Atopic Eczema/Dermatitis (Non-Specific)
Conditions
Brief summary
The study aims to investigate two new non-invasive technologies for assessing skin properties to identify and validate a range of safety biomarkers that may be considered useful as primary outcome measures for evaluating the safety of topical treatments in atopic dermatitis. The method of assessing these biomarker technologies will be to determine whether twice daily treatment with crisaborole (2%) ointment, compared to betamethasone valerate (0.1%) cream, for up to 4 weeks, may cause skin structure or function changes, like skin atrophy, in patients with atopic dermatitis (AD).
Detailed description
The first-line drug treatment for mild-moderate AD are currently topical corticosteroids (TCS) with recognized efficacy. However, their prolonged or inappropriate use, can lead to local adverse effects. Side-effects of topical corticosteroids comprise a variety of skin changes in the sense of skin atrophy thinning of the skin and in some cases development of telangiectasia, spontaneous scars, folliculitis, striae distensae (stretch marks), contact dermatitis, acne or rosacea depending on potency, galenic formulation, patient age and body area to which the medication will be applied, exposure time. Assessing the safety (local adverse effects) of current or new treatments and new treatment approaches using existing treatments through noninvasively monitor on possible early skin (subclinical) changes associated with the local clinical adverse effects of treatment may be an effective step for an enhanced AD treatment management. Primary Aim: To further develop and validate two new non-invasive technologies for the assessment of early sub-clinical skin changes associated with adverse effects and to derive an optimum panel of safety biomarkers for use in future clinical trials of topical anti-inflammatory treatments. The safety of two topical anti-inflammatory treatments for AD will be compared in this clinical trial, with a focus on early sub-clinical signs: crisaborole 2% ointment and betamethasone valerate 0,1% cream. Step 1 involves the collection of data on the early sub-clinical skin changes using the non-invasive technologies: OCT and FTIR spectroscopy. The data from this study will then be used to identify and refine biophysical biomarkers of skin atrophy and skin barrier disruption in steps 2 and 3. Secondary Aim: To determine the relative local skin effects of crisaborole (2%) ointment compared to a potent and moderately potent TCS in participants with mild to moderate AD. The focus is on 'early biomarkers' of 'local skin changes'and not clinical efficacy, which has been established in previous trials. Rationale for selecting the two comparators are related to prescription behaviors in UK (Betamethasone valerate 0,1% cream) and with no reported TCS-like local adverse effects profile (crisaborole 2% ointment)
Interventions
DRUGcrisaborole (2%) ointment
twice daily application on one forearm for 4 weeks (randomised site allocation)
twice daily application on one forearm for 4 weeks (randomised site allocation)
Sponsors
University of Sheffield
Sheffield Teaching Hospitals NHS Foundation Trust
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
OTHER
Masking
NONE
Masking description
Allocation of the treatments to the test sites (right/left forearm) will be randomised (to avoid site position-dependent artefacts) Observer-blind - The collection of study data will be conducted in a separate area (dedicated skin barrier research suite) by a separate team (comprising skilled dermatology researchers) who will be blind.
Intervention model description
An observer-blind forearm-controlled clinical trial in 37 AD patients, wherein each participant will undergo 4 weeks treatment with crisaborole (2%) ointment on one forearm and betamethasone valerate (0.1%) cream on the other (twice daily application in each case and randomised site allocation). At the start of the study the skin of the test sites (forearms) will be clear of the signs of AD so that the investigation focuses on local adverse effects on the skin as opposed to anti-inflammatory effects (focus on local adverse effects and not clinical efficacy). The condition of the skin will be assessed before, during and after treatment.
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Volunteers with AD defined according to the UK working party diagnostic criteria * Male or female aged 18-65 years old at baseline (Visit 1) * Volunteer understands the purpose, modalities and potential risk of the trial * Participants able to read and understand English * Participants willing to sign the informed consent
Exclusion criteria
* Participants with a known allergy/hypersensitivity to any of the excipients of the trial preparations. * Participants with acne, suntan, birth marks, multiple nevi, tattoos, blemishes or dense body hair that obstruct the test areas. * Investigator assessment of eczema severity at the treatment (anatomical) sites is almost clear or greater (score ≥1) based on the Investigators static global assessment scale at screening and baseline. At the start of the study the skin of the test sites (forearms) will therefore be clear (0) of the signs of eczema * Participants with a condition that in the opinion of the investigator contradicts participation in the study. * Pregnant female participants; breastfeeding female participants; and female participants 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. * Use of any topical product on the test areas within 7 days prior to Baseline/Day 1, including cosmetic moisturizers and sunscreen. Participants using any topical products on the test areas within 7 days at the screening visit will be eligible if they are willing and able to wash-out these products for 7 days in total and for the duration of the trial. Such participants will be potentially eligible at screening and will be confirmed as eligible if adequate washout is confirmed at visit 1. Use of moisturizers and/or sunscreen is permitted during the study to manage dry skin and sun exposure in areas surrounding but not on or overlapping the test areas. * Participants who have used a tanning bed within 28 days of baseline (visit 1). Participants who have used a sunbed within 28 days at the screening visit will be eligible if they are willing and able to wash-out for 28 days in total and for the duration of the trial. Such participants will be potentially eligible at screening and will be confirmed as eligible if adequate washout is confirmed at visit 1. * Participants who have used any medication that could interfere with the trial aim prior to the start of the study (baseline/visit 1). Participants using such medication at the screening visit will be eligible if they are willing and able to wash-out these treatments for the applicable washout period as defined by in section 8.8 'Prior and Concomitant Medication' and for the duration of the trial. Such participants will be potentially eligible at screening and will be confirmed as eligible if adequate washout is confirmed at visit 1. * Participants currently participating in another interventional clinical trial. * Volunteer is incapable of giving fully informed consent. * Participants judged by the PI to be inappropriate for the trial.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Epidermal Thickness | Day 1 - Day 57 | The difference in the change in epidermal thickness, measured by structural OCT, between the sites treated with crisaborole (2%) ointment and betamethasone valerate (0.1%) cream. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| TEWL - Skin Barrier Function | Day 1, Day 15, Day 29 and Day 57 | Analysis of the change in Trans-Epidermal Water Loss (TEWL, relates to skin barrier function) during and after treatment. TEWL measurements on day 1, day 15, day 29 and day 57. |
| TEWL - After Tape-stripping | on Day 29, after 28 days treatment | The difference in skin barrier integrity (TEWLts20) after 28 days treatment. TEWL measurements after tape-stripping (TEWLts20) on day 29 |
| Comparison of TEWL - After Tape-stripping | on Day 29, after 28 days treatment | The difference in skin barrier integrity (TEWLts20) after 28 days treatment. TEWL measurements after tape-stripping (TEWLts20) on day 29 |
| Analysis of Change in Objective Erythema | Day 1, Day 15, Day 29 and Day 57 | Analysis of the difference in the change in skin redness/erythema (relating to tolerability) during and after 28 days treatment determined by Mexameter measured on day 1, day 15, day 29 and day 57. The Mexameter device has a range of 0-999AU (arbitrary units) and the lower the value, the better the condition of the skin. Objective redness can be classified using the following scale: 0-170AU - No erythema; 170-330AU - Minimal erythema; 330-450AU - Diffuse erythema; 450-570AU - High erythema; over 570AU - Extreme erythema |
| Natural Moisturising Factor (NMF) | Day 29 | The difference in Natural Moisturising Factor (NMF, filaggrin breakdown products) levels at the end of treatment. 3 NMF components were measured: Urocanic acid (UCA), Pyrrolidone carboxylic acid (PCA) and Free amino acids (FAA) and are expressed together as total NMF (tNMF). |
| Comparison of Natural Moisturising Factor (NMF) Between Treatments | Day 29 | The difference in Natural Moisturising Factor (NMF, filaggrin breakdown products) levels at the end of treatment. 3 NMF components were measured: Urocanic acid (UCA), Pyrrolidone carboxylic acid (PCA) and Free amino acids (FAA) and are expressed together as total NMF (tNMF). |
| Change in Visual Redness/Erythema During and After 28 Days Treatment | Visual skin redness scored on day 1, day 15, day 29 and day 57 | The difference in the change in visual skin redness during and after treatment. Visual skin redness scored on day 1, day 15, day 29 and day 57 by an experienced grader. Visual skin redness was scored using the following: 0 - No redness; 0.5/+ - Slight patchy erythema, barely perceptible; 1 - Slight uniform erythema, mild erythema; 2 - Moderate uniform erythema, moderate erythema; 3 - Strong erythema, marked erythema. The higher the visual redness score, the more inflamed the skin looks to the naked eye. |
| Skin Dryness | Visual skin dryness scored on day 1, day 15, day 29 and day 57 | The difference in the change in visual skin dryness during and after treatment. Visual skin dryness scored on day 1, day 15, day 29 and day 57. Visual skin dryness was scored using the following: 0 - Absent; 1 - Faint scaling, faint roughness and dull appearance; 2 - Small scales in combination with a few larger scales, slight roughness, whitish appearance; 3 - Small and larger scales uniformly distributed, definite roughness, possibly slight redness and possibly a few superficial cracks; 4 - Dominated by large scales, advanced roughness, redness present, eczematous changes and cracks. The lower the visual dryness score, the better the condition of the skin. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Superficial Plexus Depth | Day 1, Day 15, Day 29 and Day 57 | The difference in the change in superficial plexus depth (μm) measured by angiographic OCT. |
| Epidermal Thickness by Mutation Status | Day 1, Day 15, Day 29 and Day 57. | Descriptive tabulations of epidermal thickness (structural OCT derived) by mutation status. |
| Blood Vessel Diameter | Day 1, Day 15, Day 29 and Day 57. | The difference in the mean blood vessel diameter (μm) measured by angiographic OCT. |
| Blood Vessel Density | Day 1, Day 15, Day 29 and Day 57. | The difference in the change in blood vessel density (segments/mm²) measured by angiographic OCT. Angiographic OCT images taken on Day 1, Day 15, Day 29 and Day 57. |
| Collagen Matrix Index | Day 1 and Day 29. | The difference in the change in collagen matrix index measured by polarisation sensitive (PS-)OCT. This metric relates to the arrangement and density of collagen fibres within the skin and is informed by birefringence data. Inhibition of collagen synthesis is an adverse effect associated with epidermal atrophy that occurs following long-term use of topical corticosteroids. There is no range for this measurement. The higher the level of change, the more damage has been done to the epidermis. |
| Carboxylate 1 Levels | Day 1, Day 15, Day 29 and Day 57. | The difference in the change in carboxylate 1 levels (indirect measure of NMF levels, not to be confused with direct quantification from stratum corneum samples by HPLC) in the stratum corneum measured by FTIR spectroscopy. FTIR spectra of the skin surface taken on Day 1, Day 15, Day 29 and Day 57. Carboxylate 1 is a component of Natural Moisturising Factors and relates to how well the skin retains water. There is no range for this measurement. The greater the value, the less able the skin is to hold onto water. |
| Carboxylate 2 Levels | Day 1, Day 15, Day 29 and Day 57. | The difference in the change in carboxylate 2 levels (indirect measure of NMF levels, not to be confused with direct quantification from stratum corneum samples by HPLC) in the stratum corneum measured by FTIR spectroscopy. FTIR spectra of the skin surface taken on Day 1, Day 15, Day 29 and Day 57. Carboxylate 2 is a component of Natural Moisturising Factors and relates to how well the skin retains water. There is no range for this measurement. The greater the value, the less able the skin is to hold onto water. |
| Stratum Corneum Lipid Structure | Day 29 | The difference in stratum corneum lipid structure measured by FTIR spectroscopy in conjunction with tape-stripping. FTIR spectra taken through the stratum corneum during tape-stripping on Day 29. Lipid chain structure was assessed by quantifying the mean frequency of the lipid peak at 2850 cm-1 (corresponding to the CH2 group of lipids). There is no range for this measurement. The higher the absorbance, the less ordered the lipid packing and weaker the structural integrity of the skin. |
| FLG Mutation Carriers | Saliva samples at Day 1 | Number of FLG loss-of-function mutation carriers |
| Descriptive Tabulations of TEWL by Mutation Status | Day 1, Day 15, Day 29 and Day 57 | Descriptive tabulations of TEWL by mutation status. |
Countries
United Kingdom
Participant flow
Recruitment details
Recruitment started 20/11/2020 and ended 27/07/2021. 37 participants were recruited. Recruitment was conducted by the Sheffield Dermatology Research Group in several ways: General advertisement using posters. Email lists. Outpatient contact including local GP practices.
Pre-assignment details
Some participants, who were currently using treatments for eczema, needed to undergo a 'wash out' period, where the use of these treatments was stopped, prior to the first study visit. The duration of the wash-out depended on the type of treatment, and varied from 7 days for emollients to 12 weeks for intravenous biologic therapies.
Participants by arm
| Arm | Count |
|---|---|
| All Enrolled All enrolled participants | 37 |
| Total | 37 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Physician Decision | 3 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 2 |
Baseline characteristics
| Characteristic | All Enrolled | — |
|---|---|---|
| Age, Continuous | 29.4 years STANDARD_DEVIATION 12.09 | — |
| Atopic dermatitis as defined by UK working party diagnostic criteria | 37 Participants | — |
| Race and Ethnicity Not Collected | — | — Participants |
| Region of Enrollment United Kingdom | 37 participants | — |
| Sex: Female, Male Female | 24 Participants | — |
| Sex: Female, Male Male | 13 Participants | — |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 37 | 0 / 37 | 0 / 37 |
| other Total, other adverse events | 7 / 37 | 7 / 37 | 32 / 37 |
| serious Total, serious adverse events | 0 / 37 | 0 / 37 | 1 / 37 |
Outcome results
Primary
Change in Epidermal Thickness
The difference in the change in epidermal thickness, measured by structural OCT, between the sites treated with crisaborole (2%) ointment and betamethasone valerate (0.1%) cream.
Time frame: Day 1 - Day 57
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Betamethasone Valerate (0.1%) Cream | Change in Epidermal Thickness | Day 1 to Day 29 | -31.66 µm |
| Betamethasone Valerate (0.1%) Cream | Change in Epidermal Thickness | Day 1 to Day 15 | -28.65 µm |
| Betamethasone Valerate (0.1%) Cream | Change in Epidermal Thickness | Day 29 to Day 57 | 24.94 µm |
| Crisaborole (2%) Ointment | Change in Epidermal Thickness | Day 1 to Day 29 | -13.76 µm |
| Crisaborole (2%) Ointment | Change in Epidermal Thickness | Day 1 to Day 15 | -14.41 µm |
| Crisaborole (2%) Ointment | Change in Epidermal Thickness | Day 29 to Day 57 | 11.63 µm |
Secondary
Analysis of Change in Objective Erythema
Analysis of the difference in the change in skin redness/erythema (relating to tolerability) during and after 28 days treatment determined by Mexameter measured on day 1, day 15, day 29 and day 57. The Mexameter device has a range of 0-999AU (arbitrary units) and the lower the value, the better the condition of the skin. Objective redness can be classified using the following scale: 0-170AU - No erythema; 170-330AU - Minimal erythema; 330-450AU - Diffuse erythema; 450-570AU - High erythema; over 570AU - Extreme erythema
Time frame: Day 1, Day 15, Day 29 and Day 57
Population: 35 participants had complete data at Day 1. Each participant was expected to complete 56 days of treatment. A total of 5 participants were withdrawn before this point and so only 32 participants had data available for analysis at Day 29 and 57.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Betamethasone Valerate (0.1%) Cream | Analysis of Change in Objective Erythema | Baseline to Day 29 | -27.61 AU |
| Betamethasone Valerate (0.1%) Cream | Analysis of Change in Objective Erythema | Baseline to Day 15 | -45.04 AU |
| Betamethasone Valerate (0.1%) Cream | Analysis of Change in Objective Erythema | Day 29 to Day 57 | 37.66 AU |
| Crisaborole (2%) Ointment | Analysis of Change in Objective Erythema | Baseline to Day 29 | -1.16 AU |
| Crisaborole (2%) Ointment | Analysis of Change in Objective Erythema | Baseline to Day 15 | -23.61 AU |
| Crisaborole (2%) Ointment | Analysis of Change in Objective Erythema | Day 29 to Day 57 | 2.84 AU |
Secondary
Change in Visual Redness/Erythema During and After 28 Days Treatment
The difference in the change in visual skin redness during and after treatment. Visual skin redness scored on day 1, day 15, day 29 and day 57 by an experienced grader. Visual skin redness was scored using the following: 0 - No redness; 0.5/+ - Slight patchy erythema, barely perceptible; 1 - Slight uniform erythema, mild erythema; 2 - Moderate uniform erythema, moderate erythema; 3 - Strong erythema, marked erythema. The higher the visual redness score, the more inflamed the skin looks to the naked eye.
Time frame: Visual skin redness scored on day 1, day 15, day 29 and day 57
Population: Frequency of visual dryness scores on Day 1, Day 15, Day 29 and Day 57.
| Arm | Measure | Group | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|---|
| Betamethasone Valerate (0.1%) Cream | Change in Visual Redness/Erythema During and After 28 Days Treatment | Day 29 | 0 | 18 Participants |
| Betamethasone Valerate (0.1%) Cream | Change in Visual Redness/Erythema During and After 28 Days Treatment | Day 1 | 0.5 | 13 Participants |
| Betamethasone Valerate (0.1%) Cream | Change in Visual Redness/Erythema During and After 28 Days Treatment | Day 29 | 0.5 | 11 Participants |
| Betamethasone Valerate (0.1%) Cream | Change in Visual Redness/Erythema During and After 28 Days Treatment | Day 15 | 0.5 | 9 Participants |
| Betamethasone Valerate (0.1%) Cream | Change in Visual Redness/Erythema During and After 28 Days Treatment | Day 29 | 1 | 3 Participants |
| Betamethasone Valerate (0.1%) Cream | Change in Visual Redness/Erythema During and After 28 Days Treatment | Day 1 | 1 | 0 Participants |
| Betamethasone Valerate (0.1%) Cream | Change in Visual Redness/Erythema During and After 28 Days Treatment | Day 57 | 0 | 16 Participants |
| Betamethasone Valerate (0.1%) Cream | Change in Visual Redness/Erythema During and After 28 Days Treatment | Day 1 | 0 | 24 Participants |
| Betamethasone Valerate (0.1%) Cream | Change in Visual Redness/Erythema During and After 28 Days Treatment | Day 57 | 0.5 | 15 Participants |
| Betamethasone Valerate (0.1%) Cream | Change in Visual Redness/Erythema During and After 28 Days Treatment | Day 15 | 1 | 0 Participants |
| Betamethasone Valerate (0.1%) Cream | Change in Visual Redness/Erythema During and After 28 Days Treatment | Day 57 | 1 | 1 Participants |
| Betamethasone Valerate (0.1%) Cream | Change in Visual Redness/Erythema During and After 28 Days Treatment | Day 15 | 0 | 26 Participants |
| Crisaborole (2%) Ointment | Change in Visual Redness/Erythema During and After 28 Days Treatment | Day 57 | 1 | 1 Participants |
| Crisaborole (2%) Ointment | Change in Visual Redness/Erythema During and After 28 Days Treatment | Day 15 | 0 | 24 Participants |
| Crisaborole (2%) Ointment | Change in Visual Redness/Erythema During and After 28 Days Treatment | Day 1 | 0 | 22 Participants |
| Crisaborole (2%) Ointment | Change in Visual Redness/Erythema During and After 28 Days Treatment | Day 1 | 0.5 | 15 Participants |
| Crisaborole (2%) Ointment | Change in Visual Redness/Erythema During and After 28 Days Treatment | Day 15 | 0.5 | 11 Participants |
| Crisaborole (2%) Ointment | Change in Visual Redness/Erythema During and After 28 Days Treatment | Day 15 | 1 | 0 Participants |
| Crisaborole (2%) Ointment | Change in Visual Redness/Erythema During and After 28 Days Treatment | Day 29 | 0 | 21 Participants |
| Crisaborole (2%) Ointment | Change in Visual Redness/Erythema During and After 28 Days Treatment | Day 29 | 0.5 | 9 Participants |
| Crisaborole (2%) Ointment | Change in Visual Redness/Erythema During and After 28 Days Treatment | Day 29 | 1 | 2 Participants |
| Crisaborole (2%) Ointment | Change in Visual Redness/Erythema During and After 28 Days Treatment | Day 57 | 0 | 20 Participants |
| Crisaborole (2%) Ointment | Change in Visual Redness/Erythema During and After 28 Days Treatment | Day 57 | 0.5 | 11 Participants |
| Crisaborole (2%) Ointment | Change in Visual Redness/Erythema During and After 28 Days Treatment | Day 1 | 1 | 0 Participants |
Secondary
Comparison of Natural Moisturising Factor (NMF) Between Treatments
The difference in Natural Moisturising Factor (NMF, filaggrin breakdown products) levels at the end of treatment. 3 NMF components were measured: Urocanic acid (UCA), Pyrrolidone carboxylic acid (PCA) and Free amino acids (FAA) and are expressed together as total NMF (tNMF).
Time frame: Day 29
Population: Full Analysis Set
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Betamethasone Valerate (0.1%) Cream | Comparison of Natural Moisturising Factor (NMF) Between Treatments | Pyrrolidone Carboxylic Acid (PCA) | 0.156 nmoles/µg protein |
| Betamethasone Valerate (0.1%) Cream | Comparison of Natural Moisturising Factor (NMF) Between Treatments | Free Amino Acids (FAA) | 1.111 nmoles/µg protein |
| Betamethasone Valerate (0.1%) Cream | Comparison of Natural Moisturising Factor (NMF) Between Treatments | Urocanic Acid (UCA) | 0.032 nmoles/µg protein |
| Betamethasone Valerate (0.1%) Cream | Comparison of Natural Moisturising Factor (NMF) Between Treatments | Total Natural Moisturising Factors (NMF) | 1.299 nmoles/µg protein |
| Crisaborole (2%) Ointment | Comparison of Natural Moisturising Factor (NMF) Between Treatments | Free Amino Acids (FAA) | 1.135 nmoles/µg protein |
| Crisaborole (2%) Ointment | Comparison of Natural Moisturising Factor (NMF) Between Treatments | Urocanic Acid (UCA) | 0.039 nmoles/µg protein |
| Crisaborole (2%) Ointment | Comparison of Natural Moisturising Factor (NMF) Between Treatments | Total Natural Moisturising Factors (NMF) | 1.331 nmoles/µg protein |
| Crisaborole (2%) Ointment | Comparison of Natural Moisturising Factor (NMF) Between Treatments | Pyrrolidone Carboxylic Acid (PCA) | 0.157 nmoles/µg protein |
Secondary
Comparison of TEWL - After Tape-stripping
The difference in skin barrier integrity (TEWLts20) after 28 days treatment. TEWL measurements after tape-stripping (TEWLts20) on day 29
Time frame: on Day 29, after 28 days treatment
Population: Full Analysis Set
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Betamethasone Valerate (0.1%) Cream | Comparison of TEWL - After Tape-stripping | 45.44 g/m²/h |
| Crisaborole (2%) Ointment | Comparison of TEWL - After Tape-stripping | 34.13 g/m²/h |
Secondary
Natural Moisturising Factor (NMF)
The difference in Natural Moisturising Factor (NMF, filaggrin breakdown products) levels at the end of treatment. 3 NMF components were measured: Urocanic acid (UCA), Pyrrolidone carboxylic acid (PCA) and Free amino acids (FAA) and are expressed together as total NMF (tNMF).
Time frame: Day 29
Population: Full Analysis Set
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Betamethasone Valerate (0.1%) Cream | Natural Moisturising Factor (NMF) | Total Natural Moisturising Factors (NMF) | 1.299 moles/µg protein | Standard Deviation 0.608 |
| Betamethasone Valerate (0.1%) Cream | Natural Moisturising Factor (NMF) | Pyrrolidone Carboxylic Acid (PCA) | 0.156 moles/µg protein | Standard Deviation 0.844 |
| Betamethasone Valerate (0.1%) Cream | Natural Moisturising Factor (NMF) | Urocanic Acid (UCA) | 0.032 moles/µg protein | Standard Deviation 0.0218 |
| Betamethasone Valerate (0.1%) Cream | Natural Moisturising Factor (NMF) | Free Amino Acids (FAA) | 1.111 moles/µg protein | Standard Deviation 0.5164 |
| Crisaborole (2%) Ointment | Natural Moisturising Factor (NMF) | Free Amino Acids (FAA) | 1.135 moles/µg protein | Standard Deviation 0.5215 |
| Crisaborole (2%) Ointment | Natural Moisturising Factor (NMF) | Total Natural Moisturising Factors (NMF) | 1.331 moles/µg protein | Standard Deviation 0.5885 |
| Crisaborole (2%) Ointment | Natural Moisturising Factor (NMF) | Urocanic Acid (UCA) | 0.039 moles/µg protein | Standard Deviation 0.0208 |
| Crisaborole (2%) Ointment | Natural Moisturising Factor (NMF) | Pyrrolidone Carboxylic Acid (PCA) | 0.157 moles/µg protein | Standard Deviation 0.0708 |
Secondary
Skin Dryness
The difference in the change in visual skin dryness during and after treatment. Visual skin dryness scored on day 1, day 15, day 29 and day 57. Visual skin dryness was scored using the following: 0 - Absent; 1 - Faint scaling, faint roughness and dull appearance; 2 - Small scales in combination with a few larger scales, slight roughness, whitish appearance; 3 - Small and larger scales uniformly distributed, definite roughness, possibly slight redness and possibly a few superficial cracks; 4 - Dominated by large scales, advanced roughness, redness present, eczematous changes and cracks. The lower the visual dryness score, the better the condition of the skin.
Time frame: Visual skin dryness scored on day 1, day 15, day 29 and day 57
Population: Frequency of visual dryness scores on Day 1, Day 15, Day 29 and Day 57.
| Arm | Measure | Group | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|---|
| Betamethasone Valerate (0.1%) Cream | Skin Dryness | Day 29 | 1 | 2 Participants |
| Betamethasone Valerate (0.1%) Cream | Skin Dryness | Day 1 | 0 | 36 Participants |
| Betamethasone Valerate (0.1%) Cream | Skin Dryness | Day 1 | 1 | 1 Participants |
| Betamethasone Valerate (0.1%) Cream | Skin Dryness | Day 1 | 2 | 0 Participants |
| Betamethasone Valerate (0.1%) Cream | Skin Dryness | Day 15 | 0 | 34 Participants |
| Betamethasone Valerate (0.1%) Cream | Skin Dryness | Day 15 | 1 | 1 Participants |
| Betamethasone Valerate (0.1%) Cream | Skin Dryness | Day 15 | 2 | 0 Participants |
| Betamethasone Valerate (0.1%) Cream | Skin Dryness | Day 29 | 0 | 30 Participants |
| Betamethasone Valerate (0.1%) Cream | Skin Dryness | Day 29 | 2 | 0 Participants |
| Betamethasone Valerate (0.1%) Cream | Skin Dryness | Day 57 | 0 | 28 Participants |
| Betamethasone Valerate (0.1%) Cream | Skin Dryness | Day 57 | 1 | 3 Participants |
| Betamethasone Valerate (0.1%) Cream | Skin Dryness | Day 57 | 2 | 1 Participants |
| Crisaborole (2%) Ointment | Skin Dryness | Day 15 | 1 | 0 Participants |
| Crisaborole (2%) Ointment | Skin Dryness | Day 15 | 0 | 35 Participants |
| Crisaborole (2%) Ointment | Skin Dryness | Day 29 | 0 | 31 Participants |
| Crisaborole (2%) Ointment | Skin Dryness | Day 57 | 2 | 1 Participants |
| Crisaborole (2%) Ointment | Skin Dryness | Day 29 | 2 | 0 Participants |
| Crisaborole (2%) Ointment | Skin Dryness | Day 1 | 0 | 35 Participants |
| Crisaborole (2%) Ointment | Skin Dryness | Day 15 | 2 | 0 Participants |
| Crisaborole (2%) Ointment | Skin Dryness | Day 1 | 1 | 2 Participants |
| Crisaborole (2%) Ointment | Skin Dryness | Day 57 | 1 | 2 Participants |
| Crisaborole (2%) Ointment | Skin Dryness | Day 1 | 2 | 0 Participants |
| Crisaborole (2%) Ointment | Skin Dryness | Day 29 | 1 | 1 Participants |
| Crisaborole (2%) Ointment | Skin Dryness | Day 57 | 0 | 29 Participants |
Secondary
TEWL - After Tape-stripping
The difference in skin barrier integrity (TEWLts20) after 28 days treatment. TEWL measurements after tape-stripping (TEWLts20) on day 29
Time frame: on Day 29, after 28 days treatment
Population: Full Analysis Set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Betamethasone Valerate (0.1%) Cream | TEWL - After Tape-stripping | 45.4 g/m²/h | Standard Deviation 23.01 |
| Crisaborole (2%) Ointment | TEWL - After Tape-stripping | 34.1 g/m²/h | Standard Deviation 14.67 |
Secondary
TEWL - Skin Barrier Function
Analysis of the change in Trans-Epidermal Water Loss (TEWL, relates to skin barrier function) during and after treatment. TEWL measurements on day 1, day 15, day 29 and day 57.
Time frame: Day 1, Day 15, Day 29 and Day 57
Population: 35 participants had complete data at Day 1. Each participant was expected to complete 56 days of treatment. A total of 5 participants were withdrawn before this point and so only 32 participants had data available for analysis at Day 29 and 57.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Betamethasone Valerate (0.1%) Cream | TEWL - Skin Barrier Function | Baseline to Day 29 | -0.52 g/m²/h |
| Betamethasone Valerate (0.1%) Cream | TEWL - Skin Barrier Function | Baseline to Day 15 | -0.92 g/m²/h |
| Betamethasone Valerate (0.1%) Cream | TEWL - Skin Barrier Function | Day 29 to Day 57 | 2.25 g/m²/h |
| Crisaborole (2%) Ointment | TEWL - Skin Barrier Function | Baseline to Day 29 | 2.06 g/m²/h |
| Crisaborole (2%) Ointment | TEWL - Skin Barrier Function | Baseline to Day 15 | 1.66 g/m²/h |
| Crisaborole (2%) Ointment | TEWL - Skin Barrier Function | Day 29 to Day 57 | 0.21 g/m²/h |
Other Pre-specified
Blood Vessel Density
The difference in the change in blood vessel density (segments/mm²) measured by angiographic OCT. Angiographic OCT images taken on Day 1, Day 15, Day 29 and Day 57.
Time frame: Day 1, Day 15, Day 29 and Day 57.
Population: Full Analysis Set
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Betamethasone Valerate (0.1%) Cream | Blood Vessel Density | Day 1 to Day 29 | -1.27 segments/mm² | Standard Deviation 18.381 |
| Betamethasone Valerate (0.1%) Cream | Blood Vessel Density | Day 1 to Day 15 | -1.12 segments/mm² | Standard Deviation 17.769 |
| Betamethasone Valerate (0.1%) Cream | Blood Vessel Density | Day 29 to Day 57 | 4.79 segments/mm² | Standard Deviation 17.677 |
| Crisaborole (2%) Ointment | Blood Vessel Density | Day 1 to Day 29 | 3.37 segments/mm² | Standard Deviation 15.842 |
| Crisaborole (2%) Ointment | Blood Vessel Density | Day 1 to Day 15 | -0.56 segments/mm² | Standard Deviation 16.825 |
| Crisaborole (2%) Ointment | Blood Vessel Density | Day 29 to Day 57 | -0.15 segments/mm² | Standard Deviation 17.63 |
Other Pre-specified
Blood Vessel Diameter
The difference in the mean blood vessel diameter (μm) measured by angiographic OCT.
Time frame: Day 1, Day 15, Day 29 and Day 57.
Population: Full Analysis Set
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Betamethasone Valerate (0.1%) Cream | Blood Vessel Diameter | Day 1 to Day 29 | -1.02 µm | Standard Deviation 4.432 |
| Betamethasone Valerate (0.1%) Cream | Blood Vessel Diameter | Day 1 to Day 15 | -0.37 µm | Standard Deviation 4.195 |
| Betamethasone Valerate (0.1%) Cream | Blood Vessel Diameter | Day 29 to Day 57 | 1.36 µm | Standard Deviation 3.32 |
| Crisaborole (2%) Ointment | Blood Vessel Diameter | Day 29 to Day 57 | 0.13 µm | Standard Deviation 3.393 |
| Crisaborole (2%) Ointment | Blood Vessel Diameter | Day 1 to Day 29 | -1.04 µm | Standard Deviation 4.518 |
| Crisaborole (2%) Ointment | Blood Vessel Diameter | Day 1 to Day 15 | -0.69 µm | Standard Deviation 3.964 |
Other Pre-specified
Carboxylate 1 Levels
The difference in the change in carboxylate 1 levels (indirect measure of NMF levels, not to be confused with direct quantification from stratum corneum samples by HPLC) in the stratum corneum measured by FTIR spectroscopy. FTIR spectra of the skin surface taken on Day 1, Day 15, Day 29 and Day 57. Carboxylate 1 is a component of Natural Moisturising Factors and relates to how well the skin retains water. There is no range for this measurement. The greater the value, the less able the skin is to hold onto water.
Time frame: Day 1, Day 15, Day 29 and Day 57.
Population: Full Analysis Set
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Betamethasone Valerate (0.1%) Cream | Carboxylate 1 Levels | Day 1 to Day 29 | -6.75 absorbance units | Standard Deviation 5.8 |
| Betamethasone Valerate (0.1%) Cream | Carboxylate 1 Levels | Day 1 to Day 15 | -3.1 absorbance units | Standard Deviation 4.887 |
| Betamethasone Valerate (0.1%) Cream | Carboxylate 1 Levels | Day 29 to Day 57 | 6.97 absorbance units | Standard Deviation 4.594 |
| Crisaborole (2%) Ointment | Carboxylate 1 Levels | Day 1 to Day 29 | -4.88 absorbance units | Standard Deviation 5.45 |
| Crisaborole (2%) Ointment | Carboxylate 1 Levels | Day 1 to Day 15 | -3.52 absorbance units | Standard Deviation 4.675 |
| Crisaborole (2%) Ointment | Carboxylate 1 Levels | Day 29 to Day 57 | 4.88 absorbance units | Standard Deviation 4.686 |
Other Pre-specified
Carboxylate 2 Levels
The difference in the change in carboxylate 2 levels (indirect measure of NMF levels, not to be confused with direct quantification from stratum corneum samples by HPLC) in the stratum corneum measured by FTIR spectroscopy. FTIR spectra of the skin surface taken on Day 1, Day 15, Day 29 and Day 57. Carboxylate 2 is a component of Natural Moisturising Factors and relates to how well the skin retains water. There is no range for this measurement. The greater the value, the less able the skin is to hold onto water.
Time frame: Day 1, Day 15, Day 29 and Day 57.
Population: Full Analysis Set
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Betamethasone Valerate (0.1%) Cream | Carboxylate 2 Levels | Day 29 to Day 57 | 3.75 absorbance units | Standard Deviation 7.672 |
| Betamethasone Valerate (0.1%) Cream | Carboxylate 2 Levels | Day 1 to Day 29 | -2.45 absorbance units | Standard Deviation 4.989 |
| Betamethasone Valerate (0.1%) Cream | Carboxylate 2 Levels | Day 1 to Day 15 | -0.07 absorbance units | Standard Deviation 4.779 |
| Crisaborole (2%) Ointment | Carboxylate 2 Levels | Day 29 to Day 57 | -0.58 absorbance units | Standard Deviation 10.127 |
| Crisaborole (2%) Ointment | Carboxylate 2 Levels | Day 1 to Day 29 | 1.31 absorbance units | Standard Deviation 10.269 |
| Crisaborole (2%) Ointment | Carboxylate 2 Levels | Day 1 to Day 15 | 2.55 absorbance units | Standard Deviation 8.839 |
Other Pre-specified
Collagen Matrix Index
The difference in the change in collagen matrix index measured by polarisation sensitive (PS-)OCT. This metric relates to the arrangement and density of collagen fibres within the skin and is informed by birefringence data. Inhibition of collagen synthesis is an adverse effect associated with epidermal atrophy that occurs following long-term use of topical corticosteroids. There is no range for this measurement. The higher the level of change, the more damage has been done to the epidermis.
Time frame: Day 1 and Day 29.
Population: Full Analysis Set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Betamethasone Valerate (0.1%) Cream | Collagen Matrix Index | 100.0 AU | Standard Deviation 102.11 |
| Crisaborole (2%) Ointment | Collagen Matrix Index | -4.0 AU | Standard Deviation 78.55 |
Other Pre-specified
Descriptive Tabulations of TEWL by Mutation Status
Descriptive tabulations of TEWL by mutation status.
Time frame: Day 1, Day 15, Day 29 and Day 57
Population: Full Analysis Set
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Betamethasone Valerate (0.1%) Cream | Descriptive Tabulations of TEWL by Mutation Status | Day 15 | 12.7 g/m²/h | Standard Deviation 2.86 |
| Betamethasone Valerate (0.1%) Cream | Descriptive Tabulations of TEWL by Mutation Status | Day 57 | 13.8 g/m²/h | Standard Deviation 3.9 |
| Betamethasone Valerate (0.1%) Cream | Descriptive Tabulations of TEWL by Mutation Status | Day 1 | 13.7 g/m²/h | Standard Deviation 5.08 |
| Betamethasone Valerate (0.1%) Cream | Descriptive Tabulations of TEWL by Mutation Status | Day 29 | 11.8 g/m²/h | Standard Deviation 2.42 |
| Crisaborole (2%) Ointment | Descriptive Tabulations of TEWL by Mutation Status | Day 1 | 14.1 g/m²/h | Standard Deviation 5.94 |
| Crisaborole (2%) Ointment | Descriptive Tabulations of TEWL by Mutation Status | Day 29 | 14.2 g/m²/h | Standard Deviation 5.07 |
| Crisaborole (2%) Ointment | Descriptive Tabulations of TEWL by Mutation Status | Day 15 | 15.5 g/m²/h | Standard Deviation 5.27 |
| Crisaborole (2%) Ointment | Descriptive Tabulations of TEWL by Mutation Status | Day 57 | 15.2 g/m²/h | Standard Deviation 4.76 |
| Betamethasone Valerate (0.1%) Cream Without FLG Mutation | Descriptive Tabulations of TEWL by Mutation Status | Day 1 | 13.0 g/m²/h | Standard Deviation 3.77 |
| Betamethasone Valerate (0.1%) Cream Without FLG Mutation | Descriptive Tabulations of TEWL by Mutation Status | Day 15 | 12.3 g/m²/h | Standard Deviation 2.66 |
| Betamethasone Valerate (0.1%) Cream Without FLG Mutation | Descriptive Tabulations of TEWL by Mutation Status | Day 29 | 12.5 g/m²/h | Standard Deviation 3.44 |
| Betamethasone Valerate (0.1%) Cream Without FLG Mutation | Descriptive Tabulations of TEWL by Mutation Status | Day 57 | 14.9 g/m²/h | Standard Deviation 4.26 |
| Crisaborole (2%) Ointment Without FLG Mutation | Descriptive Tabulations of TEWL by Mutation Status | Day 15 | 15.0 g/m²/h | Standard Deviation 3.33 |
| Crisaborole (2%) Ointment Without FLG Mutation | Descriptive Tabulations of TEWL by Mutation Status | Day 1 | 13.0 g/m²/h | Standard Deviation 4.2 |
| Crisaborole (2%) Ointment Without FLG Mutation | Descriptive Tabulations of TEWL by Mutation Status | Day 57 | 15.3 g/m²/h | Standard Deviation 6.33 |
| Crisaborole (2%) Ointment Without FLG Mutation | Descriptive Tabulations of TEWL by Mutation Status | Day 29 | 14.65 g/m²/h | Standard Deviation 3.48 |
Other Pre-specified
Epidermal Thickness by Mutation Status
Descriptive tabulations of epidermal thickness (structural OCT derived) by mutation status.
Time frame: Day 1, Day 15, Day 29 and Day 57.
Population: Full Analysis Set
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Betamethasone Valerate (0.1%) Cream | Epidermal Thickness by Mutation Status | Day 15 | 68.9 µm | Standard Deviation 11.02 |
| Betamethasone Valerate (0.1%) Cream | Epidermal Thickness by Mutation Status | Day 57 | 91.0 µm | Standard Deviation 14.47 |
| Betamethasone Valerate (0.1%) Cream | Epidermal Thickness by Mutation Status | Day 29 | 64.4 µm | Standard Deviation 12.42 |
| Betamethasone Valerate (0.1%) Cream | Epidermal Thickness by Mutation Status | Day 1 | 101.6 µm | Standard Deviation 20.75 |
| Crisaborole (2%) Ointment | Epidermal Thickness by Mutation Status | Day 1 | 100.9 µm | Standard Deviation 17.94 |
| Crisaborole (2%) Ointment | Epidermal Thickness by Mutation Status | Day 29 | 78.5 µm | Standard Deviation 17.96 |
| Crisaborole (2%) Ointment | Epidermal Thickness by Mutation Status | Day 15 | 83.5 µm | Standard Deviation 137.71 |
| Crisaborole (2%) Ointment | Epidermal Thickness by Mutation Status | Day 57 | 100.1 µm | Standard Deviation 17.1 |
| Betamethasone Valerate (0.1%) Cream Without FLG Mutation | Epidermal Thickness by Mutation Status | Day 1 | 99.4 µm | Standard Deviation 13.92 |
| Betamethasone Valerate (0.1%) Cream Without FLG Mutation | Epidermal Thickness by Mutation Status | Day 15 | 71.7 µm | Standard Deviation 11.25 |
| Betamethasone Valerate (0.1%) Cream Without FLG Mutation | Epidermal Thickness by Mutation Status | Day 29 | 67.7 µm | Standard Deviation 11.68 |
| Betamethasone Valerate (0.1%) Cream Without FLG Mutation | Epidermal Thickness by Mutation Status | Day 57 | 91.6 µm | Standard Deviation 9.92 |
| Crisaborole (2%) Ointment Without FLG Mutation | Epidermal Thickness by Mutation Status | Day 1 | 100.8 µm | Standard Deviation 18.39 |
| Crisaborole (2%) Ointment Without FLG Mutation | Epidermal Thickness by Mutation Status | Day 15 | 86.8 µm | Standard Deviation 12.46 |
| Crisaborole (2%) Ointment Without FLG Mutation | Epidermal Thickness by Mutation Status | Day 57 | 96.0 µm | Standard Deviation 11.24 |
| Crisaborole (2%) Ointment Without FLG Mutation | Epidermal Thickness by Mutation Status | Day 29 | 87.7 µm | Standard Deviation 12.94 |
Other Pre-specified
FLG Mutation Carriers
Number of FLG loss-of-function mutation carriers
Time frame: Saliva samples at Day 1
Population: Full Analysis Set
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Betamethasone Valerate (0.1%) Cream | FLG Mutation Carriers | wt/wt | 24 Participants |
| Betamethasone Valerate (0.1%) Cream | FLG Mutation Carriers | wt/flg | 9 Participants |
| Betamethasone Valerate (0.1%) Cream | FLG Mutation Carriers | wt/unknown | 4 Participants |
Other Pre-specified
Stratum Corneum Lipid Structure
The difference in stratum corneum lipid structure measured by FTIR spectroscopy in conjunction with tape-stripping. FTIR spectra taken through the stratum corneum during tape-stripping on Day 29. Lipid chain structure was assessed by quantifying the mean frequency of the lipid peak at 2850 cm-1 (corresponding to the CH2 group of lipids). There is no range for this measurement. The higher the absorbance, the less ordered the lipid packing and weaker the structural integrity of the skin.
Time frame: Day 29
Population: Full Analysis Set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Betamethasone Valerate (0.1%) Cream | Stratum Corneum Lipid Structure | 2849.739 absorbance units | Standard Deviation 0.414 |
| Crisaborole (2%) Ointment | Stratum Corneum Lipid Structure | 2849.681 absorbance units | Standard Deviation 0.4475 |
Other Pre-specified
Superficial Plexus Depth
The difference in the change in superficial plexus depth (μm) measured by angiographic OCT.
Time frame: Day 1, Day 15, Day 29 and Day 57
Population: Full Analysis Set
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Betamethasone Valerate (0.1%) Cream | Superficial Plexus Depth | Day 1 to Day 29 | -20.3 µm | Standard Deviation 17.44 |
| Betamethasone Valerate (0.1%) Cream | Superficial Plexus Depth | Day 1 to Day 15 | -22.3 µm | Standard Deviation 16.42 |
| Betamethasone Valerate (0.1%) Cream | Superficial Plexus Depth | Day 29 to Day 57 | 13.4 µm | Standard Deviation 20.6 |
| Crisaborole (2%) Ointment | Superficial Plexus Depth | Day 1 to Day 29 | -9.5 µm | Standard Deviation 20.76 |
| Crisaborole (2%) Ointment | Superficial Plexus Depth | Day 1 to Day 15 | -13.1 µm | Standard Deviation 19.11 |
| Crisaborole (2%) Ointment | Superficial Plexus Depth | Day 29 to Day 57 | 7.3 µm | Standard Deviation 17.25 |