Study to Evaluate the Safety of BF-200 ALA (Ameluz®) for Photodynamic Therapy (PDT) in the Treatment of Expanded Fields of Actinic Keratosis (AK)

An Open-label Phase I Study to Evaluate the Pharmacokinetics of 5-aminolevulinic Acid and Protoporphyrin IX in Human Plasma Under Maximal Use Conditions After Topical Application of 3 Tubes of BF-200 ALA 10% Gel for Photodynamic Therapy (PDT) in Subjects Suffering From Actinic Keratosis

The aim of this study is to assess the pharmacokinetics (PK) of the parent drug 5-aminolevulinic acid (ALA) and its active metabolite protoporphyrin IX (PpIX) during photodynamic therapy with 3 tubes of BF-200 ALA 10% gel (Ameluz®) in combination with the BF-RhodoLED® lamp in the systemic circulation of diseased individuals presenting with actinic keratosis (AK) on the face/scalp or in the periphery (neck/trunk/extremities) along with subjects' safety/tolerability during and after treatment.

Inclusion Criteria:

1. Subjects with at least 12 distinctive and clinically confirmed mild to severe AK lesions (according to Olsen et al. 1991 (37)) with a diameter of ≥ 4 mm each, on either the face/scalp (including forehead, excluding eyes, nostrils, ears, and mouth) or the neck/trunk/extremities, within treatment field(s) of about 60 cm² in total. Treatment field(s) may be discontinuous but must be within 2 illumination areas of the BF-RhodoLED® lamp (6 cm x 16 cm each).
2. All genders 18-85 years of age (inclusive).
3. Willingness and ability of the subject to provide informed consent and to sign the Health Insurance Portability and Accountability Act (HIPAA) form. A study-specific informed consent form and HIPAA form must be obtained in writing for all subjects prior to starting any study procedures.
4. Willingness and ability to comply with study procedures, particularly willingness to receive one PDT with up to two illumination devices simultaneously.
5. Subjects with good general health and subjects with clinically stable medical conditions will be permitted to be included in the study.
6. Subjects receiving any drugs affecting coagulation (e.g. anticoagulants, anti-platelet drugs) should be on a stable dose.
7. Acceptance to abstain from extensive sunbathing and the use of solarium during the clinical study.
8. Women of child-bearing potential must have a negative serum pregnancy test and must use an adequate and highly effective or two effective methods of contraception throughout the study.

Exclusion Criteria:

1. Any known history of hypersensitivity to ALA, porphyrins or excipients of BF- 200 ALA.

2. History of soy or peanut allergy.

3. Subjects with sunburn within illumination areas (reassessment of subjects is allowed once if the sunburn is expected to resolve within the screening period. Reassessment can be done on the day of the actual treatment.).

4. Clinically significant medical conditions making implementation of the protocol or interpretation of the study results difficult or impairing subjects' safety such as:

   1. Presence of porphyria or known photodermatoses
   2. Known diagnosis of human immunodeficiency virus (HIV) based on clinical history
   3. Metastatic tumor or tumor with high probability of metastasis
   4. Infiltrating skin neoplasia (suspected or known)
   5. Unstable cardiovascular disease (New York Heart Association [NYHA] class III, IV)
   6. Unstable hematologic (including Myelodysplastic syndrome), hepatic, renal, neurologic, or endocrine condition
   7. Unstable collagen-vascular condition
   8. Unstable gastrointestinal condition
   9. Immunosuppressive condition
   10. Presence of clinically significant inherited or acquired coagulation defect

5. Clinical diagnosis of atopic dermatitis, Bowen's disease, BCC, eczema, psoriasis, rosacea, SCC, other malignant or benign tumors in the treatment field(s), or other possible confounding skin conditions (e.g. wounds, irritations, bleeding or skin infections) within or in close proximity (< 5 cm distance) to treatment field(s). (Reassessment of subjects is allowed once if wounds, irritations, bleeding or skin infections are expected to resolve within the screening period. Reassessment can be done on the day of the actual treatment.)

6. Presence of strong pigmentation, tattoos or any other abnormality that may impact lesion assessment or light penetration in the treatment field(s).

7. More than moderate smoker (e.g. > 10 cigarettes/day or equivalent).

8. Suspicion of drug or alcohol abuse. For the purpose of this study, alcohol abuse is defined as more than moderate alcohol consumption (> 1 drink/day for women and > 2 drinks/day for men).

9. Physical treatment of malignant or benign tumors of the skin within the treatment field(s) and at a distance of < 5 cm to the treatment field(s) during the last 4 weeks prior to screening.

10. Any therapy such as cryotherapy, laser therapy, electrodessication, surgical removal of lesions, curettage, or treatment with chemical peels such as trichloroacetic acid within the treatment field(s), or within a radius less than 5 cm away from the treatment field(s) 4 weeks prior to screening.

11. Any topical medical treatment of the skin within the designated time period below:

    1. Topical treatment with ALA or methyl-aminolevulinate (MAL) or an investigational drug in- and outside the treatment field(s) within 8 weeks prior to screening.
    2. Topical treatment with immunomodulatory/immunosuppressive antiinflammatory, or cytotoxic agents inside the treatment field(s) or within a radius less than 5 cm away from the treatment field(s) within 8 weeks prior to screening.
    3. Start of topical administration of medication with hypericin or other drugs with phototoxic or photoallergic potential in- and outside the treatment field(s) within 8 weeks prior to screening. Subjects may, however, be eligible if such medication was applied for more than 8 weeks prior to screening visit without evidence of an actual phototoxic/photoallergic reaction.

12. Any use of the below specified systemic treatments within the designated periods:

    1. Use of cytotoxic drugs within 24 weeks, immunomodulators or immunosuppressive therapies or use of ALA or ALA-esters (e.g. MAL) within 12 weeks, investigational drugs or drugs known to have major organ toxicity within 8 weeks, interferon or corticosteroids (oral or injectable) within 6 weeks prior to screening.
    2. Start of intake of medication with hypericin or systemically-acting drugs with phototoxic or photoallergic potential within 8 weeks prior to screening. Subjects may, however, be eligible if such medication was taken in or applied for more than 8 weeks prior to screening visit without evidence of an actual phototoxic/photoallergic reaction.

13. Laboratory values outside the reference range that are clinically significant in the opinion of the investigator (e.g., suggesting an unknown disease and requiring further clinical evaluation according to investigator), especially aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma glutamyl transpeptidase (gamma- GT).

14. Impaired renal function (Glomerular filtration rate below 50 mL/min/1.73m² estimated by Modification of Diet in Renal Disease equation (MDRD)).

15. Positive test for HIV antibodies, Hepatitis B-virus surface antigen (HBsAg) or positive Anti-hepatitis C-virus antibody (Anti-HCV) test.

16. Significant blood donation or blood loss (≥ 500 mL) within three months prior to Visit 2.

17. Breast-feeding women.

18. Subject unlikely to comply with the protocol, e.g. inability to return for visits, unlikely to complete the study, or inappropriate in the opinion of the investigator.

19. Prior participation in the study (participation is defined as having been screened).

20. A member of study site staff or sponsor staff directly involved in the conduct of the protocol or a close relative thereof.

21. Simultaneous participation in a further clinical study.

Reassessment of subjects is allowed once if sunburn, wounds, irritations, bleeding or skin infections detected at Visit 1 are expected to resolve within the screening period.

Reassessment can be done on the day of the actual treatment.

Dosing day exclusion criteria:

1. Febrile or infectious illness within 7 days prior to Visit 2.
2. Subjects with sunburn, wounds, irritations, bleeding or other confounding skin conditions within illumination areas at Visit 2.
3. Use of topical NSAIDs inside and outside the treatment field(s) or systemic intake of NSAIDs within 7 days prior to Visit 2.

In case a subject meets one of the dosing day exclusion criteria, Visit 2 can be rescheduled once within 14 days. Meeting any of the dosing day exclusion criteria on the rescheduled visit will lead to discontinuation of the trial.