Clinical Trials Register

Summary
EudraCT Number:	2017-000486-72
Sponsor's Protocol Code Number:	ALA-AK-CT010
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:	2017-06-09
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

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A. Protocol Information

A.1

Member State Concerned

Germany - BfArM

A.2

EudraCT number

2017-000486-72

A.3

Full title of the trial

A randomized, double-blind, intra-individual, multi-center phase III study to evaluate the safety and efficacy of BF 200 ALA (Ameluz®) versus placebo in the treatment of mild to severe actinic keratosis on extremities, trunk/ neck with photodynamic therapy (PDT) when using the BF-RhodoLED® lamp.

Eine randomisierte, doppelblinde, intra-individuelle, multizentrische Phase III Studie zur Beurteilung der Sicherheit und Wirksamkeit von BF-200 ALA (Ameluz®) gegenüber Placebo bei der Behandlung von milden bis schweren Aktinischen Keratosen auf den Extremitäten und Rumpf/Nacken mit photodynamischer Therapie (PDT) unter Verwendung der BF-RhodoLED® Lampe.

A.3.1

Title 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 on extremities and trunk/neck.

A.4.1

Sponsor's protocol code number

ALA-AK-CT010

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Biofrontera Bioscience GmbH
B.1.3.4	Country	Germany
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Biofrontera Bioscience GmbH
B.4.2	Country	Germany
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Biofrontera Bioscience GmbH
B.5.2	Functional name of contact point	Clinical Trial Management
B.5.3	Address:
B.5.3.1	Street Address	Hemmelrather Weg 201
B.5.3.2	Town/ city	Leverkusen
B.5.3.3	Post code	51377
B.5.3.4	Country	Germany
B.5.4	Telephone number	+492148763241
B.5.5	Fax number	+492148763290
B.5.6	E-mail	clintrialCT010@biofrontera.com

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Ameluz
D.2.1.1.2	Name of the Marketing Authorisation holder	Biofrontera Bioscience GmbH
D.2.1.2	Country which granted the Marketing Authorisation	European Union
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Ameluz
D.3.2	Product code	BF-200 ALA
D.3.4	Pharmaceutical form	Gel
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Topical use (Noncurrent)
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	5-Aminolevulinic acid
D.3.9.1	CAS number	5451-09-2
D.3.9.2	Current sponsor code	ALA
D.3.9.3	Other descriptive name	AMINOLEVULINIC ACID HYDROCHLORIDE
D.3.9.4	EV Substance Code	SUB21578
D.3.10	Strength
D.3.10.1	Concentration unit	% (W/W) percent weight/weight
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	10
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Gel
D.8.4	Route of administration of the placebo	Topical use (Noncurrent)

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Actinic keratosis (AK)

Aktinische Keratose (AK)

E.1.1.1

Medical condition in easily understood language

Keratinization of the skin caused by intensive solar radiation.

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	10000614
E.1.2	Term	Actinic keratosis
E.1.2	System Organ Class	10040785 - Skin and subcutaneous tissue disorders

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

Primary objective: To compare the efficacy of BF-200 ALA (also referred to as Ameluz®) with placebo for treatment of mild to severe actinic keratosis (AK) located on extremities and trunk/ neck with PDT when using the BF RhodoLED® lamp.

E.2.2

Secondary objectives of the trial

Secondary objective: To evaluate the safety and secondary efficacy parameters related to BF 200 ALA for treatment of mild to severe actinic keratosis (AK) located on extremities and trunk/ neck with PDT when using the BF RhodoLED® lamp.

E.2.3

Trial contains a sub-study

E.3

Principal 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 at least 4 to 10 clinically confirmed AK target lesions of mild to severe severity (according to Olsen (Olsen et al., 1991)) on one treatment field (continuously or in several patches) totaling about 20 cm2 per comparable patient’s side. Treatment fields can be allocated to the treatment areas extremities (including hands, arms, feet, legs) and/or trunk/ neck, but treatment fields on both sides of a patient must be in comparable locations (subareas) within the same treatment area (e.g. both treatment fields on hands or upper arms or lower arms or upper legs or lower legs or décolleté or back, but not for instance hand on one side of the body and arm on the other). Treatment fields on the left and on the right side should be comparable also regarding AK severity grade and AK lesion number, which should not deviate by more than 50%. AK lesions should be clearly distinguishable; however, no distance restrictions between lesions will be applied. Lesions should measure at least 0.3 cm in diameter and have an upper limit of 1.5 cm. Lesions included in the study should be entirely located within the treatment fields, leaving a minimal distance of ≥ 0.5 cm between the lesion margin and the treatment field border. At least one of the lesions on each side must have a diameter of ≥ 0.5 cm to be selected for 2 mm punch biopsies. One entire tube (2 g) of IMP will be applied to the treatment field on each of both patient’s sides at a thickness of 1 mm and lesions should be located such that the lesions and the margins can be covered.
•Willingness to undergo a 2 mm punch biopsy on each side at the end-of-study visit 12 weeks after the last PDT. One appropriate, distinct lesion on each side will be pre-selected for biopsy at visit 1. The lesions selected for the punch biopsies should have a size of ≥ 0.5 cm and should be similar with respect to size and Olsen grade.
•Free of significant physical abnormalities (e.g. tattoos, dermatoses) in the potential treatment fields that may complicate examinations or final evaluations.
•Willingness to stop the use of moisturizers and any other non-medical topical treatments within the treatment fields at least 24 h prior to the next clinical visit.
•Accept to abstain from extensive sunbathing and the use of a solarium during the period of the clinical visits. Patients experiencing sunburn within the treatment fields cannot be randomized before 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.
•For female patients with reproductive potential: Negative pregnancy test at screening.
•For female patients with reproductive potential: Effective contraception.

E.4

Principal exclusion criteria

•History of hypersensitivity to 5-ALA or any ingredient of BF-200 ALA.
•Presence of porphyria.
•Hypersensitivity to porphyrins.
•Presence of photodermatosis.
•Start of treatment with phototoxic or photoallergic drugs within 8 weeks prior to screening.
•Presence of clinically significant inherited or acquired coagulation defect.
•Clinically significant (CS) medical conditions making implementation of the protocol or interpretation of the study results difficult such as:
Known diagnosis of human immunodeficiency virus (HIV) based on clinical history, Metastatic tumor or tumor with high probability of metastasis, Cardiovascular disease (New York Heart Association [NYHA] class III, IV), Hematologic (including Myelodysplastic syndrome), hepatic, renal, neurologic, or endocrine condition, Collagen-vascular condition, Gastrointestinal condition
•Immunosuppressive condition.
•Current treatment with immunosuppressive therapy.
•Presence of malignant or benign tumors of the skin within the treatment fields (e.g. malignant melanoma, basal cell carcinoma [BCC] or squamous cell carcinoma [SCC]) within the last 4 weeks prior to PDT-1 (Visit 2) until the end of the clinical phase.
•Physical treatment of malignant or benign tumors of the skin within the treatment fields and at a distance of < 10 cm from the nearest target lesion within the treatment fields during the last 4 weeks prior to PDT-1 (Visit 2) until the end of the clinical phase.
•Any topical medical treatment of the skin within the treatment fields 12 weeks before visit 2 (PDT-1) until the end of the clinical phase. Topical non-steroidal anti-inflammatory drugs (NSAIDs) are restricted to not to be used 7 days prior and after each PDT in- and outside the treatment fields. However, diclofenac up to 2.5% may be used outside treatment fields throughout the study.
•Any topical, medical treatment of AK and NMSC inside/ outside the treatment fields (except for IMP treatment) within 12 weeks before visit 2 (PDT-1) until end of clinical phase: (i) Topical treatment with ALA (except IMP) or methyl-aminolevulinate (MAL) in- and outside the treatment fields during the clinical observation period and 12 weeks prior to PDT-1, (ii) Topical treatment with immunomodulatory, cell toxic agents (e.g. imiquimod, ingenol mebutate, 5-FU) or diclofenac/ hyaluronic acid in- and outside the treatment fields during the clinical observation period and 12 weeks prior to PDT-1.
•Any of the specified systemic treatments within the designated period before PDT-1 and during the clinical observation period (for details of the specific treatments see Clinical Study Protocol section "Protocol Outline- exclusion criteria").
•Intake and/or systemic treatment with NSAIDs is restricted to not to be used 7 days prior and after each PDT. ASS up to 100 mg/day, Ibuprofen up to 200 mg/day is allowed in this period.
•Presence of tattoos, skin inflammation, wounds, etc. in close proximity (< 10 cm distance) to treatment fields.

E.5 End points

E.5.1

Primary 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 the last PDT.

E.5.1.1

Timepoint(s) of evaluation of this end point

See definition in section E.5.1.

E.5.2

Secondary end point(s)

•Secondary endpoint A: Patient complete clearance per patient’s side 12 weeks after the last PDT, i.e. percentage of patients with all lesions cleared at the respective patient’s side.
•Secondary endpoint B: Total lesion clearance rate of moderate (according to Olsen) lesions in percent per patient’s side 12 weeks after the last PDT, i.e. percentage of individual moderate lesions with complete remission on the respective side.
•Secondary endpoint C: Total lesion clearance rate in percent per patient’s side in the treatment area extremities 12 weeks after last PDT, i.e. percentage of individual lesions in treatment area extremities with complete remission on the respective side.
•Secondary endpoint D: Total lesion clearance rate in percent per patient’s side in the treatment area neck/trunk 12 weeks after the last PDT, i.e. percentage of individual lesions in treatment area trunk/neck with complete remission on the respective side.
•Secondary endpoint E: Histopathologically confirmed lesion response (HCR) rate 12 weeks after the last PDT per patient’s side.
•Secondary endpoint F: Total lesion clearance rate in percent per patient’s side 12 weeks after PDT-1, i.e. percentage of individual lesions with complete remission on the respective side.
•Secondary endpoint G: Patient complete clearance per patient’s side, 12 weeks after PDT-1, i.e. percentage of patients with all lesions cleared at the respective patient’s side.
•Secondary endpoint H: The overall cosmetic outcome per patient’s side 12 weeks after the last PDT as assessed by the investigator.

E.5.2.1

Timepoint(s) of evaluation of this end point

See definition in section E.5.2.

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

E.8.1.6

Cross over

E.8.1.7

Other

Yes

E.8.1.7.1

Other trial design description

intra-individual

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

Yes

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

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

E.8.5

The trial involves multiple Member States

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.7

Trial has a data monitoring committee

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 planned date for last patient visit.

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

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 double-blind part of the trial has ended, the patients 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

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2017-07-28

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2017-07-17

P. End of Trial
P.	End of Trial Status	Completed

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