Skin bioMARkers for Atopic Eczema Therapy Evaluation

Atopic Eczema/Dermatitis (Non-Specific) Clinical Trial

— SMART  

Official title:

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.

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04194814
• Other study ID #: STH19966
• Secondary ID: 2019-002643-23WI
• Status: Completed
• Phase: Phase 2
• Start date: November 20, 2020
• Est. completion date: September 30, 2021

Study information

• Verified date: November 2020
• Source: Sheffield Teaching Hospitals NHS Foundation Trust
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

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)

Recruitment information / eligibility

• Status: Completed
• Enrollment: 37
• Est. completion date: September 30, 2021
• Est. primary completion date: September 30, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 65 Years

Eligibility

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.

Related Conditions & MeSH terms

• Atopic Eczema/Dermatitis (Non-Specific)
• Dermatitis
• Dermatitis, Atopic
• Eczema

Intervention

Drug:
• crisaborole (2%) ointment
twice daily application on one forearm for 4 weeks (randomised site allocation)
• betamethasone valerate 0.1% cream
twice daily application on one forearm for 4 weeks (randomised site allocation)

Locations

Country	Name	City	State
United Kingdom	Sheffield Dermatology Research, University of Sheffield Medical School, The Royal Hallamshire Hospital	Sheffield	South Yorkshire

Sponsors (2)

Lead Sponsor	Collaborator
Sheffield Teaching Hospitals NHS Foundation Trust	University of Sheffield

Country where clinical trial is conducted

United Kingdom, 

References & Publications (24)

Batchelor JM, Ridd MJ, Clarke T, Ahmed A, Cox M, Crowe S, Howard M, Lawton S, McPhee M, Rani A, Ravenscroft JC, Roberts A, Thomas KS. The Eczema Priority Setting Partnership: a collaboration between patients, carers, clinicians and researchers to identify and prioritize important research questions for the treatment of eczema. Br J Dermatol. 2013 Mar;168(3):577-82. doi: 10.1111/bjd.12040. Epub 2013 Jan 18. — View Citation

Boncheva M, Damien F, Normand V. Molecular organization of the lipid matrix in intact Stratum corneum using ATR-FTIR spectroscopy. Biochim Biophys Acta. 2008 May;1778(5):1344-55. doi: 10.1016/j.bbamem.2008.01.022. Epub 2008 Feb 11. — View Citation

Brancaleon L, Bamberg MP, Sakamaki T, Kollias N. Attenuated total reflection-Fourier transform infrared spectroscopy as a possible method to investigate biophysical parameters of stratum corneum in vivo. J Invest Dermatol. 2001 Mar;116(3):380-6. — View Citation

Byers RA, Maiti R, Danby SG, Pang EJ, Mitchell B, Carré MJ, Lewis R, Cork MJ, Matcher SJ. Sub-clinical assessment of atopic dermatitis severity using angiographic optical coherence tomography. Biomed Opt Express. 2018 Mar 29;9(4):2001-2017. doi: 10.1364/BOE.9.002001. eCollection 2018 Apr 1. — View Citation

Chittock J, Brown K, Cork MJ, Danby SG. Comparing the Effect of a Twice-weekly Tacrolimus and Betamethasone Valerate Dose on the Subclinical Epidermal Barrier Defect in Atopic Dermatitis. Acta Derm Venereol. 2015 Jul;95(6):653-8. doi: 10.2340/00015555-2048. — View Citation

Chittock J, Cooke A, Lavender T, Brown K, Wigley A, Victor S, Cork MJ, Danby SG. Development of stratum corneum chymotrypsin-like protease activity and natural moisturizing factors from birth to 4 weeks of age compared with adults. Br J Dermatol. 2016 Oct;175(4):713-20. doi: 10.1111/bjd.14568. Epub 2016 Jul 22. — View Citation

Cooke A, Cork MJ, Victor S, Campbell M, Danby S, Chittock J, Lavender T. Olive Oil, Sunflower Oil or no Oil for Baby Dry Skin or Massage: A Pilot, Assessor-blinded, Randomized Controlled Trial (the Oil in Baby SkincaRE [OBSeRvE] Study). Acta Derm Venereol. 2016 Mar;96(3):323-30. doi: 10.2340/00015555-2279. — View Citation

Cork MJ, Danby SG, Vasilopoulos Y, Hadgraft J, Lane ME, Moustafa M, Guy RH, Macgowan AL, Tazi-Ahnini R, Ward SJ. Epidermal barrier dysfunction in atopic dermatitis. J Invest Dermatol. 2009 Aug;129(8):1892-908. doi: 10.1038/jid.2009.133. Epub 2009 Jun 4. Review. — View Citation

Damien F, Boncheva M. The extent of orthorhombic lipid phases in the stratum corneum determines the barrier efficiency of human skin in vivo. J Invest Dermatol. 2010 Feb;130(2):611-4. doi: 10.1038/jid.2009.272. Epub 2009 Sep 3. — View Citation

Danby SG, AlEnezi T, Sultan A, Lavender T, Chittock J, Brown K, Cork MJ. Effect of olive and sunflower seed oil on the adult skin barrier: implications for neonatal skin care. Pediatr Dermatol. 2013 Jan-Feb;30(1):42-50. doi: 10.1111/j.1525-1470.2012.01865.x. Epub 2012 Sep 20. — View Citation

Danby SG, Brown K, Higgs-Bayliss T, Chittock J, Albenali L, Cork MJ. The Effect of an Emollient Containing Urea, Ceramide NP, and Lactate on Skin Barrier Structure and Function in Older People with Dry Skin. Skin Pharmacol Physiol. 2016;29(3):135-47. doi: 10.1159/000445955. Epub 2016 Jun 2. — View Citation

Danby SG, Chittock J, Brown K, Albenali LH, Cork MJ. The effect of tacrolimus compared with betamethasone valerate on the skin barrier in volunteers with quiescent atopic dermatitis. Br J Dermatol. 2014 Apr;170(4):914-21. doi: 10.1111/bjd.12778. — View Citation

Gupta R, Sheikh A, Strachan DP, Anderson HR. Burden of allergic disease in the UK: secondary analyses of national databases. Clin Exp Allergy. 2004 Apr;34(4):520-6. — View Citation

Hengge UR, Ruzicka T, Schwartz RA, Cork MJ. Adverse effects of topical glucocorticosteroids. J Am Acad Dermatol. 2006 Jan;54(1):1-15; quiz 16-8. Review. — View Citation

Kao JS, Fluhr JW, Man MQ, Fowler AJ, Hachem JP, Crumrine D, Ahn SK, Brown BE, Elias PM, Feingold KR. Short-term glucocorticoid treatment compromises both permeability barrier homeostasis and stratum corneum integrity: inhibition of epidermal lipid synthesis accounts for functional abnormalities. J Invest Dermatol. 2003 Mar;120(3):456-64. — View Citation

Kerr OA, Tidman MJ, Walker JJ, Aldridge RD, Benton EC. The profile of dermatological problems in primary care. Clin Exp Dermatol. 2010 Jun;35(4):380-3. doi: 10.1111/j.1365-2230.2009.03586.x. Epub 2009 Oct 23. — View Citation

Kezic S, O'Regan GM, Yau N, Sandilands A, Chen H, Campbell LE, Kroboth K, Watson R, Rowland M, McLean WH, Irvine AD. Levels of filaggrin degradation products are influenced by both filaggrin genotype and atopic dermatitis severity. Allergy. 2011 Jul;66(7):934-40. doi: 10.1111/j.1398-9995.2010.02540.x. Epub 2011 Jan 25. — View Citation

Lewis-Jones S, Mugglestone MA; Guideline Development Group. Management of atopic eczema in children aged up to 12 years: summary of NICE guidance. BMJ. 2007 Dec 15;335(7632):1263-4. Review. — View Citation

Lu Z, Kasaragod D, Matcher SJ. Conical scan polarization-sensitive optical coherence tomography. Biomed Opt Express. 2014 Feb 18;5(3):752-62. doi: 10.1364/BOE.5.000752. eCollection 2014 Mar 1. — View Citation

Odhiambo JA, Williams HC, Clayton TO, Robertson CF, Asher MI; ISAAC Phase Three Study Group. Global variations in prevalence of eczema symptoms in children from ISAAC Phase Three. J Allergy Clin Immunol. 2009 Dec;124(6):1251-8.e23. doi: 10.1016/j.jaci.2009.10.009. — View Citation

Punekar YS, Sheikh A. Establishing the sequential progression of multiple allergic diagnoses in a UK birth cohort using the General Practice Research Database. Clin Exp Allergy. 2009 Dec;39(12):1889-95. doi: 10.1111/j.1365-2222.2009.03366.x. Epub 2009 Oct 7. — View Citation

Ring A, Schreiner V, Wenck H, Wittern KP, Küpper L, Keyhani R. Mid-infrared spectroscopy on skin using a silver halide fibre probe in vivo. Skin Res Technol. 2006 Feb;12(1):18-23. — View Citation

Schmitt J, von Kobyletzki L, Svensson A, Apfelbacher C. Efficacy and tolerability of proactive treatment with topical corticosteroids and calcineurin inhibitors for atopic eczema: systematic review and meta-analysis of randomized controlled trials. Br J Dermatol. 2011 Feb;164(2):415-28. doi: 10.1111/j.1365-2133.2010.10030.x. Epub 2010 Nov 23. Review. — View Citation

Ugryumova N, Jacobs J, Bonesi M, Matcher SJ. Novel optical imaging technique to determine the 3-D orientation of collagen fibers in cartilage: variable-incidence angle polarization-sensitive optical coherence tomography. Osteoarthritis Cartilage. 2009 Jan;17(1):33-42. doi: 10.1016/j.joca.2008.05.005. Epub 2008 Jul 14. — View Citation

* Note: There are 24 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	superficial plexus depth	The difference in the change in superficial plexus depth (µm) measured by angiographic OCT	Angiographic OCT images taken on day 1, day 15, day 29 and day 57
Other	blood vessel diameter	The difference in the change in mean blood vessel diameter (µm) measured by angiographic OCT	Angiographic OCT images taken on day 1, day 15, day 29 and day 57
Other	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
Other	collagen matrix	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	Polarisation sensitive (PS)-OCT images taken on day 1 and day 29.
Other	carboxylate levels	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	FTIR spectrum of the skin surface taken on day 1 day 15, day 29 and day 57
Other	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
Other	FLG mutation carriers	Number of FLG loss-of-function mutation carriers	Saliva sample at visit 1 for FLG genotyping
Other	Descriptive tabulations of TEWL by mutation status	Descriptive tabulations of TEWL by mutation status, if sufficient participants with mutation are detected.; All the above	TEWL measured at day 1, day 15 and day 29
Other	Descriptive tabulations of epidermal thickness by mutation status	Descriptive tabulations of epidermal thickness (structural OCT derived) by mutation status , if sufficient participants with mutation are detected.; All the above	Structural OCT derived epidermal thickness measured at day 1, day 15 and day 29
Primary	epidermal thickness (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.	day 29 - day 1
Secondary	epidermal thickness (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.	on day 1, day 15, day 29 and day 57
Secondary	erythema	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	during and after 28 days
Secondary	TEWL - skin barrier function	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.	day 1, day 15, day 29 and day 57
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	on day 29, after 28 days treatment
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 scored on day 1, day 15, day 29 and day 57
Secondary	Natural Moisturising Factor (NMF)	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	Day 1 - day 29

External Links

•   Atopic eczema in children - Guideline consultation: National Institute for Clinical Excellence, Department of Health, UK
•   Danby SG, Wan H, Chittock J et al. Characterisation of the skin barrier defect in atopic dermatitis using in vivo ATR-FTIR molecular spectroscopy. J Invest Dermatol 2016; 136: S182.
•   Lu Z, et al. Optical coherence tomography demonstrates differential epidermal thinning of human forearm volar skin after 2 weeks application of a topical corticosteroid vs a non-steroidal anti-inflammatory alternative. Proc. SPIE 2013; 85
•   Takada S, Naito S, Sonoda J et al. Noninvasive In Vivo Measurement of Natural Moisturizing Factor Content in Stratum Corneum of Human Skin by Attenuated Total Reflection Infrared Spectroscopy. Applied Spectroscopy 2012; 66: 26-32.