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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
BASIC_SCIENCE
Masking
QUADRUPLE
Enrollment
40
Crisaborole ointment 2% BID for 15 days (double blind); additional 28 days (open label)
Placebo ointment (vehicle) BID for 15 days (double blind)
Innovaderm Research Incorporated
Montreal, Quebec, Canada
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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: Baseline (Day 1), Day 15
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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
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Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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).
Time frame: 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.
Time frame: From first dose of study treatment (on Day 1) to Day 15 skin biopsy collection