Methyl Aminolevulinate 8% and 16% Incubated by 1 and 3 for Actinic Keratoses Treatment

Efficacy of Topical Application of Methyl Aminolevulinate 8% and 16% Mediated by Red Light and Incubation Time of 1 and 3 Hours in the Treatment of Actinic Keratoses on the Face: A Double-Blind Randomized Controlled Clinical Protocol

The objective of this protocol is to compare the efficacy of the topical application of MAL at concentrations of 8% and 16%, mediated by red light, as well as to evaluate the impact of different incubation times (1 or 3 hours) in the treatment of actinic keratoses on the face, with a 6-month follow-up. This parallel-arm, 6-month follow-up randomized controlled clinical trial will consist of 4 groups: G1 - Control Group - MAL 16% irradiated with 643nm and 75J/cm² and 3-hour incubation time (n=36), G2 - MAL 16% and 1-hour incubation (n=36), G3 - MAL 8% - 3 hours (n=36), and G4 - MAL 8% - 1 hour (n=36). The researcher conducting the collection and the participant will be blinded to the interventions. The primary outcome will be the complete remission of the lesion at 6 months. Secondary outcomes will include treatment success (75% reduction in the initial number of lesions), recurrence rate, emergence of SCC, incidence of adverse effects, and improvement in skin texture, wrinkles, and pigmentation using a validated scale. All outcomes will be assessed at 30 days, 3, and 6 months. Quality of life will be evaluated using the Actinic Keratosis Quality of Life questionnaire (AKQoL) at 6 months.

Study Overview

• Status: Not yet recruiting
• Conditions: Actinic Keratoses
• Intervention / Treatment: Procedure: light curettage; Other: Pre irradiation of 3 hour; Other: topical application of 16% methyl aminolevulinate photosensitizer (MAL); Device: Visible light source; Other: Pre irradiation of 1 hour; Other: topical application of 8% methyl aminolevulinate photosensitizer MAL

Detailed Description

The multifocality of actinic keratosis, the unpredictability of lesion evolution with potential progression to squamous cell carcinoma (SCC), and the consequent risk of local extension and metastasis, alongside the recent development of new therapies, make the selection of a therapeutic regimen challenging. The increasing incidence associated economic costs, and impact on quality of life have fostered interest in studying protocols for treating this severe skin condition. The topical application of 16% methyl aminolevulinate (MAL) is well-established in the literature for its local therapeutic effects and ease of application. However, the high cost of medication, long incubation time, and adverse effects such as itching and burning in some patients limit the dissemination of this treatment. Studies are needed to test other protocols of this promising therapy to increase acceptance among patients and professionals. Therefore, the objective of this protocol is to compare the efficacy of the topical application of MAL at concentrations of 8% and 16%, mediated by red light, as well as to evaluate the impact of different incubation times (1 or 3 hours) in the treatment of actinic keratoses on the face, with a 6-month follow-up. This parallel-arm, 6-month follow-up randomized controlled clinical trial will consist of 4 groups: G1 - Control Group - MAL 16% irradiated with 643nm and 75J/cm² and 3-hour incubation time (n=36), G2 - MAL 16% and 1-hour incubation (n=36), G3 - MAL 8% - 3 hours (n=36), and G4 - MAL 8% - 1 hour (n=36). The researcher conducting the collection and the participant will be blinded to the interventions. The primary outcome will be the complete remission of the lesion at 6 months. Secondary outcomes will include treatment success (75% reduction in the initial number of lesions), recurrence rate, emergence of SCC, incidence of adverse effects, and improvement in skin texture, wrinkles, and pigmentation using a validated scale. All outcomes will be assessed at 30 days, 3, and 6 months. Quality of life will be assessed using the Actinic Keratosis Quality of Life questionnaire (AKQoL) at 6 months. If data are normal, they will be subjected to 3-way ANOVA and presented as means ± standard deviation (SD). Otherwise, they will be presented as median and interquartile range and compared using the Kruskall-Wallis and Friedman tests. Categorical variables will be evaluated with the chi-square test, Fisher's exact test, or likelihood ratio test. A p-value < 0.05 will be considered significant.

• Study Type: Interventional
• Enrollment (Estimated): 144
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Ricardo Hideyoshi Kitamura, PhD; Phone Number: 11982807810; Email: annacrth@gmail.com
• Study Contact Backup: Name: Anna CR Horliana, PhD; Phone Number: 13981999848; Email: annacrth@gmail.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• Individuals of both sexes,
• Aged between 40 and 90 years,
• Fitzpatrick skin phototypes I to IV,
• Photodamaged skin with at least five clinically evident actinic keratosis lesions on the face to be treated,
• No prior treatment for at least six months.

Exclusion Criteria:

• Clinically diagnosed infiltrative lesions, as the gold standard treatment is surgical with histopathological evaluation of the lesion (surgery will be performed at no cost to the participant), who will receive guidance and referral for appropriate treatment.
• Photosensitive diseases, such as systemic lupus erythematosus, dermatomyositis, porphyria, among others.
• History of arsenic exposure,
• Known allergy to MAL or similar photosensitizing agents,
• Psychoactive drug abuse,
• Previous radiotherapy at the lesion site(s),
• Participation in another clinical trial,
• Intense tanning at the time of treatment,
• Pregnant or breastfeeding women,
• Local or systemic infection,
• Immunosuppression: uncompensated chronic diseases or emotional disorders considered contraindications to treatment,
• Skin conditions on the neck and anterior chest.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: - Control Group (gold standard - 16% MAL with 3-hour incubation time); Participants will be treated with 16% topical MAL photosensitizer with a 3-hour incubation period. The light source used for skin illumination will be a visible light source (LED) with a wavelength of 643nm (Hygialux LLT1601®, KLD - ANVISA registration number 10245239012).	Procedure: light curettage; Before the treatment, the treated area will be degreased with 0.2% aqueous chlorhexidine. Next, a light curettage will be performed on the face with a sterile curette.; Other: Pre irradiation of 3 hour; A thin layer of the photosensitizing medication, approximately 1 mm thick, will be applied to the participant's facial lesion sites. Then an occlusive dressing will be used to enhance MAL penetration, which will be covered with aluminum foil to prevent ambient light from influencing the protoporphyrin production process. For the PDT technique, the dressing will remain on the face for 3 hour.; Other: topical application of 16% methyl aminolevulinate photosensitizer (MAL); Participants will be treated with 16% topical MAL photosensitizer; Device: Visible light source; Skin illumination will be performed using a visible light source (LED) with a wavelength of 643 nm
Experimental: Experimental Group (16% MAL incubation time - 1 hour); Participants will be treated with 16% topical MAL photosensitizer with a 1-hour incubation period. The light source used for skin illumination will be a visible light source (LED) with a wavelength of 643nm (Hygialux LLT1601®, KLD - ANVISA registration number 10245239012).	Procedure: light curettage; Before the treatment, the treated area will be degreased with 0.2% aqueous chlorhexidine. Next, a light curettage will be performed on the face with a sterile curette.; Other: topical application of 16% methyl aminolevulinate photosensitizer (MAL); Participants will be treated with 16% topical MAL photosensitizer; Device: Visible light source; Skin illumination will be performed using a visible light source (LED) with a wavelength of 643 nm; Other: Pre irradiation of 1 hour; A thin layer of the photosensitizing medication, approximately 1 mm thick, will be applied to the participant's facial lesion sites. Then an occlusive dressing will be used to enhance MAL penetration, which will be covered with aluminum foil to prevent ambient light from influencing the protoporphyrin production process. For the PDT technique, the dressing will remain on the face for 1 hour.
Experimental: Experimental Group (8% MAL incubation time - 3 hour); Participants will be treated with 8% topical MAL photosensitizer with a 3-hour incubation period. The light source used for skin illumination will be a visible light source (LED) with a wavelength of 643nm (Hygialux LLT1601®, KLD - ANVISA registration number 10245239012).	Procedure: light curettage; Before the treatment, the treated area will be degreased with 0.2% aqueous chlorhexidine. Next, a light curettage will be performed on the face with a sterile curette.; Other: Pre irradiation of 3 hour; A thin layer of the photosensitizing medication, approximately 1 mm thick, will be applied to the participant's facial lesion sites. Then an occlusive dressing will be used to enhance MAL penetration, which will be covered with aluminum foil to prevent ambient light from influencing the protoporphyrin production process. For the PDT technique, the dressing will remain on the face for 3 hour.; Device: Visible light source; Skin illumination will be performed using a visible light source (LED) with a wavelength of 643 nm; Other: topical application of 8% methyl aminolevulinate photosensitizer MAL; Participants will be treated with 8% topical MAL photosensitizer
Experimental: Experimental Group (8% MAL incubation time - 1 hour); Participants will be treated with 8% topical MAL photosensitizer with a 1-hour incubation period. The light source used for skin illumination will be a visible light source (LED) with a wavelength of 643nm (Hygialux LLT1601®, KLD - ANVISA registration number 10245239012).	Procedure: light curettage; Before the treatment, the treated area will be degreased with 0.2% aqueous chlorhexidine. Next, a light curettage will be performed on the face with a sterile curette.; Device: Visible light source; Skin illumination will be performed using a visible light source (LED) with a wavelength of 643 nm; Other: Pre irradiation of 1 hour; A thin layer of the photosensitizing medication, approximately 1 mm thick, will be applied to the participant's facial lesion sites. Then an occlusive dressing will be used to enhance MAL penetration, which will be covered with aluminum foil to prevent ambient light from influencing the protoporphyrin production process. For the PDT technique, the dressing will remain on the face for 1 hour.; Other: topical application of 8% methyl aminolevulinate photosensitizer MAL; Participants will be treated with 8% topical MAL photosensitizer

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Complete remission baseline	Quantitative evaluation: A count of the number of lesions with complete response, i.e., those that show total disappearance measurable after treatment, will be performed. These lesions will be clinically evaluated and the number of lesions at these periods will be compared with the initial value (baseline). Both the absolute and relative number of lesions will be considered. To avoid variability in counting, only one researcher will perform the counts.	baseline
Complete remission -30 days	Quantitative evaluation: A count of the number of lesions with complete response, i.e., those that show total disappearance measurable after treatment, will be performed. These lesions will be clinically evaluated and the number of lesions at these periods will be compared with the initial value (baseline). Both the absolute and relative number of lesions will be considered. To avoid variability in counting, only one researcher will perform the counts.	30 days
Complete remission - 3 months	Quantitative evaluation: A count of the number of lesions with complete response, i.e., those that show total disappearance measurable after treatment, will be performed. These lesions will be clinically evaluated and the number of lesions at these periods will be compared with the initial value (baseline). Both the absolute and relative number of lesions will be considered. To avoid variability in counting, only one researcher will perform the counts.	3 months
Complete remission - 6 months	Quantitative evaluation: A count of the number of lesions with complete response, i.e., those that show total disappearance measurable after treatment, will be performed. These lesions will be clinically evaluated and the number of lesions at these periods will be compared with the initial value (baseline). Both the absolute and relative number of lesions will be considered. To avoid variability in counting, only one researcher will perform the counts.	6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Treatment success baseline	Evaluation of the proportion of participants who show at least a 75% reduction in the initial number of actinic keratosis lesions in the treatment area after the last day of treatment.	baseline
Treatment success 30 days	Evaluation of the proportion of participants who show at least a 75% reduction in the initial number of actinic keratosis lesions in the treatment area after the last day of treatment.	30 days
Treatment success 3 months	Evaluation of the proportion of participants who show at least a 75% reduction in the initial number of actinic keratosis lesions in the treatment area after the last day of treatment.	3 months
Treatment success 6 months	Evaluation of the proportion of participants who show at least a 75% reduction in the initial number of actinic keratosis lesions in the treatment area after the last day of treatment.	6 months
Actinic keratoses recurrence rate 30 days	Defined as the reappearance of lesions in previously treated areas. Recurrence evaluation will occur at the same follow-up periods of the study, i.e., at 30 days, 3 months, and 6 months after the end of treatment. Recurrent lesions will be quantified, considering both the absolute and relative number of lesions. These lesions will be monitored and re-treated at the end of the study, unless malignization occurs, in which case they will be treated immediately.	30 days
Actinic keratoses recurrence rate 3 months	Defined as the reappearance of lesions in previously treated areas. Recurrence evaluation will occur at the same follow-up periods of the study, i.e., at 30 days, 3 months, and 6 months after the end of treatment. Recurrent lesions will be quantified, considering both the absolute and relative number of lesions. These lesions will be monitored and re-treated at the end of the study, unless malignization occurs, in which case they will be treated immediately.	3 months
Actinic keratoses recurrence rate 6 months	Defined as the reappearance of lesions in previously treated areas. Recurrence evaluation will occur at the same follow-up periods of the study, i.e., at 30 days, 3 months, and 6 months after the end of treatment. Recurrent lesions will be quantified, considering both the absolute and relative number of lesions. These lesions will be monitored and re-treated at the end of the study, unless malignization occurs, in which case they will be treated immediately.	6 months
Prevention of squamous cell carcinoma 30 days	If malignization of the lesion occurs during the follow-up period, the gold standard treatment, which consists of surgical intervention, will be applied. Participants will be continuously monitored to prevent the development of squamous cell carcinoma in the treatment area throughout the study. The participation of these participants will be maintained, as the follow-ups consist only of follow-up evaluations. The quantification of malignant lesions will be carried out, considering both the absolute and relative numbers.	30 days
Prevention of squamous cell carcinoma 3 months	If malignization of the lesion occurs during the follow-up period, the gold standard treatment, which consists of surgical intervention, will be applied. Participants will be continuously monitored to prevent the development of squamous cell carcinoma in the treatment area throughout the study. The participation of these participants will be maintained, as the follow-ups consist only of follow-up evaluations. The quantification of malignant lesions will be carried out, considering both the absolute and relative numbers.	3 months
Prevention of squamous cell carcinoma 6 months	If malignization of the lesion occurs during the follow-up period, the gold standard treatment, which consists of surgical intervention, will be applied. Participants will be continuously monitored to prevent the development of squamous cell carcinoma in the treatment area throughout the study. The participation of these participants will be maintained, as the follow-ups consist only of follow-up evaluations. The quantification of malignant lesions will be carried out, considering both the absolute and relative numbers.	6 months
Incidence of adverse effects 30 days	The incidence of adverse effects, such as erythema, edema, itching, and peeling, will be monitored through a personal diary filled out by the participant, in which detailed descriptions of any adverse effects will be recorded. This method, as recommended by Jansen et al. (2019), will allow participants to report their symptoms individually. The responsible researcher, a dermatologist specializing in this type of treatment, will offer continuous assistance and follow-up, remaining accessible whenever necessary.	30 days
Incidence of adverse effects 3 months	The incidence of adverse effects, such as erythema, edema, itching, and peeling, will be monitored through a personal diary filled out by the participant, in which detailed descriptions of any adverse effects will be recorded. This method, as recommended by Jansen et al. (2019), will allow participants to report their symptoms individually. The responsible researcher, a dermatologist specializing in this type of treatment, will offer continuous assistance and follow-up, remaining accessible whenever necessary.	3 months
Incidence of adverse effects 6 months	The incidence of adverse effects, such as erythema, edema, itching, and peeling, will be monitored through a personal diary filled out by the participant, in which detailed descriptions of any adverse effects will be recorded. This method, as recommended by Jansen et al. (2019), will allow participants to report their symptoms individually. The responsible researcher, a dermatologist specializing in this type of treatment, will offer continuous assistance and follow-up, remaining accessible whenever necessary.	6 months
Subjective pain assessment 30 days	Subjective pain assessment will be conducted using the Visual Analog Scale (VAS), consisting of a 10 mm line with closed ends, indicating '0' for no pain and '10' for unbearable pain, the worst pain ever felt. Instructions for marking will be consistently provided by the same operator. Each participant will be instructed to mark with a vertical line the point that best reflects the intensity of the pain at the time of evaluation (Heller et al., 2016). These evaluations will be performed weekly until 30 days after treatment, followed by assessments at 3 and 6 months.	30 days
Subjective pain assessment 3 months	Subjective pain assessment will be conducted using the Visual Analog Scale (VAS), consisting of a 10 mm line with closed ends, indicating '0' for no pain and '10' for unbearable pain, the worst pain ever felt. Instructions for marking will be consistently provided by the same operator. Each participant will be instructed to mark with a vertical line the point that best reflects the intensity of the pain at the time of evaluation (Heller et al., 2016). These evaluations will be performed weekly until 30 days after treatment, followed by assessments at 3 and 6 months.	3 months
Subjective pain assessment 6 months	Subjective pain assessment will be conducted using the Visual Analog Scale (VAS), consisting of a 10 mm line with closed ends, indicating '0' for no pain and '10' for unbearable pain, the worst pain ever felt. Instructions for marking will be consistently provided by the same operator. Each participant will be instructed to mark with a vertical line the point that best reflects the intensity of the pain at the time of evaluation (Heller et al., 2016). These evaluations will be performed weekly until 30 days after treatment, followed by assessments at 3 and 6 months.	6 months
Rescue medication 30 days	Rescue medication will be evaluated by the standardized amount of analgesics ingested (paracetamol). At the beginning of the study, each participant will receive a blister pack of paracetamol®, a drug with a purely analgesic effect, as recommended by Jóźwiak-Bebenista (2014). Participants are instructed to keep the blister pack until the end of the experiment and bring it to each consultation. At the end of the study, the amount of tablets used will be evaluated in each group as a parameter for measuring pain.	30 days
Rescue medication 3 months	Rescue medication will be evaluated by the standardized amount of analgesics ingested (paracetamol). At the beginning of the study, each participant will receive a blister pack of paracetamol®, a drug with a purely analgesic effect, as recommended by Jóźwiak-Bebenista (2014). Participants are instructed to keep the blister pack until the end of the experiment and bring it to each consultation. At the end of the study, the amount of tablets used will be evaluated in each group as a parameter for measuring pain.	3 months
Rescue medication 6 months	Rescue medication will be evaluated by the standardized amount of analgesics ingested (paracetamol). At the beginning of the study, each participant will receive a blister pack of paracetamol®, a drug with a purely analgesic effect, as recommended by Jóźwiak-Bebenista (2014). Participants are instructed to keep the blister pack until the end of the experiment and bring it to each consultation. At the end of the study, the amount of tablets used will be evaluated in each group as a parameter for measuring pain.	6 months
Evaluation of skin texture, wrinkles, and pigmentation 30 days	This will be conducted at 30 days, 3 months, and 6 months, using the Tina Alster et al. (2005) scale. This scale, evaluated by professionals and participants themselves, classifies improvements as minimal (<25%), moderate (25%-50%), significant (51%-75%), and excellent (>75%). These evaluations will provide a comprehensive approach to measure the treatment's effectiveness over time.	30 days
Evaluation of skin texture, wrinkles, and pigmentation 3 months	This will be conducted at 30 days, 3 months, and 6 months, using the Tina Alster et al. (2005) scale. This scale, evaluated by professionals and participants themselves, classifies improvements as minimal (<25%), moderate (25%-50%), significant (51%-75%), and excellent (>75%). These evaluations will provide a comprehensive approach to measure the treatment's effectiveness over time.	3 months
Evaluation of skin texture, wrinkles, and pigmentation 6 months	This will be conducted at 30 days, 3 months, and 6 months, using the Tina Alster et al. (2005) scale. This scale, evaluated by professionals and participants themselves, classifies improvements as minimal (<25%), moderate (25%-50%), significant (51%-75%), and excellent (>75%). These evaluations will provide a comprehensive approach to measure the treatment's effectiveness over time.	6 months
Participant satisfaction baseline	Will be assessed through the Actinic Keratosis Quality of Life questionnaire (AKQoL) (Esman et al., 2013) after 6 months and 1 year of treatment. The items will be scored on a standard 4-point Likert scale and summarized into a maximum total score of 32 points. A higher score indicates greater impairment in quality of life. The questionnaire has been translated and validated into Portuguese (Vilhena et al., 2022).	baseline
Participant satisfaction 30 days	Will be assessed through the Actinic Keratosis Quality of Life questionnaire (AKQoL) (Esman et al., 2013) after 6 months and 1 year of treatment. The items will be scored on a standard 4-point Likert scale and summarized into a maximum total score of 32 points. A higher score indicates greater impairment in quality of life. The questionnaire has been translated and validated into Portuguese (Vilhena et al., 2022).	30 days
Participant satisfaction 3 months	Will be assessed through the Actinic Keratosis Quality of Life questionnaire (AKQoL) (Esman et al., 2013) after 6 months and 1 year of treatment. The items will be scored on a standard 4-point Likert scale and summarized into a maximum total score of 32 points. A higher score indicates greater impairment in quality of life. The questionnaire has been translated and validated into Portuguese (Vilhena et al., 2022).	3 months
Participant satisfaction 6 months	Will be assessed through the Actinic Keratosis Quality of Life questionnaire (AKQoL) (Esman et al., 2013) after 6 months and 1 year of treatment. The items will be scored on a standard 4-point Likert scale and summarized into a maximum total score of 32 points. A higher score indicates greater impairment in quality of life. The questionnaire has been translated and validated into Portuguese (Vilhena et al., 2022).	6 months
Satisfaction with Facial Appearance Overall	The FACE-Q (Satisfaction with Facial Appearance Overall) scale consists of nine items assessing satisfaction with overall facial appearance and geometry, using a four-point Likert scale (1 = very dissatisfied to 4 = very satisfied). The questionnaire should be administered before and after aesthetic treatment to measure the patient's perception of symmetry, proportion, and facial freshness. The total score ranges from 9 to 36 and is converted into a 0 to 100 scale, where higher scores indicate greater satisfaction.	baseline
Satisfaction with Facial Appearance Overall	The FACE-Q (Satisfaction with Facial Appearance Overall) scale consists of nine items assessing satisfaction with overall facial appearance and geometry, using a four-point Likert scale (1 = very dissatisfied to 4 = very satisfied). The questionnaire should be administered before and after aesthetic treatment to measure the patient's perception of symmetry, proportion, and facial freshness. The total score ranges from 9 to 36 and is converted into a 0 to 100 scale, where higher scores indicate greater satisfaction.	6 months

Collaborators and Investigators

• Sponsor: University of Nove de Julho

Study record dates

Study Major Dates

• Study Start (Estimated): November 30, 2024
• Primary Completion (Estimated): November 30, 2025
• Study Completion (Estimated): May 30, 2026

Study Registration Dates

• First Submitted: July 11, 2024
• First Submitted That Met QC Criteria: July 11, 2024
• First Posted (Actual): July 18, 2024

Study Record Updates

• Last Update Posted (Actual): October 15, 2024
• Last Update Submitted That Met QC Criteria: October 9, 2024
• Last Verified: October 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Precancerous Conditions; Keratosis, Actinic; Keratosis; Dermatologic Agents; Aminolevulinic Acid; Methyl 5-aminolevulinate; Photosensitizing Agents
• Other Study ID Numbers: 6.715.052

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No