied BID for 28 days.  
This sub-study is expected to provide OCT, TEWL, and skin biomarker evidence of the 
effects of crisaborole ointment and vehicle ointment compared to TCS.
Primary Sub-Study Endpoint:

Change in epidermal thickness from Baseline/Day 1 to Day 29
Secondary Sub-Study Endpoints:

Change in epidermal thickness from Baseline/Day 1 to all sub-study time points 
except Day 29 (Days 8, 15, 22, and 60)

Intrasubject difference of change in epidermal thickness between the non-lesional 
target skin site and the OCT AD lesional target skin site from baseline to Days 8, 15, 
22, 29 and 60

Percentage change from Baseline/Day 1 in TEWL at Days 8, 15, 22, 29 and 60

Change from Baseline/Day 1 in skin biomarkers of AD at Day 15 and Day 29
3.  Sub-Study Design
This sub-study will be conducted in selected centers in the United States, the United 
Kingdom, and in Germany.  This sub-study will include approximately 60 subjects from 
Cohort 1 that are enrolled in the main study (C3291037) from the selected study centers.  
Subjects may only enroll in the sub-study during the screening phase or at the baseline visit 
of the main study prior to any sub-study evaluations or procedure.  Subjects that do not 
qualify for the main study may not participate in the sub-study.  Based on the randomization 
schema from the main study, it is expected that the sample size for this sub-study will include 
approximately 15 subjects in the crisaborole ointment, 2% arm, 15 subjects in the crisaborole 
vehicle ointment arm, and 30 subjects in the hydrocortisone butyrate 0.1% cream arm.  
Subjects will follow the main study assessments and visits as per the schedule of activities 
for the main study but will also follow additional procedures as described in this appendix.  
Subjects that are in the main study (C3291037) that are not enrolled in the sub-study will not 
participate in sub-study procedures or evaluations.
The telephone call at Day 60 in the main study is replaced with an in-clinic visit for sub-
study participants.


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Sub-study Schedule of Activities
The following activities are to be performed in addition to the activities specified for the 
main study.
Day
[relative to start of study treatment 
(Day 1)]
Within 
35 days 
prior to 
Day 1
Baseline/
Day 1
Day 
8
Day 
15
Day 
22
Day 29
Day 
43
Day 60a
Window
1 d 3 d 3 d
3 d
5 d
3 d
Visit
Screening
Baseline
End of 
Treatment/
Early 
Termination
Sub-study Informed consent, 
including assentb
X
X
Review of Sub-study Inclusion 
Criteria
X
X
Identify and document sub-study 
target skin sites.  
X
CLINICAL EVALUATION OF 
AD
Target skin sites local ISGA
X
X
X
X
X
X
EASI (global) c
X
SKIN IMAGING
OCT images in triplicate at OCT 
lesional and non-lesional target skin 
sites
X
X
X
X
X
X
Transepidermal Water Lossd at OCT 
lesional and non-lesional target skin 
sites
X
X
X
X
X
X
TAPE STRIP BIOMARKER 
COLLECTION
Tape strips at tape strips lesional 
target skin site
X
X
X
Tape strips at non-lesional target skin 
site
X
PHOTOGRAPHY
Photography of all sub-study target 
skin  sitese
X
X
X
a.Sub-study subjects will be evaluated in clinic.
b.Sub-study subjects may consent during the Screening Phase or at the Baseline visit, prior to any sub-study evaluations or procedures.
c An EASI assessment will be performed on Day 60 in addition to Days specified in the main protocol (Days 1, 8, 15, 22, 29, and 43)
d TEWL will be performed only at selected sub-study investigative centers.
e In addition to photography for the main study, the sub-study target skin sites will be photographed.


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5.  Subject Eligibility Criteria
Subjects will be enrolled in the sub-study after meeting the eligibility criteria of the main 
study during the screening phase.  Subjects must sign a separate informed consent document 
for the sub-study and meet the following Inclusion Criteria:
A. Subject who is enrolled in Cohort 1.
B. Subject is between the ages of 2 to <18 years.
C. Subject is able to sit or lie still during the collection of images for approximately 30 
minutes per visit for OCT imaging and photography, additional 30 minutes for TEWL 
(if applicable) measurements and additional 10 minutes for the tape-strips procedure.
D. Subject has an AD lesional target skin site with a local ISGA score of 2 or 3 at the 
cubital fossa, that is accessible with the OCT probe head.  This target skin site should 
be a minimum of 3 cm in each diameter.  The target skin site must not include the 
area from which blood is drawn.  This site is the OCT AD lesional target skin site.  
E. Subject has a non-lesional target skin site at the left or right volar forearm with a 
circumference clear of AD at screening and at Baseline/Day 1 that is accessible with 
the OCT probe head.  This target skin site will have a local ISGA score of 0.  The 
target skin site must not include the area from which blood is drawn.  This site is the 
non-lesional target skin site. 
F. Subject has an AD lesional target skin site separate, but preferably adjacent to the AD 
lesional target skin site area for tape-strips procedure.  This area will also have a local 
ISGA score of 2 or 3 and will be a minimum of 3 cm in each diameter.  If there are 
not two adjacent lesional target skin sites for OCT and tape-strips, an alternate 
location for tape strips may be located at an AD lesional target skin site bilateral to 
the OCT lesional target skin site.  The target skin site should not include the area 
from which blood is drawn.  This site is the tape strips AD lesional target skin site. 
G. 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 sub-study.
6.  Sub-Study Procedures
While the Day 60 visit for non-sub-study participants is completed via telephone, the Day 60 
visit for subjects enrolled in the sub-study will be completed by a clinic visit to accommodate 
sub-study procedures.
Identification of target skin sites for OCT and biomarker tape strips 
Target skin sites for all sub-study procedures will be identified prior to any sub-study 
evaluations by the blinded assessor that will also perform the assessments.  Target skin sites 


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will not have striae or other signs of prior TCS treatment.  They must not involve the area 
from which blood is drawn.  
1. The OCT AD lesional target skin site at the cubital fossa will have a local ISGA 
score of 2 or 3 and will be accessible with the OCT probe head.  The same target skin 
site will be used for all evaluations throughout the duration of the sub-study.  This 
target skin site will be recorded on a sub-study body map for reference so that the 
location is used consistently for all subsequent evaluations.  This area should be >3 
cm in each diameter.
2. The non-lesional target skin site will be at the left or right volar forearm and will be 
accessible with the OCT probe head.  This target skin site must not include the area 
from which blood is drawn.  This target skin site will have a local ISGA score of 0.  
In choosing between the right and left volar forearm, the side furthest away from any 
signs of AD should be selected.  The same target skin site will be used for all 
evaluations throughout the duration of the sub-study.  This target skin site will be 
recorded on a sub-study body map for reference so that the location is used 
consistently for all subsequent imaging.  This area should be >3 cm in each diameter.
3. The tape-strips lesional target skin site will preferably be adjacent to the AD 
lesional target skin site and will have a local ISGA score of 2 or 3.  If there are not 
two adjacent target skin sites for OCT and tape-strips, an alternate location for tape-
strips may be located at the site bilateral to the OCT target skin site.  The same target 
skin site will be used for all tape-strip collections throughout the duration of the sub-
study.  This target skin site will be recorded on a sub-study body map for reference so 
that the location is used consistently for all subsequent collections.  This area should 
be >3 cm in each diameter without overlapping with the AD lesional target skin site.
Treatment of target skin sites
The OCT AD lesional target skin site and the tape-strips AD lesional target skin site will be 
included in the main study treatment area and will be treated for 28 days with investigational 
product even if the AD resolves during the course of treatment.
The non-lesional target skin site at the volar forearm will be free of AD, however this area 
will be treated with investigational product for the duration of the 28-day treatment period.
Treatment with investigational product on all target skin sites should be withheld on all study
visit days until after the study visit procedures.  The time since last investigational product 
treatment of the target skin sites and the time of study visit procedures will be collected.  
Local ISGA score
A local target ISGA score will be obtained and recorded for all three target skin sites on 
Baseline/Day 1, Day 8, Day 15, Day 22, Day 29, and Day 60 in addition to the overall ISGA.


Crisaborole (PF-06930164)
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EASI assessment
An EASI assessment will be performed on Day 60 in addition to the Days specified in the 
main protocol (Baseline/Day 1, Day 8, Day 15, Day 22, Day 29 and Day 43).
Photography of target skin sites
Each sub-study target skin site will be photographed in addition to any photography 
performed for the main study at Baseline/Day 1, Day 15, and Day 29.  Each photograph will 
be labeled with the corresponding target skin site. 
OCT measurements, TEWL, and Tape-strips
Technical detail and set-up of the OCT measurements, TEWL, and the tape-strip procedure 
will be provided to participating centers in Laboratory Manuals.  All sub-study evaluations 
will be completed after and in addition to main study procedures completed at those clinic 
visits.  Both the operator and the accessor of images will be blinded.  OCT measurements 
will be obtained first, followed by TEWL (if applicable) at OCT AD lesional and non-
lesional target skin sites.  Tape-strips for biomarkers will be conducted after OCT and TEWL 
measurements at the tape-strips target skin site.
Both the OCT AD lesional target skin site and the non-lesional target skin site will be imaged 
by OCT in triplicate on Baseline/Day 1, Day 8, Day 15, Day 22, Day 29, and Day 60.  The 
operator should be consistent across all imaging taken for each individual subject. An 
Imaging partner will be responsible for standardizing the OCT image acquisition, training the 
centers on the imaging protocol, ensuring equipment and image quality assurance and quality 
control. Image analysis will be conducted by a central reader(s) who will be blinded.  
Detailed procedures for obtaining and processing the OCT image, conducting image quality 
assurance/quality control and endpoint analyses will be described in study specific 
documents and provided as appropriate to the study centers.
TEWL will be measured at both the OCT AD lesional target skin site and the non-lesional 
target skin site (not at the tape-strips lesional target skin site) on Baseline/Day 1, Day 8, Day 
15, Day 22, Day 29, and Day 60 at selected sub-study centers.  The operator should be 
consistent across all measurements taken for each individual subject.
Tape-strips for biomarker collection will be completed at the non-lesional target skin site on 
Baseline/Day 1 only.  Tape-strips for biomarker collection will be completed at the tape-
strips lesional target skin site on Baseline/Day 1, Day 15, and Day 29.  The operator should 
be consistent across all tape-strip collections for each individual subject.  The operator will 
be blinded.  A tape strips biomarker partner will be responsible for standardizing the 
collection and analysis of biomarkers.  Detailed procedures for biomarker collection, 
processing and analysis will be described in a separate document and provided to the study 
centers.


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Prior and concomitant treatments
Prior and concomitant topical treatments (per section 5.8) used on sub-study target skin sites 
will be recorded in the CRF.  In addition to restrictions regarding concomitant medications 
described in section 5.8.4 of protocol, all effort should be made to not apply AD treatments 
to sub-study defined target skin sites after the treatment phase until the Day 60, End of Study 
Visit, even if other lesions are necessary to treat with concurrent treatment for AD.
7.  Data Analysis/Statistical Methods
Approximately 60 subjects (15, 15, 30 in vehicle, crisaborole, hydrocortisone groups 
respectively) will participate this sub-study from Cohort 1.  This sub-study is a pilot and 
there is no formal hypothesis testing.  The sample size is not based on a power calculation 
and an estimation approach will be used for data analysis and interpretation.  
The analysis of change from baseline to Day 8, Day 15, Day 22, Day 29, and Day 60 in 
epidermal skin thickness, will be analyzed using mixed model repeated measure (MMRM) 
with treatment, visit, treatment by visit interaction as factors and baseline value as a 
covariate, separately for OCT AD lesional target skin site and non-lesional target skin site.  
Within-subject variability will be accounted for using a random effect with the first order 
autoregressive (AR(1)) covariance matrix.
The same models as above will be used for percentage change from baseline in TEWL at 
Baseline/Day 1, Day 8, Day 15, Day 22, Day 29 and Day 60.  No baseline value will be 
included as a covariate in the model.
Intra-subject difference of change from baseline to Day 8, Day 15, Day 22, Day 29, and Day 
60 in epidermal skin thickness between OCT AD lesional target skin site and non-lesional 
target skin site will be analyzed using MMRM model with visit as a factor for each treatment 
group.
For the tape-strip biomarkers, Log2-scale quantitative reverse transcription polymerase chain 
reaction expression data will be modeled by a linear mixed effect model with visit, treatment, 
visit by treatment interaction as fixed effects and a random effect for each subject.  Means of 
each group will be estimated using least squares means and comparisons of interest will be 
tested using contrast.
This sub-study will be reported independently from the main Clinical Study Report.  
References
1. Chittock J, Brown, K, Cork MJ, Danby SG. Comparing the effect of a twice-
weekly tacrolimus and beta-methasone valerate dose on the subclinical epidermal 
barrier defect in atopic dermatitis.  Acta Derm Venereol 2015; 95:653-658.


Crisaborole (PF-06930164)
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PFIZER CONFIDENTIAL
Page 111
2. Lu Z, Boadi J, Danby S et al. Optical coherence tomography demonstrates 
differential epidermal thinning of human forearm volar skin after 2 weeks 
application of a topical corticosteroid vs a non -steroidal anti -inflammatory 
alternative. Proc. SPIE 2013; 8565:85650C.
3. Imhof et al. TEWL, Closed-Chamber Methods: AquaFlux and VapoMeter
(Springer 2013).

SAP_001.pdf: 
Protocol C3291037 (PF-06930164) Statistical Analysis Plan
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Protocol C3291037
A PHASE 3B/4, MULTICENTER, RANDOMIZED, ASSESSOR BLINDED, 
VEHICLE AND ACTIVE (TOPICAL CORTICOSTEROID AND CALCINEURIN 
INHIBITOR) CONTROLLED, PARALLEL GROUP STUDY OF THE EFFICACY,
SAFETY, AND LOCAL TOLERABILITY OF CRISABOROLE OINTMENT, 2% IN 
PEDIATRIC AND ADULT SUBJECTS (AGES 2 YEARS AND OLDER) WITH MILD 
TO MODERATE ATOPIC DERMATITIS
Statistical Analysis Plan 
(SAP)
Version:
3
Date:
10-NOV-2020


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TABLE OF CONTENTS
TABLE OF CONTENTS...........................................................................................................2
LIST OF TABLES.....................................................................................................................6
LIST OF FIGURES ...................................................................................................................6
1. VERSION HISTORY............................................................................................................7
2. INTRODUCTION .................................................................................................................7
2.1. Study Objectives .......................................................................................................7
2.2. Study Design .............................................................................................................9
3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS ................................................................................................................12
3.1. Primary Endpoint(s) ................................................................................................12
3.1.1. Efficacy Endpoint .......................................................................................12
3.1.2. Safety Endpoints.........................................................................................12
3.2. Secondary Endpoint(s) ............................................................................................12
3.2.1. Efficacy Endpoints......................................................................................12
3.2.2. Patient Reported Outcomes (PRO) Endpoints............................................12
3.4. Baseline Variables...................................................................................................14
3.5. Safety Endpoints .....................................................................................................15
3.5.1. Adverse Events ...........................................................................................15
3.5.2. Laboratory Data..........................................................................................16
3.5.3. Physical Examination .................................................................................16
4. ANALYSIS SETS ...............................................................................................................16
4.1. Full Analysis Set .....................................................................................................16
4.2. Safety Analysis Set..................................................................................................16
5. GENERAL METHODOLOGY AND CONVENTIONS....................................................17
5.1. Hypotheses and Decision Rules ..............................................................................17
5.2. General Methods .....................................................................................................17
5.2.1. Analyses for Binary Data............................................................................17
5.2.2. Analyses for Continuous Data....................................................................17
5.2.3. Analyses for Categorical Data....................................................................17
5.2.4. Analyses for Time to Event Data................................................................18
5.3. Methods to Manage Missing Data ..........................................................................18
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5.3.1. Binary Endpoints ........................................................................................18
5.3.2. Continuous Endpoints.................................................................................18
5.3.3. Time to Event Endpoints ............................................................................18
6. ANALYSES AND SUMMARIES ......................................................................................18
6.1. Efficacy Endpoints ..................................................................................................18
6.1.1. Percent Change from Baseline in EASI at Days 8, 15, 22, and 29.............18
6.1.2. Percent Change from Day 29 to Day 43 in EASI.......................................18
6.1.3. ISGA of Success at Days 8, 15, 22, and 29 ................................................19
6.1.4. ISGA of Clear or Almost Clear at Days 8, 15, 22, and 29 .........................19
6.1.5. EASI75 at Days 8, 15, 22, and 29...............................................................19
6.1.6. Time to EASI75..........................................................................................19
6.1.7. Change from Baseline in %BSA at Days 8, 15, 22, and 29 .......................19
6.2. PRO Endpoints........................................................................................................19
6.2.1. Change from Baseline in Weekly Average Peak Pruritus NRS/Scale .......19
6.2.2. Change from Baseline in Weekly Average Patient Reported Itch 
Severity Scale...................................................................................................19
6.2.3. Change from Baseline in Weekly Average Observer Reported Itch 
Severity Scale...................................................................................................19
6.2.4. ≥2-Point Improvement in Weekly Average Peak Pruritus NRS ................19
6.2.5. ≥3-Point Improvement in Weekly Average Peak Pruritus NRS ................20
6.2.6. Change from Baseline in DLQI at Days 8, 15, 22, and 29.........................20
6.2.7. Change from Baseline in CDLQI at Days 8, 15, 22, and 29 ......................20
6.2.8. Change from Baseline in DFI at Days 8, 15, 22, and 29 ............................20
6.4. Subset Analyses.......................................................................................................20
6.5. Baseline and Other Summaries and Analyses.........................................................20
6.5.1. Baseline Summaries....................................................................................20
6.5.2. Study Conduct and Subject Disposition .....................................................20
6.5.3. Study Treatment Exposure .........................................................................20
6.5.4. Concomitant Medications and Non-drug Treatments.................................21
6.6. Safety Summaries and Analyses .............................................................................21
6.6.1. Adverse Events ...........................................................................................21
6.6.2. Laboratory Data..........................................................................................21
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6.6.3. Vital Signs ..................................................................................................21
6.6.4. Physical Examination .................................................................................21
7. INTERIM ANALYSES.......................................................................................................21
7.1. Data Monitoring Committee ...................................................................................21
7.2. Interim Analyses and Summaries............................................................................22
8. REFERENCES ....................................................................................................................22
9. APPENDICES .....................................................................................................................22
TABLE OF CONTENTS...........................................................................................................2
LIST OF TABLES.....................................................................................................................6
LIST OF FIGURES ...................................................................................................................6
1. VERSION HISTORY............................................................................................................7
2. INTRODUCTION .................................................................................................................7
2.1. Study Objectives .......................................................................................................7
2.2. Study Design .............................................................................................................9
3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS ................................................................................................................12
3.1. Primary Endpoint(s) ................................................................................................12
3.1.1. Efficacy Endpoint .......................................................................................12
3.1.2. Safety Endpoints.........................................................................................12
3.2. Secondary Endpoint(s) ............................................................................................12
3.2.1. Efficacy Endpoints......................................................................................12
3.2.2. Patient Reported Outcomes (PRO) Endpoints............................................12
3.4. Baseline Variables...................................................................................................14
3.5. Safety Endpoints .....................................................................................................15
3.5.1. Adverse Events ...........................................................................................15
3.5.2. Laboratory Data..........................................................................................16
3.5.3. Physical Examination .................................................................................16
4. ANALYSIS SETS ...............................................................................................................16
4.1. Full Analysis Set .....................................................................................................16
4.2. Safety Analysis Set..................................................................................................16
5. GENERAL METHODOLOGY AND CONVENTIONS....................................................17
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5.1. Hypotheses and Decision Rules ..............................................................................17
5.2. General Methods .....................................................................................................17
5.2.1. Analyses for Binary Data............................................................................17
5.2.2. Analyses for Continuous Data....................................................................17
5.2.3. Analyses for Categorical Data....................................................................17
5.2.4. Analyses for Time to Event Data................................................................18
5.3. Methods to Manage Missing Data ..........................................................................18
5.3.1. Binary Endpoints ........................................................................................18
5.3.2. Continuous Endpoints.................................................................................18
5.3.3. Time to Event Endpoints ............................................................................18
6. ANALYSES AND SUMMARIES ......................................................................................18
6.1. Efficacy Endpoints ..................................................................................................18
6.1.1. Percent Change from Baseline in EASI at Days 8, 15, 22, and 29.............18
6.1.2. Percent Change from Day 29 to Day 43 in EASI.......................................18
6.1.3. ISGA of Success at Days 8, 15, 22, and 29 ................................................19
6.1.4. ISGA of Clear or Almost Clear at Days 8, 15, 22, and 29 .........................19
6.1.5. EASI75 at Days 8, 15, 22, and 29...............................................................19
6.1.6. Time to EASI75..........................................................................................19
6.1.7. Change from Baseline in %BSA at Days 8, 15, 22, and 29 .......................19
6.2. PRO Endpoints........................................................................................................19
6.2.1. Change from Baseline in Weekly Average Peak Pruritus NRS/Scale .......19
6.2.2. Change from Baseline in Weekly Average Patient Reported Itch 
Severity Scale...................................................................................................19
6.2.3. Change from Baseline in Weekly Average Observer Reported Itch 
Severity Scale...................................................................................................19
6.2.4. ≥2-Point Improvement in Weekly Average Peak Pruritus NRS ................19
6.2.5. ≥3-Point Improvement in Weekly Average Peak Pruritus NRS ................20
6.2.6. Change from Baseline in DLQI at Days 8, 15, 22, and 29.........................20
6.2.7. Change from Baseline in CDLQI at Days 8, 15, 22, and 29 ......................20
6.2.8. Change from Baseline in DFI at Days 8, 15, 22, and 29 ............................20
6.4. Subset Analyses.......................................................................................................20
6.5. Baseline and Other Summaries and Analyses.........................................................20
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6.5.1. Baseline Summaries....................................................................................20
6.5.2. Study Conduct and Subject Disposition .....................................................20
6.5.3. Study Treatment Exposure .........................................................................20
6.5.4. Concomitant Medications and Non-drug Treatments.................................21
6.6. Safety Summaries and Analyses .............................................................................21
6.6.1. Adverse Events ...........................................................................................21
6.6.2. Laboratory Data..........................................................................................21
6.6.3. Vital Signs ..................................................................................................21
6.6.4. Physical Examination .................................................................................21
7. INTERIM ANALYSES.......................................................................................................21
7.1. Data Monitoring Committee ...................................................................................21
7.2. Interim Analyses and Summaries............................................................................22
8. REFERENCES ....................................................................................................................22
9. APPENDICES .....................................................................................................................22
LIST OF TABLES
Table 1.
Summary of Major Changes in SAP Amendments ....................................7
Table 2.
Study Objectives and Endpoints.................................................................8
LIST OF FIGURES
Figure 1.
Study Design Schematic...........................................................................11


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1. VERSION HISTORY
This SAP for Study C3291037 is based on the protocol amendment 3 dated 12AUG2019.
Table 1.
Summary of Major Changes in SAP Amendments
Version/Date
Associated 
Protocol 
Amendment
Specific Changes
Rationale
1
16MAY2018
Original
16MAR2018
Not Applicable
Not 
Applicable
2
27SEP2019
Protocol 
Amendment 3
12 Aug 2019
Removal of telephone follow-up at
Day 36; addition of a clinic visit at 
Day 43; addition of restrictions to 
concurrent medications during the 
follow-up phase; and changes to the 
pruritis scale descriptions, endpoints, 
and analysis.
Per Protocol 
Amendment 3
3
10NOV2020
Protocol 
Amendment 3
12 Aug 2019
Modifications of efficacy and patient 
reported outcomes endpoints:
Only descriptive summary will 
be provided for primary efficacy 
and selected secondary 
endpoints.
No summary/analysis will be 
done for tertiary/exploratory 
endpoints.
Appendix 8 Listing of Abbreviations 
was added
Study 
termination
2. INTRODUCTION
This SAP provides the detailed methodology for summary and statistical analyses of the data 
collected in Study C3291037.  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
Study objectives and corresponding endpoints are provided in the Table 2 below.


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Table 2.
Study Objectives and Endpoints
Primary Efficacy Objective
Primary Efficacy Endpoint
To compare the efficacy of crisaborole 
ointment, 2% applied twice daily (BID) 
versus vehicle in pediatric and adult subjects 
(ages 2 years and older) with mild to 
moderate Atopic Dermatitis (AD).
Percent change from baseline in the Eczema Area and Severity Index 
(EASI) total score at Day 29.
Primary Safety Objectives
Primary Safety Endpoints
To evaluate the safety and local tolerability 
of crisaborole ointment, 2% applied BID 
versus vehicle in pediatric and adult subjects 
(ages 2 years and older) with mild to 
moderate AD.
To evaluate the safety and local tolerability 
of hydrocortisone butyrate cream 0.1% and 
pimecrolimus cream 1% applied BID in
pediatric and adult subjects (ages 2 years 
and older) with mild to moderate AD.
Adverse Events (AEs), Serious Adverse Events (SAEs), local 
tolerability, discontinuations 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 over time in 
pediatric and adult subjects (ages 2 years 
and older) with mild to moderate AD.
To evaluate the efficacy of crisaborole 
ointment, 2% BID versus hydrocortisone 
butyrate cream 0.1% and pimecrolimus 
cream 1% applied BID in pediatric and adult 
subjects (ages 2 years and older) with mild 
to moderate AD.
Efficacy endpoints:
Percent change from baseline in EASI total score by scheduled time 
points except Day 29.
Achievement of success in the Investigator’s Static Global 
Assessment (ISGA) (defined as an ISGA score of Clear (0) or Almost 
Clear (1) with at least a 2-grade improvement from baseline) by 
scheduled time points.
Achievement of ISGA score of clear (0) or almost clear (1) by 
scheduled time points.
Achievement of EASI75 (75% improvement from baseline) by 
scheduled time points.
Time to EASI75.
Change from baseline in %BSA by scheduled time points.
To evaluate the effect of crisaborole 
ointment, 2% applied BID versus vehicle, 
hydrocortisone butyrate cream 0.1% and
pimecrolimus cream 1% applied BID on 
patient/observer reported outcomes over 
time in pediatric and adult subjects (ages 2 
years and older) with mild to moderate AD.
Patient/observer reported outcomes (PRO) endpoints:
Change from Baseline in Peak Pruritus Numerical Rating Scale 
(NRS) – for subjects >12 years by scheduled time points.
Change from Baseline in Patient Reported Itch Severity Scale - for 
subjects age 6-11 years Scale by scheduled time points.
Change from Baseline in Observer Reported Itch Severity Scale – for 
subjects <6 years by scheduled time points.
Time to ≥2-point improvement from Baseline in Peak Pruritus NRS 
for subjects >12 years.
Time to ≥3-point improvement from Baseline in Peak Pruritus NRS 
for subjects >12 years.
Time ≥2 point to improvement from Baseline in Observer Reported 
Itch Severity Scale - for subjects <6 years.
Time to ≥3-point improvement from Baseline in Observer Reported 
Itch Severity Scale - for subjects <6 years.
Achievement of ≥2-point improvement from Baseline in Peak 
Pruritus NRS for subjects >12 years.
Achievement of ≥3-point improvement from Baseline in Peak 
Pruritus NRS for subjects >12 years.
Achievement of ≥2-point improvement from Baseline in Observer 
Reported Itch Severity Scale - for subjects <6 years.
Achievement of ≥3-point improvement from Baseline in Observer 
Reported Itch Severity Scale - for subjects <6 years.
Change from baseline in Dermatology Life Quality Index (DLQI) 
(for Subjects 16 years and older), Children’s Dermatology Life 
Quality Index (CDLQI) (for Subjects 4-15 years), and Dermatitis 
Family Impact Questionnaire (DFI) (Completed by parent/caregiver 


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Table 2.
Study Objectives and Endpoints
of Subjects 2-17 years) by scheduled time points.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2.2. Study Design
This is a Phase 3b/4, multicenter, randomized, assessor blinded, vehicle and active (topical 
corticosteroid [TCS] and topical calcineurin inhibitor [TCI]) controlled study of the efficacy, 
safety and local tolerability of crisaborole ointment, 2% in pediatric and adult subjects, ages 
2 years and older, with mild to moderate AD involving at least 5% treatable body surface 
area (%BSA).  Treatment will be clinical assessor blinded for all treatment arms and double 
blinded for crisaborole ointment, 2% and vehicle treatment arms.
A total of approximately 600 subjects will be enrolled in the study, of which at least 
150 subjects aged 2-6; at least 140 subjects aged 7-11; at least 120 subjects aged 12-17, and 
up to 90 subjects will be adults.  Following the screening period (up to 35 days prior to 
Baseline/Day 1), eligible subjects will be randomized at the Baseline/Day 1 visit.  
Randomization will be stratified by eligibility for TCS or TCI treatment as per national 
approved labels and eligibility provided in Section 4 of the protocol.  Cohort 1 will be for 
subjects who are eligible for TCS therapy, and Cohort 2 will be for subjects who are not 
eligible for TCS therapy but eligible for TCI therapy.  The investigational product will be 
applied BID for 28 days to the Treatable BSA identified at Baseline/Day 1.  Any new AD on 
treatment eligible locations occurring following Baseline/Day 1 should also be treated with 
the study drug after consultation with the Investigator at the next visit.
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The primary efficacy endpoint is the percent change from baseline in the EASI total score at 
Day 29.
For the efficacy comparison of crisaborole versus vehicle, subjects from both Cohort 1 and 
Cohort 2 are included in the analysis, adjusted for cohort effect.  For the efficacy comparison 
of crisaborole versus TCS, only subjects from Cohort 1 are included in the analysis.  For the 
comparison of crisaborole versus TCI, only subjects from Cohort 2 are included in the 
analysis.
Safety and efficacy assessments will be conducted at the investigator site by a clinical 
assessor blinded for treatment arms.
A sub-study will be conducted at selected investigator sites to evaluate differences of 
changes in epidermal skin thickness as measured by Optical Coherence Tomography (OCT) 
between treatment groups in Cohort 1. Detailed statistical analysis for sub-study will be 
given in a separate SAP.
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) and Day 43 or 14 Days after 
last dose if subject is terminated early from treatment.  A follow up telephone call will be 
made by site staff to the subjects/caregivers on Day 60 or at least 28 days after last dose if 
subject is terminated early from treatment.  Subjects enrolled in the OCT sub-study will 
attend the clinic on Day 60 and do not require a telephone call on Day 60.
A schematic of the study design is shown in Figure 1.


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Figure 1.
Study Design Schematic
1
Crisaborole ointment, 2% BID (n = 75)
Crisaborole Vehicle ointment BID (n = 75)
Hydrocortisone butyrate cream 0.1% BID (n = 150)
Crisaborole Vehicle ointment BID (n = 75)
Pimecrolimus 1% cream BID (n = 150)
Crisaborole ointment, 2% BID (n = 75)
Double-blind treatment period
Follow-
up
Screening/
Washout
Randomization/
Start of Treatment
End of Treatment
Day
Cohort 1
Cohort 2
-35
15
29
60
8
1
22
43
a. Treatment will be clinical assessor blinded for all treatment arms and double blinded for crisaborole ointment, 
2% and vehicle treatment arms.


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3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS
3.1. Primary Endpoint(s)
3.1.1. Efficacy Endpoint
The primary efficacy endpoint is:

Percent change from baseline in EASI total score at Day 29.
3.1.2. Safety Endpoints
The primary safety endpoints are:

AEs, SAEs, local tolerability, discontinuations and clinically significant changes in 
vital signs and clinical laboratory parameters.
3.2. Secondary Endpoint(s)
3.2.1. Efficacy Endpoints
The secondary efficacy endpoints are:

Percent change from baseline in EASI total score by scheduled time points except 
Day 29;

Achievement of success in ISGA (score of clear (0) or almost clear (1) with at least a 
2-grade improvement from baseline) by scheduled time points;

Achievement of ISGA score of clear (0) or almost clear (1) by scheduled time points;

Achievement of EASI75 by scheduled time points;

Time to EASI75;

Change from baseline in %BSA by scheduled time points.
3.2.2. Patient Reported Outcomes (PRO) Endpoints
The secondary PRO endpoints are:
(Note: The peak pruritus NRS (11-category numeric rating scale) is subject reported for 
12 years and older subjects.  A 5-category subject reported peak pruritus scale has been 
developed for subjects 6 and <12 years of age.  The observer reported peak pruritus NRS 
will be completed by a caregiver for subjects <6 years old.  The peak pruritus data will be 
analyzed separately for these three age groups):


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
Change from baseline in peak pruritus NRS by scheduled time points for:

Subjects ≥12 years.

Change from baseline in Patient Reported Itch Severity Scale for:

Subjects ≥6 and <12 years.

Change from baseline in Observer Reported Itch Severity Scale for:

Subjects <6 years.

Time to ≥2-point improvement from baseline in peak pruritus NRS for:

Subjects ≥12 years;

Subjects <6 years.

Time to ≥3-point improvement from baseline in peak pruritus NRS for:

Subjects ≥12 years;

Subjects <6 years.

Achievement of ≥2-point improvement from baseline in peak pruritus NRS by 
scheduled time points for:

Subjects ≥12 years;

Subjects <6 years.

Achievement of ≥3-point improvement from baseline in peak pruritus NRS by 
scheduled time points for:

Subjects ≥12 years;

Subjects <6 years.

Change from baseline in DLQI (for subjects ≥16 years) by schedule time points;

Change from baseline in CDLQI (for subjects 4-15 years) by schedule time points;

Change from baseline in DFI (completed by parent/caregiver of subjects 2-17 years) 
by schedule time points.


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3.4. Baseline Variables
Demographic and baseline characteristics include:
•
Age (years);
•
Sex;
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•
Race;
•
Ethnicity;
•
Height (cm);
•
Weight (kg);
•
Body Mass Index (kg/m2);
•
Duration of disease (years);
•
Prior treatment history (treatment naïve vs treatment [eg, TCS and/or TCI]);
•
Geographic region;
•
Country;
•
ISGA;
•
EASI;
•
%BSA
•
PROs (Peak Pruritus NRS, DLQI, CDLQI, DFI).
For multiple pre-treatment data besides peak pruritus and
 baseline will be 
defined as the last evaluation taken before the first dose of investigational product.  For peak 
pruritus and
the average of 7-day scores immediately prior to Day 1 (Day -6 to 
Day 1) will be used as the baseline.
3.5. Safety Endpoints
Safety will be assessed by the spontaneous reporting of AEs, physical examinations, 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.
3.5.1. Adverse Events
An adverse event is considered treatment-emergent adverse event (TEAE) to a given 
treatment if the event started during the effective duration of treatment. All events that start 
on or after the first dosing day and time/start time, if collected, but before end of study will 
be flagged as TEAEs.
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Safety endpoints will be assessed by the spontaneous reporting of:

TEAEs;

Local tolerability AEs/SAEs;

SAEs and AEs leading to discontinuation.
3.5.2. Laboratory Data
Below is a list of hematology and serum chemistry test parameters at Screening, Baseline/
Day 1 and Day 29/End of treatment/Early termination visit.

Hematology: hemoglobin, hematocrit, red blood cell count, platelet count, white 
blood cell count (% and absolute for neutrophils, eosinophils, monocytes, basophils, 
lymphocytes).

Serum chemistry: blood urea nitrogen/urea, glucose (non-fasting), creatinine, sodium, 
potassium, chloride, Bicarbonate or Total CO2, alanine aminotransferase, aspartate 
aminotransferase, total bilirubin, alkaline phosphatase, albumin, and total protein.
3.5.3. Physical Examination
A detailed physical examination at Screening, Baseline/ Day 1 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.
4. ANALYSIS SETS
Data for all subjects will be assessed to determine if subjects meet the criteria for inclusion in 
each analysis population prior to unblinding and releasing the database and classifications 
will be documented per standard operating procedures.
4.1. Full Analysis Set
The primary analysis population for efficacy data will be the Full Analysis Set (FAS) defined 
as all randomized subjects receiving at least one dose of investigational product.  All efficacy
and PRO endpoints will be analyzed based on the FAS.
For each specific endpoint, only participants who have data at ≥1 timepoint for that endpoint 
will be included in the analysis. 
For a binary endpoint with a threshold requirement for change from baseline, only 
participants with a baseline value ≥the threshold will be included in the analysis.
4.2. Safety Analysis Set
The Safety analysis set (SAF) is defined as those subjects who received at least one dose of 
the investigational product according to actual treatment received.


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5. GENERAL METHODOLOGY AND CONVENTIONS
Final analyses will occur after database lock after Last Subject Last Visit (LSLV).
5.1. Hypotheses and Decision Rules
This study was terminated. The termination decision was made for business reasons only 
and was not related to any safety or efficacy concerns regarding crisaborole. Only 40% of 
planned participants were enrolled at termination. Due to small sample size, no hypotheses 
testing and decision rules. No statistical analysis and comparison will be performed. Only 
descriptive summary will be generated for safety data and some efficacy endpoints.
5.2. General Methods
In general, number and percent will be presented for binary and categorical variables.  
Number, mean, standard deviation, standard error of the mean, median, minimum, and 
maximum will be presented for continuous variables.  In addition, graphics may be used to 
present the data – specific details will be outlined in the study List of Table (LOT).
Descriptive statistics will be provided for:

Crisaborole ointment, 2% applied BID (Cohort 1);

Crisaborole ointment, 2% applied BID (Cohort 2);

Crisaborole ointment, 2% applied BID (combined Cohorts 1 and 2);

Vehicle (combined Cohorts 1 and 2);

Hydrocortisone butyrate cream, 0.1% BID (TCS, Cohort 1);

Pimecrolimus cream, 1% BID (TCI, Cohort 2);

Total – only for disposition, evaluation, demographic and baseline characteristics.
5.2.1. Analyses for Binary Data
Number and percentage of subjects will be summarized.  Line plots of proportions may be 
provided.
5.2.2. Analyses for Continuous Data
Number, mean, standard deviation, standard error of the mean, median, minimum, and 
maximum will be presented.  Line plots of means and standard errors may be provided.
5.2.3. Analyses for Categorical Data
The frequency and percentage for each category will be presented.


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5.2.4. Analyses for Time to Event Data
Time to event endpoints will be summarized using the Kaplan-Meier (KM) method and 
estimated survival curves will be displayed graphically when appropriate.  Graphs will 
describe the number of patients at risk over time.  The median, quartiles, 95% confidence 
interval (CI) for median and quartiles will be estimated by the KM method.
5.3. Methods to Manage Missing Data
In general, for analyses using descriptive statistics, missing values will not be imputed.  In 
addition, for safety endpoints, missing values will not be imputed.  Other methods for 
handling missing values are discussed below.
5.3.1. Binary Endpoints
For binary endpoints analyzed at each scheduled visit separately, if a subject has no data for a 
binary endpoint at a scheduled visit, this subject will be classified as a non-responder (NR)
for that endpoint at that visit.
5.3.2. Continuous Endpoints
Observed data will be used for all continuous endpoints.
5.3.3. Time to Event Endpoints
For time-to-event endpoints, subjects who complete the study without the event of interest or 
those who withdraw before experiencing the event of interest will have their event times right 
censored at the last available measurement time (or visit) used to define whether the subject 
experienced the associated event (ie, the event of interest is presumed to have occurred
beyond this time point).
6. ANALYSES AND SUMMARIES
Due to study termination, only 40% of participants were enrolled. No statistical analysis and 
comparison will be performed. Only descriptive summary will be performed for selected 
efficacy and PRO endpoints.
Summary of selected efficacy and PRO endpoints will be based on FAS population.  
Section 5.2 provides treatment groups for summary.
6.1. Efficacy Endpoints
6.1.1. Percent Change from Baseline in EASI at Days 8, 15, 22, and 29
Descriptive statistics and graph will be provided for observed percent change from baseline 
in EASI.
6.1.2. Percent Change from Day 29 to Day 43 in EASI 
Descriptive statistics will be provided for observed percent change from Day 29 to Day 43 in 
EASI.


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6.1.3. ISGA of Success at Days 8, 15, 22, and 29
Achievement of success in the ISGA (defined as an ISGA score of clear (0) or almost clear 
(1) with at least a 2-grade improvement from baseline) at Days 8, 15, 22, and 29 will be 
summarized.  Missing data will be classified as non-responder.
6.1.4. ISGA of Clear or Almost Clear at Days 8, 15, 22, and 29
Achievement of ISGA of clear (0) or almost clear (1) at Days 8, 15, 22, and 29 will be 
summarized.  Missing data will be classified as non-responder.
6.1.5. EASI75 at Days 8, 15, 22, and 29
Achievement of EASI75 at Days 8, 15, 22, and 29 will be summarized.  Missing data will be 
classified as non-responder.  Graph depicting proportions will be provided.
6.1.6. Time to EASI75
Time to event endpoints will be summarized using the KM method and estimated survival 
curves will be provided for time to EASI75.  The median, quartiles, 95% CI for median and 
quartiles be estimated by the KM method.
6.1.7. Change from Baseline in %BSA at Days 8, 15, 22, and 29
Descriptive statistics will be provided for observed change from baseline in %BSA.
6.2. PRO Endpoints
6.2.1. Change from Baseline in Weekly Average Peak Pruritus NRS/Scale
For peak pruritus NRS/Scale, weekly average score will be used in the analyses of change 
from baseline.  Observed change from baseline in weekly average peak pruritus NRS/Scale at 
Days 8 (Week 1 average of Days 2-8), 15 (Week 2 average of Days 9-15), 22 (Week 3
average of Days 16-22), and 29 (Week 4 average of Days 23-29) for subjects ≥12 years will 
be summarized.
6.2.2. Change from Baseline in Weekly Average Patient Reported Itch Severity Scale
Due to the low enrollment, Patient Reported Itch Severity Scale will not be summarized.
6.2.3. Change from Baseline in Weekly Average Observer Reported Itch Severity Scale
Due to the low enrollment, Observer Reported Itch Severity Scale will not be summarized.
6.2.4. ≥2-Point Improvement in Weekly Average Peak Pruritus NRS
Achievement of ≥2-point improvement from baseline in weekly average peak pruritus NRS
at Days 8 (Week 1 average of Days 2-8), 15 (Week 2 average of Days 9-15), 22 (Week 3
average of Days 16-22), and 29 (Week 4 average of Days 23-29) will be summarized for 
subjects ≥12 years.  Missing data will be classified as non-responder.


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6.2.5. ≥3-Point Improvement in Weekly Average Peak Pruritus NRS
Achievement of ≥3-point improvement from baseline in weekly average peak pruritus NRS
at Days 8 (Week 1 average of Days 2-8), 15 (Week 2 average of Days 9-15), 22 (Week 3 
average of Days 16-22), and 29 (Week 4 average of Days 23-29) will be summarized for 
subjects ≥12 years.  Missing data will be classified as non-responder.
6.2.6. Change from Baseline in DLQI at Days 8, 15, 22, and 29
Descriptive statistics will be provided for observed change from baseline in DLQI for 
subjects ≥16 years.
6.2.7. Change from Baseline in CDLQI at Days 8, 15, 22, and 29
Descriptive statistics will be provided for observed change from baseline in CDLQI for 
subjects 4-15 years.
6.2.8. Change from Baseline in DFI at Days 8, 15, 22, and 29
Descriptive statistics will be provided for observed change from baseline in DFI completed 
by parent/caregiver of subjects 2-17 years.
 
6.4. Subset Analyses
Summary of percentage change from baseline in EASI will be summarized by treatment and 
by cohort, age group, sex, race, baseline ISGA, and geographic region.
6.5. Baseline and Other Summaries and Analyses
6.5.1. Baseline Summaries
Demographics and baseline characteristics including variables defined in Section 3.4 will be 
summarized by treatment group according to Pfizer standards.
6.5.2. Study Conduct and Subject Disposition
Subjects evaluation, disposition, discontinuation will be summarized according to Pfizer 
standards.
6.5.3. Study Treatment Exposure
The exposure to study drug will be summarized by total number of applications, the total 
number of days of dosing, total amount of study drug used, and number and percentage of 
subjects who are compliant with the dosing regimen.
A subject will be considered compliant with the dosing regimen if he/she receives at least 
45 but no more than 67 investigational product doses (ie, 80–120%, inclusive, of the 
expected number of doses) administered in accordance with the protocol.
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6.5.4. Concomitant Medications and Non-drug Treatments
Prior drug and non-drug treatment, concomitant drug and non-drug treatment will be 
summarized according to Pfizer standards.
6.6. Safety Summaries and Analyses
Safety analysis will be based on the SAF.
Safety data will be presented in tabular and/or graphical format and summarized 
descriptively, where appropriate.  All safety endpoints will be listed and summarized in 
accordance with Pfizer Standards.  Categorical outcomes (eg, AEs) will be summarized by 
subject counts and percentage.  Continuous outcome (eg, blood pressure, pulse rate, etc) will 
be summarized using N, mean, median, standard deviation, etc.  Change from baseline in 
laboratory data, and vital signs will also be summarized.  Subject listings will be produced 
for these safety endpoints accordingly.  Cohort 1 and cohort 2 will be combined for 
crisaborole and vehicle arms for all safety summaries and analyses.
6.6.1. Adverse Events
The safety data will be summarized in accordance with Pfizer Data Standards.  All safety 
data will be summarized descriptively through appropriate data tabulations, descriptive 
statistics, categorical summaries, and graphical presentations.  Safety endpoints for the study 
include:

Treatment-emergent AEs and SAEs;

Local tolerability AEs/SAEs;

Withdrawals from treatment/study due to AEs.
6.6.2. Laboratory Data
Laboratory data will be listed and summarized in accordance with the Pfizer reporting 
standards.
6.6.3. Vital Signs
Vital signs will be summarized at baseline, Day 29/End of treatment/Early termination visits.
6.6.4. Physical Examination
Physical examinations will be summarized at baseline, Day 29/End of treatment/Early 
termination visits.
7. INTERIM ANALYSES
7.1. Data Monitoring Committee
This study uses an external data monitoring committee (E-DMC).


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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.
7.2. Interim Analyses and Summaries
There is no plan for an interim analysis.
8. REFERENCES
None.
9. APPENDICES


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Appendix 1. Definition and Use of Visit Windows in Reporting
Visit windows will be used for efficacy variables, and for any safety data that 
display/summarize by study visit.  
Visit Label
Target Day
Definition [Day window]
Screening
Days -35 to Day -1
Baseline
Day 1, Baseline
Day 1*
Day 8
8
Days 2 to 11
Day 15
15
Days 12 to 18
Day 22
22
Days 19 to 25
Day 29/
End of Treatment/
Early Termination
29
Days 26 to last dose +7
Day 43
43
Last dose +8 to end of study
* The baseline of Peak pruritus NRS/scale and
 is the average of 7-day scores 
immediately prior to Day 1 (Day -6 to Day 1)
For the lab values, if the calculated study Day for the labelled baseline visit is not study 
Day 1 but falls within 28 days before the start of the study dosing, then that data should be 
used for the baseline instead of leaving baseline missing.
For the other values, if the calculated study day for the labelled baseline visit is not study 
Day 1, but falls before the start of the study dosing, then that data should be used for the 
baseline instead of leaving baseline missing.
If two or more visits fall into the same window, keep the one closest to the Target Day.  If 
two visits are equaled distant from the Target Day in absolute value, the later visit should be 
used.
Safety analysis may follow Pfizer standards.
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Appendix 2. Investigator’s Static Global Assessment (ISGA)
The ISGA, a five-point global assessment of AD severity, will be assessed at times specified 
in the Study Procedure section of study protocol to characterize subjects’ overall disease 
severity across all treatable AD lesions (excluding the scalp).
The ISGA will be a static evaluation without regard to the score at a previous visit.  It must 
be completed by a clinical assessor blinded for treatment arms.  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.
ISGA Score
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
The ISGA will exclude scalp from the assessment/scoring.


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Appendix 3. Eczema Area and Severity Index (EASI)
The EASI quantifies the severity of a subject’s AD 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.
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 the table below.
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 
%BSA with Atopic Dermatitis: 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.


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Handprint Determination of Body Region Surface Area for Subjects 8 Years
Body Region
Total Number of Handprints 
in Body Region
Surface Area of Body 
Region Equivalent of One 
Handprint
Head and Neck
10
10%
Upper Limbs
20
5%
Trunk (including axillae)
30
3.33%
Lower Limbs (including buttocks)
40
2.5%
Handprint Determination of Body Region Surface Area for Subjects <8 Years
Body Region
Total Number of Handprints 
in Body Region*
Surface Area of Body 
Region Equivalent of One 
Handprint
Head and Neck
20
5%
Upper Limbs
20
5%
Trunk (including axillae)
30
3.33%
Lower Limbs (including buttocks)
30
3.33%
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.
Eczema Area and Severity Index (EASI) Area Score Criteria
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
Body Region Weighting: Each body region is weighted according to its approximate 
percentage of the whole body.
EASI Body Region Weighting
Body Region
Body Region Weighting for 
Subjects 8 Years
Body Region Weighting 
for Subjects <8 Years
Head and Neck
0.1
0.2
Upper Limbs
0.2
0.2
Trunk (including axillae)
0.3
0.3
Lower Limbs (including buttocks)
0.4
0.3


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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 equations below.
Equation 1 (subjects 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 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 0.1 and range from 0.0 to 72.0, with higher scores 
representing greater severity of AD.  Since the scalp will be excluded from the EASI 
assessment in this study, the maximum possible score will be less than 72.0.


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Appendix 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

skin created problems with your 
A lot

partner or any of your close friends
A little

or relatives? 
Not at all

Not relevant 


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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.


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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 
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 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
□
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
□
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
□


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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
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.


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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 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/careers.
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/careers.
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 career and partner or
A little

between the main career and other children
Not at all

in the family.


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10.
Over the last week, how much effect has helping
Very much

with your child’s treatment had on the
A lot

main career’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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CCI


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C
C
I


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CCI


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Appendix 8. Listing of Abbreviations
Abbreviation
Term
AD
Atopic Dermatitis 
AE
Adverse Event
BID
Twice Daily
%BSA
Percent 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
EASI75
Eczema Area And Severity Index ≥75% improvement from Baseline
E-DMC
External Data Monitoring Committee 
FAS
Full Analysis Set
ISGA
Investigator’S Static Global Assessment
KM
Kaplan-Meier
LOT
List of Table
LSLV
Last Subject Last Visit
NR
Non-responder
NRS
Numeric Rating Scale
OCT
Optical Coherence Tomography
PRO
Patient Reported Outcome
SAE
Serious Adverse Event
SAF
Safety Analysis Set
SAP
Statistical Analysis Plan
TCI
topical calcineurin inhibitor
TCS
topical corticosteroid
TEAE
Treatment-Emergent Adverse Event
CCI
CCI
CCI
CCI