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

Study Overview
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Brief Summary
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This is a Phase 1 parallel-cohort study of crisaborole ointment 2% to evaluate the skin irritation potential in adult Japanese healthy subjects in Cohort 1, and to evaluate the safety, tolerability and PK in adult Japanese subjects with mild to moderate AD in Cohort 2.

Official Title
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A Phase 1, Single-center, Randomized, Vehicle-controlled, Parallel-cohort Study Of Crisaborole Ointment 2% To Evaluate The Skin Irritation Potential In Adult Japanese Healthy Subjects, And To Evaluate The Safety, Tolerability And Pharmacokinetics In Adult Japanese Subjects With Mild To Moderate Atopic Dermatitis

Conditions
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Healthy, Atopic Dermatitis

Intervention / Treatment
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* Drug: Crisaborole ointment 2%
* Drug: Vehicle


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Cohort 1 Healthy male Japanese subjects who, at the time of screening, are between the ages of 20 and 55 years, inclusive. Healthy skin on which reddening can be easily recognized in the area of the test fields. Cohort 2 Male or female Japanese subjects aged 20 years to 55 years (inclusive) at the time of screening, and in generally good health except for AD. Diagnosis of AD based on the criteria of Hanifin and Rajka (1980). Has at least 25% Treatable %BSA on Day 1 (excluding the scalp and designated venous access areas). Has an Investigator's static global assessment (ISGA) score of Mild (2) or Moderate (3) on Day 1. Exclusion Criteria: Cohort 1 Subjects who have any visible skin disease at the application site which, in the opinion of the investigative personnel, will interfere with the evaluation of the test site reaction. Subjects who have psoriasis and/or active AD/eczema. Subjects who have a history of AD. Subjects who have damaged skin in or around the test sites, including sunburn, excessively deep tans, uneven skin tones, tattoos, scars, excessive hair, numerous freckles, or other disfigurations of the test site. Known sensitivity to any of the components of the investigational products. History of the rash to the adhesive plaster, contact dermatitis to metal, or cosmetic and household articles. Cohort 2 Has any clinically significant medical disorder, condition, disease (including active or potentially recurrent dermatological conditions other than AD), significant physical examination or laboratory findings that may interfere with study objectives, in the Investigator's opinion. Has unstable AD or a consistent requirement for strong to strongest potency topical corticosteroids to manage AD signs and symptoms. Has a significant active systemic or localized infection, including known actively infected AD. Has a history or evidence of clinically significant or severe allergies (eg, seasonal, pet dander, environmental, food) requiring acute or chronic treatment. Has recent or anticipated concomitant use of topical or systemic therapies that might alter the course of AD. Has a history of recent (within 4 weeks of Day 1) sunbathing, tanning bed use, or ultraviolet (UV) light B therapy (UVB) or psoralen plus UVA [PUVA]). Has a known sensitivity to any of the components of crisaborole ointment 2%. Pregnant female subjects; breastfeeding female subjects; female subjects of childbearing potential who are unwilling or unable to use a highly effective method of contraception as outlined in this protocol for the duration of the study and for at least 28 days after the last dose of investigational product.

Ages Eligible for Study
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Minimum Age: 20 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Crisaborole ointment 2%<br> | Drug: Crisaborole ointment 2%<br>* Crisaborole ointment 2%<br>|
| Placebo Comparator: Vehicle<br> | Drug: Vehicle<br>* Vehicle<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cohort 1: Skin Irritation Index | 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. | Day 3 to 4 | 
| Cohort 2: Number of Participants With Treatment-Emergent Adverse Events (AEs) And Serious Adverse Events (SAEs) | 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. | Baseline up to Day 36 | 
| Cohort 2: Number of Participants With Clinically Significant Vital Signs Abnormalities | Vital signs included pulse rate and blood pressure. Clinical significance of vital signs was determined at the investigator's discretion. | Baseline up to end of treatment (Day 8) | 
| Cohort 2: Number of Participants With Laboratory Tests Abnormalities | 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). | Baseline up to end of treatment (Day 8) | 
| Cohort 2: Number of Participants With Clinically Significant Electrocardiogram (ECG) Abnormalities | 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. | Baseline up to end of treatment (Day 8) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cohort 1: Number of Participants With Treatment-Emergent Adverse Events (AEs) And Serious Adverse Events (SAEs) | 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. | Baseline up to Day 29 | 
| Cohort 2: Maximum Observed Plasma Concentration (Cmax) of Crisaborole and Its Identified Main Oxidative Metabolites | AN7602 and AN8323 were the main identified oxidative metabolites of Crisaborole. | Pre-dose, 3, 12 and 24 hours post-dose on Day 1 and Day 8 | 
| Cohort 2: Time to Reach Maximum Observed Plasma Concentration (Tmax) of Crisaborole and Its Metabolites | AN7602 and AN8323 were the main identified oxidative metabolites of Crisaborole. | Pre-dose, 3, 12 and 24 hours post-dose on Day 1 and Day 8 | 
| 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 and AN8323 were the main identified oxidative metabolites of Crisaborole. | Pre-dose, 3, 12 and 24 hours post-dose on Day 1 and Day 8 | 
| 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 and AN8323 were the main identified oxidative metabolites of Crisaborole. | Pre-dose, 3, 12 and 24 hours post-dose on Day 1 and Day 8 | 
| 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 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. | Pre-dose, 3, 12 and 24 hours post-dose on Day 1 and Day 8 | 
| Cohort 2: Accumulation Ratio for Cmax (Rac [Cmax]) of Crisaborole and Its Identified Main Oxidative Metabolites | 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. | Pre-dose, 3, 12 and 24 hours post-dose on Day 1 and 8 | 
| Cohort 2: Accumulation Ratio for AUCtau (Rac [AUCtau]) of Crisaborole and Its Identified Main Oxidative Metabolites | 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. | Pre-dose, 3, 12 and 24 hours post-dose on Day 1 and 8 |