Study to Evaluate the Safety and Efficacy of BF-200 ALA (Ameluz®) and BF-RhodoLED® in the Treatment of Moderate to Severe Acne Vulgaris With Photodynamic Therapy in Adults

Study Overview
=================
Brief Summary
-----------------
The aim of this study is to test the safety and efficacy of photodynamic therapy (PDT) for the medication Ameluz® performed with the PDT-lamp BF-RhodoLED® in comparison to the respective placebo treatment for moderate to severe Acne vulgaris.

Official Title
-----------------
A Randomized, Double Blind, Vehicle-controlled, Multicenter Phase II Study to Evaluate the Safety and Efficacy of BF-200 ALA (Ameluz®) and BF-RhodoLED® in the Treatment of Moderate to Severe Acne Vulgaris in Adults With Photodynamic Therapy (PDT)

Conditions
-----------------
Acne Vulgaris

Intervention / Treatment
-----------------
* Combination Product: 1h Incubation Photodynamic therapy (PDT) (ALA-PDT, Ameluz®-PDT)
* Combination Product: 1h Incubation Photodynamic therapy (PDT) (vehicle to BF-200 ALA containing no active ingredient)
* Combination Product: 3h Incubation Photodynamic therapy (PDT) (ALA-PDT, Ameluz®-PDT)
* Combination Product: 3h Incubation Photodynamic therapy (PDT) (vehicle to BF-200 ALA containing no active ingredient)


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: 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 and HIPAA form must be obtained in writing prior to starting any study procedures. Minors under 18 years of age must be accompanied by the parent(s) or legal guardian(s) at the time of consent signing. The parent(s) or legal guardian(s) must also provide informed consent/HIPAA for the subject. Subjects with moderate to severe acne on the face (IGA ≥3). Presence of ≥20 inflammatory and ≥20 non-inflammatory (open and closed comedones) Acne vulgaris lesions on the face (should be located within not more than 2 illumination areas) as assessed by investigator. All sexes, ≥16 years of age. Willingness and ability to comply with study procedures, particularly willingness to receive up to 3 PDTs within 8 to 10 weeks. Subjects with good general health or with clinically stable medical conditions will be permitted to be included in the study. Willingness to stop topical facial treatments other than medical cleansers (i.e. face washes etc.) at least 14 days prior to randomization visit (Visit 2, baseline) and discontinue medical cleansers in the face at least 1 week prior to randomization visit (Visit 2, baseline) and thereafter until the end of study (use of soap is allowed but the product used should not be changed during the study). Females of reproductive 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. (If hormonal contraception is used, the same product and dose should be taken for at least 6 months before the first treatment and throughout the entire study.) Exclusion Criteria: Any known history of hypersensitivity to ALA, porphyrins or excipients of BF-200 ALA. History of soy or peanut allergy. Subjects with sunburn 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. (Reassessment of subjects is allowed once if the sunburn or other confounding skin conditions is/are expected to resolve within the screening period. Reassessment can be done on the day of the actual treatment.) Clinical diagnosis of atopic dermatitis and other cutaneous conditions (e.g. lupus erythematosus), Bowen's disease, BCC, eczema, psoriasis, acne conglobate, acne fulminans, or secondary acne (steroid-induced acne, perioral dermatitis, acne rosacea), squamous cell carcinoma, other malignant or benign tumors in the treatment field. Clinically significant (CS) medical conditions making implementation of the protocol or interpretation of the study results difficult or impairing subject's safety such as: Presence of photodermatoses or porphyria Metastatic tumor or tumor with high probability of metastasis Infiltrating skin neoplasia (suspected or known) Unstable cardiovascular disease (New York Heart Association class III, IV) Unstable hematologic (including Myelodysplastic syndrome), hepatic, renal, neurologic, or endocrine condition Unstable collagen-vascular condition Unstable gastrointestinal condition Immunosuppressive condition Presence of clinically significant inherited or acquired coagulation defect Beard or other facial hair that might interfere with the study assessments unless subject agrees to be clean-shaven throughout the entire study period. (Reassessment of subjects is allowed once if assessment of acne lesions is impaired by facial hair at screening. Reassessment can be performed on the day of the actual treatment). Facial procedures such as dermabrasion, chemical or laser peels as well as exposure to UV radiation (other than sunlight) at least 4 weeks prior to randomization visit (Visit 2, baseline). Presence of strong artificial pigmentation (e.g. tattoos) or any other abnormality that may impact lesion assessment or light penetration in the treatment field. Suspicion of drug or alcohol abuse. Any topical medication of the skin prior to screening as defined below: Topical treatment with ALA or ALA-esters (e.g. MAL) or an investigational drug in- and outside the treatment field within 8 weeks prior to screening. Topical treatment with immunosuppressive, cytostatic or cytotoxic drugs inside the treatment field within 8 weeks prior to screening. Start of a regular and continuous topical administration of medication with hypericin or other drugs with phototoxic or photoallergic potential inside the treatment field within 4 weeks prior to screening. Subjects may, however, be eligible if such medication was regularly applied for more than 4 weeks prior to screening visit without evidence of an actual phototoxic/photoallergic reaction or if such medication is only administered for a limited time (e.g. an antibiotic) Any use of the below specified systemic treatments within the designated periods: Systemic acne therapy (oral antibiotics within 8 weeks or oral isotretinoin within 6 months or start with hormonal therapy for acne within 6 months prior to Visit 2). Use of cytotoxic or cytostatic drugs within 6 months, 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 glycocorticosteroids (oral or injectable) within 6 weeks prior to screening. Start of long-term intake of medication with hypericin or systemically acting drugs with phototoxic or photoallergic potential within 8 weeks prior to screening. Subjects may, however, be screened and randomized if such medication was taken in or was regularly applied for more than 8 weeks prior to screening visit without evidence of an actual phototoxic/photoallergic reaction or if such a drug is only used for a limited time (e.g. an antibiotic). Breast feeding women. Subject unlikely to comply with protocol, e.g. inability to return for visits, unlikely to complete the study, or inappropriate in the opinion of the investigator. Prior randomization in the study. A member of study site staff or sponsor staff directly involved in the conduct of the protocol or a close relative thereof. Simultaneous participation in a further clinical study. Four or more nodular acne lesions on the face. Unwillingness or inability to limit sun exposure for 48 hours post PDT treatment. Dosing Day exclusion criteria: Febrile or infectious disease within 7 days prior to PDT visits. Subjects with sunburn, wounds, irritations, bleeding or other confounding skin conditions within illumination areas at PDT visits. Application of topical glycocorticosteroids in- and outside the treatment field within 7 days prior to PDT visits Administration of (topical or systemic) medication with phototoxic/photoallergic potential for a limited time. After discontinuing the medication, a wash out period of the medications 5-fold half-life time should be applied prior to the next PDT.

Ages Eligible for Study
-----------------
Minimum Age: 16 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1h incubation BF-200 ALA<br>Topical application of BF-200 ALA containing 7.8% 5-ALA (5-aminolevulinic acid) red light photodynamic therapy (PDT) utilizing BF-RhodoLED® after 1h incubation. | Combination Product: 1h Incubation Photodynamic therapy (PDT) (ALA-PDT, Ameluz®-PDT)<br>* Facial acne lesions will be cleansed with gauze soaked with ethanol or isopropanol. Afterwards, approximately 1 tube of study medication will be applied as a thin layer to the whole face. After drug application, subjects should stay inside for 1 hour. Post incubation, red light illumination with BF-RhodoLED® will be performed according to the lamps user manual until a total light energy of 37 J/cm2 was applied. To cover the whole face 2 illuminations will be required which can either be performed subsequentially or in parallel (with 2 lamps). Other Names: ALA-PDT, Ameluz®-PDT<br>|
| Experimental: 3h incubation BF-200 ALA<br>Topical application of BF-200 ALA containing 7.8% 5-ALA (5-aminolevulinic acid) red light photodynamic therapy (PDT) utilizing BF-RhodoLED® after 3h incubation. | Combination Product: 3h Incubation Photodynamic therapy (PDT) (ALA-PDT, Ameluz®-PDT)<br>* Facial acne lesions will be cleansed with gauze soaked with ethanol or isopropanol. Afterwards, approximately 1 tube of study medication will be applied as a thin layer to the whole face. After drug application, subjects should stay inside for 3 hours. Post incubation, red light illumination with BF-RhodoLED® will be performed according to the lamps user manual until a total light energy of 37 J/cm2 was applied. To cover the whole face 2 illuminations will be required which can either be performed subsequentially or in parallel (with 2 lamps). Other Names: ALA-PDT, Ameluz®-PDT<br>|
| Placebo Comparator: 1h incubation vehicle<br>Topical application of vehicle to BF-200 ALA red light photodynamic therapy (PDT) utilizing BF-RhodoLED® after 1h incubation. | Combination Product: 1h Incubation Photodynamic therapy (PDT) (vehicle to BF-200 ALA containing no active ingredient)<br>* Facial acne lesions will be cleansed with gauze soaked with ethanol or isopropanol. Afterwards, approximately 1 tube of study medication will be applied as a thin layer to the whole face. After drug application, subjects should stay inside for 1h. Post incubation, red light illumination with BF-RhodoLED® will be performed according to the lamps user manual until a total light energy of 37 J/cm2 was applied. To cover the whole face 2 illuminations will be required which can either be performed subsequentially or in parallel (with 2 lamps).<br>|
| Placebo Comparator: 3h incubation vehicle<br>Topical application of vehicle to BF-200 ALA red light photodynamic therapy (PDT) utilizing BF-RhodoLED® after 3h incubation. | Combination Product: 3h Incubation Photodynamic therapy (PDT) (vehicle to BF-200 ALA containing no active ingredient)<br>* Facial acne lesions will be cleansed with gauze soaked with ethanol or isopropanol. Afterwards, approximately 1 tube of study medication will be applied as a thin layer to the whole face. After drug application, subjects should stay inside for 3h. Post incubation, red light illumination with BF-RhodoLED® will be performed according to the lamps user manual until a total light energy of 37 J/cm2 was applied. To cover the whole face 2 illuminations will be required which can either be performed subsequentially or in parallel (with 2 lamps).<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Relative change in the number of inflammatory lesions (relative change from baseline) 8 weeks after the last PDT as assessed by investigator. | Outcome 1 is the relative change in the number of inflammatory lesions at the final visit with respect to baseline as assessed by the investigator. | 8 weeks after the last PDT | 
| Treatment success defined by a minimum improvement of the modified investigator global assessment (mIGA) score by at least 2 assessed 8 weeks after the last PDT and resulting at an mIGA score of 0 (clear) or 1 (almost clear). | Treatment success is defined as a minimum improvement of the mIGA score by at least 2 and resulting at an mIGA score of 0 (clear) or 1 (almost clear). | 8 weeks after the last PDT | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in the number of inflammatory and/or non-inflammatory lesions (absolute change and/or percentage change from baseline) as assessed by investigator. | In particular, the following will be assessed: Inflammatory lesions - 4 weeks after the last PDT Inflammatory lesions - 8 weeks after the last PDT Non-inflammatory lesions - 4 weeks after the last PDT Non-inflammatory lesions - 8 weeks after the last PDT Inflammatory & non-inflammatory lesions - 4 weeks after the last PDT Inflammatory & non-inflammatory lesions - 8 weeks after the last PDT | 4 or 8 weeks after the last PDT | 
| Change in the number of inflammatory and/or non-inflammatory lesions (absolute change and/or percentage change from baseline) as assessed by the Canfield algorithm | In particular, the following will be assessed: Inflammatory lesions - 4 weeks after the last PDT Inflammatory lesions - 8 weeks after the last PDT Non-inflammatory lesions - 4 weeks after the last PDT Non-inflammatory lesions - 8 weeks after the last PDT Inflammatory & non-inflammatory lesions - 4 weeks after the last PDT Inflammatory & non-inflammatory lesions - 8 weeks after the last PDT | 4 or 8 weeks after the last PDT | 
| Change in the number of inflammatory and/or non-inflammatory lesions for subjects with no remaining inflammatory lesions (subjects receiving only 1 PDT; absolute change and percentage change from baseline) as assessed by investigator. | In particular, the following will be assessed: Inflammatory lesions - 4 weeks after the 1st PDT Inflammatory lesions - 8 weeks after the 1st PDT Non-Inflammatory lesions - 4 weeks after the 1st PDT Non-Inflammatory lesions - 8 weeks after the 1st PDT Inflammatory & non-inflammatory lesions - 4 weeks after the 1st PDT Inflammatory & non-inflammatory lesions - 8 weeks after the 1st PDT | 4 or 8 weeks after the 1st PDT | 
| Change in the number of inflammatory and/or non-inflammatory lesions for subjects with no remaining inflammatory lesions (subjects receiving 2 PDTs; absolute change and percentage change from baseline) as assessed by investigator. | In particular, the following will be assessed: Inflammatory lesions - 4 weeks after the 2nd PDT Inflammatory lesions - 8 weeks after the 2nd PDT Non-Inflammatory lesions - 4 weeks after the 2nd PDT Non-Inflammatory lesions - 8 weeks after the 2nd PDT Inflammatory & non-inflammatory lesions - 4 weeks after the 2nd PDT Inflammatory & non-inflammatory lesions - 8 weeks after the 2nd PDT | 4 or 8 weeks after the 2nd PDT | 
| Change in the number of inflammatory and/or non-inflammatory lesions for subjects with no remaining inflammatory lesions (subjects receiving 3 PDTs; absolute change and percentage change from baseline) as assessed by investigator. | In particular, the following be assessed: Inflammatory lesions - 4 weeks after the 3rd PDT Inflammatory lesions - 8 weeks after the 3rd PDT Non-Inflammatory lesions - 4 weeks after the 3rd PDT Non-Inflammatory lesions - 8 weeks after the 3rd PDT Inflammatory & non-inflammatory lesions - 4 weeks after the 3rd PDT Inflammatory & non-inflammatory lesions - 8 weeks after the 3rd PDT | 4 or 8 weeks after the 3rd PDT | 
| Change in the number of nodules & cysts | Absolute change and percentage change from baseline (Visit 2) as per investigator assessment. | 8 weeks after the last PDT | 
| Treatment success defined by a minimum improvement of the IGA and mIGA by at least 2. | Treatment success is defined as a minimum improvement of the IGA and mIGA score by at least 2 (from baseline (Visit 2) as per investigator assessment). | 8 weeks after the last PDT | 
| Treatment success defined by a minimum improvement of the PAS and mPAS equivalent to an improvement of IGA and mIGA by at least 2, assessed by the Canfield algorithm | In particular, the following will be assessed: a. Across all subjects, irrespective of the final parametric acne score (PAS) and modified PAS (mPAS) PAS/mPAS are equivalent to the IGA/mIGA but results from the automated assessment of acne severity based on pictures taken with the canfield system | 8 weeks after the last PDT | 
| Improvement of scar severity and overall esthetic appearance. | As assessed by the investigator via a physical global scale for acne scars (PGA) | 8 weeks after last PDT | 
| Improvement of texture as assessed by Canfield algorithm. | Based on pictures taken during the study visits. Pictures will be analyzed with respect to areas of facial roughness and raised topography of acne lesions. | 8 weeks after last PDT | 
| Satisfaction regarding esthetic outcome and treatment. | As reported by the subject. | 8 weeks after the last PDT. | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
ALA-PDT