Skin biomarkers for atopic eczema therapy evaluation study 2

Plain English Summary

Background and study aims
The first-choice drug treatment for mild-moderate eczema is currently a topical corticosteroid. By topical, we mean the treatment is intended for application directly to the skin. Whilst topical corticosteroids are effective at treating eczema, they have been found to cause unwanted skin changes, such as skin thinning, if used inappropriately over long periods of time. Exactly how much unwarranted thinning is caused by different treatment routines is unclear, so we want to use some new non-invasive ways to measure skin thinning to better understand the problem. One of these ways is to take a 3D image of the skin using a technique called OCT, which is similar to ultrasound. Because the methods are so sensitive, the signs of skin thinning can be seen before the skin becomes visibly damaged.
Crisaborole ointment is a new non-steroidal drug treatment for eczema that appears to be as effective as some topical corticosteroids, and is not expected to cause abnormal skin thinning. Betamethasone valerate cream is one of the most commonly prescribed topical corticosteroids for eczema in the UK, and is available in a number of preparations with different potencies or strengths. Therefore, the aim of the SMART program of studies is to conduct trials in eczema patients involving treatment of separate areas of their skin with either crisaborole ointment or betamethasone valerate cream of different potencies. The effects of the treatments will be assessed using the non-invasive skin imaging techniques.
Both types of treatment have already been tested in clinical trials for clinical efficacy, and so efficacy will not be assessed again here. This study will confirm whether or not crisaborole ointment causes the same unwarranted skin thinning caused by the moderately potent betamethasone valerate 0.025% cream in a direct comparison.

Who can participate?
Patients aged 18 – 64 years, with atopic dermatitis (eczema)

What does the study involve?
Not provided at time of registration

What are the possible benefits and risks of participating?
Benefits:
Not provided at time of registration
Risks:
In order to determine a set of safety biomarkers it is necessary to characterise an unsafe treatment scenario, which raises important ethical questions about asking participants to undertake a treatment that may cause them harm. It is important to highlight that this study focuses on early transient signs of skin atrophy, and so there is no intention to induce visible adverse effects. We have already established that 4 weeks of treatment with betamethasone valerate 0.1% induces sub-clinical (invisible) skin thinning without inducing visible adverse effects. In this study the less potent topical corticosteroid (TCS), betamethasone valerate 0.025%, will be used following the same regimen.

The regimen proposed for the antecubital fossa and volar forearms (4 weeks twice daily) conforms to the current marketing licence. However, the duration of treatment proposed for the cheeks (2 weeks twice daily) exceeds the guidance in the SmPC, which suggests treatment is restricted to ≤5 days. This is important so that we can better derive this arbitrarily determined treatment cut-off using our precision equipment. The regimen proposed is in line with current clinical practice, making a strong ethical argument to identify any potential harm, or absence of harm, using this product may have under the proposed conditions.

Skin thinning induced during short courses of TCS treatment is transient, with skin returning to pre-treatment thickness within a matter of weeks following cessation, and so the risks of this controlled short burst of treatment are minimal. To further mitigate the risks we will stop treatment on the cheeks after 1 week if epidermal thinning reaches ≥30%. As a precaution we will also review epidermal thickness data collected after the 5th and 10th participants and adjust the treatment duration down if excessive levels of epidermal thinning are observed. This will ensure the study is conducted safely whilst also establishing whether the 5-day limit on application is appropriate for the cheeks. A more detailed justification can be found in the protocol (section 2.8).

Crisaborole:
Crisaborole has been well tolerated across completed clinical studies (28 to date, involving 2558 participates from 3 months to adults >18 years of age). No clinically important systemic safety signals have been identified. Most adverse events (AEs) have been mild, and most considered unrelated or unlikely to be related to study drug. Studies in pregnant or lactating populations have not been conducted, and so this group will be excluded from participation and steps taken to reduce the risk of pregnancy whilst using the study medication.

The skin procedures:
This study involves a series of non-invasive procedures to test the biophysical properties of the skin. These procedures have all been used safely in previous clinical studies, and so the risks of harm are minimal. The OCT and PS-OCT equipment comprises a class 1M laser and Class 3 laser attenuated down to class 1 AEL respectively, making them safe for the proposed testing under normal operating conditions. A regular maintenance plan and risk assessment has been developed to mitigate the risks of participants becoming exposed to the unattenuated Class 3 laser.
Sample collection:
Three types of samples will be collected: (1) superficial stratum corneum (skin) samples by skin tape-stripping (STS), (2) saliva samples by buccal swabbing, and (3) skin biopsy collection. STS is a painless procedure, that removes the dead cells from the surface of the skin that will eventually be lost/shed as a result of normal desquamation. STS will not be performed on broken skin. The collection of skin biopsy samples may cause both physical and psychological harm to participants; however, the risk of any physical harm is minimal due to the procedure being routine in dermatology clinics and being performed by an experienced clinician. Ten adult participants, out of 40 recruited, are required to provide 2 biopsies each. The procedure will be treated as optional (although it will be compulsory for the final recruits to ensure 10 sets of biopsies are obtained), on a first come first served basis, and require specific consent. Additional remuneration of £100 per biopsy will be provided in recognition of the burden of providing the samples. Obtaining the biopsies is necessary to validate the non-invasive techniques under investigation against histological analysis (current gold standard). By providing a robust validation of the non-invasive techniques under investigation here the need to collect biopsies in future clinical studies could be avoided.
Potential burden:
Due to the number of site visits and the frequency of compliance checks there is a significant burden on participants’ time. This burden will be lessened by providing taxi transport to and from the test centre. Participants will also be remunerated for the burden they endure, which may involve time taken out of work.

Where is the study run from?
Sheffield Teaching Hospitals NHS Foundation Trust (UK)

When is the study starting and how long is it expected to run for?
July 2022 to December 2024

Who is funding the study?
Pfizer (USA)

Who is the main contact?
Dr Simon Danby, s.danby@sheffield.ac.uk

Contact information

Study information

Eligibility

Locations

Countries of recruitment

• United Kingdom

Study participating centre

Sponsor information

Sheffield Teaching Hospitals NHS Foundation Trust
Hospital/treatment centre

Glossop Road
Sheffield
S10 2JF
England
United Kingdom

Phone	+44 114 226 5945
Email	aimee.card@nhs.net
Website	http://www.sth.nhs.uk/
"ROR"	https://ror.org/018hjpz25

Funders

Funder type

Industry

Results and Publications

Study outputs

Editorial Notes

02/12/2022: Internal review.
14/07/2022: Trial's existence confirmed by NHS HRA.