Potential Impact of Patient Vitamin D Status in AK Response to MAL-PDT
Study Details
Study Description
Brief Summary
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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
N/A |
Detailed Description
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.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Other: Conventional MAL-PDT Conventional topical PDT with Methylaminolevulinate 16% in one half of the scalp with multiple AKs. |
Other: 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
|
| Other: 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 |
Other: 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
|
Outcome Measures
Primary Outcome Measures
- Changes From Baseline in Actinic Keratosis - Lesion Base Count. [Change from baseline, 90 days, 180 days and 12 months after the PDT]
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.
- Percentage of Actinic Keratosis (AK) Lesions Cleared [Change from baseline, 90 days, 6 months and 12 months after PDT]
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.
Secondary Outcome Measures
- Pain Scores Immediately Post Illumination [immediately after intervention]
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.
- Change From Baseline in Fluorescence Intensity of PPIX [Baseline and 10 minutes after illumination]
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.
Eligibility Criteria
Criteria
Inclusion Criteria:
-
male gender
-
at least six AKs per field
Exclusion Criteria:
-
history of photosensitivity related disorders
-
active infectious disease,
-
immunosuppression
-
laser or any cosmetic treatment in the previous 6 months
-
other topical agents in the treatment area such as retinoids, 5-fluorouracil,imiquimod or diclofenac sodium in the previous 3 months
-
allergy to MAL or excipients of the cream
-
poor patient compliance.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Universidade de Sao Paulo | Sao Paulo | SP | Brazil | 04543120 |
| 2 | Hospital Das Clinicas Universidade Sao Paulo | Sao Paulo | SP | Brazil |
Sponsors and Collaborators
- University of Sao Paulo
Investigators
- Principal Investigator: Luis A Torezan, MD, Hospital das Clinicas FMUSP Sao Paulo
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- 08/2016
Study Results
Participant Flow
| Recruitment Details | 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). |
|---|---|
| Pre-assignment Detail |
| Arm/Group Title | Calcipotriol Assisted MAL-PDT | Conventional MAL-PDT |
|---|---|---|
| Arm/Group Description | Calcipotriol + MAL-PDT half scalp | MAL-PDT alone half scalp |
| Period Title: Overall Study | ||
| STARTED | 20 | 20 |
| COMPLETED | 20 | 20 |
| NOT COMPLETED | 0 | 0 |
Baseline Characteristics
| Arm/Group Title | All Participants |
|---|---|
| Arm/Group Description | 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 |
| Overall Participants | 20 |
| Age (Count of Participants) | |
| <=18 years |
0
0%
|
| Between 18 and 65 years |
5
25%
|
| >=65 years |
15
75%
|
| Sex: Female, Male (Count of Participants) | |
| Female |
0
0%
|
| Male |
20
100%
|
| Race (NIH/OMB) (Count of Participants) | |
| American Indian or Alaska Native |
0
0%
|
| Asian |
0
0%
|
| Native Hawaiian or Other Pacific Islander |
0
0%
|
| Black or African American |
0
0%
|
| White |
20
100%
|
| More than one race |
0
0%
|
| Unknown or Not Reported |
0
0%
|
| Region of Enrollment (participants) [Number] | |
| Brazil |
20
100%
|
| number of AKs at baseline (number of lesions) [Number] | |
| CAL-PDT side |
290
|
| Conventional PDT |
284
|
| CAL-PDT side grade I |
223
|
| CAL-PDT side grade II |
67
|
| Conventional PDT grade I |
222
|
| Conventional PDT grade II |
62
|
Outcome Measures
| Title | Changes From Baseline in Actinic Keratosis - Lesion Base Count. |
|---|---|
| Description | 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. |
| Time Frame | Change from baseline, 90 days, 180 days and 12 months after the PDT |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Calcipotriol Assisted MAL-PDT | Conventional MAL-PDT |
|---|---|---|
| Arm/Group Description | Calcipotriol 15 days before - once a day intervention: MAL-PDT plus curettage Illumination LED 635 nm 37J/cm2 | intervention: MAL-PDT plus curettage Illumination LED 635 nm 37J/cm2 |
| Measure Participants | 20 | 20 |
| 3 months outcome |
1.15
(0.99)
|
2.65
(1.35)
|
| 6 months outcome |
1.15
(0.93)
|
2.60
(1.14)
|
| 12 months outcome |
1.35
(1.04)
|
3.20
(1.44)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Calcipotriol Assisted MAL-PDT, Conventional MAL-PDT |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | <0.001 |
| Comments | significance level of 5% | |
| Method | Chi-squared | |
| Comments | also, Fisher's exact test and Mann-Whtiney were used for comparing the other variables in the study | |
| Title | Percentage of Actinic Keratosis (AK) Lesions Cleared |
|---|---|
| Description | 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. |
| Time Frame | Change from baseline, 90 days, 6 months and 12 months after PDT |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Calcipotriol Assisted MAL-PDT | Conventional MAL-PDT |
|---|---|---|
| Arm/Group Description | Calcipotriol 15 days before - once a day intervention: MAL-PDT plus curettage Illumination LED 635 nm 37J/cm2 | intervention: MAL-PDT plus curettage Illumination LED 635 nm 37J/cm2 |
| Measure Participants | 20 | 20 |
| 3 months outcome |
92.1
|
82
|
| 6 months outcome |
92.1
|
81.7
|
| 12 months outcome |
90.7
|
77.5
|
| Title | Pain Scores Immediately Post Illumination |
|---|---|
| Description | 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. |
| Time Frame | immediately after intervention |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Calcipotriol Assisted MAL-PDT | Conventional MAL-PDT |
|---|---|---|
| Arm/Group Description | ||
| Measure Participants | 20 | 20 |
| Mean (Standard Deviation) [units on a scale] |
5.4
(1.4)
|
4.0
(0.69)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Calcipotriol Assisted MAL-PDT, Conventional MAL-PDT |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | =0.001 |
| Comments | significance level of 5% | |
| Method | Fisher Exact | |
| Comments | ||
| Title | Change From Baseline in Fluorescence Intensity of PPIX |
|---|---|
| Description | 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. |
| Time Frame | Baseline and 10 minutes after illumination |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Calcipotriol Assisted MAL-PDT | Conventional MAL-PDT |
|---|---|---|
| Arm/Group Description | ||
| Measure Participants | 20 | 20 |
| Mean (Standard Deviation) [arbitrary units] |
3422.85
(1775.19)
|
2688.35
(1746.12)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Calcipotriol Assisted MAL-PDT, Conventional MAL-PDT |
|---|---|---|
| Comments | Student's t-test or the Mann-Whitney test was used according to the assumption of normality of data for PpIX fluorescence intensity | |
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | =0.048 |
| Comments | ||
| Method | Wilcoxon (Mann-Whitney) | |
| Comments | ||
Adverse Events
| Time Frame | side effects collected over 10 days | |||
|---|---|---|---|---|
| Adverse Event Reporting Description | 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 | |||
| Arm/Group Title | Calcipotriol Assisted MAL-PDT | Conventional MAL-PDT | ||
| Arm/Group Description | 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 | 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 | ||
All Cause Mortality |
||||
| Calcipotriol Assisted MAL-PDT | Conventional MAL-PDT | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | / (NaN) | / (NaN) | ||
Serious Adverse Events |
||||
| Calcipotriol Assisted MAL-PDT | Conventional MAL-PDT | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 0/20 (0%) | 0/20 (0%) | ||
Other (Not Including Serious) Adverse Events |
||||
| Calcipotriol Assisted MAL-PDT | Conventional MAL-PDT | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 15/20 (75%) | 12/20 (60%) | ||
| Skin and subcutaneous tissue disorders | ||||
| local skin reactions | 15/20 (75%) | 22 | 12/20 (60%) | 20 |
Limitations/Caveats
More Information
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
| Name/Title | Dr Luis Torezan Associate Professor Dermatology |
|---|---|
| Organization | University of Sao Paulo Medical School Brazil |
| Phone | +551138491888 |
| torezanluis@uol.com.br |
- 08/2016