This was a placebo controlled, double blind, randomized phase II dose-response study to evaluate the efficacy and safety of BF-200 ALA (containing the active ingredient 5 - aminolevulinic acid- ALA) used with photodynamic therapy (PDT) in patients with actinic keratosis (AK).

The study was performed to define the effective therapeutic dose of the active pharmaceutical ingredient (ALA) in a nanoemulsion formulation in the treatment of actinic keratosis (AK) with topical PDT and to assess the efficacy of topical PDT with a new nanoemulsion formulation of ALA in the treatment of AK. The efficacy of BF-200 ALA was calculated by the AK clearance rate, defined as the proportion of AK lesions showing complete remission 12 weeks after PDT treatment.

Subjects of two study centres provided plasma and urine samples for the quantification of ALA and its metabolite, the active photosensitizer protoporphyrin IX (PpIX).

Inclusion Criteria:

• The subjects were willing and able to sign the informed consent form.
• Men and women aged between 18 and 85 years.
• Had a general good and stable health condition as confirmed by a physical examination and by medical history.
• The subjects accepted to abstain from sunbathing and the solarium during the study.
• The subjects had at least 3 but not more than 10 clinically confirmed AK target lesion of mild to moderate intensity within the face or bald scalp (excluding eyelids, lips and mucosa), i.e. AK grade I and II. Grade I AK lesions presented as flat, pink maculae without signs of hyperkeratosis and erythema.
• The AK lesions had to be discrete and quantifiable; the distance from one lesion to its neighbour lesion was greater than 1.5 cm.
• The diameter of each AK lesion was not less than 0.5 cm and not greater than 1.5 cm.
• The subjects were free of any significant physical abnormalities (e.g., tattoos, dermatoses) in the potential treatment area that could cause difficulty with examination or final evaluation.
• The subjects were willing to stop using moisturizers and any other topical treatments with anti-aging products, vitamin A, vitamin C, and/or vitamin E containing ointments and creams, and green tea preparations during the study within the treatment area. Sunscreens was allowed, but was not to be applied in the treatment area within approximately 24 hours of a clinic visit with lesion count.
• Only women of childbearing potential who used a highly effective method of contraception and who had a negative serum pregnancy test were allowed to participate in this study.

Exclusion Criteria:

• Had a known hypersensitivity to ALA.

• Had received any other medication known to affect AK 3 months before or during the study.

• Were under immunosuppressive therapy.

• Suffered from porphyria.

• Showed hypersensitivity to porphyrins.

• Suffered from photodermatoses.

• Had inherited or acquired coagulation defects.

• Received medication with hypericin or systemically acting drugs with phototoxic or photoallergic potential within 8 weeks prior to treatment with study drug and PDT

• Had evidence of clinically significant, unstable medical conditions such as

  • a metastatic tumour or a tumour with a high probability of metastatic spread
  • cardiovascular (NYHA class III, IV)
  • immunosuppressive
  • haematological, hepatic, renal, neurological, endocrine
  • collagen-vascular
  • gastrointestinal.

• Subjects with clinically stable medical conditions including, but not limited to the following diseases were allowed to be included into the study, if the medication taken for the treatment of the disease did not match the criteria of the excluded or disallowed medications listed in points 11 and 12 below:

  • controlled hypertension
  • diabetes mellitus type II
  • hypercholesterinaemia
  • osteoarthritis

• Had currently other malignant or benign tumours of the skin within the treatment area (e.g., malignant melanoma, basal cell carcinoma, squamous cell carcinoma).

• Had received the following treatments for any indication in the treatment area within the designated time period before PDT treatment with ALA:

• Topical steroids - 4 weeks

• Topical retinoids - 6 weeks

• Topical diclofenac preparations - 6 weeks

• Topical 5-fluorouracil preparations - 6 weeks

• Topical immunomodulators - 6 weeks

• Surgical excision (except biopsy for diagnostic confirmation) - 6 weeks

• Curettage - 4 weeks

• Cryo-, thermo- or chemodestruction - 6 weeks

• PDT - 6 weeks

• Therapeutic UV-Radiation - 6 weeks

• Had received the following systemic treatments within the designated period before PDT treatment with ALA:

• Interferon - 6 weeks

• Immunomodulators or immunosuppressive therapies - 10 weeks

• Cytotoxic drugs - 6 months

• Investigational drugs - 8 weeks

• Drugs known to have major organ toxicity - 8 weeks

• Corticosteroids (oral or injectable) - 6 weeks

• Inhaled corticosteroids (>1200 µg/day for beclomethasone, or >600 µg/day for fluticasone) - 4 weeks

• A previous treatment with ALA.

• Known allergy to polysorbate 80, caprylic/capric acid triglycerides, isopropyl alcohol, disodium phosphate dihydrate, sodium hydroxide, hydrochloric acid, propylene glycol, methyl parahydroxybenzoate, or propyl parahydroxybenzoate.

• Were known to be pregnant or lactating (currently or within the past 3 months).

• Had any dermatological disease in the treatment area or surrounding area that might be exacerbated by treatment with topical ALA or cause difficulty with examination (e.g. psoriasis, eczema).

• Show cornu cutaneum like alterations of the skin in the face or on the bald scalp (target area).

• Were currently or within the past 8 weeks participating in another clinical study.

• Had active chemical dependency or alcoholism as assessed by the investigator.

  • Topical steroids for the treatment of dermatological diseases (e.g. atopic dermatitis, lichen planus) in locations other than in treatment area were allowed during the study provided the amount used did not exceed 2 mg fluorinated steroids daily for more than 1 week or 6 mg beclomethasone for more than 1 week.