Topical Application of Imiquimod Gel at Different Concentrations in Actinic Cheilitis

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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Actinic Cheilitis

Intervention / Treatment
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* Drug: Vehicle Gel Base
* Drug: Imiquimod 5% gel
* Drug: Imiquimod 0,05% gel
* Drug: Imiquimod nanoencapsulated 0,05% gel
* Drug: Lip sunscreen 30 Sun Protector Factor (SPF)
* Drug: Dexpanthenol


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Placebo & Standard Treatment<br> | Drug: Vehicle Gel Base<br>* Apply 0.5ml of gel stored in a 1ml syringe over the lip 3 times a week (Mondays, Wednesdays and Fridays) at night for a period of 4 weeks. Gel components: medium molecular weight chitosan, lactic acid 85% and water.<br>Drug: Lip sunscreen 30 Sun Protector Factor (SPF)<br>* Apply sunscreen on the lip 30 minutes every day before sun exposure. Protects against both UVA (ultraviolet A) and UVB (ultraviolet B rays).<br>Drug: Dexpanthenol<br>* Apply dexpanthenol on the lip, two (2) times a day, once in the morning and once in the afternoon. Reduces transepidermic water loss and maintaining the natural smoothness and elasticity of the skin. It accelerates the cell renewal, rebuilds damaged tissues and promote the normal keratinisation of the skin and hair.<br>|
| Experimental: Imiquimod 5% & Standard Treatment<br> | Drug: Imiquimod 5% gel<br>* Apply 0.5ml of gel stored in a 1ml syringe over the lip 3 times a week (Mondays, Wednesdays and Fridays) at night for a period of 4 weeks. Gel components: medium molecular weight chitosan, lactic acid 85% and free form imiquimod 5%.<br>Drug: Lip sunscreen 30 Sun Protector Factor (SPF)<br>* Apply sunscreen on the lip 30 minutes every day before sun exposure. Protects against both UVA (ultraviolet A) and UVB (ultraviolet B rays).<br>Drug: Dexpanthenol<br>* Apply dexpanthenol on the lip, two (2) times a day, once in the morning and once in the afternoon. Reduces transepidermic water loss and maintaining the natural smoothness and elasticity of the skin. It accelerates the cell renewal, rebuilds damaged tissues and promote the normal keratinisation of the skin and hair.<br>|
| Experimental: Imiquimod 0.05% & Standard Treatment<br> | Drug: Imiquimod 0,05% gel<br>* Apply 0.5ml of gel stored in a 1ml syringe over the lip 3 times a week (Mondays, Wednesdays and Fridays) at night for a period of 4 weeks. Gel components: medium molecular weight chitosan, lactic acid 85% and imiquimod 0.05% free form.<br>Drug: Lip sunscreen 30 Sun Protector Factor (SPF)<br>* Apply sunscreen on the lip 30 minutes every day before sun exposure. Protects against both UVA (ultraviolet A) and UVB (ultraviolet B rays).<br>Drug: Dexpanthenol<br>* Apply dexpanthenol on the lip, two (2) times a day, once in the morning and once in the afternoon. Reduces transepidermic water loss and maintaining the natural smoothness and elasticity of the skin. It accelerates the cell renewal, rebuilds damaged tissues and promote the normal keratinisation of the skin and hair.<br>|
| Experimental: Imiquimod nanoencapsulated 0.05% & Standard Treatment<br> | Drug: Imiquimod nanoencapsulated 0,05% gel<br>* Apply 0.5ml of gel stored in a 1ml syringe over the lip 3 times a week (Mondays, Wednesdays and Fridays) at night for a period of 4 weeks. Gel components: medium molecular weight chitosan, lactic acid 85% and imiquomod in a nanoencapsulated suspension at concentration of 0,05%<br>Drug: Lip sunscreen 30 Sun Protector Factor (SPF)<br>* Apply sunscreen on the lip 30 minutes every day before sun exposure. Protects against both UVA (ultraviolet A) and UVB (ultraviolet B rays).<br>Drug: Dexpanthenol<br>* Apply dexpanthenol on the lip, two (2) times a day, once in the morning and once in the afternoon. Reduces transepidermic water loss and maintaining the natural smoothness and elasticity of the skin. It accelerates the cell renewal, rebuilds damaged tissues and promote the normal keratinisation of the skin and hair.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical Response | Clinical analysis of lip photographs based on a classification. The lesions will be graded as: AC Grade I. Dryness and desquamation on the vermilion of lips. AC Grade II. Atrophy on the vermilion's border, presenting soft surfaces and pallid areas with eruptions. Blurred limit between the lip's vermilion border and the skin, or a dark line demarking that limit can be seen. This melanotic line should be different from ephelides or other pigmented lesions. AC Grade III. Rough and squamous areas on the drier parts of the vermilion and hyperkeratotic areas, especially when they spread to the wet lip's mucosa (border between mucosa and semimucosa). AC Grade IV. Ulceration present in one or more sites of the lip's vermillion or Leukoplakia, mainly in more traumatic places, due to the history of pipe or cigarettes consumption. These lesions could suggest that a malignization process would be in progress, especially when they are accompanied by endured areas on palpation. | 30 days after conclusion of treatment | 
| Clinical Response | Clinical analysis of lip photographs based on a classification. The lesions will be graded as: AC Grade I. Dryness and desquamation on the vermilion of lips. AC Grade II. Atrophy on the vermilion's border, presenting soft surfaces and pallid areas with eruptions. Blurred limit between the lip's vermilion border and the skin, or a dark line demarking that limit can be seen. This melanotic line should be different from ephelides or other pigmented lesions. AC Grade III. Rough and squamous areas on the drier parts of the vermilion and hyperkeratotic areas, especially when they spread to the wet lip's mucosa (border between mucosa and semimucosa). AC Grade IV. Ulceration present in one or more sites of the lip's vermillion or Leukoplakia, mainly in more traumatic places, due to the history of pipe or cigarettes consumption. These lesions could suggest that a malignization process would be in progress, especially when they are accompanied by endured areas on palpation. | 180 days after conclusion of treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| General Satisfaction about the medication: Visual Analogue Scale (VAS) | Satisfaction will be self-reported by VAS scale. The visual analogue scale (VAS) will be used to measure general satisfaction of participants to treatment. Participants will be asked to point in to a white paper with a 10cm line, where 0 represents none satisfaction and 10 maximum satisfaction. | VAS scale will be generated at 14 days after beginning of the treatment. | 
| General Satisfaction about the medication: Visual Analogue Scale (VAS) | Satisfaction will be self-reported by VAS scale. The visual analogue scale (VAS) will be used to measure general satisfaction of participants to treatment. Participants will be asked to point in to a white paper with a 10cm line, where 0 represents none satisfaction and 10 maximum satisfaction. | VAS scale will be generated at 28 days after beginning of the treatment. | 
| General Satisfaction about the medication: Visual Analogue Scale (VAS) | Satisfaction will be self-reported by VAS scale. The visual analogue scale (VAS) will be used to measure general satisfaction of participants to treatment. Participants will be asked to point in to a white paper with a 10cm line, where 0 represents none satisfaction and 10 maximum satisfaction. | VAS scale will be generated at 60 days after beginning of the treatment. | 
| General Satisfaction about the medication: Visual Analogue Scale (VAS) | Satisfaction will be self-reported by VAS scale. The visual analogue scale (VAS) will be used to measure general satisfaction of participants to treatment. Participants will be asked to point in to a white paper with a 10cm line, where 0 represents none satisfaction and 10 maximum satisfaction. | VAS scale will be generated at 210 days after beginning of the treatment. | 
| Adverse Events Severity | Adverse effects will be assessed during clinical evaluation at follow-up and with an adverse effects questionnaire.The questionnaire is based on self-reported events followed by a quantification of severity of local and systemic events. The participants are asked to classify the events in a scale of 0 to 3. 0= no sympton, 1- mild, 2-moderate and 3-severe. | The adverse events questionnaire is applied in 14 days after beginning of the treatment. | 
| Adverse Events Severity | Adverse effects will be assessed during clinical evaluation at follow-up and with an adverse effects questionnaire.The questionnaire is based on self-reported events followed by a quantification of severity of local and systemic events. The participants are asked to classify the events in a scale of 0 to 3. 0= no sympton, 1- mild, 2-moderate and 3-severe. | The adverse events questionnaire is applied in 28 days after beginning of the treatment. | 
| Adverse Events Severity | Adverse effects will be assessed during clinical evaluation at follow-up and with an adverse effects questionnaire.The questionnaire is based on self-reported events followed by a quantification of severity of local and systemic events. The participants are asked to classify the events in a scale of 0 to 3. 0= no sympton, 1- mild, 2-moderate and 3-severe. | The adverse events questionnaire is applied in 60 days after beginning of the treatment. | 
| Adverse Events Severity | Adverse effects will be assessed during clinical evaluation at follow-up and with an adverse effects questionnaire.The questionnaire is based on self-reported events followed by a quantification of severity of local and systemic events. The participants are asked to classify the events in a scale of 0 to 3. 0= no sympton, 1- mild, 2-moderate and 3-severe. | The adverse events questionnaire is applied in 210 days after beginning of the treatment. | 
| Maturation epithelial pattern | Upon confirmation of the diagnosis of actinic cheilitis, participants will undergo a noninvasive procedure called exfoliative cytology. With this examination it is possible to analyze morphological changes of the collected cells by light microscopy. The lip mucosa is scraped with cytobrush, which is then used to smear two glass slides. From one of the obtained smears, Papanicolaou stain will be performed. Papanicoloau staining allows assessing different cell types, which are quantified to evaluate epithelial differentiation. | Maturation epithelial pattern analysis will be performed at 28 days after beginning of the treatment. | 
| Maturation epithelial pattern | Upon confirmation of the diagnosis of actinic cheilitis, participants will undergo a noninvasive procedure called exfoliative cytology. With this examination it is possible to analyze morphological changes of the collected cells by light microscopy. The lip mucosa is scraped with cytobrush, which is then used to smear two glass slides. From one of the obtained smears, Papanicolaou stain will be performed. Papanicoloau staining allows assessing different cell types, which are quantified to evaluate epithelial differentiation. | Maturation epithelial pattern analysis will be performed at 60 days after beginning of the treatment. | 
| Maturation epithelial pattern | Upon confirmation of the diagnosis of actinic cheilitis, participants will undergo a noninvasive procedure called exfoliative cytology. With this examination it is possible to analyze morphological changes of the collected cells by light microscopy. The lip mucosa is scraped with cytobrush, which is then used to smear two glass slides. From one of the obtained smears, Papanicolaou stain will be performed. Papanicoloau staining allows assessing different cell types, which are quantified to evaluate epithelial differentiation. | Maturation epithelial pattern analysis will be performed at 210 days after beginning of the treatment. | 
| Cell proliferation - mAgNOR | Upon confirmation of the diagnosis of actinic cheilitis, participants will undergo a noninvasive procedure called exfoliative cytology. The lip mucosa is scraped with cytobrush, which is then used to smear two glass slides. One slide will be stained with AgNOR. With this examination it is possible to analyze cell proliferation activity. From the quantification of AgNORs, the average AgNORs / core (mAgNOR) will be calculated. The low average of AgNOR stained cells indicates lower cell proliferation and a higher average indicates greater proliferation. | mAgNOR analysis will be performed at 28 days after beginning of the treatment. | 
| Cell proliferation - mAgNOR | Upon confirmation of the diagnosis of actinic cheilitis, participants will undergo a noninvasive procedure called exfoliative cytology. The lip mucosa is scraped with cytobrush, which is then used to smear two glass slides. One slide will be stained with AgNOR. With this examination it is possible to analyze cell proliferation activity. From the quantification of AgNORs, the average AgNORs / core (mAgNOR) will be calculated. The low average of AgNOR stained cells indicates lower cell proliferation and a higher average indicates greater proliferation. | mAgNOR analysis will be performed at 60 days after beginning of the treatment. | 
| Cell proliferation - mAgNOR | Upon confirmation of the diagnosis of actinic cheilitis, participants will undergo a noninvasive procedure called exfoliative cytology. The lip mucosa is scraped with cytobrush, which is then used to smear two glass slides. One slide will be stained with AgNOR. With this examination it is possible to analyze cell proliferation activity. From the quantification of AgNORs, the average AgNORs / core (mAgNOR) will be calculated. The low average of AgNOR stained cells indicates lower cell proliferation and a higher average indicates greater proliferation. | mAgNOR analysis will be performed at 210 days after beginning of the treatment. | 
| Cell proliferation - pAgNOR | Upon confirmation of the diagnosis of actinic cheilitis, participants will undergo a noninvasive procedure called exfoliative cytology. The lip mucosa is scraped with cytobrush, which is then used to smear two glass slides. One slide will be stained with AgNOR. With this examination it is possible to analyze cell proliferation activity. A second evaluation parameter will be the percentage of cells with more than 1, 2, 3 and 4 AgNORs / nucleus (pAgNOR). A higher percentage of cells with more than 3 and 4 AgNORs per nucleus indicate greater proliferation. | pAgNOR analysis will be performed at 28 days after beginning of the treatment. | 
| Cell proliferation - pAgNOR | Upon confirmation of the diagnosis of actinic cheilitis, participants will undergo a noninvasive procedure called exfoliative cytology. The lip mucosa is scraped with cytobrush, which is then used to smear two glass slides. One slide will be stained with AgNOR. With this examination it is possible to analyze cell proliferation activity. A second evaluation parameter will be the percentage of cells with more than 1, 2, 3 and 4 AgNORs / nucleus (pAgNOR). A higher percentage of cells with more than 3 and 4 AgNORs per nucleus indicate greater proliferation. | pAgNOR analysis will be performed at 60 days after beginning of the treatment. | 
| Cell proliferation - pAgNOR | Upon confirmation of the diagnosis of actinic cheilitis, participants will undergo a noninvasive procedure called exfoliative cytology. The lip mucosa is scraped with cytobrush, which is then used to smear two glass slides. One slide will be stained with AgNOR. With this examination it is possible to analyze cell proliferation activity. A second evaluation parameter will be the percentage of cells with more than 1, 2, 3 and 4 AgNORs / nucleus (pAgNOR). A higher percentage of cells with more than 3 and 4 AgNORs per nucleus indicate greater proliferation. | pAgNOR analysis will be performed at 210 days after beginning of the treatment. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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imiquimod, nanoencapsulation