Evaluation of Efficacy and Safety of BF-200 ALA Used With Photodynamic Therapy in Patients With Actinic Keratosis.

A Randomized, Double-Blind, Phase III Multi-Center Study Evaluating the Safety and Efficacy of BF-200 ALA Versus Placebo in the Treatment of Actinic Keratosis (AK) When Using PDT

The aim of the study was to evaluate the efficacy and safety of BF-200 ALA (Ameluz) used with photodynamic therapy (PDT) in patients suffering from actinic keratosis.

The treatment comprised of one PDT session. If 12 weeks after PDT all lesions were cleared the patient entered the follow-up period. In case of remaining lesions or not completely cleared lesions the patient received a second PDT on the same day. The final assessment was performed 12 weeks after the last PDT and the patient moved to the follow-up phase.

Inclusion Criteria:

• Subjects were willing and able to sign informed consent form.

• Men and women aged between 18 and 85 years inclusive.

• Subjects had a general good and stable health condition as confirmed by a physical examination and by medical history.

• 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 7, 10, 11 and 12 of the exclusion criteria:

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

• Subjects accepted to abstain from sunbathing and the solarium during the study.

• Subjects had at least 4 but not more than 8 clinically confirmed actinic keratosis (AK) target lesions of mild to moderate intensity within the face or bald scalp (excluding eyelids, lips and mucosa), i.e. AK grade I and II according to Olsen et. al. 1991.

• To document and confirm the diagnosis of the investigators:

  • Photodocumentation of a representative lesion had to be evaluated and confirmed by an independent expert.
  • A pre-study biopsy had to be taken from a second representative AK lesion and was histopathologically evaluated by a dermato-pathological expert.

• If the evaluation of the photo by the independent reviewer could not confirm the diagnosis of the investigator, then the biopsy result decided whether the subject was eligible for the study.

• The AK lesions had to be discrete and quantifiable; the distance from one lesion to its neighbor lesion was greater than 1.0 cm

• The diameter of each AK lesion was not less than 0.5 cm and not greater than 1.5 cm. The size of each baseline AK lesion was recorded by measuring the two largest perpendicular diameters. To describe irregular lesions (ellipsoidal) investigators measured the major and minor axis. Both axes had to be above the minimum of 0.5 cm and less than 1.5 cm.

• The subjects were free of any significant physical abnormalities (e.g., tattoos, dermatoses) in the potential treatment area that might 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 were allowed, but were not to be applied in the treatment area within approximately 24 hours before a clinical visit with lesion count.

• Women of childbearing potential were only allowed to participate in this study, if they used a highly effective method of contraception and had a negative serum pregnancy test.

Exclusion Criteria:

• Had known hypersensitivity to 5-aminolevulinic acid (ALA).

• Were subjects under immunosuppressive therapy.

• Suffered from porphyria.

• Showed hypersensitivity to porphyrins.

• Suffered from photodermatoses.

• Had inherited or acquired coagulation defects.

• Had received medication with hypericin or systemically acting drugs with phototoxic or photoallergic potential such as psoralens, tetracyclines, nalidixic acid, furosemide, amiodarone, phenothiazines, quinolones, fibrates, or phytotherapy with St. John's wort, arnica, or valerian or topically applied phototoxic substances like tar, pitch, psoralens or some dyes like thiazide, methylene blue, toluidine blue, eosine, Bengal rose, acridine within 8 weeks prior to treatment with study drug and photodynamic therapy (PDT).

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

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

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

• Used any topical treatment in the treatment area within 12 weeks before PDT treatment with BF-200 ALA; biopsy taken at the screening visit was allowed.

• Used topical treatment with ALA or MAL (methyl-aminolevulinic acid hydrochloride) outside the treatment area during participation in the study.

• Systemic treatments of one of the following within the designated period before

PDT with BF-200 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
• Methyl-aminolevulinic acid hydrochloride or ALA - 12 weeks
• Known allergy against polysorbate 80, caprylic/capric acid triglycerides, isopropyl alcohol, disodium phosphate dihydrate, sodium hydroxide, hydrochloric acid, propylene glycol; sodium benzoate.
• 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 could be exacerbated by treatment with topical ALA or caused difficulty with examination (e.g. psoriasis, eczema).
• Showed 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.
• Confirmed diagnosis of HIV.