Multiple Actinic Keratoses
Conditions
Brief summary
The aim of the study is to compare the efficacy of two photosensitizers, methyl-aminolaevulinate (MAL) and 5-aminolaevulinic nanoemulsion (BF-200 ALA) in the treatment of facial actinic keratosis. We use randomized, double-blinded prospective study design. The efficacy will be assessed clinically, histopathologically and immunohistochemically.
Detailed description
Actinic keratoses (AKs) are superficial premalignant skin lesions that can progress into an invasive or metastatic squamous cell carcinoma. AKs can be treated with photodynamic therapy (PDT), of which cure rate compares to cryo surgery with an excellent cosmesis. In PDT the AK lesions are first curettaged, then a photosensitizer is applied on the skin and let to absorb for 3 hours. The skin is illuminated using a blue or red light source light source depending on the photosensitizer, which induces activation of protoporphyrin IX (PpIX) and phototoxic reaction destroying the cancer cells. The approved photosensitizers in Europe are methyl-aminolevulinic acid cream, (MAL, Metvix™, Galderma), a patch containing 5-aminolevulinic acid (5-ALA, Alacare®, Spirig AG) and 5-aminolevulinic acid gel (BF-200 ALA, Ameluz®, Biofrontera AG) to be used with a red LED light (630-635 nm). In North America a 5-aminolevulinic acid stick (5-ALA, Levulan® Kerastick) can also be used with a blue light source (417 nm). PpIX absorption peaks are within the visual spectrum of light, which allows PpIX daylight activation. During natural daylight PDT (NDL-PDT) protocol, PpIX is continuously activated during its development, whereas in conventional PDT (LED-PDT) using red LED lamps, large amounts of accumulated PpIX are momentarily activated. Since skin field cancerization refers to presence of different degrees of visible and invisible dysplastic changes, the whole area should be treated to prevent the development of non-melanoma skin cancers (NMSCs). NDL-PDT enables treatment of field cancerization in one sitting whereas LED-PDT may need repeated illuminations to cover the whole area. NDL-PDT results in enhanced cost-efficacy due to reduced staff expenses, since there's no need for sensitizer absorption and illumination. At the moment two photosensitizers have marketing authorization in Finland, ALA (Ameluz®) and MAL (Metvix™). We are piloting a study comparing the efficacy of these two light sensitizers in NDL-PDT. The efficacy of the treatments will be assessed clinically, histopathologically and immunohistochemically.
Interventions
DRUGBF-200 ALA cream
The symmetrical treatment areas will be randomized for treatments. First the treatment area will be wiped ethanol. Then sun protection factor (SPF) 20 cream will be applied on all sun-exposed areas of the skin. Then a 0,25mm layer application of Ameluz cream on the area. After appropriate absorption time of 30 minutes, the patients will be taken to the hospital balcony for 2 hour illumination with daylight to accomplish the phototoxic reaction. Maximum dosage will be 2 grams. The treatment will be repeated after 2 weeks for thicker gr II-III lesions with the same protocol.
DRUGMAL cream
The symmetrical treatment areas will be randomized for treatments. First the treatment area will be wiped ethanol. Then SPF20 sun protection cream will be applied on all sun-exposed areas of the skin. Then a 0,25mm layer application of Metvix cream on the area. After appropriate absorption time of 30 minutes, the patientswill be taken to the hospital balcony for 2 hour illumination with daylight to accomplish the phototoxic reaction. Maximum dosage will be 2 grams. The treatment will be repeated after 2 weeks for thicker gr II-III lesions with the same protocol.
Sponsors
Joint Authority for Päijät-Häme Social and Health Care
Study design
Allocation
RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* actinic keratoses symmetrically on face or scalp * age over 18 years * there must be at minumum one ak sized 6mm2 symmetrically on both sides * patients must be able to make the decision to attend independently
Exclusion criteria
* pregnancy * lactation * lack of compliance
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Histological Lesion Clearance | 0 (baseline) and 3 months | Punch biopsies were taken symmetrically on both treatment fields from equally graded \>6 mm AKs prior to treatment and again at 3 months, blinded observer (pathologist). HE- and p53-stainings. Samples not fulfilling the criteria of an AK were defined as healthy or completely cleared. The p53 reactivity expressed as average percentage of positive nuclei in three consecutive high power fields from the region of highest reactivity (\<10 % normal) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Pain | 12 hours | Pain using visual analog scale (VAS 0-10, where 0 is no pain and 10 is the worst pain imaginable) on both treatment sides is assessed in every 30 minutes during 2-hour sun-exposure and afterwards once in two hours until 9 p.m. (treatment day). Of these values, the mean maximal pain is assessed. |
| Clinical Lesion Clearance | 3 months | Clinical lesion clearance is observed by a blinded observer |
Other
| Measure | Time frame | Description |
|---|---|---|
| Adverse Reactions | 1 week | Adverse reactions are evaluated by blinded observer at one week after treatment. A dermatologist will assess which side of the face or scalp presents a stronger reaction. |
Countries
Finland
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| BF-200 ALA vs MAL BF-200 ALA cream and MAL (Metvix, Galderma) used in a randomized split-face design | 13 |
| Total | 13 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | BF-200 ALA vs MAL |
|---|---|
| Age, Continuous | 79.8 years |
| Number of AKs | 177 Number of actinic keratoses (AKs) |
| Sex: Female, Male Female | 6 Participants |
| Sex: Female, Male Male | 7 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 13 / 13 |
| serious Total, serious adverse events | 0 / 13 |
Outcome results
Primary
Histological Lesion Clearance
Punch biopsies were taken symmetrically on both treatment fields from equally graded \>6 mm AKs prior to treatment and again at 3 months, blinded observer (pathologist). HE- and p53-stainings. Samples not fulfilling the criteria of an AK were defined as healthy or completely cleared. The p53 reactivity expressed as average percentage of positive nuclei in three consecutive high power fields from the region of highest reactivity (\<10 % normal)
Time frame: 0 (baseline) and 3 months
Population: Punch biopsies bilaterally on treatment fields
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| BF200 ALA vs MAL | Histological Lesion Clearance | BF-200 ALA | 61.5 percentage of complete clearance |
| BF200 ALA vs MAL | Histological Lesion Clearance | MAL | 38.5 percentage of complete clearance |
p-value: 0.375McNemar
Secondary
Clinical Lesion Clearance
Clinical lesion clearance is observed by a blinded observer
Time frame: 3 months
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| BF200 ALA vs MAL | Clinical Lesion Clearance | BF-200 ALA treated lesions | 84.5 percentage of complete clearance |
| BF200 ALA vs MAL | Clinical Lesion Clearance | MAL treated lesions | 74.2 percentage of complete clearance |
Secondary
Pain
Pain using visual analog scale (VAS 0-10, where 0 is no pain and 10 is the worst pain imaginable) on both treatment sides is assessed in every 30 minutes during 2-hour sun-exposure and afterwards once in two hours until 9 p.m. (treatment day). Of these values, the mean maximal pain is assessed.
Time frame: 12 hours
Population: Patients
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| BF200 ALA vs MAL | Pain | BF-200 ALA treatment sides | 1.7 units on a scale |
| BF200 ALA vs MAL | Pain | MAL treatment sides | 1.9 units on a scale |
Other Pre-specified
Adverse Reactions
Adverse reactions are evaluated by blinded observer at one week after treatment. A dermatologist will assess which side of the face or scalp presents a stronger reaction.
Time frame: 1 week
Population: One week after the first photodynamic therapy (PDT), seven patients had more severe reactions (erythema, crusting) at the site treated with BF-200 ALA, five patients had more severe reactions at the MAL site and one patient showed no difference between sites.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| BF200 ALA vs MAL | Adverse Reactions | MAL treated areas | 5 participants |
| BF200 ALA vs MAL | Adverse Reactions | No difference between the sides | 1 participants |
| BF200 ALA vs MAL | Adverse Reactions | BF-200 ALA treated areas | 7 participants |