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    Clinical Trial Results:
    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

    Summary
    EudraCT number
    		 2017-000486-72
    Trial protocol
    		 DE  
    Global end of trial date

    Results information
    Results version number
    		 v1(current)
    This version publication date
    03 Jul 2019
    First version publication date
    03 Jul 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    ALA-AK-CT010
    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 Management, Biofrontera Bioscience GmbH, +49 2148763210, clintrialCT010@biofrontera.com
    Scientific contact
    Clinical Trial Management, Biofrontera Bioscience GmbH, +49 2148763210, clintrialCT010@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
    Interim
    Date of interim/final analysis
    09 Jan 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    09 Jan 2019
    Global end of trial reached?
    No
    General information about the trial
    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. Secondary objective: To evaluate the safety and secondary efficacy parameters related to BF 200 ALA for treatment of AK on extremities and trunk/neck with PDT when using the BF-RhodoLED® lamp.
    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
    18 Sep 2017
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy
    Long term follow-up duration
    		 9 Months
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Germany: 56
    Worldwide total number of subjects
    56
    EEA total number of subjects
    56
    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)
    10
    From 65 to 84 years
    45
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 Trial was conducted in Germany with a total of 6 sites that recruited subjects. Recruitment of subjects started on 18 September 2017.

    Pre-assignment
    Screening details
    		 Subjects were screened at Visit 1 for eligibility which was approx. 2 weeks prior to assignment to treatment (PDT-1). Of the 56 subjects screened in the study, 50 subjects were randomized, and 48 subjects completed the study regularly.

    Pre-assignment period milestones
    Number of subjects started
    		 56
    Number of subjects completed
    		 50

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 Adverse event, non-fatal prior to treatment: 1
    Reason: Number of subjects
    		 Consent withdrawn by subject prior to treatment: 1
    Reason: Number of subjects
    		 Screening failure: 4
    Period 1
    Period 1 title
    Clinical observation period (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor
    Blinding implementation details
    Although verum and placebo are indistinguishable by appearance, the intensity of adverse events (AEs) is likely to differ. To guarantee the blind status of the investigator assessing the efficacy of the treatment in this intra-individual study, PDT and all safety assessments were to be performed by a second investigator. Patients were to be instructed to report AEs during the illumination(s) and the coming days only to the second investigator.

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 BF-200 ALA (Verum)
    Arm description
    		 A nanoemulsion containing 7.8% 5-aminolevulinic acid (5-ALA)
    Arm type
    		 Experimental

    Investigational medicinal product name
    BF-200 ALA
    Investigational medicinal product code
    BF-200 ALA
    Other name
    Ameluz®
    Pharmaceutical forms
    Gel
    Routes of administration
    Topical use
    Dosage and administration details
    • BF-200 ALA gel (2g) was administered (about 1 mm thickness) according to randomization schedule, covering lesions and surroundings • Treatment field on one side did not have to be continuous, but had to cover a total area of approx. 20 cm² and had to be within the 6x16 cm² illumination field to allow illumination in a single step • Treatment field on each patient’s side could be located on all parts of extremities or trunk/neck, but treatment fields on both sides had to be located in comparable locations (treatment subareas) • Treatment subareas included back of the hands, lower arms, upper arms, lower legs, upper legs, décolleté, neck or other comparable parts of the trunk • Application near genitalia was to be avoided • IMP dried for approx. 10 min • Lesions were occluded with a light-tight dressing • Subjects had to stay in a well-tempered environment during 3h incubation • Dressing was removed; remnant gel wiped off • Illumination with BF-RhodoLED®(10 min; 37 J/cm²)

    Arm title
    		 Placebo
    Arm description
    		 A nanoemulsion formulation similar to BF-200 ALA but without the active ingredient ALA.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Vehicle
    Pharmaceutical forms
    Gel
    Routes of administration
    Topical use
    Dosage and administration details
    • Placebo gel (2g) was administered (about 1 mm thickness) according to randomization schedule, covering lesions and surroundings • Treatment field on one side did not have to be continuous, but had to cover a total area of approx. 20 cm² and had to be within the 6x16 cm² illumination field to allow illumination in a single step • Treatment field on each patient’s side could be located on all parts of extremities or trunk/neck, but treatment fields on both sides had to be located in comparable locations (treatment subareas) • Treatment subareas included back of the hands, lower arms, upper arms, lower legs, upper legs, décolleté, neck or other comparable parts of the trunk • Application near genitalia was to be avoided • IMP dried for approx. 10 min • Lesions were occluded with a light-tight dressing • Subjects had to stay in a well-tempered environment during 3h incubation • Dressing was removed; remnant gel wiped off • Illumination with BF-RhodoLED®(10 min; 37 J/cm²)

    Number of subjects in period 1
    		BF-200 ALA (Verum) Placebo
    Started
    50
    50
    Completed
    48
    48
    Not completed
    2
    2
         Consent withdrawn by subject
    2
    2

    Baseline characteristics

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    Baseline characteristics reporting groups [1]
    Reporting group title
    Clinical observation period
    Reporting group description
    		 -

    Notes
    [1] - The number of subjects reported to be in the baseline period is not equal to the worldwide number of subjects enrolled in the trial. It is expected that these numbers will be the same.
    Justification: 56 patients were screened, but only 50 patients were randomized. Due to non-randomized subjects, the number of enrolled subjects is not equal to the number of subjects in the clinical observation period (subjects reported in baseline period).
    Reporting group values
    		 Clinical observation period Total
    Number of subjects
    		 50 50
    Age categorical
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 10 10
        From 65-84 years
    		 40 40
        85 years and over
    		 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 70.8 ± 8.3 -
    Gender categorical
    Units: Subjects
        Female
    		 26 26
        Male
    		 24 24
    Fitzpatrick skin type
    Units: Subjects
        Type I to III
    		 48 48
        Type IV to VI
    		 2 2

    End points

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    End points reporting groups
    Reporting group title
    BF-200 ALA (Verum)
    Reporting group description
    		 A nanoemulsion containing 7.8% 5-aminolevulinic acid (5-ALA)

    Reporting group title
    Placebo
    Reporting group description
    		 A nanoemulsion formulation similar to BF-200 ALA but without the active ingredient ALA.

    Primary: Total lesion clearance rate in percent per patient’s side 12 weeks after last PDT (FAS)

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    End point title
    		 Total lesion clearance rate in percent per patient’s side 12 weeks after last PDT (FAS)
    End point description
    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. The full analysis set (FAS) consists of all patients randomized and treated at least with one assigned IMP (IMP application and illumination) after randomization. In accordance with the intent-to-treat (ITT) principle, the assignment of patients’ sides to the treatment groups will be as randomized.
    End point type
    Primary
    End point timeframe
    12 weeks after last PDT
    End point values
    		 BF-200 ALA (Verum) Placebo
    Number of subjects analysed
    49
    49
    Units: percent
        arithmetic mean (standard deviation)
    86.0 ± 23.2
    32.9 ± 37.1
    Statistical analysis title
    		 One-sided Wilcoxon signed rank test (FAS)
    Statistical analysis description
    The Wilcoxon signed rank test (one-sided, alpha=0.025) was applied (using the location parameter mu0 of 0%). Due to the intra-individual design, the number of subjects reflects the number of subjects' sides.
    Comparison groups
    BF-200 ALA (Verum) v Placebo
    Number of subjects included in analysis
    98
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 One-sided Wilcoxon signed rank test
    Confidence interval
    Statistical analysis title
    		 Non-parametric, one-sided 97.5% CI (FAS)
    Statistical analysis description
    Additionally, a non-parametric, one-sided 97.5% confidence interval (CI) for the median difference in response rates rALA - rPla was calculated. If the lower bound of this CI is greater than 0, it indicates superiority of BF-200 ALA PDT to placebo PDT. The application of the non-parametric CI was subordinate. Due to the intra-individual design, the number of subjects reflects the number of subjects' sides.
    Comparison groups
    BF-200 ALA (Verum) v Placebo
    Number of subjects included in analysis
    98
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Median difference (final values)
    Point estimate
    60
    Confidence interval
         level
    		 97.5%
         sides
    1-sided
         lower limit
    		 33.3
         upper limit
    		 -

    Secondary: Patient complete clearance per patient’s side 12 weeks after the last PDT (FAS)

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    End point title
    		 Patient complete clearance per patient’s side 12 weeks after the last PDT (FAS)
    End point description
    Confirmatory hypothesis testing of secondary variables measured during the clinical study period was to be done only after the test of the primary efficacy variable was passed (superiority of BF-200 ALA PDT over placebo PDT confirmed for FAS), and was to be done strictly in the given order to ensure the family wise error rate. Confirmatory hypothesis testing in the pre-defined order would have stopped once the first non-significant test result had been obtained. The first secondary efficacy variable in the hierarchic test procedure was the patient complete clearance per patient’s side, defined as the percentage of patients with all lesions cleared at the respective patient’s side. The full analysis set (FAS) consists of all patients randomized and treated at least with one assigned IMP (IMP application and illumination) after randomization. In accordance with the intent-to-treat (ITT) principle, the assignment of patients’ sides to the treatment groups was as randomized.
    End point type
    Secondary
    End point timeframe
    12 weeks after the last PDT
    End point values
    		 BF-200 ALA (Verum) Placebo
    Number of subjects analysed
    49
    49
    Units: patients
        number (not applicable)
    33
    6
    Statistical analysis title
    		 McNemar’s test (FAS)
    Statistical analysis description
    Due to the intra-individual design, the number of subjects reflects the number of subjects' sides.
    Comparison groups
    BF-200 ALA (Verum) v Placebo
    Number of subjects included in analysis
    98
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Mcnemar
    Confidence interval

    Secondary: Total lesion clearance rate of moderate (according to Olsen) lesions in percent per patient’s side 12 weeks after the last PDT (FAS)

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    End point title
    		 Total lesion clearance rate of moderate (according to Olsen) lesions in percent per patient’s side 12 weeks after the last PDT (FAS)
    End point description
    The second secondary efficacy variable in the hierarchic test procedure was the total lesion clearance rate of moderate lesions in percent per patient’s side, defined as the percentage of moderate lesions at baseline with complete remission on the respective side of the patient 12 weeks after the last PDT. The full analysis set (FAS) consists of all patients randomized and treated at least with one assigned IMP (IMP application and illumination) after randomization. In accordance with the intent-to-treat (ITT) principle, the assignment of patients’ sides to the treatment groups was as randomized.
    End point type
    Secondary
    End point timeframe
    12 weeks after the last PDT
    End point values
    		 BF-200 ALA (Verum) Placebo
    Number of subjects analysed
    44
    43
    Units: percent
        arithmetic mean (standard deviation)
    84.3 ± 28.6
    27.2 ± 36.5
    Statistical analysis title
    		 One-sided Wilcoxon signed rank test (FAS)
    Statistical analysis description
    Due to the intra-individual design, the number of subjects reflects the number of subjects' sides.
    Comparison groups
    BF-200 ALA (Verum) v Placebo
    Number of subjects included in analysis
    87
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 One-sided Wilcoxon signed rank test
    Confidence interval
    Statistical analysis title
    		 Non-parametric, one-sided 97.5% CI (FAS)
    Statistical analysis description
    The application of the non-parametric CI was subordinate. Due to the intra-individual design, the number of subjects reflects the number of subjects' sides.
    Comparison groups
    BF-200 ALA (Verum) v Placebo
    Number of subjects included in analysis
    87
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Median difference (final values)
    Point estimate
    75
    Confidence interval
         level
    		 97.5%
         sides
    1-sided
         lower limit
    		 33.3
         upper limit
    		 -

    Secondary: Total lesion clearance rate in percent per patient’s side in the treatment area extremities 12 weeks after the last PDT (FAS)

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    End point title
    		 Total lesion clearance rate in percent per patient’s side in the treatment area extremities 12 weeks after the last PDT (FAS)
    End point description
    The third secondary efficacy variable in the hierarchic test procedure was the total lesion clearance rate in percent per patient’s side in the treatment area extremities, defined as the percentage of individual lesions in the treatment area extremities with complete remission on the respective side of the patient. The full analysis set (FAS) consists of all patients randomized and treated at least with one assigned IMP (IMP application and illumination) after randomization. In accordance with the intent-to-treat (ITT) principle, the assignment of patients’ sides to the treatment groups was as randomized.
    End point type
    Secondary
    End point timeframe
    12 weeks after the last PDT
    End point values
    		 BF-200 ALA (Verum) Placebo
    Number of subjects analysed
    39
    39
    Units: percent
        arithmetic mean (standard deviation)
    83.5 ± 24.7
    27.1 ± 33.1
    Statistical analysis title
    		 One-sided Wilcoxon signed rank test (FAS)
    Statistical analysis description
    Due to the intra-individual design, the number of subjects reflects the number of subjects' sides.
    Comparison groups
    BF-200 ALA (Verum) v Placebo
    Number of subjects included in analysis
    78
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 One-sided Wilcoxon signed rank test
    Confidence interval
    Statistical analysis title
    		 Non-parametric, one-sided 97.5% CI (FAS)
    Statistical analysis description
    The application of the non-parametric CI was subordinate. Due to the intra-individual design, the number of subjects reflects the number of subjects' sides.
    Comparison groups
    Placebo v BF-200 ALA (Verum)
    Number of subjects included in analysis
    78
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Median difference (final values)
    Point estimate
    66.7
    Confidence interval
         level
    		 97.5%
         sides
    1-sided
         lower limit
    		 35
         upper limit
    		 -

    Secondary: Total lesion clearance rate in percent per patient’s side in the treatment area trunk/neck 12 weeks after the last PDT (FAS)

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    End point title
    		 Total lesion clearance rate in percent per patient’s side in the treatment area trunk/neck 12 weeks after the last PDT (FAS)
    End point description
    The fourth secondary efficacy variable in the hierarchic test procedure was the total lesion clearance rate in percent per patient’s side in the treatment area trunk/neck, defined as the percentage of individual lesions in the treatment area trunk/neck with complete remission on the respective side of the patient. The full analysis set (FAS) consists of all patients randomized and treated at least with one assigned IMP (IMP application and illumination) after randomization. In accordance with the intent-to-treat (ITT) principle, the assignment of patients’ sides to the treatment groups was as randomized.
    End point type
    Secondary
    End point timeframe
    12 weeks after the last PDT
    End point values
    		 BF-200 ALA (Verum) Placebo
    Number of subjects analysed
    10
    10
    Units: percent
        arithmetic mean (standard deviation)
    96.0 ± 12.6
    55.5 ± 44.8
    Statistical analysis title
    		 One-sided Wilcoxon signed rank test (FAS)
    Statistical analysis description
    Due to the intra-individual design, the number of subjects reflects the number of subjects' sides.
    Comparison groups
    Placebo v BF-200 ALA (Verum)
    Number of subjects included in analysis
    20
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0156
    Method
    		 One-sided Wilcoxon signed rank test
    Confidence interval
    Statistical analysis title
    		 Non-parametric, one-sided 97.5% CI (FAS)
    Statistical analysis description
    The application of the non-parametric CI was subordinate. Due to the intra-individual design, the number of subjects reflects the number of subjects' sides.
    Comparison groups
    BF-200 ALA (Verum) v Placebo
    Number of subjects included in analysis
    20
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Median difference (final values)
    Point estimate
    18.3
    Confidence interval
         level
    		 97.5%
         sides
    1-sided
         lower limit
    		 0
         upper limit
    		 -

    Secondary: Histopathologically confirmed lesion response (HCR) rate 12 weeks after the last PDT per patient’s side (FAS)

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    End point title
    		 Histopathologically confirmed lesion response (HCR) rate 12 weeks after the last PDT per patient’s side (FAS)
    End point description
    The fifth secondary efficacy variable in the hierarchic test procedure was the histopathologically confirmed lesion response (HCR) rate per patient’s side 12 weeks after the last PDT. The full analysis set (FAS) consists of all patients randomized and treated at least with one assigned IMP (IMP application and illumination) after randomization. In accordance with the intent-to-treat (ITT) principle, the assignment of patients’ sides to the treatment groups was as randomized.
    End point type
    Secondary
    End point timeframe
    12 weeks after the last PDT
    End point values
    		 BF-200 ALA (Verum) Placebo
    Number of subjects analysed
    47
    47
    Units: patients
        number (not applicable)
    40
    30
    Statistical analysis title
    		 McNemar’s test (FAS)
    Statistical analysis description
    Due to the intra-individual design, the number of subjects reflects the number of subjects' sides.
    Comparison groups
    BF-200 ALA (Verum) v Placebo
    Number of subjects included in analysis
    94
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0032
    Method
    		 Mcnemar
    Confidence interval

    Secondary: Total lesion clearance rate in percent per patient’s side 12 weeks after PDT-1 (FAS)

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    End point title
    		 Total lesion clearance rate in percent per patient’s side 12 weeks after PDT-1 (FAS)
    End point description
    The sixth secondary efficacy variable in the hierarchic test procedure was 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 at Visit 4 (12 weeks after PDT-1), irrespective if patient received re-treatment or not. The full analysis set (FAS) consists of all patients randomized and treated at least with one assigned IMP (IMP application and illumination) after randomization. In accordance with the intent-to-treat (ITT) principle, the assignment of patients’ sides to the treatment groups was as randomized.
    End point type
    Secondary
    End point timeframe
    12 weeks after PDT-1
    End point values
    		 BF-200 ALA (Verum) Placebo
    Number of subjects analysed
    49
    49
    Units: percent
        arithmetic mean (standard deviation)
    67.5 ± 31.2
    27.6 ± 33.4
    Statistical analysis title
    		 One-sided Wilcoxon signed rank test (FAS)
    Statistical analysis description
    Due to the intra-individual design, the number of subjects reflects the number of subjects' sides.
    Comparison groups
    Placebo v BF-200 ALA (Verum)
    Number of subjects included in analysis
    98
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 One-sided Wilcoxon signed rank test
    Confidence interval
    Statistical analysis title
    		 Non-parametric, one-sided 97.5% CI (FAS)
    Statistical analysis description
    The application of the non-parametric CI was subordinate. Due to the intra-individual design, the number of subjects reflects the number of subjects' sides.
    Comparison groups
    BF-200 ALA (Verum) v Placebo
    Number of subjects included in analysis
    98
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Median difference (final values)
    Point estimate
    50
    Confidence interval
         level
    		 97.5%
         sides
    1-sided
         lower limit
    		 25
         upper limit
    		 -

    Secondary: Patient complete clearance per patient’s side, 12 weeks after PDT-1 (FAS)

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    End point title
    		 Patient complete clearance per patient’s side, 12 weeks after PDT-1 (FAS)
    End point description
    The seventh secondary efficacy variable in the hierarchic test procedure was the patient complete clearance per patient’s side, defined as the percentage of patients with all lesions cleared at the respective patient’s side at Visit 4 (12 weeks after PDT-1), irrespective if patient received re-treatment or not. The full analysis set (FAS) consists of all patients randomized and treated at least with one assigned IMP (IMP application and illumination) after randomization. In accordance with the intent-to-treat (ITT) principle, the assignment of patients’ sides to the treatment groups was as randomized.
    End point type
    Secondary
    End point timeframe
    12 weeks after PDT-1
    End point values
    		 BF-200 ALA (Verum) Placebo
    Number of subjects analysed
    49
    49
    Units: patients
        number (not applicable)
    18
    4
    Statistical analysis title
    		 McNemar’s test (FAS)
    Statistical analysis description
    Due to the intra-individual design, the number of subjects reflects the number of subjects' sides.
    Comparison groups
    BF-200 ALA (Verum) v Placebo
    Number of subjects included in analysis
    98
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0003
    Method
    		 Mcnemar
    Confidence interval

    Secondary: The overall cosmetic outcome per patient’s side 12 weeks after the last PDT (FAS)

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    End point title
    		 The overall cosmetic outcome per patient’s side 12 weeks after the last PDT (FAS)
    End point description
    The eighth secondary efficacy variable in the hierarchic test procedure was the overall cosmetic outcome per patient's side 12 weeks after the last PDT as assessed by the investigator. The full analysis set (FAS) consists of all patients randomized and treated at least with one assigned IMP (IMP application and illumination) after randomization. In accordance with the intent-to-treat (ITT) principle, the assignment of patients’ sides to the treatment groups was as randomized.
    End point type
    Secondary
    End point timeframe
    12 weeks after the last PDT
    End point values
    		 BF-200 ALA (Verum) Placebo
    Number of subjects analysed
    49
    49
    Units: patients
    number (not applicable)
        Very good
    19
    7
        Good
    9
    3
        Satisfactory
    9
    20
        Unsatisfactory
    4
    9
        Impaired
    8
    10
    Statistical analysis title
    		 One-sided Wilcoxon signed rank test (FAS)
    Statistical analysis description
    A Wilcoxon signed rank test was applied to compare patient’s sides 12 weeks after the last PDT. Each 'very good' was counted as 0, each 'good' as 1, each 'satisfactory' as 2, each 'unsatisfactory' as 3, and each 'impaired' as 4. Due to the intra-individual design, the number of subjects reflects the number of subjects' sides.
    Comparison groups
    BF-200 ALA (Verum) v Placebo
    Number of subjects included in analysis
    98
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 One-sided Wilcoxon signed rank test
    Confidence interval
    Statistical analysis title
    		 Non-parametric, one-sided 97.5% CI (FAS)
    Statistical analysis description
    The application of the non-parametric CI was subordinate. Due to the intra-individual design, the number of subjects reflects the number of subjects' sides.
    Comparison groups
    BF-200 ALA (Verum) v Placebo
    Number of subjects included in analysis
    98
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Median difference (final values)
    Point estimate
    0
    Confidence interval
         level
    		 97.5%
         sides
    1-sided
         lower limit
    		 0
         upper limit
    		 -

    Other pre-specified: Lesion complete response per treatment arm (percentage of completely cleared individual lesions, in relation to number of lesions at baseline [Visit 2]) assessed 12 weeks after the last PDT (FAS)

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    End point title
    		 Lesion complete response per treatment arm (percentage of completely cleared individual lesions, in relation to number of lesions at baseline [Visit 2]) assessed 12 weeks after the last PDT (FAS)
    End point description
    A tertiary efficacy variable was the lesion complete response per treatment arm (percentage of completely cleared individual lesions, in relation to number of lesions at baseline [Visit 2]) assessed 12 weeks after the last PDT. The full analysis set (FAS) consists of all patients randomized and treated at least with one assigned IMP (IMP application and illumination) after randomization. In accordance with the intent-to-treat (ITT) principle, the assignment of patients’ sides to the treatment groups was as randomized. To realistically reflect the result, the number of subjects (shown below) was replaced by the number of lesions for this analysis.
    End point type
    Other pre-specified
    End point timeframe
    12 weeks after the last PDT
    End point values
    		 BF-200 ALA (Verum) Placebo
    Number of subjects analysed
    49 [1]
    49 [2]
    Units: lesions
        number (not applicable)
    219
    88
    Notes
    [1] - This is the number of patients that received BF-200 ALA. They had 258 lesions in total.
    [2] - This is the number of patients that received placebo. They had 268 lesions in total.
    No statistical analyses for this end point

    Other pre-specified: Patient’s satisfaction with treatment applied to his/her respective side (FAS)

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    End point title
    		 Patient’s satisfaction with treatment applied to his/her respective side (FAS)
    End point description
    A tertiary efficacy variable was the patient’s satisfaction with treatment applied to his/her respective side. The full analysis set (FAS) consists of all patients randomized and treated at least with one assigned IMP (IMP application and illumination) after randomization. In accordance with the intent-to-treat (ITT) principle, the assignment of patients’ sides to the treatment groups was as randomized.
    End point type
    Other pre-specified
    End point timeframe
    12 weeks after last PDT
    End point values
    		 BF-200 ALA (Verum) Placebo
    Number of subjects analysed
    46
    46
    Units: patients
    number (not applicable)
        Patient would choose treatment again
    38
    32
    No statistical analyses for this end point

    Other pre-specified: Application site pain during PDT-1 reported by the patients per patient’s side (SAF)

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    End point title
    		 Application site pain during PDT-1 reported by the patients per patient’s side (SAF)
    End point description
    Safety endpoint: Patient's pain intensity during PDT is assessed at the end of each illumination period using a numeric rating pain scale ranging from no pain at all (0) to worst possible pain (10). If the patient could not indicate the specific side of pain sensation, the worst pain experienced for patient’s both (left and right) side (and treatment areas) was documented equally. One patient was treated incorrectly at PDT-2, but with the correct treatment at PDT-1. Within the Safety Analysis Set (SAF), this patient is allocated to BF-200 ALA for both sides.
    End point type
    Other pre-specified
    End point timeframe
    During PDT-1
    End point values
    		 BF-200 ALA (Verum) Placebo
    Number of subjects analysed
    50 [3]
    49
    Units: points
        arithmetic mean (standard deviation)
    4.5 ± 3.2
    1.2 ± 2.5
    Notes
    [3] - Subj. analysed: 51 (in SAF 1 pat. was allocated to verum for both sides -> incorrect IMP administr.)
    No statistical analyses for this end point

    Other pre-specified: Application site pain during PDT-2 reported by the patients per patient’s side (SAF)

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    End point title
    		 Application site pain during PDT-2 reported by the patients per patient’s side (SAF)
    End point description
    Safety endpoint: Patient's pain intensity during PDT is assessed at the end of each illumination period using a numeric rating pain scale ranging from no pain at all (0) to worst possible pain (10). If the patient could not indicate the specific side of pain sensation, the worst pain experienced for patient’s both (left and right) side (and treatment areas) was documented equally. One patient was treated incorrectly at PDT-2, but with the correct treatment at PDT-1. Within the Safety Analysis Set (SAF), this patient is allocated to BF-200 ALA for both sides.
    End point type
    Other pre-specified
    End point timeframe
    During PDT-2
    End point values
    		 BF-200 ALA (Verum) Placebo
    Number of subjects analysed
    29
    27
    Units: points
        arithmetic mean (standard deviation)
    4.0 ± 3.4
    1.1 ± 2.2
    No statistical analyses for this end point

    Other pre-specified: Total lesion clearance rate in percent per patient’s side 12 weeks after last PDT (PPS)

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    End point title
    		 Total lesion clearance rate in percent per patient’s side 12 weeks after last PDT (PPS)
    End point description
    Sensitivity analysis of primary endpoint. 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. The per protocol set (PPS) consists of all patients of the FAS without any major protocol deviations. Patients will be included in the PPS if they fulfill all of the following criteria: • Treated with investigational products and PDT mode according to the randomization plan. • The 2 patient sides (R & L) are comparable and the number of AK lesions varies not more than 50%. • At least one AK lesion assessment after the first, and if retreated after the second PDT, is available. • No forbidden concomitant medications or therapies.
    End point type
    Other pre-specified
    End point timeframe
    12 weeks after last PDT
    End point values
    		 BF-200 ALA (Verum) Placebo
    Number of subjects analysed
    43
    43
    Units: percent
        arithmetic mean (standard deviation)
    90.0 ± 20.0
    28.5 ± 36.7
    Statistical analysis title
    		 One-sided Wilcoxon signed rank test (PPS)
    Statistical analysis description
    The Wilcoxon signed rank test (one-sided, alpha=0.025) was applied (using the location parameter mu0 of 0%). Due to the intra-individual design, the number of subjects reflects the number of subjects' sides.
    Comparison groups
    BF-200 ALA (Verum) v Placebo
    Number of subjects included in analysis
    86
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 One-sided Wilcoxon signed rank test
    Confidence interval
    Statistical analysis title
    		 Non-parametric, one-sided 97.5% CI (PPS)
    Statistical analysis description
    Additionally, a non-parametric, one-sided 97.5% confidence interval (CI) for the median difference in response rates rALA - rPla was calculated. If the lower bound of this CI is greater than 0, it indicates superiority of BF-200 ALA PDT to placebo PDT. The application of the non-parametric CI was subordinate. Due to the intra-individual design, the number of subjects reflects the number of subjects' sides.
    Comparison groups
    Placebo v BF-200 ALA (Verum)
    Number of subjects included in analysis
    86
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Median difference (final values)
    Point estimate
    66.7
    Confidence interval
         level
    		 97.5%
         sides
    1-sided
         lower limit
    		 50
         upper limit
    		 -

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    18 September 2017 (study initiation date/first patient signed informed consent) until 09 January 2019 (study completion date for observer blind part).
    Adverse event reporting additional description
    TEAEs (treatment emergent adverse events) are defined as all AEs or SAEs with time of onset or worsening on or after the time of first IMP application. All safety analyses are based on the safety analysis set, which consists of all subjects treated at least with one IMP application. The assignment of subjects' sides was as actually treated.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22.0
    Reporting groups
    Reporting group title
    TEAEs related to side treated with BF-200 ALA
    Reporting group description
    		 -

    Reporting group title
    TEAEs related to side treated with Placebo
    Reporting group description
    		 -

    Reporting group title
    TEAEs with relation to side not applicable
    Reporting group description
    		 -

    Reporting group title
    TEAEs with relation to side unknown
    Reporting group description
    		 -

    Serious adverse events
    		 TEAEs related to side treated with BF-200 ALA TEAEs related to side treated with Placebo TEAEs with relation to side not applicable TEAEs with relation to side unknown
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 50 (4.00%)
    0 / 50 (0.00%)
    2 / 50 (4.00%)
    0 / 50 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Injury, poisoning and procedural complications
    Humerus fracture
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    1 / 50 (2.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    1 / 50 (2.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Actinic keratosis
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Intervertebral disc protrusion
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    1 / 50 (2.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 4%
    Non-serious adverse events
    		 TEAEs related to side treated with BF-200 ALA TEAEs related to side treated with Placebo TEAEs with relation to side not applicable TEAEs with relation to side unknown
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    50 / 50 (100.00%)
    23 / 50 (46.00%)
    11 / 50 (22.00%)
    3 / 50 (6.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal cell carcinoma
         subjects affected / exposed
    1 / 50 (2.00%)
    1 / 50 (2.00%)
    0 / 50 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    1
    1
    0
    0
    General disorders and administration site conditions
    Application site erosion
         subjects affected / exposed
    2 / 50 (4.00%)
    2 / 50 (4.00%)
    0 / 50 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    2
    2
    0
    0
    Application site erythema
         subjects affected / exposed
    45 / 50 (90.00%)
    7 / 50 (14.00%)
    0 / 50 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    71
    9
    0
    0
    Application site exfoliation
         subjects affected / exposed
    12 / 50 (24.00%)
    2 / 50 (4.00%)
    0 / 50 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    14
    2
    0
    0
    Application site induration
         subjects affected / exposed
    3 / 50 (6.00%)
    2 / 50 (4.00%)
    0 / 50 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    3
    2
    0
    0
    Application site oedema
         subjects affected / exposed
    16 / 50 (32.00%)
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    21
    0
    0
    0
    Application site pain
         subjects affected / exposed
    50 / 50 (100.00%)
    20 / 50 (40.00%)
    0 / 50 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    148
    47
    0
    0
    Application site paraesthesia
         subjects affected / exposed
    1 / 50 (2.00%)
    2 / 50 (4.00%)
    0 / 50 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    1
    2
    0
    0
    Application site pruritus
         subjects affected / exposed
    24 / 50 (48.00%)
    9 / 50 (18.00%)
    0 / 50 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    37
    13
    0
    0
    Application site scab
         subjects affected / exposed
    15 / 50 (30.00%)
    2 / 50 (4.00%)
    0 / 50 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    21
    3
    0
    0
    Application site vesicles
         subjects affected / exposed
    9 / 50 (18.00%)
    3 / 50 (6.00%)
    0 / 50 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    15
    3
    0
    0
    Pain
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    2 / 50 (4.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Swelling
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    1
    0
    0
    1
    Eye disorders
    Eczema eyelids
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    2 / 50 (4.00%)
         occurrences all number
    0
    0
    0
    2
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    2 / 50 (4.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Skin and subcutaneous tissue disorders
    Actinic keratosis
         subjects affected / exposed
    1 / 50 (2.00%)
    1 / 50 (2.00%)
    0 / 50 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    7 / 50 (14.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    0
    7
    0
    Urinary tract infection
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    2 / 50 (4.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    0
    2
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    28 Jul 2017
    Substantial Protocol Amendment resulting in Clinical Study Protocol (CSP) 2.0 dated 20-Jul-2017 to further define the extent of adverse events that had to be documented during the follow-up period. Approved by German Competent Authority (CA) on 28-Jul-2017. Recruitment of patients started after the approval of CSP V2.0 by CA and Ethics Committee.
    06 Aug 2018
    Substantial Protocol Amendment resulting in CSP 3.0 dated 23-Jul-2018 to change the order of two secondary endpoints. Approved by German Competent Authority on 06-Aug-2018.

    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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