Crisaborole Ointment 2% Skin Biomarker Biopsy Study in Atopic Dermatitis

Study Overview
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Brief Summary
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This study is being conducted to characterize the mechanism of action of crisaborole ointment 2%, by evaluation of efficacy and changes in key skin biomarkers in atopic dermatitis (AD) lesions treated with crisaborole ointment 2% over vehicle, in subjects with mild to moderate AD. Two identified AD skin lesions for each subject will be treated for the first 15 days, one with crisaborole ointment 2% and one with vehicle, in a blinded manner, and biopsies for biomarker analysis will be performed on the lesions. Following completion of the blinded treatment period, subjects will start the 28 day open label period during which all AD affected skin lesions will be treated with crisaborole ointment 2% twice daily.

Official Title
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A PHASE 2A, RANDOMIZED, DOUBLE-BLIND, VEHICLE-CONTROLLED STUDY, TO CHARACTERIZE THE MECHANISM OF ACTION OF CRISABOROLE OINTMENT 2%, BY EVALUATION OF EFFICACY AND CHANGES IN SKIN BIOMARKERS, IN ADULT SUBJECTS WITH MILD TO MODERATE ATOPIC DERMATITIS, WITH A 4 WEEK OPEN-LABEL EXTENSION

Conditions
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Dermatitis, Atopic

Intervention / Treatment
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* Drug: Crisaborole ointment 2% BID
* Drug: Placebo ointment (vehicle)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Confirmed diagnosis of active atopic dermatitis (AD) with at least 6 month history prior to Screening and that has been clinically stable for 1 month. Investigator's Static Global Assessment (ISGA) of 2 (mild) or 3 (moderate) at Baseline. Body surface area (BSA) covered with AD of at least 0.5% and no more than 10% at Baseline, calculation excluding face, scalp, axilla, genitals, groin area, palms, back of the hands, and soles. Two lesions of AD at least 3 cm x 3 cm in size and at least 5 cm apart, with identical Lesion ISGA score of greater than/equal to 3. Exclusion Criteria: Clinically infected AD or requires high potency topical corticosteroids or systemic (oral/injectable) corticosteroids to manage AD. History of angioedema or anaphylaxis to topical products or known sensitivity to components of crisaborole ointment 2%. History of cancer (except squamous or basal cell carcinoma or carcinoma in situ of the skin). Previous treatment with any topical or systemic PDE4 inhibitor unless stopped for the reason of lack of efficacy.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Crisaborole ointment<br> | Drug: Crisaborole ointment 2% BID<br>* Crisaborole ointment 2% BID for 15 days (double blind); additional 28 days (open label)<br>|
| Placebo Comparator: Placebo ointment (vehicle)<br> | Drug: Placebo ointment (vehicle)<br>* Placebo ointment (vehicle) BID for 15 days (double blind)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Lesion Total Sign Score (TSS) for Target Lesions Treated With Crisaborole Ointment 2% or Vehicle at Day 15 | The lesion TSS is an assessment of target lesion severity based on the severity of the following 4 clinical signs: (1) erythema, (2) induration/papulation, (3) excoriation, and (4) lichenification, each of which was rated on a scale of 0 to 3 (0=none, 1=mild, 2=moderate, 3=severe). These 4 ratings were then added to create the TSS, which ranges from 0 (none) to 12 (most severe), with higher score representing greater severity. | Baseline (Day 1), Day 15 | 
| Change From Baseline in Key Skin Biomarker Chemokine Ligand (CCL)17 Expression in Target Lesions Treated With Crisaborole Ointment 2% or Vehicle at Day 15 | CCL17 is one of the key skin biomarkers of atopic dermatitis. Expression levels tested by Taqman low density array (TLDA) reverse-transcriptase (RT) polymerase chain reaction (PCR) were normalized to the housekeeping gene ribosomal protein lateral stalk subunit P0 (RPLP0) and log2-transformed prior to analysis. | Baseline (Day 1), Day 15 | 
| Change From Baseline in Key Skin Biomarker CCL18 Expression in Target Lesions Treated With Crisaborole Ointment 2% or Vehicle at Day 15 | CCL18 is one of the key skin biomarkers of atopic dermatitis. Expression levels tested by TLDA RT PCR were normalized to the housekeeping gene RPLP0 and log2-transformed prior to analysis. | Baseline (Day 1), Day 15 | 
| Change From Baseline in Key Skin Biomarker CCL22 Expression in Target Lesions Treated With Crisaborole Ointment 2% or Vehicle at Day 15 | CCL22 is one of the key skin biomarkers of atopic dermatitis. Expression levels tested by TLDA RT PCR were normalized to the housekeeping gene RPLP0 and log2-transformed prior to analysis. | Baseline (Day 1), Day 15 | 
| Change From Baseline in Key Skin Biomarker Interleukin (IL)-13 Expression in Target Lesions Treated With Crisaborole Ointment 2% or Vehicle at Day 15 | IL-13 is one of the key skin biomarkers of atopic dermatitis. Expression levels tested by TLDA RT PCR were normalized to the housekeeping gene RPLP0 and log2-transformed prior to analysis. | Baseline (Day 1), Day 15 | 
| Change From Baseline in Key Skin Biomarker Keratin 16 (KRT16) Expression in Target Lesions Treated With Crisaborole Ointment 2% or Vehicle at Day 15 | KRT16 is one of the key skin biomarkers of atopic dermatitis. Expression levels tested by TLDA RT PCR were normalized to the housekeeping gene RPLP0 and log2-transformed prior to analysis. | Baseline (Day 1), Day 15 | 
| Change From Baseline in Key Skin Biomarker Elafin/Peptidase Inhibitor 3 (PI3) Expression in Target Lesions Treated With Crisaborole Ointment 2% or Vehicle at Day 15 | Elafin/PI3 is one of the key skin biomarkers of atopic dermatitis. Expression levels tested by TLDA RT PCR were normalized to the housekeeping gene RPLP0 and log2-transformed prior to analysis. | Baseline (Day 1), Day 15 | 
| Change From Baseline in Key Skin Biomarker S100 Calcium Binding Protein A12 (S100A12) Expression in Target Lesions Treated With Crisaborole Ointment 2% or Vehicle at Day 15 | S100A12 is one of the key skin biomarkers of atopic dermatitis. Expression levels tested by TLDA RT PCR were normalized to the housekeeping gene RPLP0 and log2-transformed prior to analysis. | Baseline (Day 1), Day 15 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Expression of Other Skin Biomarker (Epidermal Thickness) in Target Lesions Treated With Crisaborole Ointment 2% or Vehicle at Day 15 | Epidermal thickness was one of the other skin biomarkers of atopic dermatitis and was studied using immunohistochemistry (IHC). Expression data were log2-transformed. | Baseline (Day 1), Day 15 | 
| Change From Baseline in Expression of Other Skin Biomarkers (CD11c, CD3, FceR1, Ki67, Langerin) in Target Lesions Treated With Crisaborole Ointment 2% or Vehicle at Day 15 | CD11c+ dendritic cells (DCs), CD3+ T cells, FcEpsilon + DCs, Ki 67+ cells, and langerin+ cells (for langerhans cells) were studied using IHC. These parameters were referred to as CD11c, CD3, FceR1, Ki67, langerin, respectively, in the outcome measure title above and data table below. Expression data were log2-transformed. | Baseline (Day 1), Day 15 | 
| Change From Baseline in Expression of Other Skin Biomarkers (CCL13, Etc) in Target Lesions Treated With Crisaborole Ointment 2% or Vehicle at Day 15 | TLDA RT PCR was used to analyze the following other skin biomarkers: CCL13, CCL20, CCL26, CRLF2, CXCL1, CXCL2, CXCL9, CXCL10, DEFB4A, filaggrin (FLG), FOXP3, IFNG, IL-1B, IL-2, IL-2RA, IL-5, IL-6, IL-8, IL-9, IL-10, IL-12A, IL-15, IL-15RA, IL-17A, IL-17F, IL-19, IL-22, IL-23A, IL-31, IL-32, LOR, MMP-12, PDE4A, PDE4B, PDE4D, PPL, RNA18SP5, S100A7, S100A8, and S100A9. Expression levels were normalized to the housekeeping gene RPLP0 and log2-transformed prior to analysis. | Baseline (Day 1), Day 15 | 
| Number of Participants With Categorical Filaggrin (FLG) Expression at Day 15 | FLG expression was studied using IHC and categorized as no change, partial normalization, full normalization, or worsening by a blinded expert pathologist based on visual scoring. | Day 15 | 
| Number of Participants With Categorical Histological Response at Day 15 | Histological response was studied using IHC and categorized as non-responder or responder by a blinded expert pathologist based on a global assessment of all thickness, KRT16 and FLG stains. | Day 15 | 
| Number of Participants With Categorical KRT16 Expression at Day 15 | KRT16 expression was studied using IHC and categorized as no change, slight improvement, good improvement, excellent improvement, or worsening by a blinded expert pathologist based on visual scoring. | Day 15 | 
| Change From Baseline in Lesion Severity as Measured by TSS at Day 8 | The lesion TSS is an assessment of target lesion severity based on the severity of the following 4 clinical signs: (1) erythema, (2) induration/papulation, (3) excoriation, and (4) lichenification, each of which was rated on a scale of 0 to 3 (0=none, 1=mild, 2=moderate, 3=severe). These 4 ratings were then added to create the TSS, which ranges from 0 (none) to 12 (most severe), with higher score representing greater severity. | Baseline (Day 1), Day 8 | 
| Change From Baseline in Lesion Severity as Measured by Investigator Static Global Assessment (ISGA) at Day 8 and Day 15 | The lesion ISGA is an assessment of target lesion severity of atopic dermatitis. The lesion ISGA score ranges from 0 to 4 (0=clear, 1=almost clear, 2=mild, 3=moderate, 4=severe), with higher score representing greater severity. | Baseline (Day 1), Days 8 and 15 | 
| Change From Baseline in Lesion Severity as Measured by Pruritus Numerical Rating Scale (NRS) at Each Visit up to Day 15 | The intensity of pruritus was assessed by an NRS, which was a numeric rating scale ranging from 0 (no itching) to 10 (worst imaginable itching), with higher score indicating greater severity. | Baseline (Day 1), Days 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, and 15 | 
| Number of Participants With Treatment Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) by Treatment Groups | 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; life-threatening (immediate risk of death); initial or prolonged inpatient hospitalization; persistent or significant disability/incapacity; congenital anomaly/birth defect. AEs included both SAEs and non-serious AEs. Treatment-emergent AEs were those with initial onset or increasing in severity on or after the first dose of study treatment. Each participant received both crisaborole (for one target lesion) and vehicle (for the other target lesion) on the same days during double-blind period, and only crisaborole during open-label period; therefore AEs were reported for each treatment group for participants to capture all AEs, instead of each treatment for treated area as it only captures AEs occurred at treated areas (see next Outcome Measure). | From first dose of study treatment up to Day 71 | 
| Number of Participants With Treatment Emergent Adverse Events (AEs) by Medical Dictionary for Regulatory Activities (MedDRA) Preferred Term, Which Occurred in the Treatment Area During the Double-Blind Period | An AE was any untoward medical occurrence in a participant who received study treatment without regard to possibility of causal relationship. Treatment-emergent AEs were those with initial onset or increasing in severity on or after the first dose of study treatment. During double-blind period, there were a total of 2 treatment areas (for target lesions) for each participant. For this outcome measure, treatment-emergent AEs occurred at each treated area during double-blind period were summarized. MedDRA version 21.0 coding dictionary was used. | From first dose of study treatment (on Day 1) to Day 15 skin biopsy collection | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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eczema, atopic dermatitis, atopic eczema, topical treatment, skin diseases, phosphodiesterase-4 inhibitor, PDE-4 inhibitor, crisaborole