Clinical trial NCT03954158
Conditions: Atopic Dermatitis
Sponsor: Pfizer
Start date: 2019-06-15; Completion date: 2019-12-16
Enrollment: 81 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a Phase 2b, multi-center, randomized, double-blind, vehicle-controlled, intraparticipant study to evaluate efficacy and safety of two regimens of crisaborole ointment 2% in Japanese pediatric and adult participants (cohort 1: 12 years and older, cohort 2: 2 to under 12 years old) with mild to moderate Atopic Dermatitis (AD).

Detailed description:

Arms: arm 1: intra-participant comparison, treatment will be randomly assigned to target lesion 1 and lesion 2. arm 2: Intra-participant comparison, treatment will be randomly assigned to target lesion 1 and lesion 2.
Interventions: intervention 1: Crisaborole ointment 2% intervention 2: Vehicle intervention 3: Crisaborole ointment 2% intervention 4: Vehicle
Intervention descriptions: intervention 1: BID regimen intervention 2: BID regimen intervention 3: QD regimen intervention 4: QD regimen

Protocol documents:
Prot_001.pdf: 
PF-06930164 (Crisaborole)
Protocol C3291028
Final Protocol, 22 Feb 2019
Page 1
A PHASE 2B, MULTI-CENTER, 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 (2 YEARS AND OLDER) 
WITH MILD TO MODERATE ATOPIC DERMATITIS
Investigational Product Number:
PF-06930164
Investigational Product Name:
Crisaborole
United States (US) Investigational New 
Drug (IND) Number:
Not Applicable (N/A)
European Clinical Trials Database 
(EudraCT) Number:
Not Applicable (N/A)
Protocol Number:
C3291028
Phase:
Phase 2b
Short Title: A Phase 2b, Multi-Center, 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 (2 Years and Older) with Mild 
to Moderate Atopic Dermatitis


PF-06930164 (Crisaborole)
Protocol C3291028
Final Protocol, 22 Feb 2019
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Protocol Amendment Summary of Changes Table
Document History
Document
Version Date
Summary of Changes and Rationale
Original protocol
22 Feb 2019
Not applicable (N/A)


PF-06930164 (Crisaborole)
Protocol C3291028
Final Protocol, 22 Feb 2019
Page 3
TABLE OF CONTENTS
LIST OF TABLES.....................................................................................................................6
LIST OF FIGURES ...................................................................................................................7
1. PROTOCOL SUMMARY.....................................................................................................8
1.1. Synopsis ....................................................................................................................8
1.2. Schema ......................................................................................................................8
1.3. Schedule of Activities (SoA).....................................................................................9
2. INTRODUCTION ...............................................................................................................12
2.1. Study Rationale .......................................................................................................12
2.2. Background .............................................................................................................12
2.2.1. Nonclinical Safety Studies..........................................................................13
2.2.2. Pharmacokinetics........................................................................................14
2.2.3. Cutaneous Sensitization, Irritancy Potential and Tolerability....................15
2.2.3.1. Skin Irritation Study..................................................................15
2.2.3.2. Local Tolerability in Sensitive Skin Areas ...............................15
2.2.3.3. Sensitizing and Cumulative Irritation Potential ........................15
2.2.4. Clinical Overview.......................................................................................16
2.3. Benefit/Risk Assessment.........................................................................................18
3. OBJECTIVES, ESTIMANDS, AND ENDPOINTS ...........................................................18
4. STUDY DESIGN.................................................................................................................20
4.1. Overall Design.........................................................................................................20
4.2. Scientific Rationale for Study Design.....................................................................21
4.3. Justification for Dose ..............................................................................................21
4.4. End of Study Definition ..........................................................................................21
5. STUDY POPULATION......................................................................................................22
5.1. Inclusion Criteria.....................................................................................................22
5.2. Exclusion Criteria....................................................................................................24
5.3. Lifestyle Considerations..........................................................................................25
5.3.1. Contraception..............................................................................................25
5.3.2. Other Lifestyle Requirements.....................................................................26
5.4. Screen Failures ........................................................................................................26


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Final Protocol, 22 Feb 2019
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6. STUDY INTERVENTION..................................................................................................26
6.1. Study Intervention(s) Administered........................................................................27
6.1.1. Administration............................................................................................27
6.2. Preparation/Handling/Storage/Accountability ........................................................29
6.2.1. Preparation and Dispensing........................................................................30
6.3. Measures to Minimize Bias: Randomization and Blinding.....................................30
6.3.1. Allocation to Investigational Product .........................................................30
6.3.2. Breaking the Blind......................................................................................31
6.4. Study Intervention Compliance...............................................................................32
6.5. Concomitant Therapy..............................................................................................32
6.5.1. Medications Prohibited Prior to Baseline/Day 1 ........................................32
6.5.2. Medications Prohibited During the Study (Days 1-15) ..............................33
6.5.3. Medications Allowed During the Study .....................................................34
6.6. Dose Modification...................................................................................................35
6.7. Intervention After the End of the Study..................................................................35
7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL...........................................................................35
7.1. Discontinuation of Study Intervention ....................................................................35
7.2. Participant Discontinuation/Withdrawal From the Study.......................................36
7.3. Lost to Follow-up....................................................................................................37
8. STUDY ASSESSMENTS AND PROCEDURES...............................................................37
8.1. Efficacy Assessments..............................................................................................38
8.1.1. Lesion Investigator Static Global Assessment (Lesion ISGA)...................38
8.1.2. Lesion Total Sign Score (Lesion TSS).......................................................39
8.1.3. Pruritus assessments ...................................................................................39
8.1.4. %BSA with Atopic Dermatitis ...................................................................41
8.1.5. Investigator Static Global Assessment (ISGA) ..........................................42
8.1.6. Rater Qualifications....................................................................................42
8.2. Safety Assessments .................................................................................................42
8.2.1. Physical Examinations................................................................................42
8.2.2. Vital Signs ..................................................................................................42
8.2.3. Clinical Safety Laboratory Assessments ....................................................43


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8.2.4. Pregnancy Testing ......................................................................................43
8.2.5. Photography................................................................................................43
8.3. Adverse Events and Serious Adverse Events..........................................................43
8.3.1. Time Period and Frequency for Collecting AE and SAE Information.......44
8.3.1.1. Reporting SAEs to Pfizer Safety...............................................44
8.3.1.2. Recording Nonserious AEs and SAEs on the CRF...................44
8.3.2. Method of Detecting AEs and SAEs ..........................................................45
8.3.3. Follow-up of AEs and SAEs.......................................................................45
8.3.4. Regulatory Reporting Requirements for SAEs...........................................45
8.3.5. Exposure During Pregnancy or Breastfeeding, and Occupational
Exposure ..........................................................................................................46
8.3.5.1. Exposure During Pregnancy......................................................46
8.3.5.2. Exposure During Breastfeeding ................................................46
8.3.5.3. Occupational Exposure .............................................................46
8.3.6. Medication Errors .......................................................................................46
8.4. Treatment of Overdose............................................................................................47
8.5. Pharmacokinetics ....................................................................................................47
8.6. Pharmacodynamics..................................................................................................47
8.7. Genetics...................................................................................................................47
8.8. Biomarkers ..............................................................................................................47
8.9. Health Economics ...................................................................................................48
9. STATISTICAL CONSIDERATIONS ................................................................................48
9.1. Estimands and Statistical Hypotheses.....................................................................48
9.1.1. Estimands....................................................................................................48
9.2. Sample Size Determination.....................................................................................48
9.3. Populations for Analysis .........................................................................................49
9.4. Statistical Analyses .................................................................................................49
9.4.1. Efficacy Analyses .......................................................................................49
9.4.2. Safety Analyses ..........................................................................................51
9.5. Interim Analyses .....................................................................................................51
9.5.1. Data Monitoring Committee.......................................................................51


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10. SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS..........................................................................................................52
10.1. Appendix 1: Regulatory, Ethical, and Study Oversight Considerations...............52
10.1.1. Regulatory and Ethical Considerations ....................................................52
10.1.1.1. Reporting of Safety Issues and Serious Breaches of the 
Protocol or ICH GCP.........................................................................52
10.1.2. Informed Consent Process ........................................................................53
10.1.3. Data Protection .........................................................................................54
10.1.4. Dissemination of Clinical Study Data ......................................................54
10.1.5. Data Quality Assurance ............................................................................55
10.1.6. Source Documents....................................................................................57
10.1.7. Study and Site Closure..............................................................................57
10.1.8. Publication Policy.....................................................................................57
10.1.9. Sponsor’s Qualified Medical Personnel ...................................................58
10.2. Appendix 2: Clinical Laboratory Tests .................................................................59
10.3. Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting ......................................................................60
10.3.1. Definition of AE .......................................................................................60
10.3.2. Definition of SAE.....................................................................................61
10.3.3. Recording/Reporting and Follow-up of AEs and/or SAEs.......................62
10.3.4. Reporting of SAEs....................................................................................65
10.4. Appendix 4: Contraceptive Guidance and Collection of Pregnancy 
Information................................................................................................................67
10.4.1. Female Participant Reproductive Inclusion Criteria.................................67
10.4.2. Woman of Childbearing Potential (WOCBP) ..........................................67
10.4.3. Contraception Methods.............................................................................68
10.5. Appendix 5: Liver Safety: Suggested Actions and Follow-up Assessments ........71
10.6. Appendix 6: Abbreviations ...................................................................................73
11. REFERENCES ..................................................................................................................76
LIST OF TABLES
Table 1.
Treatment Allocation for Intra-Participant Design...............................................31
Table 2.
Investigator’s Static Global Assessment (ISGA) .................................................38


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Table 3.
Lesion Total Sign Score (Lesion TSS).................................................................39
Table 4.
Handprint Determination of Body Region Surface Area for Participants 
aged ≥8 years old.................................................................................................41
Table 5.
Handprint Determination of Body Region Surface Area for Participants 
aged < 8 years old.................................................................................................42
Table 6.
Protocol-Required Safety Laboratory Assessments .............................................59
LIST OF FIGURES
40
 
40
 
41
CCI
CCI
CCI


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Final Protocol, 22 Feb 2019
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1. PROTOCOL SUMMARY
1.1. Synopsis
Not Applicable
1.2. Schema
Washout
Day 1
Baseline
䠉35 days
Regimen 1: QD
End of Treatment
Randomization
Start of Treatment
Screening 
Period
Vehicle-controlled, 
double-blind period
R
Day 8
Safety 
Follow-Up
Day 15
Regimen 2: BID
Day 43
EOT + 28 days
Washout
Regimen 1: QD
R
Regimen 2: BID
Cohort 1䠖
Ages 12 years and older
Cohort 2䠖
Ages 2 years to under 12 
years old
Outpatient, daily visit*1
Outpatient,  Visit Day 1, 8 and 15 *2
: Lesion 1
: Lesion 2
: Lesion 1
: Lesion 2
BID: twice daily, QD: once daily
* 1 Visit study site and application by site staff
* 2 Investigational products will be applied by parent/caregiver with site staff check (directly or via live video chat, etc.)
and/or by site staff (site staff will visit participant’s home as needed).


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1.3. Schedule of Activities (SoA)
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
Day -35 to Day -1
Screening
Day 1
Baseline
Day 8
Day 15
End of Treatment/
Early Discontinuationb
Day 43
Follow-upc
Visit Window
±1 Day
±1 Day
+3 Days
Informed consent, including assent
X
Medical history
X
X
Vital signsG
X
Physical examination
X
X
Laboratory
Hematology
X
Blood chemistry
Xe
Urinalysis
X
Pregnancy testf
X
X
X
Contraception checkg
X
X
X
X
X
Identify two target lesions
X
Randomization
X
Study treatment
Cohort 1: Site staff applies the investigational products to the 
participant at the site.h
X
→
Xi
Cohort 2: Parent/caregiver and/or the site staff applies the 
investigational products to the participant.h
X
→
Xi
Dispense Investigational Products (Cohort 2)
X
X
Collect Returned Investigational Products (Cohort 2)
X
X
Weigh Investigational Products
X
X
X
Compliance confirmation
X
→
Xj


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Final Protocol, 22 Feb 2019
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Visit Identifiera
Day -35 to Day -1
Screening
Day 1
Baseline
Day 8
Day 15
End of Treatment/
Early Discontinuationb
Day 43
Follow-upc
Visit Window
±1 Day
±1 Day
+3 Days
Assessments
%BSA for eligibility
X
X
ISGA for eligibility
X
X
Lesion ISGA for each target lesion
X
X
X
Lesion TSS for each target lesion
X
X
X
Pruritus assessments for each target lesionk
Cohort 1: Peak Pruritus NRS (age ≥12)
Cohort 2: Itch Severity Scale (age 6-11)
Cohort 2: Observer Reported Itch Severity NRS (age 2-11)
X
→
X
Photographsl
X
X
X
Review Prior/Concomitant treatment(s)
Xm
→
→
→
X
Serious and nonserious adverse event monitoring
X
→
→
→
→
Abbreviations: →= ongoing/continuous event; AD = atopic dermatitis; BID = twice daily; %BSA = percent of body surface area; FSH = follicle stimulating hormone; ISGA = 
Investigator’s Static Global Assessment; NRS = numerical rating scale; QD = once daily; TSS = Total Sign Score.
a.
Day relative to start of study treatment (Day 1).
b.
If a participant is discontinued, the efficacy evaluation at the timing of the early termination will be conducted as early as possible (the same day is preferable).
c.
Follow-up contact will be completed during 28 to 35 days from administration of the final dose of investigational products to capture any potential adverse events and to 
confirm appropriate contraception usage and concomitant treatments. Visit is planned to occur as a telephone contact.
d.
Temperature (tympanic or axillary), pulse rate, and blood pressure taken in the seated or supine position, after the participants have been sitting or lying calmly for a minimum 
of 5 minutes.  Assessment of vital signs should precede blood draw for clinical laboratory tests.
e.
Serum FSH concentration will be determined for all females who are amenorrheic only for confirmation postmenopausal status.
f.
For females of childbearing potential only.  Local urine testing will be standard for the protocol.
g.
For females of childbearing potential only.  Confirm that contraception is used consistently and correctly.
h.
Cohort 1: From Day 1 to Day 15 participants will visit the site once or twice daily to apply investigational products by site staff. If it becomes difficult for the participant to 
visit the study site, the site staff will visit participant’s home and investigational products will be applied by site staff as a backup option upon sponsor’s agreement.
Cohort 2: From Day 1 to Day 15 investigational products will be applied once or twice daily by parent/caregiver and/or site staff. When investigational products are applied 
by parent/caregiver, site staff will check the compliance directly or via live video chat. When investigational products will be applied by site staff, site staff will visit the 
participant’s home as needed.
i.
Regimen 1 (QD): Participant will be applied investigational products from Day 1 to Day 14.
Regimen 2 (BID): When participant will be applied investigational products from AM in Day 1, the last administration will be PM in Day 14. When participant will be 
applied investigational products from PM in Day 1, the last administration will be AM in Day 15.
j.
Compliance will be confirmed by parent/caregiver and/or the site staff confirmation.
k.
Pruritus assessment will be completed by participants who are ≥6 years old and by observers [parents/caregivers] for the participants (age 2-11) when applicable, once daily
from Day 1 to Day 15 before investigational products application preferably at the same time of each day if applicable.
l.
Photographs of target lesions will be obtained. Photographs will be taken by local standard procedures.


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Visit Identifiera
Day -35 to Day -1
Screening
Day 1
Baseline
Day 8
Day 15
End of Treatment/
Early Discontinuationb
Day 43
Follow-upc
Visit Window
1 Day
1 Day
+3 Days
m.
Record all treatments (including medications and non-medication therapies) used for AD 90 days prior to screening and all other medications (including bland [non-
medicated] emollients, over the counter drugs, vitamins, and antacids) used within 30 days prior to Screening.


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2. INTRODUCTION
Crisaborole, also referred to as PF-06930164 or AN2728, is a low molecular weight 
benzoxaborole anti-inflammatory phosphodiesterase-4 (PDE-4) inhibitor that penetrates into 
the skin to the sites of inflammation and is currently being investigated for topical treatment 
in patients with mild to moderate atopic dermatitis (AD).  PDE-4 inhibition results in 
increased intracellular cyclic adenosine monophosphate (cAMP) levels.  While the specific 
mechanism(s) by which crisaborole exerts its therapeutic action is not well defined, 
crisaborole reduces the production of several inflammatory cytokines implicated in the 
pathophysiology of AD.
2.1. Study Rationale 
Confirmatory evidence of efficacy and safety was provided by two well-controlled Phase 3 
studies conducted in the US in AD patients 2 years of age and older. Long-term safety was 
evaluated in an open label study that enrolled participants from the Phase 3 studies. Based 
on the outcome of these studies, crisaborole ointment 2% was approved and is on US and 
Canada market under the tradename of EUCRISA (crisaborole) ointment, 2% twice daily 
(BID) indicated for topical treatment of mild to moderate AD in patients 2 years of age and 
older.
In Japan, phase 1 study (C3291029) was conducted and safety and tolerability crisaborole 
ointment 2% BID has been shown in Japanese participants. Based on this study results, it is 
considered that similar pharmacokinetics (PK) profile and systemic exposure were shown 
between Japanese and Non-Japanese participants.
In this study, two regimens of crisaborole ointment 2%, BID and once daily (QD), will be 
compared relative to corresponding vehicle.  In addition, a descriptive comparison between 
crisaborole BID and crisaborole QD will be conducted to select the dose regimen for next 
clinical phase in each age group; adults/adolescents (12 years or older) and pediatrics 
(2 years to under 12 years) in Japanese AD patients.
2.2. Background
AD, also referred to as atopic eczema or in layperson terms as eczema, is a chronic and 
relapsing disease affecting an increasing number of patients.  Although AD affects patients of 
all ages, it is one of the most common, chronic, relapsing childhood dermatoses, impacting 
15%-30% of all children in the US with 85% of affected individuals showing signs of the 
disease before 5 years of age.1,2  Over the past 50 years, AD has become more prevalent, 
especially in industrialized, temperate countries such as the US and Japan.3,4,5
AD is an distinctive inflammatory, highly pruritic, chronic eczematous condition that usually 
occurs in people who have a personal or family history of other atopic conditions such as 
asthma or allergic rhinitis.1,4  The majority of patients (up to 90%) with AD present with mild 
to moderate disease.6  Manifestation of the disease includes intense pruritus, erythematous 
papules, excoriation, exudation, lichenification and bacterial colonization.7  Continuous 
scratching during exacerbations can lead to lichenification, excoriations, and serious skin 


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infections.  AD is often associated with other conditions including asthma, allergic rhinitis, 
and food allergy.8,9  The burden of the clinical symptoms of AD coupled with the stigma 
associated with highly visible skin lesions correlates with significant morbidity and extensive 
impairments on health related quality of life measures (HRQoL) for patients, especially in 
children, and caregivers.1,10,11,12  Psychosocial problems, depression, and anxiety are 
associated with AD in both adults and children.13
AD has a significant impact on day to day functioning, as evidenced by its impact on the 
overall well-being of the patient and their family on multiple levels; medical management 
and treatment, HRQoL, and psycho-social implications.  AD may also be a source of 
significant economic burden14 as this relapsing disease is often misdiagnosed, misunderstood, 
and ineffectively treated.4  AD is a condition associated with significant morbidity.  
Currently, there is no cure for AD.  AD is a chronic disease with treatment focused on the 
management of flares and maintenance of remissions.  Due to the chronic, relapsing nature of 
the disease, treatment may be needed for many years. 
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.
Crisaborole is a novel, non-steroidal, topical anti-inflammatory PDE-4 inhibitor that will 
serve an unmet need in the treatment of AD.  Supporting evidence of the safety and efficacy 
of this product in patients 2 years and older represent a major advancement in the treatment 
of AD given the challenges of managing this common, chronic dermatologic condition and 
the treatment-limiting effects of currently available therapies.  All primary and secondary 
efficacy endpoints were statistically significant in favor of crisaborole ointment 2% BID 
versus vehicle ointment BID in the two Phase 3 registration studies (Study AN2728-AD-301
and Study AN2728-AD-302) in the US.   Across the development program, crisaborole 
demonstrated an acceptable safety profile, with no crisaborole treatment-related serious 
adverse events (SAE) (except 1 case of drug eruption in a Phase 2 study which was classified 
as possibly related) and with the majority of adverse events (AEs) being mild and deemed 
unlikely or not related to investigational product.
2.2.1. Nonclinical Safety Studies
Crisaborole demonstrates inhibitory capacity against human leukocyte cytokine release with 
half maximal effective concentration (EC50) values ranging from high nanomolar to low 
micromolar concentrations.  Crisaborole also inhibits the release of chemokines that are 
important inflammatory mediators.  The primary mechanism of the anti-inflammatory effect 
of crisaborole is through inhibition of PDE-4, which causes elevation of cAMP in leukocytes 
and subsequent protein kinase A (PKA)-mediated phosphorylation of transcription factors 
that are important for cytokine-, chemokine-, or prostaglandin-forming enzyme synthesis and 
release from cells.  Crisaborole proved efficacious against an inflammatory challenge in vivo 
in a mouse phorbol 12-myristate 13-acetate (PMA)-induced ear edema model.  AN7602 and 
AN8323, main metabolites of crisaborole, lack anti-inflammatory activities against PDE-4 
and a panel of cytokines.


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Based on the nonclinical safety studies conducted to date, crisaborole ointment 2% has an 
acceptable safety profile.  Refer to the investigator’s brochure (IB) for further information on 
the nonclinical experience with crisaborole ointment 2%.
2.2.2. Pharmacokinetics
A total of 11 clinical pharmacology studies were conducted in healthy volunteers or in 
participants with AD or psoriasis.  The clinical pharmacology studies demonstrated that
following topical application, crisaborole penetrated through the stratum corneum, epidermis, 
and dermis of human skin, as evidenced by the presence of crisaborole and its main 
metabolites in plasma.
The efficacy of crisaborole for the treatment of AD is not dependent on systemic exposure.
The development program evaluated systemic exposure to crisaborole and its main
metabolites relative to establishing the safety of topically applied crisaborole.  Clinical 
studies in healthy adult volunteers, in pediatric and adolescent participants with AD, and in 
adults with psoriasis demonstrated similar PK profiles and systemic exposure, irrespective of 
underlying disease or age, and establish that following topical application, crisaborole 
penetrated through the stratum corneum, epidermis, and dermis of human skin, as evidenced 
by the presence of crisaborole and its main metabolites in plasma.  Upon reaching the 
systemic circulation, biotransformation of crisaborole is rapid and extensive and primarily 
consists of oxidative deboronation/hydrolysis to produce AN7602 by CYP3A4 and 
CYP1A1/2, followed by subsequent downstream oxidation of this metabolite to form 
AN8323, without notable species-related qualitative differences.  These two main
metabolites of crisaborole observed in plasma following topical application to several 
species, including humans, were found to be inactive against PDE-4.  Further, as a result of 
rapid biotransformation, systemic exposure of crisaborole is limited following topical 
application of crisaborole.
In the clinical PK study conducted under maximal use conditions (maximal use systemic 
exposure [MUSE] study) in children and adolescents aged 2-17 years with extensive AD 
(mean treatable percent body surface area [%BSA] 48.7%; range 27%-92%), absorption 
across the skin was rapid, with a median of time to reach maximum observed plasma 
concentration (Tmax) of 3.0 hours on both Day 1 and Day 8 (Study AN2728-AD-102).  
Steady state was achieved within the first 8 days of dosing, with a mean crisaborole 
maximum observed plasma concentration (Cmax) of 127 ng/mL. Minimal plasma 
accumulation of crisaborole and AN7602 was observed at steady state whereas AN8323 
displayed an approximately 3-4-fold accumulation based on Cmax and area under the 
concentration-time curve from time zero to the 12 hours (AUC12).
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 


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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.
2.2.3. Cutaneous Sensitization, Irritancy Potential and Tolerability
2.2.3.1. 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).
2.2.3.2. Local Tolerability in Sensitive Skin Areas
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), and only 0.1% of assessments graded higher than 1 (mild), with an 
overall maximum grade of 2 (moderate) (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.
2.2.3.3. Sensitizing and Cumulative Irritation Potential
In a repeat-insult patch test (RIPT) 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 with daily patch applications 
for 21 consecutive days.  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 (minimal erythema, 
barely perceptible).


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2.2.4. Clinical Overview
Eight (8) clinical trials of topical formulations of crisaborole have been completed to date in 
participants with AD.  Key study information is summarized below.

In a 4-week, multi-center, MUSE study in 34 children and adolescents aged 
2-17 years with mild to moderate AD (Study AN2728-AD-102) who applied 
crisaborole ointment 2% BID, participants had overall blood levels of crisaborole that 
were low and similar to those previously observed in adults psoriasis participants 
(Study AN2728-PSR-106) after adjusting for %BSA treated. 
A total of 63 AEs were reported in 23/34 participants (67.6%): 40 were mild, 20 were 
moderate, and 3 were severe.  No treatment emergent adverse event (TEAE) was 
considered serious, and no death occurred.  The most common TEAEs were 
application site reactions that were generally mild or moderate in severity and 
resolved spontaneously without sequelae.  The TEAEs reported for more than 
1 participant were application site pain (12/34, 35.3%), worsening of atopic dermatitis 
(7/34, 20.6%), upper respiratory tract infection (3/34, 8.8%), and application site 
paresthesia (2/34, 5.9%).  About half (36/63, 57.1%) of the TEAEs were considered 
related to study drug, two of which (application site pain) were severe and occurred in 
a 2-year-old female participant who experienced intermittent application site burning 
on Study Days 6, 7, 10, 11, and 12 (nonserious, mild to severe, possibly to definitely 
related).  On Study Day 13, this participant was withdrawn from the study at her 
father’s request.  The events resolved following the final application of study drug on 
Study Day 12.  Overall, no clinically important safety signals were observed in a 
review of TEAEs, topical TEAEs (application site reactions), and laboratory test, vital 
sign, and physical examination results.

In a 4-week, single arm, open-label, safety, tolerability and PK trial in adolescents 
with mild to moderate AD involving 10%-35%BSA, crisaborole ointment 2% BID 
improved disease severity over the 28-day treatment period (Study 
AN2728-AD-203).  A total of 19 TEAEs were reported in 43.5% (10/23) participants.
All TEAEs were either mild (57.9% [11/19]) or moderate (42.1% [8/19]).  The 
majority of TEAEs (68.4% [13/19]) were unrelated or unlikely to be related to study 
drug.  All drug-related AEs were application site reactions. The most commonly 
reported TEAEs, application site pain and nasopharyngitis, were each reported by 
3 participants.  No other TEAE was reported by more than 1 participant.  No SAEs or 
deaths were reported.  No clear correlation was observed between plasma exposure 
levels and the incidence of AEs.  Overall, no safety signals were observed in a review 
of local tolerability, AEs, TEAEs, clinical laboratory results, and vital sign results.

In a 6-week bilateral comparison trial of participants with mild to moderate AD
(Study AN2898-AD-202), 68% of AD lesions treated with crisaborole ointment 2% 
BID showed greater improvement in AD severity index (ADSI) than vehicle-treated 
lesions (20%) at 4 weeks (primary endpoint).  These defference in response rates 
compared to vehicle were similar at Day 14 and Day 42 (end of treatment). 


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
In a 4-week bilateral comparison trial of 86 adolescent participants with mild to
moderate AD (Study 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 BID was more efficacious than either 
concentration applied QD. BID shows greater improvement from baseline than QD 
group at each visit (Day 8, Day 15, Day 22 and Day 29).

In two Phase 3, multi-center, randomized, double-blind, vehicle controlled studies in 
participants ≥2 years with AD, crisaborole ointment 2% outperformed the vehicle in 
the primary efficacy analysis (success in investigator’s static global assessment 
[ISGA] defined as an ISGA score of clear or almost clear with at least a 2-grade 
improvement from Baseline) and the difference between the treatment groups was 
statistically significant (Study AN2728-AD-301 and Study AN2728-AD-302).

An additional Phase 3, multi-center, open-label, long-term extension study of 
crisaborole ointment 2% for the treatment of mild to moderate AD in adults and 
children as young as 2 years of age evaluated the long-term safety of topical 
crisaborole (Study AN2728-AD-303).  Crisaborole showed an acceptable safety 
profile for long-term topical treatment of mild to moderate AD in adults and children 
as young as 2 years of age.

Phase 1, single center, randomized, vehicle-controlled, parallel cohort study of 
crisaborole ointment 2% conducted in 2 cohorts evaluating the skin irritation potential 
in adult Japanese healthy participants in Cohort 1, and safety, tolerability and PK in 
adult Japanese participants with mild to moderate AD in Cohort 2 (Study C3291029).
In Cohort 1, there were no TEAEs.
In Cohort 2, a total of 9 participants in the crisaborole ointment 2% group and 2 
participants in the vehicle group experienced a TEAE. All AEs were mild in severity 
in the crisaborole ointment, 2% group and mild or moderate in severity in the vehicle 
group. Two participants discontinued due to a TEAE (crisaborole ointment, 2% 
group: one application site pain, vehicle treatment group: one dermatitis atopic
aggravated).  No serious TEAEs or severe TEAEs were reported in either treatment 
group. Overall, there were no clinically significant changes for laboratory values, 
vital signs or Electrocardiogram (ECG).
Based on these results, crisaborole ointment 2% BID was found to be well tolerated 
in Japanese participants with mild to moderate AD.
Crisaborole has been well tolerated across completed clinical studies.  No clinically 
important safety signals have been identified, including during a Phase 3 multi-center, 
open-label, long-term extension study of crisaborole ointment 2% for mild to moderate 
AD in adults and children as young as 2 years of age.  Most AEs have been mild, and most 
considered unrelated or unlikely to be related to investigational product.  The most common 
drug-related AEs have been application site reactions where were mild to moderate.


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In a thorough QT (TQT) study (Study AN2728TQT108) in which healthy participants were 
treated with crisaborole ointment 2% at a therapeutic dose (15 g, representing 30%BSA 
treatment) or a supratherapeutic dose (45 g, representing 60%BSA treatment), mean Cmax
values of 36.9 ng/mL and 87.4 ng/mL were observed in therapeutic and supratherapeutic 
dose groups, respectively, at Day 9. At both therapeutic and supratherapeutic doses had no 
effect on cardiac repolarization based on results from the primary assessment and the 
pharmacokinetic (PK)-pharmacodynamic (PD) analysis.
2.3. Benefit/Risk Assessment
The benefit/risk balance of crisaborole ointment 2% application in this study is considered 
favorable and supported by the following:

The expected efficacy of crisaborole ointment 2% for the treatment of AD based on 
the results of clinical studies conducted to date.

The expected limited crisaborole systemic exposure when applied topically based on 
the results of clinical studies conducted with crisaborole ointment 2% to date.

The satisfactory safety and local tolerability demonstrated in non-clinical and clinical 
studies conducted with crisaborole ointment 2% to date.
The benefit will be limited due to this study design which is an intra-participant design to 
evaluate each target lesion treated with crisaborole or vehicle. Based on the favorable 
clinical safety profile as well as the limited systemic exposure of crisaborole, the risk to 
participants treated with crisaborole is deemed to be minimal.
More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of crisaborole may be found in the IB, which is the single reference safety 
document (SRSD) for this study.
3. OBJECTIVES, ESTIMANDS, AND ENDPOINTS
Objectives
Endpoints
Estimands
Primary: 
Primary:
Primary: 

To compare the efficacy of 
crisaborole ointment 2%, 
administered QD or BID relative to 
the corresponding vehicle (QD or 
BID), on Total Sign Score (TSS) 
assessment in target lesions, in the 
treatment of mild to moderate AD in 
adults (cohort 1) and pediatrics 
(cohort 2).

Change from baseline in 
TSS in target lesions treated 
with crisaborole ointment or 
vehicle on Day 15 in each
regimen (regimen 1: QD, 
regimen 2: BID) for each 
cohort.
This estimand is the hypothetical 
estimand, which estimates the effect as if 
all participants maintain their randomized 
treatment.

Population: Participants with mild to 
moderate AD in adults (cohort 1) and 
pediatrics (cohort 2) as defined by 
the inclusion and exclusion criteria 
and are randomized and received at 
least one of the investigational 
products;


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Objectives
Endpoints
Estimands

Intercurrent event: All efficacy data 
after discontinuation of treatment 
will not be considered;

Population-level summary: 
Least-square means of intra-
participant difference between 
crisaborole ointment 2% vs 
corresponding vehicle in each 
regimen for each cohort and pooled 
cohort.
Secondary: 
Secondary:
Secondary: 

To evaluate the efficacy of 
crisaborole ointment 2% BID relative 
to crisaborole ointment 2% QD, on 
TSS assessment in target lesions, in 
the treatment of mild to moderate AD 
in adults (cohort 1) and pediatrics 
(cohort 2).

Change from baseline in 
TSS in target lesions treated 
with crisaborole ointment or 
vehicle on Day 15 in each
regimen for each cohort.
This estimand is the hypothetical 
estimand, which estimates the effect as if 
all partisipants maintain their randomized 
treatment.

Population:  Participants with mild to 
moderate AD in adults (cohort 1) and 
pediatrics (cohort 2) as defined by 
the inclusion and exclusion criteria 
and are randomized and received at 
least one of the investigational 
products;

Intercurrent event:  All efficacy data
after discontinuation of treatment 
will not be considered;

Population-level summary:  
Difference in least square means 
between crisaborole ointment 2% 
BID and crisaborole ointment 2% 
QD for each cohort and pooled 
cohort.

To evaluate the efficacy of 
crisaborole ointment 2%, 
administered QD or BID, on TSS, 
ISGA and Pruritus assessments in
target lesions, in the treatment of mild 
to moderate AD in adults (cohort 1) 
and pediatrics (cohort 2).

Change from baseline in 
TSS in target lesions treated 
with crisaborole ointment or 
vehicle on Day 8 in each
regimen for each cohort.

Change from baseline in
ISGA in target lesions 
treated with crisaborole 
ointment or vehicle at each 
visit up to Day 15 in each
regimen for each cohort.

Change from baseline in
pruritus assessments in 
target lesions treated with 
crisaborole ointment or 

The other secondary efficacy 
endpoints will be analyzed using the 
estimands described above.


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Objectives
Endpoints
Estimands
vehicle at each day up to 
Day 15 in each regimen
using following scales;
Cohort 1: Peak Pruritus 
numerical rating scale 
(NRS) (age ≥12)
Cohort 2: Itch Severity Scale 
(age 6-11)
Cohort 2: Observer Reported 
Itch Severity NRS (age 2-
11).
•
To assess the safety and local 
tolerability of crisaborole ointment 
2%, administered QD or BID, in the 
treatment of mild to moderate AD in 
adults (cohort 1) and pediatrics 
(cohort 2)
•
Incidence of TEAEs and 
SAEs in each regimen for 
each cohort.
•
There is no defined estimand for 
these endpoints and they will be 
analyzed descriptively.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
4. STUDY DESIGN
4.1. Overall Design
This is a Phase 2b, multi-center, 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 (cohort 1: 12 years and older, cohort 2: 2 to under 
12 years old) with mild to moderate AD.  After completing screening activities, including 
meeting eligibility criteria, two target lesions with same severity will be determined by the 
investigator, participants will be randomized to one of the regimens, QD or BID
(randomization ratio; 1:1), and crisaborole ointment 2% or vehicle will be randomly assigned
to each target lesion at Baseline/Day 1. Both target lesions are to be treated at the same 
assigned dosing regimen and dosing regimen is unblinded information to sponsor, 
investigators/study sites and participants.  Participants will be treated with investigational
products administered for 2 weeks and followed-up 28 days after the end of treatment.
CCI


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Cohort
Regimen
Investigational Products
N
Study Treatment
Cohort 1a
Regimen 1
Crisaborole ointment 2% QD 
vs Vehicle QD
20
Participants will visit the site once daily to 
be administered investigational products by 
site staff.
Regimen 2
Crisaborole ointment 2% 
BID vs Vehicle BID
20
Participants will visit the site twice daily to 
be administered investigational products by 
site staff.
Cohort 2b
Regimen 1
Crisaborole ointment 2% QD 
vs Vehicle QD
20
Investigational products will be applied 
once daily by parent/caregiver (site staff
will confirm the compliance directly or via
live video chat), or by site staff (site staff
will visit the participant’s home as needed).
Regimen 2
Crisaborole ointment 2% 
BID vs Vehicle BID
20
Investigational products will be applied 
twice daily by parent/caregiver (site staff
will confirm the compliance directly or via
live video chat), or by site staff (site staff
will visit the participant’s home as needed).
BID: twice daily, N: number of participants, QD: once daily
a.
ages 12 years and older
b.
ages 2 years to under 12 years old
4.2. Scientific Rationale for Study Design
Not Applicable for this study.
4.3. Justification for Dose
In this study, in each of the two cohorts, the investigational products are applied by one of 
the following two usage methods;
Regimen 1: Apply Crisaborole ointment 2% or vehicle once daily for each target lesion
Regimen 2: Apply Crisaborole ointment 2% or vehicle twice a day to each target lesion
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 commercial ointment formulation, therefore
2% is selected for dosage of this study.  In Study C3291029, the safety and tolerability in 
Japanese patients with AD were confirmed and similar PK profile and systemic exposure 
shown between Japanese and non-Japanese participants.  In this study, two regimens of 
crisaborole ointment 2%, BID and QD, will be compared relative to corresponding vehicle. 
In addition, a descriptive comparison between crisaborole BID and crisaborole QD will be 
conducted to select the dose regimen for next clinical phase in each age group; 
adults/adolescents (12 year or older) and pediatrics (2 years to under 12 years) in Japanese 
AD participants.
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 schedule of 
activities.


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The end of the study is defined as the date of the last scheduled procedures shown in the 
schedule of activities for the last participant in the trial globally.
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 ages;
  Cohort 1: 12 years and older at the time of consent.
  Cohort 2: 2 years to under 12 years old at the time of consent.

Refer to Appendix 4 (Section 10.4.1) for reproductive criteria for female 
participants.
Type of Participant and Disease Characteristics:
2. Participants who are willing and able to comply with all scheduled visits, treatment 
plan, laboratory tests, lifestyle considerations, and other study procedures.
3. Participants who have confirmed clinical diagnosis of active AD at screening and 
Baseline/Day 1 according to Hanifin and Rajka criteria and who have at least 6 month 
history prior to Screening visit and that has been clinically stable for more than 1 
month.
4. Participants who have a global ISGA of 2 (mild) or 3 (moderate) at Baseline/Day 1 
visit.
5. Participants who have AD lesions on upper limbs, lower limbs or ventral of the body 
trunk and a body surface area (BSA) covered with AD of at least 1.0% and no more 
than 30% at Baseline/Day 1, excluding scalp, genitals and groin area. The presence of 
AD on these areas (scalp, genitals and groin area) is not exclusionary, but will not be 
included in the calculation for coverage of BSA with AD.
6. Participants who have two lesions of AD at least 3 cm x 3 cm with identical Lesion 
ISGA = 3 (moderate) for each lesion. These AD lesions must be at least 10 cm apart. 


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The target lesions must not be on the face, neck, scalp, axilla, genitals, groin area, 
palms, dorsal of the hands, dorsal of the body trunk and soles. In addition, two AD 
areas on the same limb must not be selected as the Target Lesions. [Note: When 
possible, AD areas on the bilateral (left/right) area should have been selected as target 
lesions].

Cohort 2: If 0.5%BSA is smaller than 3 cm x 3 cm, 0.5%BSA is acceptable for 
each of the two AD lesions with identical Lesion ISGA = 3 (moderate) for each 
lesion.
7. Participants who received any of the following AD treatment regimens are eligible if 
the following minimum washout criteria are observed:
At least 12 Weeks or 5 half-lives (whichever is longer) prior to Baseline/Day 1:

Biological drugs.
At least 28 days prior to Baseline/Day 1:

Systemic (oral/injectable) corticosteroids (Note: use of intranasal/inhaled or 
ophthalmic corticosteroids for stable medical conditions are allowed);

Systemic immunosuppressive agents (eg, calcineurin inhibitors, cyclosporine);

Sunbathing, tanning bed use, or phototherapy (eg, narrow band ultraviolet B
[NbUVB], psoralen plus ultraviolet A [PUVA]).
At least 14 days prior to Baseline/Day 1:

Systemic antimicrobials;

Topical corticosteroids (all potencies) and topical calcineurin inhibitors.
At least 7 days prior to Baseline/Day 1:

Topical antimicrobials;

Use of antibacterial soaps (for bathing), bleach bath, bath oil, or topical 
sodium hypochlorite-based products;

Topical antihistamines;

Systemic sedating antihistamines (eg, hydroxyzine, diphenhydramine or other 
sedating antihistamines);


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
Systemic and topical traditional Chinese medicine/herbal preparation that 
might alter the course of AD.
At least 8 hours prior to 1st dose of investigational products on Baseline/Day 1:

Use of emollients and moisturizers.
Weight:
Not appricable for this study.
Informed Consent:
8. Capable of giving signed informed consent as described in Appendix 1, which 
includes compliance with the requirements and restrictions listed in the informed 
consent document (ICD) and in this protocol.
5.2. Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions:
1. Other acute or chronic medical or psychiatric condition including recent (within the 
past year) or active suicidal ideation or behavior or laboratory abnormality that may 
increase the risk associated with study participation or investigational product 
administration or may interfere with the interpretation of study results and, in the 
judgment of the investigator, would make the participant inappropriate for entry into 
this study.
2. History of angioedema or anaphylaxis to topical products or known sensitivity to any 
of the components of crisaborole ointment 2%.
3. Participants had previous treatment with any topical or systemic PDE-4 inhibitor.
4. Participants who have undergone treatment for any type of cancer (except squamous 
cell carcinoma, basal cell carcinoma or carcinoma in situ of the skin, curatively 
treated with surgical excision only).
Prior/Concomitant Therapy:
5. Participants who are receiving any of the following drugs and have to wash out to 
participate in this study:

Biological drugs;


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
Systemic (oral/injectable) corticosteroids (Note: use of intranasal/inhaled or 
ophthalmic corticosteroids for stable medical conditions are allowed);

Systemic immunosuppressive agents (eg, calcineurin inhibitors, cyclosporine);

Phototherapy (eg, NbUVB, PUVA).
6. Participants who require treatment with prohibited concomitant medication(s)
Prior/Concurrent Clinical Study Experience:
7. Previous administration with an investigational product within 30 days or 5 half-lives 
preceding the first dose of investigational products used in this study (whichever is 
longer).
8. Participants who have participated in a clinical study of crisaborole.
Diagnostic Assessments:
Not appricable for this study.
Other Exclusions:
9. Participants are not willing to minimize or avoid natural and artificial sunlight 
exposure during the study.
10. Investigator site staff members directly involved in the conduct of the study and their 
family members, site staff members otherwise supervised by the investigator, or 
Pfizer employees, including their family members, directly involved in the conduct of 
the study.
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 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.


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5.3.2. Other Lifestyle Requirements

Routine preventative immunizations are permitted during the study; however, it is 
preferred that immunizations be administered at least 28 days before the start or 
following the completion of the participation.

Participants should refrain from swimming, bathing, sauna or washing the treated 
areas for at least 4 hours after application.

Use of sunscreen is permitted, but only on other areas than target lesions.

The participants and/or parents/caregivers should avoid wiping the investigational 
products 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 products, the parent/caregiver will not be required to 
wear gloves when applying investigational products.  However, they must be 
instructed to wash their hands with mild soap and water before and after each 
application of each investigational product.

Participants will be instructed to be dressed in loose-fitting clothing and avoid 
occluding the treated areas (with dry wraps, for example). Wet wraps are not 
permitted.

Parent/caregiver should be encouraged not to put hands in the mouth to avoid 
ingestion of investigational products.  The parent/caregiver should be instructed for 
participants who are young children to avoid licking the application site of the 
investigational product.
5.4. Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but 
are not subsequently randomly assigned to investigational product. A minimal set of screen 
failure information is required to ensure transparent reporting of screen failure participants to 
meet the Consolidated Standards of Reporting Trials (CONSORT) publishing requirements 
and to respond to queries from regulatory authorities. Minimal information includes 
demography, screen failure details, eligibility criteria, and any SAE.
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened. Rescreened participants should be assigned a new participant number.
6. STUDY INTERVENTION
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to 
the study protocol.


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For the purposes of this protocol, the term investigational product may be used 
synonymously with study intervention.
6.1. Study Intervention(s) Administered
Intervention Name
Crisaborole (PF-06930164)
Vehicle
Type
Drug
Drug
Dose Formulation
Ointment
Ointment
Unit Dose Strength(s)
20 mg of crisaborole per gram 
(2%)
㸫
Dosage Level(s)
Application of a thin layer of 
crisaborole once or twice daily to 
affected areas.
Application of a thin layer of 
vehicle once or twice daily to 
affected areas.
Route of Administration
Topical
Topical
Investigational Medicinal 
Product (IMP) and 
Noninvestigational Medicinal 
Product (NIMP)
IMP
IMP
Sourcing
Crisaborole ointment 2% and vehicle will be provided in 60 g tubes by 
Pfizer.  The tubes will be labeled according to local regulatory 
requirements.
For details, please refer to investigational product manual (IP manual).
Packaging and Labeling
Both crisaborole ointment 2% and vehicle for this study are packaged 
into a carton and are labeled in a way that is consistent with the study 
design and with the regulatory requirements for Japan in which the 
study is to be performed.
For details, please refer to IP manual.
6.1.1. Administration
At Baseline/Day 1, the participants who meet Inclusion/Exclusion Criteria will be 
randomized to one of the regimens, QD or BID, and for each of two target lesion (Lesion 1
and Lesion 2) meeting the inclusion criteria identified by the investigator, the investigational
products (crisaborole ointment 2% or vehicle) will be assigned randomly.  The sponsor, 
investigators/study sites and participants will be blinded with respect to which lesion is 
receiving the crisaborole ointment 2% or vehicle.


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BID: twice daily, NA: not applicable, QD: once daily
In case of Regimen 1 (QD), once daily in the evening throughout the treatment period is acceptable as like as once daily in 
the morning throughout the treatment period. 
For cohort 1, the participants will visit the site at every dosing timing [Regimen 1(QD): once 
daily in the morning or evening, Regimen 2 (BID): twice daily in the morning and evening]
and the investigational products will be applied by the site staff.  It may allow that the site 
staff applies the investigational products at the participant’s home as a backup option upon 
sponsor’s agreement when the participant is not able to visit the site. For Regimen 2 (BID), 
dosing interval should be 124 hours.
For cohort 2, the parent/caregiver and/or the site staff will apply the investigational products.  
When the parent/caregiver applies, it will be done with confirmation of the appropriate 
application by the site staff (directly or via live video chat).  When site staff applies, site staff 
will visit the participant’s home as needed. For Regimen 2 (BID), dosing interval should be
12 4 hours.
For regimen 1 (QD), participant will be applied investigational products from Day 1 to Day 
14. For regimen 2 (BID), when participant will be applied investigational products from AM 
in Day 1, the last administration will be PM in Day 14. When participant will be applied 
investigational products from PM in Day 1, the last administration will be AM in Day 15.
In order to better standardize the amount of investigational products applied to the target 
lesions, the Principal Investigator (PI) will measure the size of each target lesion at 
Baseline/Day 1 and determine the amount of medication to be applied by using finger-tip unit.
The area of the lesion will be determined using the “handprint method”, wherein the area 
represented by the participant’s outstretched hand (including all five digits adducted 
together) equals approximately 1% of the participant’s BSA.15 Parent/caregiver for cohort 2 


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will receive verbal and written instructions on how much study medication to apply to 
treatment areas and how the investigational products should be applied.  New investigational 
product tubes will be dispensed at Baseline/Day 1 and Day 8 for parents/caregivers of cohort 
2.  Parents/caregivers for cohort 2 will be instructed to return the investigational product 
tubes at Day 8 and Day 15. 
Participants should be instructed to wait at least 15 minutes after bathing/showering allowing 
the skin to dry thoroughly prior to applying medication. Participants should not shower or 
wash off study medication within 4 hours after application. Crisaborole ointment 2% is for 
external use on the skin only.  Contact with mucous membranes (ie, inside of nostrils, mouth, 
vagina, urethra, and rectum), and in the eyes should be avoided.  Participants should avoid 
ingestion of investigational products.
The lesion size and prescribed amount of investigational products will be recorded in the 
source documentation and marked on the dosing instruction document for the 
parents/caregivers.
The investigational products will be applied only to Lesion 1 and Lesion 2, and not applied to 
other AD affected areas.
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, as 
applicable for temperature-monitored shipments. 
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 temperature since previously documented for all 
site storage locations upon return to business.
3. 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). All study 
interventions will be accounted for using investigational products accountability 
form/record.
New investigational product tubes will be dispensed at Baseline/Day 1 and Day 8 for 
parents/caregivers of cohort 2.  Parents/caregivers for cohort 2 will be instructed to 
return the investigational product tubes at Day 8 and Day 15.


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4. Further guidance and information for the final disposition of unused study 
interventions are provided in the IP manual.
5. Any storage conditions stated in the SRSD will be superseded by the storage 
conditions stated on the product label. 
6. Study interventions should be stored in their original containers and in accordance 
with the labels. 
7. Site staff will instruct participants on the proper storage requirements for take-home 
study intervention. 
8. 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 
study intervention must be quarantined and not used until Pfizer provides permission 
to use the study intervention.  It will not be considered a protocol deviation if Pfizer 
approves the use of the study intervention after the temperature excursion. Use of the 
study intervention prior to Pfizer approval will be considered a protocol deviation. 
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.
9. The sponsor or designee will provide guidance on the destruction of unused study 
intervention (eg, at the site).  If destruction is authorized to take place at the 
investigator site, the investigator must ensure that the materials are destroyed in 
compliance with applicable environmental regulations, institutional policy, and any 
special instructions provided by Pfizer, and all destruction must be adequately 
documented.
Additional details about accountability, storage, destruction, and excursion reporting can be
found in the IP manual.
6.2.1. Preparation and Dispensing
The investigational products will be dispensed using an interactive response technology 
(IRT) (interactive Web-based response [IWR]) drug management system at visit on Day 1 
and Day 8.  A qualified staff member will dispense the investigational products via unique 
container numbers in the tubes provided, in quantities appropriate for the study visit 
schedule.  For cohort 2, the parent/caregiver should be instructed to maintain and return the 
tubes to the site at the next study visit.
6.3. Measures to Minimize Bias: Randomization and Blinding
6.3.1. Allocation to Investigational Product
At Baseline/Day 1, participants will be randomized to 1 of 4 treatment arms for each cohort 
as shown in Table 1.


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Table 1.
Treatment Allocation for Intra-Participant Design
Treatment 
Arm
Cohorta
Dosing 
Regimen
Investigational 
Product:
Lesion 1b
Investigational 
Product:
Lesion 2b
Target Number 
of Particiipants 
to be 
Randomized
1
1
QD
Crisaborole ointment 2% vehicle
10
2
1
QD
vehicle
Crisaborole ointment 2%
10
3
1
BID
Crisaborole ointment 2% vehicle
10
4
1
BID
vehicle
Crisaborole ointment 2%
10
5
2
QD
Crisaborole ointment 2% vehicle
10
6
2
QD
vehicle
Crisaborole ointment 2%
10
7
2
BID
Crisaborole ointment 2% vehicle
10
8
2
BID
vehicle
Crisaborole ointment 2%
10
a.
Cohort 1: Ages 12 years and older, Cohort 2: Ages 2 years to under 12 years old.
b.
First, Lesion 1 and 2 will be determined by the investigator at Baseline/Day 1. Then, participants are
randomly assigned to one of the treatment arms.
Allocation of participants to treatment groups will proceed through the use of an IRT system.  
The site personnel (study coordinator or specified designee) will be required to enter or select 
information including but not limited to the user’s identification (ID) and password, the 
protocol number, and the participant number.  The site personnel will then be provided with a 
treatment assignment, randomization number, dosing regimen, and dispensable unit (DU) or 
container number when investigational products are being supplied via the IRT system.  The 
IRT system will provide a confirmation report containing the participant number, 
randomization number, dosing regimen, and DU or container number assigned.  The 
confirmation report must be stored in the site’s files. 
Investigational products will be dispensed at the study visits summarized in the SoA.
Returned investigational products 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.
6.3.2. Breaking the Blind
The IRT will be programmed with blind-breaking instructions. In case of an emergency, the 
investigator has the sole responsibility for determining if unblinding of a participant’s 
treatment assignment is warranted. Participant safety must always be the first consideration 
in making such a determination. If the investigator decides that unblinding is warranted, the 
investigator should make every effort to contact the sponsor prior to unblinding a 
participant’s treatment assignment unless this could delay further management of the 
participant. If a participant’s treatment assignment is unblinded, the sponsor must be notified 
within 24 hours after breaking the blind. The date and reason that the blind was broken must 
be recorded in the source documentation and case report form (CRF).
The study-specific IRT reference manual and IP manual will provide the contact information 
and further details on the use of the IRT system.


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6.4. Study Intervention Compliance
Participant compliance with investigational products will be assessed throuhout the treatment 
period. Compliance will be confirmed by parent/caregiver and/or the site staff. Deviation(s) 
from the prescribed dosage regimen should be recorded in the CRF.  Missing one or more 
dose will be reported as deviation. 
6.5. Concomitant Therapy
All prior medications, including all medications and non-medication therapies used for AD 
within 90 days prior to Screening and all other treatments, including bland (non-medicated) 
emollients, over the counter drugs, vitamins, and antacids, used within 30 days prior to 
Screening will be recorded at the screening visit.  Any changes in concomitant medications 
or dosage will be recorded at Baseline/Day 1 and at each subsequent visit.  Medication 
entries should provide the correctly spelled drug or therapy name and the dose, units, 
frequency, route of administration, start and stop date, and reason for use.  The use of any 
concomitant medication must relate to the participant’s medical history or to an AE, except 
for vitamins/nutritional supplements and routine immunizations.
Hormonal contraceptives that meet the requirements of this study are allowed to be used in 
participants who are women of childbearing potential (WOCBP) (see Appendix 4).
6.5.1. Medications Prohibited Prior to Baseline/Day 1
Classes of medications and non-medication therapies that may alter the course of AD and for 
which washout is required prior to Baseline/Day 1 are listed below.  If a participant requires 
a washout, the investigator or his/her designee will provide instructions on discontinuing the 
prohibited medication(s) or non-medication therapy(ies) at the Screening Visit. 
Medications prohibited 12 weeks or 5 half-lives (whichever is longer) prior to 
Baseline/Day 1

Biological drugs.
Medications prohibited 28 days prior to Baseline/Day 1

Use of systemic (oral, injectable) corticosteroids.
Note: Please see Section 6.5.3 for stable use (regular regimen) of 
intranasal/inhaled/ophthalmic corticosteroids.

Use of systemic immunosuppressive agents (eg, calcineurin inhibitors, cyclosporine).

Use of sunbathing, tanning bed use, or phototherapy (eg. NbUVB, PUVA).
Medications prohibited 14 days prior to Baseline/Day 1

Use of systemic antimicrobials.


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
Use of topical corticosteroids (all potencies) and topical calcineurin inhibitors, 
anywhere on the body.
Note: Please see Section 6.5.3 for use of topical corticosteroids (all potencies) and
topical calcineurin inhibitors during study.
Medications prohibited 7 days prior to Baseline/Day 1

Topical antimicrobials.

Use of antibacterial soaps (for bathing), bleach bath, bath oil, or topical sodium 
hypochlorite-based products anywhere on the body.

Use of topical antihistamines anywhere on the body.

Systemic sedating antihistamines (eg, hydroxyzine or diphenhydramine or other 
sedating antihistamines).

Systemic and topical traditional Chinese medicine/herbal preparation that might alter 
the course of AD.
Medications prohibited 8 hours prior to 1st dose of investigational products on 
Baseline/Day 1

Use of emollients and moisturizers on AD lesions.
Note: Please see Section 6.5.3 for use of emollients during study
6.5.2. Medications Prohibited During the Study (Days 1-15)
Classes of medications and non-medication therapies that may alter the course of AD and 
that are prohibited during the study [from Baseline/Day 1 through the end of 
treatment/Day 15 (until the completion of study procedures/assessments)] are listed below.

Use of systemic (oral, injectable) corticosteroids.
Note: Please see Section 6.5.3 for stable use (regular regimen) of 
intranasal/inhaled/ophthalmic corticosteroids.

Use of topical corticosteroids, or topical calcineurin inhibitors on target AD lesions.

Use of systemic immunosuppressive agents, including (eg, calcineurin inhibitors, 
cyclosporine).

Escalating, decreasing, or pro re nata (PRN) use of topical retinoids or benzoyl 
peroxide (BPO) on target AD lesions.


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Note: Please see Section 6.5.3 for stable use (regular regimen) of topical retinoid 
and/or BPO during study.

Use of systemic sedating antihistamines (eg, hydroxyzine or diphenhydramine or 
other sedating antihistamines).

Use of systemic non-sedating antihistamines in a nonstable (eg, escalating, 
decreasing, or PRN) regimen.
Note: Please see Section 6.5.3 for stable use (regular regimen) of systemic 
non-sedating antihistamines during study.

Use of systemic or topical traditional Chinese medicine/herbal preparation that might 
alter the course of AD.

Use of systemic antimicrobials.
Note: Please see Section 6.5.3 for stable use (regular regimen) of Short courses of 
systemic antimicrobials during study.

Use of topical antimicrobials on target AD lesions.

Use of antibacterial soaps (for bathing), bleach baths, bath oil or topical sodium 
hypochlorite-based products anywhere on the body.

Use of sunbathing, tanning bed use, or phototherapy (eg. NbUVB, PUVA) on target
AD lesions.

Use of topical antihistamines on target AD lesions.

Participation in another drug or device research study.
6.5.3. Medications Allowed During the Study
Classes of medications that are allowed during the study (from Baseline/Day 1 through the 
end of treatment visit on Day 15) are summarized below.

After investigator selected two target AD lesions at Baseline/Day 1, topical 
corticosteroids and topical calcineurin inhibitors can be used per product label at least
10 cm away from the selected target AD lesions throughout the remainder of the 
study.

After investigator selected two target AD lesions at Baseline/Day 1, emollients and 
moisturizer can be used at least 10 cm of away from the selected target AD lesions 
throughout the remainder of the study.


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
After investigator selected two target AD lesions at Baseline/Day 1, topical 
antimicrobials can be used at least 10 cm of away from the selected target AD lesions 
throughout the remainder of the study.

Participants on a stable regimen of inhaled, intranasal, or ocular corticosteroids, with 
≥14 days of consistent use prior to Baseline/Day 1, are permitted to continue but must 
not alter or stop their regimen during the study.

Short courses of systemic antimicrobials may be given during the course of the study, 
if clinically necessary for the treatment of new onset infections.

Participants on a stable non-sedating systemic antihistamine regimen, with ≥14 days 
of consistent use prior to Baseline/Day 1, are permitted to continue but must not alter 
or stop their regimen during the study.

Participants on a stable topical retinoid and/or BPO regimen, with ≥14 days of 
consistent use prior to Baseline/Day 1, are permitted to continue (not on target AD 
lesions) but must not alter or stop their regimen during the study.

Nonsteroidal anti-inflammatory drugs are allowed throughout the study.

Routine preventative immunizations are permitted during the study; however, it is 
preferred that immunizations be administered at least 28 days before the start or 
following the completion of the participation in study.

Oral or intrauterine hormonal methods of contraception are permitted during the 
study, for female participants of childbearing potential.

Concomitant medications for other chronic medical conditions are permitted during 
the study unless the medication/therapy is specifically prohibited by the protocol.
6.6. Dose Modification
Not applicable for this study.
6.7. Intervention After the End of the Study
No intervention will be provided to study participants at the end of the study.
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 
investigational products.  If investigational products are permanently discontinued, the 
participant will not remain in the study except to complete the early discontinuation
procedures.


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See the SoA for data to be collected at the time of intervention discontinuation and follow-up 
and for any further evaluations that need to be completed.
7.2. Participant Discontinuation/Withdrawal From the Study
A participant may withdraw from the study at any time at his/her own request, or may be 
withdrawn at any time at the discretion of the investigator for safety, behavioral, compliance, 
or administrative reasons.
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 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, but data already generated from the samples will continue to be available, and may 
be used to protect the integrity of existing analyses.  The investigator must document any 
such requests in the site study records.
If the participant withdraws from the study and also withdraws consent (see below) 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.
When a participant withdraws from the study because of an SAE, the SAE must be recorded 
on the CRF and reported on the Clinical Trial (CT) SAE Report.
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.
Withdrawal of Consent: 
Participants who request to discontinue receipt of study treatment will not remain in the study 
except to complete the early termination procedures and 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 investigational products 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, 


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publicly available information should be used to determine vital status only as appropriately 
directed in accordance with local law.
7.3. Lost to Follow-up 
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site.
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit:

The site must attempt to contact the participant and reschedule the missed visit as 
soon as possible and counsel the participant on the importance of maintaining the 
assigned visit schedule and ascertain whether or not the participant wishes to and/or 
should continue in the study;

Before a participant is deemed lost to follow-up, the investigator 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.
Discontinuation of specific sites or of the study as a whole is handled as part of Appendix 1.
8. STUDY ASSESSMENTS AND PROCEDURES
The investigator (or an appropriate delegate at the investigator site) must obtain a signed and 
dated ICD and assent if applicable before performing any study-specific procedures.  
Study procedures and their timing are summarized in the SoA. Protocol waivers or 
exemptions are not allowed.
Immediate safety concerns should be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue study 
intervention.
Adherence to the study design requirements, including those specified in the SoA, is essential 
and required for study conduct.
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.


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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 
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.
The total blood sampling volume for individual participants in this study is approximately 
15 mL.  The actual collection times of blood sampling may change.  Additional blood 
samples may be taken for safety assessments upon investigator decision provided the total
volume taken during the study does not exceed 50 mL during this study.
8.1. Efficacy Assessments
8.1.1. Lesion Investigator Static Global Assessment (Lesion ISGA)
The clinical evaluator of AD will perform an assessment of each target lesion severity of AD
and assign a lesion ISGA score and category.  For lesion ISGA assessment, refer to ISGA 
score and category as described in Table 2.  The assessment will be a static evaluation 
without regard to the score at a previous visit.
For eligibility, please note that lesion ISGA at Baseline/Day 1 should be 3 (moderate) 
whereas ISGA can be 2 (mild) or 3 (moderate).
Table 2.
Investigator’s Static Global Assessment (ISGA)
Score
Grade
Definition
0
Clear
Minor residual hypo/hyperpigmentation; no erythema or induration/papulation; 
no oozing/crusting
1
Almost Clear
Trace faint pink erythema, with barely perceptible induration/papulation and no 
oozing/crusting
2
Mild
Faint pink erythema with mild induration/papulation and no oozing/crusting
3
Moderate
Pink-red erythema with moderate induration/papulation with or without 
oozing/crusting
4
Severe
Deep or bright red erythema with severe induration/papulation and with 
oozing/crusting


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8.1.2. Lesion Total Sign Score (Lesion TSS)
The Lesion TSS is an assessment of the severity of each of the following: erythema, 
induration/papulation, excoriation, and lichenification.  Each of these is rated using the 
4-point severity scale described in Table 3.  These ratings are then added to create a total 
score (13-point scale; ranging from 0 to 12 points).
Table 3.
Lesion Total Sign Score (Lesion TSS)
Signs of Atopic Dermatitis
Erythema (Redness)
Score
Grade
Description
0
None
No redness
1
Mild
Mildly detectable erythema; pink
2
Moderate Dull red; clearly distinguishable
3
Severe
Deep, dark red; marked and extensive
Induration/Papulation
Score
Grade
Description
0
None
None
1
Mild
Slightly perceptible elevation
2
Moderate Clearly perceptible elevation but not extensive
3
Severe
Marked and extensive elevation
Excoriation (Evidence of Scratching)
Score
Grade
Description
0
None
No evidence of excoriation
1
Mild
Mild excoriation present
2
Moderate Definite excoriation present
3
Severe
Marked, deep, or extensive excoriation present
Lichenification (Epidermal Thickening)
Score
Grade
Description
0
None
No epidermal thickening
1
Mild
Minor epidermal thickening
2
Moderate Moderate epidermal thickening; accentuated skin lines
3
Severe
Severe epidermal thickening; deeply accentuated skin lines
8.1.3. Pruritus assessments
The severity of itch (pruritus) due to AD at the target lesion will be assessed using the peak 
pruritus Numerical Rating Scale (NRS), an 11-category numeric rating scale from 0 to 10,16
which is participant (12 years and older) reported.  A five-category pruritus assessment has 
been developed for participants ≥6 and <12 years of age referred to as the Itch Severity Scale.  


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The Observer Reported Itch Severity NRS will be completed by a parent/caregiver for 
participants <12 years old. It is preferred that all observer reported outcomes for a given 
participant are completed by same individual throughout the study.
The pruritus assessment (participant and observer) will be completed once daily every day 
from Day 1 to Day 15 before investigational products are applied preferably at the same time 
of each day, as noted in the Schedule of Activities (SoA).
 
 
CCI
CCI


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8.1.4. %BSA with Atopic Dermatitis
The overall BSA affected by AD will be evaluated (from 0% to 100%) to verify each 
participant’s eligibility at the screening and Baseline/Day 1 visits.  The Investigator may use 
the “handprint method” by which the area represented by the palmar (ie, outstretched) 
surface of the participant’s hand with all five digits adducted together is approximately 1% of 
the participant’s BSA.
The number of handprints of AD skin in a body region can be used to determine the 
extent (%) to which a body region is involved with AD (Table 4 and Table 5).
Table 4.
Handprint Determination of Body Region Surface Area for Participants 
aged ≥8 years old
Body Region
Total Number of Handprints 
in Body Region*
Surface Area of Body 
Region Equivalent of One 
Handprint
Head and Neck
10
10%
Upper Limbs
20
5%
Trunk (including axillae)
30
3.33%
Lower Limbs (including buttocks)
40
2.5%
*
The numbers of handprints are for the entire body region; no adjustment for body regions excluded for 
assessment.
CCI


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Table 5.
Handprint Determination of Body Region Surface Area for Participants 
aged < 8 years old
Body Region
Total Number of Handprints 
in Body Region*
Surface Area of Body 
Region Equivalent of One 
Handprint
Head and Neck
20
5%
Upper Limbs
20
5%
Trunk (including axillae)
30
3.33%
Lower Limbs (including buttocks)
30
3.33%
*
The numbers of handprints are for the entire body region; no adjustment for body regions excluded for 
assessment .
8.1.5. Investigator Static Global Assessment (ISGA)
The Investigator will perform an assessment of the overall severity of AD and assign ISGA 
score and category as described in Table 2 to verify each participant’s eligibility at the 
screening and Baseline/Day 1 visits.
8.1.6. Rater Qualifications
Clinical evaluations of AD will be performed by an experienced and certified dermatologist.  
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 AD 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).
8.2. 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 concerns.
8.2.1. Physical Examinations
A complete physical examination will include, at a minimum, assessments of the 
cardiovascular, respiratory, gastrointestinal, and neurological systems.
Investigators should pay special attention to clinical signs related to previous serious 
illnesses. 
8.2.2. Vital Signs
Vital signs will be measured with the participant in a seated or supine position after 
5 minutes of rest and will include temperature (tympanic, or axillary), systolic and diastolic 
blood pressure, and pulse rate, only performed at screening.


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8.2.3. Clinical Safety Laboratory Assessments
See Appendix 2 for the list of clinical safety laboratory tests to be performed at screening 
visit for eligibility purpose except pregnancy test.
All protocol-required laboratory assessments, as defined in Appendix 2, must be conducted 
in accordance with the SoA for timing and frequency.
If laboratory values from non-protocol-specified laboratory assessments performed at the 
institution’s local laboratory require a change in participant management or are considered 
clinically significant by the investigator (eg, SAE or AE or dose modification), then the 
results must be recorded in the CRF.
8.2.4. 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 investigational products.  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 institutional review boards (IRBs)/ethics committees (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.
8.2.5. Photography
Photographs of target lesions will be obtained at Baseline/Day 1, Day 8 and Day 15/Early 
discontinuation. Photographs will be taken by local standard procedures. Photographs will 
not be evaluated as an endpoint, but will be referred as needed, such as incident of significant 
AE.  Only for participants who consent, photographs will be utilized for illustrative purposes.
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 it 
meets the criteria for classification as an SAE or that caused the participant to discontinue the 
study (see Section 7). 


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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 investigational products), through and including 
a minimum of 28 calendar days, except as indicated below, after the last administration of the 
investigational products.
For participants who are screen failures, the active collection period ends when screen failure 
status is determined.
Medical occurrences that begin before the start of study intervention but after obtaining 
informed consent will be recorded on the Medical History/Current Medical Conditions 
section of the CRF, not the AE section.
Follow-up by the investigator continues throughout and after the active collection period and 
until the event or its sequelae resolve or stabilize at a level acceptable to the investigator, and 
Pfizer concurs with that assessment.
Investigators are not obligated to actively seek AEs or SAEs after conclusion of the study 
participation.  However, if the investigator learns of any SAE, including a death, at any time 
after a participant has been discharged from the study, and he/she considers the event to be 
reasonably related to the study intervention or study participation, the investigator must 
promptly notify the sponsor.
8.3.1.1. Reporting SAEs to Pfizer Safety
All SAEs occurring in a participant during the active collection period are reported to Pfizer 
Safety on the CT SAE Report Form immediately and under no circumstance should this 
exceed 24 hours, as indicated in Appendix 3. The investigator will submit any updated SAE 
data to the sponsor within 24 hours of it being available.
SAEs occurring in a participant after the active collection period has ended are reported to 
Pfizer Safety if the investigator becomes aware of them; at a minimum, all SAEs that the 
investigator believes have at least a reasonable possibility of being related to investigational 
products must be reported to Pfizer Safety.
8.3.1.2. Recording Nonserious AEs and SAEs on the CRF
During the active collection period, both nonserious AEs and SAEs are recorded on the CRF.


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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 suspected unexpected serious adverse 
reactions (SUSARs) according to local regulatory requirements and sponsor policy and 
forwarded to investigators as necessary.
An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAEs) from the sponsor will review 
and then file it along with the IB and will notify the IRB/EC, if appropriate according to local 
requirements.


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8.3.5. Exposure During Pregnancy or Breastfeeding, and Occupational Exposure
Exposure to the investigational products under study during pregnancy or breastfeeding and 
occupational exposure are reportable to Pfizer Safety within 24 hours of investigator 
awareness.
8.3.5.1. Exposure During Pregnancy
Details of all pregnancies in female participants will be collected after the start of study 
intervention and until the end of the active collection period.
If a pregnancy is reported, the investigator should inform the sponsor within 24 hours of 
learning of the pregnancy and should follow the procedures outlined in Appendix 4.
Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs.
8.3.5.2. Exposure During Breastfeeding
Scenarios of exposure during breastfeeding must be reported, irrespective of the presence of 
an associated SAE, to Pfizer Safety within 24 hours of the investigator’s awareness, using the 
CT SAE Report Form.  An exposure during breastfeeding report is not created when a Pfizer 
drug specifically approved for use in breastfeeding women (eg, vitamins) is administered in 
accord with authorized use.  However, if the infant experiences an SAE associated with such 
a drug’s administration, the SAE is reported together with the exposure during breastfeeding.
8.3.5.3. Occupational Exposure
An occupational exposure occurs when, during the performance of job duties, a person 
(whether a healthcare professional or otherwise) gets in unplanned direct contact with the 
product, which may or may not lead to the occurrence of an AE.
An occupational exposure is reported to Pfizer Safety within 24 hours of the investigator’s 
awareness, using the CT SAE Report Form, regardless of whether there is an associated 
SAE.  Since the information does not pertain to a participant enrolled in the study, the 
information is not recorded on a CRF; however, a copy of the completed CT SAE Report 
Form is maintained in the investigator site file.
8.3.6. Medication Errors
Medication errors may result from the administration or consumption of the investigational 
products by the wrong participant, or at the wrong time, or at the wrong dosage strength.
Exposures to the investigational products under study may occur in clinical trial settings, 
such as medication errors.


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Safety Event
Recorded on the CRF
Reported on the CT SAE Report 
Form to Pfizer Safety Within 24 
Hours of Awareness
Medication errors 
All (regardless of whether 
associated with an AE)
Only if associated with an SAE
Medication errors include:

Medication errors involving participant exposure to the investigational products;

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 immediately.
Whether or not the medication error is accompanied by an AE, as determined by the 
investigator, the medication error is recorded on the medication error page of the CRF and, if 
applicable, any associated AE(s), serious and nonserious, are recorded on an AE page of the 
CRF.
Medication errors should be reported to Pfizer Safety within 24 hours on a CT SAE Report 
Form only when associated with an SAE.
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 
PK parameters are not evaluated in this study.
8.6. Pharmacodynamics
PD parameters are not evaluated in this study.
8.7. Genetics
Genetics (specified analyses) are not evaluated in this study.
8.8. Biomarkers
Biomarkers are not evaluated in this study.


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8.9. 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 statistical analysis plan (SAP), which will be 
maintained by the sponsor.  The SAP may modify what is outlined in the protocol where 
appropriate; however, any major modifications of the primary endpoint definitions or their 
analyses will also be reflected in a protocol amendment.
9.1. Estimands and Statistical Hypotheses
9.1.1. Estimands
The primary estimand of this study is the hypothetical estimand, which estimates the effect as 
if all participants maintain their randomized treatment.  It includes the following four 
attributes: 
•
Population: Participants with mild to moderate AD in adults (cohort 1) and pediatrics 
(cohort 2) as defined by the inclusion and exclusion criteria and are randomized and 
received at least one of the investigational products;
•
Variable: Change from baseline to Day 15 in lesion severity in a continuous outcome 
measured such as TSS, ISGA and Pruritus assessment in target lesions treated with 
crisaborole ointment 2% or vehicle in each regimen for each cohort;
•
Intercurrent event: All efficacy data after discontinuation of treatment will not be 
considered;
•
Population-level summary: Least-square means of intra-participant difference 
between crisaborole ointment 2% vs corresponding vehicle in each regimen for each 
cohort and pooled cohort. Difference in least-square means between crisaborole 
ointment 2% BID and crisaborole ointment 2% QD for each cohort and pooled 
cohort.
The primary and secondary efficacy endpoints will be analyzed using this estimand.  
 
9.2. Sample Size Determination
For each cohort and for each regimen, a sample size of 16 will have at least 85% power to 
establish the superiority of crisaborole ointment 2% to vehicle as measured by the change 
from baseline in TSS between crisaborole treated lesion and the corresponding vehicle 
treated lesion at Day 15 using paired t -test at 0.025 (one-sided) significance level, assuming 
the mean of intra-participant difference is 1.8 and standard deviation is 2.2 calculated based 
CCI


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on the pooled results of C3291001 and AN2898-AD-202 studies. In addition, considering 
that the non-compliance/discontinuation rate during the treatment period is approximately 
20%, approximately 20 participants will be enrolled for each regimen, and for each cohort.
In addition, for each cohort, in the inter-participant comparison between crisaborole ointment 
2% BID treated lesion and crisaborole ointment 2% QD treated lesion, the sample size of 32
(16 per regimen) and 40 (20 per regimen) will result in a 2-sided 95% confidence interval 
width of the difference of mean for the change from baseline in TSS will be approximately 
1.32 and 1.18, respectively, assuming a common standard deviation is 1.9 based on the 
pooled results of C3291001 and AN2898-AD-202 studies and the normal approximation.
9.3. Populations for Analysis
For purposes of analysis, the following populations are defined:
Population
Description
Full Analysis Set (FAS)
All participants randomized and receiving ≥1 dose of 
investigational product.
Per-Protocol Analysis Set 
(PPAS)
All participant randomized and receiving ≥1 dose of 
investigational product, with both baseline and Day 15
primary efficacy data, and without protocol violations that 
were thought to impact the efficacy evaluation during the 
treatment period.  All protocol deviations will be reviewed 
and assessed by the study team prior to database release.
Safety Analysis Set 
All participants receiving ≥1 dose of investigational product.
9.4. Statistical Analyses
The SAP will be developed and finalized before database lock and will describe in further 
detail the participant populations to be included in the analyses, and procedures for 
accounting for missing, unused, and spurious data.  This section is a summary of the planned 
statistical analyses of the primary and secondary endpoints.
9.4.1. Efficacy Analyses
Analysis will be conducted for each cohort. The pooled analysis of cohort 1 and cohort 2 
may be conducted, as appropriate.  In the intra-participant comparison, a Mixed effect 
Models for Repeated Measures (MMRM) will be used to derive least-square means of intra-
participant difference and associated 2-sided 95% confidence intervals between crisaborole 
ointment 2% and corresponding vehicle.  In the inter-participant comparison, a MMRM will 
be used to derive difference in least-square means and associated 2-sided 95% confidence 
interval between crisaborole ointment 2% BID and crisaborole ointment 2% QD. Further 
details will be provided in the SAP.


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Endpoint
Statistical Analysis Methods
Primary

The primary efficacy endpoint will be the change from baseline in 
TSS in target lesions treated with crisaborole ointment 2% or vehicle 
on Day 15. As for the intra-participant comparison between 
crisaborole treated lesion and the corresponding vehicle treated lesion 
for each regimen, and for each cohort, the intra-participant difference 
of change from baseline in TSS between crisaborole treated lesion and 
vehicle treated lesion, will be analyzed using a MMRM that includes 
the fixed effect of visit and an unstructured variance and covariance 
matrix will be used to model the dependence among the same 
participants across different visits up to Day 15.  A MMRM analysis 
will be conducted including only the observed data in the model under 
the assumption of the missing at random (MAR) for the missing 
mechanism.
Secondary

As for the inter-participant comparison between crisaborole BID 
treated lesion and crisaborole QD treated lesion for each cohort, the 
change from baseline in TSS will be analyzed using a MMRM that 
includes the fixed effects of dosing regimen, visit, dosing regimen-by-
visit interaction, and baseline value and an unstructured variance and 
covariance matrix will be used to model the dependence among the 
same participants across different visits up to Day 15.  A MMRM 
analysis will be conducted including only the observed data in the 
model under the assumption of the MAR for the missing mechanism.

For other continuous endpoints such as change from baseline in ISGA
at all visits and pruritus assessment at all days, a MMRM will be 
applied.  As for the intra-participant comparison between crisaborole 
treated lesion and the corresponding vehicle treated lesion for each 
regimen, and for each cohort, the intra-participant difference of 
change from baseline between crisaborole treated lesion and vehicle 
treated lesion, will be analyzed using a MMRM that includes the fixed 
effect of time point (visit or day) and an unstructured variance and 
covariance matrix will be used to model the dependence among the 
same participant across different time points (visits or days) up to 
Day 15. As for the inter-participant comparison between crisaborole 
BID treated lesion and crisaborole QD treated lesion for each cohort, 
the change from baseline will be analyzed using a MMRM that 
includes the fixed effects of dosing regimen, time point (visit or day), 
dosing regimen-by-time point (visit or day) interaction, and baseline 
value and an unstructured variance and covariance matrix will be used 
to model the dependence among the same participant across different 
time points (visits or days) up to Day 15.  A MMRM analysis will be 
conducted including only the observed data in the model under the 
assumption of the MAR for the missing mechanism.


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9.4.2. Safety Analyses
All safety analyses will be performed on the safety population.  Safety data will be 
descriptively summarized, and will be presented in tabular and/or graphical format.  No 
imputation will be made for missing safety data.  The following safety data will be 
summarized:
•
TEAEs, including SAEs;
•
Withdrawals from treatment due to AEs.
9.5. Interim Analyses
No formal interim analysis will be conducted for this study.
9.5.1. Data Monitoring Committee 
This study will not use a data monitoring committee (DMC).
CCI


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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 Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines;

Applicable International Council for Harmonisation (ICH) Good Clinical Practice 
(GCP) guidelines;

Applicable laws and regulations, including applicable privacy laws.
The protocol, protocol amendments, ICD, IB, 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 Code of Federal Regulations (CFR), ICH guidelines, the IRB/EC, 
European regulation 536/2014 for clinical studies (if applicable), and all other 
applicable local regulations.
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 investigational 
product, Pfizer should be informed immediately. 
In addition, the investigator will inform Pfizer immediately of any urgent safety measures 
taken by the investigator to protect the study 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. Informed Consent Process
The investigator or his/her representative will explain the nature of the study to the 
participant or his/her legally authorized representative and answer all questions regarding the 
study.
Participants must be informed that their participation is voluntary. Participants or their 
legally authorized representative will be required to sign a statement of informed consent that 
meets the requirements of 21 CFR 50, local regulations, ICH guidelines, Health Insurance 
Portability and Accountability Act (HIPAA) requirements, where applicable, and the IRB/EC 
or study center.
The investigator must ensure that each study participant or his or her legally authorized 
representative is fully informed about the nature and objectives of the study, the sharing of 
data related to the study, and possible risks associated with participation, including the risks 
associated with the processing of the participant’s personal data. 
The participant must be informed that his/her personal study-related data will be used by the 
sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant.
The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the sponsor, by 
appropriate IRB/EC members, and by inspectors from regulatory authorities.
The investigator further must ensure that each study participant or his or her legally 
authorized representative is fully informed about his or her right to access and correct his or 
her personal data and to withdraw consent 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.
A copy of the ICD(s) must be provided to the participant or the participant’s legally 
authorized representative.
A participant who is rescreened is not required to sign another ICD if the rescreening occurs 
within 28 days from the previous ICD signature date.


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10.1.3. Data Protection
All parties will comply with all applicable laws, including laws regarding the implementation 
of organizational and technical measures to ensure protection of participant data.
Participants’ personal data will be stored at the study site in encrypted electronic and/or paper 
form and will be password protected or secured in a locked room to ensure that only 
authorized study staff have access.  The study site will implement appropriate technical and 
organizational measures to ensure that the personal data can be recovered in the event of 
disaster.  In the event of a potential personal data breach, the study site shall be responsible 
for determining whether a personal data breach has in fact occurred and, if so, providing 
breach notifications as required by law.
To protect the rights and freedoms of natural persons with regard to the processing of 
personal data, participants will be assigned a single, participant-specific numerical code.
Any participant records or 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. 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.
10.1.4. Dissemination of Clinical Study Data
Pfizer fulfills its commitment to publicly disclose clinical study results through posting the 
results of studies on www.clinicaltrials.gov (ClinicalTrials.gov), the European Clinical Trials 
Database (EudraCT), and/or www.pfizer.com, and other public registries in accordance with 
applicable local laws/regulations.  In addition, Pfizer reports study results outside of the 
requirements of local laws/regulations pursuant to its standard operating procedures (SOPs).
In all cases, study results are reported by Pfizer in an objective, accurate, balanced, and 
complete manner and are reported regardless of the outcome of the study or the country in 
which the study was conducted.
www.clinicaltrials.gov
Pfizer posts clinical trial US Basic Results on www.clinicaltrials.gov for Pfizer-sponsored 
interventional studies (conducted in patients) that evaluate the safety and/or efficacy of a 
product, regardless of the geographical location in which the study is conducted.  US Basic 
Results are generally submitted for posting within 1 year of the primary completion date 
(PCD) for studies in adult populations or within 6 months of the PCD for studies in pediatric 
populations.
PCD is defined as the date that the final participant was examined or received an intervention 
for the purposes of final collection of data for the primary outcome, whether the clinical 
study concluded according to the prespecified protocol or was terminated.


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EudraCT
Pfizer posts European Union (EU) Basic Results on EudraCT for all Pfizer-sponsored 
interventional studies that are in scope of EU requirements.  EU Basic Results are submitted 
for posting within 1 year of the PCD for studies in adult populations or within 6 months of 
the PCD for studies in pediatric populations.
www.pfizer.com
Pfizer posts public disclosure synopses [clinical study report (CSR) synopses in which any 
data that could be used to identify individual participants have been removed] on 
www.pfizer.com for Pfizer-sponsored interventional studies at the same time the US Basic 
Results document is posted to www.clinicaltrials.gov.
Documents within marketing authorization packages/submissions
Pfizer complies with the European Union Policy 0070, the proactive publication of clinical 
data to the European Medicines Agency (EMA) website.  Clinical data, under Phase 1 of this 
policy, includes clinical overviews, clinical summaries, CSRs, and appendices containing the 
protocol and protocol amendments, sample CRFs, and statistical methods.  Clinical data, 
under Phase 2 of this policy, includes the publishing of individual participant data.  Policy 
0070 applies to new marketing authorization applications submitted via the centralized 
procedure since 01 January 2015 and applications for line extensions and for new indications 
submitted via the centralized procedure since 01 July 2015.
Data Sharing
Pfizer provides researchers secure access to patient-level data or full CSRs for the purposes 
of “bona-fide scientific research” that contribute to the scientific understanding of the 
disease, target, or compound class. Pfizer will make available data from these trials 24 
months after study completion.  Patient-level data will be anonymized in accordance with 
applicable privacy laws and regulations.  CSRs will have personally identifiable information 
redacted.
Data requests are considered from qualified researchers with the appropriate competencies to 
perform the proposed analyses. Research teams must include a biostatistician. Data will not 
be provided to applicants with significant conflicts of interest, including individuals 
requesting access for commercial/competitive or legal purposes.
10.1.5. 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 
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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.
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 


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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.
10.1.6. 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 electronic CRF (eCRF) that are transcribed from 
source documents must be consistent with the source documents or the discrepancies must be 
explained. The investigator may need to request previous medical records or transfer 
records, depending on the study. Also, current medical records must be available.
Definition of what constitutes source data can be found in Study Data Monitoring Plan.
10.1.7. Study and Site Closure
The sponsor designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the sponsor. Study sites will be closed upon 
study completion. A study site is considered closed when all required documents and study 
supplies have been collected and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time upon notification to the contract 
research organization (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:

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.
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.
10.1.8. 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 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 


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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 multi-center studies only in their entirety and not as 
individual site data.  In this case, a coordinating investigator will be designated by mutual 
agreement.
Authorship of publications for the overall study results will be determined by mutual 
agreement and in line with International Committee of Medical Journal Editors authorship 
requirements. 
If publication is addressed in the clinical study agreement, the publication policy set out in 
this section will not apply.
10.1.9. Sponsor’s Qualified Medical Personnel
The contact information for the sponsor’s appropriately qualified medical personnel for the 
study is documented in the study contact list located in the supporting study documentation.
To facilitate access to appropriately qualified medical personnel on study-related medical 
questions or problems, participants are provided with a contact card.  The contact card 
contains, at a minimum, protocol and investigational product 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
The following safety laboratory tests will be performed at times defined in the SoA section of 
this protocol.  Additional laboratory results may be reported on these samples as a result of 
the method of analysis or the type of analyzer used by the clinical laboratory; or as derived 
from calculated values.  These additional tests would not require additional collection of 
blood.  Unscheduled clinical laboratory measurements may be obtained at any time during 
the study to assess any perceived safety concerns.
Table 6.
Protocol-Required Safety Laboratory Assessments
Hematology
Chemistry
Urinalysis
Other
At screening only:
Hemoglobin
Hematocrit
RBC count
Platelet count
WBC count
Total neutrophils 
(Abs)
Eosinophils (Abs)
Monocytes (Abs)
Basophils (Abs)
Lymphocytes (Abs)
At screening only:
BUN/urea and 
creatinine
Glucose
Calcium
Sodium
Potassium
Chloride
Total CO2 (bicarbonate)
AST, ALT
Total bilirubin
Alkaline phosphatase
Uric acid
Albumin
Total protein
At screening only:
pH
Glucose (qual)
Protein (qual)
Blood (qual)
Ketones
Nitrites
Leukocyte esterase
Urobilinogen
Urine bilirubin
Microscopya

Pregnancy test (β-hCG)c
At screening only:

FSHb

Urine drug screening
Abbreviations: Abs = absolute; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
-hCG = beta-human chorionic gonadotropin; BUN = blood urea nitrogen; CO2 = carbon dioxide; 
FSH = follicle-stimulating hormone; qual = qualitative; RBC = red blood cell; WBC = white blood 
cell.
a.
Only if urine dipstick is positive for blood, protein, nitrites, or leukocyte esterase.
b.
For confirmation of postmenopausal status only.
c.
Local urine testing will be standard for the protocol unless serum testing is required by 
institutional review board/ethics committee (IRB/EC).  For female participants of childbearing 
potential, 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.
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 (ie, not related to progression of 
underlying disease).

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.

“Lack of efficacy” or “failure of expected pharmacological action” per se will not be 
reported as an AE or SAE.  Such instances will be captured in the efficacy 
assessments.  However, the signs, symptoms, and/or clinical sequelae resulting from 
lack of efficacy will be reported as an AE or SAE if they fulfill the definition of an 
AE or SAE.


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Events NOT Meeting the AE Definition

Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition.

The disease/disorder being studied or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the participant’s 
condition.

Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that 
leads to the procedure is the AE.

Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).

Anticipated day-to-day fluctuations of 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.
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 


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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.
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 AEs; and (3) 
exposure to the investigational product 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.


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Safety Event
Recorded on the CRF
Reported on the CT SAE 
Report Form to Pfizer 
Safety Within 24 Hours of 
Awareness
SAE
All
All
Nonserious AE
All
None
Exposure to the 
investigational product 
under study during 
pregnancy or 
breastfeeding, and 
occupational exposure
None
All (and exposure during 
pregnancy [EDP]
supplemental form for EDP)

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.

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 


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the intensity of an event; and both AEs and SAEs can be assessed as severe.
An event is defined as “serious” when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, NOT when it is rated as severe.
Assessment of Causality

The investigator is obligated to assess the relationship between study intervention and 
each occurrence of each AE/SAE.

A “reasonable possibility” of a relationship conveys that there are facts, evidence, 
and/or arguments to suggest a causal relationship, rather than a relationship cannot be 
ruled out.

The investigator will use clinical judgment to determine the relationship.

Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study intervention 
administration will be considered and investigated.

The investigator will also consult the IB 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 investigational product caused 
the event, then the event will be handled as “related to investigational product” 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 


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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 professionals.

If a participant dies during participation in the study or during a recognized follow-up 
period, the investigator will provide Pfizer Safety with a copy of any postmortem 
findings including histopathology.

New or updated information will be recorded in the originally completed CRF.

The investigator will submit any updated SAE data to the sponsor within 24 hours of 
receipt of the information.
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.


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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 and Collection of Pregnancy Information
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 (WOCBP)
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 


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medical history interview.  The method of documentation should be recorded in the 
participant’s medical record for the study.
3. Postmenopausal female:

A postmenopausal state is defined as age 60 years or older or no menses for 
12 months without an alternative medical cause.

A high follicle-stimulating hormone (FSH) level in the postmenopausal range 
may be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormone replacement therapy (HRT).

Females 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
1. Implantable progestogen-only hormone contraception associated with inhibition of 
ovulation.*
2. Intrauterine device (IUD).
3. Intrauterine hormone-releasing system (IUS).
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;*

transdermal;*

injectable.*


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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
Collection of Pregnancy Information
For both unapproved/unlicensed products and for marketed products, an exposure during 
pregnancy (EDP) occurs if:

A female becomes, or is found to be, pregnant either while receiving or having been 
exposed (eg, because of treatment or environmental exposure) to the investigational 
product; or the female becomes or is found to be pregnant after discontinuing and/or 
being exposed to the investigational product;

An example of environmental exposure would be a case involving direct contact 
with a Pfizer product in a pregnant woman (eg, a nurse reports that she is pregnant 
and has been exposed to chemotherapeutic products).

A male has been exposed (eg, because of treatment or environmental exposure) to the 
investigational product prior to or around the time of conception and/or is exposed 
during his partner’s pregnancy.
If a participant or participant’s partner becomes or is found to be pregnant during the 
participant’s treatment with the investigational product, the investigator must report this 


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information to Pfizer Safety on the CT SAE Report Form and an EDP supplemental form, 
regardless of whether an SAE has occurred.  In addition, the investigator must submit 
information regarding environmental exposure to a Pfizer product in a pregnant woman (eg, a 
participant reports that she is pregnant and has been exposed to a cytotoxic product by 
inhalation or spillage) to Pfizer Safety using the EDP supplemental form.  This must be done 
irrespective of whether an AE has occurred and within 24 hours of awareness of the 
exposure.  The information submitted should include the anticipated date of delivery (see 
below for information related to termination of pregnancy).
Follow-up is conducted to obtain general information on the pregnancy and its outcome for 
all EDP reports with an unknown outcome.  The investigator will follow the pregnancy until 
completion (or until pregnancy termination) and notify Pfizer Safety of the outcome as a 
follow-up to the initial EDP supplemental form.  In the case of a live birth, the structural 
integrity of the neonate can be assessed at the time of birth.  In the event of a termination, the 
reason(s) for termination should be specified and, if clinically possible, the structural 
integrity of the terminated fetus should be assessed by gross visual inspection (unless 
preprocedure test findings are conclusive for a congenital anomaly and the findings are 
reported).
If the outcome of the pregnancy meets the criteria for an SAE (ie, ectopic pregnancy, 
spontaneous abortion, intrauterine fetal demise, neonatal death, or congenital anomaly [in a 
live-born baby, a terminated fetus, an intrauterine fetal demise, or a neonatal death]), the 
investigator should follow the procedures for reporting SAEs.
Additional information about pregnancy outcomes that are reported to Pfizer Safety as SAEs 
follows:

Spontaneous abortion includes miscarriage and missed abortion;

Neonatal deaths that occur within 1 month of birth should be reported, without regard 
to causality, as SAEs.  In addition, infant deaths after 1 month should be reported as 
SAEs when the investigator assesses the infant death as related or possibly related to 
exposure to the investigational product.
Additional information regarding the EDP may be requested by the sponsor.  Further 
follow-up of birth outcomes will be handled on a case-by-case basis (eg, follow-up on 
preterm infants to identify developmental delays).  In the case of paternal exposure, the 
investigator will provide the participant with the Pregnant Partner Release of Information 
Form to deliver to his partner.  The investigator must document in the source documents that 
the participant was given the Pregnant Partner Release of Information Form to provide to his 
partner.


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10.5. Appendix 5: Liver Safety: Suggested Actions and Follow-up Assessments
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 drug-induced 
liver injury (DILI).  Participants who experience a transaminase elevation above 3 times the 
upper limit of normal (× ULN) should be monitored more frequently to determine if they are 
an “adaptor” or are “susceptible.”
Liver function tests (LFTs) are not required as a routine safety monitoring procedure in this 
study.  However, should an investigator deem it necessary to assess LFTs because a 
participant presents with clinical signs/symptoms, such LFT results should be managed and 
followed as described below.
In the majority of DILI cases, elevations in aspartate aminotransferase (AST) and/or alanine 
aminotransferase (ALT) precede total bilirubin (TBili) elevations (>2 × ULN) by several 
days or weeks.  The increase in TBili typically occurs while AST/ALT is/are still elevated 
above 3 × ULN (ie, AST/ALT and TBili values will be elevated within the same 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).


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
Preexisting values of TBili above the normal range: TBili level increased from 
baseline value by an amount of at least 1 × ULN or if the value reaches 
>3 × ULN (whichever is smaller).
Rises in AST/ALT and TBili separated by more than a few weeks should be assessed 
individually based on clinical judgment; any case where uncertainty remains as to whether it 
represents a potential Hy’s law case should be reviewed with the sponsor.
The 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, creatine kinase (CK), direct and 
indirect bilirubin, gamma-glutamyl transferase (GGT), prothrombin time (PT)/international 
normalized ratio (INR), total bile acids, and alkaline phosphatase.  Consideration should also 
be given to drawing a separate tube of clotted blood and an anticoagulated tube of blood for 
further testing, as needed, for further contemporaneous analyses at the time of the recognized 
initial abnormalities to determine etiology.  A detailed history, including relevant 
information, such as review of ethanol, acetaminophen (either by itself or as a coformulated 
product in prescription or over-the-counter medications), recreational drug, supplement 
(herbal) use and consumption, family history, sexual history, travel history, history of contact 
with a jaundiced person, surgery, blood transfusion, history of liver or allergic disease, and 
potential occupational exposure to chemicals, should be collected.  Further testing for acute
hepatitis A, B, C, D, and E infection and liver imaging (eg, biliary tract) and collection of 
serum sample for acetaminophen drug and/or protein adduct levels may be warranted.
All cases demonstrated on repeat testing as meeting the laboratory criteria of AST/ALT and 
TBili elevation defined above should be considered potential DILI (Hy’s law) cases if no 
other reason for the 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
Abs
absolute
AD
atopic dermatitis
ADSI
atopic dermatitis severity index
AE
adverse event
ALT
alanine aminotransferase
AST
aspartate aminotransferase
AUC
area under the curve
-hCG
beta-human chorionic gonadotropin
BID
twice daily
BPO
benzoyl peroxide
BSA
body surface area
BUN
blood urea nitrogen
cAMP
cyclic adenosine monophosphate
CFR
Code of Federal Regulations
CIOMS
Council for International Organizations of Medical Sciences
CK
creatine kinase
Cmax
maximum observed concentration
CO2
carbon dioxide (bicarbonate)
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
DU
dispensable unit
EC
ethics committee
EC50
half maximal effective concentration
ECG
Electrocardiogram
eCRF
electronic case report form
EDP
exposure during pregnancy
EMA
European Medicines Agency
EU
European Union
EudraCT
European Clinical Trials Database
FAS
Full Analysis Set
FSH
follicle-stimulating hormone
GCP
Good Clinical Practice
GGT
gamma-glutamyl transferase
HIPAA
Health Insurance Portability and Accountability Act


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Protocol C3291028
Final Protocol, 22 Feb 2019
Page 74
Abbreviation
Term
HRQoL
health related quality of life measures
HRT
hormone replacement therapy
IB
investigator’s brochure
ICD
informed consent document
ICH
International Council for Harmonisation
ID
Identification
IMP
investigational medicinal product
IND
investigational new drug application
INR
international normalized ratio
IP manual
investigational product manual
IRB
institutional review board
IRT
interactive response technology
ISGA
investigator’s static global assessment
IUD
intrauterine device
IUS
Intrauterine hormone-releasing system
IWR
interactive Web-based response
LFT
liver function test
MAR
missing at random
MMRM
mixed effect models for repeated measures
MUSE
maximal use systemic exposure
N/A
not applicable
NbUVB
narrow band ultraviolet B
NIMP
noninvestigational medicinal product
NRS
numerical rating scale
PCD
primary completion date
PD
pharmacodynamic(s)
PDE-4
phosphodiesterase-4
PI
principal investigator
PK
pharmacokinetic(s)
PKA
protein kinase A
PMA
phorbol 12-myristate 13-acetate
PPAS
Per-Protocol Analysis Set
PRN
pro re nata
PT
prothrombin time
PUVA
psoralen plus ultraviolet A
QD
once daily
qual
Qualitative
RBC
red blood cell
RIPT
repeat-insult patch test
SAE
serious adverse event
SAP
statistical analysis plan
SoA
schedule of activities


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Final Protocol, 22 Feb 2019
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Abbreviation
Term
SOP
standard operating procedure
SRSD
single reference safety document
SUSAR
suspected unexpected serious adverse reaction
TBili
total bilirubin
TEAE
treatment-emergent adverse event
Tmax
time to reach maximum observed plasma concentration
TQT
thorough QT
TSS
Total Sign Score
ULN
upper limit of normal
US
United States
WBC
white blood cell
WOCBP
woman of childbearing potential
%BSA
percent of body surface area


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Final Protocol, 22 Feb 2019
Page 76
11. REFERENCES
1.
Bieber T. Atopic dermatitis. N Engl J Med 2008 Apr;358(14):1483-94.
2.
Lewis-Jones S. Quality of life and childhood atopic dermatitis: the misery of living with 
childhood eczema. Int J Clin Pract 2006;60(8):984-92.
3.
Eichenfield LF, Ellis CN, Mancini AJ, et al. Atopic dermatitis: epidemiology and 
pathogenesis update. Semin Cutan Med Surg 2012;31(3 Suppl):S3-5.
4.
Leicht S, Hanggi M. Atopic dermatitis. How to incorporate advances in management. 
Postgrad Med 2001;109(6):119-27.
5.
Saeki H. Management of Atopic Dermatitis in Japan. J Nippon Med Sch 2017;84(1):2-
11.
6.
Arkwright PD, Motala C, Subramanian H, et al. Management of difficult-to-treat atopic 
dermatitis. J Allergy Clin Immunol Pract. 2013;1(2):142-51.
7.
Leung DY. New insights into atopic dermatitis: role of skin barrier and immune 
dysregulation. Allergol Int 2013;62(2):151-61.
8.
Bantz SK, Zhu Z, Zheng T. The atopic march: progression from atopic dermatitis to 
allergic rhinitis and asthma. J Clin Cell Immunol 2014;5(2).
9.
Saunes M, Oien T, Dotterud CK, et al. Early eczema and the risk of childhood asthma: a 
prospective, population-based study. BMC Pediatr 2012;12:168.
10.
Garg N, Silverberg JI. Epidemiology of childhood atopic dermatitis. Clin Dermatol 
2015;33(3):281-8.
11.
Beatti PE, Lewis-Jones MS. A comparative study of impairment of quality of life in 
children with skin disease and children with other chronic childhood diseases. Br J 
Dermatol 2006;155(1):145-51.
12.
Carroll CL, Balkrishnan R, Feldman SR, et al. The burden of atopic dermatitis: impact 
on the patient, family, and society. Pediatr Dermatol 2005;22(3):192-9.
13.
Halvorsen JA, Lien L, Dalgard F, et al. Suicidal ideation, mental health problems, and 
social function in adolescents with eczema: a population-based study. J Invest Dermatol 
2014;134(7):1847-54.
14.
Watson W, Kapur S. Atopic dermatitis. Allergy Asthma Clin Immunol 2011;7(Suppl 
1):S4.
15.
Thomas CL, Finlay AY. The ’handprint’ approximates to 1% of the total body surface 
area whereas the ’palm minus the fingers’ does not. Br J Dermatol 2007;157(5):1080-1.


PF-06930164 (Crisaborole)
Protocol C3291028
Final Protocol, 22 Feb 2019
Page 77
16.
Yosipovitch G, Reaney M, Mastey V, et al. Validation of the peak pruritus numerical 
rating scale: Results from clinical studies of dupilumab in adult patients with 
moderate-to-severe atopic dermatitis. J Am Acad Dermatol 2017;76(6):AB278.

SAP_000.pdf: 
Protocol C3291028 (PF-06930164) Statistical Analysis Plan
 
Page 1
Protocol C3291028
A PHASE 2B, MULTI CENTER, 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 (2 YEARS AND OLDER) 
WITH MILD TO MODERATE ATOPIC DERMATITIS
Statistical Analysis Plan 
(SAP)
Version:
2.0
Date:
19 Dec 2019


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TABLE OF CONTENTS
LIST OF TABLES.....................................................................................................................3
APPENDICES ...........................................................................................................................4
1. VERSION HISTORY............................................................................................................5
2. INTRODUCTION .................................................................................................................5
2.1. Study Objectives, Endpoints, and Estimands............................................................5
2.2. Study Design .............................................................................................................9
3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS ................................................................................................................10
3.1. Primary Endpoint(s) ................................................................................................10
3.2. Secondary Endpoint(s) ............................................................................................10
11
11
3.4. Baseline Variables...................................................................................................11
3.5. Safety Endpoints .....................................................................................................11
3.5.1. Adverse Events ...........................................................................................11
4. ANALYSIS SETS (POPULATIONS FOR ANALYSIS)...................................................12
5. GENERAL METHODOLOGY AND CONVENTIONS....................................................12
5.1. Hypotheses and Decision Rules ..............................................................................12
5.2. General Methods .....................................................................................................12
5.2.1. Analyses for Binary Endpoints...................................................................13
5.2.2. Analyses for Continuous Endpoints ...........................................................13
5.2.3. Analyses for Categorical Endpoints ...........................................................13
5.3. Methods to Manage Missing Data ..........................................................................13
6. ANALYSES AND SUMMARIES ......................................................................................14
6.1. Primary Endpoint(s) ................................................................................................14
6.1.1. Change from Baseline in TSS in Target Lesions at Day 15 
(Comparison of Crisaborole vs Vehicle in Each Regimen).............................14
6.1.1.1. Main Analysis ...........................................................................14
6.1.1.2. Sensitivity/Supplementary Analyses.........................................15
6.2. Secondary Endpoint(s) ............................................................................................15
6.2.1. Change from Baseline in TSS in Target Lesions at Day 15 
(Comparison of Crisaborole BID vs Crisaborole QD) ....................................15
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6.2.1.1. Main Analysis ...........................................................................15
6.2.1.2. Sensitivity/Supplementary Analyses.........................................16
6.2.2. Change from Baseline in TSS in Target Lesions at Day 8.........................16
6.2.3. Change from Baseline in ISGA in Target Lesions up to Day 15 ...............16
6.2.3.1. Main Analysis ...........................................................................16
6.2.3.2. Sensitivity/Supplementary Analyses.........................................17
6.2.4. Change from Baseline in Pruritus Assessments in Target Lesions up 
to Day 15..........................................................................................................17
6.2.4.1. Main Analysis ...........................................................................17
6.2.5. Incidence of TEAEs and SAEs...................................................................18
19
19
19
6.4. Subset Analyses.......................................................................................................19
6.5. Baseline and Other Summaries and Analyses.........................................................19
6.5.1. Baseline Summaries....................................................................................19
6.5.2. Study Conduct and Participant Disposition................................................20
6.5.3. Study Treatment Exposure .........................................................................20
6.5.4. Concomitant Medications and Nondrug Treatments..................................20
6.6. Safety Summaries and Analyses .............................................................................20
6.6.1. Adverse Events...........................................................................................20
7. INTERIM ANALYSES.......................................................................................................20
7.1. Introduction .............................................................................................................20
7.2. Interim Analyses and Summaries............................................................................21
8. REFERENCES ....................................................................................................................21
9. APPENDICES .....................................................................................................................22
LIST OF TABLES
Table 1.
Summary of Changes..................................................................................5
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APPENDICES
Appendix 1. SAS Code............................................................................................................22
Appendix 2. Definition and Use of Visit Windows in Reporting............................................23


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1. VERSION HISTORY
Table 1.
Summary of Changes
Version/
Date
Associated 
Protocol 
Amendment
Rationale
Specific Changes
1
6 Jun 2019
Original
22 Feb 2019
Not Applicable
Not Applicable
2
19 Dec 2019
Original
22 Feb 2019
3.4
The baseline data of 
“Duration of disease 
(in years)” was not 
collected.
Appendix 2
The visit windows 
for analysis were not 
described.
3.4
“Duration of disease (in years)” was 
deleted.
Appendix 2
The visit windows for efficacy 
variables which were same as study 
C3291001 were added.
2. INTRODUCTION
This statistical analysis plan (SAP) provides the detailed methodology for summary and 
statistical analyses of the data collected in Study C3291028.  This document may modify the 
plans outlined in the protocol; however, any major modifications of the primary endpoint 
definition or its analysis will also be reflected in a protocol amendment.
2.1. Study Objectives, Endpoints, and Estimands
Objectives
Endpoints
Estimands
Primary: 
Primary:
Primary: 

To compare the 
efficacy of crisaborole 
ointment 2%, 
administered once 
daily (QD) or twice 
daily (BID) relative to 
the corresponding 
vehicle (QD or BID), 
on Total Sign Score 
(TSS) assessment in 
target lesions, in the 
treatment of mild to 

Change from 
baseline in TSS 
in target lesions 
treated with 
crisaborole 
ointment or 
vehicle on Day 
15 in each
regimen 
(regimen 1: QD, 

This estimand is the 
hypothetical estimand, 
which estimates the 
effect as if all 
participants maintain 
their randomized 
treatment.

Population: 
Participants with mild 
to moderate AD in 
adults (cohort 1) and 


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Objectives
Endpoints
Estimands
moderate atopic 
dermatitis (AD) in 
adults (cohort 1) and 
pediatrics (cohort 2).
regimen 2: BID)
for each cohort.
pediatrics (cohort 2) as 
defined by the 
inclusion and exclusion
criteria and are 
randomized and 
received at least one of 
the investigational
products.

Intercurrent event: All 
efficacy data after 
discontinuation of 
treatment will not be 
considered.

Population-level 
summary: Least-square 
means of intra-
participant difference 
between crisaborole 
ointment 2% vs 
corresponding vehicle 
in each regimen for 
each cohort and pooled 
cohort.
Secondary: 
Secondary:
Secondary: 

To evaluate the 
efficacy of crisaborole 
ointment 2% BID 
relative to crisaborole 
ointment 2% QD, on 
TSS assessment in 
target lesions, in the 
treatment of mild to 
moderate AD in adults
(cohort 1) and 
pediatrics (cohort 2).

Change from 
baseline in TSS 
in target lesions 
treated with 
crisaborole 
ointment or 
vehicle on Day 
15 in each
regimen for each 
cohort.

This estimand is the 
hypothetical estimand, 
which estimates the 
effect as if all 
participants maintain 
their randomized 
treatment.

Population: 
Participants with mild 
to moderate AD in 
adults (cohort 1) and 
pediatrics (cohort 2) as 
defined by the 
inclusion and exclusion
criteria and are 


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Objectives
Endpoints
Estimands
randomized and 
received at least one of 
the investigational 
products;

Intercurrent event: All 
efficacy data after 
discontinuation of 
treatment will not be 
considered.

Population-level 
summary: Difference 
in least square means 
between crisaborole 
ointment 2% BID and 
crisaborole ointment 
2% QD for each cohort
and pooled cohort.

To evaluate the 
efficacy of crisaborole 
ointment 2%, 
administered QD or 
BID, on TSS, ISGA 
and Pruritus 
assessments in target 
lesions, in the 
treatment of mild to 
moderate AD in adults 
(cohort 1) and 
pediatrics (cohort 2).

Change from 
baseline in TSS 
in target lesions 
treated with 
crisaborole 
ointment or 
vehicle on Day 8
in each regimen
for each cohort.

Change from 
baseline in ISGA
in target lesions 
treated with 
crisaborole 
ointment or 
vehicle at each 
visit up to Day 
15 in each
regimen for each 
cohort.

Change from 
baseline in

The other secondary 
efficacy endpoints will 
be analyzed using the 
estimands described 
above.


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Objectives
Endpoints
Estimands
pruritus 
assessments in 
target lesions 
treated with 
crisaborole 
ointment or 
vehicle at each 
day up to Day 15
in each regimen
using following 
scales;
Cohort 1: Peak 
Pruritus 
numerical rating 
scale (NRS) (age 
≥12)
Cohort 2: Itch 
Severity Scale 
(age 6-11)
Cohort 2:
Caregiver
Reported Itch 
Severity NRS 
(age 2-11).
•
To assess the safety 
and local tolerability of 
crisaborole ointment 
2%, administered QD 
or BID, in the 
treatment of mild to 
moderate AD in adults 
(cohort 1) and 
pediatrics (cohort 2)
•
Incidence of 
treatment 
emergent adverse 
events (TEAEs)
and serious 
adverse events 
(SAEs) in each 
regimen for each 
cohort.
•
There is no defined 
estimand for these 
endpoints and they will 
be analyzed
descriptively.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
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Objectives
Endpoints
Estimands
 
 
 
 
 
 
 
 
 
 
 
2.2. Study Design
This is a Phase 2b, multi-center, 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 (cohort 1: 12 years and older, cohort 2: 2 to under 
12 years old) with mild to moderate AD.  After completing screening activities, including 
meeting eligibility criteria, two target lesions with same severity will be determined by the 
investigator, participants will be randomized to one of the regimens, QD or BID
(randomization ratio; 1:1), and crisaborole ointment 2% or vehicle will be randomly assigned
to each target lesion at Baseline/Day 1. Both target lesions are to be treated at the same 
assigned dosing regimen and dosing regimen is unblinded information to sponsor, 
investigators/study sites and participants.  Participants will be treated with investigational
products administered for 2 weeks and followed-up 28 days after the end of treatment.
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Cohort
Regimen
Investigational Products
N
Study Treatment
Cohort 1a
Regimen 1
Crisaborole ointment 2% 
QD vs Vehicle QD
20
Participants will visit the site once daily to 
be administered investigational products
by site staff.
Regimen 2
Crisaborole ointment 2% 
BID vs Vehicle BID
20
Participants will visit the site twice daily 
to be administered investigational 
products by site staff.
Cohort 2b
Regimen 1
Crisaborole ointment 2% 
QD vs Vehicle QD
20
Investigational products will be applied 
once daily by parent/caregiver (site staff
will confirm the compliance directly or via
live video chat), or by site staff (site staff
will visit the participant’s home as 
needed).
Regimen 2
Crisaborole ointment 2% 
BID vs Vehicle BID
20
Investigational products will be applied 
twice daily by parent/caregiver (site staff
will confirm the compliance directly or via
live video chat), or by site staff (site staff
will visit the participant’s home as 
needed).
BID: twice daily, N: number of participants, QD: once daily
a.
ages 12 years and older
b.
ages 2 years to under 12 years old
3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS
3.1. Primary Endpoint(s)

Change from baseline in TSS in target lesions treated with crisaborole ointment or 
vehicle on Day 15 in each regimen for each cohort for intra-participant comparison of 
crisaborole vs vehicle.
3.2. Secondary Endpoint(s)

Change from baseline in TSS in target lesions treated with crisaborole ointment or 
vehicle on Day 15 in each regimen for each cohort for inter-participant comparison of 
crisaborole BID vs crisaborole QD.

Change from baseline in TSS in target lesions treated with crisaborole ointment or 
vehicle on Day 8 in each regimen for each cohort.

Change from baseline in ISGA in target lesions treated with crisaborole ointment or 
vehicle at each visit up to Day 15 in each regimen for each cohort.

Change from baseline in pruritus assessments in target lesions treated with 
crisaborole ointment or vehicle at each day up to Day 15 in each regimen using 
following scales:

Cohort 1: Peak Pruritus NRS (age ≥12);

Cohort 2: Itch Severity Scale (age 6-11);


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•
Cohort 2: Caregiver Reported Itch Severity NRS (age 2-11).
•
Incidence of TEAEs and SAEs in each regimen for each cohort.
 
 
3.4. Baseline Variables
Demographic and baseline characteristics include:
•
Age (in years);
•
Sex;
•
Race; 
•
Ethnicity;
•
ISGA (global and target lesions);
•
%BSA (global);
•
TSS (target lesions);
•
Peak pruritus NRS (target lesions) for cohort 1;
•
Itch severity scale (target lesions) for cohort 2 (6 to 11 years old only);
•
Caregiver reported itch severity NRS (target lesions) for cohort 2.
3.5. Safety Endpoints
3.5.1. Adverse Events
AEs will be captured and reported in accordance with Pfizer data standards.
An AE is considered a treatment-emergent adverse event (TEAE) if the event started during 
the effective duration of treatment.
All events that start on or after the first dosing day and time/start time, if collected, but before 
the last dose plus the lag time will be flagged as TEAEs.  The algorithm will not consider any 
events that started prior to the first dose date.  If an AE starts on the same day as the first 
dose date, it will be considered treatment emergent unless the case report form (CRF) data 
indicates otherwise via explicitly recording time for AE onset and treatment dosing.
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The effective duration of treatment starts at the date of the first dose of study treatment and 
ends at the date of the last dose of study treatment plus the lag time.  An infinite lag will be 
used for this study.
4. ANALYSIS SETS (POPULATIONS FOR ANALYSIS)
Data for all participants will be assessed to determine if participants meet the criteria for 
inclusion in each analysis population prior to unblinding and releasing the database and 
classifications will be documented per standard operating procedures.
Population
Description
Full Analysis Set (FAS)
All participants randomized and receiving 1 dose of 
investigational product.
Per-Protocol Analysis Set 
(PPAS)
All participant randomized and receiving 1 dose of 
investigational product, with both baseline and Day 15
primary efficacy data, and without protocol violations that 
were thought to impact the efficacy evaluation during the 
treatment period.  All protocol deviations will be reviewed 
and assessed by the study team prior to database release.
Safety Analysis Set 
All participants receiving 1 dose of investigational 
product.
5. GENERAL METHODOLOGY AND CONVENTIONS
The final analysis will be performed at study participant dataset release after last participant 
last visit.
5.1. Hypotheses and Decision Rules
The primary analysis in each regimen for each cohort will be a superiority test to demonstrate 
crisaborole ointment 2% is more efficacious than vehicle in the target lesion in participants 
with mild to moderate AD as measured by change from baseline in TSS between crisaborole 
treated lesion and vehicle treated lesion. The null hypothesis in each regimen for each cohort 
is that there is no difference between crisaborole ointment 2% and vehicle, and the 
alternative hypothesis in each regimen for each cohort is that there is difference between 
crisaborole ointment 2% and vehicle as measured by change from baseline in TSS at Day 15.  
In each regimen for each cohort the difference between crisaborole and vehicle in TSS 
change from baseline at Day 15 is statistically significant if p-value<0.05 (two-sided). 
5.2. General Methods
In general, number and percentage will be presented for categorical variables. Number, 
mean, standard deviation, minimum, 1st, 2nd and 3rd quartiles and maximum will be 
presented for continuous variables.


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5.2.1. Analyses for Binary Endpoints
The binary endpoints will be descriptively summarized using number, percentage and 95% 
confidence interval (CI) of percentage at each time point.
For the intra-participant comparison of crisaborole vs vehicle in each regimen at each time 
point, the binary endpoints will be compared using McNemar’s test. For the inter-participant 
comparison of regimen 1 vs regimen 2 at each time point, the binary endpoints will be 
compared using Chi-squared test.
5.2.2. Analyses for Continuous Endpoints
The continuous endpoints will be descriptively summarized using number, mean, standard 
deviation, minimum, 1st, 2nd and 3rd quartiles and maximum.
For the intra-participant comparison of crisaborole vs vehicle in each regimen at each time 
point, a Mixed effect Models for Repeated Measures (MMRM) will be used to derive least-
square mean of intra-participant difference and associated 2-sided 95% CI between 
crisaborole ointment 2% and corresponding vehicle.  A MMRM will include the fixed effect 
of time point (visit or day) and an unstructured variance and covariance matrix will be used 
to model the dependence among the same participants across different visits up to Day 15.  If 
there is convergence issue for unstructured variance and covariance matrix, first order 
autoregressive (AR(1)) variance and covariance matrix will be used.
For the inter-participant comparison of regimen 1 vs regimen 2 at each time point, a MMRM
will be used to derive difference in least-square means and associated 2-sided 95% CI 
between regimen 1 and regimen 2.  A MMRM will include the fixed effects of dosing 
regimen, time point (visit or day), dosing regimen-by-time point (visit or day) interaction, 
and baseline value of the corresponding endpoint and an unstructured variance and 
covariance matrix will be used to model the dependence among the same participants across 
different visits up to Day 15.  If there is convergence issue for unstructured variance and 
covariance matrix, AR(1) variance and covariance matrix will be used.
5.2.3. Analyses for Categorical Endpoints
Categorical endpoints will be descriptively summarized using number and percentage. Shift 
table from baseline to Day 8 and Day 15 will be provided.
5.3. Methods to Manage Missing Data
Missing data will not be imputed for efficacy descriptive summary.
For the statistical comparison of continuous endpoints, a MMRM analysis will be conducted 
including only the observed data in the model under the assumption of the missing at random 
(MAR) for the missing mechanism.
Non responder imputation (NRI) will be used for missing values of lesion ISGA response of 
clear or almost clear and at least a 2 grade improvement from baseline at Day 8 and Day 15.


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In addition, missing values for safety endpoints will not be imputed.
6. ANALYSES AND SUMMARIES
6.1. Primary Endpoint(s)
6.1.1. Change from Baseline in TSS in Target Lesions at Day 15 (Comparison of 
Crisaborole vs Vehicle in Each Regimen)
6.1.1.1. Main Analysis

Estimand strategy: Hypothetical (Section 2.1).

Analysis time point: Day 15.

Analysis set: FAS (Section 4).

Analysis methodology: For the intra-participant comparison of crisaborole vs vehicle 
in each regimen for each cohort, the intra-participant difference of change from 
baseline in TSS in target lesions between crisaborole and vehicle up to Day 15 will be 
analyzed using a MMRM that includes the fixed effect of visit specified in Section 
5.2.2.

Intercurrent events and missing data: All efficacy data after discontinuation of 
treatment will not be considered (Section 2.1).  Observed data will be included in the 
model, and the missing values will be handled in the model, where the values are
assumed to be MAR (Section 5.3).

Supporting objective and decision rule: Primary objective, crisaborole is superior to 
vehicle for the TSS change at Day 15 if the change for crisaborole is greater than for 
vehicle and if p-value<0.05 (two-sided).

Reporting results:

Observed score: The sample size, mean, standard error (SE), standard deviation, 
median, Q1, Q3, minimum and maximum at baseline and post-baseline visits will 
be presented for each treatment.

Change from baseline: The sample size, mean, SE, standard deviation, median, 
Q1, Q3, minimum and maximum at post-baseline visits will be presented for each 
treatment.  The least-squares mean of difference and the corresponding SE, 95% 
CI, p-value will be presented for all post-baseline visits.

Figures: 1) Line plots of the mean change (SE) from baseline to Day 8 and 15
for two treatments (ie, crisaborole vs vehicle) in one figure.  Figures will be 
developed in each regimen for each cohort, separately.  In addition, 2) line plots 
of the mean change (SE) from baseline to Day 8 and 15 for four treatments (ie, 
crisaborole BID vs crisaborole QD vs vehicle BID vs vehicle QD) in one figure.  
Figures will be developed for each cohort, separately.


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6.1.1.2. Sensitivity/Supplementary Analyses
To support the interpretation of the main analysis the following analyses will be performed.
6.1.1.2.1. Analysis for PPAS
Except that analysis set is PPAS, the same estimand strategy, analysis time point, analysis 
methodology, intercurrent events and missing data, supporting objective and decision rule
and reporting results as the main analysis (Section 6.1.1.1) will be used.
6.1.1.2.2. Analysis for Pooled Cohort
The same analysis as the main analysis (Section 6.1.1.1) will be conducted for the pooled 
cohort of cohort 1 and cohort 2.
6.2. Secondary Endpoint(s)
6.2.1. Change from Baseline in TSS in Target Lesions at Day 15 (Comparison of 
Crisaborole BID vs Crisaborole QD)
6.2.1.1. Main Analysis

Estimand strategy: Hypothetical (Section 2.1).

Analysis time point: Day 15.

Analysis set: FAS (Section 4).

Analysis methodology: For the inter-participant comparison of crisaborole BID vs
crisaborole QD for each cohort, the change from baseline in TSS in target lesions
between crisaborole BID and crisaborole QD up to Day 15 will be analyzed using a 
MMRM that includes the fixed effects of dosing regimen, visit, dosing regimen-by-
visit interaction, and baseline value specified in Section 5.2.2.

Intercurrent events and missing data: All efficacy data after discontinuation of 
treatment will not be considered (Section 2.1).  Observed data will be included in the 
model, and the missing values will be handled in the model, where the values are
assumed to be MAR (Section 5.3).

Reporting results:

Observed score: The sample size, mean, SE, standard deviation, median, Q1, Q3, 
minimum and maximum at baseline and post-baseline visits will be presented for 
each treatment.

Change from baseline: The sample size, mean, SE, standard deviation, median, 
Q1, Q3, minimum and maximum at post-baseline visits will be presented for each 
treatment.  The least-squares mean and the corresponding SE, 95% CI for each  
treatment, the difference between the least-squares means of treatments and the 
corresponding SE, 95% CI, p-value will be presented for all post-baseline visits.


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
Figures: Line plots of the mean change (SE) from baseline to Day 8 and 15 for 
two treatments (ie, crisaborole BID vs crisaborole QD) in one figure.  Figures will 
be developed for each cohort, separately. 
6.2.1.2. Sensitivity/Supplementary Analyses
To support the interpretation of the main analysis the following analyses will be performed.
6.2.1.2.1. Analysis for PPAS
Except that analysis set is PPAS, the same estimand strategy, analysis time point, analysis 
methodology, intercurrent events and missing data and reporting results as the main analysis 
(Section 6.2.1.1) will be used.
6.2.1.2.2. Analysis for Pooled Cohort
The same analysis as the main analysis (Section 6.2.1.1) will be conducted for the pooled 
cohort of cohort 1 and cohort 2.
6.2.2. Change from Baseline in TSS in Target Lesions at Day 8
For the intra-participant comparison of crisaborole vs vehicle in each regimen for each 
cohort, Day 8 is a time point in the mixed model for the primary analysis for TSS change 
from baseline at Day 15.  The analysis for TSS change from baseline at Day 8 is from the 
same model, and data reporting is same as for Day 15.  See Section 6.1.1.
For the inter-participant comparison of crisaborole BID vs crisaborole QD for each cohort, 
Day 8 is a time point in the mixed model for the secondary analysis for TSS change from 
baseline at Day 15.  The analysis for TSS change from baseline at Day 8 is from the same 
model, and data reporting is same as for Day 15.  See Section 6.2.
6.2.3. Change from Baseline in ISGA in Target Lesions up to Day 15
6.2.3.1. Main Analysis

Estimand strategy: Hypothetical (Section 2.1).

Analysis time point: Day 8 and Day 15.

Analysis set: FAS (Section 4).

Analysis methodology: For the intra-participant comparison of crisaborole vs vehicle 
in each regimen for each cohort, the intra-participant difference of change from 
baseline in ISGA in target lesions between crisaborole and vehicle up to Day 15 will 
be analyzed using a MMRM that includes the fixed effect of visit specified in Section 
5.2.2.  For the inter-participant comparison of crisaborole BID vs crisaborole QD for 
each cohort, the change from baseline in ISGA in target lesions between crisaborole
BID and crisaborole QD up to Day 15 will be analyzed using a MMRM that includes 
the fixed effects of dosing regimen, visit, dosing regimen-by-visit interaction, and 
baseline value specified in Section 5.2.2.


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
Intercurrent events and missing data: All efficacy data after discontinuation of 
treatment will not be considered (Section 2.1).  Observed data will be included in the 
model, and the missing values will be handled in the model, where the values are
assumed to be MAR (Section 5.3).

Reporting results:

Observed score: The sample size, number and percentage for each category at 
baseline and post-baseline visits will be presented for each treatment.  The sample 
size, mean, SE, standard deviation, median, Q1, Q3, minimum and maximum at 
baseline and post-baseline visits will be presented for each treatment as well.

Change from baseline: The sample size, mean, SE, standard deviation, median, 
Q1, Q3, minimum and maximum at post-baseline visits will be presented for each 
treatment.  For the intra-participant comparison of crisaborole vs vehicle in each 
regimen for each cohort, the least-squares mean of difference and the 
corresponding SE, 95% CI, p-value will be presented for all post-baseline visits.  
For the inter-participant comparison of crisaborole BID vs crisaborole QD for 
each cohort, the least-squares mean and the corresponding SE, 95% CI for each 
treatment, the difference between the least-squares means of treatments and the 
corresponding SE, 95% CI, p-value will be presented for all post-baseline visits.

Shift table: Number and percentage from each category at baseline to each 
category at Day 8 and Day 15 will be presented.
6.2.3.2. Sensitivity/Supplementary Analyses
To support the interpretation of the main analysis, the same analysis as the main analysis 
(Section 6.2.3.1) will be conducted for the pooled cohort of cohort 1 and cohort 2.
6.2.4. Change from Baseline in Pruritus Assessments in Target Lesions up to Day 15
The following analysis will be conducted for each of the 3 endpoints of peak pruritus NRS
(11-point scale), itch severity scale (5-point scale) and caregiver reported itch severity NRS
(11-point scale), separately.
6.2.4.1. Main Analysis

Estimand strategy: Hypothetical (Section 2.1).

Analysis time point: Day 2 to Day 15.

Analysis set: FAS (Section 4).


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
Analysis methodology: For the intra-participant comparison of crisaborole vs vehicle 
in each regimen for each cohort, the intra-participant difference of change from 
baseline in pruritus in target lesions between crisaborole and vehicle up to Day 15 
will be analyzed using a MMRM that includes the fixed effect of day specified in 
Section 5.2.2.  For the inter-participant comparison of crisaborole BID vs crisaborole 
QD for each cohort, the change from baseline in pruritus in target lesions between 
crisaborole BID and crisaborole QD up to Day 15 will be analyzed using a MMRM
that includes the fixed effects of dosing regimen, day, dosing regimen-by-day
interaction, and baseline value specified in Section 5.2.2.

Intercurrent events and missing data: All efficacy data after discontinuation of 
treatment will not be considered (Section 2.1).  Observed data will be included in the 
model, and the missing values will be handled in the model, where the values are
assumed to be MAR (Section 5.3).

Reporting results:

Observed score: The sample size, mean, SE, standard deviation, median, Q1, Q3, 
minimum and maximum at baseline and post-baseline days will be presented for 
each treatment.

Change from baseline: The sample size, mean, SE, standard deviation, median, 
Q1, Q3, minimum and maximum at post-baseline days will be presented for each 
treatment.  For the intra-participant comparison of crisaborole vs vehicle in each 
regimen for each cohort, the least-squares mean of difference and the 
corresponding SE, 95% CI, p-value will be presented for all post-baseline days.  
For the inter-participant comparison of crisaborole BID vs crisaborole QD for 
each cohort, the least-squares mean and the corresponding SE, 95% CI for each 
treatment, the difference between the least-squares means of treatments and the 
corresponding SE, 95% CI, p-value will be presented for all post-baseline days.

Figures: The following figures will be developed for each of the 3 endpoints of 
NRS assessment, separately. For the intra-participant comparison of crisaborole 
vs vehicle, 1) line plots of the mean change (SE) from baseline up to Day 15 for 
two treatments (ie, crisaborole vs vehicle) in one figure.  Figures will be 
developed in each regimen for each cohort, separately.  In addition, 2) line plots 
of the mean change (SE) from baseline up to Day 15 for four treatments (ie, 
crisaborole BID vs crisaborole QD vs vehicle BID vs vehicle QD) in one figure.  
Figures will be developed for each cohort, separately.  For the inter-participant 
comparison of crisaborole BID vs crisaborole QD, 3) line plots of the mean 
change (SE) from baseline up to Day 15 for two treatments (ie, crisaborole BID 
vs crisaborole QD) in one figure.  Figures will be developed for each cohort, 
separately.
6.2.5. Incidence of TEAEs and SAEs
See Section 6.6.1.


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6.4. Subset Analyses
Not Applicable.
6.5. Baseline and Other Summaries and Analyses
6.5.1. Baseline Summaries
In each regimen for each cohort, demographic and baseline characteristics will be 
summarized for safety analysis set according to Pfizer data standards. Lesion baseline data 
will be summarized by treatment in each regimen for each cohort.
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6.5.2. Study Conduct and Participant Disposition
Participants evaluation, disposition, discontinuation will be summarized for safety analysis 
set according to Pfizer data standards.
6.5.3. Study Treatment Exposure
For participants in regimen 1, a total of 14 doses are expected to be applied.  For participants 
in regimen 2, a total of 28 doses are expected to be applied.  A participant will be considered 
compliant with the dosing regimen if they receive, at least 12 but no more than 16 
investigational product doses for regimen 1, at least 23 but no more than 33 investigational 
product doses for regimen 2 (ie, 80̢120%, inclusive, of the expected number of doses).
In each regimen for each cohort, the exposure to study drug in each treatment group will be 
summarized by total number of applications, the total number of days of dosing and number 
and percentage of participants who are compliant with the dosing regimen.
For cohort 2, total number of applications without comfirmation by site staff will be 
summarized.
6.5.4. Concomitant Medications and Nondrug Treatments
Prior drug and non-drug treatment, concomitant drug and non-drug treatment will be 
summarized according to Pfizer data standards.
6.6. Safety Summaries and Analyses
6.6.1. Adverse Events
Adverse events will be summarized according to Pfizer data standards.
•
TEAEs.
•
SAEs.
TEAEs and SAEs occurred in the target lesions will be summarized by treatment in each 
regimen for each cohort and pooled cohort. General TEAEs and SAEs will be summarized 
for overall safety analysis set in each regimen for each cohort.
It should be recognized that most studies are not designed to reliably demonstrate a causal 
relationship between the use of a pharmaceutical product and an adverse event or a group of 
adverse events. Except for select events in unique situations, studies do not employ formal 
adjudication procedures for the purpose of event classification. As such, safety analysis is 
generally considered as an 
 and its purpose is to generate hypotheses for 
further investigation.
7. INTERIM ANALYSES
7.1. Introduction
No formal interim analysis will be conducted for this study.
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7.2. Interim Analyses and Summaries
Not Applicable.
8. REFERENCES
Not Applicable.


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9. APPENDICES
Appendix 1. SAS Code
For the intra-participant comparison of crisaborole vs vehicle for each regimen, the following 
SAS code can be used for analysis of mixed model repeated measure for lesion TSS change 
from baseline up to Day 15 and other similar continuous endpoint shown in Section 3.
proc mixed data=dataset;
   class subjid visit;
   model difference = visit;
   
   repeated visit/subject=subjid type=un;/*If there is a convergence issue  
for type=un, it can be replaced by type=AR(1)*/
   lsmeans visit/cl;
run;
Note: difference is the intra-participant difference of change from baseline at each time point 
up to Day 15 between crisaborole and vehicle.
For the inter-participant comparison of crisaborole BID vs crisaborole QD, the following 
SAS code can be used for analysis of mixed model repeated measure for lesion TSS change 
from baseline up to Day 15 and other similar continuous endpoint shown in Section 3.
proc mixed data=dataset;
   class subjid regimen visit;
   model difference = regimen visit regimen*visit baseline;
   
   repeated visit/subject=subjid type=un;/*If there is a convergence issue  
for type=un, it can be replaced by type=AR(1)*/
   lsmeans regimen*visit/cl diff cl;
run;
Note: difference is change from baseline at each time point up to Day 15 of each regimen.


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Appendix 2. Definition and Use of Visit Windows in Reporting
Visit windows will be used for efficacy variables.
If more than one observation from the same participant falls into the same visit window, the 
value closest to the targeted day will be used as the observation for that time point.  All 
observations will, however, be included in the listings.
TSS and ISGA
Visit Label
Targeted Day
Analysis window for data sets
Baseline [Screening (Day -35) 
to up to first dosing date)
Day 1
Last observation up to and 
including first dosing date
Day 8
Day 8
Day 2 – Day 11
Day 15
Day 15
Day 12 – end of study
Pruritus Assessment
Visit Label
Targeted Day
Analysis window for data sets
Baseline [Screening (Day -35) 
to up to first dosing date)
Day 1
Last observation up to and 
including first dosing date
Day 2
Day 2
Day 2
…
…
…
Day 14
Day 14
Day 14
Day 15
Day 15
Day 15*
* if the measurement value of pruritus assessment is collected after Day 15, the value will be 
used as the observation for the day.