A PHASE 3, MULTICENTER, OPEN-LABEL STUDY OF THE LONG-TERM SAFETY OF CRISABOROLE OINTMENT, 2% IN JAPANESE PEDIATRIC AND ADULT PARTICIPANTS WITH MILD TO MODERATE ATOPIC DERMATITIS
Phase: PHASE3
Conditions: Atopic Dermatitis
Sponsor: Pfizer

Crisaborole (PF-06930164)
Protocol C3291027
Final Protocol, 20 May 2020
PFIZER CONFIDENTIAL
Page 1
Title Page
A PHASE 3, MULTICENTER, OPEN-LABEL STUDY OF THE LONG-TERM 
SAFETY OF CRISABOROLE OINTMENT, 2% IN JAPANESE PEDIATRIC AND 
ADULT PARTICIPANTS WITH MILD TO MODERATE ATOPIC DERMATITIS
Study Intervention Number:
PF-06930164
Study Intervention Name:
Crisaborole
US IND Number:
N/A
EudraCT Number:
N/A
Protocol Number:
C3291027
Phase:
3
Short Title: A Phase 3, Multicenter, Open-Label Study of the Long-Term Safety of 
Crisaborole Ointment, 2% in Japanese Pediatric and Adult Participants with Mild 
to Moderate Atopic Dermatitis
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.

Crisaborole (PF-06930164)
Protocol C3291027
Final Protocol, 20 May 2020
PFIZER CONFIDENTIAL
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Protocol Amendment Summary of Changes Table
Document History
Document
Version Date
Summary and Rationale for Changes
Original protocol
20 May 2020
N/A

Crisaborole (PF-06930164)
Protocol C3291027
Final Protocol, 20 May 2020
PFIZER CONFIDENTIAL
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TABLE OF CONTENTS
LIST OF TABLES.....................................................................................................................7
LIST OF FIGURES ...................................................................................................................7
1. PROTOCOL SUMMARY.....................................................................................................8
1.1. Synopsis ....................................................................................................................8
1.2. Schema ....................................................................................................................10
1.3. Schedule of Activities .............................................................................................11
2. INTRODUCTION ...............................................................................................................15
2.1. Study Rationale .......................................................................................................15
2.2. Background .............................................................................................................16
2.2.1. Drug Development......................................................................................17
2.2.2. Nonclinical Studies.....................................................................................17
2.2.3. Pharmacokinetics........................................................................................18
2.2.4. Cutaneous Sensitization, Irritancy Potential and Tolerability....................19
2.2.4.1. Skin Irritation Study..................................................................19
2.2.4.2. Local Tolerability in Sensitive Skin Area.................................19
2.2.4.3. Sensitizing and Cumulative Irritation Potential ........................19
2.2.5. Clinical Overview.......................................................................................20
2.3. Benefit/Risk Assessment.........................................................................................21
2.3.1. Risk Assessment.........................................................................................22
2.3.2. Benefit Assessment.....................................................................................22
2.3.3. Overall Benefit/Risk Conclusion................................................................22
3. OBJECTIVES, ESTIMANDS, AND ENDPOINTS ...........................................................22
4. STUDY DESIGN.................................................................................................................24
4.1. Overall Design.........................................................................................................24
4.2. Scientific Rationale for Study Design.....................................................................24
4.3. Justification for Dose ..............................................................................................24
4.4. End of Study Definition ..........................................................................................25
5. STUDY POPULATION......................................................................................................25
5.1. Inclusion Criteria.....................................................................................................25
5.2. Exclusion Criteria....................................................................................................26

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Protocol C3291027
Final Protocol, 20 May 2020
PFIZER CONFIDENTIAL
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5.3. Lifestyle Considerations..........................................................................................27
5.3.1. Contraception..............................................................................................27
5.3.2. General Care ...............................................................................................27
5.4. Screen Failures ........................................................................................................28
6. STUDY INTERVENTION..................................................................................................28
6.1. Study Intervention(s) Administered........................................................................28
6.1.1. Administration............................................................................................29
6.2. Preparation/Handling/Storage/Accountability ........................................................32
6.2.1. Preparation and Dispensing........................................................................33
6.3. Measures to Minimize Bias: Randomization and Blinding.....................................33
6.3.1. Allocation to Study Intervention ................................................................33
6.4. Study Intervention Compliance...............................................................................34
6.5. Concomitant Therapy..............................................................................................34
6.5.1. Medications/Therapies Prohibited During the Study (Day 1-Week 
52/EOT) ...........................................................................................................35
6.5.2. Medications/Therapies Allowed During the Study ....................................35
6.5.3. Rescue Medicine.........................................................................................36
6.6. Dose Modification...................................................................................................36
6.7. Intervention After the End of the Study..................................................................36
7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL...........................................................................37
7.1. Discontinuation of Study Intervention ....................................................................37
7.2. Participant Discontinuation/Withdrawal From the Study.......................................37
7.2.1. Withdrawal of Consent...............................................................................38
7.3. Lost to Follow-up....................................................................................................38
8. STUDY ASSESSMENTS AND PROCEDURES...............................................................39
8.1. Efficacy Assessments..............................................................................................40
8.1.1. Rater Qualifications....................................................................................40
8.1.2. Calculation of Treatable %Body Surface Area (BSA)...............................40
8.1.3. Investigator’s Static Global Assessment (ISGA) .......................................40
8.1.4. Regional ISGA-Face...................................................................................41
8.1.5. Eczema Area and Severity Index (EASI) ...................................................41

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Protocol C3291027
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8.1.6. Body Site Checklist for Atopic Dermatitis.................................................44
8.1.7. Patient/Observer Reported Outcomes........................................................44
8.1.7.1. Pruritus Assessment ..................................................................44
8.2. Safety Assessments .................................................................................................45
8.2.1. Physical Examinations................................................................................45
8.2.2. Pregnancy Testing ......................................................................................45
8.3. Adverse Events and Serious Adverse Events..........................................................45
8.3.1. Time Period and Frequency for Collecting AE and SAE Information.......46
8.3.1.1. Reporting SAEs to Pfizer Safety...............................................46
8.3.1.2. Recording Nonserious AEs and SAEs on the CRF...................47
8.3.2. Method of Detecting AEs and SAEs ..........................................................47
8.3.3. Follow-up of AEs and SAEs.......................................................................47
8.3.4. Regulatory Reporting Requirements for SAEs...........................................47
8.3.5. Exposure During Pregnancy or Breastfeeding, and Occupational 
Exposure ..........................................................................................................48
8.3.5.1. Exposure During Pregnancy......................................................48
8.3.5.2. Exposure During Breastfeeding ................................................49
8.3.5.3. Occupational Exposure .............................................................50
8.3.6. Cardiovascular and Death Events...............................................................50
8.3.7. Disease Related Events and/or Disease Related Outcomes Not 
Qualifying as AEs or SAEs..............................................................................50
8.3.8. Adverse Events of Special Interest.............................................................50
8.3.8.1. Lack of Efficacy........................................................................50
8.3.9. Medical Device Deficiencies......................................................................50
8.3.10. Medication Errors.....................................................................................51
8.4. Treatment of Overdose............................................................................................51
8.5. Pharmacokinetics ....................................................................................................51
8.6. Pharmacodynamics..................................................................................................52
8.7. Genetics...................................................................................................................53
8.8. Biomarkers ..............................................................................................................53
8.9. Immunogenicity Assessments.................................................................................53
8.10. Health Economics .................................................................................................53

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Protocol C3291027
Final Protocol, 20 May 2020
PFIZER CONFIDENTIAL
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9. STATISTICAL CONSIDERATIONS ................................................................................53
9.1. Estimands and Statistical Hypotheses.....................................................................53
9.1.1. Estimands....................................................................................................53
9.2. Sample Size Determination.....................................................................................53
9.3. Analysis Sets ...........................................................................................................53
9.4. Statistical Analyses .................................................................................................54
9.4.1. General Considerations...............................................................................54
9.4.2. Primary Endpoint(s)....................................................................................54
9.4.3. Secondary Endpoint(s)................................................................................54
9.4.4. Tertiary/Exploratory Endpoint(s) ...............................................................54
9.4.4.1. Efficacy Endpoints ....................................................................54
9.4.4.2. Pharmacokinetic Endpoints.......................................................55
9.4.5. Other Safety Analyses ................................................................................55
9.5. Interim Analyses .....................................................................................................55
9.6. Data Monitoring Committee or Other Independent Oversight Committee.............55
10. SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS..........................................................................................................56
10.1. Appendix 1: Regulatory, Ethical, and Study Oversight Considerations...............56
10.1.1. Regulatory and Ethical Considerations ....................................................56
10.1.1.1. Reporting of Safety Issues and Serious Breaches of the 
Protocol or ICH GCP.........................................................................56
10.1.2. Financial Disclosure .................................................................................57
10.1.3. Informed Consent Process ........................................................................57
10.1.4. Data Protection .........................................................................................58
10.1.5. Dissemination of Clinical Study Data ......................................................58
10.1.6. Data Quality Assurance ............................................................................60
10.1.7. Source Documents....................................................................................61
10.1.8. Study and Site Start and Closure ..............................................................61
10.1.9. Publication Policy.....................................................................................62
10.1.10. Sponsor’s Qualified Medical Personnel .................................................63
10.2. Appendix 2: Clinical Laboratory Tests .................................................................64

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Protocol C3291027
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10.3. Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting ......................................................................65
10.3.1. Definition of AE .......................................................................................65
10.3.2. Definition of SAE.....................................................................................66
10.3.3. Recording/Reporting and Follow-up of AEs and/or SAEs.......................68
10.3.4. Reporting of SAEs....................................................................................71
10.4. Appendix 4: Contraceptive Guidance ...................................................................72
10.4.1. Female Participant Reproductive Inclusion Criteria.................................72
10.4.2. Woman of Childbearing Potential ............................................................72
10.4.3. Contraception Methods.............................................................................73
10.5. Appendix 5: Liver Safety: Suggested Actions and Follow-up Assessments ........75
10.6. Appendix 6: Abbreviations ...................................................................................77
11. REFERENCES ..................................................................................................................80
LIST OF TABLES
Table 1.
Investigator’s Static Global Assessment ..............................................................41
Table 2.
Clinical Sign Severity Scoring Criteria for EASI.................................................42
Table 3.
Handprint Determination of Body Region Surface Area .....................................43
Table 4.
Eczema Area and Severity Index (EASI) Area Score Criteria.............................43
Table 5.
Eczema Area and Severity Index (EASI) Body Region Weighting.....................43
Table 6.
Protocol-Required Safety Laboratory Assessments .............................................64
LIST OF FIGURES
Figure 1.
Diagram of Study Intervention Allocation by Visit ..........................................30

Crisaborole (PF-06930164)
Protocol C3291027
Final Protocol, 20 May 2020
PFIZER CONFIDENTIAL
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1. PROTOCOL SUMMARY
1.1. Synopsis
Short Title: A Phase 3, Multicenter, Open-Label Study of the Long-Term Safety of 
Crisaborole Ointment, 2% in Japanese Pediatric and Adult Participants with Mild to 
Moderate Atopic Dermatitis
Rationale
Crisaborole development as a topical therapy for patients with mild to moderate AD is based 
on its mechanism of action and the results obtained from 11 AD clinical studies conducted in 
Japan and foreign countries to date.
In Japan, a phase 2 study (C3291028) in pediatric and adult participants with mild to 
moderate AD was completed and it showed superiority of crisaborole ointment, 2% relative 
to the corresponding vehicle in both regimens (QD and BID) for both age groups of 12 years 
and older and 2 to under 12 years old.  In addition, in the descriptive comparison of BID and 
QD regimens, crisaborole ointment, 2% BID was more effective than crisaborole ointment,
2% QD for both age groups, and both regimens were well-tolerated.
An Asia regional phase 3 study (C3291032) is planned to support the registration of 
crisaborole in China, Japan and other Asian countries/region.  In this study, the efficacy and 
safety of crisaborole ointment, 2% BID will be investigated in Asian pediatric and adult 
participants (ages 2 years and older) with mild to moderate AD.
In addition, a global phase 3 study (C3291031) is also planned to assess the efficacy, safety, 
and local tolerability of crisaborole ointment, 2%, applied twice a day in participants who are 
1 month to less than 24 months of age with mild to moderate AD.
The purpose of this long-term extension study (C3291027) is to assess the one-year long-
term safety of crisaborole ointment, 2% BID in Japanese AD pediatric and adult participants 
who completed study intervention period in the studies C3291032 or C3291031.
Objectives, Estimands, and Endpoints
Objectives
Estimands
Endpoints
Primary: 
Primary:
Primary: 
To study the safety of crisaborole 
ointment, 2% applied BID in Japanese 
pediatric and adult participants with 
mild to moderate AD
There is no defined estimand 
for this objective and these 
endpoints will be analyzed 
descriptively.
The incidence of treatment emergent 
adverse events and serious adverse
events

Crisaborole (PF-06930164)
Protocol C3291027
Final Protocol, 20 May 2020
PFIZER CONFIDENTIAL
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Overall Design
This study is a Phase 3, multicenter, open-label, long-term safety extension study of Studies 
C3291032 and C3291031 in Japanese pediatric and adult participants with mild to moderate 
AD to support the registration of crisaborole in Japan.  After completion of the study 
intervention period in Study C3291032 or Study C3291031 and confirmed Study C3291027 
eligibility, participants will be offered participation in the study from investigator sites in 
Japan. Scheduled study visits will occur every 4 weeks (1 cycle) with On-Treatment or Off-
Treatment cycles to be decided by the investigator based on the ISGA score.  PK blood 
sampling will be conducted at the selected study sites for the participants aged between 2 
years old and 11 years old at the time of signing the ICD in Study C3291032.
When the investigator assessment of ISGA is Almost Clear (1) or greater, an On-Treatment 
Cycle will be initiated. When the investigator assessment of ISGA is Clear (0), crisaborole 
ointment, 2% treatment will not be initiated and the participant will enter an Off-Treatment 
Cycle.  Based on the ISGA score throughout the study, a participant may be administered a 
variable number of cycles of crisaborole ointment, 2% treatment (On-Treatment Cycle) 
during their up to 52 weeks of study participation.
On Week 56 (EOS), a follow-up telephone call will be made by site staff to assess for AEs 
that may have occurred since the last visit.
Number of Participants
Sample size will be determined by the number of participants who enroll from the qualifying 
parent studies.  It is estimated that at least 150 participants (ie, 20 participants for under 2
years old and 130 participants for 2 years and older) are expected to join from the currently 
planned qualifying parent studies.  Analyses performed, including interim evaluations, if any, 
will primarily be for safety though some measures of efficacy may be analyzed.
Intervention Groups and Duration
All participants will receive crisaborole ointment, 2% BID for up to 52 weeks.
The expected total duration of participation in the study is 56 weeks, including an open label 
intervention period of 52 weeks and a follow up period of 4 weeks after EOT.
Data Monitoring Committee or Other Independent Oversight Committee: Yes
Statistical Methods
The primary endpoint of incidence of safety events will be analyzed using descriptive 
measures such as percentages and exposure-adjusted incidence rates along with confidence 
intervals.  No statistical hypotheses will be tested.

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Protocol C3291027
Final Protocol, 20 May 2020
PFIZER CONFIDENTIAL
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All the safety data will be summarized descriptively through appropriate data tabulations, 
descriptive statistics, and graphical presentations.
Efficacy analyses will be descriptive in nature; there will be no formal hypothesis testing, 
though 95% two-sided confidence intervals will be reported.
1.2. Schema

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Protocol C3291027
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1.3. Schedule of Activities
The SoA table provides an overview of the protocol visits and procedures.  Refer to the STUDY ASSESSMENTS AND 
PROCEDURES section of the protocol for detailed information on each procedure and assessment required for compliance with the 
protocol.
The investigator may schedule visits (unplanned visits) in addition to those listed in the SoA table, in order to conduct evaluations or 
assessments required to protect the well-being of the participant.
Visit Identifiera
Abbreviations used in this table may 
be found in Appendix 6.
Enrollment 
Visit
Intervention Period
Follow-up Contactb
Visit 1
Visit 2-13
Unplanned
Visit 
to initiate study 
intervention 
during Off-
Treatment 
Cycle
Visit 14
Visit 15
Day 1c
Weeks 4, 8, 12, 16, 20, 24, 28, 32, 
36, 40, 44, 48
Week 52/ 
EOT/ET
Week 56/EOS
Days 29, 57, 85, 113, 141, 169, 197, 225, 253, 
281, 309, 337
Day 365/ 
EOT/ET
Day 393/EOS
At least 28 days after 
last study dose
Start Day of 
On-Treatment Cyclec
Start Day of 
Off-Treatment Cyclec
Visit Window
±7 days based on Day 1
±7 days based 
on Day 1
+7 days based on 
Week 52/EOT/ET
Informed consent, including assent
Xd
Registration
X
Demographics and medical history 
including AD history/prior AD 
treatment (including reasons of stop)
Xe
Current/prior treatments for 
current/prior medical history other 
than AD
Xe
Inclusion/exclusion criteria
X
Physical examination
Xe
X (Week 24 only)
X (Week 24 only)
X
Weight (age ≥18)
X
X
Height and Weight (age <18)
Xe
X (Weeks 12, 24, 
36, 48 only)
X (Weeks 12, 24, 
36, 48 only)
X
Laboratory
Pregnancy testf
Xe
X
X
X

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Protocol C3291027
Final Protocol, 20 May 2020
PFIZER CONFIDENTIAL
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Visit Identifiera
Abbreviations used in this table may 
be found in Appendix 6.
Enrollment 
Visit
Intervention Period
Follow-up Contactb
Visit 1
Visit 2-13
Unplanned
Visit 
to initiate study 
intervention 
during Off-
Treatment 
Cycle
Visit 14
Visit 15
Day 1c
Weeks 4, 8, 12, 16, 20, 24, 28, 32, 
36, 40, 44, 48
Week 52/ 
EOT/ET
Week 56/EOS
Days 29, 57, 85, 113, 141, 169, 197, 225, 253, 
281, 309, 337
Day 365/ 
EOT/ET
Day 393/EOS
At least 28 days after 
last study dose
Start Day of 
On-Treatment Cyclec
Start Day of 
Off-Treatment Cyclec
Visit Window
±7 days based on Day 1
±7 days based 
on Day 1
+7 days based on 
Week 52/EOT/ET
Contraception checkg
X
X
X
X
X
Study intervention
Body Site Checklist of AD lesions
X
X
X
X
Record treatable AD areas
X
X
X
Study Intervention Dispensingh
Xi
X
X
Instruction for dosing and dispense 
dosing diary
Xi
X
X
Weigh the investigational product 
tube(s) and dispense
Xi
X
X
Study intervention administration
Xi
BID, throughout 
On-Treatment Cyclej,k
BID, for the 
remainder of a 
treatment cyclej,k
Review dosing diary; assess 
compliance
Xl
Xl
Xl
Collect and weigh returned 
investigational product tubes, 
including empty, partially used and 
unused tubes
Xl
Xl
Xl
Assessments
Calculate and record treatable 
%BSA
Xe
X
X
X
X
ISGAm
Xe
X
X
X
X
Regional ISGA-facem,o
Xe
X
X
X
EASIm
Xe
X
X
X

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Protocol C3291027
Final Protocol, 20 May 2020
PFIZER CONFIDENTIAL
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Visit Identifiera
Abbreviations used in this table may 
be found in Appendix 6.
Enrollment 
Visit
Intervention Period
Follow-up Contactb
Visit 1
Visit 2-13
Unplanned
Visit 
to initiate study 
intervention 
during Off-
Treatment 
Cycle
Visit 14
Visit 15
Day 1c
Weeks 4, 8, 12, 16, 20, 24, 28, 32, 
36, 40, 44, 48
Week 52/ 
EOT/ET
Week 56/EOS
Days 29, 57, 85, 113, 141, 169, 197, 225, 253, 
281, 309, 337
Day 365/ 
EOT/ET
Day 393/EOS
At least 28 days after 
last study dose
Start Day of 
On-Treatment Cyclec
Start Day of 
Off-Treatment Cyclec
Visit Window
±7 days based on Day 1
±7 days based 
on Day 1
+7 days based on 
Week 52/EOT/ET
Peak Pruritus NRS/Patient 
Reported Itch Severity Scale/ 
Observer Reported Itch Severity 
Scalen
Xe
X
X
X
Concomitant treatment(s)
Xe




X
Serious and nonserious adverse event 
monitoring
Xe





Review lifestyle considerations
X
X
X
X
X
Schedule/reconfirm next study visit or 
contact
X
X
X
X
Remind to bring all investigational 
product tubes and the dosing diary to 
the next visit
Xi
X
Xp
X
Blood sampling to obtain plasma for 
crisaborole and metabolites PK
Xq
a.
Day relative to start of study intervention (Day 1).
b.
Contact may occur via telephone contact and must occur 28 to 35 days from Week 52/EOT/ET Visit.
c.
Day 1 will be the same day as EOT visit of Study C3291032 or C3291031.  Procedure done at Day 1 Visit of next treatment cycle.  Depending upon ISGA 
score and investigator’s judgment, participant will initiate an “On-treatment Cycle” or “Off-treatment Cycle”.
d.
Obtain written informed consent (from adult participant or parent/legal guardian of pediatric participant) and assent (from pediatric participant, as 
applicable) before any study procedures are performed.
e.
Procedure done at Day 29 (concomitant treatment, physical examination, %BSA, ISGA, Regional ISGA-face, EASI, Peak Pruritus NRS/Patient Reported 
Itch Severity Scale/ Observer Reported Itch Severity Scale, urine pregnancy test and AE/SAE) and Screening (medical history including AD history/prior 
AD treatment) of Study C3291032 or  procedure done at Week 24 (concomitant medications/therapies, physical examination, height/length and 

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Protocol C3291027
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Visit Identifiera
Abbreviations used in this table may 
be found in Appendix 6.
Enrollment 
Visit
Intervention Period
Follow-up Contactb
Visit 1
Visit 2-13
Unplanned
Visit 
to initiate study 
intervention 
during Off-
Treatment 
Cycle
Visit 14
Visit 15
Day 1c
Weeks 4, 8, 12, 16, 20, 24, 28, 32, 
36, 40, 44, 48
Week 52/ 
EOT/ET
Week 56/EOS
Days 29, 57, 85, 113, 141, 169, 197, 225, 253, 
281, 309, 337
Day 365/ 
EOT/ET
Day 393/EOS
At least 28 days after 
last study dose
Start Day of 
On-Treatment Cyclec
Start Day of 
Off-Treatment Cyclec
Visit Window
±7 days based on Day 1
±7 days based 
on Day 1
+7 days based on 
Week 52/EOT/ET
weight, %BSA, EASI, ISGA, Observer Reported Itch Severity Scale, and AE/SAE) and Screening (medical history including AD history/prior AD 
treatment) of Study C3291031 will serve as Enrollment Visit data for Study C3291027.
f.
For all female participants biologically capable of having children (refer to Section 10.4.2 for definition of a female of childbearing potential).  The 
participant and his/her parent/legal guardian will be instructed regarding the contraception method requirement and informed of the requirement to conduct a 
urine pregnancy test.  Pediatric female participant who has not experienced menarche is not required to perform pregnancy testing.  If the pediatric female 
participant starts menarche during the study, pregnancy testing will be performed.
g.
For studies enrolling pediatric participants, it is the opportunity to assess changing potential to father/bear children and allows for implementing 
contraception and pregnancy testing as children mature physically and behaviorally during conduct of the study.
h.
Study coordinator or specified designee will contact IRT to register the visit and, if applicable, obtain the next investigational product tube(s) assignment.
i.
Participant who will start “On-treatment Cycle” from Enrollment Visit.
j.
At home dosing by participant or his/her parent/legal guardian.  Investigational product application BID through the evening before the day of visit.  After 
the procedure/assessment of the visit, the participant or his/her parent/legal guardian can apply the investigational product, if applicable.
k.
In the event the scheduled Start Day of the next treatment cycle visit does not fall exactly on the scheduled date, the participant or his/her parent/legal 
guardian will be instructed to continue investigational product application BID through the evening before the actual visit date.
l.
Performed only for those participants completing a previous On-Treatment Cycle (e.g., Previous “On-treatment” and continue “On-treatment”, or previous 
“On-treatment” and initiate “Off-treatment”).
m. The ISGA should be completed prior to Regional ISGA-face and EASI assessments, whenever possible.
n.
Peak Pruritus NRS will be completed by participants ≥12 years of age at the time of signing the ICD in the prior study, Patient Reported Itch Severity Scale 
will be completed by participants ≥6 years and <12 years at the time of signing the ICD in the prior study, and Observer Reported Itch Severity Scale will be 
completed by the observers (caregivers of participants) for participants <6 years of age at the time of signing the ICD in the prior study.
o.
Only for participants who completed study intervention for Study C3291032 and had AD in face at Day 1 Visit of Study C3291032.
p.
Performed to remind the participants initiating “Off-treatment Cycle” to bring back dosing diary which records concomitant medication usage.
q.
PK blood sampling will be conducted at the selected study sites in participants aged between 2 years old and 11 years old at the time of signing the ICD in 
Study C3291032.  The date and time for most recent dose (last dose in C3291032 study) will be collected.

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2. INTRODUCTION
Crisaborole, also referred to as PF-06930164 and AN2728, is a low molecular weight 
benzoxaborole anti-inflammatory PDE-4 inhibitor that penetrates 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 TNF-α, IL-2, IL-4, IL-5, and IFN-γ, implicated in the pathogenesis of AD.  
Crisaborole applied to human skin ex vivo or on 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 MMP-12.  The specific 
mechanism(s) by which crisaborole exerts its therapeutic action for AD is not well defined.1
Crisaborole ointment, 2% (20 mg/g) (referred to as crisaborole hereafter), is an approved 
therapy in the US and Canada (EUCRISA®), and EU, Israel and Australia (STAQUIS®) as a 
topical treatment in patients 2 years of age and older with mild to moderate AD.1  In 2020, 
crisaborole also obtained supplemental approval for treatment in patients as young as 3 
months of age in US.2  It is currently being developed worldwide as a topical therapy for 
patients with mild to moderate AD.
2.1. Study Rationale
Crisaborole development as a topical therapy for patients with mild to moderate AD is based 
on its mechanism of action and the results obtained from 11 AD clinical studies conducted in 
Japan and foreign countries to date.
In Japan, a phase 2 study (C3291028) in pediatric and adult participants with mild to 
moderate AD was completed and it showed superiority of crisaborole ointment, 2% relative 
to the corresponding vehicle in both regimens (QD and BID) for both age groups of 12 years 
and older and 2 to under 12 years old. In addition, in the descriptive comparison of BID and 
QD regimens, crisaborole ointment, 2% BID was more effective than crisaborole ointment,
2% QD for both age groups, and both regimens were well-tolerated.
An Asia regional phase 3 study (C3291032) is planned to support the registration of 
crisaborole in China, Japan and other Asian countries/region.  In this study, the efficacy and 
safety of crisaborole ointment, 2% BID will be investigated in Asian pediatric and adult 
participants (ages 2 years and older) with mild to moderate AD.
In addition, a global phase 3 study (C3291031) is also planned to assess the efficacy, safety, 
and local tolerability of crisaborole ointment, 2%, applied twice a day in participants who are 
1 month to less than 24 months of age with mild to moderate AD.
The purpose of this long-term extension study (C3291027) is to assess the one-year long-
term safety of crisaborole ointment, 2% BID in Japanese AD pediatric and adult participants 
who completed study intervention period in Study C3291032 or Study C3291031.

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2.2. Background
AD, also referred to as atopic eczema, is a chronic and relapsing disease affecting an 
increasing number of persons.  Although AD affects patients of all ages, it is one of the most 
common, chronic, relapsing childhood dermatoses.  The lifetime prevalence of AD is 
estimated to be 15% to 30% in children while the incidence of AD has increased by 2- to 3-
fold during the past 3 decades in industrialized countries.3 Over the past 50 years, AD has 
become more prevalent, especially in industrialized, temperate countries such as the US and 
Japan.4-6
AD is a distinctive inflammatory, highly pruritic, chronic eczematous condition that usually 
occurs in people who have a personal or family history of other atopic conditions such as 
asthma or allergic rhinitis.5,7  The majority of patients (up to 90%) with AD present with mild 
to moderate disease.8  Manifestation of the disease includes intense pruritus, erythematous 
papules, excoriation, exudation, lichenification, and bacterial colonization.9 Continuous 
scratching during exacerbations can lead to lichenification, excoriations, and serious skin 
infections.  AD is often associated with other conditions including asthma, allergic rhinitis, 
and food allergy.10,11
AD is a condition associated with significant morbidity.  The burden of the clinical 
symptoms of AD coupled with the stigma associated with highly visible skin lesions 
correlates with significant morbidity and extensive impairments on HRQOL for patients, 
especially in children, and caregivers.7,12-14  Psychosocial problems, depression, and anxiety 
are associated with AD in both adults and children.15 The negative impact on HRQOL 
caused by childhood AD exceeds that in asthma, epilepsy, and diabetes, is comparable to that 
in renal disease or cystic fibrosis, and is equal (child) or exceeds (parents) that in 
psoriasis.13,16,17  The hallmark symptom of itching causes scratching which is associated with 
sleep disturbance in greater than 60% of patients.  Sleep deprivation leads to physical and 
mental exhaustion in patients and other family members resulting in loss of concentration 
and impaired performance at school or work.18,19  AD is often associated with significant 
childhood behavioral problems and psychological disorders including depression, attention 
deficit hyperactivity disorder, anxiety, stress, and autism.15 Preschool children with AD 
show a significant increase in behavioral symptoms compared with age-matched controls.20  
Absolon et al21 reported that the rate of psychological disturbance in school age children with 
AD doubled compared with age-matched matched controls.  For older children with AD, in 
addition to problems associated with itching and sleep disturbance, their social and school 
life may be substantially affected.  Social embarrassment, due to visible signs of the disease 
(crusted, excoriated, oozing, bleeding lesions), teasing, and bullying, often results in social 
isolation leading to depression.16
AD has a significant impact on day to day functioning, as evidenced by its impact on the 
overall wellbeing of the patient and their family on multiple levels; medical management and 
treatment; HRQOL; and psychosocial implications.  In summary, AD is a disease with
multiple comorbidities and significant impact on the health, day to day functioning, and 
HRQOL of AD patients, their caregivers, and family members.

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AD may also be a source of significant economic burden22 as this relapsing disease is often 
misdiagnosed, misunderstood, and ineffectively treated.5
Currently, there is no cure for AD.  AD is a chronic disease with treatment focused on the 
management of flares and maintenance of remissions.  Due to the chronic, relapsing nature of 
the disease, treatment may be needed for many years.
Crisaborole is a novel, non-steroid, topical anti-inflammatory PDE-4 inhibitor that will serve 
an unmet need in the treatment of AD.  Supporting evidence of the safety and efficacy of this 
product in patients 2 years and older represent a major advancement in the treatment of AD 
given the challenges of managing this common, chronic dermatologic condition and the 
limitations on patient age, location, duration of use and line of therapy of currently available 
therapies.  All primary and secondary efficacy endpoints were statistically significant in 
favor of crisaborole ointment, 2% BID versus vehicle ointment BID in the two Phase 3 
pivotal studies, AN2728-AD-301 and AN2728-AD-302.23 Across the development program, 
crisaborole demonstrated an acceptable safety profile; the majority of AEs was mild and 
deemed unlikely or not related to study intervention, with no crisaborole treatment-related 
SAEs (except 1 case of drug eruption in a Phase 2 study which was classified as possibly 
related).  Efficacy, safety and tolerability of crisaborole ointment, 2% BID in patients 
younger than 2 years of age was investigated in Study C3291002 (NCT03356977) conducted 
in participants aged 3 months to less than 24 months.  This product was well-tolerated, and 
overall the safety profile and efficacy observed in this study was consistent with that
observed in previous studies of crisaborole in participants 2 years of age and older.
2.2.1. Drug Development
Crisaborole has been formulated as a topical ointment.  Crisaborole has demonstrated clinical 
benefit in 10 AD clinical studies in Phases 1, 2, and 3.  Details of the nonclinical and clinical 
data are provided in the investigator’s brochure.
2.2.2. Nonclinical Studies
Crisaborole demonstrated inhibitory capacity against human leukocyte cytokine release with 
IC50 and EC50 values ranging from high nanomolar to low micromolar concentrations.
Crisaborole also inhibits the release of chemokines that are important inflammatory 
mediators. The primary mechanism of the anti-inflammatory effect of crisaborole is through 
inhibition of PDE-4, which causes elevation of cAMP in leukocytes and subsequent protein 
kinase A mediated phosphorylation of transcription factors that are important for cytokine-, 
chemokine-, or prostaglandin-forming enzyme synthesis and release from cells.  Crisaborole 
proved efficacious against an inflammatory challenge in vivo in a mouse PMA-induced ear 
edema model. AN7602 and AN8323, the predominant oxidative metabolites of crisaborole, 
lack anti-inflammatory activities against PDE-4 and a panel of cytokines.
Based on the nonclinical safety studies conducted to date, crisaborole ointment, 2% has an 
acceptable safety profile.

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2.2.3. Pharmacokinetics
The efficacy of crisaborole for the topical treatment of AD is not by systemic exposure. The 
development program evaluated systemic exposure to crisaborole and its main metabolites 
relative to establishing the safety of topically applied crisaborole. Systemic exposures to 
crisaborole following topical application were assessed in healthy volunteers and patients 
(AD and psoriasis).  Crisaborole was shown to have penetrated through the stratum corneum, 
epidermis, and dermis of human skin and had measurable systemic exposures.
A review of the PK data across the studies reveals an apparent relationship between exposure 
and %BSA treated with crisaborole topical ointment, 2%.  In studies conducted in AD 
patients (AN2728-AD-203 and AN2728-AD-102), absorption of crisaborole across the skin 
was rapid, as evidenced by median Tmax values of 3.0 hours or less following single and 
multiple doses of crisaborole topical ointment, 2%.  Crisaborole was rapidly metabolized to 
AN7602 and then to AN8323; both metabolites are inactive as PDE-4 inhibitors.  Exposure 
to crisaborole and AN7602 was limited, while AN8323 was the predominant metabolite in 
plasma, as shown by comparison of Cmax and AUC values both following single and multiple 
doses of crisaborole topical ointment, 2%.  Overall, the extent of systemic exposure (Cmax
and AUC) of crisaborole, AN7602, and AN8323 increased with higher %BSA treated.  
Minimal accumulation of crisaborole or AN7602 occurred over 8 days of dosing.  AN8323 
displayed moderate accumulation, consistent with its long t½ (33.5 hours on Day 8 in 
Study AN2728-AD-203).  Steady state was apparently achieved within 4 to 6 days for all 
3 analytes in both studies.  The systemic exposure of crisaborole following topical 
administration was higher in participants with AD relative to healthy volunteers.  Based on 
observed systemic exposures observed in healthy adults, children, adolescent participants (2 
to 17 years of age) with AD, and adult participants with psoriasis, at similar percent treated 
BSA, crisaborole systemic exposures across age groups are expected to be in a similar range.  
Crisaborole systemic exposure in children (≥2 years) at maximum possible dose are unlikely 
to exceed the exposures at the maximum possible dose in adults.
In the 8-days, safety, tolerability and PK study (Cohort 2 in Study C3291029), 10 adult 
Japanese participants with mild to moderate AD (20-55 years old) received crisaborole 
ointment, 2% (mean treatable %BSA 63.9%; range 35%-87%), absorption across the skin 
was rapid, with a median of time to reach Tmax of 3.0 hours on both Day 1 and Day 8.  Mean 
Cmax values in plasma were 199 ng/mL on Day 1, and 185 ng/mL on Day 8, respectively. 
Overall, the extent of systemic exposure (plasma Cmax and AUC) of crisaborole, AN7602, 
and AN8323 increased with higher %BSA treated. Minimal plasma accumulation of 
crisaborole and AN7602 was observed at steady state whereas AN8323 displayed an 
approximately 3-fold accumulation based on Cmax and AUC12. Steady state was achieved by 
Day 7 for crisaborole and its metabolites.  The %BSA normalized systemic exposure of 
crisaborole, AN7602, and AN8323 (Cmax and AUC12) were similar between C3291029 study 
and AD-102 study.
The PK profiles of crisaborole and its metabolites were assessed in 3 months to 2-year-old 
infants as a PK sub-study in a Phase 4, multicenter, open label safety study (Study 
C3291002). The participants in the PK sub study ranged in age from 3 to 23 months with 

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7 participants <9 months of age and 14 participants of 9 to 24 months of age.  The %treatable 
BSA ranged from 35% to 79% at baseline. Following multiple BID administration systemic 
exposures were characterized on Day 8.  Crisaborole systemic exposures in children (> 3 
months of age) at maximum possible dose are unlikely to exceed the systemic exposures at 
the maximum possible dose in adults.
2.2.4. Cutaneous Sensitization, Irritancy Potential and Tolerability
2.2.4.1. Skin Irritation Study
The investigational products (crisaborole ointment, 2% and vehicle) were applied topically to 
1-side of the infrascapular area of the back once on Day 1 and remained under occlusion for 
48 hours (Cohort 1 in Study C3291029) to Japanese healthy participants.  The skin irritancy 
was to be evaluated approximately 30 minutes after removal of the patches on Day 3 and 24 
hours after removal of the patches on Day 4.  The degree of erythema, edema and other signs 
of skin irritation at the application site was evaluated using the visual scale.  All participants 
for the crisaborole ointment, 2% patch had a maximum irritation score of 0 (No reaction) or 
0.5 (Mild erythema) except for the 3 participants with a maximum irritation score of 2
(Erythema + edema, papula).
2.2.4.2. Local Tolerability in Sensitive Skin Area
In a study of healthy participants (16 men and 16 women) who applied crisaborole ointment,
2% or vehicle for 21 days to sensitive area application sites (including extensor areas,
intertriginous areas, genitals, and face/hairline), 99% of assessments of local tolerability 
were graded as 0 (none), with an overall maximum grade of 2 (moderate) and only 0.1% of 
assessments graded higher than 1 (mild) (Study AN2728-PSR-107). There were no marked 
differences in burning/stinging, erythema, or pruritus at any of the application sites over the 
course of the study between participants who received crisaborole ointment, 2% or vehicle.  
Overall, crisaborole ointment, 2% was well tolerated over 21 days of dosing in sensitive skin
areas of healthy participants.
2.2.4.3. Sensitizing and Cumulative Irritation Potential
In a repeat-insult patch test and cumulative irritation study in healthy participants 
(Study AN2728-RIPT-101), the potential for inducing cutaneous sensitization was assessed 
in 238 participants randomized in Cohort 1. None of the participants demonstrated cutaneous 
evidence of sensitization potential (a reaction of at least Grade 4 [definite edema] or a pattern 
suggestive of contact sensitization in the opinion of the Investigator) to the investigational 
products, crisaborole ointment, 2% or vehicle. The potential for causing cutaneous irritation 
was evaluated among 40 participants randomized in Cohort 2. There were no statistically 
significant differences in irritation between the crisaborole ointment, 2% and vehicle.  
Crisaborole ointment, 2% and vehicle showed no evidence of sensitization and only very 
minimal irritation.

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2.2.5. Clinical Overview
Eleven (11) clinical trials of topical formulations of crisaborole have been completed to date 
in participants with AD.  Key study information is summarized below.

In a multicenter, MUSE study in 34 pediatric participants with mild to moderate AD 
involving ≥35% BSA (ages 2 to 11 years) or ≥25% BSA (ages 12 to 17 years), who 
applied crisaborole ointment, 2% BID (AN2728-AD-102), participants had overall 
plasma levels of crisaborole that were low and similar to those previously observed in 
adults after adjusting for %BSA treated.  Absorption across the skin was rapid, with a 
median Tmax of 3.0 hours on both Day 1 and Day 8.  Systemic levels of crisaborole and its 
main metabolites, AN7602 and AN8323, were similar among 3 age cohorts.

In a 4-week, single arm, open-label safety, tolerability, and PK trial in adolescents with 
mild to moderate AD involving 10% to 35% BSA (AN2728-AD-203), disease severity 
improved over the 28-day treatment period.

In a PK study conducted in adult Japanese participants with mild to moderate AD 
(C3291029 Cohort 2) having at least 25% treatable BSA, crisaborole showed minimal 
accumulation and steady state was achieved by Day 7.  Absorption across the skin was 
rapid, with a median Tmax of 3.0 hours on both Day 1 and Day 8.  Systemic levels of 
crisaborole and its metabolites were in the same range as that observed for non-Japanese 
participants in the MUSE study (AN2728-AD-102).

In a 6-week, randomized, vehicle-controlled intra-participant efficacy and biomarker 
study of adult participants with mild to moderate AD (C3291001), crisaborole ointment, 
2% applied BID statistically significantly improved lesion TSS more than vehicle at 
Day 15 (primary efficacy endpoint).  Crisaborole significantly reduced 7 key skin 
biomarkers of AD from Baseline to Day 15 (primary biomarker endpoint).

In a 6-week bilateral comparison trial of participants with mild to moderate AD 
(AN2898-AD-202), 68% of AD lesions treated with crisaborole ointment, 2% BID 
showed greater improvement in ADSI than vehicle treated lesions (20%) at 4 weeks 
(primary endpoint).  These response rates were similar at Day 14 and Day 42 (EOT).

In a 4-week bilateral comparison trial of 86 adolescent participants with mild to moderate 
AD (AN2728-AD-204), crisaborole ointment, 2% BID showed greater improvement than 
the lower concentration of crisaborole ointment, 0.5% applied BID for 29 days, and was 
more efficacious than either concentration applied QD.

In two Phase 3 multicenter, randomized, double-blind, vehicle-controlled studies in 
participants ≥2 years of age and older with mild to moderate AD, crisaborole ointment, 
2% BID outperformed the vehicle in the primary efficacy analysis of success in ISGA 
and the difference between the treatment groups was statistically significant (AN2728-
AD-301, AN2728-AD-302).

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
An additional Phase 3 multicenter, open-label, long-term extension study of crisaborole 
ointment, 2% BID for the treatment of mild to moderate AD in adults and children as 
young as 2 years of age affirmed the long-term safety of topical crisaborole (AN2728-
AD-303).  No clinically important systemic safety signals were identified by this study.

In a Phase 4, multicenter, open-label safety study to evaluate the safety of crisaborole
ointment, 2% in children 3 to <24 months of age, with mild to-moderate AD involving 
≥5% treatable BSA, exploratory efficacy was assessed and results showed that the 
treatment response of crisaborole in this population of participants 3 to <24 months of 
age is consistent with that from the Phase 3 studies. In this study, crisaborole was well-
tolerated, no evidence of propylene glycol-related AEs, such as cardiac or neurologic 
disorders, was apparent in the 3 to <24 month age group (C3291002). Overall the safety 
profile observed in this study was consistent with that observed in previous studies of 
crisaborole in participants 2 years of age and older.

In a Phase 2b, multicenter, randomized, double-blind, vehicle-controlled, intra-participant
study to evaluate efficacy and safety of two regimens of crisaborole ointment, 2% in 
Japanese pediatric and adult participants with mild to moderate AD involving at least 
1.0% and no more than 30% treatable %BSA (C3291028), superiority of crisaborole 
ointment, 2% relative to the corresponding vehicle was shown in both regimens (QD and 
BID) for both age groups of 12 years and older and 2 to under 12 years old, and its 
primary endpoint was met.  In addition, in the descriptive comparison of BID and QD 
regimens under unblinded, crisaborole ointment, 2% BID was more effective than 
crisaborole ointment, 2% QD for both age groups, and both regimens were well-tolerated.
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 
young as 3 months of age.  Most AEs have been mild and most considered unrelated or 
unlikely to be related to study intervention.  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 investigator’s 
brochure.
2.3. Benefit/Risk Assessment
More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of crisaborole may be found in the investigator’s brochure, which is the SRSD 
for this study.

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2.3.1. Risk Assessment
Potential Risk of Clinical 
Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Study Intervention(s): crisaborole ointment, 2%
There are no important 
identified risks nor
important potential risks for 
crisaborole.
The most common drug-related AEs from the Phase 
3 clinical trials 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 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.
N/A
2.3.2. Benefit Assessment
The expected efficacy of crisaborole ointment, 2% BID for the treatment of AD is based on 
the results of clinical studies conducted to date.
Clinical efficacy of a BID regimen of crisaborole ointment, 2% was demonstrated in two
Phase 3, randomized, double-blind, vehicle-controlled studies (AN2728-AD-301 and 
AN2728-AD-302), and a Phase 3 open-label long-term safety study up to 48 weeks 
(AN2728-AD-303) in participants with mild to moderate AD aged 2 years and older. In 
addition, a Phase 2b study (C3291028) also demonstrated efficacy of a BID regimen of 
crisaborole ointment, 2% in Japanese patients with mild to moderate AD aged 2 years and 
older. Furthermore, exploratory efficacy assessments of Phase 4 open-label study in 
participants with mild to moderate AD aged 3 to <24 months (C3291002) showed results that 
were consistent with the results observed in the Phase 3 studies.
2.3.3. Overall Benefit/Risk Conclusion
The benefit/risk is favorable in adults and children ≥3 months of age.  In Study C3291027, 
the benefit/risk is further being assessed in Japanese adult and pediatric AD patients.  Study 
participants will be monitored closely during the study for safety and local tolerability AEs 
by the investigators, sponsor, and an E-DMC.
3. OBJECTIVES, ESTIMANDS, AND ENDPOINTS
Objectives
Estimands
Endpoints
Primary: 
Primary:
Primary: 
To study the safety of crisaborole 
ointment, 2% applied BID in Japanese 
There is no defined estimand 
for this objective and these 
The incidence of treatment emergent 
adverse events and serious adverse 
events

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Objectives
Estimands
Endpoints
pediatric and adult participants with 
mild to moderate AD
endpoints will be analyzed 
descriptively.
Tertiary/Exploratory: 
Tertiary/Exploratory:
Tertiary/Exploratory: 
To characterize the efficacy of long-
term administration of crisaborole 
ointment, 2%
To characterize the patient/observer 
reported outcomes for pruritus of long-
term administration of crisaborole 
ointment, 2%
There is no defined estimand 
for this objective and these 
endpoints will be analyzed 
descriptively.
Efficacy*
% change from baseline in EASI over 
time
Achievement of EASI50 (≥50% 
improvement from baseline) over time
Achievement of EASI75 (≥75% 
improvement from baseline) over time
Change from baseline in Treatable 
%BSA over time
Achievement of success in ISGA 
[defined as an ISGA score of Clear (0) 
or Almost Clear (1) with at least a 2-
grade improvement from baseline] 
over time
Achievement of improvement in 
ISGA [defined as an ISGA score of 
Clear (0) or Almost Clear (1)] over 
time
Achievement of success in Regional 
ISGA-face [defined as a Regional 
ISGA-face score of Clear (0) or 
Almost Clear (1) with at least a 2-
grade improvement from baseline] 
over time
Achievement of improvement in 
Regional ISGA-face [defined as a 
Regional ISGA-face score of Clear (0) 
or Almost Clear (1)] over time
Incidence of the use of rescue 
medication (topical corticosteroids or 
topical calcineurin inhibitors)
Patient/Observer Reported Outcomes
Change from baseline in Peak Pruritus 
NRS over time - for participants ≥12 
years
Changes from baseline in Patient 
Reported Itch Severity Scale over time 
- for participants ≥6 years and <12 
years
Change from baseline in Observer 
Reported Itch Severity Scale over time 
- for participants <6 years
To assess the PK profile of crisaborole 
and its identified main oxidative 
metabolites (AN7602 and AN8323) 
following multiple topical doses of 
crisaborole ointment, 2% BID from 
C3291032 on Day 1
There is no defined estimand 
for this objective and these 
endpoints will be analyzed 
descriptively.
Plasma concentrations of crisaborole 
and its identified main oxidative 
metabolites (AN7602 and AN8323) 
on Day 1
* Baseline refers to the baseline data of Study C3291032 or Study C3291031.

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4. STUDY DESIGN
4.1. Overall Design
This study is a Phase 3, multicenter, open-label, long-term safety extension study of Studies
C3291032 and C3291031 in Japanese pediatric and adult participants with mild to moderate 
AD to support the registration of crisaborole in Japan.  After completion of the study 
intervention period in Study C3291032 or Study C3291031 and confirmed Study C3291027 
eligibility, participants will be offered participation in the study from investigator sites in 
Japan. The sample size of this study is approximately 150 participants but will be 
determined by the number of participants who complete Study C3291032 treatment period or 
Study C3291031 treatment period and meet eligibility criteria of this study. Scheduled study 
visits will occur every 4 weeks (1 cycle) with On-Treatment or Off-Treatment cycles to be 
decided by the investigator based on the ISGA score.  PK blood sampling will be conducted
at the selected study sites for the participants aged between 2 years old and 11 years old at 
the time of signing the ICD in Study C3291032.
When the investigator assessment of ISGA is Almost Clear (1) or greater, an On-Treatment 
Cycle will be initiated. When the investigator assessment of ISGA is Clear (0), crisaborole 
ointment, 2% treatment will not be initiated and the participant will enter an Off-Treatment 
Cycle.  Based on the ISGA score throughout the study, a participant may be administered a 
variable number of cycles of crisaborole ointment, 2% treatment (On-Treatment Cycle) 
during their up to 52 weeks of study participation.
On Week 56 (End of Study), a follow-up telephone call will be made by site staff to assess 
for AEs that may have occurred since the last visit.
4.2. Scientific Rationale for Study Design
Crisaborole ointment, 2% BID is approved for use in atopic dermatitis in Australia, Canada, 
EU, Israel and US without any contraceptive precautions. There is no suspicion of human 
teratogenicity based on the results of nonclinical studies and the route of administration. See 
Appendix 4 for contraceptive requirements.
4.3. Justification for Dose
In this study, the participants will apply crisaborole ointment, 2% BID during On-Treatment 
Cycle.
Crisaborole ointment, 2% BID is selected as the highest well-tolerated dose to maximize the 
potential for efficacy with minimal safety risk based on the results of foreign clinical studies, 
and 2% was technically the maximum dose for ointment formulation.  In addition, the 
descriptive comparison of BID and QD regimens in Japanese AD patients was conducted in 
Study C3291028, crisaborole ointment, 2% BID was more effective than crisaborole 
ointment, 2% QD for Japanese adults and pediatrics participants. Regarding safety, 
crisaborole ointment, 2% BID was safe and tolerable for both Japanese adults and pediatric 
participants. Parent studies C3291032 and C3291031 are conducted using crisaborole 
ointment, 2% BID.

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This study also has Off-Treatment Cycle to evaluate long term safety and efficacy of 
crisaborole in a condition close to real world clinical practice.
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 last visit or the last scheduled procedure shown in the SoA.
The end of the study is defined as the date of the last visit of the last participant in the study.
5. STUDY POPULATION
This study can fulfill its objectives only if appropriate participants are enrolled.  The 
following eligibility criteria are designed to select participants for whom participation in the 
study is considered appropriate.  All relevant medical and nonmedical conditions should be 
taken into consideration when deciding whether a particular participant is suitable for this 
protocol.
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 and Sex:
1. Male or female participants;
who were patients with mild to moderate AD aged 2 years old or older and met 
eligibility criteria for Study C3291032 at the time when entering Study C3291032,
and completed treatment period in Study C3291032 without safety issues.
OR
who were patients with mild to moderate AD aged 1 months to <24 months and met 
eligibility criteria for Study C3291031 at the time when entering Study C3291031,
and completed treatment period in Study C3291031 without safety issues (see 
Exclusion Criteria 5).

Refer to Appendix 4 for reproductive criteria for female (Section 10.4.1) 
participants.
Type of Participant and Disease Characteristics:
2. Participants who are willing and able to comply with all scheduled visits, treatment 
plan, lifestyle considerations, and other study procedures.

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Informed Consent:
3. The investigator, or a person designated by the investigator, will obtain written 
informed consent from each study participant, parent(s), or legal guardian and the 
subject’s assent, when applicable, before any study-specific activity is performed. 
The investigator will retain the original copy of each participant's signed 
consent/assent document.
5.2. Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions:
1. Other medical or psychiatric condition including recent (within the past year) or 
active suicidal ideation/behavior or laboratory abnormality that may increase the risk 
of study participation or, in the investigator’s judgment, make the participant 
inappropriate for the study.
Prior/Concomitant Therapy:
2. Has an anticipated concomitant use of topical or systemic therapies that might alter 
the course of AD.
Prior/Concurrent Clinical Study Experience:
3. Participates in other studies involving investigational drug(s) during study 
participation other than the parent studies C3291032 and C3291031.
Diagnostic Assessments:
Not applicable for this study.
Other Exclusions:
4. Investigator site staff or Pfizer employees directly involved in the conduct of the 
study, site staff otherwise supervised by the investigator, and their respective family 
members.
5. Experienced a treatment related AE or SAE during participation in Study C3291032 
or C3291031, which precludes treatment with investigational product in the judgment 
of the investigator (see Inclusion Criteria 1).
6. Early discontinuation from Study C3291032 treatment or C3291031 treatment, for 
any reason.

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7. Has a significant active systemic or localized infection, including known actively 
infected AD.
8. Had a history of significant noncompliance during the Study C3291032 or C3291031
with investigational product dosing, concomitant medication restrictions, or study 
procedures, in the judgment of the investigator.
5.3. Lifestyle Considerations
5.3.1. Contraception
The investigator or his or her designee, in consultation with the participant, will confirm that 
the participant has selected an appropriate method of contraception for the individual 
participant from the permitted list of contraception methods (see Appendix 4 Section 10.4.3)
and will confirm that the participant has been instructed in its consistent and correct use.  At 
time points indicated in the SoA, the investigator or designee will inform the participant of 
the need to use highly effective contraception consistently and correctly and document the 
conversation and the participant’s affirmation in the participant’s chart (participants need to 
affirm their consistent and correct use of at least 1 of the selected methods of contraception).  
In addition, the investigator or designee will instruct the participant to call immediately if the 
selected contraception method is discontinued or if pregnancy is known or suspected in the 
participant or partner.
5.3.2. General Care

The participant or his/her parent/legal guardian will be instructed to avoid occluding 
the treated areas (with dry wraps, for example). Wet wraps are not permitted.

Participants must avoid exposing the target treatment areas to water (e.g., swimming, 
bathing or washing) for at least 4 hours after investigational product application.
Applying emollients/moisturizers, sunscreen, or make-up to facial lesions should also 
be avoided within 60 minutes before and after the applying study intervention.

The participant or his/her parent/legal guardian should avoid wiping the 
investigational product off the skin. In the case of any investigational product 
inadvertently being wiped off, it should not be reapplied to wiped areas until the next 
scheduled dose.

When applying investigational product, the participant or his/her parent/legal 
guardian will not be required to wear gloves when applying investigational product at 
home.  However, they must be instructed to wash their hands with mild soap and 
water before and after each application. 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, and by taking care when handling the child after study intervention 
has been applied.

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
Loose fitting socks or mitts may be used on treated hands or feet to prevent 
inadvertent ingestion or contact with the eyes.

If there are treated lesions on the hands or feet, participants should be encouraged, as 
much as possible, not to put these areas in the mouth to avoid ingestion of the study 
intervention.

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. Using
diaper rash creams, lotions, ointments, powders, etc. where AD lesions are present
should be avoided within 60 minutes before and after applying study intervention. In 
the case of rash in the diaper area without AD involvement, standard treatments may 
be applied.

Routine preventative immunizations/vaccinations are permitted during the study.
5.4. Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but 
are not subsequently enrolled in the study. A minimal set of screen failure information is 
required to ensure transparent reporting of screen failure participants to meet the CONSORT 
publishing requirements and to respond to queries from regulatory authorities. Minimal 
information includes demography, screen failure details, eligibility criteria, and any SAE.
6. STUDY INTERVENTION
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, medical device(s), or study procedure(s) intended to be administered to a study 
participant according to the study protocol.
For the purposes of this protocol, study intervention refers to crisaborole ointment, 2%.
6.1. Study Intervention(s) Administered
Intervention Name
Crisaborole ointment, 2%
Type
Drug
Dose Formulation
Ointment
Unit Dose Strength(s)
2% (20 mg/g)
Dosage Level(s)
BID
Route of Administration
Topical
Use
Experimental
IMP or NIMP
IMP
Sourcing
Provided centrally by Sponsor
Packaging and Labeling
Study intervention will be provided in 60-gram tubes in cartons.  Each 
tube and carton will be labeled as required per country requirement.
Aliases
PF-06930164 or AN2728

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6.1.1. Administration
For this study, the investigational product is crisaborole ointment, 2%. Crisaborole ointment,
2% is formulated to contain PF-06930164 (2%), white petrolatum, propylene glycol, mono-
and diglycerides, paraffin wax, butylated hydroxytoluene, and edetate calcium disodium.
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.
The investigator will determine whether the participant will receive crisaborole ointment, 2%
(Figure 1), specified as follows:

If the participant is assessed as Almost Clear (1) or greater on the ISGA, the participant
will begin a 4 week On-Treatment Cycle, with a sufficient quantity of crisaborole 
ointment, 2% tubes dispensed to the participant or his/her parent/legal guardian to meet 
anticipated use based on the investigator identified AD-involved areas. The investigator 
will review the dosing instructions with the participant or his/her parent/legal guardian. 
Study intervention administration will be performed BID at home.

If the participant is assessed as Clear (0) on the ISGA, treatment will NOT be initiated 
and the participant will begin a 4-week Off-Treatment Cycle, during which the 
participant is allowed to use emollient(s)/moisturizer(s) in all areas (AD-involved and 
uninvolved), as needed.
Any new lesion(s) that develop during an On-Treatment Cycle should also be treated.

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Figure 1.
Diagram of Study Intervention Allocation by Visit
If a participant has AD that becomes intolerable:

If a participant has AD that becomes intolerable during an On-Treatment Cycle, the 
investigator may instruct the participant or his/her parent/legal guardian to discontinue 
crisaborole ointment, 2%. After study intervention discontinuation, weak- to strong-
potency topical corticosteroids and/or topical calcineurin inhibitors could be prescribed 
up to 28 days based on clinical judgment is permitted (refer to Section 6.5.3).

If a participant has AD that becomes intolerable during an Off-Treatment Cycle and 
cannot wait for the next scheduled visit to be treated by crisaborole ointment, 2%, the 
participant or his/her parent/legal guardian will be instructed to contact the study site to 
arrange an Unplanned Visit to initiate a regimen of crisaborole ointment, 2% BID for the 
remainder of a given 4 weeks interval. Depending upon the participant’s AD condition, a 
weak- to strong-potency topical corticosteroids and/or topical calcineurin inhibitors could 
be prescribed directly based on clinical judgment by the investigator. Topical 
corticosteroids and topical calcineurin inhibitors must not be used on the same lesions 
concurrently, crisaborole ointment, 2% and topical corticosteroids or topical calcineurin 
inhibitors must not be used concurrently. In this case, the procedure for rescue treatment 

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during an Off-Treatment Cycle follows the instruction given for participants using rescue 
medication during an On-Treatment Cycle (refer to Section 6.5.3).

At any treatment cycle, participant will be discontinued from the study when she/he 
requires prohibited medication usage or continuous rescue medication treatment >28 
days.
Emollients/Moisturizer:

During On-Treatment Cycle, continued use of emollient(s)/moisturizer(s) is permitted to 
manage dry skin, but use of them on treatable AD lesion should be avoided within 60 
minutes before and after the applying study intervention.

During Off-Treatment Cycle, use of emollient(s)/moisturizer(s) is permitted in all areas 
(AD-involved and uninvolved), as needed.

During the use of rescue medication, use of emollient(s)/moisturizer(s) is permitted in all 
areas, as needed.
AD skin area in the scalp:

Use of emollient(s)/moisturizer(s), weak- to strong-potency topical corticosteroids or 
topical calcineurin inhibitors is permitted on clinical judgment by investigator (see 
Section 6.5.2).
Crisaborole ointment, 2% is for external use on the skin only. Participant should avoid 
contact with mucous membranes (i.e., inside of nostrils, mouth, vagina, urethra, and rectum), 
and in the eyes. Participant should avoid ingestion of investigational product.
At the Start Day of each treatment cycle, the designated areas for treatment will be identified 
and documented in the source document. The participant or his/her parent/legal guardian 
will be provided with documentation of designated treatment areas. The documentation of 
the investigator identified treatable areas will be updated for any new AD lesions that appear 
after the Start Day of treatment cycle.
Crisaborole ointment, 2% will be applied at home. Those participants applying crisaborole 
ointment, 2% at home and having difficulty reaching a treatment area (e.g., back) may be 
assisted by another person who will need to apply it to the participant according to the 
instruction. The instruction for at home dosing will be reviewed with the participant or 
his/her parent/legal guardian at applicable study visit during a given 4 weeks On-Treatment 
Cycle. In the event the scheduled Start Day of the next treatment cycle visit does not fall 
exactly on the scheduled date, the participant or his/her parent/legal guardian will be 
instructed to continue investigational product application BID through the evening before the 
actual visit date.

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Participant or his/her parent/legal guardian will be provided appropriate training for 
investigational product application and will be instructed to apply an even layer of 
crisaborole to all areas of the body with AD (except scalp) identified at Day 1 of the On-
Treatment Cycle and at any Unplanned Visit where crisaborole ointment, 2% treatment is 
initiated, regardless of whether they become clinically clear during any given 4 weeks On-
Treatment Cycle and the remainder of a given 4 weeks interval. If needed, additional amount 
of crisaborole ointment, 2% will be applied as needed (PRN) to ensure coverage of any 
newly identified treatable AD lesions that appear after Day 1 of the On-Treatment Cycle or
any Unplanned Visit where crisaborole ointment, 2% is dispensed.
The dosing regimen is BID.  The dosing interval should be at least 8 hours apart within each 
24-hour day.
If 1 or more doses are withheld or missed due to a safety concern, then the AE or other 
reason must be documented and noted as having led to a dosing interruption.
Participant or his/her parent/legal guardian will apply at home all doses of any emollients or 
investigator prescribed weak- to strong-potency topical corticosteroids and/or topical 
calcineurin inhibitors.
If participants require continuous weak- to strong-potency topical corticosteroids or topical 
calcineurin inhibitors treatment for >28 days at any time during the study, they then will be
discontinued from study. The use of weak- to strong-potency topical corticosteroids and/or 
topical calcineurin inhibitors for AD on the scalp will not have any limitation in duration of 
use, which should be based on investigator’s discretion.
6.2. Preparation/Handling/Storage/Accountability
1. The investigator or designee must confirm appropriate temperature conditions have 
been maintained during transit for all study interventions 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 
interventions must be stored in a secure, environmentally controlled, and monitored 
(manual or automated recording) area in accordance with the labeled storage 
conditions with access limited to the investigator and authorized site staff.  At a 
minimum, daily minimum and maximum temperatures for all site storage locations 
must be documented and available upon request.  Data for nonworking days must 
indicate the minimum and maximum temperatures since previously documented for 
all site storage locations upon return to business.
3. Any excursions 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 storage conditions 
described in the labeling, as soon as possible.  Once an excursion is identified, the 

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study intervention must be quarantined and not used until Pfizer provides permission 
to use the study intervention.  Specific details regarding the definition of an excursion 
and information the site should report for each excursion will be provided to the site 
in the IP manual.
4. Any storage conditions stated in the SRSD will be superseded by the storage 
conditions stated on the label.
5. Study interventions should be stored in their original containers.
6. Site staff will instruct participants on the proper storage requirements for take-home 
study intervention.
7. The investigator, institution, or the head of the medical institution (where applicable) 
is responsible for study intervention accountability, reconciliation, and record 
maintenance (ie, receipt, reconciliation, and final disposition records), such as the 
IPAL or sponsor-approved equivalent. All study interventions will be accounted for 
using a study intervention accountability form/record.  All crisaborole ointment, 2%
that is taken home by the participant, both used and unused, must be returned to the 
investigator by the participant.  Returned study intervention must not be redispensed 
to the participants.
8. Further guidance and information for the final disposition of unused study 
interventions are provided in the IP manual. All destruction must be adequately 
documented.  If destruction is authorized to take place at the investigator site, the 
investigator must ensure that the materials are destroyed in compliance with 
applicable environmental regulations, institutional policy, and any special instructions 
provided by Pfizer.
Upon identification of a product complaint, notify the sponsor within 1 business day of 
discovery as described in the IP Manual.
6.2.1. Preparation and Dispensing
A qualified staff member will dispense the study intervention in the tube using an IRT 
system via unique container numbers provided, in quantities appropriate at Day 1 of the 
On-Treatment Cycle and at Unplanned Visit where crisaborole ointment, 2% BID treatment 
is initiated.  A second staff member will verify the dispensing.  The participant/parent/legal 
guardian should be instructed to maintain the product in the tube provided throughout the 
course of dosing and return the tube to the site at the next study visit.
6.3. Measures to Minimize Bias: Randomization and Blinding
6.3.1. Allocation to Study Intervention
This is an open-label, single arm study, and IRT will be used for the study intervention 
dispensing.  The site will contact the IRT at Day 1 of each Treatment Cycle and at 
Unplanned Visit where crisaborole ointment, 2% BID treatment is initiated with or without 

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the study intervention dispensing.  The site will record the study intervention assignment on 
the applicable CRF, if required.  Specific measures to reduce potential bias will not be taken.
Study intervention will be dispensed at the study visits summarized in the SoA.
Returned study intervention must not be redispensed to the participants.
The study-specific IRT reference manual and IP manual will provide the contact information 
and further details on the use of the IRT system.
6.4. Study Intervention Compliance
Compliance with the dose regimen will not be assessed; although all dispensed study 
intervention supplies in its original package (both used and unused) will be weighed and 
dosing diary will be recorded. If a participant has missed applications between the previous 
and the current visit, the investigator/designee is to counsel the participant’s parent(s)/legal 
guardian to improve adherence. Deviation(s) from the prescribed dosage regimen should be 
recorded in the CRF.
A record of the number of tubes dispensed to and taken by each participant must be 
maintained and reconciled with study intervention and compliance records.  Intervention start 
and stop dates will also 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 sponsor 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, 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 sponsor if required.

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6.5.1. Medications/Therapies Prohibited During the Study (Day 1-Week 52/EOT)

Biological drugs (e.g., dupilumab)

Use of systemic (oral, parenteral) corticosteroids.

Topical corticosteroids or topical calcineurin inhibitors, unless prescribed by the 
investigator as rescue therapy and treatment for the scalp

Systemic immunosuppressive agents (e.g., methotrexate, cyclosporine, azathioprine, 
hydroxychloroquine, and mycophenolate mofetil)

Topical JAK inhibitor on AD lesions

Topical PDE-4 inhibitor on AD lesions

Topical retinoid or benzoyl peroxide on AD lesions

Herbal preparation that might alter the course of AD

Use of systemic antibiotics for more than 14 consecutive days.

Topical antibiotics (unless required for AE treatment)

Use of topical antibacterial medications or products, including soaps, bleach baths, or 
topical sodium hypochlorite-based products anywhere on the body.

Use of sunbathing, tanning bed use, light therapy (UV, UV-B, PUVA) anywhere on the 
body.

Participation in another drug or device research study.
6.5.2. Medications/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 intranasal, ophthalmic and inhaled corticosteroids.

Emollient(s)/moisturizer(s) is permitted during the study as detailed in Section 6.1.1. 
Written instruction will be provided to participant or his/her parent/legal guardian at the 
beginning of the treatment period regarding the appropriate application of emollients.

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
The use of weak- to strong- potency topical corticosteroids and/or topical calcineurin 
inhibitors is permitted during the study to treatment of the AD skin area in the scalp.

Short courses (up to 14 days) of systemic antibiotics may be given during the course of 
the study, if clinically necessary for the treatment of new onset infections.

Stable use (regular regimen) of systemic antihistamine regimen. If seasonal allergy, a 
stable regimen during certain period will be permitted.

Topical antihistamine

Nonsteroidal anti-inflammatory drug

Routine preventative immunizations

Concomitant medications for other chronic medical conditions are permitted during the 
study unless the medication/therapy is specifically prohibited by the protocol.

Hormonal contraceptives that meet the requirements of this study are allowed to be used 
in participants who are WOCBP (see Appendix 4).
6.5.3. Rescue Medicine
For participants with ISGA score >1 (i.e., mild, moderate or severe), crisaborole ointment,
2% therapy may be discontinued per investigator judgment to allow initiation of weak- to 
strong-potency topical corticosteroids and/or topical calcineurin inhibitors as rescue therapy 
for up to 28 days, after which crisaborole ointment, 2% BID may be restarted. Participants
who continuously use topical corticosteroids or topical calcineurin inhibitors treatment >28 
days will be discontinue from the study. The rescue medication prescription and relevant 
assessment should be recorded in the participant’s source documents and in the CRF.
Crisaborole ointment, 2% and topical corticosteroids or topical calcineurin inhibitors must 
not be used concurrently. Topical corticosteroids and topical calcineurin inhibitors must not 
be used on the same lesions concurrently.
Participant or his/her parent/legal guardian will be instructed on the dosage and 
administration requirements for any topical corticosteroids and/or topical calcineurin 
inhibitors prescribed by the investigator during the study. Instruction should follow the 
approved labeling for the indication and the product package insert, if provided.
6.6. Dose Modification
This study design includes 4 week cycles with On-Treatment or Off-Treatment to be decided 
by the investigator based on the ISGA score.  See Section 6.1.1 for details.
6.7. Intervention After the End of the Study
No intervention will be provided to study participants at the end of the study.

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7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL
7.1. Discontinuation of Study Intervention
In rare instances, it may be necessary for a participant to permanently discontinue study 
intervention (definitive discontinuation). Reasons for definitive discontinuation of study 
intervention include the following:

The occurrence of AEs that require the participant to stop participation in the study, 
due to availability for, or intolerance to, the study procedures;

AEs that are considered to be clinically significant by the investigator and/or 
physician in charge, and/or might be harmful to the participant’ health;

Need the continuous rescue therapy for >28 days;

Concurrent disease that requires use of a prohibited medication.
If study intervention is definitively discontinued, the participant will not remain in the study 
for further evaluation. See the SoA for data to be collected at the time of discontinuation of 
study intervention.
7.2. Participant Discontinuation/Withdrawal From the Study
A participant may withdraw from the study at any time at his/her own request.  Reasons for 
discontinuation from the study include the following:

Refused further follow-up;

Lost to follow-up;

Death;

Study terminated by sponsor;

The occurrence of AEs that require the participant to stop participation in the study, 
due to availability for, or intolerance to, the study procedures;

AEs that are considered to be clinically significant by the investigator and/or 
physician in charge, and/or might be harmful to the participant’ health;

Need the continuous rescue therapy for >28 days;

Concurrent disease that requires use of a prohibited medication.

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At the time of discontinuing from the study, if possible, an early discontinuation visit should 
be conducted. See the SoA for assessments 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 a participant withdraws from the study, he/she may request destruction of any remaining 
samples taken and not tested, and the investigator must document any such requests in the 
site study records and notify the sponsor accordingly.
If the participant withdraws from the study and also withdraws consent (see Section 7.2.1) 
for disclosure of future information, no further evaluations should be performed and no 
additional data should be collected.  The sponsor may retain and continue to use any data 
collected before such withdrawal of consent.
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.
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:

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
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 or 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.
8. STUDY ASSESSMENTS AND PROCEDURES
The investigator (or an appropriate delegate at the investigator site) must obtain a signed and 
dated ICD before performing any study-specific procedures.
Study procedures and their timing are summarized in the SoA. Protocol waivers or 
exemptions are not allowed.
Safety issues should be discussed with the sponsor immediately upon occurrence or 
awareness to determine whether 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 ICD 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.
Every effort should be made to ensure that protocol-required tests and procedures are 
completed as described.  However, it is anticipated that from time to time there may be 
circumstances outside the control of the investigator that may make it unfeasible to perform 
the test.  In these cases, the investigator must take all steps necessary to ensure the safety and 
well-being of the participant.  When a protocol-required test cannot be performed, the 
investigator will document the reason for the missed test and any corrective and preventive 

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actions that he or she has taken to ensure that required processes are adhered to as soon as 
possible.  The study team must be informed of these incidents in a timely manner.
For samples being collected and shipped, detailed collection, processing, storage, and 
shipment instructions and contact information will be provided to the investigator site prior 
to initiation of the study.
Blood sampling will be occurred only for PK assessment at the selected study sites in 
participants aged between 2 years old and 11 years old at the time of signing the ICD in 
Study C3291032, and the total blood sampling volume for individual participants in this 
study is approximately 2 mL.  Unscheduled samples may be taken for safety reasons for all 
participants.
8.1. Efficacy Assessments
8.1.1. Rater Qualifications
Clinical evaluations of AD will be performed by an experienced and certified physician, 
dermatologist, or medical professional.  The evaluator must have received documented 
training to conduct the protocol AD specific clinical evaluations prior to performing these 
evaluations.  To assure consistency and reduce variability, the same evaluator must assess all 
clinical evaluation of atopic dermatitis for any individual participant throughout the study; a 
backup experienced and qualified, protocol trained evaluator will only be allowed and 
documented in case of emergency or special situation when the designated evaluator is 
unable to perform the evaluation.  Identity (eg, initials) of the evaluator will be captured on 
the source documentation (eg, scale worksheet).
8.1.2. Calculation of Treatable %Body Surface Area (BSA)
The treatable %BSA is defined as the percentage of the participant’s total BSA that is AD 
involved, excluding the scalp, and will be calculated at times specified in the SoA. The 
treatable %BSA should be evaluated based on all AD lesions present on the day of the visit, 
excluding the scalp.  Score 0 in the ISGA definition will not be evaluated as BSA while 
Score 1-4 will be.
To estimate the treatable %BSA, the investigator or designee will use “handprint method”, 
by which the area represented by the palmar (i.e., outstretched) surface of the participant’s 
hand with all five digits adducted together is approximately 1% of the participant’s BSA, 
regardless of the participant’s age.
8.1.3. Investigator’s Static Global Assessment (ISGA)
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 1).  ISGA will be assessed at 
times specified in the SoA to characterize participants’ overall disease severity across all 
treatable AD lesions (excluding the scalp). ISGA should be completed prior to assessment of 
Regional ISGA-Face and EASI, whenever possible.  The assessment will be a static 
evaluation without regard to the score at a previous visit.

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Table 1.
Investigator’s Static Global Assessment
Score
Grade
Definition
0
Clear
Minor residual hypo/hyperpigmentation; no erythema or 
induration/papulation; no oozing/crusting
1
Almost Clear
Trace faint pink erythema, with barely perceptible induration/papulation and 
no oozing/crusting
2
Mild
Faint pink erythema with mild induration/papulation and no oozing/crusting
3
Moderate
Pink-red erythema with moderate induration/papulation with or without 
oozing/crusting
4
Severe
Deep or bright red erythema with severe induration/papulation and with 
oozing/crusting
8.1.4. Regional ISGA-Face
Severity of AD on the face will be assessed by evaluating the severity of all lesions occurring 
within that body region. The Regional ISGA-Face score will be assessed only for 
participants who completed Study C3291032 and had AD in face at Day 1 Visit of Study 
C3291032. At every scheduled visit, the Regional ISGA score will be documented for the 
face regardless of the presence or absence of AD in face. The Regional ISGA-Face 
assessment should use the scale in Table 1.
The assessment will be a static evaluation without regard to the score at a previous visit.
8.1.5. Eczema Area and Severity Index (EASI)
The EASI24 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 
severity of lesions.  Assessment of these 4 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 2.

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Table 2.
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
Note: 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 3).  The handprint as a unit is defined by the area represented by the palmar (ie, 
outstretched) surface of the participant’s hand with all 5 digits adducted (not spread apart) 
together equaling approximately 1% of the participant’s BSA, regardless of the participants 
age.

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The extent (%) to which each of the 4 body regions is involved with AD is categorized using 
a nonlinear scaling method to derive a numerical area score according to the BSA scoring 
criteria (Table 4).
Table 4.
Eczema Area and Severity Index (EASI) Area Score Criteria
Treatable Percent Body Surface Area with Atopic Dermatitis in a Body 
Region
Area Score
0%
0
>0% to <10%
1
10% to <30%
2
30% to <50%
3
50% to <70%
4
70% to <90%
5
90% to 100%
6
Body Region Weighting: Each body region is weighted according to its approximate 
percentage of the whole body (Table 5).
Table 5.
Eczema Area and Severity Index (EASI) Body Region Weighting
Body Region
Body Region Weighting
≥8 years of age
<8 years of age
Head and Neck
0.1
0.2
Upper Limbs
0.2
0.2
Trunk (including axillae and groin/genitals)
0.3
0.3
Lower Limbs (including buttocks)
0.4
0.3
Table 3.
Handprint Determination of Body Region Surface Area
Body Region
Total Number of 
Handprints in 
Body Regiona
Surface Area of 
Body Region 
Equivalent of 
One Handprint
Total Number of 
Handprints in 
Body Regiona
Surface Area of 
Body Region 
Equivalent of 
One Handprint
≥8 years of age
<8 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%
a.
The number of handprints will be for the entire body region; these values will not be adjusted for 
exclusion of scalp from the BSA assessment.

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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 
4 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 <8 years old):  EASI =0.2Ah(Eh+Ih+Exh+Lh) + 
0.2Au(Eu+Iu+Exu+Lu) + 0.3At(Et+It+Ext+Lt) + 0.3Al(El+Il+Exl+Ll)
A = Area Score; E = erythema; I = induration/papulation; Ex = excoriation; L = lichenification; h = head and 
neck; u = upper limbs; t = trunk; l = lower limbs.
8.1.6. Body Site Checklist for Atopic Dermatitis
A checklist of body areas currently affected by AD will be completed at times specified in 
the SoA. Location of skin lesions will be selected from a pre-specified list of body locations.
Any new lesion should be recorded and updated in the checklist.  Study site staff (or the 
investigator) will determine whether a new AD lesion is reported as an AE or as part of the 
underlying disease based on medical judgement.  The AD lesion checklist will be recorded in 
the participant’s source documents and data entered onto the CRF.
8.1.7. Patient/Observer Reported Outcomes
The Patient/Observer Reported Outcomes questionnaires in this study include Peak pruritus 
NRS/Patient Reported Itch Severity Scale/Observer Reported Itch Severity Scale.  They will 
be performed at the time points defined in the SoA. The age cut-offs are based on the age at 
Screening visit/informed consent/assent in the prior study.
On study visit days, participants or observers (ie, the one who provides the information to 
complete the questionnaires other than participant, eg, his/her parent/legal guardian/other 
caregiver) should complete the patient/observer reported outcomes at the clinic prior to any 
procedures being performed.  The one who completed the questionnaires should be captured 
and stored in the database and available for analysis.  It’s preferred that all observer reported 
outcomes for a given participant are completed by same individual throughout the study.
8.1.7.1. Pruritus Assessment
Participants will be asked to assess their worst itch or scratching due to AD over the past 
24 hours.

Peak Pruritus NRS25 is an 11-point scale and must be completed by participants ≥12 
years of age at the time of signing the ICD in the prior study.

Patient reported Itch Severity Scale is a 5-point scale must be completed by 
participants ≥6 years and <12 years at the time of signing the ICD in the prior study.

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
Observer reported Itch Severity Scale is an 11-point scale and must be completed by 
the observers (caregivers of participants) for participants <6 years of age at the time 
of signing the ICD in the prior study.
8.2. Safety Assessments
Planned time points for all safety assessments are provided in the SoA.  Unscheduled clinical 
laboratory measurements may be obtained at any time during the study to assess any 
perceived safety issues.
8.2.1. Physical Examinations
A complete physical examination will include, at a minimum, assessments of the 
cardiovascular, respiratory, gastrointestinal, and neurological systems. In addition, an 
assessment will be made of the condition of all AD-involved skin.  Weight for participants 
aged 18 years old or older and height and weight for participants aged under 18 years old will 
also be measured and recorded.
Investigators should pay special attention to clinical signs related to previous serious 
illnesses.
For measuring weight, a scale with appropriate range and resolution is used and must be 
placed on a stable, flat surface. Participants must remove shoes, bulky layer or clothing, and 
jackets so that only light clothing remains. They must also remove the contents of their 
pockets and remain still during measurement of weight.
8.2.2. Pregnancy Testing
Pregnancy tests may be urine or serum tests, but must have a sensitivity of at least 
25 mIU/mL.  Pregnancy tests will be performed in WOCBP at the times listed in the SoA.  
Following a negative pregnancy test result at screening, appropriate contraception must be 
commenced and a second negative pregnancy test result will be required at the baseline visit 
prior the participant’s receiving the study intervention.  Pregnancy tests will also be done 
whenever 1 menstrual cycle is missed during the active treatment period (or when potential 
pregnancy is otherwise suspected) and at the end of the study.  Pregnancy tests may also be 
repeated if requested by IRBs/ ECs or if required by local regulations.  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 if the serum pregnancy result is positive.
8.3. Adverse Events and Serious Adverse Events
The definitions of an AE and an SAE can be found in Appendix 3.
AEs 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 the 

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event meets the criteria for classification as an SAE or caused the participant to discontinue 
the study intervention (see Section 7.1).
Each participant/parent/legal guardian will be questioned about the occurrence of AEs in a 
nonleading manner.
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, 
which is obtained before the participant’s participation in the study (ie, before undergoing 
any study-related procedure and/or receiving study intervention), through and including a 
minimum of 28 calendar days, except as indicated below, after the last administration of the 
study intervention.
Follow-up by the investigator continues throughout and after the active collection period and 
until the AE or SAE or its sequelae resolve or stabilize at a level acceptable to the 
investigator and Pfizer concurs with that assessment.
For participants who are screen failures, the active collection period ends when screen failure 
status is determined.
If the participant withdraws from the study and also withdraws consent for the collection of 
future information, the active collection period ends when consent is withdrawn.
If a participant definitively discontinues or temporarily discontinues study intervention 
because of an AE or SAE, the AE or SAE must be recorded on the CRF and the SAE 
reported using the CT SAE Report Form.
Investigators are not obligated to actively seek AEs or SAEs after the participant has 
concluded study participation. However, if the investigator learns of any SAE, including a 
death, at any time after a participant has completed the study, and he/she considers the event 
to be reasonably related to the study intervention, the investigator must promptly report the 
SAE to Pfizer using the CT SAE Report Form.
8.3.1.1. Reporting SAEs to Pfizer Safety
All SAEs occurring in a participant during the active collection period as described in 
Section 8.3.1 are reported to Pfizer Safety on the CT SAE Report Form immediately upon 
awareness 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.

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8.3.1.2. Recording Nonserious AEs and SAEs on the CRF
All nonserious AEs and SAEs occurring in a participant during the active collection period,
which begins after obtaining informed consent as described in Section 8.3.1, will be recorded 
on the AE section of the CRF.
The investigator is to record on the CRF all directly observed and all spontaneously reported 
AEs and SAEs reported by the participant.
8.3.2. Method of Detecting AEs and SAEs
The method of recording, evaluating, and assessing causality of AEs and SAEs 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 
nonleading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences.
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 an 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, IRBs/ECs, and investigators.
Investigator safety reports must be prepared for SUSARs according to local regulatory 
requirements and sponsor policy and forwarded to investigators as necessary.

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An investigator who receives SUSARs or other specific safety information (eg, summary or 
listing of SAEs) from the sponsor will review and then file it along with the SRSD(s) for the 
study and will notify the IRB/EC, if appropriate according to local requirements.
8.3.5. Exposure During Pregnancy or Breastfeeding, and Occupational Exposure
Exposure to the study intervention 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
An EDP occurs if:

A female participant is found to be pregnant while receiving or after discontinuing 
study intervention.

A male participant who is receiving or has discontinued study intervention exposes a 
female partner prior to or around the time of conception.

A female is found to be pregnant while being exposed or having been exposed to 
study intervention due to environmental exposure. Below are examples of 
environmental exposure during pregnancy:

A female family member or healthcare provider reports that she is pregnant after 
having been exposed to the study intervention by ingestion, inhalation or skin 
contact.

A male family member or healthcare provider who has been exposed to the study 
intervention by ingestion, inhalation or skin contact then exposes his female 
partner prior to or around the time of conception.
The investigator must report EDP to Pfizer Safety within 24 hours of the investigator’s 
awareness, irrespective of whether an SAE has occurred. The initial information submitted 
should include the anticipated date of delivery (see below for information related to 
termination of pregnancy).

If EDP occurs in a participant or a participant’s partner, 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. Details of the 
pregnancy will be collected after the start of study intervention and until at least 5 
terminal half-lives after the last dose.

If EDP occurs in the setting of environmental exposure, the investigator must report 
information to Pfizer Safety using the CT SAE Report Form and EDP Supplemental 
Form. Since the exposure information does not pertain to the participant enrolled in 

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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.
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 
preprocedure test findings are conclusive for a congenital anomaly and the findings are 
reported).
Abnormal pregnancy outcomes are considered SAEs. If the outcome of the pregnancy meets 
the criteria for an SAE (ie, ectopic pregnancy, spontaneous abortion, intrauterine fetal 
demise, neonatal death, or congenital anomaly in a live-born baby, a terminated fetus, an 
intrauterine fetal demise, or a neonatal death), the investigator should follow the procedures 
for reporting SAEs. Additional information about pregnancy outcomes that are reported to 
Pfizer Safety as SAEs follows:

Spontaneous abortion including miscarriage and missed abortion;

Neonatal deaths that occur within 1 month of birth should be reported, without regard 
to causality, as SAEs. In addition, infant deaths after 1 month should be reported as 
SAEs when the investigator assesses the infant death as related or possibly related to 
exposure to the study intervention.
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.
8.3.5.2. Exposure During Breastfeeding
An exposure during breastfeeding occurs if:

A female participant is found to be breastfeeding while receiving or after 
discontinuing study intervention.

A female is found to be breastfeeding while being exposed or having been exposed to 
study intervention (ie, environmental exposure). An example of environmental 
exposure during breastfeeding is a female family member or healthcare provider who 

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reports that she is breastfeeding after having been exposed to the study intervention 
by inhalation or skin contact.
The investigator must report exposure during breastfeeding to Pfizer Safety within 24 hours 
of the investigator’s awareness, irrespective of whether an SAE has occurred. The 
information must be reported using the CT SAE Report Form. When exposure during 
breastfeeding occurs in the setting of environmental exposure, the exposure information does 
not pertain to the participant enrolled in the study, so 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.
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, the 
SAE is reported together with the exposure during breastfeeding.
8.3.5.3. Occupational Exposure
An occupational exposure occurs when a person receives unplanned direct contact with the 
study intervention, which may or may not lead to the occurrence of an AE.  Such persons 
may include healthcare providers, family members, and other roles that are involved in the 
trial participant’s care.
The investigator must report occupational exposure to Pfizer Safety within 24 hours of the 
investigator’s awareness, regardless of whether there is an associated SAE.  The information 
must be reported using the CT SAE Report Form.  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. Cardiovascular and Death Events
Not applicable
8.3.7. Disease Related Events and/or Disease Related Outcomes Not Qualifying as AEs 
or SAEs
Not applicable
8.3.8. Adverse Events of Special Interest
Not applicable
8.3.8.1. Lack of Efficacy
Lack of efficacy is reportable to Pfizer Safety only if associated with an SAE.
8.3.9. Medical Device Deficiencies
Not applicable

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8.3.10. 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 study 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 within 24 hours.
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 nonserious, are recorded on the AE page of the 
CRF.
Medication errors should be reported to Pfizer Safety within 24 hours on a CT SAE Report 
Form only when associated with an SAE.
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.  Investigator should monitor the participant for any AEs/SAEs.
8.5. Pharmacokinetics
Blood samples of approximately 2 mL will be collected for measurement of plasma 
concentrations of crisaborole and its identified main oxidative metabolites (AN7602 and 
AN8323) as specified in the SoA at 1 sampling time point prior to the first dose of study 
intervention on Day 1 in C3291027 (around 12 hours post the last dose of C3291032).  

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Instructions for the collection and handling of biological samples will be provided in the 
laboratory manual or by the sponsor.  The actual date and time (24-hour clock time) of each 
sample will be recorded.
The actual times may change, but the number of samples will remain the same.  All efforts 
will be made to obtain the samples at the exact nominal time relative to dosing.  Collection of
samples up to and including 10 hours after dose administration that are obtained within 10% 
of the nominal time relative to dosing (eg, within 6 minutes of a 60-minute sample) will not 
be captured as a protocol deviation, as long as the exact time of the collection is noted on the 
source document and the CRF. Collection of samples more than 10 hours after dose
administration that are obtained ≤1 hour away from the nominal time relative to dosing will 
not be captured as a protocol deviation, as long as the exact time of the collection is noted on 
the source document and the CRF. This protocol deviation window does not apply to 
samples to be collected more than 10 hours after dose administration at outpatient/follow-up 
visits with visit windows.
The skin around venous access area must be thoroughly cleansed prior to blood sample 
collection with mild soap and water followed by an isopropyl wipe.
The date/time of the blood collection and the date/time of the last dose of study intervention 
in C3291032 captured in the CRF.
Samples will be used to evaluate the PK of crisaborole and its identified main oxidative 
metabolites (AN7602 and AN8323). Each plasma sample will be divided into 1 aliquot for
PK. Samples collected for analyses of crisaborole and its identified main oxidative 
metabolites (AN7602 and AN8323) plasma concentration may also be used to evaluate safety 
or efficacy aspects related to concerns arising during or after the study, for metabolite 
identification and/or evaluation of the bioanalytical method, or for other internal exploratory 
purposes.
Genetic analyses will not be performed on these plasma samples.  Participant confidentiality 
will be maintained.
Samples collected for measurement of plasma concentrations of crisaborole and its identified 
main oxidative metabolites (AN7602 and AN8323) will be analyzed using a validated 
analytical method in compliance with applicable SOPs.
The PK samples must be processed and shipped as indicated in the instructions provided to 
the investigator site to maintain sample integrity. Any deviations from the PK sample 
handling procedure (eg, sample collection and processing steps, interim storage or shipping 
conditions), including any actions taken, must be documented and reported to the sponsor.  
On a case-by-case basis, the sponsor may make a determination as to whether sample 
integrity has been compromised.
8.6. Pharmacodynamics
Pharmacodynamic parameters are not evaluated in this study.

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8.7. Genetics
Genetics (specified analyses) are not evaluated in this study.
8.8. Biomarkers
Biomarkers are not evaluated in this study.
8.9. Immunogenicity Assessments
Immunogenicity assessments are not included in this study.
8.10. Health Economics
Health economics/medical resource utilization and health economics parameters are not 
evaluated in this study.
9. STATISTICAL CONSIDERATIONS
Detailed methodology for summary and statistical analyses of the data collected in this study 
is outlined here and further detailed in a SAP, which will be maintained by the sponsor.  The 
SAP may modify what is outlined in the protocol where appropriate; however, any major 
modifications of the primary endpoint definitions or their analyses will also be reflected in a 
protocol amendment.
9.1. Estimands and Statistical Hypotheses
9.1.1. Estimands
The primary objective in this study is the safety evaluation.  There is no pre-specified 
estimand for the safety evaluation and the safety endpoints will be analyzed descriptively. In 
addition, there is no secondary objective in this study.
9.2. Sample Size Determination
Sample size will be determined by the number of participants who enroll from the qualifying 
parent studies.  It is estimated that at least 150 participants (ie, 20 participants for under 2 
years old and 130 participants for 2 years and older) are expected to join from the currently 
planned qualifying parent studies.  Analyses performed, including interim evaluations, if any, 
will primarily be for safety though some measures of efficacy may be analyzed.
9.3. Analysis Sets
For purposes of analysis, the following analysis sets are defined:
Participant Analysis Set
Description
Full Analysis Set
All participants who take at least one dose of study 
intervention.

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Safety
All participants who take at least one dose of study
intervention.
PK Analysis Set
All participants who take at least one dose of study 
intervention in Study C3291032 and who have at least one 
concentration value.
9.4. Statistical Analyses
The SAP will be developed and finalized before any analyses are performed and will 
describe 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. General Considerations
The efficacy objective is exploratory in this study.  Efficacy analyses will be descriptive in 
nature; there will be no formal hypothesis testing, though 95% two-sided confidence 
intervals will be reported.
For the purpose of analysis of efficacy measures, the baseline values are defined as the 
baseline values from the participant’s qualifying parent study.
9.4.2. Primary Endpoint(s)
The primary endpoint of incidence of safety events will be analyzed using descriptive 
measures such as percentages and exposure-adjusted incidence rates along with confidence 
intervals.  No statistical hypotheses will be tested.
9.4.3. Secondary Endpoint(s)
There are no secondary endpoints in this study.
9.4.4. Tertiary/Exploratory Endpoint(s)
9.4.4.1. Efficacy Endpoints
The measures of efficacy (EASI and ISGA scores and other patient/observer reported 
outcome measures) will be summarized using descriptive statistics, such as number and 
percent, mean, standard deviation and quartiles at each visit where measured.  Displays using 
stratification by participation in qualifying studies will also be included.
Exploratory analyses may also be performed.
Further details will be specified in the SAP.

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9.4.4.2. Pharmacokinetic Endpoints
Predose (Ctrough) plasma concentrations of crisaborole and its identified main oxidative 
metabolites (AN7602 and AN8323) will be listed and descriptively summarized.
9.4.5. Other Safety Analyses
For the purpose of analysis of safety measures, the baseline values are defined as the baseline 
values from the participant’s qualifying parent study.
All the safety data, including the following, will be summarized descriptively through 
appropriate data tabulations, descriptive statistics, and graphical presentations:

Adverse events will be summarized according to Pfizer standards;

Serious infections, defined as any infection (viral, bacterial and fungal) requiring 
hospitalization or parenteral antimicrobials or meets other criteria that require it to be 
classified as a serious adverse event, will be summarized.
All safety analyses will be performed on the safety population.
9.5. Interim Analyses
No formal interim analysis will be conducted for this study. As this is an open-label, long-
term extension study, the sponsor may conduct reviews of the data during the course of the 
study for the purpose of internal decision making, due to regulatory requests, or to support 
regulatory submissions.  The data cutoff may occur after 6-month follow-up data across this 
study and the parent study has been accumulated for approximately 100 participants enrolled
in this study.
9.6. Data Monitoring Committee or Other Independent Oversight Committee
This study will use a 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.
The DMC will be responsible for ongoing monitoring of the safety of participants in the 
study according to the charter.  The recommendations made by the DMC to alter the conduct 
of the study will be forwarded to the appropriate Pfizer personnel for final decision.  Pfizer 
will forward such decisions, which may include summaries of aggregate analyses of safety 
data, to regulatory authorities, as appropriate.

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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:

Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and CIOMS International Ethical Guidelines;

Applicable ICH GCP guidelines;

Applicable laws and regulations, including applicable privacy laws.
The protocol, protocol amendments, ICD, SRSD(s), and other relevant documents (eg, 
advertisements) must be reviewed and approved by the sponsor and submitted to an IRB/EC 
by the investigator and reviewed and approved by the IRB/EC before the study is initiated.
Any amendments to the protocol will require IRB/EC 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:

Providing written summaries of the status of the study to the IRB/EC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/EC;

Notifying the IRB/EC of SAEs or other significant safety findings as required by 
IRB/EC procedures;

Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/EC, European regulation 536/2014 
for clinical studies (if applicable), and all other applicable local regulations.
The investigator will be responsible for reporting cases of suspected child abuse and/or 
neglect according to local medical association (e.g., AAP) or health department guidelines.
10.1.1.1. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP
In the event of any prohibition or restriction imposed (ie, clinical hold) by an applicable 
regulatory authority in any area of the world, or if the investigator is aware of any new 
information that might influence the evaluation of the benefits and risks of the study 
intervention, 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 

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of any serious breaches of this protocol or of ICH GCP that the investigator becomes aware 
of.
10.1.2. Financial Disclosure
Investigators and subinvestigators 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 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 parent/legal guardian and answer all questions regarding the study.  The 
participant or his/her parent/legal guardian should be given sufficient time and opportunity to 
ask questions and to decide whether or not to participate in the trial.
Participants must be informed that their participation is voluntary. Participants or their 
parent(s)/legal guardian will be required to sign a statement of informed consent that meets 
the requirements of 21 CFR 50, local regulations, ICH guidelines, HIPAA requirements, 
where applicable, and the IRB/EC or study center.
The investigator must ensure that each study participant or his or her parent/legal guardian 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/EC members, and by inspectors from regulatory authorities.
The investigator further must ensure that each study participant or his or her parent/legal 
guardian is fully informed about his or her right to access and correct his or her personal data 
and to withdraw consent for the processing of his or her personal data.
The medical record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date the written consent was obtained.
The authorized person obtaining the informed consent must also sign the ICD.
Participants must be reconsented to the most current version of the ICD(s) during their 
participation in the study.

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Minor participants must be re-consented if they reach the age of majority during the course 
of the study, in order to continue participating.
A copy of the ICD(s) must be provided to the participant or the participant’s parent/legal 
guardian.
Unless prohibited by local requirements or IRB/EC decision, the ICD will contain a separate 
section that addresses the use of samples for optional additional research. The optional 
additional research does not require the collection of any further samples.  The investigator 
or authorized designee will explain to each participant the objectives of the additional
research. 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. A separate 
signature will be required to document a participant’s agreement to allow specimens to be 
used for additional research. Participants who decline to participate in this optional 
additional research will not provide this separate signature.
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 will 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 participants with regard to the processing of personal 
data, participants will be assigned a single, participant-specific numerical code. Any 
participant records or data sets 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 and medical record identification. 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 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 SOPs.

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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 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.  These results are 
submitted for posting in accordance with the format and timelines set forth by US law.
EudraCT
Pfizer posts clinical trial results on EudraCT for Pfizer-sponsored interventional studies in 
accordance with the format and timelines set forth by EU requirements.
www.pfizer.com
Pfizer posts public disclosure synopses (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 corresponding study results are
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 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 contributes to the scientific understanding of the 
disease, target, or compound class. Pfizer will make available data from these trials 
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 

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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/EC 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 ICDs, 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 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 as long as they are 
maintained.

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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 the sponsor or its agents immediately of any regulatory 
inspection notification in relation to the study.  Furthermore, the investigator will cooperate 
with the sponsor or its agents to prepare the investigator site for the inspection and will allow 
the 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 the sponsor or its agent.  Before response 
submission to the regulatory authorities, the investigator will provide the 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 site.
Data reported on the CRF or entered in the eCRF that are 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 clinical monitoring plan.
Description of the use of computerized system is documented in the Data Management Plan.
10.1.8. Study and Site Start and Closure
The study start date is the date on which the clinical study will be open for recruitment of 
participants.
The first act of recruitment is the date of the first participant’s first visit and will be the study 
start date.
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 sponsor 
or designee/CRO if requested to do so by the responsible IRB/EC or if such termination is 
required to protect the health of study participants.
Reasons for the early closure of a study site by the sponsor may include but are not limited 
to:

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
Failure of the investigator to comply with the protocol, the requirements of the 
IRB/EC or local health authorities, the sponsor’s procedures, or GCP guidelines;

Inadequate recruitment of participants by the investigator;

Discontinuation of further study intervention development.
If the study is prematurely terminated or suspended, the sponsor shall promptly inform the 
investigators, the ECs/IRBs, the regulatory authorities, and any CRO(s) used in the study of 
the reason for termination or suspension, as specified by the applicable regulatory 
requirements. The investigator shall promptly inform the participant and should assure 
appropriate participant therapy and/or follow-up.
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 1 year after the 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 submits 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 for 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.

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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/study portal or other electronic system.
To facilitate access to appropriately qualified medical personnel on study-related medical 
questions or problems, participants are provided with a contact card at the time of informed 
consent.  The contact card contains, at a minimum, protocol and study intervention
identifiers, participant 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.  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
No safety laboratory test is performed according to the SoA section of this protocol, 
excluding pregnancy test.  Unscheduled clinical laboratory measurements may be obtained at 
any time during the study to assess any perceived safety issues.
Table 6.
Protocol-Required Safety Laboratory Assessments
Other
Pregnancy test (β-hCG)a
FSHb
a.
Serum or urine -hCG for female participants of childbearing potential.  Local urine testing will 
be standard for the protocol unless serum testing is required by IRB/EC.
b.
For confirmation of postmenopausal status during study only.
Investigators must document their review of each laboratory safety report.

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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, ECG, radiological scans, vital sign measurements), 
including those that worsen from baseline, considered clinically significant in the 
medical and scientific judgment of the investigator.  Any abnormal laboratory test 
results that meet any of the conditions below must be recorded as an AE:

Is associated with accompanying symptoms.

Requires additional diagnostic testing or medical/surgical intervention.

Leads to a change in study dosing (outside of any protocol-specified dose 
adjustments) or discontinuation from the study, significant additional 
concomitant drug treatment, or other therapy.

Exacerbation of a chronic or intermittent preexisting 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.

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
The signs, symptoms, and/or clinical sequelae resulting from lack of efficacy will 
be reported as an AE or SAE if they fulfill the definition of an AE or SAE and meet 
the requirements as per Section 8.3.8.1.  Also, “lack of efficacy” or “failure of 
expected pharmacological action” does not constitute an AE or SAE.
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 preexisting 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).
An 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 that 
hypothetically might have caused death if it were more severe.

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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 preexisting 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, 
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.

Suspected transmission via a Pfizer product of an infectious agent, pathogenic or 
non-pathogenic, is considered serious.  The event may be suspected from clinical 
symptoms or laboratory findings indicating an infection in a patient exposed to a 
Pfizer product.  The terms “suspected transmission” and “transmission” are 
considered synonymous.  These cases are considered unexpected and handled as 

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serious expedited cases by pharmacovigilance personnel.  Such cases are also 
considered for reporting as product defects, if appropriate.
10.3.3. Recording/Reporting and Follow-up of AEs and/or SAEs
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 CT SAE Report Form to Pfizer Safety.  
These requirements are delineated for 3 types of events: (1) SAEs; (2) nonserious adverse 
events (AEs); and (3) exposure to the study intervention 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
Nonserious AE
All
None
Exposure to the study 
intervention under study 
during pregnancy or 
breastfeeding, and 
occupational exposure
All AEs/SAEs associated 
with exposure during 
pregnancy or breastfeeding
Occupational exposure is 
not recorded.
All (and EDP supplemental 
form for EDP)
Note:  Include all SAEs 
associated with exposure 
during pregnancy or 
breastfeeding. Include all 
AEs/SAEs associated with 
occupational exposure.

When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory reports, and diagnostic 
reports) related to the event.

The investigator will then record all relevant AE/SAE information in the CRF.

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
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 CT SAE Report 
Form/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 an 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.

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
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 and/or product 
information, for marketed products, in his/her assessment.

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 the sponsor. 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 the sponsor.

The investigator may change his/her opinion of causality in light of follow-up 
information and send an 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 study intervention caused the 
event, then the event will be handled as “related to study intervention” for reporting 
purposes, as defined by the sponsor.  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 the 
sponsor 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 healthcare providers.

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 
postmortem findings including histopathology.

New or updated information will be recorded in the originally completed CRF.

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
The investigator will submit any updated SAE data to the sponsor within 24 hours 
of receipt of the information.
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 the data
become 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.
SAE Reporting to Pfizer Safety via CT SAE Report Form

Facsimile transmission of the CT SAE Report Form is the preferred method to 
transmit this information to Pfizer Safety.

In circumstances when the facsimile is not working, notification by telephone is 
acceptable with a copy of the CT SAE Report Form sent by overnight mail or 
courier service.

Initial notification via telephone does not replace the need for the investigator to 
complete and sign the CT SAE Report Form pages within the designated reporting 
time frames.

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10.4. Appendix 4: Contraceptive Guidance
10.4.1. Female Participant Reproductive Inclusion Criteria
A female participant is eligible to participate if she is not pregnant or breastfeeding, and at 
least 1 of the following conditions applies:

Is not a WOCBP (see definitions below in Section 10.4.2).
OR

Is a WOCBP and using an acceptable contraceptive method as described below 
during the intervention period (for a minimum of 28 days 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.
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.
10.4.2. Woman of Childbearing Potential
A woman is considered fertile following menarche and until becoming postmenopausal 
unless permanently sterile (see below).
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot 
be confirmed before the 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 categories can come from the site personnel’s 
review of the participant’s medical records, medical examination, or medical history 

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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 no menses for 12 months without an alternative 
medical cause. In addition, a

high FSH level in the postmenopausal range must be used to confirm a 
postmenopausal state in women under 60 years of age and not using hormonal 
contraception or HRT.

Female on HRT and whose menopausal status is in doubt will be required to 
use one of the nonestrogen 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.
10.4.3. Contraception Methods
Contraceptive use by men or women should be consistent with local availability/regulations 
regarding the use of contraceptive methods for those participating in clinical trials.
1. Implantable progestogen-only hormone contraception associated with inhibition of 
ovulation.
2. Intrauterine device.
3. Intrauterine hormone-releasing system.
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. The spermatogenesis cycle is 
approximately 90 days.
6. Combined (estrogen- and progestogen-containing) hormonal contraception associated 
with inhibition of ovulation:

Oral;

Intravaginal*;

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
Transdermal*;

Injectable*.
7. Progestogen-only hormone contraception associated with inhibition of ovulation*:

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.
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 spermicide.
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).
* Not approved or not certificated in Japan

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10.5. Appendix 5: Liver Safety: Suggested Actions and Follow-up Assessments
Potential Cases of Drug-Induced Liver Injury
Humans exposed to a drug who show no sign of liver injury (as determined by elevations in 
transaminases) are termed “tolerators,” while those who show transient liver injury, but adapt 
are termed “adaptors.”  In some 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 DILI.  
Participants who experience a transaminase elevation above 3 × ULN should be monitored 
more frequently to determine if they are an “adaptor” or are “susceptible.”
In the majority of DILI cases, elevations in AST and/or ALT precede TBili elevations (>2 ×
ULN) by several days or weeks.  The increase in TBili typically occurs while AST/ALT 
is/are still elevated above 3 × ULN (ie, AST/ALT and TBili values will be elevated within 
the same laboratory 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:

Preexisting AST or ALT baseline values above the normal range: AST or ALT 
values >2 times the baseline values AND >3 × ULN; or >8 × ULN (whichever is 
smaller).

Preexisting values of TBili above the normal range: TBili level increased from 
baseline value by an amount of at least 1 × ULN or if the value reaches 
>3 × ULN (whichever is smaller).

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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 participant should return to the investigator site and be evaluated as soon as possible, 
preferably within 48 hours from awareness of the abnormal results.  This evaluation should 
include laboratory tests, detailed history, and physical assessment.
In addition to repeating measurements of AST and ALT and TBili for suspected cases of 
Hy’s law, additional laboratory tests should include albumin, CK, direct and indirect 
bilirubin, GGT, PT/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/paracetamol (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 samples for acetaminophen/paracetamol 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 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: Abbreviations
The following is a list of abbreviations that may be used in the protocol.
Abbreviation
Term
%BSA
percent body surface area
AAP
American Academy of Pediatrics
AD
atopic dermatitis
ADSI
Atopic Dermatitis Severity Index
AE
adverse event
ALT
alanine aminotransferase
AST
aspartate aminotransferase
AUC
area under concentration-time curve
-hCG
beta-human chorionic gonadotropin
BID
bis in diem (twice a day)
BSA
body surface area
EASI
Eczema Area and Severity Index
CFR
Code of Federal Regulations
CIOMS
Council for International Organizations of Medical Sciences
CK
creatine kinase
Cmax
maximum observed concentration
CONSORT
Consolidated Standards of Reporting Trials
CRF
case report form
CRO
contract research organization
CSR
clinical study report
CT
clinical trial
DILI
drug-induced liver injury
DMC
data monitoring committee
E-DMC
External Data Monitoring Committee
EC
ethics committee
EC50
half maximal effective concentration
eCRF
electronic case report form
ECG
electrocardiogram
EDP
exposure during pregnancy
EMA
European Medicines Agency
EOS
end of study
EOT
end of treatment
ET
early termination
EU
European Union
EudraCT
European Clinical Trials Database
FSH
follicle-stimulating hormone
GCP
Good Clinical Practice
GGT
gamma glutamyl transferase
HIPAA
Health Insurance Portability and Accountability Act

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Abbreviation
Term
HRQOL
health-related quality of life
HRT
hormone replacement therapy
IC50
half maximal inhibitory concentration
ICD
informed consent document
ICH
International Council for Harmonisation
IFN
Interferon
IL
interleukin
IMP
investigational medicinal product
IND
investigational new drug
INR
international normalized ratio
IP manual
investigational product manual
IPAL
Investigational Product Accountability Log
IRB
institutional review board
IRT
interactive response technology
ISGA
Investigator’s Static Global Assessment
JAK
Janus kinase
LFT
liver function test
MMP
matrix metalloproteinase
MUSE
maximal use, systemic exposure
N/A
not applicable
NIMP
noninvestigational medicinal product
NRS
Numeric Rating Scale
PDE
phosphodiesterase
PK
pharmacokinetic(s)
PRN
pro re nata
PT
prothrombin time
PUVA
psoralen plus ultraviolet A
QD
once a day
SAE
serious adverse event
SAP
statistical analysis plan
SOP
standard operating procedure
SRSD
single reference safety document
SoA
schedule of activities
SUSAR
suspected unexpected serious adverse reaction
t½
half-life
TBili
total bilirubin
Tmax
time to reach maximum observed plasma concentration
TNF
tumor necrosis factor
TSS
Total Sign Scores
ULN
upper limit of normal
US
United States
UV
ultraviolet

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Abbreviation
Term
UV-B
ultraviolet B
WOCBP
woman of childbearing potential

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