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Skin bioMARkers for Atopic Eczema Therapy Evaluation (SMART)

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ClinicalTrials.gov Identifier: NCT04194814
Recruitment Status : Not yet recruiting
First Posted : December 11, 2019
Last Update Posted : February 25, 2020
Sponsor:
Collaborator:
University of Sheffield
Information provided by (Responsible Party):
Sheffield Teaching Hospitals NHS Foundation Trust

Tracking Information
First Submitted Date  ICMJE December 9, 2019
First Posted Date  ICMJE December 11, 2019
Last Update Posted Date February 25, 2020
Estimated Study Start Date  ICMJE March 2020
Estimated Primary Completion Date April 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: December 9, 2019)
epidermal thickness (day 29 - day 1) [ Time Frame: day 29 - day 1 ]
The difference in the change in epidermal thickness (day 29 - day 1), measured by structural OCT, between the sites treated with crisaborole (2%) ointment and betamethasone valerate (0.1%) cream.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: December 9, 2019)
  • epidermal thickness (on day 1, day 15, day 29 and day 57) [ Time Frame: on day 1, day 15, day 29 and day 57 ]
    The difference in the change in epidermal thickness measured by structural OCT during and after 28 days treatment. OCT images of epidermal thickness taken on day 1, day 15, day 29 and day 57.
  • erythema [ Time Frame: during and after 28 days ]
    The difference in the change in skin redness/erythema (relating to tolerability) during and after 28 days treatment determined by: Visual redness/erythema score determined on day 1, day 15, day 29 and day 57 Objective redness assessed with the Mexameter measured on day 1, day 15, day 29 and day 57
  • TEWL - skin barrier function [ Time Frame: day 1, day 15, day 29 and day 57 ]
    The difference in the change in Trans-Epidermal Water Loss (TEWL, relates to skin barrier function) during and after treatment.17,18 TEWL measurements on day 1, day 15, day 29 and day 57.
  • TEWL - after tape-stripping [ Time Frame: 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
  • skin dryness [ Time Frame: 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
  • Natural Moisturising Factor (NMF) [ Time Frame: Day 1 - day 29 ]
    The difference in Natural Moisturising Factor (NMF, filaggrin breakdown products) levels at the end of treatment19 NMF will be quantified from superficial stratum corneum samples collected on day 29 using HPLC
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures
 (submitted: December 16, 2019)
  • superficial plexus depth [ Time Frame: Angiographic OCT images taken on day 1, day 15, day 29 and day 57 ]
    The difference in the change in superficial plexus depth (µm) measured by angiographic OCT
  • blood vessel diameter [ Time Frame: Angiographic OCT images taken on day 1, day 15, day 29 and day 57 ]
    The difference in the change in mean blood vessel diameter (µm) measured by angiographic OCT
  • blood vessel density [ Time Frame: Angiographic OCT images taken on day 1, day 15, day 29 and day 57 ]
    The difference in the change in blood vessel density (segments/mm2) measured by angiographic OCT
  • collagen matrix [ Time Frame: Polarisation sensitive (PS)-OCT images taken on day 1 and day 29. ]
    The difference in the change in collagen matrix index (an index derived from birefringence images of collagen density and arrangement) measured by polarisation sensitive (PS)-OCT
  • carboxylate levels [ Time Frame: FTIR spectrum of the skin surface taken on day 1 day 15, day 29 and day 57 ]
    The difference in the change in carboxylate 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
  • stratum corneum lipid structure [ Time Frame: FTIR spectra taken through the stratum corneum (during tape-stripping) on day 29 ]
    The difference in stratum corneum lipid structure measured by FTIR spectroscopy in conjunction with tape-stripping
  • FLG mutation carriers [ Time Frame: Saliva sample at visit 1 for FLG genotyping ]
    Number of FLG loss-of-function mutation carriers
  • Descriptive tabulations of TEWL by mutation status [ Time Frame: TEWL measured at day 1, day 15 and day 29 ]
    Descriptive tabulations of TEWL by mutation status, if sufficient participants with mutation are detected. All the above
  • Descriptive tabulations of epidermal thickness by mutation status [ Time Frame: Structural OCT derived epidermal thickness measured at day 1, day 15 and day 29 ]
    Descriptive tabulations of epidermal thickness (structural OCT derived) by mutation status , if sufficient participants with mutation are detected. All the above
Original Other Pre-specified Outcome Measures
 (submitted: December 9, 2019)
  • superficial plexus depth [ Time Frame: Angiographic OCT images taken on day 1, day 15, day 29 and day 57 ]
    The difference in the change in superficial plexus depth (µm) measured by angiographic OCT
  • blood vessel diameter [ Time Frame: Angiographic OCT images taken on day 1, day 15, day 29 and day 57 ]
    The difference in the change in mean blood vessel diameter (µm) measured by angiographic OCT
  • blood vessel density [ Time Frame: Angiographic OCT images taken on day 1, day 15, day 29 and day 57 ]
    The difference in the change in blood vessel density (segments/mm2) measured by angiographic OCT
  • collagen matrix [ Time Frame: Polarisation sensitive (PS)-OCT images taken on day 1 and day 29. ]
    The difference in the change in collagen matrix index (an index derived from birefringence images of collagen density and arrangement) measured by polarisation sensitive (PS)-OCT
  • carboxylate levels [ Time Frame: FTIR spectrum of the skin surface taken on day 1 day 15, day 29 and day 57 ]
    The difference in the change in carboxylate 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
  • stratum corneum lipid structure [ Time Frame: FTIR spectra taken through the stratum corneum (during tape-stripping) on day 29 ]
    The difference in stratum corneum lipid structure measured by FTIR spectroscopy in conjunction with tape-stripping
  • FLG mutation carriers [ Time Frame: Saliva sample at visit 1 for FLG genotyping ]
    Number of FLG loss-of-function mutation carriers
  • Tabulations of TEWL and epidermal thickness by mutation status [ Time Frame: TEWL and structural OCT derived epidermal thickness measured at day 1, day 15 and day 29 ]
    Descriptive tabulations of TEWL and epidermal thickness by mutation status, if sufficient participants with mutation are detected. All the above
 
Descriptive Information
Brief Title  ICMJE Skin bioMARkers for Atopic Eczema Therapy Evaluation
Official Title  ICMJE Validation of a Novel Composite of Skin Biomarkers as a Primary Outcome Measure for Evaluating the Safety of Treatments for Atopic Dermatitis: a Randomized Controlled Trial (Phase 2) Comparing the Effects of Crisaborole 2% Ointment to Betamethasone Valerate 0.1% Cream on Skin Structure and Function in Participants With Atopic Dermatitis.
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)

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Intervention Model: Single Group Assignment
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.
Masking: None (Open Label)
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.
Primary Purpose: Other
Condition  ICMJE Atopic Eczema/Dermatitis (Non-Specific)
Intervention  ICMJE
  • Drug: crisaborole (2%) ointment
    twice daily application on one forearm for 4 weeks (randomised site allocation)
    Other Name: Eucrisa
  • Drug: betamethasone valerate 0.1% cream
    twice daily application on one forearm for 4 weeks (randomised site allocation)
    Other Name: Betnovate cream
Study Arms  ICMJE crisaborole and topical Corticosteroid

crisaborole (2%) ointment on the other forearm, twice daily application for 4 weeks (randomised site allocation)

betamethasone valerate (0.1%) cream on one forearm, twice daily application for 4 weeks (randomised site allocation)

Interventions:
  • Drug: crisaborole (2%) ointment
  • Drug: betamethasone valerate 0.1% cream
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Not yet recruiting
Estimated Enrollment  ICMJE
 (submitted: December 9, 2019)
37
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE April 2021
Estimated Primary Completion Date April 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 65 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Aimee Card 01142265945 aimee.card@nhs.net
Contact: Simon Danby, PhD +44 (0) 114 21 59563 s.danby@sheffield.ac.uk
Listed Location Countries  ICMJE United Kingdom
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04194814
Other Study ID Numbers  ICMJE STH19966
2019-002643-23 ( EudraCT Number )
WI242083-UK [Eucrisa] ( Other Grant/Funding Number: Pfizer, Inc. )
269415 ( Other Identifier: IRAS )
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Sheffield Teaching Hospitals NHS Foundation Trust
Study Sponsor  ICMJE Sheffield Teaching Hospitals NHS Foundation Trust
Collaborators  ICMJE University of Sheffield
Investigators  ICMJE
Principal Investigator: Michael J Cork, MB.ChB The University of Sheffield & Sheffield Teaching Hospitals NHS FT
PRS Account Sheffield Teaching Hospitals NHS Foundation Trust
Verification Date February 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP