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    Summary
    EudraCT Number:2015-004382-83
    Sponsor's Protocol Code Number:ALA-AK-CT009
    National Competent Authority:Germany - BfArM
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2016-03-07
    Trial results View results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedGermany - BfArM
    A.2EudraCT number2015-004382-83
    A.3Full title of the trial
    A randomized, observer-blind, intra-individual phase III study to evaluate the safety and efficacy of BF 200 ALA (Ameluz®) in combination with daylight-PDT (photodynamic therapy) in comparison with Metvix® for the treatment of mild to moderate actinic keratosis
    Randomisierte, beobachterverblindete, intra-individuelle Phase-III-Studie zur Beurteilung der Sicherheit und Wirksamkeit von BF-200 ALA (Ameluz®) in Kombination mit Tageslicht–PDT (photodynamische Therapie) im Vergleich zu Metvix® für die Behandlung von leichter bis mittelschwerer aktinischer Keratose
    Estudio aleatorizado, de observador-ciego, intraindividual, de fase III para evaluar la seguridad y la eficacia de BF 200 ALA (Ameluz®) en asociación con Terapia Fotodinámica (TFD) con luz de día, en comparación con Metvix® para el tratamiento de la queratosis actínica leve a moderada
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Investigation of the effective and safe use of the drug product in the treatment of actinic keratosis with daylight
    A.4.1Sponsor's protocol code numberALA-AK-CT009
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorBiofrontera Bioscience GmbH
    B.1.3.4CountryGermany
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportBiofrontera Bioscience GmbH
    B.4.2CountryGermany
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationBiofrontera Bioscience GmbH
    B.5.2Functional name of contact pointClinical Trial Department
    B.5.3 Address:
    B.5.3.1Street AddressHemmelrather Weg 201
    B.5.3.2Town/ cityLeverkusen
    B.5.3.3Post code51377
    B.5.3.4CountryGermany
    B.5.4Telephone number+492148763241
    B.5.5Fax number+492148763290
    B.5.6E-mailclintrialCT009@biofrontera.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Ameluz®
    D.2.1.1.2Name of the Marketing Authorisation holderBiofrontera Bioscience GmbH
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameAmeluz®
    D.3.2Product code BF-200 ALA
    D.3.4Pharmaceutical form Gel
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPTopical use (Noncurrent)
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INN5-aminolaevulinic acid
    D.3.9.1CAS number 5451-09-2
    D.3.9.3Other descriptive nameAMINOLEVULINIC ACID HYDROCHLORIDE
    D.3.9.4EV Substance CodeSUB21578
    D.3.10 Strength
    D.3.10.1Concentration unit mg/g milligram(s)/gram
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number78
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 2
    D.1.2 and D.1.3IMP RoleComparator
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Metvix®
    D.2.1.1.2Name of the Marketing Authorisation holderGalderma Laboratorium GmbH
    D.2.1.2Country which granted the Marketing AuthorisationGermany
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameMetvix®
    D.3.4Pharmaceutical form Cream
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPTopical use (Noncurrent)
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNmethyl aminolevulinate
    D.3.9.1CAS number 79416-27-6
    D.3.9.3Other descriptive nameMETHYL AMINOLEVULINATE HYDROCHLORIDE
    D.3.9.4EV Substance CodeSUB21579
    D.3.10 Strength
    D.3.10.1Concentration unit mg/g milligram(s)/gram
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number160
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Actinic keratosis
    E.1.1.1Medical condition in easily understood language
    Keratinization of the skin caused by intensive solar radiation
    E.1.1.2Therapeutic area Diseases [C] - Skin and Connective Tissue Diseases [C17]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 18.1
    E.1.2Level PT
    E.1.2Classification code 10000614
    E.1.2Term Actinic keratosis
    E.1.2System Organ Class 10040785 - Skin and subcutaneous tissue disorders
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The primary objective of the study is to compare the efficacy and safety of Ameluz® treatment of mild to moderate AK with Metvix® when using daylight PDT.

    E.2.2Secondary objectives of the trial
    The secondary objectives of the study are to evaluate the safety and secondary efficacy parameters related to Ameluz® or Metvix® for the treatment of AK PDT when using daylight PDT.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    • Males or females between 18 and 85 years of age (inclusive)
    • Willing and able to sign the informed consent form. A study-specific informed consent must be obtained in writing for all patients before starting any study procedures.
    • Presence of 3 to 9 clinically confirmed AK target lesions of mild to moderate intensity, i.e. AK grade 1 or 2 according to Olsen et al 1991(Olsen et al., 1991), within each of 2 comparable treatment areas located either on opposite sides of the face (excluding eyes, nostrils, ears, and mouth) and/or the scalp. The number of lesions should not vary by more than 50% between the two sides for each patient.
    • AK lesions must be discrete and measurable; the diameter of each AK lesion should be between 0.5 cm and 1.5 cm.
    • Willingness to undergo a biopsy at each patient’s side at the end-of-clinical observation period visit 12 weeks after the last PDT
    • Free of significant physical abnormalities (e.g. tattoos, dermatoses) in the potential treatment areas that may complicate examinations or final evaluations
    • Willingness to stop the use of moisturizers and any other topical treatments within the treatment area(s) 24 h before and 48 h after PDT and within approximately 24 h before a clinical visit that involves lesion counts.
    • Accept to abstain from extensive sunbathing and the use of a solarium during the period of the clinical visits except period of daylight PDT. Patients experiencing sunburn within the treatment areas cannot be included until they have fully recovered.
    • Good general health and/or stable health condition, as confirmed by a physical examination and medical history
    • Healthy patients and patients with clinically stable medical conditions including, but not limited to, the following diseases: controlled hypertension, diabetes mellitus type II, hypercholesterolemia, and osteoarthritis will be permitted to be included into the study if the medication taken for the treatment of the disease does not match an exclusion criterion or is specified as prohibited concomitant medication.
    • Negative pregnancy test at screening, if appropriate
    • Effective contraception in women of childbearing potential
    E.4Principal exclusion criteria
    • History of hypersensitivity to 5-ALA, MAL or any ingredient of Ameluz® or Metvix®
    • Current treatment with immunosuppressive therapy
    • Presence of porphyria
    • Hypersensitivity to porphyrins
    • Presence of photodermatoses
    • Presence of other malignant or benign tumors of the skin within the treatment areas (e.g. malignant melanoma, basal cell carcinoma [BCC] or squamous cell carcinoma [SCC]) within the last 4 weeks prior to PDT (V2)).
    • Presence of an inherited or acquired coagulation defect
    • Known confirmed diagnosis of human immunodeficiency virus (HIV) based on clinical history
    • Start of treatment with phototoxic or photoallergic drugs within 8 weeks prior to screening
    • Clinically significant (CS) medical conditions (tumor disease etc.) making implementation of the protocol or interpretation of the study results difficult
    • Evidence of CS, unstable medical conditions such as:
    - 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
    • Use of any medicinal topical treatment in the treatment areas within 12 weeks before PDT
    • Any physical treatments for melanoma, AK and NMSC within the treatment areas in the last 4 weeks before PDT
    • Topical treatment with immunomodulatory or cell toxic agents (e.g. imiquimod, ingenol mebutate, 5-FU) or ALA or MAL within 12 weeks prior to the PDT session and during the clinical observation period (except the study specific treatment with Ameluz® and Metvix®)
    • Any of the specified systemic treatments within the designated period before PDT and during the clinical observation period
    • Presence of tattoos, skin inflammation, wounds etc. in close proximity to the treatment area
    E.5 End points
    E.5.1Primary end point(s)
    The primary efficacy variable is the total lesion clearance rate in percent per patient’s side, defined as the percentage of individual lesions with complete remission on the respective side of the patient assessed 12 weeks after PDT.
    E.5.1.1Timepoint(s) of evaluation of this end point
    see definition in sec. E.5.1
    E.5.2Secondary end point(s)
    • Total lesion clearance, defined as the number of completely cleared individual lesions 12 weeks after PDT per patient’s side
    • Total lesion clearance, defined as the number of completely cleared individual lesions of mild or moderate severity (according to Olsen criteria 1 or 2 ) at baseline 12 weeks after PDT per patient’s side
    • Total lesion clearance, defined as the number of completely cleared individual lesions, separately by face and scalp 12 weeks after PDT per patient’s side
    • Patient complete clearance per patient’s side, i.e. all lesions cleared at the respective patient’s side
    • Patient histologically confirmed response rate (HCR) per patient’s side
    • p53 expression per patient’s side in one biopsy on each side taken at the end-of-observer-blind period
    • Reduction of total lesion area (the size of all treated lesions added up) per patient 12 weeks after PDT per patient’s side
    • The change in skin quality assessments compared to baseline assessed 12 weeks after PDT per patient’s side
    • The overall cosmetic outcome 12 weeks after PDT per patient’s side
    • Patient’s satisfaction on cosmetic outcome (per patient side) and therapy (per patient’s side and global)
    E.5.2.1Timepoint(s) of evaluation of this end point
    see definition ind sec. E.5.2
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other Yes
    E.8.1.7.1Other trial design description
    split-face, observer-blind
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) Yes
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial1
    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.8.4.1Number of sites anticipated in Member State concerned4
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA8
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial 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
    End of trial is defined as the date for the last patient visit
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years1
    E.8.9.1In the Member State concerned months6
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years1
    E.8.9.2In all countries concerned by the trial months6
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 12
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 38
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state25
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 50
    F.4.2.2In the whole clinical trial 50
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    After participation in the in the observer blind part of the trial has ended, the patient will receive conventional treatment at the discretion of the investigator (e.g. cryotherapy, surgery or other) if needed.
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2016-03-31
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2016-06-09
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2017-09-19
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