Interest of Topical Spironolactone's Administration to Prevent Corticoid-induced Epidermal Atrophy

Cutaneous Atrophy Due to Corticosteroids Clinical Trial

— SPIREPI  

Official title:

Interest of Topical Spironolactone's Administration to Prevent Corticoid-induced Epidermal Atrophy

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01407471
• Other study ID #: P071011
• Status: Completed
• Phase: Phase 2
• First received: June 30, 2011
• Last updated: July 2, 2015
• Start date: September 2011
• Est. completion date: May 2012

Study information

• Verified date: February 2015
• Source: Assistance Publique - Hôpitaux de Paris
• Contact: n/a
• Is FDA regulated: No
• Health authority: France: Ministry of Health
• Study type: Interventional

Clinical Trial Summary

The purpose of this study is to determine whether spironolactone could significantly reduce cutaneous atrophy due to corticosteroids.

Description:

skin cutaneous atrophy due to corticosteroids limits the long-term use of highly potent topical glucocorticoids which are the treatment of choice for many inflammatory skin diseases. This atrophy results in fragile skin, delay of healing, purpura, irreversible striae, telangiectasia and secondary infections. Up to now, no treatments can prevent efficiently skin atrophy.

The mineralocorticoid receptor, belonging to the superfamily of nuclear receptors, is expressed in human epidermis but its actual function is unknown. Experimental results in animals obtained in INSERM unit U772 by Dr N FARMAN suggest that spironolactone which is a mineralocorticoid receptor antagonist 1- might limit epidermal atrophy and 2- might promote healing.

Study description We propose to test clinically these hypotheses for the first time on humans, at the CIC in BICHAT's hospital on healthy volunteers: 1- by applying on the skin a highly potent cutaneous corticosteroids in association or not with spironolactone, 2- by applying or not spironolactone on wounds after 3-mm punch biopsies.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 26
• Est. completion date: May 2012
• Est. primary completion date: May 2012
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Both
• Age group: 20 Years to 50 Years

Eligibility

Inclusion Criteria:

• Healthy volunteers of both sex, aged between 20 and 50 years

• Woman with effective contraception and pregnancy test negative before inclusion.

• Subject considered healthy after a detailed review (interview, clinical examination)

• Subject belonging to a social security scheme (beneficiary or have the right)

• Subject having signed a free and informed consent

• Integrity of the skin at forearms

• Subject available the next 7 weeks and able to go to CIC once a day from Monday to Friday

• Subject accepting four skin biopsies at D29

• no washing forearms during 2 hours after applications

Exclusion Criteria:

• Chronic Alcoholism

• Drug-addiction (comprehensive interview with a sampling in case of doubt)

• Woman pregnant or breast-feeding

• Subject involved in another trial or in exclusion period of another protocol

• Subject has already received more than 3700 Euros in compensation for damages suffered constraints in the past 12 months for his involvement in biomedical researches

• Subject has already participated in this protocol

• Phototypes 5 and 6

• Clinical skin atrophy

• History of severe chronic skin disease

• Problems of healing

• Treatment with oral corticosteroids, mineralocorticoids or spironolactone (Aldactone, Flumach, Practon, Spiroctan, Spironone, Aldactazine, ALDALIX, Practazin, Spiroctazine ...)

Study Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Crossover Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Prevention

Related Conditions & MeSH terms

• Atrophy
• Cutaneous Atrophy Due to Corticosteroids

Intervention

Drug:
• Clobetasol + Spironolactone
One application 6 days a week during 4 weeks
• Clobetasol + Placebo
One application 6 days a week during 4 weeks
• Placebo + Spironolactone
One application 6 days a week during 7 weeks
• Placebo + Placebo
One application 6 days a week during 7 weeks

Locations

Country	Name	City	State
France	Bichat Hospital	Paris

Sponsors (2)

Lead Sponsor	Collaborator
Assistance Publique - Hôpitaux de Paris	Société de Dermatologie Française

Country where clinical trial is conducted

France, 

References & Publications (13)

Bayo P, Sanchis A, Bravo A, Cascallana JL, Buder K, Tuckermann J, Schütz G, Pérez P. Glucocorticoid receptor is required for skin barrier competence. Endocrinology. 2008 Mar;149(3):1377-88. Epub 2007 Nov 26. — View Citation

Brouard M, Casado M, Djelidi S, Barrandon Y, Farman N. Epithelial sodium channel in human epidermal keratinocytes: expression of its subunits and relation to sodium transport and differentiation. J Cell Sci. 1999 Oct;112 ( Pt 19):3343-52. — View Citation

Farman N, Maubec E, Poeggeler B, Klatte JE, Jaisser F, Paus R. The mineralocorticoid receptor as a novel player in skin biology: beyond the renal horizon? Exp Dermatol. 2010 Feb;19(2):100-7. doi: 10.1111/j.1600-0625.2009.01011.x. Epub 2009 Nov 18. Review. — View Citation

Kenouch S, Lombes M, Delahaye F, Eugene E, Bonvalet JP, Farman N. Human skin as target for aldosterone: coexpression of mineralocorticoid receptors and 11 beta-hydroxysteroid dehydrogenase. J Clin Endocrinol Metab. 1994 Nov;79(5):1334-41. — View Citation

Leyvraz C, Charles RP, Rubera I, Guitard M, Rotman S, Breiden B, Sandhoff K, Hummler E. The epidermal barrier function is dependent on the serine protease CAP1/Prss8. J Cell Biol. 2005 Aug 1;170(3):487-96. — View Citation

List K, Haudenschild CC, Szabo R, Chen W, Wahl SM, Swaim W, Engelholm LH, Behrendt N, Bugge TH. Matriptase/MT-SP1 is required for postnatal survival, epidermal barrier function, hair follicle development, and thymic homeostasis. Oncogene. 2002 May 23;21(23):3765-79. — View Citation

Maubec E, Laouénan C, Deschamps L, Nguyen VT, Scheer-Senyarich I, Wackenheim-Jacobs AC, Steff M, Duhamel S, Tubiana S, Brahimi N, Leclerc-Mercier S, Crickx B, Perret C, Aractingi S, Escoubet B, Duval X, Arnaud P, Jaisser F, Mentré F, Farman N. Topical Mineralocorticoid Receptor Blockade Limits Glucocorticoid-Induced Epidermal Atrophy in Human Skin. J Invest Dermatol. 2015 Jul;135(7):1781-9. doi: 10.1038/jid.2015.44. Epub 2015 Feb 10. — View Citation

Mauro T, Guitard M, Behne M, Oda Y, Crumrine D, Komuves L, Rassner U, Elias PM, Hummler E. The ENaC channel is required for normal epidermal differentiation. J Invest Dermatol. 2002 Apr;118(4):589-94. — View Citation

Messina M, Manieri C, Musso MC, Pastorino R. Oral and topical spironolactone therapies in skin androgenization. Panminerva Med. 1990 Apr-Jun;32(2):49-55. — View Citation

Pérez P, Page A, Bravo A, Del Río M, Giménez-Conti I, Budunova I, Slaga TJ, Jorcano JL. Altered skin development and impaired proliferative and inflammatory responses in transgenic mice overexpressing the glucocorticoid receptor. FASEB J. 2001 Sep;15(11):2030-2. Epub 2001 Jul 24. — View Citation

Roudier-Pujol C, Rochat A, Escoubet B, Eugène E, Barrandon Y, Bonvalet JP, Farman N. Differential expression of epithelial sodium channel subunit mRNAs in rat skin. J Cell Sci. 1996 Feb;109 ( Pt 2):379-85. — View Citation

Sainte Marie Y, Toulon A, Paus R, Maubec E, Cherfa A, Grossin M, Descamps V, Clemessy M, Gasc JM, Peuchmaur M, Glick A, Farman N, Jaisser F. Targeted skin overexpression of the mineralocorticoid receptor in mice causes epidermal atrophy, premature skin barrier formation, eye abnormalities, and alopecia. Am J Pathol. 2007 Sep;171(3):846-60. Epub 2007 Aug 3. — View Citation

Stojadinovic O, Lee B, Vouthounis C, Vukelic S, Pastar I, Blumenberg M, Brem H, Tomic-Canic M. Novel genomic effects of glucocorticoids in epidermal keratinocytes: inhibition of apoptosis, interferon-gamma pathway, and wound healing along with promotion of terminal differentiation. J Biol Chem. 2007 Feb 9;282(6):4021-34. Epub 2006 Nov 9. — View Citation

* Note: There are 13 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	histological measure of epidermal thickness	biopsies will be performed in the center of the treated sites. Epidermal thickness will be measured from the basal lamina to the lower border of the stratum corneum. This will be determined by image analysis from the average of fields per skin section.	day 29	No
Secondary	delay of healing after skin biopsies performed on day 29		days 32, 36, 39, 43, 46, 50	No
Secondary	Dermis thickness evaluated by ultrasound		days 1, 15, 29	No
Secondary	Mineral receptors and glucoreceptors expression ratio performed by immunohistochemistry		day 29	No