Safety and Efficacy Study for the Treatment of Non-Aggressive Basal Cell Carcinoma With Photodynamic Therapy

Study Overview
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Brief Summary
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The aim of this study is to test the effectiveness and safety of the medicine Ameluz® (5-aminolevulinic acid) in comparison to methyl-aminolevulinate (MAL), used with photodynamic therapy (PDT), to treat thin, non-aggressive BCC (basal cell carcinoma).

Detailed Description
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The treatment comprises of up to 2 PDT cycles, each with two PDT sessions one week apart. If 12 weeks after the the second PDT all lesions are completely cleared the patient will enter the follow-up phase. In case of remaining lesions the patient will receive a second PDT cycle starting on the same day.

Official Title
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A Randomized, Observer Blind, Multinational Phase III Study to Evaluate the Safety and Efficacy of BF-200 ALA (Ameluz®) in Comparison to Metvix® in the Treatment of Non-aggressive Basal Cell Carcinoma (BCC) With Photodynamic Therapy (PDT)

Conditions
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Basal Cell Carcinoma (BCC)

Intervention / Treatment
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* Drug: BF-200 ALA
* Drug: methyl-aminolevulinate


Participation Criteria
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Eligibility Criteria
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Main Inclusion Criteria: Willing and able to sign informed consent form; obtained in writing before starting any study procedures Presence of 1-3 thin (≤2 mm thickness), clinically non-aggressive, primary BCC lesions (primary superficial, nodular, or mixed superficial/nodular) in the face/forehead, bald scalp, extremities and/or neck/trunk. Confirmation of non-aggressiveness and thickness of BCC through biopsies taken at screening for at least one lesion. Lesions non-eligible according to biopsy should timely be removed by surgery or cryotherapy Diameters of lesions should range between ≥0.5cm and ≤2cm; total maximal treated area is 10cm² (including 0.5-1.0cm margin surrounding each lesion) Target BCC lesions must be discrete and quantifiable and have to be located within 1-2 treatment areas Free of significant physical abnormalities (eg tattoos, dermatoses) in potential treatment area that may cause difficulty with examination or final evaluation Accept to abstain from extensive sunbathing and use of solarium during observer blind part. Patients with sunburn within treatment areas cannot be included until fully recovered Healthy patients and patients with clinically stable medical conditions, including, but not limited to controlled hypertension, diabetes mellitus type II, hypercholesterolemia, and osteoarthritis, will be permitted to be included in study if their medication is not prohibited by protocol Women of childbearing potential are permitted to participate in study only if they have a negative serum pregnancy test at screening and willingness to use a highly effective method of contraception during observer blind part Main Exclusion Criteria: History of hypersensitivity to 5-ALA or any ingredient of BF-200 ALA, MAL or any ingredient of Metvix®, including arachis oil, or to peanut or soya Hypersensitivity to porphyrins Current treatment with immunosuppression therapy Presence of porphyria Presence of BCC lesions on embryonic fusion planes (H-zone) Presence of more than 3 BCCs Presence of malignant or benign tumors of the skin other than non-aggressive BCC within the treatment area (eg malignant melanoma, squamous cell carcinoma (SCC), aggressive BCC clinically diagnosed at screening) within the last 12 weeks Gorlin Syndrome or Xeroderma pigmentosum Presence of photodermatoses Treatment of lesions (actinic keratosis (AK), BCC, SCC, Bowens disease, melanoma) ≤12 weeks prior to first PDT, except physical treatments (eg cryosurgery, excision surgery) that will not be allowed ≤6 weeks prior to first PDT (Visit 2). Lesion(s) that seemed eligible clinically which could not be confirmed by biopsy, and which are located ≥10cm to an eligible lesion should timely be removed physically only Presence of inherited or acquired coagulation defect Start of intake of medication with hypericin or systemically-acting drugs with phototoxic or photoallergic potential within 8 weeks prior to screening Clinically relevant cardiovascular, hepatic, renal, neurologic, endocrine, or other major systemic disease making implementation of protocol or interpretation of study results difficult Evidence of clinically significant (CS), unstable medical conditions, eg: Metastatic tumor or tumor with high probability of metastasis Cardiovascular disease (New York Heart Association [NYHA] class III, IV) Immunosuppressive condition Hematologic, hepatic, renal, neurologic, or endocrine condition Collagen-vascular condition Gastrointestinal condition Topical treatment with 5-ALA or MAL outside treatment area during the observer blind part Any topical treatment including diclofenac and immunomodulatory agents (eg imiquimod, ingenol mebutate) 12 weeks prior to first PDT session and during observer blind part Any physical treatment during the observer blind part within treated target areas with exception of lesion(s) determined non-eligible by biopsy

Ages Eligible for Study
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Minimum Age: 18 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 |
| --- | --- |
| 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 0.5 to 1 cm of surrounding margin. | Drug: BF-200 ALA<br>* Topical treatment for photodynamic therapy combining drug application and subsequent illumination with a narrow spectrum light source (after 3 h of drug incubation)<br>* Other names: Ameluz;|
| Active Comparator: methyl-aminolevulinate<br>Topical application of Metvix creme containing 160 mg/g methyl-aminolevulinate. Application of a 1 mm thick layer covering each lesion and 0.5 to 1 cm of surrounding margin. | Drug: methyl-aminolevulinate<br>* Topical treatment for photodynamic therapy combining drug application and subsequent illumination with a narrow spectrum light source (after 3 h of drug incubation)<br>* Other names: Metvix / Metvixia;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Patient Complete Response Rate Assessed 12 Weeks After the Last PDT | Overall patient complete response rate assessed 12 weeks after the last PDT. The indicated values give the percentage of overall complete responders. An overall complete responder is defined as a patient in whom all treated lesions were cleared. The PP set is the primary analysis set for the analyses of the primary endpoint. | 12 weeks after the last PDT (please note: 2 PDT cycles, each cycle consisting of 2 PDTs (= maximum of 4 PDTs per patient) was possible). | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Lesion Complete Response Assessed 12 Weeks After the Last PDT | Lesion complete response (completely cleared individual lesions) assessed 12 weeks after the last PDT. The indicated values give percentage of overall completely cleared individual lesions. The PP set is the primary analysis set for the analysis of the secondary endpoint. | 12 weeks after the last PDT (please note: 2 PDT cycles, each cycle consisting of 2 PDTs (= maximum of 4 PDTs per patient) was possible). | 
| Reduction of Lesion Area 12 Weeks After the Last PDT Compared to Baseline | Reduction of total lesion area (summation of sizes of all treated lesions) per patient, assessed 12 weeks after the last PDT. The PP set is the primary analysis set for the analysis of the secondary endpoint. Please note that the high SD for BF-200 ALA is due to a patient who had increased lesion area fom 63 mm² at baseline to 225 mm² 12 weeks after PDT. This lesion area included a lesion that was later confirmed to be benign skin condition (lentigo solaris). | 12 weeks after the last PDT (please note: 2 PDT cycles, each cycle consisting of 2 PDTs (= maximum of 4 PDTs per patient) was possible). | 
| Patient Complete Response 12 Weeks After PDT-2 | Patient complete response (complete clearance of all treated lesions) assessed 12 weeks after PDT-2 (first PDT cycle). The PP set is the primary analysis set for the analysis of the secondary endpoint. | 12 weeks after PDT-2 (=PDT cycle 1; please note: in this study 2 PDT cycles, each cycle consisting of 2 PDTs (= maximum of 4 PDTs per patient) was possible). | 
| Cosmetic Outcome 12 Weeks After Last PDT (Including Patients With a Sum Score of 0 at Baseline) | Overall cosmetic outcome 12 weeks after last PDT is calculated as difference between 12 weeks after PDT sum score and baseline sum score of all skin quality assessments. Each of the below skin quality characteristics are assessed on a 4-point scale from 0 (none) to 3 (severe) by the investigator at baseline and 12 weeks after last PDT: Skin surface Hyperpigmentation Hypopigmentation Mottled or irregular pigmentation Degree of scarring Atrophy Cosmetic outcome categories are: Very good: 12 weeks sum score improved by at least 2 points compared to baseline Good: 12 weeks sum score improved by 1 point compared to baseline Satisfactory: 12 weeks sum score identical to the one at baseline Unsatisfactory: 12 weeks sum score worsened by 1 point compared to baseline Impaired: 12 weeks sum score worsened by at least 2 points compared to baseline | 12 weeks after the last PDT (please note: 2 PDT cycles, each cycle consisting of 2 PDTs (= maximum of 4 PDTs per patient) was possible). | 
| Cosmetic Outcome 12 Weeks After the Last PDT (Including Patients With a Baseline Sum Score >1) | Overall cosmetic outcome 12 weeks after last PDT is calculated as difference between 12 weeks after PDT sum score and baseline sum score of all skin quality assessments. Each of the below skin quality characteristics are assessed on a 4-point scale from 0 (none) to 3 (severe) by the investigator at baseline and 12 weeks after last PDT: Skin surface Hyperpigmentation Hypopigmentation Mottled or irregular pigmentation Degree of scarring Atrophy Cosmetic outcome categories are: Very good: 12 weeks sum score improved by at least 2 points compared to baseline Good: 12 weeks sum score improved by 1 point compared to baseline Satisfactory: 12 weeks sum score identical to the one at baseline Unsatisfactory: 12 weeks sum score worsened by 1 point compared to baseline Impaired: 12 weeks sum score worsened by at least 2 points compared to baseline | 12 weeks after the last PDT (please note: 2 PDT cycles, each cycle consisting of 2 PDTs (= maximum of 4 PDTs per patient) was possible). | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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PDT, Photodynamic Therapy, non-aggressive BCC