Daylight-PDT With MAL for AK and Photodamaged Skin

University Hospital Regensburg58 enrolled

Overview

This study is a multicenter study investigating the clinical efficacy of repetitive daylight-PDT with MAL (Methylaminolevulinate) compared to cryosurgery in regard to prophylaxis and treatment of AKs (actinic keratoses) in the face. Patients will be randomly allocated to treatment groups. 5 PDT (photodynamic therapy) treatment sessions (visits 1-5) will be performed within 18 months. In the control group, cryosurgery will be performed at visit 1, and in case of non-cleared or newly occurred AKs at visits 2-5. In the PDT group the patients will apply a chemical sunscreen (SPF 50+) to the whole face and other light-exposed, unprotected areas of the skin. After at least 15 minutes a lesion preparation of AKs (removal of crusts) will be performed and MAL will be applied in a thin layer to the whole face. Within 30 min after MAL application patients expose themselves to daylight for 2 hours. In the control group, cryosurgery will be performed using liquid nitrogen spray in each AK lesion; this will be done at visit 1 and, if necessary, also at visits 2-5. At visits 2-6, the efficacy of the treatment will be evaluated by the observer by documenting all existing and newly appearing AKs in the face.

This study is a multicenter study investigating the clinical efficacy of repetitive daylight-PDT with MAL compared to cryosurgery in regard to prophylaxis and treatment of AKs in the face. Patients will be randomly allocated to treatment groups. 5 PDT treatment sessions (visits 1-5) will be performed within 18 months. In the control group, cryosurgery will be performed at visit 1, and in case of non-cleared or newly occurred AKs at visits 2-5. Before application of the photosensitizer, an organic sunscreen (Actinica® lotion, LSF 50+) without mineral filters will be applied In the entire face. After an absorption time of approximately 15 minutes and before applying MAL (Metvix®), the surface of the AK lesions will be prepared gently with a curette or a scalpel to remove scales and crusts and roughen the surface of the AK-lesions. This is to facilitate penetration of the cream and light to the AK lesions. After lesion preparation, MAL (Metvix®) will be uniformly applied on the whole face in a thin layer. Within 30 min after MAL application the patients go outside and expose themselves for 2 hours to daylight. Daylight-PDT can be performed from March until October, during non-rainy weather with an outdoor temperature of at least 10° Celsius. Daylight exposure must start at least 3 hours before sunset. At the end of the exposure, residual photosensitizer is washed off and the patients spend the rest of the day indoors. Cryosurgery of AK lesions will be investigated as standard reference therapy. Single freeze-thaw cryosurgery is performed using an open spraying procedure with liquid nitrogen with nozzle size C. After formation of an ice-ball of the required size, freeze time starts. Freeze time should lie between 5 s and 10 s.

Interventions

Daylight photodynamic therapy using Methylaminolevulinate (MAL)DRUG

In the Daylight photodynamic therapy arm the patients will apply a sunscreen to the whole face which is followed by lesion preparation of AKs. Following this, MAL will be applied in a thin layer to the whole face. Within 30 min after MAL application patients expose themselves to daylight for 2 hours. 5 photodynamic therapy treatment sessions (visits 1-5) will be performed within 18 months.

CryosurgeryPROCEDURE

In the control group, cryosurgery as standard reference therapy will be performed at visit 1, and in case of non-cleared or newly occurred AKs at visits 2-5. Cryosurgery of AK lesions will be investigated as standard reference therapy. Single freeze-thaw cryosurgery is performed using an open spraying procedure with liquid nitrogen with nozzle size C. After formation of an ice-ball of the required size, freeze time starts. Freeze time should lie between 5 s and 10 s.

Eligibility

Sex: ALLMin age: 40 Years

Medical Language ↔ Plain English

Inclusion Criteria: * Written informed consent has been signed prior to or at Screening Visit * Male and female patients with Fitzpatrick skin type I-IV * Age \> 40 years * Negative pregnancy test in women of childbearing age * Women in child-bearing age using highly efficient contraceptive methods (\<1% failure rate per year) * Clinical diagnosis of actinic keratosis (AK) * A minimum of five non-hyperkeratotic, non-pigmented AK lesions in the face. * Glogau Photodamage Classification Type II (moderate) - IV (severe) Exclusion Criteria: * Diagnosis of porphyria * Hyperkeratotic or pigmented AK in the face * Malignant skin tumors in the face or on the capillitium, requiring treatment * Patients with clinically relevant suppression of the immune system (e.g. drug induced, infection) or organ transplant patients * Pregnancy or lactation * Planned aesthetic treatments in the face in the next 24 months (filler, peeling, botulinumtoxin, skin resurfacing) * Known intolerance or allergy to MAL or to any other ingredient of Metvix® 160mg/g cream * Known intolerance to Actinica® lotion * Photosensitivity * Suspected lack of compliance (e.g. due to dementia) * Simultaneous participation in another clinical study or participation in another clinical study in the 30 days directly preceding inclusion * Concomitant UV-phototherapy * Skin diseases that might interfere with response evaluation of study treatment * Skin sun sensitivity type V or VI according to Fitzpatrick * PDT in the face during 6 months preceding study treatment * Non-permitted medication: * Topical treatment in the face during 4 weeks preceding study treatment with diclofenac, hydrochinone, peeling, 5-FU, ingenolmebutate, retinoids, podophyllin, azelaic acid, imiquimod or other agents, that could interfere with the evaluation of the efficacy of the study treatment, according to the investigator. * Systemic treatment with retinoids * Conditions that might interfere with the ability to understand the study and thus give written informed consent * Rejuvenating treatments of the face during 3 months preceding study treatment, including filler, botulinumtoxin and IPL

Outcomes

Primary Outcomes

The cumulative number of observed AKs at time points 2 to 6 (3 months after the first treatment to 24 months after the first treatment).

Newly occured AK lesions are counted at visit 2, visit 3, visit 4, visit 5 and visit 6. The number of newly occured AK lesions during the study are added up, therefore we included the term "cumulative".

Time frame: 24 months after the first treatment

Secondary Outcomes

Complete clearance of AKs on lesion basis

completely cleared AK lesions The first treatment ist performed at day 0 The second treatment is performed 3 months after the first treatment. The third treatment is performed 3 months after the second treatment. The fourth treatment is performed 6 months after the third treatment. The fifth treatment is performed 6 months after the fourth treatment.

Time frame: This outcome measure is assessed three months after the first and the second treatment and 6 months after the third, fourth and fifth treatment.

Complete clearance of AKs on patient basis

completely cleared AK lesions on patient basis The first treatment ist performed at day 0 The second treatment is performed 3 months after the first treatment. The third treatment is performed 3 months after the second treatment. The fourth treatment is performed 6 months after the third treatment. The fifth treatment is performed 6 months after the fourth treatment.

Time frame: This outcome measure is assessed three months after the first and the second treatment and 6 months after the third, fourth and fifth treatment.

Photodamage parameters (fine lines, mottled pigmentation, tactile roughness, teleangiectasias, sallowness and global score for photoaging) will be evaluated on a 5-point scale according to Dover et al.

Photodamage parameters will be evaluated on a 5-point scale according to Dover et al. at all visits during the study The first treatment ist performed at day 0 (visit 1) The second treatment is performed 3 months after the first treatment (visit 2) The third treatment is performed 3 months after the second treatment (visit 3) The fourth treatment is performed 6 months after the third treatment (visit 4) The fifth treatment is performed 6 months after the fourth treatment (visit 5) The last visit is performed 6 months after the fifth treatment (visit 6)

Time frame: This outcome measure is assessed at day 0 (= the first treatment), three months after the first and the second treatment and 6 months after the third, fourth and fifth treatment.

Visual pain score

For evaluation of tolerability of daylight-PDT and cryosurgery, a pain score (VAS) will be assessed and documented. The first treatment ist performed at day 0 (visit 1) The second treatment is performed 3 months after the first treatment (visit 2) The third treatment is performed 3 months after the second treatment (visit 3) The fourth treatment is performed 6 months after the third treatment (visit 4) The fifth treatment is performed 6 months after the fourth treatment (visit 5) The last visit is performed 6 months after the fifth treatment (visit 6)

Time frame: This outcome measure is assessed at day 0 (= the first treatment), three months after the first and the second treatment and 6 months after the third, fourth and fifth treatment

Adverse events

All adverse events and serious adverse events will be adequately documented. The first treatment ist performed at day 0 (visit 1) The second treatment is performed 3 months after the first treatment (visit 2) The third treatment is performed 3 months after the second treatment (visit 3) The fourth treatment is performed 6 months after the third treatment (visit 4) The fifth treatment is performed 6 months after the fourth treatment (visit 5) The last visit is performed 6 months after the fifth treatment (visit 6)

Time frame: This outcome measure is assessed at day 0 (= the first treatment), three months after the first and the second treatment and 6 months after the third, fourth and fifth treatment

Patient satisfaction with cosmetic results

For evaluation of satisfaction with cosmetic results, patients and investigators fill in a standardized rating scale The first treatment ist performed at day 0 (visit 1) The second treatment is performed 3 months after the first treatment (visit 2) The third treatment is performed 3 months after the second treatment (visit 3) The fourth treatment is performed 6 months after the third treatment (visit 4) The fifth treatment is performed 6 months after the fourth treatment (visit 5) The last visit is performed 6 months after the fifth treatment (visit 6)

Time frame: This outcome measure is assessed three months after day 0 and the second treatment and 6 months after the third, fourth and fifth treatment

Skin-related quality of life

For evaluation of skin-related quality of life, study participants fill in the Dermatology Life Quality Index, a 10-item questionnaire for routine clinical use. Patients are asked about the impact of their AK and photodamaged skin and its treatment on their lives. Patients' quality of life is expressed in a single score ranging from 0 (no impact) to 30 (severe impact).

Time frame: This outcome measure is assessed at day 0 and 24 months after day 0