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    Clinical Trial Results:
    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)

    Summary
    EudraCT number
    		 2013-003241-42
    Trial protocol
    		 DE   GB  
    Global end of trial date
    17 Nov 2015

    Results information
    Results version number
    		 v2(current)
    This version publication date
    25 Nov 2017
    First version publication date
    01 Dec 2016
    Other versions
    		 v1
    Version creation reason
    • Correction of full data set
    Editorial change

    Trial information

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    Trial identification
    Sponsor protocol code
    ALA-BCC-CT008
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Biofrontera Bioscience GmbH
    Sponsor organisation address
    Hemmelrather Weg 201, Leverkusen, Germany, 51377
    Public contact
    Clinical Trial Department, Biofrontera Bioscience GmbH, +49 2148763210, ameluz@biofrontera.com
    Scientific contact
    Clinical Trial Department, Biofrontera Bioscience GmbH, +49 2148763210, ameluz@biofrontera.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    17 Nov 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    17 Nov 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    17 Nov 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    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.
    Protection of trial subjects
    Subject protection was ensured by following high medical and ethical standards in accordance with the principles laid down in the Declaration of Helsinki, and that are consistent with Good Clinical Practice and applicable regulations.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    28 Jan 2014
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy
    Long term follow-up duration
    		 5 Years
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 42
    Country: Number of subjects enrolled
    Germany: 352
    Worldwide total number of subjects
    394
    EEA total number of subjects
    394
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    139
    From 65 to 84 years
    245
    85 years and over
    10

    Subject disposition

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    Recruitment
    Recruitment details
    		 Trial was conducted in Germany and Great Britain with a total of 24 sites who recruited patients. Enrollment of patients started (first patient enrolled) 28-Jan-2014.

    Pre-assignment
    Screening details
    		 Of the 394 patients enrolled in this study, 281 patients were randomized (138 patients to BF-200 ALA and 143 patients to Metvix®). 113 patients enrolled were excluded before randomization due to screening failure (104 patients), patient’s decision (7 patients), and lost to FU and “other reason” (each 1 patient). All randomized patients treated.

    Period 1
    Period 1 title
    clinical phase/ observer-blind period (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Single blind
    Roles blinded
    		 Investigator [1]
    Blinding implementation details
    Study medication randomized 1:1. IMPs have different consitencies. To guarantee the observer-blind status of the investigator assessing efficacy after each PDT session, a 2nd investigator/delegated person performed IMP application, illumination and conducted all safety evaluations during illumination period. Randomization schedule and allocation to treatment groups were not known to the investigator & sponsor until completion of study, except in case of emergency.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Metvix®
    Arm description
    		 containing 16% methyl-aminolevulinate (MAL)
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Metvix®
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Cream
    Routes of administration
    Topical use
    Dosage and administration details
    The dose for Metvix® was up to 1 g per PDT session (depending on size and number of target lesions located on neck, trunk, extremities, face or scalp, no more than 2 illumination areas with a maximum area including margin of 10 cm², and a film thickness of about 1 mm). Up to 4 administrations of study treatment, which included PDT sessions (PDT-1, PDT-2, PDT-3, and PDT-4) were applied. For all patients, PDT-1 was to be administered directly after randomization and PDT-2 was to be administered approximately 1 week later. The total number of PDT sessions per patient depended on response as follows: Complete responders (lesions totally cleared clinically) 12 weeks after PDT-2: entered the FU part of the study with no further treatment. Partial or non-responders 12 weeks after PDT-2 were retreated with the same study treatment by applying 2 additional PDTs in a second PDT cycle and then entered FU.

    Arm title
    		 BF-200 ALA
    Arm description
    		 BF-200 ALA (also referred to as Ameluz®) containing 7.8% 5-aminolevulinic acid (5-ALA)
    Arm type
    		 Experimental

    Investigational medicinal product name
    BF-200 ALA
    Investigational medicinal product code
    Other name
    Ameluz
    Pharmaceutical forms
    Gel
    Routes of administration
    Topical use
    Dosage and administration details
    The dose for BF-200 ALA was up to 1 g per PDT session (depending on size and number of target lesions located on neck, trunk, extremities, face or scalp, no more than 2 illumination areas with a maximum area including margin of 10 cm², and a film thickness of about 1 mm). Up to 4 administrations of study treatment, which included PDT sessions (PDT-1, PDT-2, PDT-3, and PDT-4) were applied. For all patients, PDT-1 was to be administered directly after randomization and PDT-2 was to be administered approximately 1 week later. The total number of PDT sessions per patient depended on response as follows: Complete responders (lesions totally cleared clinically) 12 weeks after PDT-2: entered the FU part of the study with no further treatment. Partial or non-responders 12 weeks after PDT-2 were retreated with the same study treatment by applying 2 additional PDTs in a second PDT cycle and then entered FU.

    Notes
    [1] - The roles blinded appear inconsistent with a simple blinded trial.
    Justification: During this study, the investigator assessing efficay after each PDT session was observer-blind. A second investigator or delegated person performed drug application, light treatment, and safety evaluation during illumination period. This was important since IMPs can be distinguised by their texture and consistency. IMPs have a comparable safety profile.
    Number of subjects in period 1 [2]
    		Metvix® BF-200 ALA
    Started
    143
    138
    end of clinical phase/ observer-blind
    132
    128
    Completed
    132
    128
    Not completed
    11
    10
         withdrawal due to AE, but in follow up phase
    1
    1
         several reasons were merged, clinical phase
    10
    9
    Notes
    [2] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: 394 subjects enrolled. 113 not randomized, 281 randomized (143 received Metvix, 138 received BF-200-ALA). Due to non-randomized subjects, the number of enrolled subjects is not equal to the number of subjects in the clinical phase. 11 patients (Metvix) & 10 patients (BF-200-ALA) did not complete the study. Note that 1 dropout per group to be accounted for an AE in follow up (due to AE recording until DBL). It was not possible to enter "10" for Metvix and "9" for BF-200-ALA for "not completed".

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Metvix®
    Reporting group description
    		 containing 16% methyl-aminolevulinate (MAL)

    Reporting group title
    BF-200 ALA
    Reporting group description
    		 BF-200 ALA (also referred to as Ameluz®) containing 7.8% 5-aminolevulinic acid (5-ALA)

    Reporting group values
    		 Metvix® BF-200 ALA Total
    Number of subjects
    		 143 138 281
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 54 52 106
        From 65-84 years
    		 87 82 169
        85 years and over
    		 2 4 6
    Age continuous
    Units: years
        arithmetic mean (full range (min-max))
    		 66.3 (31 to 87) 66.6 (32 to 94) -
    Gender categorical
    Units: Subjects
        Female
    		 68 54 122
        Male
    		 75 84 159

    End points

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    End points reporting groups
    Reporting group title
    Metvix®
    Reporting group description
    		 containing 16% methyl-aminolevulinate (MAL)

    Reporting group title
    BF-200 ALA
    Reporting group description
    		 BF-200 ALA (also referred to as Ameluz®) containing 7.8% 5-aminolevulinic acid (5-ALA)

    Primary: overall patient complete response assessed 12 weeks after the last PDT

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    End point title
    		 overall patient complete response assessed 12 weeks after the last PDT
    End point description
    overall patient complete response assessed 12 weeks after the last PDT. The indicated values give precentage 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.
    End point type
    Primary
    End point timeframe
    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.
    End point values
    		 Metvix® BF-200 ALA
    Number of subjects analysed
    110
    121
    Units: percent
        arithmetic mean (confidence interval 95%)
    91.8 (84.6 to 96)
    93.4 (87 to 96.9)
    Statistical analysis title
    		 Difference in % points to BF-200 ALA
    Comparison groups
    Metvix® v BF-200 ALA
    Number of subjects included in analysis
    231
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 < 0.0001
    Method
    		 Farrington and Manning (non-inferiority)
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1.6
    Confidence interval
         level
    		 97.5%
         sides
    1-sided
         lower limit
    		 -6.5
         upper limit
    		 -

    Secondary: Lesion complete response assessed 12 weeks after the last PDT

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    End point title
    		 Lesion complete response assessed 12 weeks after the last PDT
    End point description
    Lesion complete response (completely cleared individual lesions) assessed 12 weeks after the last PDT. The indicated values give precentage of overall completly cleared individual lesions. The PP set is the primary analysis set for the analyses of the secondary endpoint.
    End point type
    Secondary
    End point timeframe
    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.
    End point values
    		 Metvix® BF-200 ALA
    Number of subjects analysed
    110 [1]
    121 [2]
    Units: percent
        arithmetic mean (confidence interval 95%)
    92.9 (86.6 to 96.5)
    94.6 (89.3 to 97.5)
    Notes
    [1] - this is the number of patients that received Metvix. They had 127 lesions in total.
    [2] - This is the number of patients that received BF-200 ALA. They had 148 lesions in total.
    No statistical analyses for this end point

    Secondary: Reduction of total lesion area 12 weeks after last PDT compared to baseline

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    End point title
    		 Reduction of total lesion area 12 weeks after last PDT compared to baseline
    End point description
    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 analyses of the secondary endpoint. Please note that the high SD for BF-200 ALA is due to a patient who had increased lesion area from 63 square-mm at baseline to 225 square-mm 12 weeks after PDT. This lesion area included a lesion that was later confirmed to be benign skin condition (lentigo solaris).
    End point type
    Secondary
    End point timeframe
    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.
    End point values
    		 Metvix® BF-200 ALA
    Number of subjects analysed
    110
    121
    Units: percent
        arithmetic mean (standard deviation)
    -97 ( 13.37 )
    -94.5 ( 35.07 )
    No statistical analyses for this end point

    Secondary: Cosmetic outcome 12 weeks after last PDT (sum score at baseline of 0 to 3)

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    End point title
    		 Cosmetic outcome 12 weeks after last PDT (sum score at baseline of 0 to 3)
    End point description
    The PP set is the primary analysis set for the analyses of the secondary endpoint.
    End point type
    Secondary
    End point timeframe
    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.
    End point values
    		 Metvix® BF-200 ALA
    Number of subjects analysed
    109
    120
    Units: percent
    arithmetic mean (confidence interval 95%)
        very good
    14.7 (8.9 to 23)
    23.3 (16.3 to 32.1)
        good
    18.3 (11.8 to 27.2)
    11.7 (6.8 to 19.1)
        satisfactory
    29.4 (21.2 to 39)
    35.8 (27.4 to 45.2)
        unsatisfactory
    20.2 (13.3 to 29.2)
    14.2 (8.7 to 22)
        impaired
    17.4 (11.1 to 26.1)
    15 (9.4 to 22.9)
    No statistical analyses for this end point

    Secondary: Cosmetic oucome 12 weeks after last PDT (sum score at baseline of 1 to 3, 0 excluded)

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    End point title
    		 Cosmetic oucome 12 weeks after last PDT (sum score at baseline of 1 to 3, 0 excluded)
    End point description
    End point type
    Secondary
    End point timeframe
    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.
    End point values
    		 Metvix® BF-200 ALA
    Number of subjects analysed
    74
    70
    Units: percent
    arithmetic mean (confidence interval 95%)
        very good
    21.6 (13.2 to 33)
    40 (28.7 to 52.4)
        good
    27 (17.7 to 38.8)
    20 (11.7 to 31.6)
        satisfactory
    32.4 (22.3 to 44.4)
    22.9 (14 to 34.7)
        unsatisfactory
    12.2 (6.1 to 22.3)
    11.4 (5.4 to 21.8)
        impaired
    6.8 (2.5 to 15.7)
    5.7 (1.8 to 14.7)
    No statistical analyses for this end point

    Secondary: Patient complete response, 12 weeks after PDT-2

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    End point title
    		 Patient complete response, 12 weeks after PDT-2
    End point description
    End point type
    Secondary
    End point timeframe
    12 weeks after PDT-2. Please note, 2 PDT-cycles, each consisting of 2 PDTs (=maximum of PDTs per patient) was possible.
    End point values
    		 Metvix® BF-200 ALA
    Number of subjects analysed
    110
    121
    Units: percent
        arithmetic mean (confidence interval 95%)
    56.4 (46.6 to 65.7)
    57.9 (48.5 to 66.7)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    28-Jan-2014 (first patient's informed consent) until date of DBL (data base lock, 22-Jan-2016)
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.1
    Reporting groups
    Reporting group title
    BF-200 ALA
    Reporting group description
    		 -

    Reporting group title
    Metvix
    Reporting group description
    		 -

    Serious adverse events
    		 BF-200 ALA Metvix
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 138 (2.17%)
    7 / 143 (4.90%)
         number of deaths (all causes)
    0
    1
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal cell carcinoma
         subjects affected / exposed
    1 / 138 (0.72%)
    0 / 143 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prostate cancer
         subjects affected / exposed
    1 / 138 (0.72%)
    0 / 143 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bowen's disease
         subjects affected / exposed
    0 / 138 (0.00%)
    1 / 143 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malignant melanoma in situ
         subjects affected / exposed
    0 / 138 (0.00%)
    1 / 143 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous cell carcinoma
         subjects affected / exposed
    0 / 138 (0.00%)
    1 / 143 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Supraventricular tachycardia
         subjects affected / exposed
    1 / 138 (0.72%)
    0 / 143 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    0 / 138 (0.00%)
    1 / 143 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Death
         subjects affected / exposed
    0 / 138 (0.00%)
    1 / 143 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Eye disorders
    Glaucoma
         subjects affected / exposed
    0 / 138 (0.00%)
    1 / 143 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Colitis
         subjects affected / exposed
    0 / 138 (0.00%)
    1 / 143 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis ulcerative
         subjects affected / exposed
    0 / 138 (0.00%)
    1 / 143 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Uterine prolapse
         subjects affected / exposed
    0 / 138 (0.00%)
    1 / 143 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 BF-200 ALA Metvix
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    138 / 138 (100.00%)
    143 / 143 (100.00%)
    General disorders and administration site conditions
    Application site pain
         subjects affected / exposed
    134 / 138 (97.10%)
    143 / 143 (100.00%)
         occurrences all number
    718
    751
    Application site erythema
         subjects affected / exposed
    120 / 138 (86.96%)
    126 / 143 (88.11%)
         occurrences all number
    309
    288
    Application site pruritus
         subjects affected / exposed
    59 / 138 (42.75%)
    49 / 143 (34.27%)
         occurrences all number
    91
    84
    Application site edema
         subjects affected / exposed
    42 / 138 (30.43%)
    52 / 143 (36.36%)
         occurrences all number
    86
    108
    Application site paresthisia
         subjects affected / exposed
    40 / 138 (28.99%)
    39 / 143 (27.27%)
         occurrences all number
    64
    65
    Application site scab
         subjects affected / exposed
    34 / 138 (24.64%)
    41 / 143 (28.67%)
         occurrences all number
    45
    49
    Application site induration
         subjects affected / exposed
    32 / 138 (23.19%)
    27 / 143 (18.88%)
         occurrences all number
    63
    50
    Application site discharge
         subjects affected / exposed
    24 / 138 (17.39%)
    24 / 143 (16.78%)
         occurrences all number
    38
    32
    Application site exfoliation
         subjects affected / exposed
    22 / 138 (15.94%)
    12 / 143 (8.39%)
         occurrences all number
    25
    13
    Application site erosion
         subjects affected / exposed
    18 / 138 (13.04%)
    9 / 143 (6.29%)
         occurrences all number
    22
    10
    Application site vesicles
         subjects affected / exposed
    10 / 138 (7.25%)
    11 / 143 (7.69%)
         occurrences all number
    13
    13
    Application site discolouration
         subjects affected / exposed
    4 / 138 (2.90%)
    8 / 143 (5.59%)
         occurrences all number
    4
    10
    Skin and subcutaneous tissue disorders
    Actinic keratosis
         subjects affected / exposed
    5 / 138 (3.62%)
    9 / 143 (6.29%)
         occurrences all number
    5
    11
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    11 / 138 (7.97%)
    10 / 143 (6.99%)
         occurrences all number
    13
    10

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    14 Nov 2014
    This amendment, which affected all study sites, was dated 14 November 2014, after a total of 181 patients had been enrolled and treated. Changes and clarifications to inclusion and exclusion criteria were amended to be able to enhance patient enrollment. This change was implemented to improve recruitment. Patients enrolled after this change were expected to be comparable from a medicinal point of view and no differences in efficacy and tolerability were to be expected in comparison to those patients who had already been included in the study. This assumption was based on the fact that the applied treatment is topical and locally restricted. Thus the change in the in-/exclusion criteria was not expected to influence the composition of the enrolled population.
    07 May 2015
    This amendment, which affected all study sites, was dated 07 May 2015 (for Protocol version 4 for Germany and the 18 May 2015 for Protocol version 4.1 in the UK), after a total of 274 or 275 patients respectively had been enrolled and treated. This amendment reduced the sample size from a total of 360 patients to a total of 272 patients because a higher overall response than originally anticipated was observed during the blinded monitoring of the study. In addition, the requirement that “all the pages of the patient information had to be initialed and dated by the patient to confirm the comprehension” was deleted because signing and dating of the last page of the ICF is sufficient according to European regulations.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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