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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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

Conditions
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Actinic Keratosis

Intervention / Treatment
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* Drug: Vehicle
* Drug: BF-200 ALA


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Vehicle<br>Topical application of matched placebo gel (without containing active ingredient). Application of a 1 mm thick layer covering each lesion and a 0.5 cm to 1.0 cm surrounding margin. | Drug: Vehicle<br>* topical treatment for photodynamic therapy combining vehicle application and subsequent illumination with broad or narrow spectrum light sources (after 3 h of drug incubation).<br>|
| Active Comparator: BF-200 ALA<br>Topical application of BF-200 ALA gel containing 78 mg/g 5-aminolevulinic acid. Application of a 1 mm thick layer covering each lesion and a 0.5 cm to 1.0 cm surrounding margin. | Drug: BF-200 ALA<br>* topical treatment for photodynamic therapy combining drug application and subsequent illumination with broad or narrow spectrum light sources (after 3 h of drug incubation).<br>* Other names: Ameluz;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Total Patient Clearance Rate 12 Weeks After the Last Photodynamic Therapy (PDT) | AK clearance rate, defined as the percentage of subjects with complete remission of all AK lesions in the target area(s) assessed 12 weeks after the last PDT (12 weeks after the 1st PDT or 12 weeks after the 2nd PDT in case of retreatment). | 12 weeks after the last photodynamic therapy (PDT), up to 24 weeks | 
| Total Patient Clearance Rate 12 Weeks After the Last Photodynamic Therapy (PDT) | AK clearance rate, defined as the percentage of subjects with complete remission of all AK lesions in the target area(s) assessed 12 weeks after the last PDT (12 weeks after the 1st PDT or 12 weeks after the 2nd PDT in case of retreatment). | 12 weeks after the last PDT, up to 24 weeks | 
| Total Patient Clearance Rate Treated With Narrow Spectrum Lamp 12 Weeks After the Last Photodynamic Therapy (PDT) | AK clearance rate, defined as the percentage of subjects with complete remission of all AK lesions in the target area(s) assessed 12 weeks after the last PDT (12 weeks after the 1st PDT or 12 weeks after the 2nd PDT in case of retreatment). Analysis was for the subgroup: treated by narrow spectrum lamps only [n=15 (vehicle), n= 31 (BF-200 ALA)] | 12 weeks after the last PDT, up to 24 weeks | 
| Total Patient Clearance Rate Treated With Narrow Spectrum Lamp 12 Weeks After the Last Photodynamic Therapy (PDT) | AK clearance rate, defined as the percentage of subjects with complete remission of all AK lesions in the target area(s) assessed 12 weeks after the last PDT (12 weeks after the 1st PDT or 12 weeks after the 2nd PDT in case of retreatment). Analysis was for the subgroup: treated by narrow spectrum lamps only [n=13 (vehicle), n= 28 (BF-200 ALA)] | 12 weeks after the last PDT, up to 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of AK Lesions Showing Complete Remission 12 Weeks After the Last PDT | Percentage of individual lesions completely cleared and with no adherent scaling plaques of AK that were visible any longer 12 weeks after the last PDT (12 weeks after the 1st PDT or 12 weeks after the 2nd PDT in case of retreatment); Overall population | 12 weeks after the last PDT, up to 24 weeks | 
| Percentage of AK Lesions Showing Complete Remission Treated With Narrow Spectrum Lamp 12 Weeks After the Last PDT | Percentage of individual lesions completely cleared and with no adherent scaling plaques of AK that were visible any longer 12 weeks after the last PDT (12 weeks after the 1st PDT or 12 weeks after the 2nd PDT in case of retreatment). for subgroup analysis: patients treated with narrow spectrum lamp only. | 12 weeks after the last PDT, up to 24 weeks | 
| Change in Total Lesion Size 12 Weeks After the Last PDT | Change in the mean total lesion area 12 weeks per subject after the last PDT compared to baseline (12 weeks after the 1st PDT or 12 weeks after the 2nd PDT in case of retreatment). The outcome measure describes the mean difference between total lesion size at baseline and 12 weeks after the last PDT. Negative values indicate a reduction in the total lesion area size compared to baseline. | 12 weeks after the last PDT, up to 24 weeks | 
| Change in Total Lesion Area 12 Weeks After the Last PDT (Treated Area Face) | Change in mean total lesion area within the target treatment area per subject 12 weeks after the last PDT compared to baseline (12 weeks after the 1st PDT or 12 weeks after the 2nd PDT in case of retreatment). The outcome measure describes the mean difference between total lesion size at baseline and 12 weeks after the last PDT. Negative values indicate a reduction in the total lesion area size compared to baseline. Subgroup Analysis for patients with lesions located in the face only. | 12 weeks after the last PDT, up to 24 weeks | 
| Change in Total Lesion Area 12 Weeks After the Last PDT (Treated Area Scalp) | Change in mean total lesion area within the target treatment area per subject 12 weeks after the last PDT compared to baseline (12 weeks after the 1st PDT or 12 weeks after the 2nd PDT in case of retreatment). The outcome measure describes the mean difference between total lesion size at baseline and 12 weeks after the last PDT. Negative values indicate a reduction in the total lesion area size compared to baseline. Subgroup Analysis for patients with lesions located in the scalp only. | 12 weeks after the last PDT, up to 24 weeks | 
| Subjects With Complete Clearance 12 Weeks After the First PDT | AK clearance rate, defined as the number of subjects with complete remission of all AK lesions assessed at 12 weeks after the first PDT | 12 weeks after the first PDT | 
| Subjects With Partial Clearance 12 Weeks After the Last PDT | Percentage of subjects with clearance of at least 75% of lesions 12 weeks after the last PDT (12 weeks after the 1st PDT or 12 weeks after the 2nd PDT in case of retreatment). | 12 weeks after the last PDT, up to 24 weeks | 
| Overall Cosmetic Outcome 12 Weeks After the Last PDT | Overall Cosmetic Outcome (CO) 12 weeks after PDT (12 weeks after 1st PDT or 12 weeks after 2nd PDT). The cosmetic outcome at the end-of-study visit was calculated on the basis of skin quality assessment: skin surface, hyperpigmentation, hypopigmentation, mottled/irregular pigmentation, degree of scarring, and atrophy. The CO was rated as very good if the sum score of the previously mentioned ratings (all ratings for each sign added up) has improved by at least 2 points as compared to baseline; the CO was rated as good if the sum score at a given visit has improved by at least 1 point as compared to baseline; the cosmetic outcome is rated as satisfactory if the sum score at a given visit is identical to the one at baseline; the cosmetic outcome is rated as unsatisfactory if the sum score at a given visit has worsened by 1 point compared to baseline, the cosmetic outcome is rated as impaired if the sum score at a given visit has worsened by at least 2 points compared to baseline. | 12 weeks after the last PDT, up to 24 weeks | 
| Local Skin Reactions | Local skin reactions observed immediately after illumination by the investigator were documented using different categories (erythema, edema, induration, vesicles, erosion, ulceration, scaling/flanking, scabbing/crusting,weeping/exudates). | during and after PDT [3h - 4 h] | 
| Discomfort During and After PDT | Local discomfort experienced by the patient after illumination were documented in three categories: itching, burning, pain. | during and after PDT [3h - 4 h] | 
| Related Adverse Events /AEs) | Related treatment-emerged-adverse events (TEAEs) until 12 weeks after the last PDT (>=5%) TEAEs were reported from the day of the 1st PDT until the end-of-study (clinical part), i.e. 12 weeks after the last PDT (until 12 weeks after the 1st PDT or up to 24 weeks in case a 2nd PDT was applied). | up to 24 weeks after the 1st PDT |