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In topical photodynamic therapy (PDT) for non-melanoma skin cancers, a photosensitizing prodrug, 5-aminolaevulinic acid (ALA) or its methylated ester, methyl aminolevulinate (MAL), is converted to the endogenous photosensitizer protoporphyrinIX (PpIX).
Reduced response rates are observed in thicker skin lesions, which may be due to insufficient PpIX accumulation within the target tissue.
To enhance PpIX production,several physical and chemical pretreatments have been suggested. One of the chemical substances proposed to stimulate PpIX production is vitamin D because of its ability of being a keratinocyte pro-differentiating hormone.
Based on in vitro and in animal model studies, we propose to study the potential impact of patient vitamin D pre-treatment in AK response to MAL-PDT.
A randomized, controlled Split -scalp study with Calcipotriol Assisted MAL-PDT versus conventional MAL-PDT for actinic keratosis (AK) is proposed.
Twenty patients ( male gender only) with symmetrically distributed multiple AK lesions on the scalp will be included. Patients must have at least five AKs per field to be eligible.
After simple randomization, one half of the scalp will be treated with Calcipotriol ointment 50 mcg/g (Daivonex, Leo Pharma, Denmark) for 15 consecutive days.
After this period, the entire scalp will be submitted to topical PDT with Methylaminolevulinate 16% (Metvix, Galderma France) under occlusion for 90 minutes and then, illuminated with a light source consisting of a Light Emitting Diode device (LED) at 635 nm ( Aktilite - Photocure, Norway). The total light dose will be 37J/cm2.
Immediately before and after illumination with LED, measurements of the fluorescence intensity will be taken in 3 isolated spots in both sides of the scalp with a spectroscopy deviceUSB 2000+ ( Ocean Optics ® - Dunedin, Fl, USA).
AK lesions will be counted and mapped by a dermatologist not involved in the study before and after 3 months.
All patients will be advised to apply sunscreens 50 + 3x/day for the following 7 days after the procedure.
A 0-10 Visual Analogue Scale (VAS) will be used to measure the pain intensity during the illumination.
Records will be taken after 90 days and compared between sides: side effects, AK lesion response and pain level intensity. Also, a long term follow up will be provided at 6 and 12 months after.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Conventional MAL-PDT | Other | Conventional topical PDT with Methylaminolevulinate 16% in one half of the scalp with multiple AKs. |
|
| Calcipotriol assisted MAL-PDT | Other | Calcipotriol ointment 50 mcg/g applied once a day for 15 consecutive days in one half of the scalp, before Conventional topical PDT |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Conventional MAL-PDT | Other | Curettage of lesions and application of MAl cream 16% for 90 minutes under occlusion followed by LED 635 nm illumination at 37 J/cm2 total dose |
|
| Measure | Description | Time Frame |
|---|---|---|
| Changes From Baseline in Actinic Keratosis - Lesion Base Count. | To compare the efficacy of topical PDT alone versus Calcipotriol assisted PDT for AKs on the scalp. The values in the data table represent the mean (+sd) number of lesions on each side at 3, 6 and 12 months post intervention. Lesion counts include lesions that have not been cleared and also newly emerged lesions ( if new lesions emerge on the treated field) At baseline: number of AKs was 290 on the CAL-PDT side and 284 on the conventional side. | Change from baseline, 90 days, 180 days and 12 months after the PDT |
| Percentage of Actinic Keratosis (AK) Lesions Cleared | AK clearance after PDT and comparison between the sides The values in the data table represent the percentage of AK clearance on each side at 3, 6 and 12 months post intervention. At baseline: 290 on the CAL-PDT side and 284 on the conventional side. | Change from baseline, 90 days, 6 months and 12 months after PDT |
| Measure | Description | Time Frame |
|---|---|---|
| Pain Scores Immediately Post Illumination | Measurement of pain during LED illumination and comparison between the sides with a visual analogue scale (VAS), considering 0 as absence of pain and 10 as the most severe pain. At baseline, before the illumination, there is an absence of pain, which means Score 0 (zero) for all participants before the procedure. Pain is reffered during and after the illumination and measured with the VAS scale, reported by each patient. |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Luis A Torezan, MD | Hospital das Clinicas FMUSP Sao Paulo | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Universidade de Sao Paulo | São Paulo | São Paulo | 04543120 | Brazil | ||
| Hospital Das Clinicas Universidade Sao Paulo |
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All twenty patients completed the 12 -month study. Patients were male, Fitzpatrick skin types I-III and mean age 73.8 years (range 54-89).
| ID | Title | Description |
|---|---|---|
| FG000 | Calcipotriol Assisted MAL-PDT | Calcipotriol + MAL-PDT half scalp |
| FG001 | Conventional MAL-PDT | MAL-PDT alone half scalp |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
20 male patients were selected and enrolled in the study. The eligibility criteria were: male sex, minimum age of 50 years old, at least 6 AKs symmetrically distributed on the scalp, only AKs grades I and II and immunocompetent patients. To receive either Conventional PDT or CAL-PDT on the allocated side of the scalp (right or left)
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| ID | Title | Description |
|---|---|---|
| BG000 | All Participants | Conventional topical PDT with Methylaminolevulinate 16% in one half of the scalp with multiple AKs. Conventional MAL-PDT: Curettage of lesions and application of MAl cream 16% for 90 minutes under occlusion followed by LED 635 nm illumination at 37 J/cm2 total dose Calcipotriol ointment 50 mcg/g applied once a day for 15 consecutive days in one half of the scalp, before Conventional topical PDT Calcipotriol assisted MAL-PDT: Calcipotriol 50 mcg/g for 15 days prior to PDT. Curettage of lesions and application of MAl cream 16% for 90 minutes under occlusion followed by LED 635 nm illumination at 37 J/cm2 total dose |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Changes From Baseline in Actinic Keratosis - Lesion Base Count. | To compare the efficacy of topical PDT alone versus Calcipotriol assisted PDT for AKs on the scalp. The values in the data table represent the mean (+sd) number of lesions on each side at 3, 6 and 12 months post intervention. Lesion counts include lesions that have not been cleared and also newly emerged lesions ( if new lesions emerge on the treated field) At baseline: number of AKs was 290 on the CAL-PDT side and 284 on the conventional side. | Posted | Mean | Standard Deviation | lesions | Change from baseline, 90 days, 180 days and 12 months after the PDT |
|
side effects collected over 10 days
During light exposure patients were asked to evaluate the intensity of pain using a visual analogue scale (VAS), considering 0 as absence of pain and 10 as the most severe pain. Local skin reactions (erythema, edema, pustules, crusts, erosions and ulcerations) were recorded as well as any systemic adverse events during treatment and after follow-up visits. Clinical assessments of the local skin reactions were performed on a pre-defined scale as: 0 = no reaction, + mild, ++ moderate, +++ severe
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Calcipotriol Assisted MAL-PDT | Calcipotriol ointment 50 mcg/g applied once a day for 15 consecutive days in one half of the scalp, before Conventional topical PDT Calcipotriol assisted MAL-PDT: Calcipotriol 50 mcg/g for 15 days prior to PDT. Curettage of lesions and application of MAl cream 16% for 90 minutes under occlusion followed by LED 635 nm illumination at 37 J/cm2 total dose |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| local skin reactions | Skin and subcutaneous tissue disorders | erythema, edema, crusts and pustules. |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr Luis Torezan Associate Professor Dermatology | University of Sao Paulo Medical School Brazil | +551138491888 | torezanluis@uol.com.br |
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| ID | Term |
|---|---|
| D055623 | Keratosis, Actinic |
| D012878 | Skin Neoplasms |
| ID | Term |
|---|---|
| D011230 | Precancerous Conditions |
| D009369 | Neoplasms |
| D007642 | Keratosis |
| D012871 | Skin Diseases |
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| Calcipotriol assisted MAL-PDT | Other | Calcipotriol 50 mcg/g for 15 days prior to PDT. Curettage of lesions and application of MAl cream 16% for 90 minutes under occlusion followed by LED 635 nm illumination at 37 J/cm2 total dose |
|
| immediately after intervention |
| Change From Baseline in Fluorescence Intensity of PPIX | Measurement of PPIX fluorescence on both sides of the scalp before and immediately after LED illumination PpIX fluorescence was measured in three different spot areas on the scalp before and immediately after PDT on each side. The measurements were taken noninvasively in the areas where PpIX fluorescence was more intense, with a handheld fluorescence photometer (USB 2000+ spectroscopy device; Ocean Optics, Dunedin, FL, U.S.A.). The photometer illuminates a circular skin area with a diameter of 1 cm with blue light (400-420 nm), matching the Soret band of PpIX at 405-420 nm. By measuring excitation wavelengths at 600- 700 nm, the corresponding red PpIX fluorescence intensity at 633 nm is detected. Measurements were taken in arbitrary units. The mean PpIX fluorescence value for each side was calculated before and after the treatment. | Baseline and 10 minutes after illumination |
| São Paulo |
| São Paulo |
| Brazil |
| Participants |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| number of AKs at baseline | AKs were clinically divided in 2 categories: grade I and grade II, based on Olsen et al classification. Grade I is a thinner lesion. Grade II is a thicker lesion. Both types co-exist on the same patient and reflects the skin photodamage. | Number | number of lesions |
|
intervention: MAL-PDT plus curettage Illumination LED 635 nm 37J/cm2 |
|
|
|
| Primary | Percentage of Actinic Keratosis (AK) Lesions Cleared | AK clearance after PDT and comparison between the sides The values in the data table represent the percentage of AK clearance on each side at 3, 6 and 12 months post intervention. At baseline: 290 on the CAL-PDT side and 284 on the conventional side. | Posted | Number | percentage of lesions cleared | Change from baseline, 90 days, 6 months and 12 months after PDT |
|
|
|
| Secondary | Pain Scores Immediately Post Illumination | Measurement of pain during LED illumination and comparison between the sides with a visual analogue scale (VAS), considering 0 as absence of pain and 10 as the most severe pain. At baseline, before the illumination, there is an absence of pain, which means Score 0 (zero) for all participants before the procedure. Pain is reffered during and after the illumination and measured with the VAS scale, reported by each patient. | Posted | Mean | Standard Deviation | units on a scale | immediately after intervention |
|
|
|
|
| Secondary | Change From Baseline in Fluorescence Intensity of PPIX | Measurement of PPIX fluorescence on both sides of the scalp before and immediately after LED illumination PpIX fluorescence was measured in three different spot areas on the scalp before and immediately after PDT on each side. The measurements were taken noninvasively in the areas where PpIX fluorescence was more intense, with a handheld fluorescence photometer (USB 2000+ spectroscopy device; Ocean Optics, Dunedin, FL, U.S.A.). The photometer illuminates a circular skin area with a diameter of 1 cm with blue light (400-420 nm), matching the Soret band of PpIX at 405-420 nm. By measuring excitation wavelengths at 600- 700 nm, the corresponding red PpIX fluorescence intensity at 633 nm is detected. Measurements were taken in arbitrary units. The mean PpIX fluorescence value for each side was calculated before and after the treatment. | Posted | Mean | Standard Deviation | arbitrary units | Baseline and 10 minutes after illumination |
|
|
|
|
| 0 |
| 20 |
| 15 |
| 20 |
| EG001 | Conventional MAL-PDT | Conventional topical PDT with Methylaminolevulinate 16% in one half of the scalp with multiple AKs. Conventional MAL-PDT: Curettage of lesions and application of MAl cream 16% for 90 minutes under occlusion followed by LED 635 nm illumination at 37 J/cm2 total dose | 0 | 20 | 12 | 20 |
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| D017437 |
| Skin and Connective Tissue Diseases |
| D009371 | Neoplasms by Site |
| 12 months outcome |
|