Final Clinical Study Report
Protocol C3291028

CLINICAL STUDY REPORT SYNOPSIS
Sponsor: Pfizer, Inc.
Investigational Product: Crisaborole
Clinical Study Report Synopsis: Protocol C3291028
Protocol 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 toModerate Atopic Dermatitis
Investigators: Refer to CCI

for a list of investigators involved in this study.

Study Centers: This study was conducted at 3 centers in Japan. Refer to CCI
for a list of sites involved in this study.
Publications Based on the Study: None.
Study Initiation Date: 15 June 2019
Study Completion Date: 16 December 2019
Report Date: 13 April 2020
Previous Report Date: Not applicable
Phase of Development: Phase 2b.
Primary and Secondary Study Objectives and Endpoints:
The primary and secondary study objectives, endpoints and estimands of this study arepresented in Table S1.

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Table S1. Primary and Secondary Study Objectives, Endpoints, and Estimands
Type
Objectives
Primary
Efficacy To compare the efficacy ofcrisaborole ointment 2%,
administered QD or BID
relative to the corresponding
vehicle (QD or BID), on TSS
assessment in target lesions, inthe treatment of mild tomoderate AD in adults(Cohort 1) and pediatrics(Cohort 2)

Secondary
Efficacy To evaluate the efficacy ofcrisaborole ointment 2% BID
relative to crisaborole
ointment 2% QD, on TSS
assessment in target lesions, inthe treatment of mild tomoderate AD in adults(Cohort 1) and pediatrics(Cohort 2)

To evaluate the efficacy ofcrisaborole ointment 2%,
administered QD or BID, on
TSS, ISGA, and pruritus
assessments in target lesions,in the treatment of mild tomoderate AD in adults(Cohort 1) and pediatrics

Endpoints

Estimands

Change from baseline in TSS in target
lesions treated with crisaborole ointment orvehicle on Day 15 in each regimen(Regimen 1: QD, Regimen 2: BID) for
each cohortThis estimand was the hypothetical estimand, which estimated theeffect as if all participants maintained their randomized treatment.
 Population: Participants with mild to moderate AD in adults(Cohort 1) and pediatrics (Cohort 2) as defined by the inclusionand exclusion criteria, and were randomized and received atleast 1 of the investigational products Intercurrent event: All efficacy data after discontinuation oftreatment were not considered Population-level summary: Least-square means of
intra-participant difference between crisaborole ointment 2%
versus corresponding vehicle in each regimen for each cohortand pooled cohort

Change from baseline in TSS in target
lesions treated with crisaborole ointment orvehicle on Day 15 in each regimen foreach cohortThis estimand was the hypothetical estimand, which estimated theeffect as if all participants maintained their randomized treatment.
 Population: Participants with mild to moderate AD in adults(Cohort 1) and pediatrics (Cohort 2) as defined by the inclusionand exclusion criteria, and were randomized and received
at least 1 of the investigational products Intercurrent event: All efficacy data after discontinuation oftreatment were not 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
The other secondary efficacy endpoints were analyzed using theestimands described above

Change from baseline in TSS in target
lesions treated with crisaborole ointment orvehicle on Day 8 in each regimen for eachcohortChange from baseline in ISGA in target
lesions treated with crisaborole ointment orvehicle at each visit up to Day 15 in eachregimen for each cohort

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Table S1. Primary and Secondary Study Objectives, Endpoints, and Estimands
Type

SafetyObjectives(Cohort 2)

Endpoints
Change from baseline in pruritus
assessments in target lesions treated withcrisaborole ointment or vehicle at each day
up to Day 15 in each regimen using
following scales:
Cohort 1: Peak pruritus, NRS(Age 12 years), Cohort 2: Itch severity
scale (Age 6-11 years) Self-Report,
Cohort 2: Caregiver reported itch severity
NRS (Age 2-11 years)
Incidence of TEAEs and SAEs in eachregimen for each cohort

Estimands

To assess the safety and local
There was no defined estimand for these endpoints and they were
tolerability of crisaborole
analyzed descriptively
ointment 2%, administered
QD or BID, in the treatment ofmild to moderate AD in adults(Cohort 1) and pediatrics(Cohort 2)
Abbreviations: AD=atopic dermatitis; BID=twice daily; ISGA=Investigator Static Global Assessment; NRS=numerical rating scale; QD=once daily;
SAE=serious adverse event; TEAE=treatment-emergent adverse events; TSS=total sign score.

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CLINICAL STUDY REPORT SYNOPSISMETHODS
Study Design: This was a Phase 2b, multicenter, randomized, double-blind,vehicle-controlled, intra-participant study to evaluate efficacy and safety of 2 regimens ofcrisaborole ointment 2% in Japanese pediatric and adult participants (Cohort 1: 12 years,
Cohort 2: 2 to under 12 years old) with mild to moderate atopic dermatitis (AD). Aftercompleting screening activities, including meeting eligibility criteria, 2 target lesions thatwere moderate in severity were determined by the investigator, participants were randomized
to 1 of the 2 regimens, once daily (QD) or twice daily (BID) (randomization ratio; 1:1), andcrisaborole ointment 2% or vehicle were randomly assigned to each target lesion atbaseline/Day 1. Both target lesions were to be treated at the assigned dosing regimen anddosing regimen was unblinded information to sponsor, investigators/study sites andparticipants. Participants were treated with investigational products administered for 2 weeks
and followed-up 28 days after the end of treatment.
Diagnosis and Main Criteria for Inclusion:
Key inclusion criteria were as follows:Male or female participants ages:


Cohort 1: 12 years at the time of consent;

Cohort 2: 2 years to under 12 years old at the time of consent.

Participants who had confirmed clinical diagnosis of active AD at screening andbaseline/Day 1 according to Hanifin and Rajka criteria and who had at least 6 months
history prior to screening visit that had been clinically stable for >1 month.

Participants who had a global Investigator Static Global Assessment (ISGA) of 2 (mild)or 3 (moderate) at baseline/Day 1 visit.

Participants who had 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 not >30% atbaseline/Day 1, excluding scalp, genitals and groin area. The presence of AD on theseareas (scalp, genitals and groin area) was not exclusionary, but was not to be included in
the calculation for coverage of BSA with AD.

Participants who had 2 lesions of AD at least 3 cm × 3 cm with identical lesion
ISGA=3 (moderate) for each lesion. These AD lesions were to be at least 10 cm apart.
The target lesions were not to be on the face, neck, scalp, axilla, genitals, groin area,
palms, dorsal of the hands, dorsal of the body trunk and soles. In addition, 2 AD areas on
the same limb were not to be selected as the target lesions. (Note: When possible, AD
areas on the bilateral [left/right] area were to be selected as target lesions).

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Key exclusion criteria were as follows:

Other acute or chronic medical or psychiatric condition including recent (within the pastyear) or active suicidal ideation or behavior or laboratory abnormality that could haveincreased the risk associated with study participation or study drug administration or
could have interfered with the interpretation of study results and, in the judgment of theinvestigator, would have made the participant inappropriate for entry into this study.

History of angioedema or anaphylaxis to topical products or known sensitivity to any of
the components of crisaborole ointment 2%.

Participants had previous treatment with any topical or systemic phosphodiesterase-4
inhibitor.

Participants who had undergone treatment for any type of cancer (except squamous cell
carcinoma, basal cell carcinoma or carcinoma in situ of the skin, curatively treated withsurgical excision only).

Study Treatment:
Crisaborole (PF-06930164) ointment 2% and vehicle ointment were applied topically as athin layer QD or BID to the affected areas.
At baseline/Day 1, the participants who met the inclusion/exclusion criteria were randomized
to 1 of the regimens, QD or BID, and for each of the 2 target lesions (Lesion 1 and Lesion 2)
meeting the inclusion criteria identified by the investigator, the study interventions(crisaborole ointment 2% or vehicle) were assigned randomly.
The lesion size and prescribed amount of study interventions were recorded in the source
documentation and marked on the dosing instruction document for the parents/caregivers.
The study interventions were applied only to Lesion 1 and Lesion 2, and not applied to other
AD affected areas. Only participants enrolled in the study could receive the study
intervention and only authorized site staff could supply or administered the study
intervention.
The study drug information is provided in Table S2.

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Table S2. Study Drug Information
Investigational Product
Description
Crisaborole 2% topical ointment
in 60 g tube

Vendor Lot
Number
K072017D

Pfizer Lot
Number17-004070

Strength/Potency

Dosage Form

20 mg/gOintment

Placebo for crisaborole topicalointment in 60 g tube (axomatic)

K121917D

18-000180

0%

Ointment

Efficacy Evaluations: In this study, the lesion is specified when referring to a target lesion
assessment.
Severity of AD was characterized at screening and baseline with %BSA and global ISGA,
however, %BSA and global ISGA were not included in the efficacy evaluation. In addition,
the severity of AD lesion was characterized at baseline and throughout the study with thelesion ISGA, lesion total sign score (TSS), and peak pruritus numerical rating scale (NRS).
Lesion Investigator Static Global Assessment:
The clinical evaluator of AD performed an assessment of each target lesion severity of AD
and assigned a lesion ISGA score and category. The assessment was a static evaluation
without regard to the score at a previous visit.
For eligibility of assessment, the lesion ISGA at baseline/Day 1 was 3 (moderate) whereas,
the global ISGA could be 2 (mild) or 3 (moderate). The assessments were done at Days 1, 8
and 15.
Lesion Total Sign Score:
The lesion TSS was an assessment of the severity of each of the following: erythema,induration/papulation, excoriation, and lichenification. Each of these was rated using the
4-point severity scale. These ratings were then added to create a total score (13-point scale;ranging from 0 to 12 points). The assessments were done at baseline/Day 1, Day 8, andDay 15.
Pruritus Assessments:
The severity of itch (pruritus) due to AD at the target lesion was assessed. The assessments
were done from baseline/Day 1 till Day 15. The pruritus assessments for each target lesion
were as follows:

Peak pruritus NRS, Age ≥12 years;Itch severity scale Age 6-11 years self-report;
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CLINICAL STUDY REPORT SYNOPSISItch severity NRS (caregiver reported) for participants Age 2-11 years.

Percent Body Surface Area With Atopic Dermatitis:
The overall BSA affected by AD was evaluated (from 0% to 100%) to verify eachparticipant’s eligibility at the screening and baseline/Day 1 visits. The investigator might
have used the “handprint method” by which the area represented by the palmar (ie,outstretched) surface of the participant’s hand with all 5 digits adducted together wasapproximately 1% of the participant’s BSA.
The number of handprints of AD skin in a body region could be used to determine the extent(%) to which a body region was involved with AD.
Investigator Static Global Assessment:
The investigator performed an assessment of the overall severity of AD and assigned an
ISGA score and category to verify each participant’s eligibility at the screening andbaseline/Day 1 visits.
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and/or Other Evaluations:
The pharmacokinetic, pharmacodynamic, pharmacogenomic and/or other evaluations were
not done in the study.
Safety Evaluations: Safety assessments consisted of the collection of adverse events (AEs)and serious adverse events (SAEs), vital signs (only at screening), and conducting physicalexamination and pregnancy testing.
Statistical Methods:
The details of analysis sets in the study are as follows:
Full Analysis Set (FAS): All participants randomized and who received ≥1 dose of the study
drug.
Per-Protocol Analysis Set (PPAS): All participants randomized and who received ≥1 dose of
the study drug, 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.
Safety Analysis Set: All participants who received ≥1 dose of the study drug.
Analysis of Primary Efficacy Endpoint:
The primary endpoint was change from baseline in TSS in target lesions treated withcrisaborole ointment 2% or vehicle on Day 15. For the intra-participant comparison ofcrisaborole ointment 2% versus vehicle in each regimen for each cohort, the intra‑participant
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difference of change from baseline in TSS in target lesions between crisaborole ointment 2%
and vehicle up to Day 15 was analyzed using a Mixed effect Models for RepeatedMeasures (MMRM) that included the fixed effect of visit. The main analysis was based on
the FAS.
Crisaborole ointment 2% was superior to vehicle for the TSS change at Day 15, if the change
for crisaborole ointment 2% was greater than for vehicle and if p-value <0.05 (2-sided).
Analysis of Secondary Efficacy Endpoints:
Change From Baseline in Total Sign Score in Target Lesions at Day 15 (Comparison of
Crisaborole Twice Daily Versus Crisaborole Once Daily):
For the inter-participant comparison of crisaborole ointment 2% BID versus crisaborole
ointment 2% QD for each cohort, change from baseline in TSS in target lesions between
crisaborole ointment 2% BID and crisaborole ointment 2% QD up to Day 15 was analyzed
using an MMRM that included the fixed effects of dosing regimen, visit, dosing
regimen-by-visit interaction and baseline value. The main analysis was based on the FAS.
Change From Baseline in Total Sign Score in Target Lesions at Day 8:
The Day 8 was a time point in the mixed model for the analysis for TSS change frombaseline at Day 15. The analysis for TSS change from baseline at Day 8 was from the samemodel, and data reporting was same as for Day 15.
Change From Baseline in Investigator Static Global Assessment in Target Lesions at Day 8
and Day 15:
The intra-participant difference of change from baseline in ISGA between crisaborole
ointment 2% and vehicle and the inter-participant difference of change from baseline in
ISGA between crisaborole ointment 2% BID and crisaborole ointment 2% QD wereanalyzed. The main analysis was based on the FAS.
Change From Baseline in Pruritus Assessments in Target Lesions at Each Time Point up to
Day 15:The intra-participant difference of change from baseline in pruritus assessment between
crisaborole ointment 2% and vehicle and the inter-participant difference of change frombaseline in pruritus assessment between crisaborole ointment 2% BID and crisaborole
ointment 2% QD were analyzed. The main analysis was based on the FAS.
Safety Analysis: The safety data were summarized descriptively.

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CLINICAL STUDY REPORT SYNOPSISRESULTS
Subject Disposition and Demography:
Participant disposition is summarized in Table S3 for Cohort 1 and Cohort 2.
In Cohort 1, 20 participants were assigned to receive crisaborole ointment 2% QD andvehicle QD (referred to as "QD regimen" hereafter), and 21 participants were assigned toreceive crisaborole ointment 2% BID and vehicle BID (referred to as "BID regimen"
hereafter). All the participants completed the study.
In Cohort 2, 20 participants each were assigned to receive QD regimen and BID regimen,
and all the participants completed the study.
In Cohort 1, 11 (55.0%) male and 9 (45.0%) female participants were enrolled in QD
regimen, and 17 (81.0%) male and 4 (19.0%) female participants were enrolled in BID
regimen. The mean age (standard deviation [SD]) of participants in QD regimen and BID
regimen was 33.3 (10.36) years and 33.9 (10.96) years, respectively. In QD regimen and
BID regimen, mean treatable percent BSA (SD) of participants was 18.54 (7.368) and18.33 (7.217), respectively.
In Cohort 2, 8 (40.0%) male and 12 (60.0%) female participants were enrolled in QD
regimen, and 11 (55.0%) male and 9 (45.0%) female participants were enrolled in BID
regimen. The mean age (SD) of participants in QD regimen and BID regimen was
7.7 (2.52) years and 7.8 (2.69) years, respectively. In QD regimen and BID regimen, mean
treatable percent BSA (SD) of participants was 4.80 (2.263) and 9.19 (7.610), respectively.
In the baseline disease characteristics for each target lesion, TSS was balanced between
assigned treatments in each regimen for each cohort. All the participants (100.0%) exhibited
moderate lesion severity, based on the ISGA score.

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Table S3. Disposition Events Summary
Cohort 1

Number (%) of Subjects

Cohort 2

Crisaborole 2% QD + Vehicle
QD(N=20)

Crisaborole 2% BID + Vehicle
BID(N=21)

Crisaborole 2% QD + Vehicle Crisaborole 2% BID + Vehicle BID
QD(N=20)(N=20)

n (%)

n (%)

n (%)

n (%)

20 (100.0)

21 (100.0)

20 (100.0)

20 (100.0)

Disposition Phase: Treatment
Subjects Entered:
Discontinued

0

0

0

0

Completed20 (100.0)

21 (100.0)

20 (100.0)

20 (100.0)

20 (100.0)

21 (100.0)

20 (100.0)

20 (100.0)

Disposition Phase: Follow-Up
Subjects Entered:
Discontinued

0

0

0

0

Completed20 (100.0)

21 (100.0)

20 (100.0)

20 (100.0)

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Efficacy Results:
All participants were included in the FAS and the PPAS. The efficacy results were the samefor both analysis sets.
Primary Endpoint Results:
Change From Baseline in TSS in Target Lesions at Day 15 for Intra-Participant Comparisonof Crisaborole Ointment 2% Versus Vehicle – Cohort 1 (Age ≥12 Years):
QD Regimen:
For the QD regimen, the primary efficacy endpoint was achieved. The crisaborole ointment
2% QD treated lesions showed a statistically significant reduction in TSS at Day 15
compared to the vehicle QD treated lesions (Table S4). The least square means (LSM) of
intra-participant difference of TSS change from baseline was -1.6 with a p-value of 0.0071(Table S4).
BID Regimen:
In the BID regimen, the primary efficacy endpoint was also achieved. The crisaborole
ointment 2% BID treated lesions showed a statistically significant reduction in TSS at
Day 15 compared to the vehicle BID treated lesions (Table S4). The LSM of
intra-participant difference of TSS change from baseline was -2.0 with a p-value of 0.0029(Table S4).

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Table S4. Change From Baseline in Total Sign Score (TSS) on Day 15 for IntraParticipant Comparison of Crisaborole 2% Versus Vehicle in Cohort 1 Full Analysis Set
Regimen 1 (QD)
(N=20)
Summary Statistics at Day 15

Regimen 2 (BID)(N=21)

Crisaborole 2% Vehicle QD Crisaborole 2%
QD(N=20)
BID(N=20)(N=21)

Vehicle BID(N=21)

Change from baseline
n

20

20

21

21

Mean (standard error)-4.5 (0.60)-2.9 (0.51)-4.8 (0.53)-2.7 (0.47)

Median (range)-4.5 (-10, -1)-3.5 (-7, 1)-5.0 (-11, -1)-3.0 (-7, 1)

-1.6

-

-2.0

-

(-2.7, -0.5)-(-3.3, -0.8)-

0.0071-0.0029-

Least squares mean of intra-participant difference ofchange from baseline (Crisaborole 2% - Vehicle)
95% Confidence interval
p-Value

Baseline is defined as the last observation up to and including first dosing date.
Mixed effect Model for Repeated Measures (MMRM) includes the fixed effect of visit, and the covariance structure UN
is used.
- = Not applicable.
The Full Analysis Set includes all subjects who are randomized and receive at least one dose of investigational product.

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Change From Baseline in TSS in Target Lesions at Day 15 for Intra-Participant Comparisonof Crisaborole Ointment 2% Versus Vehicle – Cohort 2 (Age 2-11 Years):
QD Regimen:
For the QD regimen, the primary efficacy endpoint was achieved. The crisaborole
ointment 2% QD treated lesions showed a statistically significant reduction in TSS at Day 15
compared to the vehicle QD treated lesions (Table S5). The LSM of intra-participant
difference of TSS change from baseline was -1.5 with a p-value of 0.0250 (Table S5).
BID Regimen:
For the BID regimen, the primary efficacy endpoint was achieved. The crisaborole
ointment 2% BID treated lesions showed a statistically significant reduction in TSS at
Day 15 compared to the vehicle BID treated lesions (Table S5). The LSM of
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intra-participant difference of TSS change from baseline was -2.1 with a p-value of 0.0014(Table S5).

Table S5. Change From Baseline in Total Sign Score (TSS) on Day 15 for IntraParticipant Comparison of Crisaborole 2% Versus Vehicle in Cohort 2 Full Analysis Set
Regimen 1 (QD)
(N=20)
Summary Statistics at Day 15

Regimen 2 (BID)(N=20)

Crisaborole 2% Vehicle QD Crisaborole 2%
QD(N=20)
BID(N=20)(N=20)

Vehicle BID(N=20)

Change from baseline
n

20

20

20

20

Mean (standard error)-3.5 (0.47)-2.0 (0.50)-4.7 (0.50)-2.6 (0.54)

Median (range)-4.0 (-8, 0)-1.5 (-7, 1)-5.0 (-8, 1)-3.0 (-6, 2)

-1.5

-

-2.1

-

(-2.7, -0.2)-(-3.3, -0.9)-

0.0250-0.0014-

Least squares mean of intra-participant difference ofchange from baseline (Crisaborole 2% - Vehicle)
95% Confidence interval
p-Value

Baseline is defined as the last observation up to and including first dosing date.
Mixed effect Model for Repeated Measures (MMRM) includes the fixed effect of visit, and the covariance structure UN
is used.
- = Not applicable.
The Full Analysis Set includes all subjects who are randomized and receive at least one dose of investigational product.

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Secondary Endpoint Results:
Change From Baseline in TSS in Target Lesions at Day 15 for Inter-Participant Comparisonof Crisaborole Ointment 2% BID Versus Crisaborole Ointment 2% QD:
Cohort 1:
BID Regimen Versus QD Regimen:
For the comparison of the BID and QD regimens, the reduction in TSS at Day 15 in thecrisaborole ointment 2% BID treated lesions was larger than the reduction observed in the

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crisaborole ointment 2% QD treated lesions. Inter-participant LSM difference of TSSchange from baseline was -0.6.
Cohort 2:
BID Regimen Versus QD Regimen:
For the comparison of the BID and QD regimens, the reduction in TSS at Day 15 in thecrisaborole ointment 2% BID treated lesions was larger than the reduction observed in thecrisaborole ointment 2% QD treated lesions. Inter-participant LSM difference of TSSchange from baseline was -0.8.
Change From Baseline in TSS in Target Lesions at Day 8:
Cohort 1:
Intra-Participant Comparison of Crisaborole Ointment 2% Versus Vehicle:
At Day 8, in QD regimen, the LSM of intra-participant difference of TSS change frombaseline was -1.9 with a p-value of 0.0029, where as in BID regimen, the LSM of
intra-participant difference of TSS change from baseline was -1.4 with a p-value of 0.0282.
Inter-Participant Comparison of Crisaborole Ointment 2% BID Versus Crisaborole Ointment
2% QD:At Day 8, inter-participant LSM difference of TSS change from baseline of crisaborole
ointment 2% BID and crisaborole ointment 2% QD was -0.1.
Cohort 2:
Intra-Participant Comparison of Crisaborole Ointment 2% Versus Vehicle:
At Day 8, in QD regimen, the LSM of intra-participant difference of TSS change frombaseline was -1.2 with a p-value of 0.0237, where as in BID regimen, the LSM of
intra-participant difference of TSS change from baseline was -1.7 with a p-value of 0.0077.
Inter-Participant Comparison of Crisaborole Ointment 2% BID Versus Crisaborole
Ointment 2% QD:
At Day 8, inter-participant LSM difference of TSS change from baseline of crisaborole
ointment 2% BID and crisaborole ointment 2% QD was -0.1.

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Change From Baseline in ISGA in Target Lesions:
Cohort 1:
Intra-Participant Comparison of Crisaborole Ointment 2% Versus Vehicle:
At Day 15, in QD regimen, the LSM of intra-participant difference of change from baseline
was -0.9 with a p-value of 0.0005, and in BID regimen, the LSM of intra-participant
difference of change from baseline was -0.7 with a p-value of 0.0098.
At Day 8, in QD regimen, the LSM of intra-participant difference of change from baseline
was -0.5 with a p-value of 0.0084 and in BID regimen, the LSM of intra-participant
difference of change from baseline was -0.4 with a p-value of 0.0584.
Inter-Participant Comparison of Crisaborole Ointment 2% BID Versus Crisaborole
Ointment 2% QD:
At Day 15, the inter-participant LSM difference of change from baseline between crisaborole
ointment 2% BID and crisaborole ointment 2% QD was 0.0.
At Day 8, the inter-participant LSM difference of change from baseline between crisaborole
ointment 2% BID and crisaborole ointment 2% QD was 0.1.
Cohort 2:
Intra-Participant Comparison of Crisaborole Ointment 2% Versus Vehicle:
At Day 15, in QD regimen, the LSM of intra-participant difference of change from baseline
was -0.7 with a p-value of 0.0093. In BID regimen, the LSM of intra-participant differenceof change from baseline was -1.0 with a p-value of 0.0001.
At Day 8, in QD regimen, the LSM of intra-participant difference of change from baseline
was -0.3 with a p-value of 0.1435. In BID regimen, the LSM of intra-participant differenceof change from baseline was -0.4 with a p-value of 0.0569.
Inter-Participant Comparison of Crisaborole Ointment 2% BID Versus Crisaborole Ointment
2% QD:At Day 15, the inter-participant LSM difference of change from baseline between crisaborole
ointment 2% BID and crisaborole ointment 2% QD was -0.1.
At Day 8, the inter-participant LSM difference of change from baseline between crisaborole
ointment 2% BID and crisaborole ointment 2% QD was 0.2.

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Peak Pruitus NRS (Cohort 1, Age ≥12 Years):Intra-Participant Comparison of Crisaborole Ointment 2% Versus Vehicle:
In QD regimen, a greater improvement in pruritus NRS was observed for the crisaborole
treated versus the vehicle treated lesions 1 day after the first application (-1.3 versus -0.7),
and the improvement was maintained through Day 15 (-3.5 versus -2.0).
Crisaborole ointment 2% was superior to vehicle at each time point up to Day 15 withp-values <0.05, except at Day 3.
In BID regimen, a slightly greater improvement in pruritus NRS was observed for thecrisaborole treated versus the vehicle treated lesions 1 day after the first application(-0.6 versus -0.5), and the improvement was maintained through Day 15 (-3.7 versus -2.9).
Crisaborole ointment 2% was superior to vehicle at several time points but not at all days,
with p-values <0.05 up to Day 15.
Inter-Participant Comparison of Crisaborole BID Versus Crisaborole QD:
The LSM was generally greater in crisaborole ointment 2% QD than crisaborole ointment
2% BID from Day 2 to Day 12, but after Day 13, the LSM in crisaborole ointment 2% BID
was greater than crisaborole ointment 2% QD.
Itch Severity Scale (Cohort 2, Age 6-11 Years):Intra-Participant Comparison of Crisaborole Ointment 2% Versus Vehicle:
In QD regimen, the improvement in itch severity scale was observed more in the crisaborole
treated lesions than the vehicle treated lesions 1 day after the first application (-0.7
versus -0.3), and was -0.8 versus -0.6 at Day 15.
In BID regimen, the improvement in itch severity scale was observed more in the crisaborole
treated lesions than the vehicle treated lesions 1 day after the first application (-0.6
versus -0.4), and was -1.3 versus -0.9 at Day 15.
Inter-Participant Comparison of Crisaborole BID Versus Crisaborole QD:
The LSM of change from baseline of crisaborole ointment 2% BID versus crisaborole
ointment 2% QD was generally similar from Day 2 to Day 15.

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Caregiver Reported Itch Severity Numerical Rating Scale (Cohort 2, Age 2-11 Years):Intra-Participant Comparison of Crisaborole Ointment 2% Versus Vehicle:
A larger reduction was observed in crisaborole compared to the vehicle in both regimens. In
QD regimen, improvement in itch severity scale observed for the crisaborole treated wasmore versus the vehicle treated lesions 1 day after the first application (-0.5 versus -0.4), andthe improvement was maintained through Day 15 (-2.5 versus -1.3).
In BID regimen, improvement in itch severity scale observed for the crisaborole treated wasless versus the vehicle treated lesions 1 day after the first application (-0.7 versus -0.9), but
the improvement was more in crisaborole treated versus the vehicle treated lesions at Day 15(-4.3 versus -3.0).
Inter-Participant Comparison of Crisaborole BID Versus Crisaborole QD:
The LSM of change from baseline of crisaborole ointment 2% BID was generally more whencompared to the crisaborole ointment 2% QD from Day 2 to Day 15.
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, Immunogenicity and/or
Other Results:
The pharmacokinetic, pharmacodynamic, pharmacogenomic and/or other evaluations were
not done in the study.
Safety Results:
Overall Adverse Events:
Cohort 1:
A summary of all-causality treatment-emergent adverse events (TEAEs) by system organclass and preferred term is presented in Table S6.
For the QD regimen, 6 participants (30.0%) experienced a total of 9 all-causality TEAEs,
8 of which were considered as treatment-related. The most frequently reported all-causality
TEAEs by preferred term (PT) were application site irritation and application site pruritus(3 participants each), all of which were considered to be treatment-related.
For the BID regimen, 6 participants (28.6%) experienced a total of 12 all-causality TEAEs,
8 of which were considered as treatment-related. The most frequently reported all-causality
TEAEs by PT were application site irritation (4 participants) and oropharyngeal pain
(3 participants). All of the events of application site irritation were considered to betreatment-related and none of the events of oropharyngeal pain were considered to betreatment-related.

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Cohort 2:
For the QD regimen, 2 participants (10.0%) experienced a total of 2 all-causality TEAEs(arthralgia and hand-foot-and-mouth disease; 1 participant each), neither of which wereconsidered as treatment-related (Table S6).
For the BID regimen, 2 participants (10.0%) experienced a total of 3 all-causality TEAEs(Table S6), of which 2 TEAEs (application site pruritus and application site pain) wereconsidered to be treatment-related.
There were no deaths, SAEs or severe AEs reported in either cohort in the study. There wereno cases of dose reduction or temporary/permanent discontinuations due to TEAEs reported
in the study. All the TEAEs reported in the study were mild in severity.

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Table S6. Treatment-Emergent Adverse Events by System Organ Class and Preferred Term (All Causalities)
Number of Subjects Evaluable for AEs

Cohort 1

Cohort 2

Crisaborole 2% QD +Vehicle QD(N=20)

Crisaborole 2% BID +Vehicle BID(N=21)

Crisaborole 2% QD +Vehicle QD(N=20)

Crisaborole 2% BID + Vehicle
BID(N=20)

Number (%) of Subjects:
by System Organ Classand Preferred Term

n (%)

n (%)

n (%)

n (%)

With any adverse event

6 (30.0)

6 (28.6)

2 (10.0)

2 (10.0)

Gastrointestinal Disorders

1 (5.0)000

1 (5.0)000

5 (25.0)

5 (23.8)

01 (5.0)Dental caries
General Disorders And Administration Site
Conditions
Application site coldness

0

1 (4.8)0

0Application site irritation

3 (15.0)

4 (19.0)00Application site pain

1 (5.0)1 (4.8)0

1 (5.0)Application site pruritus

3 (15.0)

2 (9.5)0

1 (5.0)

Infections And Infestations

1 (5.0)1 (4.8)1 (5.0)1 (5.0)Application site folliculitis

1 (5.0)1 (4.8)00

Hand-foot-and-mouth disease00

1 (5.0)1 (5.0)Musculoskeletal And Connective Tissue
Disorders00

1 (5.0)000

1 (5.0)003 (14.3)000

3 (14.3)00Arthralgia
Respiratory, Thoracic And Mediastinal
Disorders
Oropharyngeal pain

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Table S6. Treatment-Emergent Adverse Events by System Organ Class and Preferred Term (All Causalities)
Number of Subjects Evaluable for AEs

Number (%) of Subjects:
by System Organ Classand Preferred Term

Cohort 1

Cohort 2

Crisaborole 2% QD +Vehicle QD(N=20)

Crisaborole 2% BID +Vehicle BID(N=21)

Crisaborole 2% QD +Vehicle QD(N=20)

Crisaborole 2% BID + Vehicle
BID(N=20)

n (%)

n (%)

n (%)

n (%)

Subjects are only counted once per treatment per event.
Totals for the No. of Subjects at a higher level are not necessarily the sum of those at the lower levels since a subject may report two or more different adverse events within thehigher level category.
*Percentages of gender specific events are calculated using the corresponding gender count as denominator.
Includes data up to lag days after last dose of study drug.
MedDRA v22.1 coding dictionary applied.

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Adverse Events in the Target Lesions:
Cohort 1:
For the QD regimen, 5 participants (25.0%) experienced a total of 6 TEAEs in crisaborole
ointment 2% treated lesion, and 2 participants (10.0%) experienced a total of 3 TEAEs in
vehicle treated lesion. In the crisaborole treated lesions, application site irritation andapplication site pruritus were each reported in 2 participants (10.0%), and application site
pain and application site folliculitis were each reported in 1 participant (5.0%). In vehicle
treated lesions, application site pruritus was reported in 2 participants (10.0%), andapplication site irritation was reported in 1 participant (5.0%). All of the TEAEs in bothtarget lesions were considered treatment-related but were mild in severity.
For the BID regimen, 4 participants (19.0%) experienced a total of 7 TEAEs in crisaborole
ointment 2% treated lesion, and 2 participants (9.5%) experienced a total of 3 TEAEs in
vehicle treated lesion. In the crisaborole treated lesions, application site irritation wasreported in 4 participants (19.0%), and application site pain, application site pruritus, andapplication site folliculitis were each reported in 1 participant (4.8%). In vehicle treatedlesions, application site coldness, application site irritation, and application site pruritus werereported in 1 participant (4.8%) each. All of the TEAEs in both target lesions, except for theapplication site folliculitis in the crisaborole treated lesion, were considered treatment-related
but were mild in severity.
Cohort 2:
For the QD regimen, no participant experienced TEAEs in the target lesions.
For the BID regimen, 1 participant (5.0%) experienced 2 TEAEs (application site pain andapplication site pruritus) in crisaborole ointment 2% treated lesion, both of which wereconsidered to be treatment-related and mild in severity. No participant experienced TEAEs
in vehicle treated lesion.
Conclusions:

The primary efficacy endpoint was achieved in both regimens (QD and BID) and in bothcohorts (Cohort 1: ≥12 years, Cohort 2: 2 to under 12 years old) in Japanese participants
with mild to moderate AD. The crisaborole treated lesions showed a statisticallysignificant reduction in TSS at Day 15 compared to the vehicle treated lesions. In
Cohort 1, in QD regimen, intra-participant difference of TSS change from baseline
was -1.6 with a p-value of 0.0071. In BID regimen, intra-participant difference of TSSchange from baseline was -2.0 with a p-value of 0.0029. In Cohort 2, in QD regimen,
intra-participant difference of TSS change from baseline was -1.5 with a p-valueof 0.0250. In BID regimen, intra-participant difference of TSS change from baseline
was -2.1 with a p-value of 0.0014.

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For the comparison of the BID and QD regimens, numerically larger reductions in TSS
at Day 15 were observed in crisaborole BID regimen compared to the crisaborole
QD regimen in both cohorts.

The crisaborole treated lesions showed a larger reduction in TSS at Day 8 compared to
the vehicle treated lesions in both QD and BID regimens for both cohorts. The
reductions in TSS at Day 8 was similar between the crisaborole BID and QD regimens
for both cohorts.

In the ISGA, peak pruritus NRS, itch severity scale and caregiver reported itch severity
NRS, for intra-participant comparison, larger reductions were generally observed incrisaborole compared to the vehicle in both regimens for both cohorts.

In the ISGA and itch severity scale, for inter-participant comparison, similar
improvement was observed on Day 8 and Day 15 for ISGA, and from Day 2 to Day 15
for itch severity scale between crisaborole BID regimen and crisaborole QD regimen.

In the peak pruritus NRS, for inter-participant comparison, similar improvement wasobserved, generally more in crisaborole QD regimen compared to crisaborole
BID regimen from Day 2 to Day 12, but after Day 13, generally more in crisaborole
BID regimen compared to crisaborole QD regimen.

In the caregiver reported itch severity NRS, for inter-participant comparison, a greater
improvement was generally observed from Day 2 to Day 15 in crisaborole BID regimen
compared to crisaborole QD regimen.

All the TEAEs reported in this study were mild in severity. Only the TEAEs that
occurred in the target lesion were considered treatment-related. There were no deaths,
SAEs, severe AEs or discontinuations due to TEAEs reported in the study. Crisaborole
ointment 2% was well-tolerated in Japanese pediatric and adult participants with mild tomoderate AD in both QD and BID regimens.

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