Trial Outcomes & Findings for A Study of Crisaborole Ointment 2% in Adult Japanese Healthy Subjects and Adult Japanese Subjects With Mild To Moderate Atopic Dermatitis (NCT NCT03260595)

NCT ID: NCT03260595

Last Updated: 2019-03-01

Results Overview

The skin irritation index is a common measure of skin irritation potential (safety criteria) of investigational product and derived using skin irritation scores. Individual skin irritation score ranges from 0-4, where 0 = no reaction, 0.5 = mild erythema, 1 = erythema, 2 = erythema with edema and papula, 3 = erythema with edema, papula and small water blister, 4 = large water blister, higher score indicates more skin irritation. For each investigational product, the skin irritation index was calculated as the sum of the maximum individual skin irritation scores divided by the number of evaluable participants and multiplied by 100, which ranged from 0 to 400; where, lower score indicated less skin irritation and higher score indicated more skin irritation.

• Recruitment status: COMPLETED
• Study phase: PHASE1
• Target enrollment: 32 participants
• Primary outcome timeframe: Day 3 to 4
• Results posted on: 2019-03-01

Participant Flow

Participant milestones

Measure	Cohort 1: Crisaborole Ointment 2% and Vehicle Crisaborole ointment 2 percent (%) and matching vehicle was applied topically to 2 randomly assigned, adjacent sites on the skin area field at infrascapular area of the back respectively within each healthy participant under occlusive patch condition on Day 1. Ointment and vehicle were remained under occlusion for 48 hours. Target sites were identified at Baseline (Day 1) by investigator.	Cohort 2: Crisaborole Ointment 2% Crisaborole ointment 2% was applied topically to the treatable percent body surface area (%BSA: defined as percent of a participant's total BSA that is atopic dermatitis \[AD\]-involved and is not on the scalp or in designated venous access areas) of participants with AD twice daily from Days 2 to 7 and once only on Days 1 and 8. Treatable %BSA was calculated at Baseline (Day 1) by investigator.	Cohort 2: Vehicle Vehicle matched to Crisaborole ointment 2% was applied topically to the treatable %BSA (defined as percent of a participant's total BSA that AD-involved and is not on the scalp or in designated venous access areas) of participants with AD twice daily from Days 2 to 7 and once only on Days 1 and 8. Treatable %BSA was calculated at Baseline (Day 1) by investigator.
Overall Study STARTED	20	10	2
Overall Study COMPLETED	20	10	2
Overall Study NOT COMPLETED	0	0	0

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

A Study of Crisaborole Ointment 2% in Adult Japanese Healthy Subjects and Adult Japanese Subjects With Mild To Moderate Atopic Dermatitis

Baseline characteristics by cohort

Measure	Cohort 1: Crisaborole Ointment 2% and Vehicle n=20 Participants Crisaborole ointment 2% and matching vehicle was applied topically to 2 randomly assigned, adjacent sites on the skin area field at infrascapular area of the back respectively within each healthy participant under occlusive patch condition on Day 1. Ointment and vehicle were remained under occlusion for 48 hours. Target sites were identified at Baseline (Day 1) by investigator.	Cohort 2: Crisaborole Ointment 2% n=10 Participants Crisaborole ointment 2% was applied topically to the treatable percent body surface area (%BSA: defined as percent of a participant's total BSA that is AD-involved and is not on the scalp or in designated venous access areas) of participants with AD twice daily from Days 2 to 7 and once only on Days 1 and 8. Treatable %BSA was calculated at Baseline (Day 1) by investigator.	Cohort 2: Vehicle n=2 Participants Vehicle matched to Crisaborole ointment 2% was applied topically to the treatable %BSA (defined as percent of a participant's total BSA that AD-involved and is not on the scalp or in designated venous access areas) of participants with AD twice daily from Days 2 to 7 and once only on Days 1 and 8. Treatable %BSA was calculated at Baseline (Day 1) by investigator.	Total n=32 Participants Total of all reporting groups
Age, Continuous	26.2 years STANDARD_DEVIATION 5.66 • n=93 Participants	35.0 years STANDARD_DEVIATION 11.28 • n=4 Participants	23.5 years STANDARD_DEVIATION 4.95 • n=27 Participants	28.8 years STANDARD_DEVIATION 8.72 • n=483 Participants
Sex: Female, Male Female	0 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants	0 Participants n=483 Participants
Sex: Female, Male Male	20 Participants n=93 Participants	10 Participants n=4 Participants	2 Participants n=27 Participants	32 Participants n=483 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	0 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants	0 Participants n=483 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	20 Participants n=93 Participants	10 Participants n=4 Participants	2 Participants n=27 Participants	32 Participants n=483 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants	0 Participants n=483 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants	0 Participants n=483 Participants
Race (NIH/OMB) Asian	20 Participants n=93 Participants	10 Participants n=4 Participants	2 Participants n=27 Participants	32 Participants n=483 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants	0 Participants n=483 Participants
Race (NIH/OMB) Black or African American	0 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants	0 Participants n=483 Participants
Race (NIH/OMB) White	0 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants	0 Participants n=483 Participants
Race (NIH/OMB) More than one race	0 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants	0 Participants n=483 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants	0 Participants n=483 Participants

PRIMARY outcome

Timeframe: Day 3 to 4

Population: Safety analysis population included all participants who received at least one dose of study medication. Data for this outcome measure was not planned to be collected and analyzed for Cohort 2, as pre-specified in protocol.

The skin irritation index is a common measure of skin irritation potential (safety criteria) of investigational product and derived using skin irritation scores. Individual skin irritation score ranges from 0-4, where 0 = no reaction, 0.5 = mild erythema, 1 = erythema, 2 = erythema with edema and papula, 3 = erythema with edema, papula and small water blister, 4 = large water blister, higher score indicates more skin irritation. For each investigational product, the skin irritation index was calculated as the sum of the maximum individual skin irritation scores divided by the number of evaluable participants and multiplied by 100, which ranged from 0 to 400; where, lower score indicated less skin irritation and higher score indicated more skin irritation.

Outcome measures

Measure	Cohort 1: Crisaborole Ointment 2% and Vehicle n=20 Participants Crisaborole ointment 2% and matching vehicle was applied topically to 2 randomly assigned, adjacent sites on the skin area field at infrascapular area of the back respectively within each healthy participant under occlusive patch condition on Day 1. Ointment and vehicle were remained under occlusion for 48 hours. Target sites were identified at Baseline (Day 1) by investigator.	Cohort 2: Vehicle Vehicle matched to Crisaborole ointment 2% was applied topically to the treatable %BSA (defined as percent of a participant's total BSA that AD-involved and is not on the scalp or in designated venous access areas) of participants with AD twice daily from Days 2 to 7 and once only on Days 1 and 8. Treatable %BSA was calculated at Baseline (Day 1) by investigator.
Cohort 1: Skin Irritation Index Crisaborole ointment 2%	40.0 scores on a scale	—
Cohort 1: Skin Irritation Index Vehicle	5.0 scores on a scale	—

PRIMARY outcome

Timeframe: Baseline up to Day 36

Population: Safety analysis population included all participants who received at least one dose of study medication.

An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent were events between first dose of study drug and up to 28 days after last dose of study drug (up to Day 36) that were absent before treatment or that worsened relative to pre-treatment state. AEs included both SAEs and non-serious AEs.

Outcome measures

Measure	Cohort 1: Crisaborole Ointment 2% and Vehicle n=10 Participants Crisaborole ointment 2% and matching vehicle was applied topically to 2 randomly assigned, adjacent sites on the skin area field at infrascapular area of the back respectively within each healthy participant under occlusive patch condition on Day 1. Ointment and vehicle were remained under occlusion for 48 hours. Target sites were identified at Baseline (Day 1) by investigator.	Cohort 2: Vehicle n=2 Participants Vehicle matched to Crisaborole ointment 2% was applied topically to the treatable %BSA (defined as percent of a participant's total BSA that AD-involved and is not on the scalp or in designated venous access areas) of participants with AD twice daily from Days 2 to 7 and once only on Days 1 and 8. Treatable %BSA was calculated at Baseline (Day 1) by investigator.
Cohort 2: Number of Participants With Treatment-Emergent Adverse Events (AEs) And Serious Adverse Events (SAEs) AEs	9 Participants	2 Participants
Cohort 2: Number of Participants With Treatment-Emergent Adverse Events (AEs) And Serious Adverse Events (SAEs) SAEs	0 Participants	0 Participants

PRIMARY outcome

Timeframe: Baseline up to end of treatment (Day 8)

Population: Safety analysis population included all participants who received at least one dose of study medication. Data for this outcome measure was not planned to be collected and analyzed for Cohort 1, as pre-specified in protocol.

Vital signs included pulse rate and blood pressure. Clinical significance of vital signs was determined at the investigator's discretion.

Outcome measures

Measure	Cohort 1: Crisaborole Ointment 2% and Vehicle n=10 Participants Crisaborole ointment 2% and matching vehicle was applied topically to 2 randomly assigned, adjacent sites on the skin area field at infrascapular area of the back respectively within each healthy participant under occlusive patch condition on Day 1. Ointment and vehicle were remained under occlusion for 48 hours. Target sites were identified at Baseline (Day 1) by investigator.	Cohort 2: Vehicle n=2 Participants Vehicle matched to Crisaborole ointment 2% was applied topically to the treatable %BSA (defined as percent of a participant's total BSA that AD-involved and is not on the scalp or in designated venous access areas) of participants with AD twice daily from Days 2 to 7 and once only on Days 1 and 8. Treatable %BSA was calculated at Baseline (Day 1) by investigator.
Cohort 2: Number of Participants With Clinically Significant Vital Signs Abnormalities	0 Participants	0 Participants

PRIMARY outcome

Timeframe: Baseline up to end of treatment (Day 8)

Population: Safety analysis population included all participants who received at least one dose of study medication. Data for this outcome measure was not planned to be collected and analyzed for Cohort 1, as pre-specified in protocol.

Laboratory tests abnormalities included: hematology (haemoglobin[Hb], haematocrit and erythrocytes<0.8*lower limit of normal[LLN]; erythrocyte mean corpuscular volume, erythrocyte mean corpuscular Hb and erythrocyte mean corpuscular Hb concentration <0.9*LLN and >1.1*upper limit of normal[ULN]; platelets <0.5*LLN and >1.75*ULN; leukocytes <0.6*LLN and >1.5*ULN; lymphocytes/leukocytes[%], neutrophils/leukocytes[%] <0.8*LLN and >1.2*ULN; basophils/leukocytes[%], eosinophils/leukocytes[%], monocytes/leukocytes[% ]>1.2*ULN); clinical chemistry(bilirubin>1.5*ULN; aspartate aminotransferase, alanine aminotransferase and alkaline phosphatase>3.0*ULN; protein and albumin<0.8*LLN and >1.2*ULN; urea nitrogen and creatinine >1.3*ULN; urate>1.2*ULN; sodium <0.95*LLN and >1.05*ULN; potassium, chloride and calcium <0.9*LLN and >1.1*ULN; fasting glucose <0.6*LLN and >1.5*ULN); and urinalysis (pH <4.5 and >8; glucose, ketones, protein, Hb, urobilinogen, bilirubin, nitrite and leukocyte esterase >=1).

Outcome measures

Measure	Cohort 1: Crisaborole Ointment 2% and Vehicle n=10 Participants Crisaborole ointment 2% and matching vehicle was applied topically to 2 randomly assigned, adjacent sites on the skin area field at infrascapular area of the back respectively within each healthy participant under occlusive patch condition on Day 1. Ointment and vehicle were remained under occlusion for 48 hours. Target sites were identified at Baseline (Day 1) by investigator.	Cohort 2: Vehicle n=2 Participants Vehicle matched to Crisaborole ointment 2% was applied topically to the treatable %BSA (defined as percent of a participant's total BSA that AD-involved and is not on the scalp or in designated venous access areas) of participants with AD twice daily from Days 2 to 7 and once only on Days 1 and 8. Treatable %BSA was calculated at Baseline (Day 1) by investigator.
Cohort 2: Number of Participants With Laboratory Tests Abnormalities	7 Participants	1 Participants

PRIMARY outcome

Timeframe: Baseline up to end of treatment (Day 8)

Population: Safety analysis population included all participants who received at least one dose of study medication. Data for this outcome measure was not planned to be collected and analyzed for Cohort 1, as pre-specified in protocol.

Criteria for clinically significant ECG abnormalities included: QT interval >=500 milliseconds (msec); QT interval corrected using the Fridericia's formula (QTcF) >=450 msec to <480 msec, >=480 msec and >=500 msec; increase from baseline in QTcF interval >=30 msec to <60 msec and >=60 msec.

Outcome measures

Measure	Cohort 1: Crisaborole Ointment 2% and Vehicle n=10 Participants Crisaborole ointment 2% and matching vehicle was applied topically to 2 randomly assigned, adjacent sites on the skin area field at infrascapular area of the back respectively within each healthy participant under occlusive patch condition on Day 1. Ointment and vehicle were remained under occlusion for 48 hours. Target sites were identified at Baseline (Day 1) by investigator.	Cohort 2: Vehicle n=2 Participants Vehicle matched to Crisaborole ointment 2% was applied topically to the treatable %BSA (defined as percent of a participant's total BSA that AD-involved and is not on the scalp or in designated venous access areas) of participants with AD twice daily from Days 2 to 7 and once only on Days 1 and 8. Treatable %BSA was calculated at Baseline (Day 1) by investigator.
Cohort 2: Number of Participants With Clinically Significant Electrocardiogram (ECG) Abnormalities	0 Participants	0 Participants

SECONDARY outcome

Timeframe: Baseline up to Day 29

Population: Safety analysis population included all participants who received at least one dose of study medication.

An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent were events between first dose of study drug and up to 28 days after last dose of study drug (up to Day 29) that were absent before treatment or that worsened relative to pre-treatment state. AEs included both SAEs and non-serious AEs.

Outcome measures

Measure	Cohort 1: Crisaborole Ointment 2% and Vehicle n=20 Participants Crisaborole ointment 2% and matching vehicle was applied topically to 2 randomly assigned, adjacent sites on the skin area field at infrascapular area of the back respectively within each healthy participant under occlusive patch condition on Day 1. Ointment and vehicle were remained under occlusion for 48 hours. Target sites were identified at Baseline (Day 1) by investigator.	Cohort 2: Vehicle Vehicle matched to Crisaborole ointment 2% was applied topically to the treatable %BSA (defined as percent of a participant's total BSA that AD-involved and is not on the scalp or in designated venous access areas) of participants with AD twice daily from Days 2 to 7 and once only on Days 1 and 8. Treatable %BSA was calculated at Baseline (Day 1) by investigator.
Cohort 1: Number of Participants With Treatment-Emergent Adverse Events (AEs) And Serious Adverse Events (SAEs) AEs	0 Participants	—
Cohort 1: Number of Participants With Treatment-Emergent Adverse Events (AEs) And Serious Adverse Events (SAEs) SAEs	0 Participants	—

SECONDARY outcome

Timeframe: Pre-dose, 3, 12 and 24 hours post-dose on Day 1 and Day 8

Population: PK parameter analysis population was defined as all participants randomized and treated who had at least 1 of the PK parameters of primary interest. Data for this outcome measure was not planned to be collected and analyzed for Cohort 1, as pre-specified in protocol.

AN7602 and AN8323 were the main identified oxidative metabolites of Crisaborole.

Outcome measures

Measure	Cohort 1: Crisaborole Ointment 2% and Vehicle n=9 Participants Crisaborole ointment 2% and matching vehicle was applied topically to 2 randomly assigned, adjacent sites on the skin area field at infrascapular area of the back respectively within each healthy participant under occlusive patch condition on Day 1. Ointment and vehicle were remained under occlusion for 48 hours. Target sites were identified at Baseline (Day 1) by investigator.	Cohort 2: Vehicle Vehicle matched to Crisaborole ointment 2% was applied topically to the treatable %BSA (defined as percent of a participant's total BSA that AD-involved and is not on the scalp or in designated venous access areas) of participants with AD twice daily from Days 2 to 7 and once only on Days 1 and 8. Treatable %BSA was calculated at Baseline (Day 1) by investigator.
Cohort 2: Maximum Observed Plasma Concentration (Cmax) of Crisaborole and Its Identified Main Oxidative Metabolites AN8323: Day 8	8080 nanograms per milliliter (ng/mL) Geometric Coefficient of Variation 71	—
Cohort 2: Maximum Observed Plasma Concentration (Cmax) of Crisaborole and Its Identified Main Oxidative Metabolites Crisaborole: Day 1	163.7 nanograms per milliliter (ng/mL) Geometric Coefficient of Variation 71	—
Cohort 2: Maximum Observed Plasma Concentration (Cmax) of Crisaborole and Its Identified Main Oxidative Metabolites Crisaborole: Day 8	164.9 nanograms per milliliter (ng/mL) Geometric Coefficient of Variation 56	—
Cohort 2: Maximum Observed Plasma Concentration (Cmax) of Crisaborole and Its Identified Main Oxidative Metabolites AN7602: Day 1	94.97 nanograms per milliliter (ng/mL) Geometric Coefficient of Variation 75	—
Cohort 2: Maximum Observed Plasma Concentration (Cmax) of Crisaborole and Its Identified Main Oxidative Metabolites AN7602: Day 8	68.83 nanograms per milliliter (ng/mL) Geometric Coefficient of Variation 59	—
Cohort 2: Maximum Observed Plasma Concentration (Cmax) of Crisaborole and Its Identified Main Oxidative Metabolites AN8323: Day 1	3064 nanograms per milliliter (ng/mL) Geometric Coefficient of Variation 97	—

SECONDARY outcome

Timeframe: Pre-dose, 3, 12 and 24 hours post-dose on Day 1 and Day 8

Population: PK parameter analysis population was defined as all participants randomized and treated who had at least 1 of the PK parameters of primary interest. Data for this outcome measure was not planned to be collected and analyzed for Cohort 1, as pre-specified in protocol.

AN7602 and AN8323 were the main identified oxidative metabolites of Crisaborole.

Outcome measures

Measure	Cohort 1: Crisaborole Ointment 2% and Vehicle n=9 Participants Crisaborole ointment 2% and matching vehicle was applied topically to 2 randomly assigned, adjacent sites on the skin area field at infrascapular area of the back respectively within each healthy participant under occlusive patch condition on Day 1. Ointment and vehicle were remained under occlusion for 48 hours. Target sites were identified at Baseline (Day 1) by investigator.	Cohort 2: Vehicle Vehicle matched to Crisaborole ointment 2% was applied topically to the treatable %BSA (defined as percent of a participant's total BSA that AD-involved and is not on the scalp or in designated venous access areas) of participants with AD twice daily from Days 2 to 7 and once only on Days 1 and 8. Treatable %BSA was calculated at Baseline (Day 1) by investigator.
Cohort 2: Time to Reach Maximum Observed Plasma Concentration (Tmax) of Crisaborole and Its Metabolites Crisaborole: Day 1	3.000 hours Interval 3.0 to 3.0	—
Cohort 2: Time to Reach Maximum Observed Plasma Concentration (Tmax) of Crisaborole and Its Metabolites Crisaborole: Day 8	3.000 hours Interval 3.0 to 3.0	—
Cohort 2: Time to Reach Maximum Observed Plasma Concentration (Tmax) of Crisaborole and Its Metabolites AN7602: Day 1	3.000 hours Interval 3.0 to 3.0	—
Cohort 2: Time to Reach Maximum Observed Plasma Concentration (Tmax) of Crisaborole and Its Metabolites AN7602: Day 8	3.000 hours Interval 3.0 to 3.0	—
Cohort 2: Time to Reach Maximum Observed Plasma Concentration (Tmax) of Crisaborole and Its Metabolites AN8323: Day 1	3.000 hours Interval 3.0 to 12.0	—
Cohort 2: Time to Reach Maximum Observed Plasma Concentration (Tmax) of Crisaborole and Its Metabolites AN8323: Day 8	3.000 hours Interval 3.0 to 12.0	—

SECONDARY outcome

Timeframe: Pre-dose, 3, 12 and 24 hours post-dose on Day 1 and Day 8

Population: PK parameter analysis population was defined as all participants randomized and treated who had at least 1 of the PK parameters of primary interest. Data for this outcome measure was not planned to be collected and analyzed for Cohort 1, as pre-specified in protocol.

AN7602 and AN8323 were the main identified oxidative metabolites of Crisaborole.

Outcome measures

Measure	Cohort 1: Crisaborole Ointment 2% and Vehicle n=9 Participants Crisaborole ointment 2% and matching vehicle was applied topically to 2 randomly assigned, adjacent sites on the skin area field at infrascapular area of the back respectively within each healthy participant under occlusive patch condition on Day 1. Ointment and vehicle were remained under occlusion for 48 hours. Target sites were identified at Baseline (Day 1) by investigator.	Cohort 2: Vehicle Vehicle matched to Crisaborole ointment 2% was applied topically to the treatable %BSA (defined as percent of a participant's total BSA that AD-involved and is not on the scalp or in designated venous access areas) of participants with AD twice daily from Days 2 to 7 and once only on Days 1 and 8. Treatable %BSA was calculated at Baseline (Day 1) by investigator.
Cohort 2: Area Under the Plasma Concentration-Time Curve From Time Zero Until the Last Measurable Concentration (AUClast) of Crisaborole and Its Identified Main Oxidative Metabolites Crisaborole: Day 1	1171 hours*nanograms per milliliter(hr*ng/mL) Geometric Coefficient of Variation 60	—
Cohort 2: Area Under the Plasma Concentration-Time Curve From Time Zero Until the Last Measurable Concentration (AUClast) of Crisaborole and Its Identified Main Oxidative Metabolites Crisaborole: Day 8	1527 hours*nanograms per milliliter(hr*ng/mL) Geometric Coefficient of Variation 48	—
Cohort 2: Area Under the Plasma Concentration-Time Curve From Time Zero Until the Last Measurable Concentration (AUClast) of Crisaborole and Its Identified Main Oxidative Metabolites AN7602: Day 1	601.9 hours*nanograms per milliliter(hr*ng/mL) Geometric Coefficient of Variation 60	—
Cohort 2: Area Under the Plasma Concentration-Time Curve From Time Zero Until the Last Measurable Concentration (AUClast) of Crisaborole and Its Identified Main Oxidative Metabolites AN7602: Day 8	565.5 hours*nanograms per milliliter(hr*ng/mL) Geometric Coefficient of Variation 44	—
Cohort 2: Area Under the Plasma Concentration-Time Curve From Time Zero Until the Last Measurable Concentration (AUClast) of Crisaborole and Its Identified Main Oxidative Metabolites AN8323: Day 1	57560 hours*nanograms per milliliter(hr*ng/mL) Geometric Coefficient of Variation 84	—
Cohort 2: Area Under the Plasma Concentration-Time Curve From Time Zero Until the Last Measurable Concentration (AUClast) of Crisaborole and Its Identified Main Oxidative Metabolites AN8323: Day 8	169100 hours*nanograms per milliliter(hr*ng/mL) Geometric Coefficient of Variation 68	—

SECONDARY outcome

Timeframe: Pre-dose, 3, 12 and 24 hours post-dose on Day 1 and Day 8

Population: PK parameter analysis population was defined as all participants randomized and treated who had at least 1 of the PK parameters of primary interest. Data for this outcome measure was not planned to be collected and analyzed for Cohort 1, as pre-specified in protocol.

AN7602 and AN8323 were the main identified oxidative metabolites of Crisaborole.

Outcome measures

Measure	Cohort 1: Crisaborole Ointment 2% and Vehicle n=9 Participants Crisaborole ointment 2% and matching vehicle was applied topically to 2 randomly assigned, adjacent sites on the skin area field at infrascapular area of the back respectively within each healthy participant under occlusive patch condition on Day 1. Ointment and vehicle were remained under occlusion for 48 hours. Target sites were identified at Baseline (Day 1) by investigator.	Cohort 2: Vehicle Vehicle matched to Crisaborole ointment 2% was applied topically to the treatable %BSA (defined as percent of a participant's total BSA that AD-involved and is not on the scalp or in designated venous access areas) of participants with AD twice daily from Days 2 to 7 and once only on Days 1 and 8. Treatable %BSA was calculated at Baseline (Day 1) by investigator.
Cohort 2: Area Under the Plasma Concentration-Time Curve From Time Zero to the 24 Hours Post-Dose (AUC24) of Crisaborole and Its Identified Main Oxidative Metabolites (AN7602 and AN8323) Crisaborole: Day 1	1171 hr*ng/mL Geometric Coefficient of Variation 60	—
Cohort 2: Area Under the Plasma Concentration-Time Curve From Time Zero to the 24 Hours Post-Dose (AUC24) of Crisaborole and Its Identified Main Oxidative Metabolites (AN7602 and AN8323) Crisaborole: Day 8	1527 hr*ng/mL Geometric Coefficient of Variation 48	—
Cohort 2: Area Under the Plasma Concentration-Time Curve From Time Zero to the 24 Hours Post-Dose (AUC24) of Crisaborole and Its Identified Main Oxidative Metabolites (AN7602 and AN8323) AN7602: Day 1	601.9 hr*ng/mL Geometric Coefficient of Variation 60	—
Cohort 2: Area Under the Plasma Concentration-Time Curve From Time Zero to the 24 Hours Post-Dose (AUC24) of Crisaborole and Its Identified Main Oxidative Metabolites (AN7602 and AN8323) AN7602: Day 8	565.5 hr*ng/mL Geometric Coefficient of Variation 44	—
Cohort 2: Area Under the Plasma Concentration-Time Curve From Time Zero to the 24 Hours Post-Dose (AUC24) of Crisaborole and Its Identified Main Oxidative Metabolites (AN7602 and AN8323) AN8323: Day 1	57560 hr*ng/mL Geometric Coefficient of Variation 84	—
Cohort 2: Area Under the Plasma Concentration-Time Curve From Time Zero to the 24 Hours Post-Dose (AUC24) of Crisaborole and Its Identified Main Oxidative Metabolites (AN7602 and AN8323) AN8323: Day 8	169100 hr*ng/mL Geometric Coefficient of Variation 68	—

SECONDARY outcome

Timeframe: Pre-dose, 3, 12 and 24 hours post-dose on Day 1 and Day 8

Population: PK parameter analysis population was defined as all participants randomized and treated who had at least 1 of the PK parameters of primary interest. Data for this outcome measure was not planned to be collected and analyzed for Cohort 1, as pre-specified in protocol.

AN7602 and AN8323 were the main identified oxidative metabolites of Crisaborole. AUC tau was defined as area under the plasma concentration-time curve from time 0 to time tau, the dosing interval, where tau =12 hours.

Outcome measures

Measure	Cohort 1: Crisaborole Ointment 2% and Vehicle n=9 Participants Crisaborole ointment 2% and matching vehicle was applied topically to 2 randomly assigned, adjacent sites on the skin area field at infrascapular area of the back respectively within each healthy participant under occlusive patch condition on Day 1. Ointment and vehicle were remained under occlusion for 48 hours. Target sites were identified at Baseline (Day 1) by investigator.	Cohort 2: Vehicle Vehicle matched to Crisaborole ointment 2% was applied topically to the treatable %BSA (defined as percent of a participant's total BSA that AD-involved and is not on the scalp or in designated venous access areas) of participants with AD twice daily from Days 2 to 7 and once only on Days 1 and 8. Treatable %BSA was calculated at Baseline (Day 1) by investigator.
Cohort 2: Area Under the Plasma Concentration-Time Curve From Time Zero to Tau (12 Hours Dosing Interval) (AUCtau) of Crisaborole and Its Identified Main Oxidative Metabolites Crisaborole: Day 1	928.9 hr*ng/mL Geometric Coefficient of Variation 65	—
Cohort 2: Area Under the Plasma Concentration-Time Curve From Time Zero to Tau (12 Hours Dosing Interval) (AUCtau) of Crisaborole and Its Identified Main Oxidative Metabolites Crisaborole: Day 8	1123 hr*ng/mL Geometric Coefficient of Variation 51	—
Cohort 2: Area Under the Plasma Concentration-Time Curve From Time Zero to Tau (12 Hours Dosing Interval) (AUCtau) of Crisaborole and Its Identified Main Oxidative Metabolites AN7602: Day 1	500.4 hr*ng/mL Geometric Coefficient of Variation 66	—
Cohort 2: Area Under the Plasma Concentration-Time Curve From Time Zero to Tau (12 Hours Dosing Interval) (AUCtau) of Crisaborole and Its Identified Main Oxidative Metabolites AN7602: Day 8	434.9 hr*ng/mL Geometric Coefficient of Variation 50	—
Cohort 2: Area Under the Plasma Concentration-Time Curve From Time Zero to Tau (12 Hours Dosing Interval) (AUCtau) of Crisaborole and Its Identified Main Oxidative Metabolites AN8323: Day 1	29360 hr*ng/mL Geometric Coefficient of Variation 92	—
Cohort 2: Area Under the Plasma Concentration-Time Curve From Time Zero to Tau (12 Hours Dosing Interval) (AUCtau) of Crisaborole and Its Identified Main Oxidative Metabolites AN8323: Day 8	90360 hr*ng/mL Geometric Coefficient of Variation 68	—

SECONDARY outcome

Timeframe: Pre-dose, 3, 12 and 24 hours post-dose on Day 1 and 8

Population: PK parameter analysis population was defined as all participants randomized and treated who had at least 1 of the PK parameters of primary interest. Data for this outcome measure was not planned to be collected and analyzed for Cohort 1, as pre-specified in protocol.

AN7602 and AN8323 were the main identified oxidative metabolites of Crisaborole. Accumulation ratio for Cmax (Rac, Cmax) was calculated as Cmax on Day 8 divided by Cmax on Day 1. Cmax was the maximum plasma concentration of Crisaborole and its identified main oxidative metabolites.

Outcome measures

Measure	Cohort 1: Crisaborole Ointment 2% and Vehicle n=9 Participants Crisaborole ointment 2% and matching vehicle was applied topically to 2 randomly assigned, adjacent sites on the skin area field at infrascapular area of the back respectively within each healthy participant under occlusive patch condition on Day 1. Ointment and vehicle were remained under occlusion for 48 hours. Target sites were identified at Baseline (Day 1) by investigator.	Cohort 2: Vehicle Vehicle matched to Crisaborole ointment 2% was applied topically to the treatable %BSA (defined as percent of a participant's total BSA that AD-involved and is not on the scalp or in designated venous access areas) of participants with AD twice daily from Days 2 to 7 and once only on Days 1 and 8. Treatable %BSA was calculated at Baseline (Day 1) by investigator.
Cohort 2: Accumulation Ratio for Cmax (Rac [Cmax]) of Crisaborole and Its Identified Main Oxidative Metabolites Crisaborole	1.007 ratio Geometric Coefficient of Variation 32	—
Cohort 2: Accumulation Ratio for Cmax (Rac [Cmax]) of Crisaborole and Its Identified Main Oxidative Metabolites AN7602	0.7247 ratio Geometric Coefficient of Variation 24	—
Cohort 2: Accumulation Ratio for Cmax (Rac [Cmax]) of Crisaborole and Its Identified Main Oxidative Metabolites AN8323	2.638 ratio Geometric Coefficient of Variation 52	—

SECONDARY outcome

Timeframe: Pre-dose, 3, 12 and 24 hours post-dose on Day 1 and 8

Population: PK parameter analysis population was defined as all participants randomized and treated who had at least 1 of the PK parameters of primary interest. Data for this outcome measure was not planned to be collected and analyzed for Cohort 1, as pre-specified in protocol.

AN7602 and AN8323 were the main identified oxidative metabolites of Crisaborole. Accumulation ratio for AUCtau (Rac) was calculated as area under the curve from time zero to end of dosing interval (AUCtau) on Day 8 divided by AUCtau on Day 1. Dosing interval = 12 hours.

Outcome measures

Measure	Cohort 1: Crisaborole Ointment 2% and Vehicle n=9 Participants Crisaborole ointment 2% and matching vehicle was applied topically to 2 randomly assigned, adjacent sites on the skin area field at infrascapular area of the back respectively within each healthy participant under occlusive patch condition on Day 1. Ointment and vehicle were remained under occlusion for 48 hours. Target sites were identified at Baseline (Day 1) by investigator.	Cohort 2: Vehicle Vehicle matched to Crisaborole ointment 2% was applied topically to the treatable %BSA (defined as percent of a participant's total BSA that AD-involved and is not on the scalp or in designated venous access areas) of participants with AD twice daily from Days 2 to 7 and once only on Days 1 and 8. Treatable %BSA was calculated at Baseline (Day 1) by investigator.
Cohort 2: Accumulation Ratio for AUCtau (Rac [AUCtau]) of Crisaborole and Its Identified Main Oxidative Metabolites Crisaborole	1.209 ratio Geometric Coefficient of Variation 25	—
Cohort 2: Accumulation Ratio for AUCtau (Rac [AUCtau]) of Crisaborole and Its Identified Main Oxidative Metabolites AN7602	0.8688 ratio Geometric Coefficient of Variation 19	—
Cohort 2: Accumulation Ratio for AUCtau (Rac [AUCtau]) of Crisaborole and Its Identified Main Oxidative Metabolites AN8323	3.080 ratio Geometric Coefficient of Variation 48	—

Adverse Events

Cohort 1: Crisaborole Ointment 2% and Vehicle

Serious events: 0 serious events

Other events: 0 other events

Deaths: 0 deaths

Cohort 2: Crisaborole Ointment 2%

Serious events: 0 serious events

Other events: 9 other events

Deaths: 0 deaths

Cohort 2: Vehicle

Serious events: 0 serious events

Other events: 2 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Measure	Cohort 1: Crisaborole Ointment 2% and Vehicle n=20 participants at risk Crisaborole ointment 2% and matching vehicle was applied topically to 2 randomly assigned, adjacent sites on the skin area field at infrascapular area of the back respectively within each healthy participant under occlusive patch condition on Day 1. Ointment and vehicle were remained under occlusion for 48 hours. Target sites were identified at Baseline (Day 1) by investigator.	Cohort 2: Crisaborole Ointment 2% n=10 participants at risk Crisaborole ointment 2% was applied topically to the treatable percent body surface area (%BSA: defined as percent of a participant's total BSA that is AD-involved and is not on the scalp or in designated venous access areas) of participants with AD twice daily from Days 2 to 7 and once only on Days 1 and 8. Treatable %BSA was calculated at Baseline (Day 1) by investigator.	Cohort 2: Vehicle n=2 participants at risk Vehicle matched to Crisaborole ointment 2% was applied topically to the treatable %BSA (defined as percent of a participant's total BSA that AD-involved and is not on the scalp or in designated venous access areas) of participants with AD twice daily from Days 2 to 7 and once only on Days 1 and 8. Treatable %BSA was calculated at Baseline (Day 1) by investigator.
Eye disorders Eyelid oedema	0.00% 0/20 • Baseline up to Day 29 for Cohort 1 and Day 36 for Cohort 2	10.0% 1/10 • Baseline up to Day 29 for Cohort 1 and Day 36 for Cohort 2	0.00% 0/2 • Baseline up to Day 29 for Cohort 1 and Day 36 for Cohort 2
General disorders Application site coldness	0.00% 0/20 • Baseline up to Day 29 for Cohort 1 and Day 36 for Cohort 2	10.0% 1/10 • Baseline up to Day 29 for Cohort 1 and Day 36 for Cohort 2	50.0% 1/2 • Baseline up to Day 29 for Cohort 1 and Day 36 for Cohort 2
General disorders Application site irritation	0.00% 0/20 • Baseline up to Day 29 for Cohort 1 and Day 36 for Cohort 2	70.0% 7/10 • Baseline up to Day 29 for Cohort 1 and Day 36 for Cohort 2	50.0% 1/2 • Baseline up to Day 29 for Cohort 1 and Day 36 for Cohort 2
General disorders Application site pain	0.00% 0/20 • Baseline up to Day 29 for Cohort 1 and Day 36 for Cohort 2	40.0% 4/10 • Baseline up to Day 29 for Cohort 1 and Day 36 for Cohort 2	50.0% 1/2 • Baseline up to Day 29 for Cohort 1 and Day 36 for Cohort 2
General disorders Application site pruritus	0.00% 0/20 • Baseline up to Day 29 for Cohort 1 and Day 36 for Cohort 2	0.00% 0/10 • Baseline up to Day 29 for Cohort 1 and Day 36 for Cohort 2	50.0% 1/2 • Baseline up to Day 29 for Cohort 1 and Day 36 for Cohort 2
Infections and infestations Nasopharyngitis	0.00% 0/20 • Baseline up to Day 29 for Cohort 1 and Day 36 for Cohort 2	0.00% 0/10 • Baseline up to Day 29 for Cohort 1 and Day 36 for Cohort 2	50.0% 1/2 • Baseline up to Day 29 for Cohort 1 and Day 36 for Cohort 2
Skin and subcutaneous tissue disorders Dermatitis atopic	0.00% 0/20 • Baseline up to Day 29 for Cohort 1 and Day 36 for Cohort 2	0.00% 0/10 • Baseline up to Day 29 for Cohort 1 and Day 36 for Cohort 2	50.0% 1/2 • Baseline up to Day 29 for Cohort 1 and Day 36 for Cohort 2

Additional Information

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Results disclosure agreements

• Principal investigator is a sponsor employee Pfizer has the right to review disclosures, requesting a delay of less than 60 days. Investigator will postpone single center publications until after disclosure of pooled data (all sites), less than 12 months from study completion/termination at all participating sites. Investigator may not disclose previously undisclosed confidential information other than study results.
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Restriction type: OTHER