Conditions: Atopic Dermatitis
Keywords: Eczema Crisaborole
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 620
Healthy volunteers: no

Brief summary:
This study will evaluate crisaborole therapy once daily (QD) as a long-term topical maintenance therapy for the reduction of flare in responders to crisaborole twice daily (BID) treatment.

Detailed description:
Approximately 700 participants will be enrolled in an run-in period to receive crisaborole, BID for up to a maximum of 8 weeks to identify crisaborole responders. A responder is defined as a participant who achieves both ISGA and EASI50 success. ISGA success is defined as achieving a score of 0 or 1 with at least 2 grade improvement from baseline; and the EASI50 success is defined as at least 50% improvement from baseline. Non responders at the end of the 8-week run-in period will be discontinued from the study.

Approximately 250 responders will be randomized (1:1 ratio) to enter the double-blind maintenance treatment period to receive crisaborole or vehicle QD for 52 weeks, with follow-up assessments every 4 weeks. If a flare occurs and if the participant meets the criteria for having a flare (ISGA ≥2), the participant will switch to enter a flare treatment period to receive open-label crisaborole BID for up to 12 weeks with follow-up assessments every 4 weeks. If the flare has resolved (ISGA ≤1) the participant will resume maintenance treatment and respective visit schedule. If a flare does not resolve after 3 consecutive treatment courses the participant will discontinue the study. A flare treatment period may comprise up to 3 consecutive treatment courses with crisaborole BID (each course is 4 weeks).

An end of study (EOS) safety follow-up is required 4 weeks after the last study treatment of any treatment period.

Arms:
arm 1: Crisaborole 2% ointment applied once daily (QD) arm 2: Vehicle ointment applied once daily (QD)

Interventions: intervention 1: Crisaborole 2% intervention 2: Vehicle
Intervention descriptions: intervention 1: Crisaborole ointment 2% intervention 2: Vehicle ointment

Protocol document:
Prot_000.pdf: 
Crisaborole (PF-06930164)
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TITLE PAGE
Protocol Title: A Phase 3, Randomized, Double-Blind, Vehicle-Controlled Study to 
Evaluate the Efficacy and Safety of Maintenance Treatment and Flare Reduction with 
Crisaborole Ointment, 2%, Once Daily Over 52 Weeks in Pediatric and Adult Participants 
(Ages 3 Months and Older) with Mild-to-Moderate Atopic Dermatitis, who Responded to 
Twice Daily Crisaborole Ointment, 2%, Treatment
Protocol Number: C3291035
Amendment Number: 1
Compound Number: PF-06930164/AN2728
Study Phase: Phase 3
Short Title: Study Evaluating Long-Term Maintenance Treatment and Flare Reduction with 
Crisaborole Ointment 2% in Pediatric and Adult Participants with Mild-to-Moderate Atopic 
Dermatitis
Acronym: CrisADe Control
Sponsor Name: Pfizer, Inc
Legal Registered Address: 235 East 42nd Street, New York, NY 10017-5755, USA
Regulatory Agency Identifier Number(s)
Registry
ID
IND
77,537
EudraCT
2019-000443-28
Approval Date: 19 May 2020
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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Protocol Amendment Summary of Changes Table
DOCUMENT HISTORY
Document
Date
Amendment 1
19 May 2020
Original Protocol
04 April 2019
Amendment 1 (XX May 2020)
Overall Rationale for the Amendment:
Section # and 
Name
Description of Change
Brief Rationale
Protocol Title, 
Section 1.1. 
Synopsis, 
Section 2.1. 
Study Rationale, 
Section 3. 
Objectives, 
Estimands, and 
Endpoints, 
Section 5.1. 
Inclusion 
Criteria, Section 
8.1.3. Eczema 
Area and 
Severity Index 
(EASI), Section 
8.1.6. Patient 
Reported 
Outcomes 
(PROs), Section 
9.4.1.1. Testing 
Procedures for 
Multiple 
Comparisons, 
Section 10.8. 
Appendix 8: 
Country-Specific 
Requirements
The age of the study participant 
population was extended to 3 months 
of age and older.
This is in alignment with an FDA 
recommendation and the agreed initial 
Pediatric Study Plan in the US. The inclusion 
of the age group of 3 months to <24 months to 
the C3291035 study is supported by the 
recently completed Study C3291002 in 3 
months to <24 months in participants with 
mild and moderate atopic dermatitis. The 
C3291002 study showed a comparable benefit 
risk profile as that observed in the pivotal 
Phase 3 clinical trials in participants aged 2 
years and older.
Section 1.1. 
Synopsis, 
Section 9.2. 
Sample Size 
Determination
It was clarified that to yield a total of 
162 first flares in the double-blind 
maintenance period of the study, it is
estimated that approximately 700 
participants will be enrolled in the 
open-label period for responder 
identification and that 250 participants 
will be randomized into the double-
blind maintenance period. It is possible 
that less than 700 or up to 860 
Administrative update to improve on clarity 
pertaining to explicit description of the event-
driven design of the trial, for which the 
numbers of study participants enrolled into 
run-in treatment and further randomized into 
double-blind study will be driven by 162 
events (first flares during double-blind study) 
achieved.


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Section # and 
Name
Description of Change
Brief Rationale
participants will be enrolled in the 
open-label period. 
Section 1.3. 
Schedule of 
Activities (SoA), 
Section 10.9. 
Appendix 9: 
Alternative Study 
Procedures 
during COVID-
19 Pandemic
Alternative study visit procedures 
pertaining to the COVID-19 pandemic
period of the study were provided.
Administrative update to incorporate Protocol 
Administrative Change Letter dated 25 March 
2020. 
Section 2. 
Introduction
The introduction was modified to 
reflect approval of crisaborole in the 
United States as a topical treatment 
therapy in patients 3 months of age and 
older with mild to moderate atopic 
dermatitis (AD) and in the European 
Union as a topical treatment therapy in 
patients 2 years of age and older with 
mild-to-moderate AD. In addition, text 
was added to describe the mode of 
action of crisaborole study 
(C3291001).
Administrative update to current marketing 
authorization approvals and to incorporate 
information from the C3291001 mode of 
action study.
Section 2.2.1.2. 
Pharmacokinetics
Text was added to state that the PK of 
crisaborole ointment in infants of 3 to 
<24 months of age was similar to that 
observed for participants 2 years of 
age and older. 
Administrative update to reflect current 
Investigator’s Brochure.
Section 2.2.1.3. 
Clinical 
Experience, 
Section 2.3. 
Benefit/Risk 
Assessment, 
Section 4.3. 
Justification for 
Dose
Text was added noting that in a Phase 
4 open-label safety study of 
crisaborole ointment in participants 3 
to <24 months of age (C3291002), the 
safety profile 
 
results were consistent with the Phase 
3 studies
Administrative update to reflect current 
Investigator’s Brochure.
Section 5.2. 
Exclusion 
Criteria
It was clarified that either a history of 
cancer or cancer treatment within 5 
years is exclusionary. 
Administrative update to improve clarity and 
readability.
Section 6.1.1. 
Dosing 
Application
Additional dosing application 
instructions added. 
To provide additional guidance on dosing 
application for caregivers.
Section 7.2. 
Participant 
Discontinuation/ 
Withdrawal from 
the Study, 
Additional clarification and procedure 
information have been added. 
To provide further clarification and guidance 
on participant discontinuation and withdrawal 
of consent.
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Section # and 
Name
Description of Change
Brief Rationale
Section 7.2.1. 
Withdrawal of 
Consent
Section 8.1.6. 
Patient Reported 
Outcomes 
(PROs)
Recall periods for Patient Reported 
Outcomes were updated to match 
recall periods on questionnaires 
provided to participants.
Administrative update to reflect the correct 
recall periods.
Section 8.2.5. 
Clinical Safety 
Laboratory 
Assessments
This section was not modified per the 
Protocol Administrative Change Letter 
dated 28 August 2019.
The changes outlined in this Protocol 
Administrative Change Letter are already 
incorporated in Appendix 2 of the original 
protocol. 
Section 8.3.5.1. 
Exposure During 
Pregnancy
Text updated to add female family 
members and healthcare providers to 
pregnancy reporting after study 
intervention exposure.
To include female family members and 
healthcare providers in pregnancy reporting 
after study intervention exposure.
Section 8.4. 
Treatment of 
Overdose
The treatment of overdose was updated 
to state that if excess crisaborole is 
applied, it can be wiped off. 
Administrative update to incorporate Protocol 
Administrative Change Letter 07 May 2019.
Section 9. 
Statistical 
Considerations
The Enrolled and Safety – Double-
Blind populations were added.
“Duration of the BID treatment in 
open-label period” was added as a 
stratification factor for the primary and 
secondary analyses.
Sensitivity/supplementary analyses for 
the primary analysis were added.  
Administrative updates to Section 9 
‘Statistical Consideration’ to improve overall 
clarity and readability. 
Additional updates made per FDA 
recommendations following review of the 
protocol.
Section 10.2. 
Appendix 2: 
Clinical 
Laboratory Tests
Updated to provide specific 
requirements for repeat laboratory 
assessments for alanine 
aminotransferase (ALT), aspartate 
aminotransferase (AST), total 
bilirubin, and creatinine in the event of 
≥30% increase from baseline value.
Update on additional safety laboratory 
monitoring requirements.
Section 10.8. 
Appendix 8: 
Country-Specific 
Requirements
An Appendix was added to clarify that 
enrollment for study participants of 3 
months to <24 months will be open to 
all participating sites except for those 
in Europe (Austria, France, Spain).
To specify the exclusion of European Union 
(EU) countries from enrollment of age group 3 
months to <24 months due to the competing 
study C3291031 in a similar age group. 
C3291031 is an agreed study in the EU 
Paediatric Investigational Plan.   


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TABLE OF CONTENTS
LIST OF TABLES.....................................................................................................................9
1. PROTOCOL SUMMARY...................................................................................................10
1.1. Synopsis ..................................................................................................................10
1.2. Schema ....................................................................................................................12
1.3. Schedule of Activities (SoA)...................................................................................13
2. INTRODUCTION ...............................................................................................................19
2.1. Study Rationale .......................................................................................................19
2.2. Background .............................................................................................................19
2.2.1. Drug Development......................................................................................20
2.2.1.1. Nonclinical Studies and Phase 1 Data.......................................20
2.2.1.2. Pharmacokinetics ......................................................................20
2.2.1.3. Clinical Experience ...................................................................21
2.3. Benefit/Risk Assessment.........................................................................................22
3. OBJECTIVES, ESTIMANDS AND ENDPOINTS ............................................................23
4. STUDY DESIGN.................................................................................................................25
4.1. Overall Design.........................................................................................................25
4.2. Scientific Rationale for Study Design.....................................................................27
4.3. Justification for Dose ..............................................................................................27
4.4. End of Study Definition ..........................................................................................28
5. STUDY POPULATION......................................................................................................28
5.1. Inclusion Criteria.....................................................................................................28
5.2. Exclusion Criteria....................................................................................................29
5.3. Lifestyle Considerations..........................................................................................31
5.3.1. Meals and Dietary Restrictions...................................................................31
5.3.2. Caffeine, Alcohol, and Tobacco .................................................................32
5.3.3. Activity .......................................................................................................32
5.4. Screen Failures ........................................................................................................32
6. STUDY INTERVENTION..................................................................................................32
6.1. Study Intervention(s) Administered........................................................................32
6.1.1. Dosing Application.....................................................................................33
6.1.2. Preparation and Dispensing........................................................................34


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6.2. Preparation/Handling/Storage/Accountability ........................................................34
6.3. Measures to Minimize Bias: Randomization and Blinding.....................................35
6.4. Study Intervention Compliance...............................................................................36
6.5. Concomitant Therapy..............................................................................................36
6.5.1. Medications Prohibited Prior to Baseline of Run-In Treatment.................36
6.5.2. Medications/Therapies Prohibited During All Study Periods ....................38
6.5.3. Medications and Therapies Allowed During the Study..............................39
6.5.4. Rescue Medications....................................................................................39
6.6. Dose Modification...................................................................................................39
6.7. Intervention after the End of the Study...................................................................39
7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL...........................................................................40
7.1. Discontinuation of Study Intervention ....................................................................40
7.2. Participant Discontinuation/Withdrawal from the Study........................................40
7.2.1. Withdrawal of Consent...............................................................................41
7.3. Lost to Follow up ....................................................................................................41
8. STUDY ASSESSMENTS AND PROCEDURES...............................................................42
8.1. Efficacy Assessments..............................................................................................42
8.1.1. Rater Qualifications....................................................................................42
8.1.2. Investigator’s Static Global Assessment ....................................................43
8.1.3. Eczema Area and Severity Index (EASI) ...................................................43
8.1.4. Checklist of AD Lesions and Body Map....................................................46
8.1.5. Photography of Atopic Dermatitis Lesions (At Selected Study Sites).......46
8.1.6. Patient Reported Outcomes (PROs) ...........................................................47
8.1.6.1. Pruritus and Itch Assessments...................................................47
8.1.6.2. Night Time Itch Scale ...............................................................47
8.1.6.3. AD Skin Pain NRS....................................................................48
8.1.6.4. Patient/Observer Global Impression of Severity 
(PGIS/OGIS) .....................................................................................48
8.1.6.5. Dermatology Quality of Life Assessments ...............................48
8.1.6.6. Patient Oriented Eczema Measure (POEM)..............................48
8.1.6.7. Patient/Observer Global Impression of Change 
(PGIC/OGIC) ....................................................................................48


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8.1.6.8. Medical Outcomes Study (MOS) Sleep Scale ..........................49
8.1.6.9. EuroQoL-5 Dimension (EQ-5D)...............................................49
8.1.6.10. Hospital Anxiety and Depression Scale (HADS) ...................49
8.1.6.11. Work and Classroom Productivity..........................................49
8.2. Safety Assessments .................................................................................................49
8.2.1. Medical History ..........................................................................................50
8.2.2. Physical Examinations................................................................................50
8.2.3. Vital Signs ..................................................................................................50
8.2.4. Electrocardiograms.....................................................................................50
8.2.5. Clinical Safety Laboratory Assessments ....................................................51
8.2.5.1. Pregnancy Testing.....................................................................51
8.2.6. Suicidal Ideation and Behavior Risk Monitoring.......................................52
8.3. Adverse Events and Serious Adverse Events..........................................................52
8.3.1. Time Period and Frequency for Collecting AE and SAE Information.......52
8.3.1.1. Reporting SAEs to Pfizer Safety...............................................53
8.3.1.2. Recording Non-serious AEs and SAEs on the CRF .................53
8.3.2. Method of Detecting AEs and SAEs ..........................................................53
8.3.3. Follow-up of AEs and SAEs.......................................................................54
8.3.4. Regulatory Reporting Requirements for SAEs...........................................54
8.3.5. Exposure During Pregnancy or Breastfeeding, and Occupational 
Exposure ..........................................................................................................54
8.3.5.1. Exposure During Pregnancy......................................................54
8.3.5.2. Exposure During Breastfeeding ................................................55
8.3.5.3. Occupational Exposure .............................................................55
8.3.6. Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as AEs............................................................................................55
8.3.7. Wearable Device Incidents.........................................................................56
8.3.8. Medication Errors .......................................................................................56
8.4. Treatment of Overdose............................................................................................57
8.5. Pharmacokinetics ....................................................................................................57
8.6. Pharmacodynamics..................................................................................................57
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8.7. Genetics...................................................................................................................57
8.8. Biomarkers ..............................................................................................................57
8.9. Health Economics OR Medical Resource Utilization and Health Economics........57
9. STATISTICAL CONSIDERATIONS ................................................................................58
9.1. Estimands and Statistical Hypotheses.....................................................................58
9.1.1. Estimands....................................................................................................58
9.2. Sample Size Determination.....................................................................................59
9.3. Populations for Analyses.........................................................................................60
9.4. Statistical Analyses .................................................................................................60
9.4.1. Efficacy Analyses .......................................................................................60
9.4.1.1. Testing Procedure for Multiple Comparisons ...........................60
9.4.1.2. Analysis Methods......................................................................61
9.4.2. Safety Analyses ..........................................................................................62
9.5. Interim Analyses .....................................................................................................62
9.5.1. Data Monitoring Committee (DMC)..........................................................63
10. SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS..........................................................................................................64
10.1. Appendix 1: Regulatory, Ethical, and Study Oversight Considerations...............64
10.1.1. Regulatory and Ethical Considerations ....................................................64
10.1.2. Financial Disclosure .................................................................................65
10.1.3. Informed Consent Process ........................................................................65
10.1.4. Data Protection .........................................................................................66
10.1.5. Dissemination of Clinical Study Data ......................................................66
10.1.6. Data Quality Assurance ............................................................................68
10.1.7. Source Documents....................................................................................69
10.1.8. Study and Site Closure..............................................................................69
10.1.9. Publication Policy.....................................................................................70
10.1.10. Sponsor’s Qualified Medical Personnel .................................................70
10.2. Appendix 2: Clinical Laboratory Tests .................................................................72
10.3. Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting ......................................................................74
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10.3.1. Definition of AE .......................................................................................74
10.3.2. Definition of SAE.....................................................................................75
10.3.3. Recording and Follow-Up of AE and/or SAE..........................................76
10.3.4. Reporting of SAEs....................................................................................79
10.4. Appendix 4: Contraceptive Guidance and Collection of Pregnancy 
Information................................................................................................................80
10.5. Appendix 5: Liver Safety: Suggested Actions and Follow-up Assessments ........84
10.6. Appendix 6: Hanifin and Rajka’s Diagnostic Criteria for Atopic 
Dermatitis33................................................................................................................86
10.8. Appendix 8: Country-Specific Requirements .......................................................90
10.9. Appendix 9: Alternative Study Procedures during COVID-19 Pandemic............91
10.10. Appendix 10: Abbreviations ...............................................................................92
11. REFERENCES ..................................................................................................................96
LIST OF TABLES
Table 1.
Schedule of Activities...............................................................................13
Table 2.
Investigator’s Static Global Assessment ..................................................43
Table 3.
Clinical Sign Severity Scoring Criteria for EASI.....................................44
Table 4.
Handprint Determination of Body Region Surface Area .........................45
Table 5.
EASI Area Score Criteria .........................................................................45
Table 6.
EASI Body Region Weighting .................................................................45
Table 7.
Protocol-Required Safety Laboratory Assessments .................................72
Table 8.
Maximum Blood Volume by Test Parameter...........................................73
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1. PROTOCOL SUMMARY
1.1. Synopsis
Protocol Title: A Phase 3, Randomized, Double-Blind, Vehicle-Controlled Study to 
Evaluate the Efficacy and Safety of Maintenance Treatment and Flare Reduction with 
Crisaborole Ointment, 2%, Once Daily Over 52 Weeks in Pediatric and Adult Participants 
(Ages 3 Months and Older) with Mild-to-Moderate Atopic Dermatitis, who Responded to 
Twice Daily Crisaborole Ointment, 2%, Treatment
Short Title: Study Evaluating Long-Term Maintenance Treatment and Flare Reduction with 
Crisaborole Ointment 2% in Pediatric and Adult Participants with Mild-to-Moderate Atopic 
Dermatitis
Rationale:
Crisaborole is a phosphodiesterase-4 (PDE-4) inhibitor and is being developed as a topical 
treatment for patients with mild-to-moderate atopic dermatitis (AD).
This study will specifically evaluate crisaborole therapy once daily (QD) as a long-term 
topical maintenance therapy for the reduction of flare in responders to crisaborole twice daily 
(BID) treatment.
Objectives, Estimands and Endpoints
Primary Objectives
Primary Endpoints
Efficacy: To evaluate the long-term efficacy 
of crisaborole ointment, 2%, QD for 
maintenance therapy and flare reduction in 
pediatric and adult participants ≥3 months
of age with mild-to-moderate AD who 
responded to crisaborole ointment, 2%, BID 
treatment.
- Flare-free maintenance until onset of first 
flare during the 52-week double-blind 
period
Safety: To evaluate the safety and local 
tolerability of crisaborole ointment, 2%, QD 
for maintenance therapy and flare reduction 
in pediatric and adult participants ≥3 
months of age with mild-to-moderate AD
- Incidence of treatment emergent adverse 
events
The primary and secondary estimands are hypothetical estimands defined according to the 
primary and secondary objectives and are in alignment with the primary endpoint and 
secondary endpoints.
Log-rank test and product limit approach will be used for analysis of the primary endpoint 
flare-free maintenance and secondary endpoint pruritus response maintenance. An analysis of 
covariance (ANCOVA) model will be used for the analysis of secondary endpoint of 
flare-free days. Wilcoxon rank sum test will be used for the analysis of the secondary 
endpoint of number of flares.


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Overall Design:
Eligible participants will be enrolled to receive crisaborole BID in an open-label run-in 
period of up to a maximum of 8 weeks in duration. Responders to run-in treatment at any 
time during this period will be randomized into the double-blind maintenance period in a 1:1 
ratio to receive QD crisaborole or vehicle for 52 weeks. Non-responders at the end of the 8-
week run-in period will be discontinued from the study. To yield a total of 162 first flare 
events in the double-blind maintenance period of the study, it is estimated that approximately 
700 participants will be enrolled in the open-label period for responder identification and that 
approximately 250 participants will be randomized into the double-blind maintenance period. 
Once adequate participants have been randomized, recruitment will stop; it is possible that 
less than 700 or up to 860 participants will be enrolled in the open-label period.
Participants will be instructed to contact their study site as soon as possible to arrange an 
unscheduled clinic visit if a flare is suspected (eg, recurring or worsening AD signs or 
symptoms). In the maintenance period, all confirmed flare(s) will be treated with crisaborole 
BID in an open-label setting for up to 12 weeks (flare treatment period). Responders to flare 
treatment will resume double-blind treatment with the same allocation, until completion at 
52 weeks. Non-responders to flare treatment period will discontinue from the study.
An end-of-study (EOS) safety follow-up by phone will be required 4 weeks after the 
discontinuation of last study dose of any treatment period.
 
Disclosure Statement:
This is a Parallel Treatment study with 2 Arms that are Participant, Investigator, and Sponsor 
blinded.
Number of Participants:
Approximately 700 participants will be enrolled in the run-in period for responder 
qualification. Approximately 250 participants will be randomized into the maintenance 
period of the study.
 
Intervention Groups and Duration:
For the run-in period, all participants will receive crisaborole BID for up to 8 weeks.
For the maintenance period:
Group 1 (N=125): Crisaborole ointment, 2% (weight by weight) QD for 52 weeks
Group 2 (N=125): Vehicle (ointment) QD for 52 weeks
The total duration of participation in the study, 
 
 is up to 68 weeks, including up to 4 weeks for screening, run-in period of up to 
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8 weeks, 52-week double-blind maintenance period, and follow-up period 4 weeks after 
treatment completion. 
Data Monitoring Committee: Yes
1.2. Schema


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1.3. Schedule of Activities (SoA)
Participants can become responders at any of the end of run-in (EORI) visits. For responders entering into the maintenance period, the 
Randomization Day 1 is the same day as the last EORI visit; all assessments including the additional assessments required for Day 1 
are mandatory.  
The in-clinic visits can be both scheduled and unscheduled. Visits on weeks 20, 28, 36, and 44 will be conducted by phone calls.
Alternative study visit information pertaining to the COVID-19 pandemic is described in Appendix 9.
Table 1.
Schedule of Activities
Period
Screening
Run-in
(Open-label)
Maintenance
(Double-Blind)
End-of-Study
(Follow-up)
Notes
Phone visits at weeks 20, 28, 
36, and 44 (Section 8).
Day
-28 to -1
1
15    29    43  57
(End of Run-in)
1
29  57  85  113  141
      
          
169
197  225  253  281 309 337
                           
365
By phone
at least 28 days
after last study 
dose of any 
period
Week(s)
0
   2     4     6   8
0
4    8    12   16    20
24
  28   32    36   40   44    48
52
Window(days)
±1
±3
±3 / visit
±3
±3 / visit
±3
+3
ENROLLMENT PROCEDURES
Informed consent / assent
X
See Appendix 10.1.3
Demographics, and medical history 
including AD history and prior AD 
treatment (incl. reasons of stop)
X
Up to run-in Day 1, pre-dose
Inclusion and exclusion criteria 
X
X
X
Confirmation required at 
Run-in baseline and 
Maintenance baseline. See 
Section 5
Register enrollment using IRT
X
See Section 6.3
Randomization using IRT
X
See Section 6.3
MEDICAL PROCEDURES
Vital signs
X
X -------------------------------- every in-clinic visit ---------------------------------- X
See Section 8.2.3


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Table 1.
Schedule of Activities
Period
Screening
Run-in
(Open-label)
Maintenance
(Double-Blind)
End-of-Study
(Follow-up)
Notes
Phone visits at weeks 20, 28, 
36, and 44 (Section 8).
Day
-28 to -1
1
15    29    43  57
(End of Run-in)
1
29  57  85  113  141
      
          
169
197  225  253  281 309 337
                           
365
By phone
at least 28 days
after last study 
dose of any 
period
Week(s)
0
   2     4     6   8
0
4    8    12   16    20
24
  28   32    36   40   44    48
52
Window(days)
±1
±3
±3 / visit
±3
±3 / visit
±3
+3
Physical examination (PE)
X
X -------------------------------- every in-clinic visit ---------------------------------- X
Complete PE for screening, 
targeted PE for all follow-up. 
See Section 8.2.2
Height and weight
X
X
X
X
X
See Section 8.2.2
LABORATORY TESTING
Serum chemistry and hematology
X
Only if clinically indicated
See Appendix 2, 
Section 8.2.5
Serum pregnancy test
X
For pregnancy status confirmation
For all WOCBP 
(Appendix 4)
Urine dipstick pregnancy test
X
X ---------------------------- every in-clinic visit ------------------------------- X
For all WOCBP. See 
Section 8.2.5.1 and 
Appendix 4.
Follicle-stimulating hormone
X
WONCBP confirmation 
(Appendix 4)
CLINICAL ASSESSMENTS
Investigator’s Static Global 
Assessment (ISGA)
X
X
X ---------------------------- every in-clinic visit ------------------------------- X
See Section 8.1.2
Eczema Area and Severity Index 
(EASI)
X
X ---------------------------- every in-clinic visit ------------------------------- X
See Section 8.1.3
Treatable AD %BSA
X
X
X ---------------------------- every in-clinic visit ------------------------------- X
See Table 4
Record most commonly affected 
AD %BSA
X
X
X
See Section 6.1.1, Table 4


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Table 1.
Schedule of Activities
Period
Screening
Run-in
(Open-label)
Maintenance
(Double-Blind)
End-of-Study
(Follow-up)
Notes
Phone visits at weeks 20, 28, 
36, and 44 (Section 8).
Day
-28 to -1
1
15    29    43  57
(End of Run-in)
1
29  57  85  113  141
      
          
169
197  225  253  281 309 337
                           
365
By phone
at least 28 days
after last study 
dose of any 
period
Week(s)
0
   2     4     6   8
0
4    8    12   16    20
24
  28   32    36   40   44    48
52
Window(days)
±1
±3
±3 / visit
±3
±3 / visit
±3
+3
Record and review AD lesion 
checklist including new lesions
X
X ---------------------------- every in-clinic visit ------------------------------- X
See Section 8.1.4
Record and review body map of 
AD lesions
X
X ---------------------------- every in-clinic visit ------------------------------- X
See Section 8.1.4
PATIENT REPORTED OUTCOMES (PROs)
Columbia Suicide Severity Rating 
Scale (C-SSRS) 
X
See Section 8.2.6 and 
exclusion criterion 4
Pruritus and itch assessments
X --------------------------------------- daily ------------------------------------------- X
See Section 8.1.6.1
Night Time Itch
See Section 8.1.6.2
AD Skin Pain
See Section 8.1.6.3
Patient/Observer Global Impression 
of Severity (PGIS/OGIS)
See Section 8.1.6.4
Dermatology Quality of Life 
Assessments
X ------------------------------------- weekly------------------------------------------- X
See Section 8.1.6.5
Patient-Oriented Eczema Measure 
(POEM)
See Section 8.1.6.6
Patient/Observer Global Impression 
of Change (PGIC/OGIC)
X -------------------------- all in-clinic and phone visits ---------------------------- X
See Section 8.1.6.7
Medical Outcomes Study (MOS) 
Sleep Scale
See Section 8.1.6.8
EuroQoL - 5 Dimensions (EQ-5D)
X -------------------------- all in-clinic and phone visits ---------------------------- X
See Section 8.1.6.9
Work and Classroom Productivity
See Section 8.1.6.11


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Table 1.
Schedule of Activities
Period
Screening
Run-in
(Open-label)
Maintenance
(Double-Blind)
End-of-Study
(Follow-up)
Notes
Phone visits at weeks 20, 28, 
36, and 44 (Section 8).
Day
-28 to -1
1
15    29    43  57
(End of Run-in)
1
29  57  85  113  141
      
          
169
197  225  253  281 309 337
                           
365
By phone
at least 28 days
after last study 
dose of any 
period
Week(s)
0
   2     4     6   8
0
4    8    12   16    20
24
  28   32    36   40   44    48
52
Window(days)
±1
±3
±3 / visit
±3
±3 / visit
±3
+3
Hospital Anxiety and Depression 
Scale (HADS) 
X
X
(last EORI)
X
X
At or nearest to weeks 8, 16, and 32
X
Participants who do not 
enter maintenance period
will complete assessment 
only once at last EORI. See 
Section 8.1.6.10
SAFETY
Serious and non-serious AE 
monitoring and contraception 
check
    X ----------------------------------------------------------------------------------------------------------------------- X
See Section 8.3 and 
Appendix 3
STUDY INTERVENTION
Concomitant medications / 
therapies
    X ----------------------------------------------------------------------------------------------------------------------- X
See Section 6.5
In-clinic dose application training
X
X
If required
See Section 6.1.1
At-home dosing
X ----------------------------------------- daily ------------------------------------------ X
Unless applied in-clinic
Issue and review eDiary for 
treatment compliance
X --------------------------------- every in-clinic visit -------------------------------- X
Drug dispensing
X -----------------------------  every in-clinic visit --------------------------- X
Drug accountability
X --------------------------------- every in-clinic visit -------------------------------- X


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Table 1.
Schedule of Activities
Period
Screening
Run-in
(Open-label)
Maintenance
(Double-Blind)
End-of-Study
(Follow-up)
Notes
 Phone visits at weeks 20, 28, 
36, and 44 (Section 8).
Day
-28 to -1
1
15    29    43  57
(End of Run-in)
1
29  57  85  113  141
      
          
169
197  225  253  281 309 337
                           
365
By phone
at least 28 days
after last study 
dose of any 
period
Week(s)
0
   2     4     6   8
0
4    8    12   16    20
24
  28   32    36   40   44    48
52
Window(days)
±1
±3
±3 / visit
±3
±3 / visit
±3
+3
Flare treatment
•
Unscheduled visits may be required instead of 
scheduled visits. It should include a start of flare 
treatment followed by monthly visits until flare 
resolution for up to 12 weeks.
•
Flare treatment visits will include all 
assessments/procedures as required on Day 29 of 
the maintenance period.
•
For week 24 scheduled assessments, if interrupted 
by flare visits, the assessments are performed at 
the nearest unscheduled visit within ±14 days 
[instead of ±3 days])
•
Photography of AD lesions (see below)
See Section 4.1 for Flare 
treatment
See Section 8.1.5 for 
photography details
PHOTOGRAPHY (SELECTED STUDY SITES)
Photography of AD lesions
X
X
(last EORI)
X
(once at start and once at end of each flare)
See Section 8.1.5
 
        
 
CCI
CCI


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Table 1.
Schedule of Activities
Period
Screening
Run-in
(Open-label)
Maintenance
(Double-Blind)
End-of-Study
(Follow-up)
Notes
Phone visits at weeks 20, 28, 
36, and 44 (Section 8).
Day
-28 to -1
1
15    29    43  57
(End of Run-in)
1
29  57  85  113  141
      
          
169
197  225  253  281 309 337
                           
365
By phone
at least 28 days
after last study 
dose of any 
period
Week(s)
0
   2     4     6   8
0
4    8    12   16    20
24
  28   32    36   40   44    48
52
Window(days)
±1
±3
±3 / visit
±3
±3 / visit
±3
+3
= phone visit; AD = atopic dermatitis; AE = adverse event; BSA = body surface area; C-SSRS = Columbia Suicide Severity Rating Scale; EASI = Eczema Area and 
Severity Index; EORI = end of run-in; EQ = EuroQoL; HADS = Hospital Anxiety and Depression Scale; IRT = interactive response technology; ISGA = Investigator’s Static 
Global Assessment; MOS = Medical Outcomes Study; OGIC = Observer Global Impression of Change; OGIS = Observer Global Impression of Severity; PGIC = Patient 
Global Impression of Change; PGIS = Patient Global Impression of Severity; PE = physical examination; POEM = Patient Oriented Eczema Measure; PRO = patient reported 
outcome; WOCBP = women of childbearing potential, WONCBP = women of non-child bearing potential


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2. INTRODUCTION
Crisaborole, also referred to as PF-06930164 or AN2728, is a low molecular weight 
benzoxaborole anti-inflammatory phosphodiesterase (PDE)-4 inhibitor that penetrates into 
the skin to the sites of inflammation. PDE-4 inhibition results in increased intracellular cyclic 
adenosine monophosphate levels, which suppresses inflammation and secretion of certain 
cytokines, such as tumor necrosis factor-α, interleukin (IL)-2, IL-4, IL-5, and interferon
(IFN)-γ, implicated in the pathogenesis of AD. Crisaborole applied to human skin ex vivo or 
on atopic dermatitis (AD) lesions of patients reduces expression of key drivers of atopic 
inflammation, including T-cell derived cytokines IL-13, IL-31, and IFN-γ as well as innate 
markers of inflammation such as matrix metalloproteinase-12. The specific mechanism(s) by 
which crisaborole exerts its therapeutic action for AD is not well defined.1 A Phase 2 clinical 
trial (C3291001) evaluating the mode of action of crisaborole ointment, 2%, showed that 
crisaborole significantly reduced all 7 prespecified key skin biomarkers involved in AD 
pathophysiology (S100A12, chemokine [C-C motif] ligand [CCL] 17, CCL18, CCL22, 
Keratin 16, elafin/peptidase inhibitor 3, and IL-13).
Crisaborole ointment, 2% (weight by weight) (20 mg/g) (referred to as crisaborole hereafter), 
is approved in the United States (US; EUCRISA®) as a topical treatment therapy in patients 3 
months of age and older with mild to moderate AD; and in Canada (EUCRISA®), Israel, the 
European Union (EU), and Australia (STAQUIS®) as a topical treatment therapy in patients 
2 years of age and older with mild-to-moderate AD.1, 2 It is currently being developed 
worldwide as a topical therapy for patients with mild to moderate AD.
Additional information can be found in the Investigator’s Brochure (IB).
2.1. Study Rationale
Crisaborole is being developed worldwide as a topical therapy for patients with 
mild-to-moderate AD based on its mechanism of action and the results obtained from 10 AD 
clinical trials to date (Section 2.2.1.3). This study will specifically evaluate crisaborole once 
daily (QD) regimen as a long-term maintenance therapy for the reduction of flares in patients 
3 months of age and older with mild-to-moderate AD who respond to crisaborole twice daily 
(BID) treatment.
2.2. Background
AD, often known as eczema, is a chronic, inflammatory skin disorder characterized by flaky 
skin lesions, intense pruritus, and a general deterioration in quality of life (QoL). AD flares 
occur at variable and unpredictable intervals. Patients with moderate AD may experience 
approximately 8 flares per year, each lasting approximately 14 days.3
Over the past 50 years, AD has become more prevalent, especially in industrialized, 
temperate countries such as the US.4, 5 AD is one of the most common, chronic, relapsing 
childhood dermatoses, impacting 15-30% of all children in the US and many have disease 
that persists into adulthood. Earlier reports indicated that, in up to 70% of cases, the disease 
greatly improved or resolved by late childhood, however more recent findings suggest that 
disease activity remains manifest for a prolonged period of time. Based on a total of 


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7157 patients enrolled in the Pediatric Eczema Elective Registry study, comprising a total of 
22,550 person-years, it was concluded that symptoms associated with AD seem to persist 
well into the second decade of life and likely longer.6 The majority of studies conducted 
across multiple age groups suggest a continued decrease in prevalence with older age.7
Adult-onset AD does also occur, though it is less common. The prevalence of AD in adults is 
estimated to be 10%.8
Other treatment options for mild-to-moderate AD include regular use of emollients, topical 
corticosteroids (TCSs) of low-to-moderate potency, and topical calcineurin inhibitors (TCIs) 
(eg, pimecrolimus, tacrolimus) as a second line treatment. TCSs and TCIs have limitations 
for long term use due to safety concerns of TCS (striae rubrae, skin atrophy, telangiectasia, 
skin burning, erythema, and acneiform or rosacea-like eruptions) and TCI (inhibition of 
immune surveillance in the skin or systemically and warnings regarding potential for 
malignancies) adverse effects.9, 10 Additional treatments generally reserved for more severe 
AD include phototherapy (eg, ultraviolet (UV)-A light with or without psoralen, UV-B light 
narrowband or broadband) and systemic agents (eg, corticosteroids, cyclosporine, 
recombinant interferon-γ, mycophenolate mofetil, methotrexate, azathioprine, intravenous 
immunoglobulin and dupilumab).11 Of the currently available therapies, none offers a 
long-term maintenance solution without long-term use safety concerns for mild-to-moderate 
AD.12, 13
The AD skin is often immunologically abnormal even when it appears clinically normal.5
Despite adherence to treatment, treatment modalities often fail to achieve stable long-term 
disease control, hence the significant impact on the QoL. Being proactive to prevent flares is 
recommended by guidelines,14 but safety concerns have limited the long-term use of many 
available therapies. Based on the safety and efficacy data to date, crisaborole offers a
potential option for long-term maintenance use and for the reduction in the occurrence of AD 
flares. 
2.2.1. Drug Development
Crisaborole has been formulated as a topical ointment. Crisaborole has demonstrated clinical 
benefit in Phase 1, 2, and 3 AD clinical studies. Details of the non-clinical and clinical data 
are provided in the current IB.
2.2.1.1. Nonclinical Studies and Phase 1 Data
Data from nonclinical and Phase 1 programs support the ongoing and planned clinical 
development of crisaborole in Phase 2, Phase 3, and Phase 4 studies. Further information is 
provided in the current IB.
2.2.1.2. Pharmacokinetics
The efficacy of crisaborole for the topical treatment of AD is dependent on local skin 
absorption and not on systemic exposure. Following topical application, crisaborole 
penetrated through the stratum corneum, epidermis, and dermis of human skin. Based on 
observed systemic exposures observed in healthy adults, in children and adolescent 
participants (3 months-17 years of age) with AD, and in adult participants with psoriasis, at 


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similar % treated body surface area (BSA), crisaborole systemic exposures across age groups 
are expected to be in a similar range. Systemic absorption does not cause any clinically 
relevant pharmacological effects.
Of note, AD participants 2-17 years of age in Study AN2728-AD-203 treated with 
crisaborole ointment, 2% BID at a dose of approximately 3 mg/cm2 to a mean 17.6% BSA 
for up to 28 days showed that the overall plasma levels of crisaborole were low and similar to 
those observed in adults (BSA-adjusted). An analysis of variance showed no statistically 
significant differences in pharmacokinetic (PK) parameters between the age cohorts 
(12-17 years; 6-11 years and 2-5 years). Absorption across the skin was rapid with median 
time to reach maximum observed plasma concentration (Tmax) of 3.0 hours on both Day 1 
and Day 8. The extent of systemic exposure (plasma maximum observed plasma 
concentration [Cmax] and area under the plasma concentration-time curve [AUC]) of 
crisaborole and its 2 main metabolites, AN7602, and AN8323, increased as the amount of 
crisaborole applied increased. There was minimal accumulation of crisaborole and AN7602 
over 8 days of dosing, whereas AN8323 displayed moderate accumulation, consistent with its 
long half-life (t1/2) (33.5 hours). Steady state was achieved within 4-6 days for crisaborole, 
AN7602, and AN8323. PK of crisaborole ointment was also evaluated in infants of 3 months 
to <24 months of age with mild to moderate disease with treatable BSA of ≥35%.  The Cmax
and AUC in 3 month to <24 month infants was in the same range as that observed for 
participants 2 years of age and older.
Of note, no PDE4 inhibitory activity was detected in vitro for AN7602 and AN8323 and no 
off-target pharmacology was observed for AN8323. Both metabolites have toxicological 
coverages (ie, higher concentrations at the no-observed-adverse-effect level doses of 
crisaborole) in nonclinical studies.
Further information is provided in the current IB.
2.2.1.3. Clinical Experience
Ten clinical trials of topical crisaborole have been completed to date in participants with 
mild-to-moderate AD.
Clinical efficacy of a BID regimen of crisaborole ointment 2% was demonstrated in two 
Phase 3, randomized, double-blind, vehicle-controlled studies in participants 2 years of age 
and older (AN2728-AD-301 and AN2728-AD-302), and a Phase 3 open-label long-term 
safety study up to 48 weeks in participants 2 years of age and older (AN2728-AD-303). A 
Phase 4 open-label safety study of crisaborole ointment 2% in participants 3 to <24 months 
of age (C3291002) with the BID regimen showed a safety profile and exploratory efficacy 
results consistent with the Phase 3 studies (Section 4.2). In addition, a Phase 2 study 
(AN2728-AD-204) also demonstrated efficacy of a QD regimen of crisaborole ointment 2%, 
albeit with a slower onset of action and lower magnitude of clinical efficacy compared with 
the BID regimen.
In summary, crisaborole has been well-tolerated across completed clinical studies.  No 
clinically important systemic safety signals have been identified in adults and children as 


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young as 3 months of age.  Most adverse events (AEs) have been mild, and most considered 
unrelated or unlikely to be related to investigational product (IP).  The most common 
drug-related AEs were application site reactions, such as application site pain (stinging or 
burning) and application site pruritus.
Full details of crisaborole clinical trial data are provided in the current IB.
2.3. 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 clinical 
development program data. 
The crisaborole dose strength and regimen (2% BID) of crisaborole for this study has been 
shown to have a favorable safety profile and to be well tolerated in participants 3 months of 
age and older who participated in previously conducted studies. Crisaborole ointment, 2% 
BID regimen was studied in two Phase 3, randomized, double-blind, vehicle-controlled 
studies in participants 2 years of age and older (AN2728-AD-301 and AN2728-AD-302), a 
Phase 3 open-label long-term safety study in participants 2 years of age and older (AN2728-
AD-303) up to 48 weeks, and a Phase 4 open-label safety study in participants 3 to <24 
months of age (C3291002). 
Data from the 2 controlled studies (AN2728-AD-301 and AN2728-AD-302) showed no 
systemic safety concerns in participants aged 2 years and older. The safety profile from the 
open-label long-term clinical study (AN2728-AD-303) was consistent with that of the 
2 controlled pivotal clinical studies with no new clinically important safety signals identified.
The safety profile observed in the Phase 4 open-label study in participants 3 to <24 months of 
age (C3291002) was consistent with previous studies in participants 2 years of age and older 
with no new clinically important safety signals identified.
The most common drug-related AEs from the 2 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.
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.


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Studies in renal or hepatic impaired patient populations have not been conducted. Studies to 
date did not include sufficient numbers of participants aged 65 years and over to determine 
whether they respond differently from younger participants.
Hypersensitivity, including contact urticaria, has occurred in participants treated with 
crisaborole.  As per protocol, participants with a history of angioedema or anaphylaxis to 
topical products or known sensitivity to any of the components of the IPs are excluded.
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 3 
clinical Study C3291035. Participants will be monitored closely during the study for safety 
and local tolerability AEs of the IPs by the Investigators, Sponsor, and external Data 
Monitoring Committee (DMC) to ensure participant safety.
More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of crisaborole ointment, 2%, is provided in the current IB, which is the single 
reference safety document (SRSD) for this study.
3. OBJECTIVES, ESTIMANDS AND ENDPOINTS
Objectives
Endpoints
Primary

Efficacy: To evaluate the long-term 
efficacy of crisaborole ointment, 2%, 
QD for maintenance therapy and flare 
reduction in pediatric and adult 
participants ≥3 months of age with 
mild-to-moderate AD who responded 
to crisaborole ointment, 2%, BID 
treatment.

Flare-free maintenance until onset of 
first flare during the 52-week double-
blind period

Safety: To evaluate the safety and 
local tolerability of crisaborole 
ointment, 2%, QD for maintenance 
therapy and flare reduction in 
pediatric and adult participants ≥3 
months of age with mild-to-moderate 
AD

Incidence of treatment emergent 
adverse events
Secondary

To evaluate other long-term efficacy 
parameters for maintenance therapy 
and flare reduction of crisaborole 
ointment, 2%, QD in pediatric and 
adult participants ≥3 months of age 
Key secondary endpoints during the 52-
week double-blind period:

Number of flare-free days 

Number of flares


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with mild-to-moderate AD who 
responded to crisaborole 
ointment, 2%, BID treatment

Pruritus response maintenance until 
onset of first flare
Other secondary endpoints during the 52-
week double-blind period:

≥50% reduction in Eczema Area and
Severity Index (EASI)50 response 
maintenance

Maintenance of Dermatology Quality 
of Life Assessments

Maintenance of Patient Oriented 
Eczema Measure (POEM)
The following will be assessed during flare 
treatment period:

Severity of flare on Investigator’s 
Static Global Assessment (ISGA) and 
EASI

Duration of flare episode
Additional Secondary

To evaluate the long-term efficacy of 
crisaborole ointment, 2%, QD for 
maintenance therapy and flare 
reduction in participants ≥3 months of 
age with mild-to-moderate AD
The following will be assessed as change 
from baseline of each respective treatment 
period (run-in, double-blind, and flare 
treatment):

EASI scores

ISGA scores

Treatable AD %BSA

Most commonly affected AD %BSA

To evaluate the long-term health 
impact of crisaborole ointment, 2%, 
QD for maintenance therapy and flare 
reduction in participants ≥3 months of 
age with mild-to-moderate AD
The following patient reported outcomes 
(PROs) will be assessed:

Night Time Itch

AD Skin Pain

Patient Global Impression of Severity

Patient Global Impression of Change

Medical Outcomes Study Sleep Scale

EuroQoL EQ-5D

Work and Classroom Productivity

Hospital Anxiety and Depression


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The primary and secondary estimands are hypothetical estimands defined according to the 
primary and secondary objectives and are in alignment with the primary endpoint and 
secondary endpoints.
Log-rank test and product limit approach will be used for analysis of the primary endpoint 
flare-free maintenance and secondary endpoint pruritus response maintenance. An analysis of 
covariance (ANCOVA) model will be used for the analysis of the secondary endpoint of 
flare-free days. Wilcoxon rank sum test will be used for the analysis of secondary endpoint 
number of flares.
Section 9 provides further details on statistical consideration on primary and secondary 
endpoints.
4. STUDY DESIGN
     
4.1. Overall Design
This is a Phase 3, randomized, double-blind, vehicle-controlled study to assess the efficacy 
and safety of crisaborole ointment, 2%, QD as maintenance treatment and for the reduction 
of flare occurrence in participants (3 months of age and older) with mild-to-moderate AD.  
To yield a total of 162 first flare events in the double-blind maintenance period of the study, 
it is estimated that approximately 700 participants will be enrolled in the open-label run-in 
period to receive crisaborole, BID for up to a maximum of 8 weeks to identify crisaborole 
responders. Approximately 250 participants will be randomized into the double-blind 
maintenance period. Once adequate participants have been randomized, recruitment will 
stop; it is possible that less than 700 or up to 860 participants will be enrolled in the 
open-label period.
Participants (approximately n=250) identified as responders at any study visit (i.e., 2, 4, 6 or 
8 weeks) of the run-in period will be randomized (1:1 ratio) to enter the double-blind 
maintenance period to receive crisaborole QD or vehicle QD for 52 weeks. Non-responders 
at the end of the 8-week run-in period will be discontinued from the study. During the 
maintenance period, participants will return to the clinic or have phone contact with the 
investigative site once per month. However, at any time of the maintenance period, if a flare
is suspected (eg, recurring or worsening AD signs or symptoms) by a participant or caregiver 
of a participant, the participant/caregiver should contact their study site as soon as possible to 
arrange an unscheduled clinic visit. If the participant meets the criteria for having a flare 
(Investigator’s Static Global Assessment [ISGA] ≥2), the participant will switch to enter a 
flare treatment period during which the participant will receive open-label crisaborole 
ointment, 2%, BID for up to 12 weeks. During flare treatment periods, a participant will 
return to the investigative site after 4 weeks for assessment. If the flare has resolved (ISGA 
clear or almost clear), the participant will resume treatment with their original assigned 
blinded QD therapy and return to the maintenance period visit schedule. A flare treatment 
period may comprise up to 3 consecutive 4-week treatment courses with crisaborole BID. If a 


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flare does not resolve after 3 consecutive treatment courses with crisaborole BID, the 
participant will be withdrawn from the study. 
During the open-label run-in period, a responder is defined as a participant who achieves 
both ISGA success (achieving a score of clear [0] or almost clear [1] with a ≥2 grade 
improvement from the run-in baseline) and at least 50% improvement from the run-in 
baseline in Eczema Area Severity Index (EASI) score (EASI50). 
An end of study (EOS) safety follow-up by phone is required for participants who 
discontinue from the study at any study period (run-in, maintenance, or flare treatment), 
4 weeks after the last study treatment.
Flare Treatment Period
When flares occur during the maintenance period, the participants assigned to either QD 
treatment arm will be switched to receive flare rescue treatment with crisaborole BID in an 
open-label setting until resumption of double-blind maintenance treatment. The flare 
treatment is for up to a maximum of 3 treatment courses each lasting 4 weeks (maximum of 
12 weeks).
Flare definition: ISGA ≥2
Resolution of flare: ISGA clear (0) or almost clear (1)
During treatment of flares, participants will be assessed every 4 weeks for the following 
outcomes:
•
If ISGA of clear (0) or almost clear (1) is achieved at the end of any of the 4-week 
treatment courses with crisaborole BID, the participant will resume treatment with 
their assigned double-blind maintenance therapy.
•
If ISGA of clear (0) or almost clear (1) is NOT achieved at the end of 12 weeks of
treatment with crisaborole BID, the participant will be discontinued from the study. 
For flare treatments that cannot be completed by Week 52 or flares that begin at Week 52, 
then a maximum of one treatment course (4 weeks) is allowed. Any flare occurring after 
Week 52 will not be treated for flare treatment by protocol, and the participants should 
discontinue from the study. EOS follow-up is required in both situations.
The total duration of participation in the study, 
 
 including up to 4 weeks for screening, run-in period of up to 
8 weeks, 52-week double-blind maintenance period, and follow up period 4 weeks after 
treatment completion.
See Schema for overall study design (Section 1.2).
See Schedule of Activities (SoA) and details of study assessments in Section 8.
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4.2. Scientific Rationale for Study Design
This study will specifically evaluate if the crisaborole ointment, 2%, QD regimen is safe and 
efficacious for maintenance therapy and flare reduction during long-term treatment for 
52 weeks. The primary and key secondary endpoints are based on the comparison of flare 
events between crisaborole and vehicle treatments.
The rationale for a QD regimen of crisaborole ointment, 2%, as a maintenance and flare 
reduction therapy is supported by the efficacy observed in a Phase 2 study 
(AN2728-AD-204). In Study AN27278-AD-204, crisaborole QD demonstrated that the 
efficacy onset of response was slower after 1, 2, and 3 weeks of treatment and did not show 
the same magnitude of AD signs and symptom improvement as BID at the end of 4 weeks of 
treatment. It was therefore considered that the BID regimen was more suitable for acute 
treatment of mild-to-moderate AD than the QD regimen. If a flare occurs during the 
double-blind maintenance period, then BID crisaborole will be provided as a rescue therapy 
for each flare episode. In the long-term open-label study (AN2728-AD-303) the median time 
to regain an ISGA score of clear or almost clear after AD relapse following no crisaborole 
treatment was 84 days. In this study each episode of flare will be treated with crisaborole 
BID for up to 12 weeks to ensure opportunity for participants to regain the treatment 
response status before resuming blinded QD maintenance treatment. 
The long-term safety of crisaborole ointment, 2%, BID was demonstrated in an open-label 
extension study (AN2728-AD-303) where participants were treated with on-treatment and 
off-treatment cycles (corresponding to relapsing-remitting status of AD) for up to 52 weeks. 
In this study 7 and 8 participants received continuous crisaborole treatment for the entire 48
and 52 weeks, respectively. In this long-term study, no new clinically important safety signal 
was identified that had not already been identified in the short-term pivotal Phase 3 studies 
AN2728-AD-301 and AN2728-AD-302. It is therefore considered suitable to evaluate the 
long-term safety for 52 weeks in this study with crisaborole ointment, 2%, QD. 
4.3. Justification for Dose
The crisaborole dose strength and regimens selected for this study have been demonstrated to 
be well-tolerated and efficacious in mild-to-moderate AD patients of 3 months of age and 
older in previous 8 clinical trials (see IB).
The crisaborole ointment, 2%, BID dose regimen was evaluated in 2 pivotal Phase 3 studies 
in patients 2 years of age and older with mild-to-moderate AD (AN2728-AD-301 and 
AN2728-AD-302) and was confirmed to be well-tolerated and efficacious. A long-term 
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safety study (AN2728-AD-303) of crisaborole BID demonstrated the long-term safety of 
intermittent use of crisaborole for up to 48 weeks. In a Phase 4 open-label safety study 
(C3291002) of crisaborole BID in participants 3 to <24 months of age, exploratory efficacy 
assessments showed results consistent with those in the Phase 3 studies and a consistent 
safety profile was observed. There were no new clinically important safety signals identified. 
The Phase 2 study (AN2728-AD-204) showed that the QD regimen demonstrated efficacy 
although onset of response was slower and did not achieve the same magnitude of AD signs 
and symptom improvement as the BID regimen. 
Therefore crisaborole 2% BID has been selected in this study for treatment of active AD 
signs and symptoms during the run-in period as well as a rescue treatment to treat flares 
during the double-blind maintenance period.
This study will specifically evaluate if crisaborole ointment, 2%, QD is suitable for 
maintenance treatment and flare reduction of mild-to-moderate AD following an initial 
response to crisaborole BID treatment.
4.4. End of Study Definition
A participant is considered to have completed the study if he/she has completed all phases of 
the study including the Day 393 phone follow-up of the maintenance period.
The end of the study is defined as the date of the last scheduled procedure shown in the SoA 
for the last participant in the study globally.
5. STUDY POPULATION
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
5.1. Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria apply:
Age
1. Participant must be 3 months of age or older at the time of signing the informed 
consent/assent (see Appendix 8 for country-specific requirements).
Type of Participant and Disease Characteristics
2. Participant who meets the following AD criteria:
a.
Confirmed clinical diagnosis of AD according to the criteria of Hanifin and 
Rajka (see Appendix 6).
b. AD treatment naïve, prior non-responder to emollient use, or has been 
previously treated with TCSs or TCIs.
c.
AD involvement of ≥5% Treatable % BSA (excluding the scalp) (see Table 4) 
at entry into the run-in period.


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d. ISGA score of Mild (2) or Moderate (3) at entry into the open-label run-in 
period.
Sex
3. Male or Female
Contraceptive use by men or women should be consistent with local regulations 
regarding the methods of contraception for those participating in clinical studies.
     
a.
Male participants:
No contraception methods are required for male participants in this study.
b. Female participants:

A female participant is eligible to participate if she is not pregnant or breastfeeding, 
and at least one of the following conditions applies:
o
Is not a woman of childbearing potential (WOCBP) 
OR
o
Is a WOCBP and using an acceptable contraceptive method as described in 
Appendix 4 during the intervention period (at a minimum until after the last dose of 
study intervention). The investigator should evaluate the effectiveness of the 
contraceptive method in relationship to the first dose of study intervention.
o
A WOCBP must have a negative highly sensitive (Appendix 2) pregnancy test (urine 
or serum as required by local regulations) within 7 days before the first dose of study 
intervention. If a urine test cannot be confirmed as negative (eg, an ambiguous result), 
a serum pregnancy test is required. In such cases, the participant must be excluded 
from participation if the serum pregnancy result is positive. 

Additional requirements for pregnancy testing during and after study intervention are 
located in Appendix 2.

The investigator is responsible for review of medical history, menstrual history, and 
recent sexual activity to decrease the risk for inclusion of a woman with an early 
undetected pregnancy
Informed Consent
4. Capable of giving signed informed consent/assent as described in Appendix 1 which 
includes compliance with the requirements and restrictions listed in the informed 
consent form (ICF) and in this protocol
5.2. Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:


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Medical Conditions
1. Participant has any clinically significant medical disorder, condition, or disease 
(including active or potentially recurrent non-AD dermatological conditions and 
known genetic dermatological conditions that overlap with AD, such as Netherton 
syndrome) or clinically significant physical examination finding at Screening that in 
the investigator’s/designee’s opinion may interfere with study objectives (eg, expose 
participant to unacceptable risk by study participation, confound evaluation of 
treatment response or AEs, or interfere with participant’s ability to complete the 
study)
2. Participant has unstable AD or any consistent requirement for high-potency TCS to 
manage AD signs and symptoms
3. Participant 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 study intervention or 
may interfere with the interpretation of study results and, in the judgment of the 
investigator, would make the participant inappropriate for entry into this study 
including the following:
a.
For participants 7-11 years of age, suicidal ideation associated with actual 
intent and a method or plan in the past 6 months: “Yes” answers on items 4 
or 5 of the Columbia Suicide Severity Rating Scale (C-SSRS) 
(Section 8.2.6) or a previous history of suicidal behaviors in their lifetime: 
“Yes” answer to any of the suicidal behavior items of the C-SSRS.
b. For participants ≥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 (Section 8.2.6) 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. Participant has a history of cancer or has undergone treatment for any type of cancer
within 5 years (except squamous cell carcinoma of the skin, basal cell carcinoma of 
the skin, or carcinoma in situ of the skin, curatively treated with cryosurgery or 
surgical excision only).
6. Participant has a history of angioedema or anaphylaxis to topical products or known 
sensitivity to any of the components of the IPs.
7. Participant has a known lack of efficacy to crisaborole.
Prior/Concomitant Therapy
8. Participant has a history of use of biologic therapy including intravenous 
immunoglobulin or dupilumab at any time prior to study
9. Participant has recent or anticipated concomitant use of systemic therapies or 
therapies that might alter the course of AD, as specified in the protocol 


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10. Participant has received any of the prohibited medications/therapies that may alter the 
course of AD without the required minimum washout period (see Section 6.5.1) or 
anticipated concomitant use of any of the prohibited medications/therapy (see 
Section 6.5.2).
11. Participant has any planned surgical or medical procedure that would overlap with 
study participation, from Screening through the end of study.
Prior/Concurrent Clinical Study Experience
12. Participation in other studies involving investigational drug(s) within 30 days prior to 
study entry and/or during study participation.
Diagnostic assessments
13. Other acute or chronic medical or laboratory abnormality that may increase the risk 
associated with study participation or study intervention administration or may 
interfere with the interpretation of study results and, in the judgment of the 
investigator, would make the participant inappropriate for entry into this study. 
Other Exclusions
14. Pregnant female participants, breastfeeding female participants, and female 
participants 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 study intervention.
15. 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 
participants who are Pfizer employees, including their family members, directly 
involved in the conduct of the study.
5.3. Lifestyle Considerations
1. Participant must avoid swimming or taking a shower or bath within 4 hours after 
applying study intervention. Applying moisturizers, sunscreen, or make-up to facial 
lesions should also be avoided within 60 minutes before and after the applying study 
intervention.
2. Participant must avoid sunbathing or tanning bed use that may interfere with their AD 
disease activity.
3. Women of childbearing potential must comply with contraception use required in this 
study.
5.3.1. Meals and Dietary Restrictions
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5.3.2. Caffeine, Alcohol, and Tobacco
Participants should refrain from excessive caffeine, alcohol, and tobacco consumption that 
may interfere with their AD disease activity.
5.3.3. Activity
Participants must avoid applying study intervention during exercise-induced sweating.
5.4. Screen Failures
Screen failures are defined as participants who consent/assent to participate in the clinical 
study but are not subsequently entered into the run-in period of the study. A minimal set of 
screen failure information is required to ensure transparent reporting of screen failure 
participants to meet the Consolidated Standards of Reporting Trials (CONSORT) publishing 
requirements and to respond to queries from regulatory authorities. Minimal information 
includes demography, screen failure details, eligibility criteria, and any serious adverse event 
(SAE).
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened. Rescreened participants should be assigned a new participant number as for the 
initial screening.
6. STUDY INTERVENTION
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to 
the study protocol. For the purposes of this protocol, the term IP may be used synonymously 
with study intervention. The following sections provide details on crisaborole, and permitted 
and prohibited concomitant medications and therapies. 
 
 
6.1. Study Intervention(s) Administered
ARM Name
Crisaborole Ointment 
2%, BID (Run-in and 
Flare Treatment) 
Crisaborole Ointment 
2%, QD (Maintenance 
Treatment)
Crisaborole Vehicle QD 
(Maintenance Treatment)
Intervention 
Name
Crisaborole 2%
Crisaborole 2%
Crisaborole Vehicle
Type 
Small molecule
Small molecule
Other
Dosage Form
Ointment
Ointment
Ointment
Dose Strength
2% wt/wt, (20 mg/g)
2% wt/wt, (20 mg/g)
Not applicable
Dosage
BID
QD
QD
Route of 
Administration
Topical
Topical
Topical
IMP and NIMP
IMP
IMP
IMP
Sourcing
Provided centrally by 
Sponsor
Provided centrally by 
Sponsor
Provided centrally by 
Sponsor
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Packaging and 
Labeling
Study intervention will 
be provided in 60-gram 
tubes in cartons in an 
open label fashion. 
Each tube and carton 
will be labeled as 
required per country 
requirement.
Study intervention will 
be provided in 60-gram 
tubes in cartons in 
blinded fashion with 
blinded labels. Each tube 
and carton will be 
labeled as required per 
country requirement.
Study intervention will 
be provided in 60-gram 
tubes in cartons in 
blinded fashion with 
blinded labels. Each tube 
and carton will be 
labeled as required per 
country requirement.
Aliases
PF-06930164 or 
AN2728
PF-06930164 or AN2728
Vehicle for PF-06930164
See IB for crisaborole ingredients. Vehicle contains the excipients of crisaborole ointment, 
and the base of crisaborole ointment has no difference in appearance, texture, color, or odor 
to crisaborole ointment, 2%.
6.1.1. Dosing Application
Ointment should be applied as an even layer of approximately 3 mg/cm2.
The tool to standardize the calculation of the amount of ointment required for each 
participant will be provided by the sponsor to the study sites, which is based on each 
participant’s own AD %BSA adjusted by height and weight.
Before the first dosing application the study staff will calculate the amount of ointment 
required for each participant based on the treatable AD skin areas to be treated. During the 
maintenance period, the amount of ointment required should be calculated based on the 
%BSA of the most commonly affected skin areas that are identified and recorded on the 
AD lesion checklist (Section 8.1.4).
During any treatment period, all treatable lesions listed in the AD lesion checklist 
(Section 8.1.4) should be treated, even when the skin appears normal. During the 
maintenance period, it is especially important to continue to apply ointment to the most 
commonly affected skin areas even if they appear normal. Any new lesion(s) occurring 
during any treatment period should also be treated. 
When participants are following the BID dosing regimen (ie, during the run-in and flare 
treatment periods), the dosing application should be at least 8 hours apart within each 
24-hour day. When following the QD dosing regimen, it is recommended that dosing 
application is at the same time each day. 
Under no circumstances will the dose regimens described in this protocol be modified.
For dosing application provided by site staff or caregivers, it is recommended that site staff 
and caregivers wear gloves for application or wash hands following application of dose.
If there are AD lesions in the diaper area, they should be treated with the study intervention; 
however, following diaper change, any study intervention inadvertently wiped off soiled skin 
should not be reapplied until the next scheduled dose.  


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Caregivers who are pregnant, or women of childbearing potential who are trying to become 
pregnant, should avoid accidental exposure by either avoiding applying the study 
intervention or wearing gloves during its application.
Caregivers who are breastfeeding the participants where study intervention is applied to the 
face of the participants, should avoid accidental exposure by either avoiding direct 
breastfeeding (eg, using a milk pump) or breastfeed at least 60 minutes after the study drug 
application and use a wet cloth to clean the participant’s face prior to breastfeeding and the 
breast area following breastfeeding.
Use of routine emollients is allowed under restriction during study treatments, as described in 
Section 6.5.3. Details on lifestyle considerations and use of other topical products are (eg, 
cream or make-up) are described in Section 5.3.
6.1.2. Preparation and Dispensing
Within this protocol, preparation refers to the investigator site activities performed to make 
the IP ready for dispensing to the participant by qualified staff.  Dispensing is defined as the 
provision of IP, concomitant treatments, and accompanying information by qualified staff 
member(s) to a healthcare provider, participant, or caregiver in accordance with this protocol.  
Local health authority regulations or investigator site guidelines may use alternative terms for 
these activities.
The IP will be dispensed in an open label fashion for run-in and flare treatment periods and 
in a blinded fashion during maintenance period, using an interactive response technology 
(IRT) system. A qualified staff member will dispense the IP via unique container numbers on 
the cartons provided, in quantities appropriate for the study visit schedule, based on the total 
%BSA, adjusted for height and weight, for participants with mild-to-moderate AD. 
Further guidance and information are provided in the IP Manual.
6.2. Preparation/Handling/Storage/Accountability
1. The investigator/designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received and any discrepancies are 
reported and resolved before use of the study intervention.
2. Only participants enrolled in the study may receive study intervention and only 
authorized site staff may supply or administer study intervention. All study 
intervention must be stored in a secure, environmentally controlled, and monitored 
(manual or automated) area in accordance with the labeled storage conditions with 
access limited to the investigator and authorized site staff.
3. Any storage conditions stated in the SRSD will be superseded by the storage 
conditions stated on the product label.
4. Study interventions should be stored in their original containers and in accordance 
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5. At a minimum, daily minimum and maximum temperature for all site storage 
locations must be documented and available upon request. Data for nonworking days 
must indicate the minimum and maximum temperature since previously documented 
for all site storage locations upon return to business.
6. Any excursion from the study intervention label storage conditions should be reported 
to Pfizer upon discovery along with any actions taken.  The site should actively 
pursue options for returning the study intervention to the required storage conditions, 
as soon as possible. Once an excursion is identified, the study intervention must be 
quarantined and not be used until Pfizer provides further guidance.
7. Site staff will instruct participants on the proper storage requirements for take-home 
study intervention.
8. The investigator, institution, or the head of the medical institution (where applicable) 
is responsible for study intervention accountability, reconciliation, and record 
maintenance (i.e., receipt, reconciliation, and final disposition records).
9. All study interventions will be accounted for using an IP accountability form. 
Detailed IP accountability records, including dispensed and returned (empty or 
unused), will be maintained at study site and available for the study monitor’s review. 
Any discrepancies noted between drug dispensing records and the drug inventory 
must be reported to Pfizer.
10. Returned IP tubes by participants must not be re-dispensed to the participants.
11. Further guidance and information for the final disposition of unused study 
interventions are provided in the IP Manual.
6.3. Measures to Minimize Bias: Randomization and Blinding
IRT for enrollment and 
randomization, and 
allocation of study 
intervention
All participants will be centrally enrolled into the open-label 
run-in period and subsequently randomized into the double-
blind maintenance period using an Interactive Response 
Technology (IRT). 
The IRT is the source of participant number, randomization 
number and IP allocation dispensed at the study visits per SoA. 
The site personnel will be responsible to register participants 
onto the IRT system.  
The IRT manual will provide the contact information and 
further details on the use of the IRT system.
Blind Break
The study site will be instructed on the method for blind 
breaking.  The method will be an electronic process using the 
IRT system. 
The IRT will be programmed with blind-breaking instructions. 
In case of an emergency, the investigator has the sole 
responsibility for determining if unblinding of a participants’ 
treatment assignment is warranted. Participant safety must 


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always be the first consideration in making such a 
determination. If the investigator decides that unblinding is 
warranted, the investigator should make every effort to contact 
the sponsor prior to unblinding unless necessary for any 
emergency treatment. If a participant’s treatment assignment is 
unblinded, the sponsor must be notified within 24 hours after 
breaking the blind. The date and reason that the blind was 
broken must be recorded in the source documentation and case 
report form (CRF), as applicable.
Participants whose code is broken will be discontinued from 
the study, See Section 7.2 for study discontinuation 
procedures.
6.4. Study Intervention Compliance
A participant will be considered compliant with the dosing regimen if they receive 
80%-120% of the expected number of doses in accordance with the protocol. 
Participant adherence with study intervention will be verified and monitored by review of the 
participant dosing diary. If a participant has missed applications between the previous and the 
current visit, the investigator/designee is to counsel the participant to improve adherence. 
Deviation(s) from the prescribed dosage regimen should be recorded in the CRF.
6.5. Concomitant Therapy
Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements), or any non-medication therapies such as light treatment that the 
participant is receiving at the time of enrollment or receives during the study must be 
recorded along with:

Reason for use

Start and end dates

Dosage and regimen
The medical monitor should be contacted if there are any questions regarding concomitant or 
prior therapy.
Participants must abstain from taking prescription or nonprescription drugs (including 
vitamins and dietary or herbal supplements) per Section 6.5.1 and Section 6.5.2, unless, in 
the opinion of the investigator and sponsor, the medication will not interfere with the study.
Other concomitant medication may be considered on a case-by-case basis by the investigator 
in consultation with the medical monitor if required.
6.5.1. Medications Prohibited Prior to Baseline of Run-In Treatment
Classes of medications and non-medication therapies that may alter the course of AD and for 
which washout is required prior to Run-in Baseline are listed below.  If a participant requires 


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a washout, the investigator/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 Run-in 
Baseline

Biological drugs (Note: prior dupilumab use is exclusionary)
Medications/Therapies Prohibited 28 Days Prior to Run-in Baseline

Use of systemic (oral, parenteral) corticosteroids
Note: Participants on a stable (dose and regimen) of intranasal/inhaled/ophthalmic 
corticosteroids for at least 14 days prior to Baseline are permitted to continue use 
of intranasal/inhaled/ophthalmic corticosteroids. Participants should maintain a 
consistent dose and regimen of these treatments during the study

Use of systemic immunosuppressive agents, including but not limited to, 
methotrexate, cyclosporin, azathioprine, hydroxychloroquine, and mycophenolate 
mofetil (MMF)

Use of sunbathing, tanning bed use, or light therapy (UV, UV-B, psoralen–UV-A)

Escalating, decreasing, or as-needed (PRN) use of topical retinoids or benzoyl 
peroxide (BPO) on treatable AD lesions
Note: Participants on a stable regimen of topical retinoids and/or BPO regimen for 
at least 14 days of consistent use prior to Baseline are permitted to continue the 
topical retinoids or BPO regimen (not on the AD lesions). Participants should 
maintain a consistent dose and regimen of these treatments during the study
Medications Prohibited 14 Days Prior to Run-in Baseline

Use of systemic antibiotics

Use of TCS or TCI anywhere on the body

Use of topical antihistamines anywhere on the body 

Use of any other oral or topical PDE-4 inhibitor

Use of crisaborole ointment anywhere on the body
Medications Prohibited 7 Days Prior to Run-in Baseline

Use of topical antibacterial medications or products, including soaps, bleach baths, 
or topical sodium hypochlorite-based products anywhere on the body

Escalating, decreasing, or PRN use of systemic antihistamines
Note: Participants on stable dose of oral antihistamines for at least 7 days of 
consistent use prior to Baseline are permitted to continue use with minimum 
alteration of dose/regimen during the study, except as medically necessary

Escalating, decreasing, or PRN use of systemic leukotriene inhibitors


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Note: Participants on stable dose of oral leukotriene inhibitors for at least 7 days of 
consistent use prior to Baseline are permitted to continue with minimum alteration 
of dose/regimen during the study, except as medically necessary
Medications Prohibited 1 Day Prior to Run-in Baseline

Use of non-medicated emollients on treatable AD lesion areas  (see Section 6.5.3
for permitted use of non-medicated emollients)
6.5.2. Medications/Therapies Prohibited During All Study Periods
Classes of medications and non-medication therapies that may alter the AD disease course 
are prohibited during the study from run-in Baseline (Day 1) through to the end-of-treatment
(last dose of study intervention).

Use of systemic (oral, parenteral) corticosteroids, unless on stable 
intranasal/inhaled/ophthalmic regimen (see note in Section 6.5.1)

Use of TCS or TCI anywhere on the body

Use of systemic immunosuppressive agents, including but not limited to 
methotrexate, cyclosporin, azathioprine, hydroxychloroquine, or MMF

Escalating, decreasing, or PRN use of topical retinoids or BPO on treatable AD 
lesions, unless on stable regimen (see note in Section 6.5.1)

Use of systemic antihistamines, unless on stable regimen (see note in 
Section 6.5.1)

Use of topical antihistamines anywhere on the body

Use of any other PDE-4 inhibitor topically or systemically, with the exception of 
study intervention in this study

Use of systemic antibiotics for more than 14 consecutive days
Note: Short courses (28 days in total duration) 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 sunbathing, tanning bed use, light therapy (UV, UV-B, psoralen UV-A) 
anywhere on the body

Use of bland (non-medicated) emollients, moisturizers, or sunscreen on AD lesions 
within 60 minutes before and after dosing with study intervention

Participation in another drug or device research study


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6.5.3. Medications and Therapies Allowed During the Study
Classes of medications/therapies that are allowed during the study are recorded as 
concomitant medications/therapies on CRF. Participants on certain stable regimens should 
minimize alteration of the stable regimen during the study. Any changes in stable dosages 
and/or regimens should be recorded on CRF.  The permitted medications/therapies are 
summarized below:

Stable regimen of bland (non-medicated) emollient(s) is permitted during the study 
to manage dry skin, provided that it is not used on the AD lesion areas within 
60 minutes before or after dosing with study intervention

Stable regimen of intranasal/inhaled/ophthalmic corticosteroids

Stable regimen of oral antihistamine

Stable regimen of leukotriene inhibitors

Short courses (28 days) of systemic antibiotics if clinically necessary for the 
treatment of new onset infections

Stable topical retinoid and/or BPO regimen that is not on AD lesions

Nonsteroidal anti-inflammatory drugs (except for any other PDE-4 inhibitors)

Routine preventative immunizations provided that the injection site is not on or 
near AD lesions

Oral transdermal, intrauterine, injected, or implanted hormonal methods of 
contraception for WOCBP

Concomitant medications for other chronic medical conditions are permitted 
during the study unless specifically prohibited by the protocol
6.5.4. Rescue Medications
Rescue medications for AD treatment are not permitted in the study, with the exception of 
crisaborole ointment, 2%, BID during flare treatment periods (Section 4.1).
6.6. Dose Modification
This protocol does not permit any intended dose or regimen modification outside the protocol 
dosing regimen for each study period.
6.7. Intervention after the End of the Study
Study intervention will not be provided at the end of this study.


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7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL
     
7.1. Discontinuation of Study Intervention
In certain instances, it may be necessary for a participant to permanently discontinue study 
intervention. If study intervention is permanently discontinued, the participant will remain in 
the study to undergo an end of treatment assessment (Day 365) followed by an end of study 
safety follow-up.
See the SoA for data to be collected at the time of intervention discontinuation and follow up 
and for any further evaluations that need to be completed.     
7.2. Participant Discontinuation/Withdrawal from the Study

A participant may withdraw from the study at any time at his/her own request, or 
may be withdrawn at any time at the discretion of the investigator for safety, 
behavioral, compliance, or administrative reasons. This is expected to be 
uncommon.

At the time of discontinuing from the study, if possible, an early discontinuation
visit should be conducted, as shown in the SoA. See SoA for data to be collected at 
the time of study discontinuation and follow-up and for any further evaluations that 
need to be completed.

The early discontinuation visit applies only to participants who are 
enrolled/randomized and then are prematurely withdrawn from the study.  
Participants should be questioned regarding their reason for withdrawal.  

The participant will be permanently discontinued both from the study intervention
and from the study at that time.

If the participant withdraws consent/assent 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 a 
withdrawal of consent/assent. Lack of completion of all or any of the 
withdrawal/early termination procedures will not be viewed as protocol deviations 
so long as the participant’s safety was preserved.

If a participant withdraws from the study, he/she may request destruction of any 
remaining samples but data already generated from the samples will continue to be 
available, and may be used to, to protect the integrity of existing analyses. The 
investigator must document any such requests in the site study records.

When a participant withdraws from the study because of an SAE, the SAE must be 
recorded on the CRF and reported on the Clinical Trial (CT) SAE Report.


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7.2.1. Withdrawal of Consent
Participants who request to discontinue receipt of study intervention 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 participant specifically withdraws consent for any further contact 
with him or her or persons previously authorized by the participant to provide this 
information.  Participants 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 study intervention or also from study procedures 
and/or posttreatment study follow-up, and entered on the appropriate CRF page.  In the event 
that vital status (whether the participant is alive or dead) is being measured, publicly 
available information should be used to determine vital status only as appropriately directed 
in accordance with local law.
7.3. Lost to Follow up
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site.
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit:

The site must attempt to contact the participant and reschedule the missed visit as 
soon as possible and counsel the participant on the importance of maintaining the 
assigned visit schedule and ascertain whether or not the participant wishes to and/or 
should continue in the study.

Before a participant is deemed lost to follow up, the investigator/designee must 
make every effort to regain contact with the participant (where possible, 3 telephone 
calls and, if necessary, a certified letter to the participant’s last known mailing 
address or local equivalent methods). These contact attempts should be documented 
in the participant’s medical record.

Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study. 
Discontinuation of specific sites or of the study as a whole are handled as part of Appendix 1.


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8. STUDY ASSESSMENTS AND PROCEDURES

Study procedures and their timing are summarized in the SoA. Protocol waivers or 
exemptions are not allowed.

Immediate safety concerns should be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or 
discontinue study intervention.

Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.

All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening 
log to record details of all participants screened and to confirm eligibility or record 
reasons for screening failure, as applicable.

Procedures conducted as part of the participant’s routine clinical management 
(eg, blood count) and obtained before signing of the consent/assent may be utilized 
for screening or baseline purposes provided the procedures met the protocol-
specified criteria and were performed within the time frame defined in the SoA.

The maximum amount of blood collected from each participant by test parameter is 
summarized in Appendix 2. Repeat or unscheduled samples may be taken for safety 
reasons or for technical issues with the samples.

If blood collection is difficult for individual participants, venipuncture will be 
limited to 3 attempts, with additional attempts within 3–5 business days unless there 
is a medical emergency.

For pediatric participants, low volume pediatric tubes will be used where possible 
and every effort should be made to ensure that blood volume collections do not 
exceed 1% of the total blood volume at any single time and 3% of the total blood 
volume during any period of 4 weeks.

Urine pregnancy test using dipstick must be performed for all WOCBP 
(Appendix 4) during the study, if positive, a serum pregnancy test is required to 
confirm pregnancy (Appendix 2). 

All in-clinic visits, scheduled and unscheduled, will be conducted at study sites.

Phone visits will occur at Days 141, 197, 253, and 309 (Weeks 20, 28, 36, and 44, 
respectively), and as a minimum, the participants should be assessed for any 
AE/SAE, concomitant medications/therapies, study treatment compliance, and any 
suspected flare (which will require an in-clinic visit for assessment).
8.1. Efficacy Assessments
8.1.1. Rater Qualifications
Clinical evaluations of AD will be performed by an experienced and qualified dermatologist 
(board certified or equivalent). An experienced and qualified non-dermatologist physician or 


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experienced medical professional with experience in the conduct of AD clinical trials may be 
permitted to perform the clinical evaluations of AD when designated by the 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 participant 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.
8.1.2. Investigator’s Static Global Assessment
The ISGA is a 5-point scale (0-4), reflecting a global assessment of AD severity based on 
erythema, induration/papulation, and oozing/crusting (Table 2). ISGA will be assessed at 
times specified in the SoA to characterize participants’ 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.
Table 2.
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
8.1.3. Eczema Area and Severity Index (EASI)
The EASI15 quantifies the severity of a participant’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 4 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. 
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.
The EASI will be assessed at times specified in the SoA.  
Lesion Severity by Clinical Signs: The basic characteristics of AD lesions erythema, 
induration/papulation, excoriation, and lichenification provide a means for assessing the 


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severity of lesions.  Assessment of these four main clinical signs is performed separately for 
4 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 3.
Table 3.
Clinical Sign Severity Scoring Criteria for 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 AD 
(Table 4).
The handprint as a unit refers to a participant’s own hand with fingers in a closed position.


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Table 4.
Handprint Determination of Body Region Surface Area 
Body Region
Total Number 
of Handprints 
in Body 
Region*
Surface Area of 
Body Region 
Equivalent of 
One Handprint
Total Number of 
Handprints in 
Body Region*
Surface Area of 
Body Region 
Equivalent of 
One Handprint
≥8 years of age
3 months-7 years of age
Head and Neck
10
10%
20
5%
Upper Limbs
20
5%
20
5%
Trunk (including 
axillae)
30
3.33%
30
3.33%
Lower Limbs 
(including buttocks)
40
2.5%
30
3.33%
*The number of handprints will be for the entire body region; these values will not be adjusted for exclusion of 
scalp, palms, and soles from the BSA assessment.
The extent (%) to which each of the 4 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.
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.
EASI Body Region Weighting
Body Region
Body Region Weighting for 
participants ≥8 years of age
Body Region Weighting for 
participants 3 months-7 years of 
age
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 Equation 1 and Equation 2:
Equation 1 (participants 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 (participants aged 3 months-7 years old):  EASI =0.2Ah(Eh+Ih+Exh+Lh) + 
0.2Au(Eu+Iu+Exu+Lu) + 0.3At(Et+It+Ext+Lt) + 0.3Al(El+Il+Exl+Ll)
A = Area Score; E = erythema; I = induration/papulation; Ex = excoriation; L = lichenification; h = head and 
neck; u = upper limbs; t = trunk; l = lower limbs
8.1.4. Checklist of AD Lesions and Body Map
A checklist of treatable AD areas will be completed at run-in baseline (Day 1) and reviewed 
at each study visit for updates. The most commonly affected skin areas must be 
documented at randomization Day 1, Day 169, and Day 365 of the maintenance period. 
Any new lesion should be recorded and updated in the checklist. 
Study site staff (or the investigator/designee) will determine whether a new AD lesion is 
reported as an AE or as part of the underlying disease based on medical judgement
(Section 8.3.6).
The AD lesion checklist will be recorded in the participant’s source documents and data 
entered onto CRF. 
Body map:
The investigators/designees will be provided with a body map to draw skin areas affected by 
AD for each participant. The original body map must be kept in the source medical file at the 
site; a copy of the body map will be provided to the participant and/or caregiver to take home 
for guidance and the participants must bring the copy back at the next study visit for 
investigator review and update in the source record. The participants must be instructed to 
record any new lesion on the body map. 
The most commonly affected skin areas with the corresponding lesion recorded in AD 
lesion checklist should be shown in the body map at all time.
8.1.5. Photography of Atopic Dermatitis Lesions (At Selected Study Sites) 
Photographs of AD lesions will be obtained during the run-in period and during flare 
treatment periods. For the run-in period, photographs should be obtained on Day 1 and at the 
last EORI visit. For the flare treatment period, photographs should be obtained once at the 
start time of the flare onset and once following resolution of the flare (eg, last flare visit).


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AD areas photographed should be consistent across each assessment for the same body 
region and recorded in study source documents. 
Photographic instruments, instruction, and training will be provided by a central photography 
vendor selected by the sponsor.  Detailed procedures will be provided separately in a 
photography manual.
8.1.6. Patient Reported Outcomes (PROs)
The PROs will be evaluated using questionnaires designed to be completed by participants or
by observers (parents/caregivers) about the participant’s experience to assess AD symptoms 
and health impact due to AD.
The PROs to be completed at home are fixed regular time points of daily, weekly, or phone 
visits. The total time required to complete all questionnaires at each time point is 
approximately 3-10 minutes. The participants/observers must be instructed on how to 
complete the questionnaires. 
The PROs to be completed at in-clinic visits (scheduled or unscheduled) will be completed at 
study site and may require approximately 10-15 minutes. The investigator/designee should 
oversee the first-time PRO completion by the participants/observers and provide further 
completion instruction as required during the subsequent visits. The PROs should be 
completed after ISGA assessment but prior to any other clinical assessment.
Note: age-specific PRO instrument must be selected according to age at the time of 
consent/assent. The instrument must not be changed during the study even if age changes.
See SoA for the PRO schedule.
8.1.6.1. Pruritus and Itch Assessments
Participants will be asked to assess their worst itch or scratching due to AD.

Peak Pruritus Numerical Rating Scale (NRS)16 is an 11-point scale and must be 
completed by participants ≥12 years of age, assessed over the previous 24 hours. 

Patient reported Itch Severity Scale is a 5-point scale must be completed by
participants 6-11 years of age, assessed for today. 

Observer reported Itch Severity Scale is an 11-point scale and must be completed by 
the observers (caregivers of participants) for participants 3 months-5 years of age, 
assessed over the previous 24 hours. 
8.1.6.2. Night Time Itch Scale
The severity and frequency of itch (pruritus) during the night due to AD will be assessed 
using a horizontal scale. Participants 12 years of age or older will be asked to assess their 
worst itching and frequency of itching due to AD during their most recent night’s sleep on a
scale.


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8.1.6.3. AD Skin Pain NRS
Participants 12 years of age or older will be asked to assess their worst skin pain due to AD 
at the present time, (ie, ‘AD skin pain right now’).
8.1.6.4. Patient/Observer Global Impression of Severity (PGIS/OGIS)
The PGIS/OGIS is a single item patient- or observer-rated measure of the participant’s AD 
condition severity at a given point in time.
This single item instrument uses a 7-point rating scale. The PGIS/OGIS will be used as an 
anchor for defining a ‘clinically important difference’ on the pruritus and itch assessments
and can also be used to create severity categorization for pruritus and itch assessments to 
enhance interpretation. 

The PGIS will be completed by all participants ≥12 years of age.

The OGIS will be completed by the observer for participants 3 months-11 years of 
age.
8.1.6.5. Dermatology Quality of Life Assessments
The Dermatology Life Quality Index (DLQI) is a validated general dermatology 
questionnaire that consists of 10 items to assess participant-reported health-related QoL 
(daily activities, personal relationships, symptoms and feelings, leisure, work and school, and 
treatment).17 These instruments are used to assess quality of life over the last week.

The DLQI will be completed by participants ≥16 years of age.

The Children’s Dermatology Life Quality Index (CDLQI) will be completed by 
participants 4-15 years of age and assisted by observers, if required.

The Infant’s Dermatitis Quality of Life Index (IDQoL) will be completed by
observers for participants 3 months–3 years of age.
8.1.6.6. Patient Oriented Eczema Measure (POEM)
The POEM18-20 is a validated 7-item measure used to assess the impact of AD over the last
week.

The POEM will be completed by participants ≥12 years of age.

The proxy POEM will be completed by observers for participants 3 months-11 years 
of age.
8.1.6.7. Patient/Observer Global Impression of Change (PGIC/OGIC)
This single item instrument is a 7-point rating scale and will be used to determine global 
improvement at a given point in time since the start of study drug. It will be used as an 
anchor to define a responder definition for the pruritus and itch assessments for ‘clinically 
important responder’ and as a sensitivity analysis for defining a ‘clinically important 
difference’ for pruritus and itch assessments.

The PGIC will be completed by participants ≥12 years of age.


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•
The OGIC will be completed by the observer for participants 3 months-11 years of 
age.
8.1.6.8. Medical Outcomes Study (MOS) Sleep Scale
The Medical Outcomes Study sleep scale is patient-reported measure consisting of 12 items 
that assess the key constructs of sleep over the past week. The scale has been found reliable 
and valid with good overall measurement properties.21, 22
Participants 12 years of age or older will be asked to recall sleep-related activities over the 
past one week.
8.1.6.9. EuroQoL-5 Dimension (EQ-5D)
The EQ-5D-5L is a validated, standardized, generic instrument that is the most widely used 
preference based health related quality of life questionnaire in cost effectiveness and health 
technologies assessment.23-26 Recently, a version was developed and validated for use in 
children and adolescents, EQ-5D-Youth (EQ-5D-Y).27-29 For participants 2-7 years, a proxy 
version of this version will be used. All of the  EQ-5D assessments are completed for recall 
period of today.
•
The EQ-5D-5L (5 levels) will be completed by participants ≥18 years of age.
•
The EQ-5D-Y (3 levels) will be completed by participants 8-17 years of age and 
assisted by observers, if required.
•
EQ-5D-Y Proxy (3 levels) will be completed by observers for participants 2-7 years 
of age.
8.1.6.10. Hospital Anxiety and Depression Scale (HADS)
The HADS is a validated 14-item PRO measure used to assess states of anxiety and 
depression over the past week.30 The HADS must be completed by participants ≥12 years of 
age. 
8.1.6.11. Work and Classroom Productivity
The Work Productivity and Activity Impairment Questionnaire plus Classroom Impairment 
Questions: Atopic Dermatitis, Version 2 (WPAI+CIQ:AD, V2)31 will be used to collect 
participant reports on burdens with respect to possible impact of AD on work/school 
performance during the past 7 days. The WPAI+CIQ:AD is validated for respondents 
12 years of age and older and must only be completed by participants ≥12 years of age.
 
8.2. Safety Assessments
Planned time points for all safety assessments are provided in the SoA.
CCI


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8.2.1. Medical History

Medical history includes diagnosis and disease duration, intolerance/allergy to any 
drug or food, history of any significant alcohol, tobacco, controlled substance use.

Complete AD disease history: AD diagnosis; the use of topical treatments, systemic 
treatments, and other treatments for AD (within 90 days prior to Screening); and 
reason for discontinuation. 

Medication history will be recorded on the concomitant medication CRF page and 
will include all prescription or non-prescription drugs, and dietary and herbal 
supplements taken within 28 days prior to the planned first dose; and for vaccines 
and biological drugs taken within 12 weeks prior to the planned first dose.
8.2.2. Physical Examinations

A complete physical examination will include, at a minimum, assessments of 
general appearance, skin, head, ears, eyes, nose, throat, mouth, skin, heart, lung, 
breast, lymph nodes, extremities, abdomen, external genitalia (optional), and 
neurological function. In addition, an assessment will be made for skin 
abnormalities other than AD, including scalp. 

A targeted physical examination will include, at a minimum, assessments of the 
skin, heart, lungs, and abdomen and examination of body systems where there are 
symptom complaints by the participant.

Height and weight will also be measured and recorded. For both measurements, the 
investigator or examiner should be trained in measuring height/length and weight as 
well as in calibration procedures. 

Investigators should pay special attention to clinical signs related to previous serious 
illnesses.
8.2.3. Vital Signs

Temperature and pulse rate will be assessed. Ideally, the same method should be 
used consistently throughout the study. 

Temperature and pulse measurements should be preceded by at least 5 minutes of 
rest for the participant in a quiet setting without distractions (eg, television, cell 
phones). Participants should refrain from smoking or ingesting caffeine 30 minutes 
before the measurements.
8.2.4. Electrocardiograms

Not required.


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8.2.5. Clinical Safety Laboratory Assessments

See Appendix 2 for the list of clinical laboratory tests to be performed and to the 
SoA for the timing and frequency.

Details on sampling collection, labeling, storage, and shipment to the central 
laboratory can be found in the laboratory manual. 

The skin must be thoroughly cleansed prior to blood sample collection. At the 
discretion of the investigator/designee, a lidocaine based topical aesthetic (eg,
lidocaine 4% cream) may be used prior to blood sample draws to decrease potential 
discomfort to the participant provided with the anaesthetic. The use of topical 
lidocaine based anesthetics must be recorded in the CRF.

The investigator must review the laboratory report, document this review, and 
record any clinically relevant changes occurring during the study in the AE section 
of the CRF. The laboratory reports must be filed with the source documents. 
Clinically significant abnormal laboratory findings are those which are not 
associated with the underlying disease, unless judged by the investigator to be more 
severe than expected for the participant's condition.

All laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 24 hours after the last dose of study intervention 
should be repeated until the values return to normal or baseline or are no longer 
considered clinically significant by the investigator or medical monitor.
o
If such values do not return to normal/baseline within a period of time judged 
reasonable by the investigator, the etiology should be identified and the sponsor 
notified.
o
All protocol-required laboratory assessments, as defined in Appendix 2, must be 
conducted in accordance with the laboratory manual and the SoA. 
o
If laboratory values from non-protocol specified laboratory assessments 
performed at the institution’s local laboratory require a change in participant 
management or are considered clinically significant by the investigator (eg, SAE 
or AE or dose modification), then the results must be recorded in the CRF.
8.2.5.1. Pregnancy Testing 
For all WOCBP (see definition in Appendix 4), a serum or urine pregnancy test will be 
required for eligibility, with a test sensitivity of at least 25 mIU/mL. Serum pregnancy test 
will be performed in central lab. Urine pregnancy tests will be conducted at site with the test 
kit provided by the central laboratory in accordance with instructions provided in its package 
insert.  
During the study, pregnancy tests will be done using urine pregnancy test kit for all WOCBP. 


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Urine pregnancy tests will also be done whenever 1 menstrual cycle is missed or when 
potential pregnancy is otherwise suspected.  Pregnancy tests may also be repeated if 
requested by institutional review boards (IRBs)/ independent ethics committees (IECs) or if 
required by local regulations.
Participants who have missed a menstrual period or who show an indeterminate or positive 
result on the urine test may not further progress with the study treatment until pregnancy is 
ruled out using further diagnostic testing (eg, a negative quantitative serum pregnancy test.
If the investigator judges that the participant is not pregnant, the participant may resume 
study treatment.
In the case of a positive confirmed pregnancy, the participant will be withdrawn from the 
study.
8.2.6. Suicidal Ideation and Behavior Risk Monitoring
For study exclusionary purposes (Section 5.2, Exclusion Criterion #4), participants 7 years of 
age or older will be assessed for suicidal ideation and behavior risks using the Columbia 
Suicide Severity Rating Scale (C-SSRS).32 The C-SSRS is a validated PRO tool to evaluate 
suicidal ideation and behavior in this age range. For younger participants under 7 years of 
age, the investigator/designee should assess the suicidal ideation and behavior risks clinically 
in consultation with their parents/caregivers.
8.3. Adverse Events and Serious Adverse Events
The definitions of an AE or SAE can be found in Appendix 3. For AD-related AEs, see 
Section 8.3.6.
AE will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or the 
participant's legally authorized representative).
The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible to pursue 
and obtain adequate information both to determine the outcome and to assess whether it 
meets the criteria for classification as an SAE, or that caused the participant to discontinue 
the study intervention/study (see Section 7).
In addition, the investigator may be requested by Pfizer Safety to obtain specific follow-up 
information in an expedited fashion. 
8.3.1. Time Period and Frequency for Collecting AE and SAE Information
The time period for actively eliciting and collecting AEs and SAEs (“active collection 
period”) for each participant begins from the time the participant provides informed 
consent/assent, which is obtained before the participant’s participation in the study (ie, before 
undergoing any study-related procedure and/or receiving IP), through and including a 


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minimum of 28 calendar days; except as indicated below after the last administration of the 
IP.
For participants who are screen failures, the active collection period ends when screen failure 
status is determined.
Medical occurrences that begin before the start of study intervention but after obtaining 
informed consent will be recorded on the Medical History/Current Medical Conditions 
section of the CRF not the AE section.
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.
Investigators are not obligated to actively seek AE or SAE after conclusion of the study 
participation. However, if the investigator learns of any SAE, including a death, at any time 
after a participant has been discharged from the study, and he/she considers the event to be 
reasonably related to the study intervention or study participation, the investigator must 
promptly notify the sponsor.
8.3.1.1. Reporting SAEs to Pfizer Safety 
All SAEs occurring in a participant during the active collection period are reported to Pfizer
Safety on the Clinical Trial (CT) SAE Report Form immediately and under no circumstance 
should this exceed 24 hours, as indicated in Appendix 3. The investigator will submit any 
updated SAE data to the sponsor within 24 hours of it being available.
All SAEs occurring in a participant during the active collection period are reported to Pfizer 
Safety on the CT SAE Report Form.
SAEs occurring in a participant 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 IP must be 
reported to Pfizer Safety.
8.3.1.2. 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.
8.3.2. Method of Detecting AEs and SAEs
The method of recording, evaluating, and assessing causality of AE and SAE and the 
procedures for completing and transmitting SAE reports are provided in Appendix 3.
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences.


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8.3.3. Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. For each event, the investigator must pursue and 
obtain adequate information until resolution, stabilization, the event is otherwise explained, 
or the participant is lost to follow-up (as defined in Section 7.3).
In general, follow-up information 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 participant death, a summary of available 
autopsy findings must be submitted as soon as possible to Pfizer Safety. 
Further information on follow-up procedures is given in Appendix 3.
8.3.4. Regulatory Reporting Requirements for SAEs

Prompt notification by the investigator to the sponsor of a SAE is essential so that 
legal obligations and ethical responsibilities towards the safety of participants and 
the safety of a study intervention under clinical investigation are met.

The sponsor has a legal responsibility to notify both the local regulatory authority 
and other regulatory agencies about the safety of a study intervention under clinical 
investigation. The sponsor will comply with country-specific regulatory 
requirements relating to safety reporting to the regulatory authority, Institutional 
Review Boards (IRB)/Independent Ethics Committees (IEC), and investigators.

Investigator safety reports must be prepared for suspected unexpected serious 
adverse reactions (SUSAR) according to local regulatory requirements and sponsor 
policy and forwarded to investigators as necessary.

An investigator who receives an investigator safety report describing a 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/IEC, if appropriate according to local requirements.
8.3.5. Exposure During Pregnancy or Breastfeeding, and Occupational Exposure
Exposure to the IP under study during pregnancy or breastfeeding and occupational exposure 
are reportable to Pfizer Safety within 24 hours of investigator awareness.
8.3.5.1. Exposure During Pregnancy

Details of all pregnancies in female participants, female partners of male 
participants, female family members, and healthcare providers who have been 
exposed to study intervention will be collected after the start of study intervention 
and until the end of the active collection period.


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
If a pregnancy is reported, the investigator should inform the sponsor within 
24 hours of learning of the pregnancy and should follow the procedures outlined in 
Appendix 4.

Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs.
8.3.5.2. Exposure During Breastfeeding
Scenarios of exposure during breastfeeding must be reported, irrespective of the presence of 
an associated SAE, to Pfizer Safety within 24 hours of the investigator’s awareness, using the 
CT SAE Report Form.  An exposure during breastfeeding report is not created when a Pfizer 
drug specifically approved for use in breastfeeding women (eg, vitamins) is administered in 
accord with authorized use. However, if the infant experiences an SAE associated with such 
a drug’s administration, the SAE is reported together with the exposure during breastfeeding.
8.3.5.3. 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 participant enrolled in the study, the 
information is not recorded on a CRF; however, a copy of the completed CT SAE Report 
Form is maintained in the investigator site file.
8.3.6. Disease-Related Events and/or Disease-Related Outcomes Not Qualifying as AEs
The following disease related events are common in participants with AD:

AD

Eczema

Flare of AD
Because these events are expected in this remitting and relapsing disease, they will not be 
reported as AEs. These events should be documented and recorded on the appropriate CRF 
as occurrence of a flare of AD during the maintenance period represents the efficacy outcome 
measure.
NOTE: However, if either of the following conditions applies, then the event must be 
recorded and reported as an AE:

In the investigator’s opinion, the event is of greater intensity or severity than the 
individual participant’s condition at baseline (Day 1 of the run-in period).


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OR

The investigator considers that there is a reasonable possibility that the event was 
related to study intervention.
8.3.7. Wearable Device Incidents
A wearable device incident is an incident associated with a study device, including any
malfunction or deterioration in the characteristics and/or performance of a device as well as 
any inadequacy in the labeling or the instructions for use which, directly or indirectly, might 
lead to or might have led to the death of a participant/user/other person or to a serious 
deterioration in his/her state of health.
Reporting of wearable device incidents will follow AE and SAE reporting procedures.
NOTE: Incidents fulfilling the definition of an AE/SAE will also follow the processes 
outlined in Section 8.3.3 and Appendix 3 of the protocol.
8.3.8. Medication Errors
Medication errors may result from the administration or consumption of the study 
intervention by the wrong participant, or at the wrong time, or at the wrong dosage strength.
Exposures to the study intervention 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
Medication errors include:

Medication errors involving participant exposure to the study intervention;

Potential medication errors or uses outside of what is foreseen in the protocol that do 
or do not involve the participating participant.
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.


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Medication errors should be reported to Pfizer Safety within 24 hours on a CT SAE Report 
Form only when associated with an SAE.
8.4. Treatment of Overdose
While overdose following topical administration is unlikely, there is a possibility that an 
excess of crisaborole may be applied. If too much crisaborole has been applied, the excess 
can be wiped off. The investigator should monitor participant for any AEs/SAEs.
8.5. Pharmacokinetics
PK parameters are not evaluated in this study.
8.6. Pharmacodynamics
Pharmacodynamic parameters are not evaluated in this study.
8.7. Genetics
Genetics (or specified genetics) are not evaluated in this study.
8.8. Biomarkers
Biomarkers are not evaluated in this study.
8.9. Health Economics OR Medical Resource Utilization and Health Economics
See Section 8.1.6.9 and Section 8.1.6.11 for assessments of EQ-5D and WPAI+CIQ:AD, V2, 
respectively.


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9. STATISTICAL CONSIDERATIONS
9.1. Estimands and Statistical Hypotheses
9.1.1. Estimands
Estimand 1: The primary estimand of the main study is a hypothetical estimand, defined 
according to the primary objective and is in alignment with the primary endpoint. It includes 
the following 4 attributes: 

Population: Participants who are treated with crisaborole 2% BID up to 8 weeks 
and achieve response defined by the criteria;

Variable: Duration of flare-free maintenance up until the onset of the first flare 
during the maintenance period. 

Intercurrent events: If an event (eg, death, dropout, loss to follow up, or end of 
study) occurs before the first flare, the duration of flare-free maintenance is the 
time from randomization to the first intercurrent event and is censored. When a 
flare occurs first, or a prohibited treatment is used before a flare, the duration of 
flare-free maintenance is the time from randomization to the earlier one of first 
flare or a prohibited treatment use and is not censored.

Population-level summary: Median duration of flare-free maintenance during the 
double-blind period, proportion of participants who are flare-free by time point in 
each treatment group.
Estimand 2: The second estimand of the study for the secondary endpoint of number of 
flare-free days during the double-blind period is a hypothetical estimand. It includes the 
following 4 attributes: 

Population: Participants who are treated with crisaborole 2% BID up to 8 weeks 
and achieve response defined by the criteria;

Variable: Flare-free days during the double-blind period. It is the sum of the 
duration of flare-free maintenance of all QD periods during the maintenance
period for each participant.

Intercurrent events: Addressing of events for the duration of flare-free 
maintenance at each QD period is the same as that for the primary endpoint 
during the first QD period.

Population-level summary: Difference in least-square means between crisaborole
ointment, 2%, QD and vehicle QD for flare-free days over 52 weeks.


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Estimand 3: The third estimand of the study for the secondary endpoint of number of flares 
during the double-blind period is a hypothetical estimand. It includes the following 
4 attributes: 

Population: Participants who are treated with crisaborole 2% BID up to 8 weeks 
and achieve response defined by the criteria;

Variable: number of flares during the maintenance period.

Intercurrent events: It will be counted as a flare if a prohibited treatment is used 
during a QD period.

Population-level summary: Median difference between crisaborole ointment, 2%,
QD and vehicle QD for number of flares over 52 weeks.
Estimand 4: The fourth estimand of the study for the secondary endpoint of pruritus response 
maintenance up until the onset of the first flare (ISGA ≥2) is a hypothetical estimand.  It 
includes the following 4 attributes: 

Population: Participants who are treated with crisaborole 2% BID up to 8 weeks 
and achieve pruritus response defined by the criteria;

Variable: Duration of pruritus response maintenance up until the onset of the first 
flare (ISGA ≥2). 

Intercurrent events: If an event (eg, death, prohibited treatment, dropout, first flare
[ISGA ≥2], lost to follow up, or end of study) occurs before loss of pruritus 
response for the first QD period, the duration of pruritus response maintenance is 
the time from randomization to the first intercurrent event and is censored. When 
loss of pruritus response occurs first, the duration of pruritus response 
maintenance is not censored.

Population-level summary: Median duration of pruritus response maintenance up 
until the onset of the first flare during the double-blind period, proportion of 
participants who maintain pruritus response by time point in each treatment 
group.
9.2. Sample Size Determination
A total of 162 events will provide approximately 96% power to detect a 1.8 ratio of median 
time of being flare-free (hazard ratio of 0.556) in the first QD period between crisaborole and 
vehicle at a significance level of 0.05 (2-sided, log-rank test). To get 162 events (first flare), 
approximately 250 participants who are eligible responders will be randomized (ratio=1:1) 
into the double-blind maintenance period of the study. When 162 events are observed, the 
randomization will be stopped even if less than 250 participants are randomized. On the other 
hand, if 250 participants are randomized, but 162 events cannot be reached, more participants 
will be randomized.   


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9.3. Populations for Analyses
For purposes of analysis, the following populations are defined:
Population
Description
Enrolled
All participants who sign the ICF.
Evaluable – Open Label 
(Evaluable-OL)
All participants receiving at least 1 dose of study intervention in the open-
label run-in period
Evaluable – Double-Blind 
(Evaluable-DB)
All randomized participants receiving at least 1 dose of study intervention 
in the double-blind maintenance period. Participants will be analyzed 
according to the intervention they are randomized to.
Safety – Double-Blind 
(Safety-DB)
All participants randomly assigned to study intervention and who take at 
least 1 dose of study intervention in the double-blind maintenance period. 
Participants will be analyzed according to the intervention they actually 
received.
Safety – Double-Blind 
Maintenance Period 
(excluding data from flare 
treatment period) (Safety-QD)
All participants randomly assigned to study intervention and who take at 
least 1 dose of study intervention in the double-blind maintenance period 
(excluding data from the flare treatment period). Participants will be 
analyzed according to the intervention they actually received. Safety data 
from flare treatment periods will be summarized separately.
Safety – flare treatment period 
(Safety-flare)
All participants who receive at least 1 dose of study intervention in the 
flare treatment period during the double-blind maintenance period.
Participants will be analyzed according to the intervention they received in 
QD period.
9.4. Statistical Analyses
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 and key secondary 
endpoints definitions or their analyses will also be reflected in a protocol amendment.
The SAP will be developed and finalized before database lock and will describe the 
participant populations to be included in the analyses, and procedures for accounting for 
missing, unused, and spurious data. This section is a summary of the planned statistical 
analyses of the primary and secondary endpoints.
9.4.1. Efficacy Analyses
9.4.1.1. Testing Procedure for Multiple Comparisons
A step-down closed testing procedure and Bonferroni’s method will be used for Type I error 
control for testing the primary endpoint and the secondary endpoints. The order of testing is 
as follows:
1. Flare-free maintenance up until the onset of the first flare during the maintenance period


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2. Number of flare-free days over 52 weeks
3. Number of flares over 52 weeks
4. Pruritus response maintenance up until the onset of the first flare (ISGA ≥2), defined as 
the maintenance of improvement ≥50%. Analysis will be performed for 5 subgroups: 
a) ≥12 years of age: ≥3 points reduction for responders
b) ≥12 years of age: ≥4 points reduction for responders
c) 6-11 years of age: ≥2 points reduction for responders
d) 3 months-5 years of age: ≥3 points reduction for responders
e) 3 months-5 years of age: ≥4 points reduction for responders
The statistical significance can be claimed for a given endpoint only if the prior endpoint is 
significant. For the endpoints of 1-3, the significance level is 0.05. For pruritus response 
maintenance, Bonferroni’s method is used to adjust the significance level. The significance 
level is 0.01 for each subgroup, there is no testing order. Only the subgroup with p-value 
≤0.01 can claim significance after the primary endpoint and other two secondary endpoints 
are statistically significant.
9.4.1.2. Analysis Methods
Endpoint
Statistical Analysis Methods
Primary
Primary Analysis
Time of flare-free maintenance in the first QD period up until the onset of the first flare 
during the 52-week maintenance period will be analyzed using a log-rank test, stratified 
by age group, duration of the BID treatment in open-label period, and ISGA score (clear 
[0], almost clear [1]) at randomization to test the difference between crisaborole QD 
versus vehicle QD. The proportion of participants maintaining flare-free at each month 
until the first flare onset in the maintenance period will be estimated by the product limit 
method; the median time of flare-free up until the first flare onset will also be estimated 
by this method. This analysis will be based on Estimand 1 using the Evaluable-DB
population (see Section 9.1 and Section 9.3 for estimands and populations).
Sensitivity/Supplementary Analysis
For the above primary analysis, the flare is based on the investigator assessment of ISGA;
time of flare is ISGA assessment time. Before investigator assessment, the flare may 
already have occurred. As a sensitivity analysis, flare is defined as participants reported 
AD worsening event. Analysis method and intercurrent events handling are the same as 
above for the primary analysis.  
Another sensitivity analysis is interval censoring survival analysis. Time of flare is
between the time of participants reported AD worsening and the time of investigator
confirmed ISGA ≥2. This analysis will be based on Estimand 1 using the Evaluable-DB 
population.   
Secondary
Number of flare-free days will be analyzed using an analysis of covariance model, with 
treatment, age, duration of the BID treatment in open-label period, and ISGA score (clear 
[0], almost clear [1]) at randomization as factors. The number of flare-free days is total 
duration across the double-blind QD periods in the study for each participant. This 
analysis will be based on Estimand 2 using the Evaluable-DB population.


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Endpoint
Statistical Analysis Methods
Number of flares, will be analyzed using Wilcoxon rank sum test stratified by age group, 
duration of the BID treatment in open-label period, and ISGA score (clear [0], almost 
clear [1]) at randomization. Participants will be ranked according to the number of flares 
adjusted for length of time in the maintenance period (ie, if participants have same 
number of flares: the participant with longer time in maintenance period will receive a 
higher rank; if participants have the same time in maintenance period as well, the 
participant with longer time in QD period will receive a higher rank; participants who 
prematurely discontinue the study for efficacy reasons will be ranked below others). This 
analysis will be based on Estimand 3 using the Evaluable-DB population.
Time of pruritus response maintenance up until the first flare onset during the 52-week 
maintenance period will be analyzed separately for each age and responders subgroup 
using the same approach as the analysis for the primary endpoint.
For PROs: Dermatology Quality of Life Assessments, POEM, and EASI50 response, 
time of maintaining of each response will be analyzed using the same approach as the 
analysis for the primary endpoint. Dermatology Quality of Life Assessments and POEM 
response maintenance is defined as the response that does not lose more than Minimal 
Clinical Important Difference. EASI50 response maintenance is defined as EASI score
that does not lose more than 50% of achieved reduction from the Day 1/Baseline run-in 
EASI score. This analysis will be based on Estimand 4 using the Evaluable-DB 
population.
Analysis of other secondary endpoints will be summarized in the SAP. 
Additional 
Secondary
Additional secondary endpoints will be descriptively summarized by QD period, flare 
treatment period, and double-blind treatment assignment.  
9.4.2. Safety Analyses
All safety analyses will be performed on the Safety Population.
Endpoint
Statistical Analysis Methods
Primary
AEs, SAEs, local tolerability, discontinuations, and clinically significant changes in vital 
signs will be descriptively summarized and will be presented in tabular and/or graphical 
format by open-label run-in period, flare treatment period in the maintenance period, and 
QD period. No imputation will be made for missing safety data.  
 
 
9.5. Interim Analyses
There is no planned interim analysis.
CCI


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9.5.1. Data Monitoring Committee (DMC)
This study will use a data monitoring committee (DMC). The DMC is independent of the 
study team and includes only external members. The DMC charter describes the role of the 
DMC in more detail.  


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10. SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS
10.1. Appendix 1: Regulatory, Ethical, and Study Oversight Considerations
10.1.1. Regulatory and Ethical Considerations

This study will be conducted in accordance with the protocol and with the 
following:
o
Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines
o
Applicable International Council for Harmonisation (ICH) Good Clinical Practice 
(GCP) Guidelines
o
Applicable laws and regulations, including applicable privacy laws.

The protocol, protocol amendments, ICF, Investigator Brochure, and other relevant 
documents (eg, advertisements) must be reviewed and approved by the sponsor and 
submitted to an IRB/IEC by the investigator and reviewed and approved by the 
IRB/IEC before the study is initiated.

Any amendments to the protocol will require IRB/IEC approval before 
implementation of changes made to the study design, except for changes necessary 
to eliminate an immediate hazard to study participants.

The investigator will be responsible for the following:
o
Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC
o
Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures
o
Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 Code of Federal Regulations (CFR), ICH guidelines, the 
IRB/IEC, European regulation 536/2014 for clinical studies (if applicable), and all 
other applicable local regulations

In the event of any prohibition or restriction imposed (i.e., 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 IP, 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 participants against any 
immediate hazard, and of any serious breaches of this protocol or of ICH GCP that 
the investigator becomes aware of.


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10.1.2. Financial Disclosure
Investigators and sub-investigators will provide the sponsor with sufficient, accurate 
financial information as requested to allow the sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate local regulatory authorities. 
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study.
10.1.3. Informed Consent Process

The investigator or his/her representative will explain the nature of the study to the 
participant or his/her legally authorized representative and answer all questions 
regarding the study.

Participants must be informed that their participation is voluntary. Participants or 
their legally authorized representative will be required to sign a statement of 
informed consent/assent that meets the requirements, where applicable, of 21 CFR 
50, local regulations, ICH guidelines, Health Insurance Portability and 
Accountability Act (HIPAA) requirements, and the IRB/IEC or study center.

The investigator must ensure that each study participant or his or her legally 
authorized representative is fully informed about the nature and objectives of the 
study, the sharing of data related to the study and possible risks associated with 
participation, including the risks associated with the processing of the participant’s 
personal data. The participant must be informed that his/her personal study-related 
data will be used by the sponsor in accordance with local data protection law. The 
level of disclosure must also be explained to the participant.

The participant must be informed that his/her medical records may be examined by 
Clinical Quality Assurance auditors or other authorized personnel appointed by the 
sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory 
authorities.

The investigator further must ensure that each study participant or his or her legally 
authorized representative is fully informed about his or her right to access and 
correct his or her personal data and to withdraw consent/assent for the processing of 
his or her personal data.

The medical record must include a statement that written informed consent/assent 
was obtained before the participant was enrolled in the study and the date the 
written consent/assent was obtained. The authorized person obtaining the informed 
consent/assent must also sign the ICF.

Participants must be re-consented/re-assented to the most current version of the 
ICF(s) during their participation in the study.

A copy of the ICF(s) must be provided to the participant or the participant’s legally 
authorized representative.


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A participant who is rescreened is not required to sign another ICF if the rescreening occurs 
within 28 days from the Day 1 run-in treatment.
 
 
Participants will be told that they are 
free to refuse to participate and may withdraw their consent at any time and for any reason 
during the storage period. 
 
10.1.4. Data Protection
•
All parties will comply with all applicable laws, including laws regarding the 
implementation of organizational and technical measures to ensure protection of 
participant data.
•
Participants’ 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.
•
To protect the rights and freedoms of natural persons with regard to the processing 
of personal data, participants will be assigned a single, participant-specific 
numerical code. Any participant records or datasets that are transferred to the 
sponsor will contain the numerical code; participant names will not be transferred. 
All other identifiable data transferred to the sponsor will be identified by this single, 
participant-specific code. The study site will maintain a confidential list of 
participants who participated in the study, linking each participant’s numerical code 
to his or her actual identity. In case of data transfer, the sponsor will protect the 
confidentiality of participants’ personal data consistent with the Clinical Study 
Agreement and applicable privacy laws.
10.1.5. Dissemination of Clinical Study Data
Pfizer fulfills its commitment to publicly disclose clinical study results through posting the 
results of studies on www.clinicaltrials.gov (ClinicalTrials.gov), the European Clinical Trials 
Database (EudraCT), and/or www.pfizer.com, and other public registries in accordance with 
applicable local laws/regulations.  In addition, Pfizer reports study results outside of the 
requirements of local laws/regulations pursuant to its standard operating procedures (SOPs).
CCI
CCI


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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 
product, regardless of the geographical location in which the study is conducted.  US Basic 
Results are generally submitted for posting within 1 year of the primary completion date 
(PCD) for studies in adult populations or within 6 months of the PCD for studies in pediatric 
populations.
PCD is defined as the date that the final participant 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 pre-specified 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 [CSR] synopses in which any 
data that could be used to identify individual participants have been removed) on 
www.pfizer.com for Pfizer-sponsored interventional studies at the same time the US Basic 
Results document is posted to www.clinicaltrials.gov.
Documents within marketing authorization packages/submissions
Pfizer complies with the European Union Policy 0070, the proactive publication of clinical 
data to the European Medicines Agency (EMA) website.  Clinical data, under Phase 1 of this 
policy, includes clinical overviews, clinical summaries, CSRs, and appendices containing the 
protocol and protocol amendments, sample CRFs, and statistical methods.  Clinical data, 
under Phase 2 of this policy, includes the publishing of individual participant data.  Policy 
0070 applies to new marketing authorization applications submitted via the centralized 
procedure since 01 January 2015 and applications for line extensions and for new indications 
submitted via the centralized procedure since 01 July 2015.
Data Sharing
Pfizer provides researchers secure access to patient-level data or full CSRs for the purposes 
of “bona-fide scientific research” that contribute to the scientific understanding of the 
disease, target, or compound class.  Pfizer will make available data from these trials 


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24 months after study completion.  Patient-level data will be anonymized in accordance with 
applicable privacy laws and regulations.  CSRs will have personally identifiable information 
redacted.
Data requests are considered from qualified researchers with the appropriate competencies to 
perform the proposed analyses.  Research teams must include a biostatistician.  Data will not 
be provided to applicants with significant conflicts of interest, including individuals 
requesting access for commercial/competitive or legal purposes.
10.1.6. Data Quality Assurance

All participant data relating to the study will be recorded on printed or electronic 
CRF unless transmitted to the sponsor or designee electronically (eg, laboratory 
data). The investigator is responsible for verifying that data entries are accurate and 
correct by physically or electronically signing the CRF.

The investigator must maintain accurate documentation (source data) that supports 
the information entered in the CRF.

The investigator must ensure that the CRFs are securely stored at the study site in 
encrypted electronic and/or paper form and are password protected or secured in a 
locked room to prevent access by unauthorized third parties.

The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents. 
This verification may also occur after study completion. 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.

Monitoring details describing strategy (eg, risk-based initiatives in operations and 
quality such as Risk Management and Mitigation Strategies and Analytical 
Risk-Based Monitoring), methods, responsibilities and requirements, including 
handling of noncompliance issues and monitoring techniques (central, remote, or 
on-site monitoring) are provided in the Monitoring Plan.

The sponsor or designee is responsible for the data management of this study 
including quality checking of the data.

Study monitors will perform ongoing source data verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and 
verifiable from source documents; that the safety and rights of participants are being 
protected; and that the study is being conducted in accordance with the currently 
approved protocol and any other study agreements, ICH GCP, and all applicable 
regulatory requirements.

Records and documents, including signed ICFs, pertaining to the conduct of this 
study must be retained by the investigator for 15 years after study completion unless 
local regulations or institutional policies require a longer retention period. No 


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records may be destroyed during the retention period without the written approval of 
the sponsor. No records may be transferred to another location or party without 
written notification to the sponsor. The investigator must ensure that the records 
continue to be stored securely for so long as they are maintained.

When participant data are to be deleted, the investigator will ensure that all copies 
of such data are promptly and irrevocably deleted from all systems.

The investigator(s) will notify sponsor or its agents immediately of any regulatory 
inspection notification in relation to the study.  Furthermore, the investigator will 
cooperate with sponsor or its agents to prepare the investigator site for the 
inspection and will allow sponsor 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 participant's 
medical records.  The investigator will promptly provide copies of the inspection 
findings to sponsor or its agent.  Before response submission to the regulatory 
authorities, the investigator will provide sponsor or its agents with an opportunity to 
review and comment on responses to any such findings.
10.1.7. Source Documents

Source documents provide evidence for the existence of the participant and 
substantiate the integrity of the data collected. Source documents are filed at the 
investigator’s site.

Data reported on the CRF or entered in the CRF that are transcribed from source 
documents must be consistent with the source documents or the discrepancies must 
be explained. The investigator may need to request previous medical records or 
transfer records, depending on the study. Also, current medical records must be 
available.

Definition of what constitutes source data can be found in the Monitoring Plan.
10.1.8. Study and Site Closure
The sponsor designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study 
supplies have been collected and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time upon notification to the clinical 
research organization if requested to do so by the responsible IRB/IEC or if such termination 
is required to protect the health of Study Participants.


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Reasons for the early closure of a study site by the sponsor may include but are not limited 
to:

Failure of the investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the sponsor's procedures, or GCP guidelines

Inadequate recruitment of participants by the investigator

Discontinuation of further study intervention development
Study termination is also provided for in the clinical study agreement.  If there is any conflict 
between the contract and this protocol the contract will control as to termination rights.
10.1.9. Publication Policy

The results of this study may be published or presented at scientific meetings by the 
Investigator after publication of the overall study results or one year after end of the 
study (or study termination), whichever comes first. 

The investigator agrees to refer to the primary publication in any subsequent 
publications such as secondary manuscripts, and submit all manuscripts or abstracts 
to the sponsor 30 days before submission. This allows the sponsor to protect 
proprietary information and to provide comments and the Investigator will, on 
request, remove any previously undisclosed confidential information before 
disclosure, except for any study- or Pfizer intervention-related information 
necessary to the appropriate scientific presentation or understanding of the study 
results.

For all publications relating to the study, the Investigator will comply with 
recognized ethical standards concerning publications and authorship, including 
those established by the International Committee of Medical Journal Editors.

The sponsor will comply with the requirements for publication of the overall study 
results covering all Investigator sites. In accordance with standard editorial and 
ethical practice, the sponsor will support publication of multicenter studies only in 
their entirety and not as individual site data. In this case, a coordinating investigator 
will be designated by mutual agreement.

Authorship of publications for the overall study results will be determined by 
mutual agreement and in line with International Committee of Medical Journal 
Editors authorship requirements.

If publication is addressed in the clinical study agreement, the publication policy set 
out in this section will not apply.
10.1.10. 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. 


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To facilitate access to appropriately qualified medical personnel on study-related medical 
questions or problems, participants are provided with a contact card.  The contact card 
contains, at a minimum, protocol and IP identifiers, participant 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 participant’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.  For sites other than 
a Pfizer Clinical Research Unit, the contact number is not intended for use by the participant 
directly, and if a participant calls that number, he or she will be directed back to the 
investigator site.


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10.2. Appendix 2: Clinical Laboratory Tests
The tests detailed in Table 7 will be performed by a central laboratory. Urine pregnancy test 
will be performed at the site, with test kits provided by the central laboratory.

Local laboratory results can be used for medical decision making if the central 
laboratory results are not available in time. The local laboratory reports must be kept 
in source documents and made available for medical review as required. It is 
important that the sample for central analysis is obtained at the same time.

Protocol-specific requirements for inclusion or exclusion of participants are detailed 
in Section 5 of the protocol.

Additional tests may be performed at any time during the study as determined 
necessary by the investigator or required by local regulations.

Pregnancy Testing 
o
Refer to Section 5.1 Inclusion Criteria for screening pregnancy criteria.
Table 7.
Protocol-Required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
Platelet Count
Red blood cell (RBC) Count
Hemoglobin
Hematocrit
White blood cell (WBC) count (% and absolute:
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
Clinical Chemistry
Albumin 
Blood urea nitrogen (BUN)
Potassium
Alanine Aminotransferase (ALT) 
Alkaline phosphatase 
Total bilirubin
Aspartate Aminotransferase (AST) 
Total Protein 
Calcium
Sodium
Creatinine
Chloride
Glucose (non-fasting)
Bicarbonate or total CO2
Note: During the study, if any ALT, AST, total bilirubin, or creatinine value is ≥30% 
higher than the baseline value at screening, a repeat clinical laboratory sample must be 
collected and analyzed by the central laboratory and the event must be followed until 
resolution. 
Urine Pregnancy

For all WOCBP: Test kit (dipsticks) provided by the central laboratory. The results
of the urine dipstick test must be recorded in the source document and made 
available for study review.
Other Tests

Follicle-stimulating hormone (only for post-menopausal status confirmation at 
screening)

Serum beta human chorionic gonadotropin (β-hCG) pregnancy test (for all 
WOCBP at screening, and for pregnancy status confirmation if urine dipstick 
pregnancy test is positive or if a urine dipstick test cannot be confirmed as negative 
[eg, an ambiguous result])
Investigators must document their review of each laboratory safety report.


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Table 8.
Maximum Blood Volume by Test Parameter
Test Parameter
Volume (mL)
Serum Pregnancy Test (-hCG), if applicable
1.1
Hematology
1.2
Serum Chemistry
1.1
Follicle-Stimulating Hormone, if applicable
2.0


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10.3. Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
10.3.1. Definition of AE
AE Definition

An AE is any untoward medical occurrence in a patient or clinical study 
participant, temporally associated with the use of study intervention, whether or not 
considered related to the study intervention.

NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) 
temporally associated with the use of study intervention.
Events Meeting the AE Definition

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) 
or other safety assessments (eg, electrocardiogram, radiological scans, vital signs 
measurements), including those that worsen from baseline, considered clinically 
significant in the medical and scientific judgment of the investigator (ie, not related 
to progression of underlying disease).

Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. Overdose per se will not be reported as 
an AE/SAE unless it is an intentional overdose taken with possible suicidal/self-
harming intent. Such overdoses should be reported regardless of sequelae.

“Lack of efficacy” or “failure of expected pharmacological action” per se will not 
be reported as an AE or SAE. Such instances will be captured in the efficacy 
assessments. However, the signs, symptoms, and/or clinical sequelae resulting from 
lack of efficacy will be reported as AE or SAE if they fulfil the definition of an AE 
or SAE.

The signs, symptoms, and/or clinical sequelae resulting from lack of efficacy will 
be reported as AE or SAE if they fulfil the definition of an AE or SAE. Also, “lack 
of efficacy” or “failure of expected pharmacological action” also constitutes an AE 
or SAE.


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Events NOT Meeting the AE Definition

Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition.

The disease/disorder being studied or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the 
participant’s condition.

Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that 
leads to the procedure is the AE.

Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) 
present or detected at the start of the study that do not worsen.
10.3.2. Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (eg, hospitalization for signs/symptoms of the disease under study, death 
due to progression of disease).
A SAE is defined as any untoward medical occurrence that, at any dose:
a.
Results in death
b.
Is life-threatening
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, which 
hypothetically might have caused death, if it were more severe.
c.
Requires inpatient hospitalization or prolongation of existing hospitalization
In general, hospitalization signifies that the participant has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate in the physician’s office or 
outpatient setting. Complications that occur during hospitalization are AEs. If a 
complication prolongs hospitalization or fulfills any other serious criteria, the event is 
serious. When in doubt as to whether “hospitalization” occurred or was necessary, the AE 
should be considered serious.
Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
baseline is not considered an AE.
d.
Results in persistent disability/incapacity

The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.

This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, 


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influenza, and accidental trauma (eg, sprained ankle) which may interfere with or 
prevent everyday life functions but do not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect
f.
Other situations:

Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that 
may not be immediately life-threatening or result in death or hospitalization but 
may jeopardize the participant or may require medical or surgical intervention to 
prevent one of the other outcomes listed in the above definition. These events 
should usually be considered serious.
Examples of such events include invasive or malignant cancers, 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.
10.3.3. Recording and Follow-Up of AE and/or SAE
AE and SAE Recording/Reporting
The table below summarizes the requirements for recording adverse events on the CRF 
and for reporting serious adverse events on the Clinical Trial 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 IP under study during 
pregnancy or breastfeeding, and occupational exposure.  
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
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 IP under 
study during pregnancy 
or breastfeeding, and 
occupational exposure
None
All (And exposure during 
pregnancy [EDP]
supplemental form for EDP)  


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
When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory reports, and diagnostics 
reports) related to the event.

The investigator will then record all relevant AE/SAE information in the CRF.

It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to Pfizer Safety in lieu of completion of the AE/SAE CRF page.

There may be instances when copies of medical records for certain cases are 
requested by Pfizer Safety. In this case, all participant identifiers, with the 
exception of the participant number, will be redacted on the copies of the medical 
records before submission to Pfizer Safety.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not 
the individual signs/symptoms) will be documented as the AE/SAE.
Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and assign it to 1 of the following categories:

Mild: An event that is easily tolerated by the participant, causing minimal 
discomfort and not interfering with everyday activities.

Moderate: An event that causes sufficient discomfort and interferes with normal 
everyday activities.

Severe: An event that prevents normal everyday activities. An AE that is assessed 
as severe should not be confused with a SAE. Severe is a category utilized for 
rating the intensity of an event; and both AEs and SAEs can be assessed as severe.
An event is defined as ‘serious’ when it meets at least 1 of the predefined outcomes 
as described in the definition of an SAE, NOT when it is rated as severe.
Assessment of Causality

The investigator is obligated to assess the relationship between study intervention 
and each occurrence of each AE/SAE.

A “reasonable possibility” of a relationship conveys that there are facts, evidence, 
and/or arguments to suggest a causal relationship, rather than a relationship cannot 
be ruled out.

The investigator will use clinical judgment to determine the relationship.

Alternative causes, such as underlying disease(s), concomitant therapy, and other 
risk factors, as well as the temporal relationship of the event to study intervention 
administration will be considered and investigated.

The investigator will also consult the Investigator’s Brochure (IB) and/or Product 
Information, for marketed products, in his/her assessment.


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
For each AE/SAE, the investigator must document in the medical notes that he/she 
has reviewed the AE/SAE and has provided an assessment of causality.

There may be situations in which an SAE has occurred and the investigator has 
minimal information to include in the initial report to Pfizer Safety. However, it is 
very important that the investigator always make an assessment of causality 
for every event before the initial transmission of the SAE data to Pfizer Safety.

The investigator may change his/her opinion of causality in light of follow-up
information and send a SAE follow-up report with the updated causality 
assessment.

The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.

If the investigator does not know whether or not the IP caused the event, then the 
event will be handled as “related to IP” for reporting purposes, as defined by the 
sponsor" and "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.
Follow-up of AEs and SAEs

The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by Pfizer 
Safety to elucidate the nature and/or causality of the AE or SAE as fully as 
possible. This may include additional laboratory tests or investigations, 
histopathological examinations, or consultation with other health care 
professionals.

If a participant dies during participation in the study or during a recognized follow-
up period, the investigator will provide Pfizer Safety with a copy of any 
post-mortem findings including histopathology.

New or updated information will be recorded in the originally completed CRF.

The investigator will submit any updated SAE data to the sponsor within 24 hours 
of receipt of the information.


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10.3.4. Reporting of SAEs
SAE Reporting to Pfizer Safety via an Electronic Data Collection Tool

The primary mechanism for reporting an SAE to Pfizer Safety will be the electronic 
data collection tool.

If the electronic system is unavailable, then the site will use the paper SAE data 
collection tool (see next section) in order to report the event within 24 hours.

The site will enter the SAE data into the electronic system as soon as it becomes 
available.

After the study is completed at a given site, the electronic data collection tool will 
be taken off-line to prevent the entry of new data or changes to existing data.

If a site receives a report of a new SAE from a study participant or receives updated 
data on a previously reported SAE after the electronic data collection tool has been 
taken off-line, then the site can report this information on a paper SAE form (see 
next section) or to Pfizer Safety by telephone.

Contacts for SAE reporting can be found in the investigator site file.
SAE Reporting to Pfizer Safety via Paper CRF

Facsimile transmission of the SAE paper CRF is the preferred method to transmit 
this information to Pfizer Safety.

In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by 
overnight mail or courier service.

Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames.

Contacts for SAE reporting can be found in the investigator site file.


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10.4. Appendix 4: Contraceptive Guidance and Collection of Pregnancy Information
Definitions:
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming post-menopausal 
unless permanently sterile (see below).
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot 
be confirmed before first dose of study intervention, additional evaluation should be 
considered.
Women in the following categories are not considered WOCBP
1. Premenarchal
2. Premenopausal female with 1 of the following:

Documented hysterectomy

Documented bilateral salpingectomy

Documented bilateral oophorectomy
For individuals with permanent infertility due to an alternate medical cause other than 
the above, (eg, mullerian agenesis, androgen insensitivity), investigator discretion 
should be applied to determining study entry.
Note: Documentation for any of the above conditions can come from the site 
personnel’s review of the participant’s medical records, medical examination, or 
medical history interview. The method of documentation should be recorded in the 
participant’s medical record for the study.
3. Postmenopausal female

A postmenopausal state is defined as age 60 or older or no menses for 12 months 
without an alternative medical cause.

A high follicle-stimulating hormone level in the postmenopausal range 
may be used to confirm a postmenopausal state in women not using 
hormonal contraception or hormonal replacement therapy (HRT).

Females on HRT and whose menopausal status is in doubt will be required to use 
one of the non-estrogen hormonal highly effective contraception methods if they 
wish to continue their HRT during the study. Otherwise, they must discontinue 
HRT to allow confirmation of postmenopausal status before study enrollment.


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Contraception Guidance:
CONTRACEPTIVESa ALLOWED DURING THE STUDY INCLUDE:
Highly Effective Methodsb That Have Low User Dependency Failure rate of <1% per year when used 
consistently and correctly.
1. Implantable progestogen-only hormone contraception associated with inhibition of ovulationb
2. Intrauterine device (IUD)
3. Intrauterine hormone-releasing system (IUS) b
4. Bilateral tubal occlusion
5. Vasectomized partner
(Vasectomized partner is a highly effective contraceptive method provided that the partner is the sole 
sexual partner of the woman of childbearing potential and the absence of sperm has been confirmed. If 
not, an additional highly effective method of contraception should be used. Spermatogenesis cycle is 
approximately 90 days.)
Highly Effective Methodsb That Are User Dependent Failure rate of <1% per year when used 
consistently and correctly.
6. Combined (estrogen- and progestogen-containing) hormonal contraception associated with inhibition of 
ovulationc

oral

intravaginal

transdermal

injectable
7. Progestogen-only hormone contraception associated with inhibition of ovulationc

oral

injectable
8. Sexual abstinence
(Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual 
intercourse during the entire period of risk associated with the study intervention. The reliability of 
sexual abstinence needs to be evaluated in relation to the duration of the study and the preferred and 
usual lifestyle of the participant.)
ACCEPTABLE METHODSd
9. Progestogen-only oral hormonal contraception where inhibition of ovulation is not the primary mode of 
action
10. Male or female condom with or without spermicidee
11. Cervical cap, diaphragm, or sponge with spermicide
12. A combination of male condom with either cervical cap, diaphragm, or sponge with spermicide (double-
barrier methods)c
a) Contraceptive use by men or women should be consistent with local regulations regarding the use of 
contraceptive methods for those participating in clinical studies.
b) Failure rate of <1% per year when used consistently and correctly. Typical use failure rates differ from 
those when used consistently and correctly.
c)
If locally required, in accordance with Clinical Trial Facilitation Group (CTFG) guidelines, acceptable 
contraceptive methods are limited to those which inhibit ovulation as the primary mode of action.
d) Considered effective, but not highly effective - failure rate of ≥1% per year.  Periodic abstinence 
(calendar, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), spermicides only, and 
lactational amenorrhoea method (LAM) are not acceptable methods of contraception. 
e) Male condom and female condom should not be used together (due to risk of failure with friction).


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Collection of Pregnancy Information:
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 IP; or the 
female becomes or is found to be pregnant after discontinuing and/or being exposed 
to the IP;

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 IP prior to or around the time of conception and/or is exposed during his 
partner’s pregnancy. 
If a participant or participant’s partner becomes or is found to be pregnant during the 
participant’s treatment with the IP, 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 participant reports 
that she is pregnant and has been exposed to a cytotoxic product by inhalation or spillage) to 
Pfizer Safety using the EDP supplemental form.  This must be done irrespective of whether 
an AE has occurred and within 24 hours of awareness of the exposure.  The information 
submitted should include the anticipated date of delivery (see below for information related 
to termination of pregnancy).
Follow-up is conducted to obtain general information on the pregnancy and its outcome for 
all EDP reports with an unknown outcome.  The investigator will follow the pregnancy until 
completion (or until pregnancy termination) and notify Pfizer Safety of the outcome as a 
follow-up to the initial EDP supplemental form.  In the case of a live birth, the structural 
integrity of the neonate can be assessed at the time of birth.  In the event of a termination, the 
reason(s) for termination should be specified and, if clinically possible, the structural 
integrity of the terminated fetus should be assessed by gross visual inspection (unless pre-
procedure test findings are conclusive for a congenital anomaly and the findings are 
reported).
If the outcome of the pregnancy meets the criteria for an SAE (i.e., 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;


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
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 IP.
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 participant with the Pregnant Partner Release of Information Form to deliver 
to his partner.  The investigator must document in the source documents that the participant 
was given the Pregnant Partner Release of Information Form to provide to his partner.


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10.5. Appendix 5: Liver Safety: Suggested Actions and Follow-up Assessments
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 participants, transaminase elevations are a harbinger of a 
more serious potential outcome.  These participants fail to adapt and therefore are 
"susceptible" to progressive and serious liver injury, commonly referred to as drug-induced 
liver injury (DILI).  Participants 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 (i.e., 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 
participant’s individual baseline values and underlying conditions.  Participants who present 
with the following laboratory abnormalities should be evaluated further as potential DILI 
(Hy’s law) cases to definitively determine the etiology of the abnormal laboratory values:

Participants 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 participants 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:
o
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).
o
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 Hepatic Injury 
Council (HIC) should be informed if such a situation occurs during the study; the HIC will 
provide the necessary support to the study team. The participant should return to the 


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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 for suspected cases of 
Hy’s Law, additional 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, and alkaline phosphatase. 
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) and collection of serum sample for acetaminophen drug and/or protein 
adduct levels may be warranted.
All cases demonstrated on repeat testing as meeting the laboratory criteria of AST/ALT and 
TBili elevation defined above should be considered potential DILI (Hy’s law) cases if no 
other reason for the liver function test (LFT) abnormalities has yet been found.  Such 
potential DILI (Hy’s law) cases are to be reported as SAEs, irrespective of availability 
of all the results of the investigations performed to determine etiology of the LFT 
abnormalities.  
A potential DILI (Hy’s law) case becomes a confirmed case only after all results of 
reasonable investigations have been received and have excluded an alternative etiology.


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10.6. Appendix 6: Hanifin and Rajka’s Diagnostic Criteria for Atopic Dermatitis33
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 immunoglobulin E
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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10.8. Appendix 8: Country-Specific Requirements
Enrollment for participants 3 months of age and older will be open to all participating sites, 
except for those in Europe (Austria, France, and Spain), where a separate pediatric 
crisaborole study is planned in participants 1 month to <24 months of age (C3291031). Sites 
in Austria, France, and Spain will continue to enroll participants 2 years of age and older.


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10.9. Appendix 9: Alternative Study Procedures during COVID-19 Pandemic
In response to the COVID-19 pandemic, associated local or regional travel restrictions, and 
public health concerns, the following changes were incorporated into this protocol to clarify 
study procedures during the COVID-19 pandemic.  These changes apply to the time period 
of the COVID-19 pandemic only when an in-clinic visit is not possible; after this time period 
normal study procedures should resume.  

In the event that the in-clinic study visits cannot be conducted, every effort should be 
made to follow-up on the safety of study participants by phone contact at the scheduled 
or unscheduled visits per the protocol Schedule of Activities. Video contact can be used 
if permitted by local regulations. During the phone (or video) contact, the following 
assessments should be performed:
a.
Review and record study treatment including compliance and missed doses.
b. Review and record any AEs and SAEs since last contact, including but not limited 
to COVID-19 related events. The AE and SAE reporting process should be 
followed per protocol (Section 8.3 and Appendix 3).
c.
Review and record contraceptive method and results of urine pregnancy tests for 
female participants who are women of childbearing potential (See protocol 
Appendix 4). 
d. Review and record any changes or new concomitant medications since last 
contact. 
e.
Record the review of the Bodymap with the participants, including information on 
any new lesions, and collect the Bodymaps in the participant’s medical record 
when possible (See protocol Section 8.1.4). 
f.
Review eDiary for completion. 
Note: For the participant to be randomized into the double-blind maintenance period of 
the study, the Randomization Day 1 visit must be an in-person visit with study site staff, 
which could be conducted as an in-home visit or an in-person visit at an alternative clinic, 
provided that these are permitted according to local regulations. 

If courier delivery of the study medication from study sites is allowable by law and local 
guidance, the study participants must provide verbal consent for providing the contact 
details for shipping purposes. The verbal consent should be documented in the source 
document. Tracking records of shipment including the chain of custody of the study 
medication must be kept in the participant’s medical records. 

If the sponsor determines that the impact of COVID-19 on protocol visits and procedures 
and associated timeframe needs to be reported on a CRF, this will be requested. 


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10.10. Appendix 10: Abbreviations
The following is a list of abbreviations that may be used in the protocol.
Abbreviation
Term
β-hCG
beta human chorionic gonadotropin
AD
atopic dermatitis
AE
adverse event
ALT
alanine aminotransferase
ANCOVA
analysis of covariance
AST
aspartate aminotransferase
AUC
area under the plasma concentration-time curve
BID
twice daily
BPO
benzoyl peroxide
BSA
body surface area
CCL
chemokine (C-C motif) ligand 
CDLQI
Children’s Dermatology Life Quality Index
CFR
Code of Federal Regulations
CIOMS
Council for International Organizations of Medical Sciences
COVID-19
Coronavirus Disease 2019
CK
creatine kinase
CONSORT
Consolidated Standards of Reporting Trials
C-SSRS
Columbia Suicide Severity Rating Scale
Cmax
maximum observed plasma concentration
CRF
case report form
CSR
clinical study report
CT
clinical trial
CTFG
Clinical Trial Facilitation Group
DILI
drug-induced liver injury
DLQI
Dermatology Life Quality Index
DMC
data monitoring committee 
EASI
Eczema Area and Severity Index


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Abbreviation
Term
EASI50
≥50% improvement in Eczema Area and Severity Index score
eDiary
electronic diary
EDP
exposure during pregnancy
EMA
European Medicines Agency
EQ-5D-5L
EuroQol-5 Dimensions-5 Levels
ED-5D-Y
EuroQol-5 Dimensions-Youth
EORI
end of run-in
EOS
end of study
EU
European Union
EudraCT
European Clinical Trials Database
Evaluable-DB
Evaluable – Double-Blind
Evaluable-OL
Evaluable – Open-Label
FDA
Food and Drug Administration
GCP
Good Clinical Practice
GGT
Gamma-glutamyl transferase
HADS
Hospital Anxiety and Depression Scale
HIC
Hepatic Injury Council
HIPAA
Health Insurance Portability and Accountability Act
HRT
hormone replacement therapy
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Council for Harmonisation
IEC
independent ethics committee
IDQoL
Infant’s Dermatitis Quality of Life Index
IFN
interferon
IL
interleukin
IMP
investigational medicinal product
IND
investigational new drug application
INR
international normalized ratio
IP
investigational product


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Abbreviation
Term
IRB
institutional review board
IRT
interactive response technology
ISGA
Investigator’s Static Global Assessment
IUD
intrauterine device
IUS
intrauterine hormone-releasing system
LAM
lactational amenorrhoea method
LFT
liver function test
MMF
mycophenolate mofetil
MOS
Medical Outcomes Study
NIMP
non-investigational medicinal product
NRS
numerical rating scale
OGIC
Observer Reported Global Impression of Change
OGIS
Observer Reported Global Impression of Severity
PCD
primary completion date
PDE-4
phosphodiesterase 4
PGIC
Patient Global Impression of Change
PGIS
Patient Global Impression of Severity
PK
pharmacokinetic(s)
POEM
Patient Oriented Eczema Measure
PP-NRS
Peak Pruritus Numerical Rating Scale
PRN
as needed
PRO
patient reported outcome
PT
prothrombin time
QD
once daily
QoL
quality of life
SAE
serious adverse event
Safety-DB
Safety – Double-blind
Safety-flare
Safety – flare treatment period
Safety-QD
Safety – Double-Blind Maintenance Period (excluding data from 
flare treatment period)


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Abbreviation
Term
SAP
statistical analysis plan
SoA
schedule of activities
SRSD
single reference safety document
SUSAR
suspected unexpected serious adverse reactions
TBili
total bilirubin
TCI
topical calcineurin inhibitor
TCS
topical corticosteroid
t1/2
half-life
Tmax
time to reach maximum observed plasma concentration
ULN
upper limit of normal
US
United States
UV
ultraviolet
WASO
wake after sleep onset
WOCBP
women of childbearing potential
WPAI+CIQ:AD, V2
Work Productivity and Activity Impairment Questionnaire plus 
Classroom Impairment Questions: Atopic Dermatitis, Version 2


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SAP_001.pdf: 
Protocol C3291035 (Crisaborole; PF-06930164) Statistical Analysis Plan
PFIZER CONFIDENTIAL
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Protocol C3291035
A PHASE 3, RANDOMIZED, DOUBLE-BLIND, VEHICLE CONTROLLED STUDY 
TO EVALUATE THE EFFICACY AND SAFETY OF MAINTENANCE 
TREATMENT AND FLARE REDUCTION WITH CRISABOROLE OINTMENT, 
2%, ONCE DAILY OVER 52 WEEKS IN PEDIATRIC AND ADULT 
PARTICIPANTS (AGES 3 MONTHS AND OLDER) WITH MILD-TO-MODERATE 
ATOPIC DERMATITIS, WHO RESPONDED TO TWICE DAILY CRISABOROLE 
OINTMENT, 2%, TREATMENT
Statistical Analysis Plan 
(SAP)
Version:
4
Date:
20 January 2022


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TABLE OF CONTENTS
TABLE OF CONTENTS...........................................................................................................2
LIST OF TABLES.....................................................................................................................4
LIST OF FIGURES ...................................................................................................................4
1. VERSION HISTORY............................................................................................................5
2. INTRODUCTION .................................................................................................................8
2.1. Study Objectives, Endpoints, and Estimands............................................................8
2.1.1. Estimand 1 for the Primary Endpoint .........................................................11
2.1.2. Estimands for Secondary Endpoints...........................................................11
2.2. Study Design ...........................................................................................................13
3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND
CONVENTIONS ................................................................................................................14
3.1. Primary Endpoint ....................................................................................................14
3.2. Secondary Endpoints...............................................................................................14
3.2.1. Key Secondary Endpoints...........................................................................14
3.2.2. Other Secondary Endpoints........................................................................15
3.3. Additional Secondary Endpoints.............................................................................15
3.3.1. Efficacy Endpoints......................................................................................15
3.3.2. Patient Reported Outcome Endpoints.........................................................16
3.5. Baseline Variables...................................................................................................16
3.6. Safety Endpoints .....................................................................................................17
3.6.1. Adverse Events ...........................................................................................17
3.6.2. Laboratory Data..........................................................................................18
3.6.3. Vital Signs ..................................................................................................18
3.6.4. Physical Examinations................................................................................18
4. ANALYSIS SETS (POPULATIONS FOR ANALYSIS)...................................................19
5. GENERAL METHODOLOGY AND CONVENTIONS....................................................19
5.1. Hypotheses and Decision Rules ..............................................................................19
5.1.1. Statistical Decision Rules for Multiple Comparisons.................................19
5.2. General Methods .....................................................................................................20
5.2.1. Analyses for Binary Data............................................................................20
5.2.2. Analyses for Continuous Data....................................................................20
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5.2.3. Analyses for Categorical Data....................................................................21
5.2.4. Analyses for Time-to-Event Data...............................................................21
5.3. Methods to Manage Missing Data ..........................................................................21
6. ANALYSES AND SUMMARIES ......................................................................................21
6.1. Primary Endpoint ....................................................................................................21
6.1.1. Main Analysis.............................................................................................21
6.1.2. Sensitivity/Supplementary Analysis...........................................................22
6.2. Key Secondary Endpoints .......................................................................................22
6.2.1. Number of Flare-Free Days........................................................................22
6.2.2. Total Number of Flares...............................................................................22
6.2.3. Maintenance of Pruritus Response until Onset of First Flare (ISGA 
ı2) ..................................................................................................................23
6.3. Other Secondary Endpoints.....................................................................................24
6.3.1. Maintenance of EASI Response .................................................................24
6.3.2. Maintenance of Dermatology Quality of Life Assessments.......................25
6.3.3. Maintenance of Patient Oriented Eczema Measure (POEM).....................25
6.3.4. Endpoints during Flare Treatment Period...................................................26
6.4. Additional Secondary Endpoints.............................................................................27
6.4.1. EASI ...........................................................................................................27
6.4.2. ISGA...........................................................................................................27
6.4.3. Treatable AD %BSA ..................................................................................28
6.4.4. Most Commonly Affected AD %BSA .......................................................28
6.4.5. Duration of Flare-free periods ....................................................................29
6.4.6. Patient Reported Outcome Endpoints.........................................................29
6.5. Subset Analyses.......................................................................................................30
6.6. Baseline and Other Summaries and Analyses.........................................................30
6.6.1. Baseline Summaries....................................................................................30
6.6.2. Study Conduct and Participant Disposition................................................31
6.6.3. Study Intervention Compliance..................................................................31
6.6.4. Concomitant Medications and Nondrug Treatments..................................31
6.7. Safety Summaries and Analyses .............................................................................31
6.7.1. Adverse Events ...........................................................................................31
6.7.2. Laboratory Data..........................................................................................32


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6.7.3. Vital Signs ..................................................................................................32
6.7.4. Physical Examination .................................................................................32
7. INTERIM ANALYSES.......................................................................................................32
7.1.1. Data Monitoring Committee.......................................................................32
8. REFERENCES ....................................................................................................................33
9. APPENDICES .....................................................................................................................34
Appendix 1:
Summary of Efficacy Endpoints .......................................................34
Appendix 2:
Definition and Use of Visit Windows in Reporting ..........................35
Appendix 3:
Examples of Summary Table Shells for DB Period..........................38
Appendix 4:
Listing of Abbreviations....................................................................39
LIST OF TABLES
Table 1.
Summary of Major Changes in SAP Amendments ....................................5
Table 2.
Study Objectives and Endpoints.................................................................8
LIST OF FIGURES
Figure 1.
Study Design Schematic...........................................................................14


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1. VERSION HISTORY
This SAP for Study C3291035 is based on the protocol Amendment 1 dated 19MAY2020.
Table 1.
Summary of Major Changes in SAP Amendments
Version/Date
Associated 
Protocol 
Amendment
Specific Changes
Rationale
1
13Jun2019
Original
04Apr2019
Not Applicable
Not Applicable
2
17July2020
Amendment 1
19May2020
The age of the study 
participant population was 
extended to 3 months of 
age and older.
It was clarified that to yield 
a total of 162 first flares in 
the double-blind 
maintenance period of the 
study, it is estimated that 
approximately 700 
participants will be 
enrolled in the open-label 
period for responder
identification and that 250 
participants will be 
randomized into the 
double-blind maintenance 
period. It is possible that 
less than 700 or up to 860 
participants will be 
enrolled in the open-label 
period.
Sensitivity/supplementary 
analyses for the primary
analysis were added.
“Analysis Set” was 
changed as Analysis 
Population;
Population definitions were 
Per protocol Amendment 1.
Per Pfizer’s new template 
and guidance for estimand


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modified;
Estimands were updated.
Separate listings and/or 
summaries may be 
produced for participants 
who are impacted by 
COVID-19, have protocol 
deviations, discontinue 
from study or study 
treatment due to the 
COVID-19 pandemic.
Appendix 3 Listing of 
Abbreviations was added.  
Some editorial changes.
COVID-19 pandemic.
3
23Sep2021
Amendment 1
19May2020
For POEM and 
Dermatology Quality of 
Life Assessments during 
open-label period:

No change from 
baseline

Modify to weekly
analyses
Additional significant 
changes are:

Removed 
maintenance 
IDQoL response

Only participants 
with ISGA success 
and EASI50 at 
randomization be 
included in the 
Evaluable-DB
population.

Annualized data 
analysis for total 

Almost all subjects 
have no baseline 
data.

Data were collected 
weekly.

MCID is not 
available for IDQoL

Based on 
randomization 
criteria

Take early


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flare-free days and 
number of flares as 
primary analysis

Treat duration of 
per flare period and 
duration of per QD
period as 
continuous
endpoints, not as 
time-to-event

Additional 
summary for overall 
DB period for 
efficacy/PRO 
endpoints

LOCF data will be 
used for OL period 
efficacy summary.

Added additional 
age subgroup 
analyses for 
primary and key 
secondary efficacy 
endpoints, 
evaluation and 
disposition groups, 
demographic and 
baseline 
characteristics, AE 
data
discontinuation into 
consideration

May have too many 
censor data

Provide 
efficacy/PRO 
summary for overall 
DB period

Based on study 
design (ie, 
responders at any
time during OL
period will be 
randomized into the 
DB period)

Per Article 46 
requirement
4
20Jan2022
Amendment 1
19May2020

Summary of vital 
signs (including 
height and weight) 
and physical exam 
was removed

Added safety 
population for OL 

Team decision

For convenience
and consistency
among safety tables


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period and overall 
study.

Removed subgroup 
analysis by age
groups 3 - <24 
months, 2 - <12 
years, 12 - <18 
years, and ≥18
years

Removed subgroup 
analysis for key 
secondary endpoint 
maintenance of 
pruritus response.

Removed 
sensitivity analysis 
for number of flare-
free days and 
number of flares 
(annualized data)

Prohibited 
treatment use was 
removed from 
intercurrent events

Article 46 no longer 
apply

There are already 5 
subgroups for
maintenance of 
pruritus response. 
Sample size will be 
too small and may 
not get robust 
results by further 
subgroup analysis.

Observed data are 
more appropriate.

Difficult to identify 
prohibited 
medication 
specifically used for 
AD.
2. INTRODUCTION
This statistical analysis plan (SAP) provides the detailed methodology for summary and 
statistical analyses of the data collected in Study C3291035.  This document may modify the 
plans outlined in the protocol; however, any major modifications of the primary endpoint 
definition or its analysis will also be reflected in a protocol amendment.
2.1. Study Objectives, Endpoints, and Estimands
Study objectives and corresponding endpoints are provided in the Table 2 below.
Table 2.
Study Objectives and Endpoints
Objectives
Endpoints


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Primary

Efficacy: To evaluate the long-term 
efficacy of crisaborole ointment, 
2%, once daily (QD) for maintenance 
therapy and flare reduction in 
pediatric and adult participants 
≥3 months of age with mild-to-
moderate atopic dermatitis (AD) who 
responded to crisaborole ointment, 
2%, twice daily (BID) treatment.

Flare-free maintenance until onset of first 
flare during the 52-week double-blind 
(DB) period.

Safety: To evaluate the safety and 
local tolerability of crisaborole 
ointment, 2%, QD for maintenance 
therapy and flare reduction in 
pediatric and adult participants 
≥3 months of age with mild-to-
moderate AD.

Incidence of treatment emergent adverse 
events.


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Secondary

To evaluate other long-term efficacy 
parameters for maintenance therapy 
and flare reduction of crisaborole 
ointment, 2%, QD in pediatric and 
adult participants ≥3 months of age 
with mild-to-moderate AD who 
responded to crisaborole 
ointment, 2%, BID treatment.
Key secondary endpoints during the 52-week 
DB period:

Number of flare-free days;

Number of flares;

Maintenance of pruritus response until 
onset of first flare.
Other secondary endpoints during the 
52-week DB period:

Maintenance of ≥50% Eczema Area 
and Severity Index (EASI) response;

Maintenance of dermatology quality of 
life assessments

Maintenance of Patient Oriented 
Eczema Measure (POEM).

Most commonly affected AD %BSA
collected during the DB period only.
The following will be assessed during flare 
treatment period:

Severity of flare on Investigator’s Static 
Global Assessment (ISGA) and EASI;

Duration of flare periods.
Additional Secondary

To evaluate the long-term efficacy of 
crisaborole ointment, 2%, QD for 
maintenance therapy and flare 
reduction in participants ≥3 months of 
age with mild-to-moderate AD.
The following will be assessed as change 
from baseline of each respective treatment 
period (open-label (OL), DB, and flare 
treatment):

EASI score;

ISGA score;

Treatable AD % Body Surface Area
(BSA)

To evaluate the long-term health 
impact of crisaborole ointment, 2%, 
QD for maintenance therapy and flare 
reduction in participants ≥3 months of
age with mild-to-moderate AD.
The following patient reported outcomes 
(PROs) will be assessed:

Night Time Itch;

AD Skin Pain;


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
Patient/Observer Global Impression of 
Severity (PGIS/OGIS);

Patient/Observer Global Impression of 
Change (PGIC/OGIC);

Medical Outcomes Study Sleep 
(MOS-Sleep) Scale;

EuroQol-5 Dimensions-5 (EQ-5D);

Work and Classroom Productivity;

Hospital Anxiety and Depression Scale 
(HADS).
2.1.1. Estimand 1 for the Primary Endpoint
Estimand 1: The primary estimand of the main study is a hypothetical estimand, defined 
according to the primary objective and is in alignment with the primary endpoint. It includes 
the following 4 attributes:

Population: Patients who are treated with crisaborole 2% BID up to 8 weeks and
achieve response defined by the criteria in the protocol.

Variable: Duration of flare-free maintenance up until the onset of the first flare during 
the DB period.

Intercurrent events: intercurrent events include discontinuation of treatment. If an 
event (eg, death, dropout, loss to follow up, or end of study) occurs before the first 
flare, the duration of flare-free maintenance is the time from randomization to the first 
intercurrent event and is censored.  When a flare occurs first, the duration of flare-free 
maintenance is the time from randomization to the first flare and is not censored.

Population-level summary: Median duration of flare-free maintenance during the DB
period, proportion of participants who are flare-free by time point in each treatment 
group.
This estimand framework will be used for other time-to-event endpoints as well, such as 
maintenance of EASI response at randomization, maintenance of dermatology quality of life
and maintenance of POEM.
2.1.2. Estimands for Secondary Endpoints
2.1.2.1. Estimand 2
Estimand 2: The second estimand of the study for the secondary endpoint of number of 
flare-free days during the DB period is a hypothetical estimand. It includes the following 
4 attributes:


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
Population: Patients who are treated with crisaborole 2% BID up to 8 weeks and 
achieve response defined by the criteria in the protocol.

Variable: Flare-free days during the DB period.  It is the total days that the participant 
has no flare during the DB period for each participant.

Intercurrent events: intercurrent events include discontinuation of treatment. 
Addressing intercurrent events for the duration of flare-free maintenance at each 
flare-free period is the same as that for the primary endpoint during the first flare-free
period.

Population-level summary: Difference in least-square means between crisaborole 
ointment, 2%, QD and vehicle QD for flare-free days over 52 weeks.
2.1.2.2. Estimand 3
Estimand 3: The third estimand of the study for the secondary endpoint of number of flares 
during the DB period is a hypothetical estimand. It includes the following 4 attributes:

Population: Patients who are treated with crisaborole 2% BID up to 8 weeks and
achieve response defined by the criteria in the protocol.

Variable: number of flares during the DB period.

Intercurrent events: intercurrent events include discontinuation of treatment.

Population-level summary: Median difference between crisaborole ointment, 2%, QD
and vehicle QD for number of flares over 52 weeks.
2.1.2.3. Estimand 4
Estimand 4: The fourth estimand of the study for the secondary endpoint of maintenance of 
pruritus response up until the onset of the first flare (ISGA ≥2) is a hypothetical estimand.  It 
includes the following 4 attributes:

Population: Patients who are treated with crisaborole 2% BID up to 8 weeks and
achieved pruritus response defined as ≥2, 3, or 4 points of improvement from OL 
baseline in respective pruritus scales (See Section 3.2.1).

Variable: Duration of maintenance of pruritus response up until the onset of the first 
flare (ISGA ≥2).

Intercurrent events: intercurrent events include discontinuation of treatment, first flare 
[ISGA ≥2]. If an event (eg, death, dropout, first flare [ISGA ≥2], lost to follow up, or 
end of study) occurs before loss of pruritus response for the first flare-free period, the 
duration of maintenance of pruritus response is the time from randomization to the 
first intercurrent event and is censored. When loss of pruritus response occurs first, 
the duration of pruritus response maintenance is not censored.


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•
Population-level summary: Median duration of maintenance of pruritus response up 
until the onset of the first flare during the DB period, proportion of participants who 
maintain pruritus response by time point in each treatment group.
2.2. Study Design
Study C3291035 is a Phase 3, randomized, DB, vehicle-controlled study to assess the 
efficacy and safety of crisaborole ointment, 2%, QD as maintenance treatment and for the 
reduction of flare occurrence in participants (3 months of age and older) with mild-to-
moderate AD.
Eligible participants will be enrolled to receive crisaborole BID in an OL period of up to a 
maximum of 8 weeks in duration.  Responders to OL treatment at any time during this period 
will be randomized into the DB period in a 1:1 ratio to receive QD crisaborole or vehicle for 
52 weeks.
During the OL period, a responder is defined as a participant who achieves both ISGA 
success (achieving a score of clear [0] or almost clear [1] with a ≥2 grade improvement from 
the OL baseline) and EASI50 (at least 50% improvement from the OL baseline in EASI).
Non-responders at the end of the 8-week OL period will be discontinued from the study.  To 
yield a total of 162 first flare events in the DB period of the study, it is estimated that 
approximately 700 participants will be enrolled in the OL period for responder identification 
and that approximately 250 participants will be randomized into the DB period. Once 
adequate participants have been randomized, recruitment will stop; it is possible that less 
than 700 or up to 860 participants will be enrolled in the OL period.
 
 
 
 
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Figure 1.
Study Design Schematic
3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS
3.1. Primary Endpoint
The primary endpoint is a flare-free maintenance until onset of the first flare during the 
52-week DB period.
3.2. Secondary Endpoints
3.2.1. Key Secondary Endpoints
The key secondary endpoints during the 52-week DB period are:

Number of flare-free days;

Number of flares;

Maintenance of pruritus response (defined as the maintenance of the improvement of 
≥50% from baseline that was obtained at randomization) until onset of the first flare.
Pruritus and itch assessment are age-dependent patient (or observer) reported 
outcomes. The analysis will be performed separately for 5 age and pruritus response
subgroups:


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o
≥12 years of age with OL baseline Peak Pruritus Numerical Rating Scale 
(NRS) ≥3 and ≥3 points reduction from OL baseline to randomization in Peak 
Pruritus NRS.
o
≥12 years of age with OL baseline Peak Pruritus NRS ≥4 and ≥4 points 
reduction from OL baseline to randomization in Peak Pruritus NRS.
o
6-<12 years of age with OL baseline Patient Reported Itch Severity (PRIS)
Scale ≥2 and ≥2 points reduction from OL baseline to randomization in PRIS
Scale.
o
3 months-<6 years of age with OL baseline Observer Reported Itch Severity 
(ORIS) Scale ≥3 and ≥3 points reduction from OL baseline to randomization
in ORIS Scale.
o
3 months-<6 years of age with OL baseline ORIS Scale ≥4 and ≥4 points 
reduction from OL baseline to randomization in ORIS Scale.
3.2.2. Other Secondary Endpoints
3.2.2.1. The Other Secondary Endpoints during the 52-week Double-blind Period
Maintenance is evaluated for the Other Secondary Endpoints during the 52-week study, up 
until the time of first flare.

Maintenance of EASI response, defined as ≥50% of achieved reduction from the 
Day 1/Baseline OL period to randomization is maintained in EASI;

Maintenance of dermatology quality of life assessments, defined as no loss in 
response greater than the Minimal Clinical Important Difference (MCID);

Maintenance of POEM, defined as no loss in response greater than the MCID.

Most commonly affected AD %BSA at DB baseline, Day 169, and Day 365 only.
3.2.2.2. Endpoints During Flare Treatment Period
The following endpoints will be assessed during flare treatment period:

Severity of flare using ISGA and EASI;

Duration of flare periods.
3.3. Additional Secondary Endpoints
3.3.1. Efficacy Endpoints
The following will be assessed as change from baseline of each respective treatment period: 
OL, DB, and flare treatment.


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•
EASI score;
•
ISGA score;
•
Treatable AD %BSA;
3.3.2. Patient Reported Outcome Endpoints
The following PROs will be assessed:
•
Night Time Itch Scale for participants ≥12 years of age.
•
AD Skin Pain NRS for participants ≥12 years of age.
•
PGIS/OGIS for all participants.
•
PGIC/OGIC for all participants.
•
MOS-Sleep Scale for participants ≥12 years of age.
•
EQ-5D for 2 years and older participants.
•
Work and Classroom Productivity for participants ≥12 years of age.
•
HADS for participants ≥12 years of age.
For pruritus and itch assessment, night time itch, AD skin pain, and PGIS/OGIS, the data are 
collected daily.  Weekly average will be used for analyses that are analyzed as continuous 
endpoints. For the key secondary endpoint of maintenance of pruritus response until onset of 
the first flare, daily data will be used for analysis.
 
3.5. Baseline Variables
Below demographic and baseline characteristics will be collected at OL baseline and/or at 
randomization:
OL Baseline
DB Baseline
Demographic
Age, Sex, Race, Ethnicity, 
Country, Height, Weight, BMI, 
Duration of disease, prior 
treatment history
Height, weight, BMI, 
Baseline Disease 
Characteristics
ISGA, EASI, %BSA, pruritus
ISGA, EASI, %BSA, pruritus, 
most commonly affected AD 
%BSA
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The OL baseline value is defined as the last observation up to and including Day 1 of OL
period. The DB baseline value for DB period is defined as the last observation up to and 
including the randomization day. For daily assessed endpoints (eg, pruritus, itch, pain, etc.), 
weekly average before randomization will be used.
Age group (3 months-<12 years, ≥12 years), Duration of the BID treatment in OL period (≤
4, >4 weeks) and ISGA score (clear [0], almost clear [1]) at randomization will be used as 
covariates or stratification factors in statistical models.
3.6. Safety Endpoints
Safety will be assessed by vital signs, physical examinations, clinical laboratory tests and the 
spontaneous reporting of adverse events (AEs), in all participants who received at least one 
dose of study intervention.  Unscheduled safety assessments may be performed at any time 
during the study to assess any perceived safety concerns.  Investigators and Pfizer Clinicians 
will review individual participant data throughout the conduct of the study to ensure 
participants’ well-being.  Appendix 5 of the protocol provides liver safety (Suggested 
Actions and Follow-up Assessments) in details.
3.6.1. Adverse Events
An AE is considered treatment-emergent adverse event (TEAE) to a given treatment (for a 
participant who received at least one dose) if the event start date is on or after the treatment 
period start date and before end of study.
Safety endpoints will be assessed by the spontaneous reporting of:

Incidence of TEAEs;

Incidence of serious adverse events (SAEs);

Incidence of AEs leading to discontinuation.


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3.6.2. Laboratory Data
Laboratory testing will be performed at screening and post baseline only if clinically 
indicated. Below are the protocol-required safety laboratory assessments:
Laboratory 
Assessments
Parameters
Hematology
Platelet Count
Red blood cell (RBC) Count
Hemoglobin
Hematocrit
White blood cell (WBC) count (% and absolute:
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
Clinical 
Chemistry
Albumin
Blood urea nitrogen (BUN)
Potassium
Alanine Aminotransferase (ALT)
Alkaline phosphatase 
Total bilirubin
Aspartate Aminotransferase (AST)
Total Protein 
Calcium
Sodium
Creatinine
Chloride
Glucose (non-fasting)
Bicarbonate or total CO2
Urine Pregnancy
For all WOCBP: Test kit (dipsticks) provided by the central laboratory.  The results of 
the urine dipstick test must be recorded in the source document and made available for 
study review.
Other Tests
Follicle-stimulating hormone (only for post-menopausal status confirmation at 
screening).
Serum beta human chorionic gonadotropin (-hCG) pregnancy test (for all WOCBP at 
screening, and for pregnancy status confirmation if urine dipstick pregnancy test is 
positive or if a urine dipstick test cannot be confirmed as negative [eg, an ambiguous 
result]).
3.6.3. Vital Signs
Temperature and pulse rate will be assessed.
3.6.4. Physical Examinations
A complete physical examination will include, at a minimum, assessments of general 
appearance, skin, head, ears, eyes, nose, throat, mouth, skin, heart, lung, breast, lymph nodes, 
extremities, abdomen, external genitalia (optional), and neurological function.  In addition, 
an assessment will be made for skin abnormalities other than AD, including scalp.
A targeted physical examination will include, at a minimum, assessments of the skin, heart, 
lungs, and abdomen and examination of body systems where there are symptom complaints 
by the participant.
Height and weight will also be measured and recorded.


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4. ANALYSIS SETS (POPULATIONS FOR ANALYSIS)
For purposes of analysis, the following populations are defined:
Population
Description
Enrolled
All participants who sign the informed consent form.
Evaluable-OL (Eval-OL)
All participants receiving at least 1 dose of study intervention 
in the OL period
Safety-OL (SAF-OL)
All participants receiving at least 1 dose of study intervention 
in the OL period. It is same as Evaluable-OL
Evaluable-DB (Eval-DB)
All randomized participants with success in ISGA and 
EASI50 criteria as responders at randomization and receiving 
at least 1 dose of study intervention in the DB period. 
Participants will be analyzed according to the intervention 
they are randomized to.
Safety-DB (SAF-DB)
All randomized participants receiving at least 1 dose of study 
intervention in the DB period. Participants will be analyzed 
according to the intervention they actually received.
Safety (SAF)
All participants receiving at least 1 dose of study intervention
during the study.
5. GENERAL METHODOLOGY AND CONVENTIONS
Final analyses will occur after database release.
5.1. Hypotheses and Decision Rules
The primary objective is to establish the superiority of a crisaborole QD to a vehicle QD; 
detecting a 1.8 ratio of median time of being flare-free (hazard ratio of 0.556) in the first 
flare-free period at a significance level of 0.05 (2-sided, log-rank test).
5.1.1. Statistical Decision Rules for Multiple Comparisons
A step-down closed testing procedure and Bonferroni’s method will be used for Type I error 
control for testing the primary endpoint and the key secondary endpoints.  The order of 
testing is as follows:
1. Flare-free maintenance up until the onset of the first flare during the DB period.
2. Number of flare-free days over 52 weeks.
3. Number of flares over 52 weeks.


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4. Pruritus response maintenance up until the onset of the first flare (ISGA ≥2), defined
as the maintenance of improvement ≥50% (ie, if 50% or more of the improvement in 
pruritus from the baseline to the randomization is maintained).  Analysis will be 
performed for 5 responder subgroups:

≥12 years of age with OL baseline Peak Pruritus NRS ≥3 and ≥3 points reduction 
OL baseline to randomization in Peak Pruritus NRS.

≥12 years of age with OL baseline Peak Pruritus NRS ≥4 and ≥4 points reduction 
OL baseline to randomization in Peak Pruritus NRS.

6-<12 years of age with OL baseline PRIS Scale ≥2 and ≥2 points reduction OL 
baseline to randomization in PRIS Scale.

3 months-<6 years of age with OL baseline ORIS Scale ≥3 and ≥3 points 
reduction OL baseline to randomization in ORIS Scale.

3 months-<6 years of age with OL baseline ORIS Scale ≥4 and ≥4 points 
reduction OL baseline to randomization in ORIS Scale.
The statistical significance can be claimed for a given endpoint in the sequence only if the 
prior endpoint in the sequence is significant.  For the endpoints of 1-3, the significance level 
is 0.05.  For pruritus response maintenance, Bonferroni’s method is used to adjust the 
significance level.  The significance level is 0.01 for each subgroup, there is no testing order.  
Only the subgroup with p-value ≤0.01 can claim significance after the primary endpoint and 
other two secondary endpoints are statistically significant.
5.2. General Methods
In general, number, percent, and 95% CI (Clopper-Pearson method) will be presented for 
binary endpoints.  Descriptive summary statistics (n, Mean, Standard Deviation, Median, 
Min., Max.) will be presented for continuous endpoints.  In addition, graphics may be used to 
present the data.
5.2.1. Analyses for Binary Data
Descriptive summary will be performed for binary endpoints for this study.
5.2.2. Analyses for Continuous Data
5.2.2.1. Longitudinal Continuous Data
Descriptive summary will be performed for longitudinal continuous endpoints for this study.
5.2.2.2. Non-longitudinal Continuous Data
Analysis of covariance (ANCOVA) will be used to analyze non-longitudinal continuous data, 
such as number of flare-free days over 52-week DB period.  Age group (3 months-<12 years, 
≥12 years), duration of the BID treatment in OL period (≤4, >4 weeks), and ISGA score 
(clear [0], almost clear [1]) at randomization will be included in the model as covariates.


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Least square (LS) estimates of mean values and the LS mean differences between crisaborole
QD and vehicle QD groups will be derived from the model.  The corresponding p-value, 
standard errors and 95% CI will also be derived from the model.
5.2.3. Analyses for Categorical Data
The frequency and percentage for each category will be presented for category endpoints.
5.2.4. Analyses for Time-to-Event Data
Time-to-event analysis will be used to analyze time-to-event data.
Kaplan-Meier (product limit) method will be used for estimation of proportion of participants 
with event, time-to-event curve, median (95% CI) time-to-event.
A log-rank test, stratified by age group (3 months-<12 years, ≥12 years), duration of the BID 
treatment in OL period (≤4, >4 weeks), and ISGA score (clear [0], almost clear [1]) at 
randomization, will be used to test the difference between crisaborole QD versus vehicle QD.
5.3. Methods to Manage Missing Data
For OL period, efficacy and PRO data summary will be based on Last Observation Carried 
Forward (LOCF) imputation data. For DB period, for descriptive statistics missing values 
will not be imputed. In addition, for safety endpoints, missing values will not be imputed.
For the continuous patient/observer reported outcomes variables, rules recommended by the
developers of these instruments will be followed in the handling of missing data and in the
scoring of the questionnaires when data are missing for one or more questionnaire items.
6. ANALYSES AND SUMMARIES
6.1. Primary Endpoint
The primary endpoint is flare-free maintenance until onset of first flare during the 52-week 
double-blind period.
6.1.1. Main Analysis

Estimand strategy: Hypothetical (Section 2.1.1).

Analysis Population: Evaluable-DB.

Analysis method: Time-to-event analysis, Kaplan-Meier (product limit) method and 
log-rank test (Section 5.2.4).

Intercurrent events: intercurrent events include discontinuation of treatment. If an 
intercurrent event (eg, death, dropout, loss to follow up, or end of study) occurs
before the first flare, the duration of flare-free maintenance is the time from 
randomization to the first intercurrent event and is right censored.  When a flare 
occurs first, the duration of flare-free maintenance is the time from randomization to 
the first flare and is not censored.


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
Reporting results: At each month, the proportion of participants who had maintained 
flare-free status before the first flare , time-to-event curve, median (95% CI) time of 
maintaining flare-free, and number (%) of censored participants for each treatment 
group, and p-value from log-rank test will be presented.
6.1.2. Sensitivity/Supplementary Analysis
For the above main analysis, the definition of flare is based on the investigator assessment of 
ISGA, time of flare is the assessment time when ISGA≥2. In addition, a sensitivity analysis 
will be performed where flare definition includes an AD worsening event (preferred 
term=Dermatitis atopic or Eczema) reported by a participant prior to a confirmatory ISGA
≥2. In this analysis, the time of onset of such event will be used as the onset of the flare. If a 
participant reported an AD worsening event but the investigator assessment is not a flare at 
the subsequent visit, this event is not a flare. Estimand strategy, analysis population, analysis 
method and intercurrent events handling are the same as above for the main analysis.
Another sensitivity analysis is interval censoring survival analysis. Time of flare is between 
the time of participants reported AD worsening and the time of investigator confirmed ISGA 
≥2. Because the exact flare time is not known, the midpoint of the above interval will be 
used as the flare time. Estimand strategy, analysis population, analysis method and 
intercurrent events handling are the same as above for the main analysis.
6.2. Key Secondary Endpoints
6.2.1. Number of Flare-Free Days
The first key secondary endpoint is the number of flare-free days during the DB period.  It is 
the total flare-free days during the DB period for each participant regardless censoring or not, 
ie, the censored number of flare-free days in a flare-free period is truncated at censoring for 
the calculation of total number of flare-free days.

Estimand strategy: Hypothetical (Section 2.1.2.1).

Analysis Population: Evaluable-DB.

Analysis method: ANCOVA model (Section 5.2.2.2).

Intercurrent events: intercurrent events include discontinuation of treatment. 
Addressing intercurrent events for the duration of flare-free maintenance at each 
flare-free period is the same as that for the primary endpoint during the first flare-
free period.

Reporting results: The LS mean along with the corresponding standard error and 
95% CI for each treatment group, LS mean difference along with the corresponding 
p-value, standard error and 95% CI will be presented.
6.2.2. Total Number of Flares
The second key secondary endpoint is the number of flares during the 52-week DB period.


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
Estimand strategy: Hypothetical (Section 2.1.2.2).

Analysis Population: Evaluable-DB.

Analysis method: Wilcoxon rank sum test stratified by age group, duration of the BID 
treatment in OL period, and ISGA score at randomization.

Intercurrent events: intercurrent events include discontinuation of treatment.

Reporting results: Median for each treatment group and median difference estimated 
by the Hodges–Lehmann method2 along with the 95% CI, p-value from Wilcoxon 
rank sum test will be reported.
Participants will be ranked in descending order according to the number of flares adjusted for
length of time in the DB period, and length of time in flare-free period, ie if participants have 
same number of observed flares, below conditions will be used as tie-breaker in sequence:

Participants who prematurely discontinue the study for efficacy reasons 
(ie, discontinue due to lack of efficacy or AD worsening of AE for treated lesions) 
will be ranked below others;

The participant with longer time in the double-blind maintenance period will receive 
a higher rank;

The participant with longer time in flare-free period will receive a higher rank.
6.2.3. Maintenance of Pruritus Response until Onset of First Flare (ISGA ≥2)
The third key secondary endpoint is duration of maintenance of pruritus response. It is the 
time from randomization to the loss of pruritus response or first flare onset (ISGA ≥2) during 
the 52-week DB period for participants who are pruritus responders at randomization.
Pruritus response is maintained if ≥50% of pruritus reduction from OL baseline to 
randomization is not lost.

Estimand strategy: Hypothetical (Section 2.1.2.3).

Analysis Population: Evaluable-DB.

Analysis method: Time-to-event analysis, Kaplan-Meier (product limit) method and 
log-rank test (Section 5.2.4).

Intercurrent events: intercurrent events include discontinuation of treatment, first flare 
[ISGA ≥2]. If an event (eg, death, first flare [ISGA ≥2], lost to follow up, or end of 
study) occurs before loss of pruritus response for the first flare-free period, the 
duration of maintenance of pruritus response is the time from randomization to the 
first intercurrent event and is censored. When loss of pruritus response occurs first, 
the duration of maintenance of pruritus response is not censored.


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
Reporting results: At each month, the proportion of participants who maintained 
pruritus response in the first flare-free period, time-to-event curve, median (95% CI) 
time of maintaining pruritus response, and number (%) of censored participants for 
each treatment group, and p-value from log-rank test will be presented.
The analysis will be performed separately for each age and pruritus respondse subgroups:

≥12 years of age with OL baseline Peak Pruritus NRS ≥3 and ≥3 points reduction
from OL baseline to randomization in Peak Pruritus NRS.

≥12 years of age with OL baseline Peak Pruritus NRS ≥4 and ≥4 points reduction
from OL baseline to randomization in Peak Pruritus NRS.

6-<12 years of age with OL baseline PRIS Scale ≥2 and ≥2 points reduction from OL 
baseline to randomization in PRIS Scale.

3 months-<6 years of age with OL baseline ORIS Scale ≥3 and ≥3 points reduction
from OL baseline to randomization in ORIS Scale.

3 months-<6 years of age with OL baseline ORIS Scale ≥4 and ≥4 points reduction 
from OL baseline to randomization in ORIS Scale.
6.3. Other Secondary Endpoints
6.3.1. Maintenance of EASI Response
This endpoint is defined as ≥50% of EASI total score reduction from OL baseline to 
randomization is maintained. Only data up to the first flare onset (ISGA ≥2) during the 
maintenance period will be used for analysis.

Estimand strategy: Hypothetical (Section 2.1.1).

Analysis Population: Evaluable-DB.

Analysis method: Time-to-event analysis, Kaplan-Meier (product limit) method and 
log-rank test (Section 5.2.4).

Intercurrent events: intercurrent events include discontinuation of treatment, first 
flare. If an intercurrent event (eg, death, dropout, loss to follow up, first flare, or end 
of study) occurs before loss of EASI response, the duration of maintenance of EASI 
reduction is the time from randomization to the first intercurrent event and is right 
censored.

Reporting results: At each month, the proportion of participants maintaining ≥50% 
EASI reduction before the first flare, time-to-event curve, median (95% CI) time of 
maintaining ≥50% EASI reduction, and number (%) of censored participants for each 
treatment group, and p-value from log-rank test will be presented.


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6.3.2. Maintenance of Dermatology Quality of Life Assessments
Maintenance of dermatology quality of life assessments is defined as the response achieved 
does not lose more than MCID. Only data up to the first flare onset during the DB period
will be used for analysis.
•
Estimand strategy: Hypothetical (Section 2.1.1).
•
Analysis Population: Evaluable-DB.
•
Analysis method: Time-to-event analysis, Kaplan-Meier (product limit) method and 
log-rank test (Section 5.2.4).
•
Intercurrent events: intercurrent events include discontinuation of treatment, first
flare. If an intercurrent event (eg, death, dropout, loss to follow up, first flare, or end 
of study) occurs before loss of dermatology quality of life response, the duration of 
maintenance of dermatology quality of life assessments is the time from 
randomization to the first intercurrent event and is right censored.
•
Reporting results: At each month, the proportion of participants who maintained
dermatology quality of life assessments before the first flare, time-to-event curve, 
median (95% CI) time of maintaining dermatology quality of life assessments, and 
number (%) of censored participants for each treatment group, and p-value from log-
rank test will be presented.
The analysis will be performed separately for two age groups:
•
Participants ≥16 years of age, Dermatology Life Quality Index (DLQI).
•
Participants 4-<16 years of age, Children’s Dermatology Life Quality Index 
(CDLQI).
MCID is not available for Infant’s Dermatitis Quality of Life Index (IDQoL) for participants 
3 months̢<4 years of age. Maintenance of dermatology quality of life assessments will not 
be performed for that age group.
6.3.3. Maintenance of Patient Oriented Eczema Measure (POEM)
This endpoint is defined as the response achieved does not lose more than MCID. Only data
up to the first flare onset during the DB period will be used for analysis.
•
Estimand strategy: Hypothetical (Section 2.1.1).
•
Analysis Population: Evaluable-DB.
•
Analysis method: Time-to-event analysis, Kaplan-Meier (product limit) method and 
log-rank test (Section 5.2.4).


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
Intercurrent events: intercurrent events include discontinuation of treatment, first 
flare. If an intercurrent event (eg, death, dropout, loss to follow up, first flare, or end 
of study) occurs before loss of POEM response, the duration of maintenance of 
POEM is the time from randomization to the first intercurrent event and is right 
censored.

Reporting results: At each month, the proportion of participants who maintained
POEM response before the first flare, time-to-event curve, median (95% CI) time of 
maintaining POEM response, and number (%) of censored participants for each 
treatment group, and p-value from log-rank test will be presented.
The analysis will be performed separately for two age groups:

≥12 years of age (participant reported POEM).

3 months-<12 years of age (proxy POEM).
6.3.4. Endpoints during Flare Treatment Period
6.3.4.1. Severity of Flare on Investigator’s Static Global Assessment Score

Analysis Population: Evaluable-DB.

Method: Descriptive summary for categorical endpoint; Descriptive summary for 
continuous endpoint.

Reporting results:

ISGA as a categorical endpoint: the number and percent of participants for the 
first flare period and each time point by ISGA categories and DB treatment 
assignment group and overall group;

ISGA as a continuous endpoint: the number of participants, mean, standard 
deviation, median, minimum, maximum for the first flare period and each time 
point by DB treatment assignment group and overall group for observed and 
change from initiated of the first flare period. The summary is performed by the 
time point relative to the start of first flare period (ie, Weeks 0, 4, 8, 12 in the first 
flare period).
6.3.4.2. Severity of Flare on Eczema Area and Severity Index Score

Analysis Population: Evaluable-DB.

Method: Descriptive summary for continuous endpoint.

Reporting results: The number of participants, mean, standard deviation, median, 
minimum, maximum for the first flare period and each time point by DB treatment 
assignment group and overall group for observed and change from initiated of the 


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first flare period. The summary is performed by the time point relative to the start of 
first flare period (ie, Weeks 0, 4, 8, 12 in the first flare period).
6.3.4.3. Duration of Flare Periods

Analysis Population: Evaluable-DB.

Method: Descriptive summary for continuous endpoint. The average duration of flare 
periods (sum of durations/number of flares) will be calculated for each participant, 
then summarize the average duration. 

Reporting results: The number of participants, mean, standard deviation, median, 
minimum, maximum by DB treatment assignment and overall.
6.4. Additional Secondary Endpoints
Analyses of secondary endpoints for OL period will be based on LOCF data.
Analyses of secondary endpoints for DB period will be based on observed data.  
6.4.1. EASI

OL period:

Analysis Population: Evaluable-OL.

Method: Descriptive summary for continuous endpoint.

Reporting results: The number of participants, mean, standard deviation, median, 
minimum, maximum for observed value and change from OL baseline by time 
point.

DB period, First flare-free period, and First flare period:

Analysis Population: Evaluable-DB.

Method: Descriptive summary for continuous endpoint.

Reporting results: The number of participants, mean, standard deviation, median, 
minimum, maximum for observed value and change from randomization in the 
DB period (Flare-free/Flare), the first flare-free period, and first flare period. For 
the first flare period, the change is the change from the start of first flare period, 
summary is performed by the time point relative to the start of first flare period 
(ie, Weeks 0, 4, 8, 12 in the first flare period).
6.4.2. ISGA

OL period:

Analysis Population: Evaluable-OL.

Method: Descriptive summary for binary endpoint; Descriptive summary for 
continuous endpoint.

Reporting results:


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
ISGA success and ISGA clear/almost: the number and percent (95% CI) by 
time point.

ISGA as a categorical endpoint: the number and percent of participants.

ISGA as a continuous endpoint: the number of participants, mean, standard 
deviation, median, minimum, maximum for observed value and change from 
OL baseline by time point.

DB period, First flare-free period, and First flare period:

Analysis Population: Evaluable-DB.

Method: Descriptive summary for categorical and continuous endpoints.

Reporting results:

ISGA as a categorical endpoint: the number and percent of participants.

ISGA as a continuous endpoint: the number of participants, mean, standard 
deviation, median, minimum, maximum for observed value and change from 
randomization in the DB period (Flare-free/Flare), the first flare-free period,
and first flare period. For the first flare period, the change is the change from 
the start of first flare period, summary is performed by the time point relative 
to the start of first flare period (ie, Weeks 0, 4, 8, 12 in the first flare period).
6.4.3. Treatable AD %BSA

OL period:

Analysis Population: Evaluable-OL.

Method: Descriptive summary for continuous endpoint.

Reporting results: The number of participants, mean, standard deviation, median, 
minimum, maximum for observed value and change from OL baseline by time 
point.

DB period, First flare-free period, and First flare period:

Analysis Population: Evaluable-DB.

Method: Descriptive summary for continuous endpoint.

Reporting results: The number of participants, mean, standard deviation, median, 
minimum, maximum for observed value and change from randomization in the 
DB period (Flare-free/Flare), the first flare-free period, and the first flare period.  
For the first flare period, the change is the change from the start of first flare 
period, summary is performed by the time point relative to the start of first flare 
period (ie, Weeks 0, 4, 8, 12 in the first flare period).
6.4.4. Most Commonly Affected AD %BSA
Most commonly affected AD %BSA is collected at randomization, DB Days 169 and 365.

Analysis Population: Evaluable-DB.


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
Method: Descriptive summary for continuous endpoint.

Reporting results: The number of participants, mean, standard deviation, median, 
minimum, maximum by DB treatment assignment for observed value and change 
from randomization to Days 169 and 365.
6.4.5. Duration of Flare-free periods

Analysis Population: Evaluable-DB.

Method: Descriptive summary for continuous endpoint.  The average duration of 
flare-free periods (sum of durations/number of flare-frees) will be calculated for each 
participant, then summarize the average duration.  

Reporting results: The number of participants, mean, standard deviation, median,
minimum, maximum.
6.4.6. Patient Reported Outcome Endpoints
PRO endpoints include:

Pruritus and Itch Assessments, will be analyzed separately by age group:

Peak Pruritus NRS for participants ≥12 years of age;

PRIS Scale for participants 6-<12 years of age;

ORIS Scale for participants 3 months-<6 years of age.

Night Time Itch Scale for participants ≥12 years of age.

AD Skin Pain NRS for participants ≥12 years of age.

PGIS/OGIS for all participants, will be analyzed separately by age group:

PGIS for participants ≥12 years of age;

OGIS for participants 3 months-<12 years of age.

PGIC/OGIC for all participants, will be analyzed separately by age group:

PGIC for participants ≥12 years of age;

OGIC for participants 3 months-<12 years of age.

MOS-Sleep Scale for participants ≥12 years of age.

EQ-5D for all participants, will be analyzed separately by age group:

The EQ-5D-5L (5 levels) for participants ≥18 years of age;

The EQ-5D-Y (3 levels) for participants 8-<18 years of age;

The EQ-5D-Y Proxy (3 levels) for participants 2-<8 years of age.


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
Work and Classroom Productivity for participants ≥12 years of age.

HADS for participants ≥12 years of age.

Dermatology quality of life assessments, will be analyzed separately by age group:

DLQI for participants ≥16 years of age;

CDLQI for participants 4-<16 years of age;

IDQoL for participants 3 months-<4 years of age.

POEM: POEM for Proxy Completion (e.g., by parent), participants ages 3 months-
<12 years of age, and POEM for Self Completion, participants ≥12 years of age.
All these PRO endpoints will be summarized as below:

OL period:

Analysis Population: Evaluable-OL.

Method: Descriptive summary for continuous endpoint.

Reporting results: The number of participants, mean, standard deviation, median, 
minimum, maximum for observed value and change (except dermatology quality 
of life assessments, POEM and PGIC/OGIC) from OL baseline by time point.

DB period, First flare-free period, and First flare period:

Analysis Population: Evaluable-DB.

Method: Descriptive summary for continuous endpoint.

Reporting results: The number of participants, mean, standard deviation, median, 
minimum, maximum for observed value and change (except PGIC/OGIC) from 
randomization in the DB period (Flare-free/Flare), the first flare-free period, and 
the first flare period.  For the first flare period, the change is the change from the 
start of first flare period, summary is performed by the time point relative to the 
start of first flare period (ie, Weeks 0, 4, 8, 12 in the first flare period).
6.5. Subset Analyses
The primary endpoint (main analysis only) and key secondary endpoints number of flare-free
days and number of flares will be analyzed by age group (3 months-<12 years, ≥12 years), 
ISGA score (clear, almost clear) at randomization, race (White, Black, Asian, Other), 
ethnicity (Hispanic, Non-Hispanic), and number of OL weeks (≤4, >4) before 
randomization.
6.6. Baseline and Other Summaries and Analyses
6.6.1. Baseline Summaries
Demographics and baseline characteristics listed in Section 3.5 will be summarized for SAF-
OL, and SAF-DB by QD treatment group according to Pfizer standards.


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For Evaluable-DB, the efficacy and PRO data at randomization will be summarized by QD
treatment group according to Pfizer standards. For daily assessed endpoints (eg, pruritus,
itch, pain, etc.), weekly average before randomization will be used.
6.6.2. Study Conduct and Participant Disposition
Participants evaluation, disposition, discontinuation will be summarized, separately for OL 
period and DB period according to Pfizer standards.
6.6.3. Study Intervention Compliance
A participant will be considered compliant with the dosing regimen if they receive
80%-120% of the expected number of doses in accordance with the protocol. The number 
and percentage of participants who are compliant with the dosing regimen, number of dosing 
days and number of applications, and amount of intervention used will be summarized by OL
period, QD period, and flare treatment period.
6.6.4. Concomitant Medications and Nondrug Treatments
Prior drug and non-drug treatment, concomitant drug and non-drug treatment will be 
summarized according to Pfizer standards.
6.7. Safety Summaries and Analyses
Safety analyses will be based on the SAF-OL, SAF-DB, according to the period and 
endpoint.
All clinical AEs, SAEs, TEAEs, withdrawal due to AEs, vital signs and safety laboratory 
data will be reviewed on an ongoing basis during the study to evaluate the safety of 
participants.
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 
participant counts and percentage.  Continuous outcome will be summarized using N, mean, 
median, standard deviation, etc.    Participant listings will be produced for these safety 
endpoints accordingly.
Separate listings and/or summaries may be produced for participants who are impacted by 
COVID-19, have protocol deviations, discontinue from study or study treatment due to the 
COVID-19 pandemic.
6.7.1. Adverse Events
The safety data will be summarized separately by period: OL period for SAF-OL, DB QD
period for SAF-DB, and flare treatment period for SAF-DB in accordance with Pfizer Data 
Standards.  All safety data will be summarized descriptively through appropriate data 
tabulations, descriptive statistics, categorical summaries, and graphical presentations. The
safety data will be summarized for overall events and treatment area events. Safety 
endpoints for the study include:


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
Incidence of TEAEs.

Incidence of SAEs and AEs leading to discontinuation.
6.7.2. Laboratory Data
Laboratory data will be listed in accordance with the Pfizer reporting standards.
6.7.3. Vital Signs
Vital signs data will be listed.
6.7.4. Physical Examination
Physical examination data will be listed.
7. INTERIM ANALYSES
There is no planned interim analysis.
7.1.1. Data Monitoring Committee
This study uses an External Data Monitoring Committee (E-DMC).  The E-DMC will be 
responsible for ongoing monitoring of the safety of participants in the study according to the
charter.  The recommendations made by the E-DMC to alter the conduct of the study will be 
forwarded to Pfizer for final decision.  Pfizer will forward such decisions, which may include 
summaries of aggregate analyses of endpoint events and of safety data that are not endpoints, 
to regulatory authorities, as appropriate.


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8. REFERENCES
1.
Pfizer Protocol Amendment 1 C3291035.
2.
Hodges. JR, Lehmann EL. Estimates of location based on rank tests. Ann Math Stat 
1963; 34:598–611.


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9. APPENDICES
Appendix 1: Summary of Efficacy Endpoints
The table below summarizes analyses of primary and secondary efficacy endpoints.
Endpoint
Analysis Population
Statistical Method
Type
Time-to-flare
Evaluable-DB
Time-to-event
Primary
Number of flare-free days
Evaluable-DB
ANCOVA
Key secondary
Total number of flares
Evaluable-DB
Wilcoxon
Key secondary
Time from randomization to loss 
of ≥50% pruritus response up to 
first flare by subgroups
Evaluable-DB participants 
who achieved pruritus 
response
Time-to-event
Key secondary
Maintenance of dermatology 
quality of life assessments up to 
first flare by subgroups
Evaluable-DB participants 
who achieved 
dermatology quality of 
life assessments response
Time-to-event
Secondary
Maintenance of POEM up to first 
flare
Evaluable-DB participants 
who achieved POEM 
response
Time-to-event
Secondary


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Appendix 2: Definition and Use of Visit Windows in Reporting
Below visit windows will be used for ISGA, EASI, and %BSAduring OL period.
OL Visit Label
Target Day
Definition [Day window]
Screening
Days -28 to -1
OL Weeks 0-8
Days of OL Period
OL_Day 1/Week 0
Day 1, Baseline
Day 1
OL_Week 2
15
Days 2 to 22
OL_Week 4
29
Days 23 to 36
OL_Week 6
43
Days 37 to 50
OL_Week 8
57
Day 51 to end of OL
End of OL
OL discontinuation or double-blind 
randomization.
IF participants don’t enter maintenance period, 
the follow up period is included in OL.
Below visit windows will be used for Dermatology Quality of Life Assessments and POEM
during OL period.
OL Visit Label
Target Day
Definition [Day window]
Screening
Days -28 to -1
OL Weeks 0-8
Days of OL Period
OL_Day 1/Week 0
Day 1, Baseline
Day 1
OL_Week 1
8
Days 2 to 11
OL_Week 2
15
Days 12 to 18
OL_Week 3
22
Days 19 to 25
OL_Week 4
29
Days 26 to 32
OL_Week 5
36
Days 33 to 39
OL_Week 6
43
Days 40 to 46
OL_Week 7
50
Days 47 to 53
OL_Week 8
57
Day 54 to end of OL
End of OL
OL discontinuation or double-blind
randomization.
IF participants don’t enter maintenance period, 
the follow up period is included in OL.


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Below visit windows will be used for efficacy variables during DB period.
Target Day
Definition [Day window]
DB Weeks 0-52
Days of DB Period
DB Day 1/Week 0
1
Day 1
DB_Week 4
29
Days 2 to 43
DB_Week 8
57
Days 44 to 71
DB_Week 12
85
Days 72 to 99
DB_Week 16
113
Days 100 to 127
DB_Week 20
141
Days 128 to 155
DB_Week 24
169
Days 156 to 183
DB_Week 28
197
Days 184 to 211
DB_Week 32
225
Days 212 to 239
DB_Week 36
253
Days 240 to 267
DB_Week 40
281
Days 268 to 295
DB_Week 44
309
Days 296 to 323
DB_Week 48
337
Days 324 to 351
DB_Week 52
365
Days 352 to last available data
Note: Participants will have an end-of-study (follow-up) by phone at least 28 days after the last study dose 
of any period.
For the time points just prior and after initiation of a new episode, the initiation date of the episode is the 
cutoff date for the visit windows.
Below visit windows will be used for efficacy variables during first flare period.
Target Day
Definition [Day window]
First Flare Weeks
Days of First Flare Period
First Flare Day 1/Week 0
1
First Day of first flare period
First Flare_Week 4
29
Days 2 to 43
First Flare_Week 8
57
Days 44 to 71
First Flare_Week 12
85
Days 72 to end of first flare 
period or end of DB period
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.


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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 will follow Pfizer standards.


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Appendix 3: Examples of Summary Table Shells for DB Period
Summary of Endpoint Data in the DB Period (Flare-free/Flare) by Time Point in DB Period
Maintenance Flare-free
Period
Flare Period
Timepoint
Crisaborole 
QD
Vehicle QD
Crisaborole 
BID
DB Day 1/Week 0
N
138
137
0
…
DB Week 4
N
130
120
20
…
DB Week 8
N
…
DB Week 52
Summary of Endpoint Data in the First Flare-free Period by Time Point in DB Period
First Flare-free Period(1)
Timepoint
Crisaborole QD
Vehicle QD
DB Day 1/Week 0
N
138
137
…
DB Week 4
N
123
112
…
DB Week 8
N
…
DB Week 52
(1) Include only the data in the first Flare-free period
Summary of Endpoint Data in the First Flare Period by Time Point in DB Period
DB Treatment Assignment
Total
Timepoint
Crisaborole QD
Vehicle QD
First Flare Day 1/Week 
0
N
13
…
First Flare Week 4
N
9
…
First Flare Week 8
N
First Flare Week 12
(1) Include only the data in the first flare period


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Appendix 4: Listing of Abbreviations
Abbreviation
Term
AD
atopic dermatitis
AE
adverse event
ALT
alanine aminotransferase
ANCOVA
analysis of covariance
AST
aspartate aminotransferase
BID
twice daily
BSA
body surface area 
CDLQI
children’s dermatology life quality index
CI
confidence interval
DB
double-blind
DLQI
dermatology life quality index
DMC
data monitoring committee
EASI
eczema area and severity index
EASI50
≥50% reduction in eczema area and severity index
E-DMC
external data monitoring committee 
EQ-5D
EuroQol-5 Dimensions
Eval
evaluable
HADS
hospital anxiety and depression scale
IDQoL
infant’s dermatitis quality of life index
ISGA
investigator’s static global assessment
LOCF
Last Observation Carried Forward
LS
least squares
MCID
minimal clinical important difference 
MOS
medical outcomes study
NRS
numerical rating scale
OGIC
observer global impression of change 
OGIS
observer global impression of severity
OL
open label
ORIS
observer reported itch severity
PGIC
patient global impression of change
PGIS
patient global impression of severity
POEM
maintenance of patient oriented eczema measure 
PRIS
patient reported itch severity
PRO
patient reported outcome
QD
once daily
SAE
serious adverse event
SAF
safety
SAP
statistical analysis plan
TEAE
treatment-emergent adverse event