Clinical trial NCT04219358: Topical Application of Imiquimod Gel at Different Concentrations in Actinic Cheilitis
Official title: Evaluation of Topical Application of 5% Imiquimod, 0.05% Imiquimod and 0.05% Nanoencapsulated Imiquimod Gel in the Treatment of Actinic Cheilitis: a Randomized Controlled Trial
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
Conditions: Actinic Cheilitis
Keywords: imiquimod
nanoencapsulation
Lead sponsor: Hospital de Clinicas de Porto Alegre
Sponsor class: OTHER
Collaborators: name: Federal University of Rio Grande do Sul
First posted: 2020-01-07
Enrollment: 49
Sex: ALL
Minimum age (years): 18
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Actinic cheilitis is a potentially malignant lesion on the lower lip, which can progress to more serious illnesses such as cancer if not treated. Usually treatment of this condition is only based on clinical appearance, but there is no established cure treatment. Topical imiquimod is a medicine indicated for the treatment of skin diseases, but it has not yet been proven to treat actinic cheilitis. In this research, the investigator's aim is to evaluate the response to actinic cheilitis treatment with the current standard treatment compared to high and low concentration imiquimod topical formulations.

Detailed description: Three formulations are used in this research: imiquimod 5%, imiquimod 0.05% e imiquimod nanoencapsulated 0.05%. Nanoencapsulation is a process that concentrates the drug into a capsule not visible to the naked eye, allowing it to penetrate skin more easily and will only release the drug at the lesion site. The drug is presented in a free form inside the gel in the others formulations.

Eligibility criteria: Inclusion Criteria:

* Individuals with clinical and histopathological diagnosis of actinic cheilitis;
* No previous lip treatment with Imiquimod.

Exclusion Criteria:

* Present lesions suspected of squamous cell carcinoma of the lip.
* Previous history of lip cancer treatment.
* Prior treatment other than standard treatment.
* History of allergic reactions to imiquimod or any other component of the formulas.

Primary outcomes:
measure: Clinical Response
timeFrame: 30 days after conclusion of treatment
measure: Clinical Response
timeFrame: 180 days after conclusion of treatment
Secondary outcomes:
measure: General Satisfaction about the medication: Visual Analogue Scale (VAS)
timeFrame: VAS scale will be generated at 14 days after beginning of the treatment.
measure: General Satisfaction about the medication: Visual Analogue Scale (VAS)
timeFrame: VAS scale will be generated at 28 days after beginning of the treatment.
measure: General Satisfaction about the medication: Visual Analogue Scale (VAS)
timeFrame: VAS scale will be generated at 60 days after beginning of the treatment.
measure: General Satisfaction about the medication: Visual Analogue Scale (VAS)
timeFrame: VAS scale will be generated at 210 days after beginning of the treatment.
measure: Adverse Events Severity
timeFrame: The adverse events questionnaire is applied in 14 days after beginning of the treatment.
measure: Adverse Events Severity
timeFrame: The adverse events questionnaire is applied in 28 days after beginning of the treatment.
measure: Adverse Events Severity
timeFrame: The adverse events questionnaire is applied in 60 days after beginning of the treatment.
measure: Adverse Events Severity
timeFrame: The adverse events questionnaire is applied in 210 days after beginning of the treatment.
measure: Maturation epithelial pattern
timeFrame: Maturation epithelial pattern analysis will be performed at 28 days after beginning of the treatment.
measure: Maturation epithelial pattern
timeFrame: Maturation epithelial pattern analysis will be performed at 60 days after beginning of the treatment.
measure: Maturation epithelial pattern
timeFrame: Maturation epithelial pattern analysis will be performed at 210 days after beginning of the treatment.
measure: Cell proliferation - mAgNOR
timeFrame: mAgNOR analysis will be performed at 28 days after beginning of the treatment.
measure: Cell proliferation - mAgNOR
timeFrame: mAgNOR analysis will be performed at 60 days after beginning of the treatment.
measure: Cell proliferation - mAgNOR
timeFrame: mAgNOR analysis will be performed at 210 days after beginning of the treatment.
measure: Cell proliferation - pAgNOR
timeFrame: pAgNOR analysis will be performed at 28 days after beginning of the treatment.
measure: Cell proliferation - pAgNOR
timeFrame: pAgNOR analysis will be performed at 60 days after beginning of the treatment.
measure: Cell proliferation - pAgNOR
timeFrame: pAgNOR analysis will be performed at 210 days after beginning of the treatment.
Other outcomes:
Locations:
city: Porto Alegre
country: Brazil
facility: Hospital de Clínicas de Porto Alegre
state: Rio Grande Do Sul
city: Porto Alegre
country: Brazil
facility: School of Dentistry - Universidade Federal do Rio Grande do Sul
state: Rio Grande Do Sul
Study officials:
affiliation: Federal University of Rio Grande do Sul
name: Fernanda Visioli, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Poitevin NA, Rodrigues MS, Weigert KL, Macedo CLR, Dos Santos RB. Actinic cheilitis: proposition and reproducibility of a clinical criterion. BDJ Open. 2017 Aug 4;3:17016. doi: 10.1038/bdjopen.2017.16. eCollection 2017.
citation: Bernardi A, Frozza RL, Jager E, Figueiro F, Bavaresco L, Salbego C, Pohlmann AR, Guterres SS, Battastini AM. Selective cytotoxicity of indomethacin and indomethacin ethyl ester-loaded nanocapsules against glioma cell lines: an in vitro study. Eur J Pharmacol. 2008 May 31;586(1-3):24-34. doi: 10.1016/j.ejphar.2008.02.026. Epub 2008 Feb 19.
citation: Bernardi A, Zilberstein AC, Jager E, Campos MM, Morrone FB, Calixto JB, Pohlmann AR, Guterres SS, Battastini AM. Effects of indomethacin-loaded nanocapsules in experimental models of inflammation in rats. Br J Pharmacol. 2009 Oct;158(4):1104-11. doi: 10.1111/j.1476-5381.2009.00244.x. Epub 2009 May 6.
citation: Bernardi A, Braganhol E, Jager E, Figueiro F, Edelweiss MI, Pohlmann AR, Guterres SS, Battastini AM. Indomethacin-loaded nanocapsules treatment reduces in vivo glioblastoma growth in a rat glioma model. Cancer Lett. 2009 Aug 18;281(1):53-63. doi: 10.1016/j.canlet.2009.02.018. Epub 2009 Mar 14.
citation: Swanson N, Abramovits W, Berman B, Kulp J, Rigel DS, Levy S. Imiquimod 2.5% and 3.75% for the treatment of actinic keratoses: results of two placebo-controlled studies of daily application to the face and balding scalp for two 2-week cycles. J Am Acad Dermatol. 2010 Apr;62(4):582-90. doi: 10.1016/j.jaad.2009.07.004. Epub 2010 Feb 4.
citation: Sotiriou E, Lallas A, Goussi C, Apalla Z, Trigoni A, Chovarda E, Ioannides D. Sequential use of photodynamic therapy and imiquimod 5% cream for the treatment of actinic cheilitis: a 12-month follow-up study. Br J Dermatol. 2011 Oct;165(4):888-92. doi: 10.1111/j.1365-2133.2011.10478.x. Epub 2011 Sep 15.
citation: Smith KJ, Germain M, Yeager J, Skelton H. Topical 5% imiquimod for the therapy of actinic cheilitis. J Am Acad Dermatol. 2002 Oct;47(4):497-501. doi: 10.1067/mjd.2002.126266.
citation: McDonald C, Laverick S, Fleming CJ, White SJ. Treatment of actinic cheilitis with imiquimod 5% and a retractor on the lower lip: clinical and histological outcomes in 5 patients. Br J Oral Maxillofac Surg. 2010 Sep;48(6):473-6. doi: 10.1016/j.bjoms.2009.08.024.
citation: Manganaro AM, Will MJ, Poulos E. Actinic cheilitis: a premalignant condition. Gen Dent. 1997 Sep-Oct;45(5):492-4.
citation: Lundeen RC, Langlais RP, Terezhalmy GT. Sunscreen protection for lip mucosa: a review and update. J Am Dent Assoc. 1985 Oct;111(4):617-21. doi: 10.14219/jada.archive.1985.0157.
citation: Lebwohl M, Dinehart S, Whiting D, Lee PK, Tawfik N, Jorizzo J, Lee JH, Fox TL. Imiquimod 5% cream for the treatment of actinic keratosis: results from two phase III, randomized, double-blind, parallel group, vehicle-controlled trials. J Am Acad Dermatol. 2004 May;50(5):714-21. doi: 10.1016/j.jaad.2003.12.010.
citation: Krawtchenko N, Roewert-Huber J, Ulrich M, Mann I, Sterry W, Stockfleth E. A randomised study of topical 5% imiquimod vs. topical 5-fluorouracil vs. cryosurgery in immunocompetent patients with actinic keratoses: a comparison of clinical and histological outcomes including 1-year follow-up. Br J Dermatol. 2007 Dec;157 Suppl 2:34-40. doi: 10.1111/j.1365-2133.2007.08271.x.
citation: Kopera D, Kerl H. Visualization and treatment of subclinical actinic keratoses with topical imiquimod 5% cream: an observational study. Biomed Res Int. 2014;2014:135916. doi: 10.1155/2014/135916. Epub 2014 May 11.
citation: Kaugars GE, Pillion T, Svirsky JA, Page DG, Burns JC, Abbey LM. Actinic cheilitis: a review of 152 cases. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 1999 Aug;88(2):181-6. doi: 10.1016/s1079-2104(99)70115-0.
citation: Jorizzo J, Dinehart S, Matheson R, Moore JK, Ling M, Fox TL, McRae S, Fielder S, Lee JH. Vehicle-controlled, double-blind, randomized study of imiquimod 5% cream applied 3 days per week in one or two courses of treatment for actinic keratoses on the head. J Am Acad Dermatol. 2007 Aug;57(2):265-8. doi: 10.1016/j.jaad.2007.01.047. Epub 2007 May 18.
citation: Greenberg HL, Cohen JL, Rosen T, Orengo I. Severe reaction to 5% imiquimod cream with excellent clinical and cosmetic outcomes. J Drugs Dermatol. 2007 Apr;6(4):452-8.
citation: Gebauer K, Shumack S, Cowen PS. Effect of dosing frequency on the safety and efficacy of imiquimod 5% cream for treatment of actinic keratosis on the forearms and hands: a phase II, randomized placebo-controlled trial. Br J Dermatol. 2009 Oct;161(4):897-903. doi: 10.1111/j.1365-2133.2009.09260.x. Epub 2009 May 26.
citation: A Gaspari A, Tyring SK, Rosen T. Beyond a decade of 5% imiquimod topical therapy. J Drugs Dermatol. 2009 May;8(5):467-74.
citation: Frank LA, Chaves PS, D'Amore CM, Contri RV, Frank AG, Beck RC, Pohlmann AR, Buffon A, Guterres SS. The use of chitosan as cationic coating or gel vehicle for polymeric nanocapsules: Increasing penetration and adhesion of imiquimod in vaginal tissue. Eur J Pharm Biopharm. 2017 May;114:202-212. doi: 10.1016/j.ejpb.2017.01.021. Epub 2017 Feb 1.
citation: Frank LA, Sandri G, D'Autilia F, Contri RV, Bonferoni MC, Caramella C, Frank AG, Pohlmann AR, Guterres SS. Chitosan gel containing polymeric nanocapsules: a new formulation for vaginal drug delivery. Int J Nanomedicine. 2014 Jun 28;9:3151-61. doi: 10.2147/IJN.S62599. eCollection 2014.
citation: Ferreira AM, de Souza Lucena EE, de Oliveira TC, da Silveira E, de Oliveira PT, de Lima KC. Prevalence and factors associated with oral potentially malignant disorders in Brazil's rural workers. Oral Dis. 2016 Sep;22(6):536-42. doi: 10.1111/odi.12488. Epub 2016 May 17.
citation: Falagas ME, Angelousi AG, Peppas G. Imiquimod for the treatment of actinic keratosis: A meta-analysis of randomized controlled trials. J Am Acad Dermatol. 2006 Sep;55(3):537-8. doi: 10.1016/j.jaad.2006.05.030. No abstract available.
citation: Eigentler TK, Kamin A, Weide BM, Breuninger H, Caroli UM, Mohrle M, Radny P, Garbe C. A phase III, randomized, open label study to evaluate the safety and efficacy of imiquimod 5% cream applied thrice weekly for 8 and 12 weeks in the treatment of low-risk nodular basal cell carcinoma. J Am Acad Dermatol. 2007 Oct;57(4):616-21. doi: 10.1016/j.jaad.2007.05.022. Epub 2007 Jul 3.
citation: Dufresne RG Jr, Curlin MU. Actinic cheilitis. A treatment review. Dermatol Surg. 1997 Jan;23(1):15-21.
citation: dos Santos LR, Cernea CR, Kowalski LP, Carneiro PC, Soto MN, Nishio S, Hojaij FC, Dutra Junior A, Britto e Silva Filho G, Ferraz AR. Squamous-cell carcinoma of the lower lip: a retrospective study of 58 patients. Sao Paulo Med J. 1996 Mar-Apr;114(2):1117-26. doi: 10.1590/s1516-31801996000200003.
citation: Daniel FI, Alves SR, Vieira DS, Biz MT, Daniel IW, Modolo F. Immunohistochemical expression of DNA methyltransferases 1, 3a, and 3b in actinic cheilitis and lip squamous cell carcinomas. J Oral Pathol Med. 2016 Nov;45(10):774-779. doi: 10.1111/jop.12453. Epub 2016 May 9.
citation: de Souza Lucena EE, Costa DC, da Silveira EJ, Lima KC. Prevalence and factors associated to actinic cheilitis in beach workers. Oral Dis. 2012 Sep;18(6):575-9. doi: 10.1111/j.1601-0825.2012.01910.x. Epub 2012 Feb 15.
citation: Contri RV, Katzer T, Ourique AF, da Silva AL, Beck RC, Pohlmann AR, Guterres SS. Combined effect of polymeric nanocapsules and chitosan hydrogel on the increase of capsaicinoids adhesion to the skin surface. J Biomed Nanotechnol. 2014 May;10(5):820-30. doi: 10.1166/jbn.2014.1752.
citation: Couvreur P, Barratt G, Fattal E, Legrand P, Vauthier C. Nanocapsule technology: a review. Crit Rev Ther Drug Carrier Syst. 2002;19(2):99-134. doi: 10.1615/critrevtherdrugcarriersyst.v19.i2.10.
citation: Contri RV, Frank LA, Kaiser M, Pohlmann AR, Guterres SS. The use of nanoencapsulation to decrease human skin irritation caused by capsaicinoids. Int J Nanomedicine. 2014 Feb 12;9:951-62. doi: 10.2147/IJN.S56579. eCollection 2014.
citation: Cavalcante AS, Anbinder AL, Carvalho YR. Actinic cheilitis: clinical and histological features. J Oral Maxillofac Surg. 2008 Mar;66(3):498-503. doi: 10.1016/j.joms.2006.09.016.
citation: Cataldo E, Doku HC. Solar cheilitis. J Dermatol Surg Oncol. 1981 Dec;7(12):989-95. doi: 10.1111/j.1524-4725.1981.tb00203.x.
citation: Bulcao RP, Freitas FA, Venturini CG, Dallegrave E, Durgante J, Goethel G, Cerski CT, Zielinsky P, Pohlmann AR, Guterres SS, Garcia SC. Acute and subchronic toxicity evaluation of poly(epsilon-caprolactone) lipid-core nanocapsules in rats. Toxicol Sci. 2013 Mar;132(1):162-76. doi: 10.1093/toxsci/kfs334. Epub 2012 Dec 12.
citation: Bulcao RP, de Freitas FA, Dallegrave E, Venturini CG, Baierle M, Durgante J, Sauer E, Cassini C, Cerski CT, Zielinsky P, Salvador M, Pohlmann AR, Guterres SS, Garcia SC. In vivo toxicological evaluation of polymeric nanocapsules after intradermal administration. Eur J Pharm Biopharm. 2014 Feb;86(2):167-77. doi: 10.1016/j.ejpb.2013.04.001. Epub 2013 May 2.
citation: Spyridonos P, Gaitanis G, Tzaphlidou M, Bassukas ID. Spatial fuzzy c-means algorithm with adaptive fuzzy exponent selection for robust vermilion border detection in healthy and diseased lower lips. Comput Methods Programs Biomed. 2014 May;114(3):291-301. doi: 10.1016/j.cmpb.2014.02.017. Epub 2014 Mar 6.