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    Clinical Trial Results:
    A randomized, observer-blind, intra-individual phase III study to evaluate the safety and efficacy of BF 200 ALA (Ameluz®) in combination with daylight-PDT (photodynamic therapy) in comparison with Metvix® for the treatment of mild to moderate actinic keratosis

    Summary
    EudraCT number
    		 2015-004382-83
    Trial protocol
    		 DE   ES  
    Global end of trial date
    07 Dec 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    11 Nov 2017
    First version publication date
    11 Nov 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    ALA-AK-CT009
    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
    07 Dec 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    07 Dec 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    07 Dec 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of the study was to compare the efficacy and safety of BF-200 ALA treatment of mild to moderate AK with Metvix® when using daylight PDT.
    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
    23 Jun 2016
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Efficacy, Safety
    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
    Spain: 6
    Country: Number of subjects enrolled
    Germany: 48
    Worldwide total number of subjects
    54
    EEA total number of subjects
    54
    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)
    6
    From 65 to 84 years
    47
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 Trial was conducted in Germany and Spain with total of 7 sites who recruited patients. Enrolment of patients started 23 June 2016.

    Pre-assignment
    Screening details
    		 Of the 54 patients enrolled in this study, 52 patients were randomized. 2 patients enrolled were excluded before randomization due to screening failure (1 patient) and sponsor decision (1 patient).

    Period 1
    Period 1 title
    clinical observation period (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Single blind
    Roles blinded
    		 Investigator [1]
    Blinding implementation details
    To guarantee the blind status the first investigator performed the initial diagnosis and all assessments on visits following PDT, a second investigator or delegated person performed the PDT, including the application of the IMP, and conducted all safety evaluations and questionnaires at the PDT day. Both investigators (or investigator and delegated person) were bound to not exchange information. The patients were strictly advised not to talk about the medication with the medical personnel.

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 BF-200 ALA
    Arm description
    		 BF-200 ALA containing 7.8% 5-aminolevulinic acid (5-ALA). As this is an intra-individual study design BF-200 ALA (verum) and Metvix® (comparator) were compared in parallel intraindividually (1:1 ratio).
    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
    This study was conducted using an intra-individual design, i.e. a split face design. BF-200 ALA gel was administered to the selected target lesions of the assigned side of the face and scalp according to the randomization schedule. BF-200 ALA was to be applied to the selected target lesions covering the AK lesions and the surrounding 0.5-1.0 cm of normal skin with a thin film using gloveprotected fingertips or a spatula. Application near the eyes, nostrils, mouth, ears or mucosa was to be avoided (keep a distance of 1 cm). No occlusive, light-tight dressing was applied as this is not necessary for daylight PDT. The gel should not be wiped off during the entire daylight PDT and remaining IMP was removed after completion of light exposure with a 0.9% saline solution. For light exposure patients should go outside within 30 minutes after application of the study medicine and stay for 2 continuous hours in full daylight.

    Arm title
    		 Metvix®
    Arm description
    		 Metvix® containing 16% methylaminolevulinate (MAL). As this is an intra-individual study design BF-200 ALA (verum) and Metvix® (comparator) were compared in parallel intraindividually (1:1 ratio).
    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
    This study was conducted using an intra-individual design, i.e. a split face design. Metvix® creme was administered to the selected target lesions of the assigned side of the face and scalp according to the randomization schedule. Metvix® creme was to be applied to the selected target lesions covering the AK lesions and the surrounding 0.5-1.0 cm of normal skin with a thin film using gloveprotected fingertips or a spatula. Application near the eyes, nostrils, mouth, ears or mucosa was to be avoided (keep a distance of 1 cm). No occlusive, light-tight dressing was applied as this is not necessary for daylight PDT. The creme should not be wiped off during the entire daylight PDT and remaining IMP was removed after completion of light exposure with a 0.9% saline solution. For light exposure patients should go outside within 30 minutes after application of the study medicine and stay for 2 continuous hours in full daylight.

    Notes
    [1] - The roles blinded appear inconsistent with a simple blinded trial.
    Justification: During this study, the investigator assessing efficacy after PDT was observer-blind. A second investigator or delegated person performed drug application and saftey evaluation. This was important since IMPs can be distinguished by their texture and consistency. IMPs have a comparable saftey profile.
    Number of subjects in period 1
    		BF-200 ALA Metvix®
    Started
    52
    52
    Completed
    52
    52

    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: 54 patients were enrolled but only 52 patients were randomized. Due to non-randomized subjects, the number of enrolled subjects is not equal to the number of subjects in the clinical phase (subjects reported in the baseline period).
    Reporting group values
    		 clinical observation period Total
    Number of subjects
    		 52 52
    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)
    		 6 6
        From 65-84 years
    		 45 45
        85 years and over
    		 1 1
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 72.2 ± 7.2 -
    Gender categorical
    Units: Subjects
        Female
    		 2 2
        Male
    		 50 50

    End points

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    End points reporting groups
    Reporting group title
    BF-200 ALA
    Reporting group description
    		 BF-200 ALA containing 7.8% 5-aminolevulinic acid (5-ALA). As this is an intra-individual study design BF-200 ALA (verum) and Metvix® (comparator) were compared in parallel intraindividually (1:1 ratio).

    Reporting group title
    Metvix®
    Reporting group description
    		 Metvix® containing 16% methylaminolevulinate (MAL). As this is an intra-individual study design BF-200 ALA (verum) and Metvix® (comparator) were compared in parallel intraindividually (1:1 ratio).

    Subject analysis set title
    FAS - BF-200 ALA
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    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.

    Subject analysis set title
    FAS - Metvix®
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    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.

    Subject analysis set title
    PPS - BF-200 ALA
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    All patients of the FAS without any major protocol deviations. Patients will be included in the PPS if they fulfil all of the following criteria: • Treated with investigational products and PDT mode according to the randomization plan. • All target lesions have grade 1 or 2 according to Olsen at baseline. • The 2 patient’s sides (R & L) are comparable and the number of AK lesions varies not more than 50%. • At least one assessment of a patient’s side after PDT is available. • No forbidden concomitant medications or therapies.

    Subject analysis set title
    PPS - Metvix®
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    All patients of the FAS without any major protocol deviations. Patients will be included in the PPS if they fulfil all of the following criteria: • Treated with investigational products and PDT mode according to the randomization plan. • All target lesions have grade 1 or 2 according to Olsen at baseline. • The 2 patient’s sides (R & L) are comparable and the number of AK lesions varies not more than 50%. • At least one assessment of a patient’s side after PDT is available. • No forbidden concomitant medications or therapies.

    Subject analysis set title
    BF-200 ALA - Treatment area Face
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Patients with lesions in the treatment area Face only.

    Subject analysis set title
    Metvix® - Treatment area Face
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Patients with lesions in the treatment area Face only.

    Subject analysis set title
    BF-200 ALA - Treatment area Scalp
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Patients with lesions in the treatment area Scalp only.

    Subject analysis set title
    Metvix® - Treatment area Scalp
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Patients with lesions in the treatment area Scalp only.

    Subject analysis set title
    BF-200 ALA - Mild AK lesion
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Patients with maximum severity grade "mild" of AK lesions at baseline.

    Subject analysis set title
    Metvix® - Mild AK lesion
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Patients with maximum severity grade "mild" of AK lesions at baseline.

    Subject analysis set title
    BF-200 ALA - Moderate AK lesion
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Patients with maximum severity grade "moderate" of AK lesions at baseline.

    Subject analysis set title
    Metvix® - Moderate AK lesion
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Patients with maximum severity grade "moderate" of AK lesions at baseline.

    Subject analysis set title
    BF-200 ALA - min temperature ≤20°C
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Patients with a minimum temperature during PDT ≤20°C.

    Subject analysis set title
    Metvix® - min temperature ≤20°C
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Patients with a minimum temperature during PDT ≤20°C.

    Subject analysis set title
    BF-200 ALA - min temperature >20°C
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Patients with a minimum temperature during PDT >20°C.

    Subject analysis set title
    Metvix® - min temperature >20°C
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Patients with a minimum temperature during PDT >20°C

    Subject analysis set title
    BF-200 ALA - Cloudy
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Patients with the worst weather condition „cloudy“ during PDT.

    Subject analysis set title
    Metvix® - Cloudy
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Patients with the worst weather condition „cloudy“ during PDT.

    Subject analysis set title
    BF-200 ALA - Sunny/cloudy mixed
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Patients with the worst weather condition „sunny/cloudy mixed“ during PDT.

    Subject analysis set title
    Metvix® - Sunny/cloudy mixed
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Patients with the worst weather condition „sunny/cloudy mixed“ during PDT.

    Subject analysis set title
    BF-200 ALA - Sunny
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Patients with the worst weather condition „sunny“ during PDT.

    Subject analysis set title
    Metvix® - Sunny
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Patients with the worst weather condition „sunny“ during PDT.

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

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    End point title
    		 Total lesion clearance rate in percent per patient’s side 12 weeks after PDT
    End point description
    Total lesion clearance rate in percent per patient’s side is defined as the percentage of completely cleared individual lesions with complete remission on the respective side of the patient assessed 12 weeks after PDT (LOCF (last observation carried forward) post-PDT).
    End point type
    Primary
    End point timeframe
    12 weeks after PDT
    End point values
    		 FAS - BF-200 ALA FAS - Metvix® PPS - BF-200 ALA PPS - Metvix® BF-200 ALA - Treatment area Face Metvix® - Treatment area Face BF-200 ALA - Treatment area Scalp Metvix® - Treatment area Scalp BF-200 ALA - Mild AK lesion Metvix® - Mild AK lesion BF-200 ALA - Moderate AK lesion Metvix® - Moderate AK lesion BF-200 ALA - min temperature ≤20°C Metvix® - min temperature ≤20°C BF-200 ALA - min temperature >20°C Metvix® - min temperature >20°C BF-200 ALA - Cloudy Metvix® - Cloudy BF-200 ALA - Sunny/cloudy mixed Metvix® - Sunny/cloudy mixed BF-200 ALA - Sunny Metvix® - Sunny
    Number of subjects analysed
    51
    51
    49
    49
    20
    20
    27
    27
    7
    7
    44
    44
    27
    27
    24
    24
    15
    15
    15
    15
    21
    21
    Units: percent
        arithmetic mean (standard deviation)
    78.7 ± 25.8
    75 ± 28.1
    79.8 ± 23.6
    76.5 ± 26.5
    85.2 ± 22.7
    84.2 ± 19.8
    72.4 ± 28.4
    65.4 ± 31.8
    93.7 ± 16.8
    91.2 ± 12.7
    76.3 ± 26.3
    72.5 ± 29.1
    77.9 ± 29.3
    75.4 ± 30.6
    79.5 ± 21.8
    74.6 ± 25.6
    74.8 ± 28.6
    65.7 ± 36.5
    74.4 ± 32.1
    73.7 ± 27.1
    84.5 ± 17.7
    82.6 ± 19.9
    Statistical analysis title
    		 One-sided non-parametric CI (PPS)
    Statistical analysis description
    The primary analysis on non-inferiority was performed on PPS. The analysis using FAS was used to test robustness of data. Evaluation of non-inferiority was primarily based on the non-parametric CIs; the one-sided Wilcoxon signed rank test is subordinate. This course of action was prespecified in case of non-normal distributed data.
    Comparison groups
    PPS - BF-200 ALA v PPS - Metvix®
    Number of subjects included in analysis
    98
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [1]
    Method
    Parameter type
    		 Median of differences
    Point estimate
    0
    Confidence interval
         level
    		 97.5%
         sides
    1-sided
         lower limit
    		 0
         upper limit
    		 -
    Notes
    [1] - Non-inferiority margin of Δ=-12.5% with a true inferiority of 0%
    Statistical analysis title
    		 One-sided non-parametric CI (FAS)
    Statistical analysis description
    The primary analysis on non-inferiority was performed on PPS. The analysis using FAS was used to test robustness of data. Evaluation of non-inferiority was primarily based on the non-parametric CIs; the one-sided Wilcoxon signed rank test is subordinate. This course of action was prespecified in case of non-normal distributed data.
    Comparison groups
    FAS - BF-200 ALA v FAS - Metvix®
    Number of subjects included in analysis
    102
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [2]
    Method
    Parameter type
    		 Median of differences
    Point estimate
    0
    Confidence interval
         level
    		 97.5%
         sides
    1-sided
         lower limit
    		 0
         upper limit
    		 -
    Notes
    [2] - Non-inferiority margin of Δ=-12.5% with a true inferiority of 0%
    Statistical analysis title
    		 One-sided Wilcoxon signed rank test (PPS)
    Statistical analysis description
    The primary analysis on non-inferiority was performed on PPS. The analysis using FAS was used to test robustness of data. Evaluation of non-inferiority was primarily based on the non-parametric CIs; the one-sided Wilcoxon signed rank test is subordinate. This course of action was prespecified in case of non-normal distributed data.
    Comparison groups
    PPS - BF-200 ALA v PPS - Metvix®
    Number of subjects included in analysis
    98
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [3]
    P-value
    		 < 0.0001
    Method
    		 Wilcoxon signed rank test
    Confidence interval
    Notes
    [3] - Non-inferiority margin of Δ=-12.5% with a true inferiority of 0%
    Statistical analysis title
    		 One-sided Wilcoxon signed rank test (FAS)
    Statistical analysis description
    The primary analysis on non-inferiority was performed on PPS. The analysis using FAS was used to test robustness of data. Evaluation of non-inferiority was primarily based on the non-parametric CIs; the one-sided Wilcoxon signed rank test is subordinate. This course of action was prespecified in case of non-normal distributed data.
    Comparison groups
    FAS - BF-200 ALA v FAS - Metvix®
    Number of subjects included in analysis
    102
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [4]
    P-value
    		 < 0.0001
    Method
    		 Wilcoxon signed rank test
    Confidence interval
    Notes
    [4] - Non-inferiority margin of Δ=-12.5% with a true inferiority of 0%

    Secondary: Patient complete clearance per patient's side

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    End point title
    		 Patient complete clearance per patient's side
    End point description
    Patient complete clearance per patient's side, i.e. all lesions cleared at the respective patient's side 12 weeks after PDT (LOCF (last observation carried forward) post PDT).
    End point type
    Secondary
    End point timeframe
    12 weeks after PDT
    End point values
    		 FAS - BF-200 ALA FAS - Metvix® BF-200 ALA - Treatment area Face Metvix® - Treatment area Face BF-200 ALA - Treatment area Scalp Metvix® - Treatment area Scalp BF-200 ALA - Mild AK lesion Metvix® - Mild AK lesion BF-200 ALA - Moderate AK lesion Metvix® - Moderate AK lesion
    Number of subjects analysed
    51
    51
    20
    20
    27
    27
    7
    7
    44
    44
    Units: patients
    22
    19
    12
    10
    9
    7
    6
    4
    16
    15
    No statistical analyses for this end point

    Secondary: Reduction of total lesion area from baseline 12 weeks after PDT

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    End point title
    		 Reduction of total lesion area from baseline 12 weeks after PDT
    End point description
    Reduction of total lesion area (the size of all treated lesions added up) from baseline per patient 12 weeks after PDT (LOCF (last observation carried forward) post PDT) per patient's side. Reduction of total lesion area is calculated as (post baseline lesion area - baseline lesion area) / baseline lesion area *100.
    End point type
    Secondary
    End point timeframe
    12 weeks after PDT
    End point values
    		 FAS - BF-200 ALA FAS - Metvix®
    Number of subjects analysed
    51
    51
    Units: percent
        arithmetic mean (standard deviation)
    -89.3 ± 15.4
    -88.3 ± 19.3
    No statistical analyses for this end point

    Secondary: Patient histologically confirmed response rate per patient's side 12 weeks after PDT according to Cockerell

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    End point title
    		 Patient histologically confirmed response rate per patient's side 12 weeks after PDT according to Cockerell
    End point description
    Patient histologically confirmed response rate per patient's side 12 weeks after PDT (LOCF (last observation carried forward) post PDT). A patients’ lesion was “not cleared”, if the histopathological evaluation of the biopsy after Cockerell (KIN I, II,III; Cockerell, C.J. (2000) J Am.Acad.Dermatol, 42, 11-17.) was positive, and “cleared”, if the biopsy was negative (“Histopathologically cleared”), irrespective of the investigator’s clinical assessment. “Other” outcomes were reviewed during a data review meeting and assigned to “cleared” or “not cleared” accordingly. A missing biopsy resulted in a missing HC response. Analysis according to Röwert-Huber (Rowert-Huber, J., Patel, M.J., Forschner, T., Ulrich, C., Eberle, J., Kerl, H., Sterry, W. & Stockfleth, E. (2007) Br J Dermatol, 156 Suppl 3, 8-12) showed identical results.
    End point type
    Secondary
    End point timeframe
    12 weeks after PDT
    End point values
    		 FAS - BF-200 ALA FAS - Metvix®
    Number of subjects analysed
    51
    51
    Units: Patients
    37
    34
    No statistical analyses for this end point

    Secondary: p53 expression per patient's side in one biopsiy taken 12 weeks after PDT

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    End point title
    		 p53 expression per patient's side in one biopsiy taken 12 weeks after PDT
    End point description
    p53 expression (% p53-positive cells) per patient's side in one biopsy on each side taken at the end-of-observerblind period. An immunostaining was performed in order to evaluate and quantify p53 expression in biopsies of preselected lesions. Biopsies were taken 12 weeks after PDT. A missing biopsy resulted in a missing p53 result. The p53 reactivity was quantified by counting the percentage of positive nuclei from the region of highest reactivity and expressed as the average of the counted areas (p53 positive cells /all counted nuclei). A p53 score <10% was considered ‘normal’ or a ‘complete response’.
    End point type
    Secondary
    End point timeframe
    12 weeks after PDT
    End point values
    		 FAS - BF-200 ALA FAS - Metvix®
    Number of subjects analysed
    50
    50
    Units: percent
        arithmetic mean (standard deviation)
    34.3 ± 32.4
    40.6 ± 31.3
    No statistical analyses for this end point

    Secondary: Overall cosmetic outcome 12 weeks after PDT per patient's side (with sum score >0 at baseline)

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    End point title
    		 Overall cosmetic outcome 12 weeks after PDT per patient's side (with sum score >0 at baseline)
    End point description
    Overall cosmetic outcome 12 weeks after PDT (LOCF (last observarion carried forward)) per patient's side (with sum score >0 at baseline). The cosmetic outcome is calculated for each patient's side on the basis of the skin quality assessment and is calculated as follows: Very good: The sum of all ratings for each skin quality sign has improved by at least 2 points as compared to baseline. If at least one sign has worsened by one point, the sum score must have improved by at least 3 points; Good: Sum score has improved by at least 1 point; Satisfactory: Sum score is identical to the one at baseline; Unsatisfactory: Sum score has worsened by 1 point; Impaired: Sum score has worsened by at least 2 points. LOCF is used to impute missing Week 12 data. If skin quality assessment is not assessed at Week 12 missing value will be imputed with the respective baseline value.
    End point type
    Secondary
    End point timeframe
    12 weeks after PDT
    End point values
    		 FAS - BF-200 ALA FAS - Metvix®
    Number of subjects analysed
    34 [5]
    34 [6]
    Units: percent
    arithmetic mean (confidence interval 95%)
        Very good
    23.5 (9.27 to 37.79)
    23.5 (9.27 to 37.79)
        Good
    17.6 (4.83 to 30.46)
    14.7 (2.8 to 26.61)
        Satisfactory
    44.1 (27.43 to 60.81)
    44.1 (27.43 to 60.81)
    Notes
    [5] - please note that categories unsatisfactory and impaired are not reported due to patient number <5
    [6] - please note that categories unsatisfactory and impaired are not reported due to patient number <5
    No statistical analyses for this end point

    Secondary: Patient's satisfaction on cosmetic outcome

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    End point title
    		 Patient's satisfaction on cosmetic outcome
    End point description
    Patient's satisfaction regarding overall cosmetic outcome 12 weeks after PDT.
    End point type
    Secondary
    End point timeframe
    12 weeks after PDT
    End point values
    		 FAS - BF-200 ALA FAS - Metvix®
    Number of subjects analysed
    51
    51
    Units: percent
    arithmetic mean (confidence interval 95%)
        Very good
    23.5 (11.89 to 35.17)
    21.6 (10.28 to 32.86)
        Good
    51 (37.26 to 64.7)
    45.1 (31.44 to 58.75)
        Satisfactory
    15.7 (5.71 to 25.67)
    23.5 (11.89 to 35.17)
        Unsatisfactory
    9.8 (1.64 to 17.97)
    9.8 (1.64 to 17.97)
    No statistical analyses for this end point

    Secondary: Patient satisfaction regarding PDT treatment 12 weeks after PDT

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    End point title
    		 Patient satisfaction regarding PDT treatment 12 weeks after PDT
    End point description
    Patient satisfaction regarding PDT treatment at Week 12 (LOCF (last obsercation carried forward) post PDT).
    End point type
    Secondary
    End point timeframe
    12 weeks after PDT
    End point values
    		 FAS - BF-200 ALA FAS - Metvix®
    Number of subjects analysed
    51
    51
    Units: percent
    arithmetic mean (confidence interval 95%)
        Patient would choose treatment again
    94.1 (87.66 to 100)
    96.1 (90.75 to 100)
    No statistical analyses for this end point

    Secondary: Total lesion clearance rate per IMP 12 weeks after PDT

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    End point title
    		 Total lesion clearance rate per IMP 12 weeks after PDT
    End point description
    Total lesion clearance rate per IMP 12 weeks after PDT (LOCF (last observation carried forward)), expressed as number of completely cleared individual lesions.
    End point type
    Secondary
    End point timeframe
    12 weeks after PDT
    End point values
    		 FAS - BF-200 ALA FAS - Metvix®
    Number of subjects analysed
    51 [7]
    51 [8]
    Units: lesions
    256
    246
    Notes
    [7] - 51 patients with 330 lesions included in the study
    [8] - 51 patients with 327 lesions included in the study
    No statistical analyses for this end point

    Secondary: Number of completely cleared individual lesions per patient's side 12 weeks after PDT

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    End point title
    		 Number of completely cleared individual lesions per patient's side 12 weeks after PDT
    End point description
    Number of completely cleared individual lesions per patient’s side 12 weeks after PDT (LOCF (last observation carried forward) post-PDT) compared to baseline.
    End point type
    Secondary
    End point timeframe
    12 weeks after PDT
    End point values
    		 FAS - BF-200 ALA FAS - Metvix® BF-200 ALA - Treatment area Face Metvix® - Treatment area Face BF-200 ALA - Treatment area Scalp Metvix® - Treatment area Scalp BF-200 ALA - Mild AK lesion Metvix® - Mild AK lesion BF-200 ALA - Moderate AK lesion Metvix® - Moderate AK lesion
    Number of subjects analysed
    51 [9]
    51 [10]
    20 [11]
    20 [12]
    27 [13]
    27 [14]
    38 [15]
    39 [16]
    43 [17]
    43 [18]
    Units: lesions
        arithmetic mean (standard deviation)
    5 ± 2.3
    4.8 ± 2.5
    5.4 ± 2.2
    5.2 ± 2
    4.4 ± 2.2
    4.1 ± 2.6
    3.7 ± 2
    3.5 ± 2.3
    2.7 ± 1.5
    2.5 ± 1.5
    Notes
    [9] - baseline values: 6.5 ± 2.2
    [10] - baseline values: 6.4 ± 2.2
    [11] - baseline values: 6.5 ± 2.3
    [12] - baseline values: 6.4 ± 2.2
    [13] - baseline values: 6.1 ± 2.2
    [14] - baseline values: 6.1 ± 2.2
    [15] - baseline values: 4.2 ± 2.1
    [16] - baseline values: 4.2 ± 2.2
    [17] - baseline values: 4.0 ± 2.1
    [18] - baseline values: 3.8 ± 2.1
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    23 June 2016 (study initiation date) until 07 December 2016 (study completion date for observer blind part)
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.0
    Reporting groups
    Reporting group title
    related to side treated with BF-200 ALA
    Reporting group description
    		 -

    Reporting group title
    related to side treated with Metvix ®
    Reporting group description
    		 -

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

    Serious adverse events
    		 related to side treated with BF-200 ALA related to side treated with Metvix ® relation to side not applicable
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 52 (0.00%)
    0 / 52 (0.00%)
    0 / 52 (0.00%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 related to side treated with BF-200 ALA related to side treated with Metvix ® relation to side not applicable
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    52 / 52 (100.00%)
    49 / 52 (94.23%)
    12 / 52 (23.08%)
    General disorders and administration site conditions
    Application site discharge
         subjects affected / exposed
    10 / 52 (19.23%)
    6 / 52 (11.54%)
    0 / 52 (0.00%)
         occurrences all number
    10
    6
    0
    Application site erosion
         subjects affected / exposed
    3 / 52 (5.77%)
    1 / 52 (1.92%)
    0 / 52 (0.00%)
         occurrences all number
    3
    1
    0
    Application site erythema
         subjects affected / exposed
    38 / 52 (73.08%)
    40 / 52 (76.92%)
    0 / 52 (0.00%)
         occurrences all number
    45
    46
    0
    Application site exfoliation
         subjects affected / exposed
    9 / 52 (17.31%)
    7 / 52 (13.46%)
    0 / 52 (0.00%)
         occurrences all number
    11
    8
    0
    Application site induration
         subjects affected / exposed
    8 / 52 (15.38%)
    6 / 52 (11.54%)
    0 / 52 (0.00%)
         occurrences all number
    8
    6
    0
    Application site oedema
         subjects affected / exposed
    7 / 52 (13.46%)
    6 / 52 (11.54%)
    0 / 52 (0.00%)
         occurrences all number
    7
    6
    0
    Application site pain
         subjects affected / exposed
    38 / 52 (73.08%)
    34 / 52 (65.38%)
    0 / 52 (0.00%)
         occurrences all number
    61
    54
    0
    Application site paraesthesia
         subjects affected / exposed
    6 / 52 (11.54%)
    4 / 52 (7.69%)
    0 / 52 (0.00%)
         occurrences all number
    6
    5
    0
    Application site pruritus
         subjects affected / exposed
    26 / 52 (50.00%)
    27 / 52 (51.92%)
    0 / 52 (0.00%)
         occurrences all number
    33
    32
    0
    Application site scab
         subjects affected / exposed
    19 / 52 (36.54%)
    17 / 52 (32.69%)
    0 / 52 (0.00%)
         occurrences all number
    22
    19
    0
    Skin and subcutaneous tissue disorders
    Actinic keratosis
         subjects affected / exposed
    4 / 52 (7.69%)
    3 / 52 (5.77%)
    1 / 52 (1.92%)
         occurrences all number
    5
    5
    1
    Musculoskeletal and connective tissue disorders
    Neck pain
         subjects affected / exposed
    0 / 52 (0.00%)
    0 / 52 (0.00%)
    3 / 52 (5.77%)
         occurrences all number
    0
    0
    3

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    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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