| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Basal cell carcinoma (BCC) |
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| E.1.1.1 | Medical condition in easily understood language |
| Rodent ulcer - small, fair papules, flesh-colored, round or oval translucent nodule, or scaly, localized plaque in frequently sun-exposed skin |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Skin and Connective Tissue Diseases [C17] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10004146 |
| E.1.2 | Term | Basal cell carcinoma |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| The primary objective of the study is to compare the efficacy of BF-200 ALA containing 7.8% 5-aminolevulinic acid (ALA) as active ingredient with the comparator Metvix®, containing 16% methyl-aminolevulinate in the treatment of thin, non-aggressive BCC with photodynamic therapy. |
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| E.2.2 | Secondary objectives of the trial |
• Lesion complete response (completely cleared individual lesions) assessed 12 weeks after the last PDT,
• Reduction of total lesion area (summation of sizes of all treated lesions) per patient, assessed 12 weeks after the last PDT,
• Patient complete response (complete clearance of all treated lesions) assessed 12 weeks after PDT-2,
• The overall cosmetic outcome 12 weeks after the last PDT.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
• Willing and able to sign a study-specific ICF, which must be obtained in writing for all patients before any study procedures
• Men or women ≥18 years of age (inclusive)
• Presence of 1- 3 primary BCC lesions in face/forehead outside H-zone , bald scalp, extremities and/or neck/trunk, all of which are, according to clinical judgment of investigator, likely to fulfil criteria for positive outcome of histological assessment (non-aggressive BCCs comprising primary superficial, nodular, or mixed superficial/nodular BCC with a thickness ≤2 mm). Only eligible lesions with confirmation by biopsy taken at screening are allowed to be included in the study, lesions assessed as non-eligible should be excised by surgery or removed by cryotherapy in a timely manner. Other treatments are not allowed for these lesions.
To document and confirm investigator’s clinical diagnosis of non-aggressive behavior and thickness of the lesions, pre-study biopsies must be taken at the screening visit from all BCC lesions . 3-mm biopsies should be taken at the region of the tumor which, according to clinical judgment, appears thickest.
Biopsy material will be histopathologically evaluated by a dermatopathological expert according to WHO classification/subtyping. Ifno clear histopathological assessment can be performed second biopsy may be taken after approval of sponsor. Hence, time interval between Visit 1 / Visit 2 has to be expanded accordingly
The result of biopsies will ultimately determine whether the patient is eligible for the study; patient may only be enrolled if the investigator’s clinical diagnosis of non-aggressive BCC with a thickness of ely determine whether the patient ie lesion by the histopathological evaluation according to WHO classification guideline
• The diameter of each lesion should range between ≥0.5 cm and ≤2 cm;total maximal treated area must not be larger than approximately 10 cm² (including a 0.5 – 1.0 cm margin surrounding each lesion).Size of each baseline BCC lesion is determined by measuring the two largest perpendicular diameters.To describe irregular lesions (ellipsoidal) the major and minor axes must be measured,which must both be within the acceptable limits defined above
• Target BCC lesions must be discrete and quantifiable and have to be located within 1 to 2 treatment areas. Target lesions must be placed within max. 2 illumination areas (illumination area is defined by the effective illumination area of the BF-RhodoLED® device with approx. 6 x 16 cm)
• Patients displaying non-eligible lesions by biopsy taken at screening should be included in the study if at least one lesion is eligible and non-eligible lesions are at least 10 cm apart from eligible lesion(s). The non-eligible lesions should timely be removed by surgery or cryotherapy.
• Willingness to undergo biopsy at the end of the observer blind part of the study 12 weeks after last PDT in case of partial or non-responding lesions
• Willingness to receive up to 4 PDTs within 3.5 months
• Free of significant physical abnormalities in the potential treatment area that may cause difficulty with examination or final evaluation
• Willingness to stop use of moisturizers and any other topical treatments within the treatment area (during observer blind part), incl. anti-aging products, vitamin A-, vitamin D-, and/or vitamin E-containing ointments /creams, and green tea preparations during the study. Sunscreens will be allowed, but should not be applied in the treatment area within approx. 24 h before a clinical visit involving lesion count
• Accept to abstain from extensive sunbathing and use of a solarium during the observer blind part of the study. Patients with sunburn within the treatment areas cannot be included until fully recovered
• Healthy patients or patients with clinically stable medical conditions as confirmed by physical examination and by medical history, including but not limited to controlled hypertension, diabetes mellitus type II, hypercholesterolemia, and osteoarthritis, will be permitted to be included in the study if their medication is not prohibited by this protocol
• Women of childbearing potential are permitted to participate in this study only if they have a negative serum pregnancy test at screening and a willingness to use a highly effective method of contraception during observer blind part of the study. A woman is considered to be of childbearing potential if she possesses a uterus and at least one ovary, has not had a tubal ligation, or is not postmenopausal for at least 3 years. Highly effective methods of birth control are defined as resulting in a low failure rate (Pearl Index below 1) when properly used. This includes methods such as implants, injectables, combined oral contraceptives, some intrauterine devices (IUDs), sexual abstinence, or sexual intercourse with a vasectomized partner. Use of condoms without spermicide coating is not considered to be a highly effective method of contraception
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| E.4 | Principal exclusion criteria |
• History of hypersensitivity to 5-ALA or any ingredient of BF-200 ALA
• History of hypersensitivity to MAL or any ingredient of Metvix® cream including arachis oil,or to peanut or soya
• Current treatment with immunosuppression therapy
• Presence of porphyria
• Hypersensitivity to porphyrins
• Presence of BCC lesions on embryonic fusion planes (H-zone)
• Presence of more than 3 BCCs
• Presence of malignant or benign tumors of skin other than non-aggressive BCC within treatment area (eg melanoma,SCC,aggressive BCC clearly diagnosed at screening visit by clinical assessment) within last 12 weeks
Treatment areas are defined as whole face (without H-zone) + forehead, bald scalp , neck, dorsal and back (neck/trunk) + extremities
• Gorlin Syndrome or Xeroderma pigmentosum
• Presence of photodermatoses
• Recurrent or pigmented BCCs or clearly clinically diagnosed aggressive BCCs incl. morpheiform BCC
• Treatment of lesions (AK,BCC,SCC,Bowens disease,melanoma) ≤12 weeks prior to first PDT, except physical treatments that will not be allowed ≤6 weeks prior to first PDT. Lesion(s) that seemed eligible by clinical judgment but could not be confirmed to be eligible by biopsy at screening, and which are located at a distance of ≥10 cm to an eligible lesion should be excised surgically or removed by cryotherapy in a timely manner. Such lesions must not be treated by PDT or topical medicaments during the observer blind part
• Presence of lesion(s) which are assessed as non-eligible by biopsy at screening less than 10 cm away from a suitable lesion
• Presence of inherited or acquired coagulation defect
• Start of intake of medication with hypericin or systemically-acting drugs with phototoxic or photoallergic potential, such as psoralenes,tetracyclines,nalidixic acid,furosemide,amiodarone,phenothiacines,chinolones,fibrates, or phytotherapy with St. John’s wort,arnica,valerian,or topically applied phototoxic substances ,within 8 weeks prior to screening. Patients may be enrolled if such medication was taken for more than 8 weeks prior to screening without evidence of a phototoxic/photoallergic reaction. Within 8 weeks prior to screening and during observer blind part, such medication must not be newly prescribed. Should such a prescription become unavoidable for medical reasons during clinical part of the trial, investigator has to consult with sponsor,who may discontinue the patient’s study participation,if deemed necessary
• 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, such as:
− Metastatic tumor or tumor with high probability of metastatic spread
− Cardiovascular disease (New York Heart Association 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 observer blind part
• Any topical treatment incl. diclofenac and immunomodulatory agents 12 weeks prior to first PDT session and during observer blind part
• Any physical treatment during observer blind part within treated area(s) with the exception of lesion(s) that could not be confirmed to be eligible by biopsy at screening and which are located at a distance of ≥creening and which are locat
• None of the following systemic treatments within designated period prior to first PDT and during observer blind part of study:
- 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)
- MAL or 5-ALA (12 weeks)
• Pregnancy
• Breast feeding
• Patients with any dermatological disease in treatment region or surrounding region that may be exacerbated by treatment with topical 5-ALA or MAL or that may cause difficulty with examinations (eg psoriasis,eczema)
• Patients showing cornu cutaneum-like alterations of the skin in face or on the bald scalp (ie treatment region)
• Participation in a clinical study within 2 months prior to screening
• Drug or alcohol abuse in the preceding 2 years
• Patient is investigator,any subinvestigator,research assistant,pharmacist,study coordinator, other staff, or relative thereof directly involved in conduct of the protocol
• Mental condition rendering the patient unable to understand nature,scope,and possible consequences of the study
• Patient is unlikely to comply with protocol,eg uncooperative attitude, inability to return for FU visits,and unlikelihood of completing study
• Confirmed diagnosis of human immunodeficiency virus (HIV)
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary efficacy variable will be the overall patient complete response assessed clinically 12 weeks after the last PDT. An overall complete responder is defined as a patient in whom all treated lesions were cleared after the last PDT. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| See definition in sec. E.5.1 |
|
| E.5.2 | Secondary end point(s) |
• Lesion complete response (completely cleared individual lesions) assessed 12 weeks after the last PDT,
• Reduction of total lesion area (summation of sizes of all treated lesions) per patient, assessed 12 weeks after the last PDT,
• Patient complete response (complete clearance of all treated lesions) assessed 12 weeks after PDT-2,
• The overall cosmetic outcome 12 weeks after the last PDT. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| See definition in sec. E.5.2 |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
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| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 21 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 26 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| The end of the study is defined as the date of the last FU visit of the last patient. |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 7 |
| E.8.9.1 | In the Member State concerned months | 3 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 7 |
| E.8.9.2 | In all countries concerned by the trial months | 7 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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