Vulvar Lichen Sclerosus: Comparison Between Clobetasol Propionate, Photodynamic Therapy and Low-Intensity Laser

Vulvar Lichen Sclerosus Clinical Trial

— VLSCBCPPTLIL  

Official title:

Vulvar Lichen Sclerosus: Therapeutic Comparison Between Clobetasol Propionate, Photodynamic Therapy and Low-Intensity Laser

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02416531
• Other study ID #: Lichen-768168
• Status: Completed
• Phase: N/A
• First received: March 25, 2015
• Last updated: October 24, 2017
• Start date: January 2015
• Est. completion date: October 2017

Study information

• Verified date: October 2017
• Source: University of Nove de Julho
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Vulvar lichen sclerosus (VLS) is a lymphocyte-mediated disease of unknown etiology that can cause intense itching as well stenosis, hindering the evacuation and urination. It can also limit the sex life due to severe local pruritus, pain and dyspareunia (pain during sexual intercourse). The standard treatment for this disease is the use of topical corticosteroids to reduce the clinical symptoms and to try to increase disease-free intervals. Photodynamic therapy (PDT), a treatment that associates a light radiation with a photosensitizing agent and low-level laser therapy (LLLT) are therapies that can promote effective immunomodulatory responses at the application site by means of photophysical and photochemical phenomena from the molecular to the systemic level, which promote their use in chronic dermatoses. The aim is to study and compare the effects of PDT, LLLT, and topical corticosteroid in VLS evaluating clinical, histological, immunohistochemical and spectroscopic responses. The study will be prospective, randomized, and controlled, in a population of 60 women with histological diagnoses of VLS, enrolled on the outpatient clinic of Genitoscopy Department of the Pérola Byington Hospital in São Paulo. There will be 3 treatments groups: PDT, LLLT and topical corticosteroid, where will be allocated by randomization 20 patients in each one. The clinical course will be monitored by measuring local temperature, itching, clamping (atrophy), and the appearance of the lesion. Histologically, the slides will be classified according to the Hewitt grading and will have the ordering of collagen fibers quantified. Immunohistochemical analysis will be done using the markers IFN-γ, TGF-β, CD4, CD8, IL-1, p53 and Ki-67. Finally, the spectroscopic evaluation will be done by reflectance. Descriptive and inferential statistical analyses will be conducted to compare the groups and for associations between different responses.

Description:

Dosimetry and Experimental Groups: There is no dosimetric protocol established for the treatment of VLS with PDT, nor with LLLT. According to the literature, energy densities range from 9 to 150 J/cm2 and power densities from 40 to 700 mW/cm2, not to mention work that do not report the dosimetry used. As such, the dosimetry to be used in this study is based on a pilot clinical study performed by our group.

The patients will be randomized into 3 groups with 20 patients in each one:

Group GC: Corticosteroid over the whole vulva. Clobetasol propionate 0.05% ointment applied once daily at a dose of 1 g/application (1 g sachets) for 4 weeks.

Group GPDT: Localized photodynamic therapy at 8 points of the vulva. Methylene blue 0.01% intralesional, λ = 660 ± 10 nm, P = 100 mW, PD = 510 mW/cm2, E = 4 J, ED = 20 J/cm2, t = 40 s, once a week for 4 weeks.

Group GLLLT: Localized low-level laser therapy at 8 points of the vulva. The same parameters as for GPDT, except for the methylene blue, once a week for 4 weeks.

Analyses: The histological and immunohistochemical analyses will be performed before and 30 days after the start of treatment, whereas clinical analysis will be performed weekly on treatment days for the GPDT and GLLLT groups. The control group will not be seen weekly because the standard treatment is performed by the patients themselves, in their own homes, for 30 days as recommended by the International Society for the Study of Vulvar Disease (ISSVD).

After treatments the patients will be followed for verification of recorrence during one year, at minimum.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 30
• Est. completion date: October 2017
• Est. primary completion date: August 2016
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• adult female patients (aged over 18 years);

• vulvar lichen sclerosus diagnosed histologically;

• normal level of cortisol confirmed by blood test.

Exclusion Criteria:

• adult female patients under the age of 18;

• patients with any kind of ongoing cancer and/or AIDS or coagulopathy, pregnant or breastfeeding women;

• patients using corticosteroids, immunosuppressants or anticoagulants;

• patients with renal, hepatic or pulmonary-cardiovascular failure;

• patients who have undergone any kind of organ transplantation in the last three years.

Related Conditions & MeSH terms

• Lichen Sclerosus et Atrophicus
• Vulvar Lichen Sclerosus

Intervention

Drug:
• Clobetasol propionate
Clobetasol propionate 0.05% ointment applied once daily at a dose of 1 g/application (1 g sachets) for 4 weeks.

Radiation:
• Photodynamic therapy
Methylene blue 0.01% intralesional, ? = 660 ± 10 nm, P = 100 mW, PD = 510 mW/cm2, E = 4 J, ED = 20 J/cm2, t = 40 s, once a week for 4 weeks
• Low level laser therapy
? = 660 ± 10 nm, P = 100 mW, PD = 510 mW/cm2, E = 4 J, ED = 20 J/cm2, t = 40 s, once a week for 4 weeks

Locations

Country	Name	City	State
Brazil	Hospital Pérola Byington	São Paulo	SP

Sponsors (2)

Lead Sponsor	Collaborator
Daniela de Fátima Teixeira da Silva	Hospital Perola Byington

Country where clinical trial is conducted

Brazil, 

References & Publications (21)

Biniszkiewicz T, Olejek A, Kozak-Darmas I, Sieron A. Therapeutic effects of 5-ALA-induced photodynamic therapy in vulvar lichen sclerosus. Photodiagnosis Photodyn Ther. 2005 Jun;2(2):157-60. doi: 10.1016/S1572-1000(05)00062-1. Epub 2005 Aug 3. — View Citation

Brodrick B, Belkin ZR, Goldstein AT. Influence of treatments on prognosis for vulvar lichen sclerosus: facts and controversies. Clin Dermatol. 2013 Nov-Dec;31(6):780-6. doi: 10.1016/j.clindermatol.2013.05.017. Review. — View Citation

Burrows LJ, Creasey A, Goldstein AT. The treatment of vulvar lichen sclerosus and female sexual dysfunction. J Sex Med. 2011 Jan;8(1):219-22. doi: 10.1111/j.1743-6109.2010.02077.x. Epub 2010 Oct 18. — View Citation

Gambichler T, Kammann S, Tigges C, Kobus S, Skrygan M, Meier JJ, Köhler CU, Scola N, Stücker M, Bechara FG, Altmeyer P, Kreuter A. Cell cycle regulation and proliferation in lichen sclerosus. Regul Pept. 2011 Apr 11;167(2-3):209-14. doi: 10.1016/j.regpep.2011.02.003. Epub 2011 Feb 15. — View Citation

Gambichler T, Terras S, Kreuter A, Skrygan M. Altered global methylation and hydroxymethylation status in vulvar lichen sclerosus: further support for epigenetic mechanisms. Br J Dermatol. 2014 Mar;170(3):687-93. doi: 10.1111/bjd.12702. — View Citation

Hantschmann P, Sterzer S, Jeschke U, Friese K. P53 expression in vulvar carcinoma, vulvar intraepithelial neoplasia, squamous cell hyperplasia and lichen sclerosus. Anticancer Res. 2005 May-Jun;25(3A):1739-45. — View Citation

Hillemanns P, Untch M, Pröve F, Baumgartner R, Hillemanns M, Korell M. Photodynamic therapy of vulvar lichen sclerosus with 5-aminolevulinic acid. Obstet Gynecol. 1999 Jan;93(1):71-4. — View Citation

Kreuter A, Wischnewski J, Terras S, Altmeyer P, Stücker M, Gambichler T. Coexistence of lichen sclerosus and morphea: a retrospective analysis of 472 patients with localized scleroderma from a German tertiary referral center. J Am Acad Dermatol. 2012 Dec;67(6):1157-62. doi: 10.1016/j.jaad.2012.04.003. Epub 2012 Apr 24. — View Citation

Lipkin D, Kwon Y. Therapies and nursing care of women with vulvar dermatologic disorders. J Obstet Gynecol Neonatal Nurs. 2014 Mar-Apr;43(2):246-52. doi: 10.1111/1552-6909.12286. Epub 2014 Feb 6. Review. — View Citation

Monsálvez V, Rivera R, Vanaclocha F. [Lichen sclerosus]. Actas Dermosifiliogr. 2010 Jan-Feb;101(1):31-8. Review. Spanish. — View Citation

Murphy R. Lichen sclerosus. Dermatol Clin. 2010 Oct;28(4):707-15. doi: 10.1016/j.det.2010.07.006. Review. — View Citation

Olejek A, Steplewska K, Gabriel A, Kozak-Darmas I, Jarek A, Kellas-Sleczka S, Bydlinski F, Sieron-Stoltny K, Horak S, Chelmicki A, Sieron A. Efficacy of photodynamic therapy in vulvar lichen sclerosus treatment based on immunohistochemical analysis of CD34, CD44, myelin basic protein, and Ki67 antibodies. Int J Gynecol Cancer. 2010 Jul;20(5):879-87. doi: 10.1111/IGC.0b013e3181d94f05. — View Citation

Osiecka BJ, Nockowski P, Jurczyszyn K, Ziólkowski P. Photodynamic therapy of vulvar lichen sclerosus et atrophicus in a woman with hypothyreosis--case report. Photodiagnosis Photodyn Ther. 2012 Jun;9(2):186-8. doi: 10.1016/j.pdpdt.2012.02.002. Epub 2012 Mar 27. — View Citation

Oyama N, Chan I, Neill SM, Hamada T, South AP, Wessagowit V, Wojnarowska F, D'Cruz D, Hughes GJ, Black MM, McGrath JA. Autoantibodies to extracellular matrix protein 1 in lichen sclerosus. Lancet. 2003 Jul 12;362(9378):118-23. — View Citation

Pérez-López FR, Ceausu I, Depypere H, Erel CT, Lambrinoudaki I, Rees M, Schenck-Gustafsson K, Tremollieres F, van der Schouw YT, Simoncini T; EMAS, Spanish Menopause society. EMAS clinical guide: vulvar lichen sclerosus in peri and postmenopausal women. Maturitas. 2013 Mar;74(3):279-82. doi: 10.1016/j.maturitas.2012.12.006. Epub 2013 Jan 3. — View Citation

Romero A, Hernández-Núñez A, Córdoba-Guijarro S, Arias-Palomo D, Borbujo-Martínez J. Treatment of recalcitrant erosive vulvar lichen sclerosus with photodynamic therapy. J Am Acad Dermatol. 2007 Aug;57(2 Suppl):S46-7. — View Citation

Selim MA, Hoang MP. A histologic review of vulvar inflammatory dermatoses and intraepithelial neoplasm. Dermatol Clin. 2010 Oct;28(4):649-67. doi: 10.1016/j.det.2010.07.005. Epub 2010 Aug 30. Review. — View Citation

Sotiriou E, Panagiotidou D, Ioannidis D. An open trial of 5-aminolevulinic acid photodynamic therapy for vulvar lichen sclerosus. Eur J Obstet Gynecol Reprod Biol. 2008 Dec;141(2):187-8. doi: 10.1016/j.ejogrb.2008.07.027. Epub 2008 Sep 7. — View Citation

Terlou A, Santegoets LA, van der Meijden WI, Heijmans-Antonissen C, Swagemakers SM, van der Spek PJ, Ewing PC, van Beurden M, Helmerhorst TJ, Blok LJ. An autoimmune phenotype in vulvar lichen sclerosus and lichen planus: a Th1 response and high levels of microRNA-155. J Invest Dermatol. 2012 Mar;132(3 Pt 1):658-66. doi: 10.1038/jid.2011.369. Epub 2011 Nov 24. — View Citation

Terras S, Gambichler T, Moritz RK, Stücker M, Kreuter A. UV-A1 phototherapy vs clobetasol propionate, 0.05%, in the treatment of vulvar lichen sclerosus: a randomized clinical trial. JAMA Dermatol. 2014 Jun;150(6):621-7. doi: 10.1001/jamadermatol.2013.7733. — View Citation

Thorstensen KA, Birenbaum DL. Recognition and management of vulvar dermatologic conditions: lichen sclerosus, lichen planus, and lichen simplex chronicus. J Midwifery Womens Health. 2012 May-Jun;57(3):260-75. doi: 10.1111/j.1542-2011.2012.00175.x. Review. — View Citation

* Note: There are 21 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change from baseline in biopsies at 1 month.	Biopsies will be performed at two points: at baseline to confirm the VLS and subsequent inclusion in the research protocol, and at the end of 30 days to investigate the prognosis after treatment.	Participants will be followed for 1 month during VLS's treatment.
Secondary	Count cells per mm2 by immunohistochemical reaction of IFN-?, TGF-ß, CD4, CD8, IL-1, p53 and Ki-67.	Once deparaffinized, the tissue samples will be subjected to antigen retrieval, endogenous enzyme blocking, background blocking, incubations of antibodies, and counter-staining according to the instructions of the manufacturers. The cells that are positively stained by the immunohistochemical reaction will be counted with the aid of ImageJ software (National Institutes of Health, Maryland, USA) by two independent pathologists without prior knowledge of the experimental groups.	Participants will be followed for 1 month during VLS's treatment.
Secondary	Percentage of relative reflectance as assessed by In-Vivo Reflectance Spectroscopy.	A portable spectrophotometer (400-900 nm) comprising a light source and a fiber-optic probe will be used directly on the surface of the vulvar skin in areas affected by VLS and in healthy areas of the same patients. Relative spectra will be obtained for the wavelengths corresponding to those of the therapeutic window, and the percentage of relative reflectance will be calculated.	Participants will be followed for 1 month during VLS's treatment.
Secondary	Temperature, as assessed by infrared thermographic camera, in Celsius degrees.	Measurements will be recorded as images in all sessions before, during, and after irradiation to observe the thermal fluctuation in the procedures.	Participants will be followed for 1 month during VLS's treatment.
Secondary	Itching, as assessed by Visual Analog Scale.	In each session, the patients will be asked about the intensity of vulvar itching to assess its severity and duration, before and after irradiation, according to a visual analog scale.	Participants will be followed for 1 month during VLS's treatment.
Secondary	Clamping, as assessed by digital caliper, in mm.	The clamping of the lesion to monitor skin atrophy will be done before irradiation at each session, using a digital caliper, transversely and longitudinally in relation to the labia majora.	Participants will be followed for 1 month during VLS's treatment.
Secondary	Area, as assessed by digital camera, in cm2.	The appearance and area of the lesion will be monitored with a digital camera at every session, before irradiation. To facilitate measurements, a metric scale will be rested on all vulvas for the photos. The areas of the lesions will be quantified using ImageJ software (National Institutes of Health, Maryland, USA).	Participants will be followed for 1 month during VLS's treatment.
Secondary	Collagen birefringence, as assessed by polarized light microscope, in nm.	The correlation between birefringence and collagen ordering has been used since the 1960s. To the present date, polarized-light microscopy is an efficient method to quantify the change in collagen birefringence due to the effects of different agents. Since atrophy of the skin is a characteristic symptom of patients with VLS, the more detailed study of collagen fibers will elucidate the interaction of radiation with this type of tissue.	Participants will be followed for 1 month during VLS's treatment.