Safety and Efficacy Study for the Field-directed Treatment of Actinic Keratosis (AK) With Photodynamic Therapy (PDT)

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the safety and efficacy of BF-200 ALA (Ameluz) versus placebo in the field-directed treatment of mild to moderate actinic keratosis with photodynamic therapy (PDT) when using the BF-RhodoLED lamp.

Detailed Description
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The study was performed as a randomized, multicentre, double-blind, placebo- controlled, parallel-group, phase III trial with BF-200 ALA and placebo in seven centres in Germany. A total of 94 patients were screened in this study; 87 were randomized (55 patients received BF-200 ALA, 32 received placebo). Patients received one PDT. If residual lesions remained at 3 months after treatment, PDT was repeated. Illumination was performed with the PDT lamp BF-RhodoLED.

Official Title
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A Randomized, Double-blind, Phase III, Multi-center Study to Evaluate the Safety and Efficacy of BF-200 ALA (Ameluz®) Versus Placebo in the Field-directed Treatment of Mild to Moderate Actinic Keratosis With Photodynamic Therapy (PDT) When Using the BF-RhodoLED® Lamp

Conditions
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Actinic Keratosis

Intervention / Treatment
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* Drug: BF-200 ALA gel
* Drug: Placebo to BF-200 ALA gel
* Procedure: Photodynamic therapy with BF-RhodoLED


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Males or females between 18 and 85 years of age (inclusive) Presence of 4 to 8 clinically confirmed actinic keratosis (AK) target lesions of mild to moderate intensity within 1-2 fields Exclusion Criteria: History of hypersensitivity to 5-ALA or any ingredient of BF-200 ALA Current treatment with immunosuppressive therapy Presence of other malignant or benign tumors of the skin within the treatment area (eg malignant melanoma, basal cell carcinoma (BCC) or squamous cell carcinoma (SCC)) within the last 4 weeks Confirmed diagnosis of SCC for the representative lesion by screening biopsy

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: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: BF-200 ALA gel<br>Photodynamic therapy with BF-RhodoLED in combination with BF-200 ALA. | Drug: BF-200 ALA gel<br>* BF-200 ALA was applied over 1-2 fields of approximately 20 cm² in total, allowed to dry for approximately 10 minutes, and covered with occlusive tape material for 3 h.<br>* Other names: Ameluz;Procedure: Photodynamic therapy with BF-RhodoLED<br>* After cleaning the lesions, the entire treatment field(s) were illuminated using the novel narrow spectrum BF-RhodoLED lamp, a red light illumination source (approximately 635 nm) developed by Biofrontera, until a total light dose of 37 J/cm² (per treated field) was achieved.<br>* Other names: PDT;|
| Placebo Comparator: Placebo to BF-200 ALA gel<br>Photodynamic therapy with BF-RhodoLED in combination with a nanoemulsion gel formulation similar to BF-200 ALA, but without the active ingredient 5-aminolevulinic acid. | Drug: Placebo to BF-200 ALA gel<br>* The reference product was a placebo (a nanoemulsion gel formulation similar to the Investigational Medicinal Product (IMP), but without the active ingredient). The placebo was packaged, assigned to each patient, and administered in the same way as the IMP.<br>Procedure: Photodynamic therapy with BF-RhodoLED<br>* After cleaning the lesions, the entire treatment field(s) were illuminated using the novel narrow spectrum BF-RhodoLED lamp, a red light illumination source (approximately 635 nm) developed by Biofrontera, until a total light dose of 37 J/cm² (per treated field) was achieved.<br>* Other names: PDT;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Patient Complete Response 12 Weeks After the Last Photodynamic Therapy (PDT) | All efficacy variables were evaluated for the FAS. The primary efficacy variable was also analyzed for the PP population. All subgroup analyses were carried out for the FAS. Data for size and grade of AK lesions were analyzed using the last observation carried forward (LOCF) approach, affecting the response rates evaluation. Due to the small amount of missing data in the study, which did not have any relevant impact on primary results, sensitivity analyses for missing data were not performed. The primary efficacy variable was the overall patient complete response 12 weeks after the last PDT. An overall complete responder was defined as a patient in whom all treated actinic keratosis (AK) lesions were cleared (Olsen score of 0) after the last PDT, i.e. after PDT 1 or after PDT 2 if re-treatment was performed. | 12 weeks after PDT 1 or 12 weeks after PDT 2 which might have been necessary because not all lesions were cleared after the first PDT | 
| Overall Patient Complete Response 12 Weeks After the Last PDT (PP) | All efficacy variables were evaluated for the FAS. The primary efficacy variable was also analyzed for the PP population. All subgroup analyses were carried out for the FAS. Data for size and grade of AK lesions were analyzed using the last observation carried forward (LOCF) approach, affecting the response rates evaluation. Due to the small amount of missing data in the study, which did not have any relevant impact on primary results, sensitivity analyses for missing data were not performed. The primary efficacy variable was the overall patient complete response 12 weeks after the last PDT. An overall complete responder was defined as a patient in whom all treated AK lesions were cleared (Olsen score of 0) after the last PDT, i.e. after PDT 1 or after PDT 2 if re-treatment was performed. | 12 weeks after PDT 1 or 12 weeks after PDT 2 which might have been necessary because not all lesions were cleared after the first PDT | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Patient Histopathological Confirmed Response Rate | For the secondary confirmatory analysis, several superiority hypotheses were tested within a pre-defined hierarchic multiple testing procedure as described in the Statistical Analysis Protocoll (SAP). The key secondary efficacy variables were tested strictly in a pre-defined order to ensure the family-wise error rate (FWER) and the testing procedure had to be stopped once the first non-significant test was obtained. The results of the confirmatory analysis are presented in the order pre-defined by the confirmatory testing procedure. Assessments of the patient histopathological confirmed response (HCR) rates were based on the results from the biopsy taken 12 weeks after the last PDT from a representative AK lesion selected at screening. If the biopsy result for a patient revealed a residual AK, the patient was considered not cleared for the analysis irrespectively of the investigator's clinical assessment. | 12 weeks after PDT 1 or 12 weeks after PDT 2 which might have been necessary because not all lesions were cleared after the first PDT | 
| Patient Complete Response 12 Weeks After PDT 1 | The second key secondary efficacy variable in the hierarchic test procedure was the patient complete response (complete clearance of all treated AK lesions) assessed at 12 weeks after PDT 1. | 12 weeks after PDT 1 | 
| Lesion Complete Response 12 Weeks After Last PDT | The third key secondary efficacy variable in the hierarchic test procedure was the lesion complete response (completely cleared individual AK lesions) assessed at 12 weeks after last PDT. | 12 weeks after PDT 1 or 12 weeks after PDT 2 which might have been necessary because not all lesions were cleared after the first PDT | 
| Patient Partial Response 12 Weeks After Last PDT | The fourth key secondary efficacy variable in the hierarchic test procedure was the patient partial response (defined as complete clearance of at least 75% of treated AK lesions) assessed at 12 weeks after last PDT. | 12 weeks after PDT 1 or 12 weeks after PDT 2 which might have been necessary because not all lesions were cleared after the first PDT | 
| Change of Total Lesion Area 12 Weeks After Last PDT | The fifth key secondary efficacy variable in the hierarchic test procedure was the change from baseline in the total lesion area per patient assessed at 12 weeks after last PDT. | 12 weeks after PDT 1 or 12 weeks after PDT 2 which might have been necessary because not all lesions were cleared after the first PDT | 
| Overall Cosmetic Outcome 12 Weeks After Last PDT for Patients With Sum Score at Baseline of 0 to 3 | Study personnel assessed and recorded the skin quality of the treated field(s) at baseline and at the end-of-study visit including skin surface, hyperpigmentation, hypopigmentation, mottled or irregular pigmentation, degree of scarring and atrophy. Upon visual examination of the treated field(s), the investigator coded the intensity of each skin parameter on a scale of 0 to 3, where 0 = none, 1 = mild, 2 = moderate, and 3 = severe. The cosmetic outcome evaluations were based on the sum score of the skin quality assessment (sum of all ratings for each skin parameter) at the end-of-study visit (Visit 4 or Visit 6, if retreated). The outcome was calculated using a 5-point scale ranging from very good (0) to impaired (4) based on the change of the skin quality assessments compared to baseline (0 = 2 points improvement; 1 = 1 point improvement; 2 = no change; 3 = 1 point worsened; 4 = at least 2 points worsened). | 12 weeks after PDT 1 or 12 weeks after PDT 2 which might have been necessary because not all lesions were cleared after the first PDT | 
| Overall Cosmetic Outcome 12 Weeks After Last PDT for Patients With Sum Score at Baseline of 1 to 3 | Study personnel assessed and recorded the skin quality of the treated field(s) at baseline and at the end-of-study visit including skin surface, hyperpigmentation, hypopigmentation, mottled or irregular pigmentation, degree of scarring and atrophy. Upon visual examination of the treated field(s), the investigator coded the intensity of each skin parameter on a scale of 0 to 3, where 0 = none, 1 = mild, 2 = moderate, and 3 = severe. The cosmetic outcome evaluations were based on the sum score of the skin quality assessment (sum of all ratings for each skin parameter) at the end-of-study visit (Visit 4 or Visit 6, if retreated). The outcome was calculated using a 5-point scale ranging from very good (0) to impaired (4) based on the change of the skin quality assessments compared to baseline (0 = 2 points improvement; 1 = 1 point improvement; 2 = no change; 3 = 1 point worsened; 4 = at least 2 points worsened). | 12 weeks after PDT 1 or 12 weeks after PDT 2 which might have been necessary because not all lesions were cleared after the first PDT | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Photodynamic Therapy, Field-directed Treatment