Neoplasms

Skin and Connective Tissue Diseases

All Conditions

Keratosis, Actinic

Keratosis

Skin Diseases

Precancerous Conditions

Dermatologic Agents

All Drugs and Chemicals

Methyl 5-aminolevulinate

Aminolevulinic Acid

Photosensitizing Agents

Metvix natural daylight photodynamic therapy and Metvix conventional photodynamic therapy

Metvix natural daylight photodynamic therapy and Metvix-placebo conventional photodynamic therapy

Metvix natural daylight photodynamic therapy

NDL-PDT

c-PDT

Metvix placebo conventional photodynamic therapy

placebo c-PDT

Nicole Basset Seguin, PhD, MD

Bibiana Perez Garcia, MD

Rianne Gerritsen, PhD, MD

Rolf-Markus Sziemies, PhD, MD

Ingrid Synnerstad, PhD, MD

This study was to be conducted as a multi-centre, randomized, investigator-blinded, active and vehicle-controlled, intra-individual (split-face/scalp) non-inferiority (regarding efficacy) and superiority (regarding pain) study.

The primary purpose of this study is to demonstrate the non-inferiority of NDL-PDT compared to c-PDT in terms of lesion complete response rate.

2 intra-individual groups:

* Metvix NDL-PDT / Metvix c-PDT
* Metvix NDL-PDT / Placebo c-PDT

Phase 3b Study of Metvix NDL-PDT Versus Metvix c-PDT in Subjects With Actinic Keratoses

Multi-centre, Randomized, Investigator-blind, Intra-individual Active and Vehicle-controlled Study, Comparing Metvix Natural Daylight Photodynamic Therapy Versus Metvix Conventional Photodynamic Therapy in Subjects With Actinic Keratosis

The lesion complete response rate was defined as the percentage of pre-existing and treated lesions at Baseline that were assessed as clear (complete disappearance of the lesion, visually and by palpation) at Week 12. New lesions or the lesions in non-complete response were not not considered in the lesion response assessment. This outcome measure was analyzed as an intra-individual comparison between Metvix NDL-PDT on one side of the face/scalp and Metvix vehicle cream (placebo) c-PDT on the contralateral side (Group I).

Galderma R&D

Metvix natural daylight photodynamic therapy treated side

Metvix conventional photodynamic therapy treated side

Placebo conventional photodynamic therapy treated side

Placebo c-PDT

AE occuring outside the treated area + systemic AE

Unspecific Treated Side

Participants applied single dose of Metvix cream topically followed by NDL-PDT (test treatment) on one half-face/scalp and on the contra-lateral side of face/scalp applied Metvix cream topically followed by c- PDT (active comparator) on Day 0 (Baseline).

Group 1

Participants applied a single dose of Metvix cream topically followed by NDL-PDT (test treatment) on one half-face/scalp and on the contra-lateral side of face/scalp applied Metvix vehicle cream (placebo) followed by c-PDT on Day 0 (Baseline).

Group 2

Total

Age, Categorical

Sex: Female, Male

Race

Fitzpatrick skin phototype is a system used to describe a person's skin type. It ranges from skin phototype I to III. Where, skin phototype I = pale white skin, always burns easily, never tans; skin phototype II = fair skin, always burns easily, tans minimally and with difficulty; skin phototype III = darker white skin, burns minimally, tans gradually and uniformly.

Phototype

Duration of AK (years)

CTA Coordinator

Participants applied topically a single dose of Metvix cream followed by NDL-PDT on Day 0 (Baseline).

Group I: Metvix NDL-PDT

Participants applied topically a single dose of Metvix cream followed by C-PDT on Day 0 (Baseline).

Group I: Metvix c-PDT

Intent-to-treat (ITT) population included entire population enrolled and randomized. ITT analysis imputed missing data using a worst case approach and considered the lesions with missed lesion response assessment as not responded (ITT/Worst-case) lesions.

Percentage (%) Change From Baseline in Total Lesion Complete Response at Week 12 in Group 1

Overall Study

Participant's AKs in facial skin or scalp are first clinically graded and demarcated in two symmetric treatment areas on different sides of face. The areas will be curettaged thinly and next a SPF20 sun protection cream is applied on all sun-exposed areas of the skin. Then a 0,25mm-thick layer of BF-200 ALA (aminolevulinic acid) gel is applied on one treatment side and MAL (methyl 5-aminolevulinate) cream on the other side. The sides will be randomized and the participant doesn't know which side is treated with which light sensitizer. After appropriate absorption time of 30 minutes the patients will be taken to the hospital balcony or yard for 2 hour illumination with natural daylight to accomplish the phototoxic reaction. Maximum dosage of light sensitizer will be 2 grams.

A 0,25mm-thick layer of BF-200 ALA (aminolevulinic acid, Ameluz®) light sensitizer gel is applied on one randomized treatment side of face.

A 0,25mm-thick layer of MAL (methyl 5-aminolevulinate, Metvix®) light sensitizer cream is applied on one randomized treatment side of face.

Janne Rasanen, Lic. Med.

Mari Gronroos, D.Med.Sc.

Noora Neittaanmaki-Perttu, D.Med.Sc.

Mari Salmivuori, Lic. Med.

Leea Ylitalo, D.Med.Sc.

Johanna Hagman, D.Med.Sc.

Ida Knutar, Lic. Med.

This study compares two photosensitizing creams' BF-200 ALA's (aminolevulinic acid, Ameluz®) and MAL's (methyl 5-aminolevulinate, Metvix®) efficacy on actinic keratoses in natural daylight photodynamic therapy (NDL-PDT). The participants' facial skin or scalp will be randomized in two sides and one side is treated with BF-200 ALA and the other side with MAL. Result of the treatment is assessed with clinical examination 12 months after treatment. The investigators will also compare delayed skin reactions after treatment and cost-effectiveness of both photosensitizer creams.

Photodynamic therapy (PDT) is a widely used method in dermatology clinics for treatment of superficial skin cancers and premalignant lesions. Actinic keratoses (AKs) are premalignant skin lesions which develop due to long-lasting sun exposure and in time can progress into squamocellular skin cancer if left untreated. The incidence of AKs and skin cancers is rapidly booming as the elderly population increases in western countries. It is crucial to treat AKs early and effectively considering their tendency to progress into malign cancer. The current general consensus for treating AKs is to treat large sun-damaged skin areas simultaneously instead of separate AK lesions. Term "skin field cancerization" refers to presence of different degrees of visible and invisible dysplastic changes in widely sun-damaged skin. Natural daylight mediated photodynamic therapy (NDL-PDT) is a well-suited method for treating large field-cancerized skin areas.

In PDT a photosensitizing cream is applied on the skin and let to absorb. After absorption to the skin cells the photosensitizer changes into protoporphyrin IX (PpIX). PpIX reacts with visible light causing a phototoxic reaction which destroys cancer cells targetedly. After absorption the skin can be illuminated using a red lamp (conventional PDT) or natural daylight (NDL-PDT) as the absorption spectrum peaks of PpIX are within the visual spectrum of light.

In Finland the approved photosensitizers for PDT are methyl 5-aminolevulinate cream (MAL, Metvix®, Galderma) and aminolevulinic acid gel (BF-200 ALA, Ameluz®, Biofrontera AG). They both have been clinically studied and proved effective in conventional PDT but in NDL-PDT mainly MAL has been in focus of studies. To our knowledge there is only research report concerning the use of BF-200 ALA in NDL-PDT (Neittaanmaki-Perttu et al 2014) which is a study of our own research group. In this study BF-200 ALA appeared to be more effective than MAL.

Daylight PDT for Actinic Keratoses: a Multicentre Study Comparing Two Photosensitizers (BF-200 ALA Versus MAL)

Daylight Mediated Photodynamic Therapy for Actinic Keratoses: a Multicentre Study Comparing Two Photosensitizers (BF-200 ALA Versus MAL)

The participants will come to clinic 5-7 days after treatment and nurse will photograph both treatment sides. Primary treatment reaction of skin will be single-blindedly assessed from the photographs. A dermatologist will assess which side of the face or scalp presents a stronger reaction.

Researchers will analyze the cost-efficacy of the treatments using decision tree, sensitivity analysis, ICER and QALY-analyses to decide with treatment modality is more preferable. The differences in cost-efficacy will most likely depend on the light sensitizer costs and their efficacy on the treated lesions.

Participant's AKs in the treatment areas are counted and categorized clinically in three grades I-III (Olsen et al. 1991) before the NDL-PDT treatment. The clinical healing of actinic keratoses will be assessed by a dermatologist 12 months after the treatment.

Participants will be asked to fill visual analogue scales (VAS) about pain experienced on both treatment sides of the face or scalp. Pain is assessed during the DL-PDT and after the treatment until the evening.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Phase 3b Study of Metvix NDL-PDT Versus Metvix c-PDT in Subjects With Actinic Keratoses	NCT01821391	Actinic Keratos...	NDL-PDT c-PDT placebo c-PDT	18 Years -	Galderma R&D
Daylight PDT for Actinic Keratoses: a Multicentre Study Comparing Two Photosensitizers (BF-200 ALA Versus MAL)	NCT02464709	Actinic Keratos... Natural Dayligh...	Aminolevulinic ... Methyl 5-aminol...	18 Years -	Joint Authority for Päijät-Häme Social and Health Care

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