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    Clinical Trial Results:
    A randomized, double-blind, phase III multi-center study to evaluate the safety and efficacy of BF-200 ALA (Ameluz®) versus placebo in the field-directed treatment of mild to moderate actinic keratosis with photodynamic therapy (PDT) when using BF-RhodoLED®

    Due to the EudraCT – Results system being out of service between 31 July 2015 and 12 January 2016, these results have been published in compliance with revised timelines.
    Summary
    EudraCT number
    		 2013-002510-12
    Trial protocol
    		 DE  
    Global end of trial date
    15 Aug 2014

    Results information
    Results version number
    		 v1(current)
    This version publication date
    17 Jul 2016
    First version publication date
    17 Jul 2016
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    ALA-AK-CT007
    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 2148763226, ameluz@biofrontera.com
    Scientific contact
    Clinical Trial Department, Biofrontera Bioscience GmbH, +49 2148763226, 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
    03 Sep 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    15 Aug 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    15 Aug 2014
    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 of BF-200 ALA (Ameluz) with placebo, for the field-directed treatment of mild to moderate AK with PDT when using the BF RhodoLED® lamp.
    Protection of trial subjects
    - During PDT, i.e. during illumination the patient wore suitably protective goggles - Pain prevention (if the pain was regarded as unbearable by the patient): * Cooling with an air stream or with nebulized water * Short interruption of the illumination to inject a local fast-acting anesthetic such as xylocaine * After PDT the treated areas could be cooled with wet or refrigerated compresses * Analgesic treatment with paracetamol or metamizol - Non- or partial responders received treatment of new or recurrent lesions with conventional therapy at the discretion of the investigator after the end of the observer-blind part
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    04 Oct 2013
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Efficacy, Safety
    Long term follow-up duration
    		 12 Months
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Germany: 94
    Worldwide total number of subjects
    94
    EEA total number of subjects
    94
    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)
    15
    From 65 to 84 years
    79
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 Trial was conducted in Germany with 7 study sites (Bonn, Dresden, Munich, Wuppertal, Mönchengladbach, Cologne, and Recklinghausen) who recruited patients.

    Pre-assignment
    Screening details
    		 94 patients were screened, 87 patients were randomized (55 patients to BF-200 ALA and 32 patients to placebo) and treated. 7 patients were screening failures: 3 withdrew consent, 2 did not meet the in-/exclusion criteria, and 2 failed for other reasons (recruitment stop).

    Pre-assignment period milestones
    Number of subjects started
    		 94
    Number of subjects completed
    		 87

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 Consent withdrawn by subject: 3
    Reason: Number of subjects
    		 Recruitment stop: 2
    Reason: Number of subjects
    		 Did not meet in-/exclusion criteria: 2
    Period 1
    Period 1 title
    Observer blind part (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Data analyst
    Blinding implementation details
    - Verum and placebo are indistiguishable. - To guarantee the blind status of the investigator assessing efficacy after each PDT session, a second investigator or delegated person performes the PDT and conducts all safety evaluations during the PDT and the telephone call 1 week after PDT (observer-blind design). - The randomization schedule and the allocation to treatment groups will not be known to the investigator and the sponsor until completion of the study, except in case of an emergency.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Verum
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ameluz 78 mg/g gel
    Investigational medicinal product code
    BF-200 ALA
    Other name
    5-aminolevulinic acid nanoemulsion
    Pharmaceutical forms
    Gel
    Routes of administration
    Topical use
    Dosage and administration details
    After lesion preparation, the entire content of 1 tube of verum was applied to the treatment fields identified for this study at screening. The verum was applied to the entire field(s) covering a size of approx. 20 cm² with a film of about 1 mm thickness. Application near the eyes, nostrils, mouth, ears, or mucosa was to be avoided (by a distance of 1 cm). After application, the IMP was allowed to dry for approx. 10 minutes before an occlusive light-tight dressing was placed over the treatment site. Following incubation of 3 hours (+/- 10 minutes) the dressing was removed and the remnant gel wiped off with a 0.9% saline solution. Thereafter illumination was performed using BF-RhodoLED lamp (635 nm) applying a total light dose of 37 J/cm² (per treated field). During illumination, the lamp was fixed at a distance of 5 to 8 cm from the skin surface as indicated in the user manual. This treatment was performed once and repeated after 12 weeks if no complete response was observed.

    Arm title
    		 Placebo
    Arm description
    		 -
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Gel
    Routes of administration
    Topical use
    Dosage and administration details
    After lesion preparation, the entire content of 1 tube of placebo was applied to the treatment fields identified for this study at screening. The placebo was applied to the entire field(s) covering a size of approx. 20 cm² with a film of about 1 mm thickness. Application near the eyes, nostrils, mouth, ears, or mucosa was to be avoided (by a distance of 1 cm). After application, the IMP was allowed to dry for approx. 10 minutes before an occlusive light-tight dressing was placed over the treatment site. Following incubation of 3 hours (+/- 10 minutes) the dressing was removed and the remnant gel wiped off with a 0.9% saline solution. Thereafter illumination was performed using BF-RhodoLED lamp (635 nm) applying a total light dose of 37 J/cm² (per treated field). During illumination, the lamp was fixed at a distance of 5 to 8 cm from the skin surface as indicated in the user manual. This treatment was performed once and repeated after 12 weeks if no complete response was observed.

    Number of subjects in period 1 [1]
    		Verum Placebo
    Started
    55
    32
    Completed
    54
    26
    Not completed
    1
    6
         Consent withdrawn by subject
    -
    5
         Lost to follow-up
    1
    1
    Notes
    [1] - 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: 94 subjects were screened but only 87 subjects entered the baseline period. The other 7 subjects were screening failures. Thus the subject numbers of the baseline period and the worldwide number of subjects are not equal.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Observer blind part
    Reporting group description
    		 Full Analysis set

    Reporting group values
    		 Observer blind part Total
    Number of subjects
    		 87 87
    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)
    		 13 13
        From 65-84 years
    		 74 74
        85 years and over
    		 0 0
    Age continuous
    Units: years
        arithmetic mean (full range (min-max))
    		 71.6 (51 to 84) -
    Gender categorical
    Units: Subjects
        Female
    		 8 8
        Male
    		 79 79
    Race
    Units: Subjects
        White
    		 87 87
    Ethnicity
    Units: Subjects
        Not Hispanic or Latino
    		 87 87
    Fitzpatrick skin type
    Units: Subjects
        Type I
    		 1 1
        Type II
    		 40 40
        Type III
    		 38 38
        Type IV
    		 7 7
        Type V to VI
    		 1 1
    History of AK therapy
    Units: Subjects
        No previous therapy
    		 10 10
        Non-surgical therapy
    		 33 33
        Surgical therapy
    		 2 2
        Non-surgical and surgical therapy
    		 42 42
    Histological confirmation of AK diagnosis by KIN grade
    Units: Subjects
        KIN I
    		 16 16
        KIN II
    		 70 70
        KIN III
    		 1 1
    Location of AK lesions
    Treatment areas are defined as follows: - Treatment area A: face and forehead - Treatment area B: bals scalp
    Units: Subjects
        Treatment area A
    		 49 49
        Treatment area B
    		 36 36
        Treatment area A and B
    		 2 2
    Maximum Olsen severity grading
    Units: Subjects
        Mild
    		 17 17
        Moderate
    		 70 70
        Severe
    		 0 0
    Weight
    Units: kg
        arithmetic mean (standard deviation)
    		 82.7 ( 11.41 ) -
    Height
    Units: cm
        arithmetic mean (standard deviation)
    		 175.3 ( 7.94 ) -
    Body mass index
    Units: kg/m^2
        arithmetic mean (standard deviation)
    		 26.9 ( 3.07 ) -
    Years since first diagnosis of AK
    Units: years
        arithmetic mean (standard deviation)
    		 5.6 ( 3.95 ) -
    AK lesions at baseline per patient
    Units: number
        arithmetic mean (standard deviation)
    		 5.4 ( 1.05 ) -

    End points

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    End points reporting groups
    Reporting group title
    Verum
    Reporting group description
    		 -

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Subject analysis set title
    Verum Per Protocol Set
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    All patients of the FAS without any major protocol deviations. Patients were included in the PP population if they fulfilled all of the following criteria: - Treated with the study medication according to the randomization plan. - All target lesions were grade I or II according to Olsen criteria at baseline. - AK confirmed by biopsy of a representative lesion taken at screening. - At least one AK lesion assessment was available, i.e. after PDT-1 or if retreated, after PDT-2. - Evaluation of the second biopsy at the end-of-study visit that did not result in a diagnosis of BCC or SCC. - No concomitant medications or therapies that might have an impact on the efficacy or safety analyses. The terms were identified during the blind data review meeting before database closure. - Treatment with BF-RhodoLED lamp.

    Subject analysis set title
    Placebo Per Protocol Set
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    All patients of the FAS without any major protocol deviations. Patients were included in the PP population if they fulfilled all of the following criteria: - Treated with the study medication according to the randomization plan. - All target lesions were grade I or II according to Olsen criteria at baseline. - AK confirmed by biopsy of a representative lesion taken at screening. - At least one AK lesion assessment was available, i.e. after PDT-1 or if retreated, after PDT-2. - Evaluation of the second biopsy at the end-of-study visit that did not result in a diagnosis of BCC or SCC. - No concomitant medications or therapies that might have an impact on the efficacy or safety analyses. The terms were identified during the blind data review meeting before database closure. - Treatment with BF-RhodoLED lamp.

    Subject analysis set title
    Verum: Maximum AK severity at baseline: Grade I
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Patients with AK severity according to Olsen Grade I (mild) treated with verum

    Subject analysis set title
    Placebo: Maximum AK severity at baseline: Grade I
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Patients with AK severity according to Olsen Grade I (mild) treated with placebo

    Subject analysis set title
    Verum: Maximum AK severity at baseline: Grade II
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Patients with AK severity according to Olsen Grade II (moderate) treated with verum

    Subject analysis set title
    Placebo: Maximum AK severity at baseline: Grade II
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Patients with AK severity according to Olsen Grade II (moderate) treated with placebo

    Subject analysis set title
    Verum: Age >65 years
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Patients >65 years treated with verum

    Subject analysis set title
    Placebo: Age >65 years
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Patients > 65 years treated with placebo

    Subject analysis set title
    Verum: Age ≤65 years
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Patients ≤65 years treated with verum

    Subject analysis set title
    Placebo: Age ≤65 years
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Patients ≤65 years treated with placebo

    Subject analysis set title
    Verum: Sex: male
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Male patients treated with verum

    Subject analysis set title
    Placebo: Sex: male
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Male patients treated with placebo

    Subject analysis set title
    Verum: Sex: female
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Female patients treated with verum

    Subject analysis set title
    Placebo: Sex: female
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Female patients treated with placebo

    Subject analysis set title
    Verum: Skin type group: I to III
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Patients with Fitzpatrick Skin Type I to III treated with verum

    Subject analysis set title
    Placebo: Skin type group: I to III
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Patients with Fitzpatrick Skin Type I to III treated with placebo

    Subject analysis set title
    Verum: Skin type group: IV or more
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Patients with Fitzpatrick Skin Type IV or more treated with verum

    Subject analysis set title
    Placebo: Skin type group: IV or more
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Patients with Fitzpatrick Skin Type IV or more treated with placebo

    Subject analysis set title
    Verum: Skin type: Type I
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Patients with Fitzpatrick Skin Type I treated with verum

    Subject analysis set title
    Placebo: Skin type: Type I
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Patients with Fitzpatrick Skin Type I treated with placebo no patients had Fitzpatrick skin type I, however it is impossible to enter "number of subjects in subject analysis set" = 0, therefore 1 is entered but incorrect!

    Subject analysis set title
    Verum: Skin type: Type II
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Patients with Fitzpatrick Skin Type II treated with verum

    Subject analysis set title
    Placebo: Skin type: Type II
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Patients with Fitzpatrick Skin Type II treated with placebo

    Subject analysis set title
    Verum: Skin type: Type III
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Patients with Fitzpatrick Skin Type III treated with verum

    Subject analysis set title
    Placebo: Skin type: Type III
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Patients with Fitzpatrick Skin Type III treated with placebo

    Subject analysis set title
    Verum: Treatment area: A
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Patients with treatment area A (face and forehead) treated with verum

    Subject analysis set title
    Placebo: Treatment area: A
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Patients with treatment area A (face and forehead) treated with placebo

    Subject analysis set title
    Verum: Treatment area: B
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Patients with treatment area B (bald scalp) treated with verum

    Subject analysis set title
    Placebo: Treatment area: B
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Patients with treatment area B (bald scalp) treated with placebo

    Subject analysis set title
    Verum: Treatment area: A and B
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Patients with treatment area A and B (face and forehead plus bald scalp) treated with verum

    Subject analysis set title
    Placebo: Treatment area: A and B
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Patients with treatment area A and B (face and forehead plus bald scalp) treated with placebo

    Subject analysis set title
    Verum: Number of AK lesions at baseline: up to 5
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Patients with up to 5 AK lesions at baseline treated with verum

    Subject analysis set title
    Placebo: Number of AK lesions at baseline: up to 5
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Patients with up to 5 AK lesions at baseline treated with placebo

    Subject analysis set title
    Verum: Number of AK lesions at baseline: 6 or more
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Patients with 6 or more AK lesions at baseline treated with verum

    Subject analysis set title
    Placebo: Number of AK lesions at baseline: 6 or more
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Patients with 6 or more AK lesions at baseline treated with placebo

    Subject analysis set title
    Verum: AK lesion area: ≤400mm^2
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Patients with AK lesion area ≤400mm^2 treated with verum

    Subject analysis set title
    Placebo: AK lesion area: ≤400mm^2
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Patients with AK lesion area ≤400mm^2 treated with placebo

    Subject analysis set title
    Verum: AK lesion area: >400mm^2
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Patients with AK lesion area >400mm^2 treated with verum

    Subject analysis set title
    Placebo: AK lesion area: >400mm^2
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Patients with AK lesion area >400mm^2 treated with placebo

    Subject analysis set title
    Verum: AK history: Naive
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Patients without AK history treated with verum

    Subject analysis set title
    Placebo: AK history: Naive
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Patients without AK history treated with placebo

    Subject analysis set title
    Verum: AK history: Non-naive
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Patients with AK history treated with verum

    Subject analysis set title
    Placebo: AK history: Non-naive
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Patients with AK history treated with placebo

    Subject analysis set title
    Verum: patients with sum score at baseline of 0 to 3
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Verum: patients with sum score at baseline of 0 to 3

    Subject analysis set title
    Placebo: patients with sum score at baseline of 0 to 3
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Placebo: patients with sum score at baseline of 0 to 3

    Subject analysis set title
    Verum: patients with sum score at baseline of 1 to 3
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Verum: patients with sum score at baseline of 1 to 3 (0 excluded)

    Subject analysis set title
    Placebo: patients with sum score at baseline of 1 to 3
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Placebo: patients with sum score at baseline of 1 to 3 (0 excluded)

    Primary: Overall patient complete response 12 weeks after the last PDT

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    End point title
    		 Overall patient complete response 12 weeks after the last PDT
    End point description
    All efficacy variables were evaluated for the FAS. The primary efficacy variable was also analyzed for the PP population. All subgroup analyses were carried out for the FAS. Data for size and grade of AK lesions were analyzed using the last observation carried forward (LOCF) approach, affecting the response rates evaluation. Due to the small amount of missing data in the study, which did not have any relevant impact on primary results, sensitivity analyses for missing data were not performed. The primary efficacy variable was the overall patient complete response 12 weeks after the last PDT. An overall complete responder was defined as a patient in whom all treated AK lesions were cleared (Olsen score of 0) after the last PDT, i.e. after PDT 1 or after PDT 2 if re-treatment was performed.
    End point type
    Primary
    End point timeframe
    12 weeks after PDT 1 or 12 weeks after PDT 2 which might have been necessary because not all lesions were cleared after the first PDT
    End point values
    		 Verum Placebo Verum Per Protocol Set Placebo Per Protocol Set
    Number of subjects analysed
    55
    32
    50
    27
    Units: percent
        arithmetic mean (confidence interval 95%)
    90.9 (80 to 97)
    21.9 (9.3 to 40)
    90 (78.2 to 96.7)
    25.9 (11.1 to 46.3)
    Statistical analysis title
    		 Superiority of verum to placebo (FAS)
    Statistical analysis description
    Primary null hypothesis (H01, two-sided): overall CR-rate assessed 12 weeks after last PDT for patients treated with BF-200 ALA is equal to that of patients treated with placebo. Primary alternate hypothesis (H11, two-sided): overall CR-rate assessed 12 weeks after last PDT for patients treated with BF-200 ALA is not equal to the response rate for patients treated with placebo. CR: complete responder A missing 12-week assessment was imputed by the preceeding 4-week assessment (LOCF approach)
    Comparison groups
    Verum v Placebo
    Number of subjects included in analysis
    87
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Fisher exact
    Parameter type
    		 Mean difference (final values)
    Point estimate
    69
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 52.8
         upper limit
    		 85.2
    Statistical analysis title
    		 Superiority of verum to placebo (PP)
    Statistical analysis description
    Primary null hypothesis (H01, two-sided): overall CR-rate assessed 12 weeks after last PDT for patients treated with BF-200 ALA is equal to that of patients treated with placebo. Primary alternate hypothesis (H11, two-sided): overall CR-rate assessed 12 weeks after last PDT for patients treated with BF-200 ALA is not equal to the response rate for patients treated with placebo. CR: complete responder A missing 12-week assessment was imputed by the preceeding 4-week assessment (LOCF approach)
    Comparison groups
    Verum Per Protocol Set v Placebo Per Protocol Set
    Number of subjects included in analysis
    77
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Fisher exact
    Parameter type
    		 Mean difference (final values)
    Point estimate
    64.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 45.6
         upper limit
    		 82.6

    Primary: Overall patient complete response 12 weeks after the last PDT (by subgroups)

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    End point title
    		 Overall patient complete response 12 weeks after the last PDT (by subgroups)
    End point description
    All subgroup analyses were carried out for the FAS. Data for size and grade of AK lesions were analyzed using the last observation carried forward (LOCF) approach, affecting the response rates evaluation. Due to the small amount of missing data in the study, which did not have any relevant impact on primary results, sensitivity analyses for missing data were not performed. The primary efficacy variable was the overall patient complete response 12 weeks after the last PDT. An overall complete responder was defined as a patient in whom all treated AK lesions were cleared (Olsen score of 0) after the last PDT, i.e. after PDT 1 or after PDT 2 if re-treatment was performed.
    End point type
    Primary
    End point timeframe
    12 weeks after PDT 1 or 12 weeks after PDT 2 which might have been necessary because not all lesions were cleared after the first PDT
    End point values
    		 Verum: Maximum AK severity at baseline: Grade I Placebo: Maximum AK severity at baseline: Grade I Verum: Maximum AK severity at baseline: Grade II Placebo: Maximum AK severity at baseline: Grade II Verum: Age >65 years Placebo: Age >65 years Verum: Age ≤65 years Placebo: Age ≤65 years Verum: Sex: male Placebo: Sex: male Verum: Sex: female Placebo: Sex: female Verum: Skin type group: I to III Placebo: Skin type group: I to III Verum: Skin type group: IV or more Placebo: Skin type group: IV or more Verum: Skin type: Type I Placebo: Skin type: Type I Verum: Skin type: Type II Placebo: Skin type: Type II Verum: Skin type: Type III Placebo: Skin type: Type III Verum: Treatment area: A Placebo: Treatment area: A Verum: Treatment area: B Placebo: Treatment area: B Verum: Treatment area: A and B Placebo: Treatment area: A and B Verum: Number of AK lesions at baseline: up to 5 Placebo: Number of AK lesions at baseline: up to 5 Verum: Number of AK lesions at baseline: 6 or more Placebo: Number of AK lesions at baseline: 6 or more Verum: AK lesion area: ≤400mm^2 Placebo: AK lesion area: ≤400mm^2 Verum: AK lesion area: >400mm^2 Placebo: AK lesion area: >400mm^2 Verum: AK history: Naive Placebo: AK history: Naive Verum: AK history: Non-naive Placebo: AK history: Non-naive
    Number of subjects analysed
    10
    7
    45
    25
    46
    26
    9
    6
    50
    29
    5
    3
    48
    31
    7
    1
    1
    0 [1]
    28
    12
    19
    19
    32
    17
    22
    14
    1
    1
    32
    18
    23
    14
    44
    26
    11
    6
    8
    2
    47
    30
    Units: percent
        arithmetic mean (confidence interval 95%)
    100 (69.2 to 100)
    71.4 (29 to 96.3)
    88.9 (75.9 to 96.3)
    8 (1 to 26)
    91.3 (79.2 to 97.6)
    23.1 (9 to 43.6)
    88.9 (51.8 to 99.7)
    16.7 (0.4 to 64.1)
    90 (78.2 to 96.7)
    24.1 (10.3 to 43.5)
    100 (47.8 to 100)
    0 (0 to 70.8)
    93.8 (82.8 to 98.7)
    22.6 (9.6 to 41.1)
    71.4 (29 to 96.3)
    0 (0 to 97.5)
    100 (2.5 to 100)
    ( to )
    89.3 (71.8 to 97.7)
    50 (21.1 to 78.9)
    100 (82.4 to 100)
    5.3 (0.1 to 26)
    96.9 (83.8 to 99.9)
    35.3 (14.2 to 61.7)
    81.8 (59.7 to 94.8)
    7.1 (0.2 to 33.9)
    100 (2.5 to 100)
    0 (0 to 97.5)
    90.6 (75 to 98)
    27.8 (9.7 to 53.5)
    91.3 (72 to 98.9)
    14.3 (1.8 to 42.8)
    88.6 (75.4 to 96.2)
    23.1 (9 to 43.6)
    100 (71.5 to 100)
    16.7 (0.4 to 64.1)
    100 (63.1 to 100)
    0 (0 to 84.2)
    89.4 (76.9 to 96.5)
    23.3 (9.9 to 42.3)
    Notes
    [1] - no patient with skin type I was treated with placebo
    Statistical analysis title
    		 Superiority of verum to placebo (FAS)
    Comparison groups
    Verum: Maximum AK severity at baseline: Grade I v Placebo: Maximum AK severity at baseline: Grade I
    Number of subjects included in analysis
    17
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1544
    Method
    		 Fisher exact
    Parameter type
    		 Mean difference (final values)
    Point estimate
    28.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.9
         upper limit
    		 62
    Statistical analysis title
    		 Superiority of verum to placebo (FAS)
    Comparison groups
    Verum: Maximum AK severity at baseline: Grade II v Placebo: Maximum AK severity at baseline: Grade II
    Number of subjects included in analysis
    70
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Fisher exact
    Parameter type
    		 Mean difference (final values)
    Point estimate
    80.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 66.8
         upper limit
    		 94.9
    Statistical analysis title
    		 Superiority of verum to placebo (FAS)
    Comparison groups
    Verum: Age >65 years v Placebo: Age >65 years
    Number of subjects included in analysis
    72
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Fisher exact
    Parameter type
    		 Mean difference (final values)
    Point estimate
    68.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 50.1
         upper limit
    		 86.4
    Statistical analysis title
    		 Superiority of verum to placebo (FAS)
    Comparison groups
    Verum: Age ≤65 years v Placebo: Age ≤65 years
    Number of subjects included in analysis
    15
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.011
    Method
    		 Fisher exact
    Parameter type
    		 Mean difference (final values)
    Point estimate
    72.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 36
         upper limit
    		 100
    Statistical analysis title
    		 Superiority of verum to placebo (FAS)
    Comparison groups
    Verum: Sex: male v Placebo: Sex: male
    Number of subjects included in analysis
    79
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Fisher exact
    Parameter type
    		 Mean difference (final values)
    Point estimate
    65.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 48.2
         upper limit
    		 83.5
    Statistical analysis title
    		 Superiority of verum to placebo (FAS)
    Comparison groups
    Verum: Sex: female v Placebo: Sex: female
    Number of subjects included in analysis
    8
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0179
    Method
    		 Fisher exact
    Parameter type
    		 Mean difference (final values)
    Point estimate
    100
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 100
         upper limit
    		 100
    Statistical analysis title
    		 Superiority of verum to placebo (FAS)
    Comparison groups
    Verum: Skin type group: I to III v Placebo: Skin type group: I to III
    Number of subjects included in analysis
    79
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Fisher exact
    Parameter type
    		 Mean difference (final values)
    Point estimate
    71.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 54.9
         upper limit
    		 87.4
    Statistical analysis title
    		 Superiority of verum to placebo (FAS)
    Comparison groups
    Verum: Skin type group: IV or more v Placebo: Skin type group: IV or more
    Number of subjects included in analysis
    8
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.375
    Method
    		 Fisher exact
    Parameter type
    		 Mean difference (final values)
    Point estimate
    71.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 38
         upper limit
    		 100
    Statistical analysis title
    		 Superiority of verum to placebo (FAS)
    Comparison groups
    Verum: Skin type: Type II v Placebo: Skin type: Type II
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0122
    Method
    		 Fisher exact
    Parameter type
    		 Mean difference (final values)
    Point estimate
    39.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 8.8
         upper limit
    		 69.8
    Statistical analysis title
    		 Superiority of verum to placebo (FAS)
    Comparison groups
    Verum: Skin type: Type III v Placebo: Skin type: Type III
    Number of subjects included in analysis
    38
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Fisher exact
    Parameter type
    		 Mean difference (final values)
    Point estimate
    94.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 84.7
         upper limit
    		 100
    Statistical analysis title
    		 Superiority of verum to placebo (FAS)
    Comparison groups
    Verum: Treatment area: A v Placebo: Treatment area: A
    Number of subjects included in analysis
    49
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Fisher exact
    Parameter type
    		 Mean difference (final values)
    Point estimate
    61.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 38.1
         upper limit
    		 85.1
    Statistical analysis title
    		 Superiority of verum to placebo (FAS)
    Comparison groups
    Verum: Treatment area: B v Placebo: Treatment area: B
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Fisher exact
    Parameter type
    		 Mean difference (final values)
    Point estimate
    74.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 53.7
         upper limit
    		 95.7
    Statistical analysis title
    		 Superiority of verum to placebo (FAS)
    Comparison groups
    Verum: Treatment area: A and B v Placebo: Treatment area: A and B
    Number of subjects included in analysis
    2
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 1
    Method
    		 Fisher exact
    Parameter type
    		 Mean difference (final values)
    Point estimate
    100
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 100
         upper limit
    		 100
    Statistical analysis title
    		 Superiority of verum to placebo (FAS)
    Comparison groups
    Verum: Number of AK lesions at baseline: up to 5 v Placebo: Number of AK lesions at baseline: up to 5
    Number of subjects included in analysis
    50
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Fisher exact
    Parameter type
    		 Mean difference (final values)
    Point estimate
    62.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 39.8
         upper limit
    		 85.9
    Statistical analysis title
    		 Superiority of verum to placebo (FAS)
    Comparison groups
    Verum: Number of AK lesions at baseline: 6 or more v Placebo: Number of AK lesions at baseline: 6 or more
    Number of subjects included in analysis
    37
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Fisher exact
    Parameter type
    		 Mean difference (final values)
    Point estimate
    77
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 55.4
         upper limit
    		 98.7
    Statistical analysis title
    		 Superiority of verum to placebo (FAS)
    Comparison groups
    Verum: AK lesion area: ≤400mm^2 v Placebo: AK lesion area: ≤400mm^2
    Number of subjects included in analysis
    70
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Fisher exact
    Parameter type
    		 Mean difference (final values)
    Point estimate
    65.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 46.8
         upper limit
    		 84.3
    Statistical analysis title
    		 Superiority of verum to placebo (FAS)
    Comparison groups
    Verum: AK lesion area: >400mm^2 v Placebo: AK lesion area: >400mm^2
    Number of subjects included in analysis
    17
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.001
    Method
    		 Fisher exact
    Parameter type
    		 Mean difference (final values)
    Point estimate
    83.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 53.8
         upper limit
    		 100
    Statistical analysis title
    		 Superiority of verum to placebo (FAS)
    Comparison groups
    Verum: AK history: Naive v Placebo: AK history: Naive
    Number of subjects included in analysis
    10
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0222
    Method
    		 Fisher exact
    Parameter type
    		 Mean difference (final values)
    Point estimate
    100
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 100
         upper limit
    		 100
    Statistical analysis title
    		 Superiority of verum to placebo (FAS)
    Comparison groups
    Verum: AK history: Non-naive v Placebo: AK history: Non-naive
    Number of subjects included in analysis
    77
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Fisher exact
    Parameter type
    		 Mean difference (final values)
    Point estimate
    66
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 48.5
         upper limit
    		 83.5

    Secondary: Patient histopathological confirmed response rate

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    End point title
    		 Patient histopathological confirmed response rate
    End point description
    For the secondary confirmatory analysis, several superiority hypotheses were tested within a pre-defined hierarchic multiple testing procedure as described in the SAP. The key secondary efficacy variables were tested strictly in a pre-defined order to ensure the FWER and the testing procedure had to be stopped once the first non-significant test was obtained. The results of the confirmatory analysis are presented in the order pre-defined by the confirmatory testing procedure. Assessments of HCR rates were based on the results from the biopsy taken 12 weeks after the last PDT from a representative AK lesion selected at screening. If the biopsy result for a patient revealed a residual AK, the patient was considered “not cleared” for the analysis irrespectively of the investigator’s clinical assessment.
    End point type
    Secondary
    End point timeframe
    12 weeks after PDT 1 or 12 weeks after PDT 2 which might have been necessary because not all lesions were cleared after the first PDT
    End point values
    		 Verum Placebo
    Number of subjects analysed
    54
    27
    Units: percent
        arithmetic mean (confidence interval 95%)
    77.8 (64.4 to 88)
    22.2 (8.6 to 42.3)
    Statistical analysis title
    		 Patient histopathological confirmed response rate
    Comparison groups
    Verum v Placebo
    Number of subjects included in analysis
    81
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Fisher exact
    Parameter type
    		 Mean difference (final values)
    Point estimate
    55.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 36.3
         upper limit
    		 74.8

    Secondary: Patient complete response 12 weeks after PDT 1

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    End point title
    		 Patient complete response 12 weeks after PDT 1
    End point description
    The second key secondary efficacy variable in the hierarchic test procedure was the patient complete response (complete clearance of all treated AK lesions) assessed at 12 weeks after PDT 1.
    End point type
    Secondary
    End point timeframe
    12 weeks after PDT 1
    End point values
    		 Verum Placebo
    Number of subjects analysed
    55
    32
    Units: percent
        arithmetic mean (confidence interval 95%)
    61.8 (47.7 to 74.6)
    9.4 (2 to 25)
    Statistical analysis title
    		 Patient complete response 12 weeks after PDT 1
    Comparison groups
    Verum v Placebo
    Number of subjects included in analysis
    87
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Fisher exact
    Parameter type
    		 Mean difference (final values)
    Point estimate
    52.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 36.1
         upper limit
    		 68.8

    Secondary: Lesion complete response 12 weeks after last PDT

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    End point title
    		 Lesion complete response 12 weeks after last PDT
    End point description
    The third key secondary efficacy variable in the hierarchic test procedure was the lesion complete response (completely cleared individual AK lesions) assessed at 12 weeks after last PDT. Please take into consideration: VERUM: number of subjects: 55 and number of lesions: 298 PLACEBO: number of subjects: 32 and number of lesions 173 To realistically reflect the result, the number of subjects (shown below) should be the number of lesions for this analysis, however, this is not possible to enter into the system.
    End point type
    Secondary
    End point timeframe
    12 weeks after PDT 1 or 12 weeks after PDT 2 which might have been necessary because not all lesions were cleared after the first PDT
    End point values
    		 Verum Placebo
    Number of subjects analysed
    55 [2]
    32 [3]
    Units: percent
        arithmetic mean (confidence interval 95%)
    94.3 (91 to 96.6)
    32.9 (26 to 40.5)
    Notes
    [2] - Not subjects but number of lesions were analyzed (no. of lesions = 298)
    [3] - Not subjects but number of lesions were analyzed (no. of lesions = 173)
    Statistical analysis title
    		 Lesion complete response 12 weeks after last PDT
    Comparison groups
    Verum v Placebo
    Number of subjects included in analysis
    87
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Fisher exact
    Parameter type
    		 Mean difference (final values)
    Point estimate
    61.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 53.9
         upper limit
    		 68.8

    Secondary: Patient partial response 12 weeks after last PDT

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    End point title
    		 Patient partial response 12 weeks after last PDT
    End point description
    The fourth key secondary efficacy variable in the hierarchic test procedure was the patient partial response (defined as complete clearance of at least 75% of treated AK lesions) assessed at 12 weeks after last PDT.
    End point type
    Secondary
    End point timeframe
    12 weeks after PDT 1 or 12 weeks after PDT 2 which might have been necessary because not all lesions were cleared after the first PDT
    End point values
    		 Verum Placebo
    Number of subjects analysed
    55
    32
    Units: percent
        arithmetic mean (confidence interval 95%)
    94.5 (84.9 to 98.9)
    25 (11.5 to 43.4)
    Statistical analysis title
    		 Patient partial response 12 weeks after last PDT
    Comparison groups
    Verum v Placebo
    Number of subjects included in analysis
    87
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Fisher exact
    Parameter type
    		 Mean difference (final values)
    Point estimate
    69.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 53.4
         upper limit
    		 85.7

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

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    End point title
    		 Reduction of total lesion area 12 weeks after last PDT
    End point description
    The fifth key secondary efficacy variable in the hierarchic test procedure was the reduction from baseline in the total lesion area per patient assessed at 12 weeks after last PDT.
    End point type
    Secondary
    End point timeframe
    12 weeks after PDT 1 or 12 weeks after PDT 2 which might have been necessary because not all lesions were cleared after the first PDT
    End point values
    		 Verum Placebo
    Number of subjects analysed
    55
    32
    Units: percent
        arithmetic mean (standard deviation)
    -98.2 ( 9.65 )
    -45.5 ( 42.96 )
    Statistical analysis title
    		 Reduct. total lesion area 12 weeks after last PDT
    Comparison groups
    Verum v Placebo
    Number of subjects included in analysis
    87
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 ANCOVA
    Confidence interval

    Secondary: Overall cosmetic outcome 12 weeks after last PDT

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    End point title
    		 Overall cosmetic outcome 12 weeks after last PDT
    End point description
    The sixth key secondary efficacy variable in the hierarchic test procedure was the overall cosmetic outcome 12 weeks after last PDT.
    End point type
    Secondary
    End point timeframe
    12 weeks after PDT 1 or 12 weeks after PDT 2 which might have been necessary because not all lesions were cleared after the first PDT
    End point values
    		 Verum: patients with sum score at baseline of 0 to 3 Placebo: patients with sum score at baseline of 0 to 3 Verum: patients with sum score at baseline of 1 to 3 Placebo: patients with sum score at baseline of 1 to 3
    Number of subjects analysed
    54
    29
    48
    26
    Units: percent
    arithmetic mean (confidence interval 95%)
        Very good
    35.2 (22.7 to 49.4)
    17.2 (5.8 to 35.8)
    39.6 (25.8 to 54.7)
    19.2 (6.6 to 39.4)
        Good
    24.1 (13.5 to 37.6)
    13.8 (3.9 to 31.7)
    27.1 (15.3 to 41.8)
    15.4 (4.4 to 34.9)
        Satisfactory
    24.1 (13.5 to 37.6)
    20.7 (8 to 39.7)
    22.9 (12 to 37.3)
    23.1 (9 to 43.6)
        Unsatisfactory
    11.1 (4.2 to 22.6)
    27.6 (12.7 to 47.2)
    6.3 (1.3 to 17.2)
    26.9 (11.6 to 47.8)
        Impaired
    5.6 (1.2 to 15.4)
    20.7 (8 to 39.7)
    4.2 (0.5 to 14.3)
    15.4 (4.4 to 34.9)
    Statistical analysis title
    		 Overall cosmetic outcome 12 weeks after last PDT
    Statistical analysis description
    Overall cosmetic outcome 12 weeks after last PDT for patients with sum score at baseline of 0 to 3
    Comparison groups
    Placebo: patients with sum score at baseline of 0 to 3 v Verum: patients with sum score at baseline of 0 to 3
    Number of subjects included in analysis
    83
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0033
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Probabilistic index
    Point estimate
    0.689
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.558
         upper limit
    		 0.82
    Statistical analysis title
    		 Overall cosmetic outcome 12 weeks after last PDT
    Statistical analysis description
    Overall cosmetic outcome 12 weeks after last PDT for patients with sum score at baseline of 1 to 3 (0 excluded)
    Comparison groups
    Verum: patients with sum score at baseline of 1 to 3 v Placebo: patients with sum score at baseline of 1 to 3
    Number of subjects included in analysis
    74
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0032
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Probabilistic index
    Point estimate
    0.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.562
         upper limit
    		 0.839

    Other pre-specified: Patient complete response 3-4 weeks after PDT 1

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    End point title
    		 Patient complete response 3-4 weeks after PDT 1
    End point description
    A tertiary efficacy variable was the patient complete response (complete clearance of all treated AK lesions) assessed 3-4 weeks after PDT-1
    End point type
    Other pre-specified
    End point timeframe
    3-4 weeks after PDT
    End point values
    		 Verum Placebo
    Number of subjects analysed
    55
    32
    Units: percent
        arithmetic mean (confidence interval 95%)
    52.7 (38.3 to 66.3)
    6.3 (0.8 to 20.8)
    No statistical analyses for this end point

    Other pre-specified: Patient complete response 3-4 weeks after PDT 2

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    End point title
    		 Patient complete response 3-4 weeks after PDT 2
    End point description
    A tertiary efficacy variable was the patient complete response (complete clearance of all treated AK lesions) assessed 3-4 weeks after PDT-2.
    End point type
    Other pre-specified
    End point timeframe
    3-4 weeks after PDT 2
    End point values
    		 Verum Placebo
    Number of subjects analysed
    21
    29
    Units: percent
        arithmetic mean (confidence interval 95%)
    76.2 (52.8 to 91.8)
    6.9 (0.8 to 22.8)
    No statistical analyses for this end point

    Other pre-specified: 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
    A tertiary efficacy variable was the patient complete response (complete clearance of all treated AK lesions) assessed and 12 weeks after PDT-2.
    End point type
    Other pre-specified
    End point timeframe
    12 weeks after PDT 2
    End point values
    		 Verum Placebo
    Number of subjects analysed
    21
    29
    Units: percent
        arithmetic mean (confidence interval 95%)
    76.2 (52.8 to 91.8)
    13.8 (3.9 to 31.7)
    No statistical analyses for this end point

    Other pre-specified: Patient complete response 3-4 weeks after last PDT

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    End point title
    		 Patient complete response 3-4 weeks after last PDT
    End point description
    A tertiary efficacy variable was the patient complete response (complete clearance of all treated AK lesions) assessed 3-4 weeks after last PDT.
    End point type
    Other pre-specified
    End point timeframe
    3-4 weeks after PDT 1 or 3-4 weeks after PDT 2 which might have been necessary because not all lesions were cleared after the first PDT
    End point values
    		 Verum Placebo
    Number of subjects analysed
    55
    32
    Units: percent
        arithmetic mean (confidence interval 95%)
    74.5 (61 to 85.3)
    9.4 (2 to 25)
    No statistical analyses for this end point

    Other pre-specified: Patient partial response 3-4 weeks after PDT 1

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    End point title
    		 Patient partial response 3-4 weeks after PDT 1
    End point description
    A tertiary efficacy variable was the patient partial response (defined as complete clearance of at least 75% of treated AK lesions) assessed 3-4 weeks after PDT-1.
    End point type
    Other pre-specified
    End point timeframe
    3-4 weeks after PDT 1
    End point values
    		 Verum Placebo
    Number of subjects analysed
    55
    32
    Units: percent
        arithmetic mean (confidence interval 95%)
    63.6 (49.6 to 76.2)
    9.4 (2 to 25)
    No statistical analyses for this end point

    Other pre-specified: Patient partial response 12 weeks after PDT 1

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    End point title
    		 Patient partial response 12 weeks after PDT 1
    End point description
    A tertiary efficacy variable was the patient partial response (defined as complete clearance of at least 75% of treated AK lesions) assessed 12 weeks after PDT-1.
    End point type
    Other pre-specified
    End point timeframe
    12 weeks after PDT 1
    End point values
    		 Verum Placebo
    Number of subjects analysed
    55
    32
    Units: percent
        arithmetic mean (confidence interval 95%)
    76.4 (63 to 86.8)
    12.5 (3.5 to 29)
    No statistical analyses for this end point

    Other pre-specified: Patient partial response 3-4 weeks after PDT 2

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    End point title
    		 Patient partial response 3-4 weeks after PDT 2
    End point description
    A tertiary efficacy variable was the patient partial response (defined as complete clearance of at least 75% of treated AK lesions) assessed 3-4 weeks after PDT-2.
    End point type
    Other pre-specified
    End point timeframe
    3-4 weeks after PDT 2
    End point values
    		 Verum Placebo
    Number of subjects analysed
    21
    29
    Units: percent
        arithmetic mean (confidence interval 95%)
    90.5 (69.6 to 98.8)
    13.8 (3.9 to 31.7)
    No statistical analyses for this end point

    Other pre-specified: Patient partial response 12 weeks after PDT 2

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    End point title
    		 Patient partial response 12 weeks after PDT 2
    End point description
    A tertiary efficacy variable was the patient partial response (defined as complete clearance of at least 75% of treated AK lesions) assessed 12 weeks after PDT-2.
    End point type
    Other pre-specified
    End point timeframe
    12 weeks after PDT 2
    End point values
    		 Verum Placebo
    Number of subjects analysed
    21
    29
    Units: percent
        arithmetic mean (confidence interval 95%)
    85.7 (63.7 to 97)
    17.2 (5.8 to 35.8)
    No statistical analyses for this end point

    Other pre-specified: Patient partial response 3-4 weeks after last PDT

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    End point title
    		 Patient partial response 3-4 weeks after last PDT
    End point description
    A tertiary efficacy variable was the patient partial response (defined as complete clearance of at least 75% of treated AK lesions) assessed 3-4 weeks after last PDT.
    End point type
    Other pre-specified
    End point timeframe
    3-4 weeks after PDT 1 or or 3-4 weeks after PDT 2 which might have been necessary because not all lesions were cleared after the first PDT
    End point values
    		 Verum Placebo
    Number of subjects analysed
    55
    32
    Units: percent
        arithmetic mean (confidence interval 95%)
    81.8 (69.1 to 90.9)
    18.8 (7.2 to 36.4)
    No statistical analyses for this end point

    Other pre-specified: Lesion complete response 3-4 weeks after PDT 1

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    End point title
    		 Lesion complete response 3-4 weeks after PDT 1
    End point description
    A tertiary efficacy variable was the lesion complete response (completely cleared individual AK lesions) assessed 3-4 weeks after PDT-1. Please take into consideration: VERUM: number of subjects: 55 and number of lesions: 298 PLACEBO: number of subjects: 32 and number of lesions 173 To realistically reflect the result, the number of subjects (shown below) should be the number of lesions for this analysis, however, this is not possible to enter into the system.
    End point type
    Other pre-specified
    End point timeframe
    3-4 weeks after PDT 1
    End point values
    		 Verum Placebo
    Number of subjects analysed
    55 [4]
    32 [5]
    Units: percent
        arithmetic mean (confidence interval 95%)
    68.5 (62.8 to 73.7)
    15 (10.1 to 21.2)
    Notes
    [4] - Not subjects but number of lesions were analyzed (no. of lesions = 298)
    [5] - Not subjects but number of lesions were analyzed (no. of lesions = 173)
    No statistical analyses for this end point

    Other pre-specified: Lesion complete response 12 weeks after PDT 1

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    End point title
    		 Lesion complete response 12 weeks after PDT 1
    End point description
    A tertiary efficacy variable was the lesion complete response (completely cleared individual AK lesions) assessed 12 weeks after PDT-1. Please take into consideration: VERUM: number of subjects: 55 and number of lesions: 298 PLACEBO: number of subjects: 32 and number of lesions 173 To realistically reflect the result, the number of subjects (shown below) should be the number of lesions for this analysis, however, this is not possible to enter into the system.
    End point type
    Other pre-specified
    End point timeframe
    12 weeks after PDT 1
    End point values
    		 Verum Placebo
    Number of subjects analysed
    55 [6]
    32 [7]
    Units: percent
        arithmetic mean (confidence interval 95%)
    84.2 (79.6 to 88.2)
    22 (16 to 28.9)
    Notes
    [6] - Not subjects but number of lesions were analyzed (no. of lesions = 298)
    [7] - Not subjects but number of lesions were analyzed (no. of lesions = 173)
    No statistical analyses for this end point

    Other pre-specified: Lesion complete response 3-4 weeks after PDT 2

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    End point title
    		 Lesion complete response 3-4 weeks after PDT 2
    End point description
    A tertiary efficacy variable was the lesion complete response (completely cleared individual AK lesions) assessed 3-4 weeks after PDT-2. Please take into consideration: VERUM: number of subjects: 21 and number of lesions: 47 PLACEBO: number of subjects: 29 and number of lesions 135 To realistically reflect the result, the number of subjects (shown below) should be the number of lesions for this analysis, however, this is not possible to enter into the system.
    End point type
    Other pre-specified
    End point timeframe
    3-4 weeks after PDT 2
    End point values
    		 Verum Placebo
    Number of subjects analysed
    21 [8]
    29 [9]
    Units: percent
        arithmetic mean (confidence interval 95%)
    66 (50.7 to 79.1)
    8.1 (4.1 to 14.1)
    Notes
    [8] - Not subjects but number of lesions were analyzed (no. of lesions = 47)
    [9] - Not subjects but number of lesions were analyzed (no. of lesions = 135)
    No statistical analyses for this end point

    Other pre-specified: Lesion complete response 12 weeks after PDT 2

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    End point title
    		 Lesion complete response 12 weeks after PDT 2
    End point description
    A tertiary efficacy variable was the lesion complete response (completely cleared individual AK lesions) assessed 12 weeks after PDT-2. Please take into consideration: VERUM: number of subjects: 21 and number of lesions: 47 PLACEBO: number of subjects: 29 and number of lesions 135 To realistically reflect the result, the number of subjects (shown below) should be the number of lesions for this analysis, however, this is not possible to enter into the system.
    End point type
    Other pre-specified
    End point timeframe
    12 weeks after PDT 2
    End point values
    		 Verum Placebo
    Number of subjects analysed
    21 [10]
    29 [11]
    Units: percent
        arithmetic mean (confidence interval 95%)
    66 (50.7 to 79.1)
    16.3 (10.5 to 23.6)
    Notes
    [10] - Not subjects but number of lesions were analyzed (no. of lesions = 47)
    [11] - Not subjects but number of lesions were analyzed (no. of lesions = 135)
    No statistical analyses for this end point

    Other pre-specified: Lesion complete response 3-4 weeks after last PDT

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    End point title
    		 Lesion complete response 3-4 weeks after last PDT
    End point description
    A tertiary efficacy variable was the lesion complete response (completely cleared individual AK lesions) assessed 3-4 weeks after last PDT. Please take into consideration: VERUM: number of subjects: 55 and number of lesions: 298 PLACEBO: number of subjects: 32 and number of lesions 173 To realistically reflect the result, the number of subjects (shown below) should be the number of lesions for this analysis, however, this is not possible to enter into the system.
    End point type
    Other pre-specified
    End point timeframe
    3-4 weeks after PDT 1 or 3-4 weeks after PDT 2 which might have been necessary because not all lesions were cleared after the first PDT
    End point values
    		 Verum Placebo
    Number of subjects analysed
    55 [12]
    32 [13]
    Units: percent
        arithmetic mean (confidence interval 95%)
    80.9 (75.9 to 85.2)
    21.4 (15.5 to 28.3)
    Notes
    [12] - Not subjects but number of lesions were analyzed (no. of lesions = 298)
    [13] - Not subjects but number of lesions were analyzed (no. of lesions = 173)
    No statistical analyses for this end point

    Other pre-specified: Reduction of total lesion area 3-4 weeks after PDT 1 compared to baseline

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    End point title
    		 Reduction of total lesion area 3-4 weeks after PDT 1 compared to baseline
    End point description
    A tertiary efficacy variable was the reduction from baseline in total lesion area per patient assessed 3-4 weeks after PDT-1.
    End point type
    Other pre-specified
    End point timeframe
    3-4 weeks after PDT 1
    End point values
    		 Verum Placebo
    Number of subjects analysed
    55
    32
    Units: percent
        arithmetic mean (standard deviation)
    -75.3 ( 37.65 )
    -27.7 ( 35.14 )
    No statistical analyses for this end point

    Other pre-specified: Reduction of total lesion area 12 weeks after PDT 1 compared to baseline

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    End point title
    		 Reduction of total lesion area 12 weeks after PDT 1 compared to baseline
    End point description
    A tertiary efficacy variable was the reduction from baseline in total lesion area per patient assessed 12 weeks after PDT-1.
    End point type
    Other pre-specified
    End point timeframe
    12 weeks after PDT 1
    End point values
    		 Verum Placebo
    Number of subjects analysed
    55
    32
    Units: percent
        arithmetic mean (standard deviation)
    -91.1 ( 19.48 )
    -34.3 ( 38.34 )
    No statistical analyses for this end point

    Other pre-specified: Reduction of total lesion area 3-4 weeks after PDT 2 compared to baseline

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    End point title
    		 Reduction of total lesion area 3-4 weeks after PDT 2 compared to baseline
    End point description
    A tertiary efficacy variable was the reduction from baseline in total lesion area per patient assessed 3-4 weeks after PDT-2.
    End point type
    Other pre-specified
    End point timeframe
    3-4 weeks after PDT 2
    End point values
    		 Verum Placebo
    Number of subjects analysed
    21
    24
    Units: percent
        arithmetic mean (standard deviation)
    -94.6 ( 15.09 )
    -30.3 ( 51.15 )
    No statistical analyses for this end point

    Other pre-specified: Reduction of total lesion area 12 weeks after PDT 2 compared to baseline

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    End point title
    		 Reduction of total lesion area 12 weeks after PDT 2 compared to baseline
    End point description
    A tertiary efficacy variable was the reduction from baseline in total lesion area per patient assessed 12 weeks after PDT-2.
    End point type
    Other pre-specified
    End point timeframe
    12 weeks after PDT 2
    End point values
    		 Verum Placebo
    Number of subjects analysed
    21
    24
    Units: percent
        arithmetic mean (standard deviation)
    -95.3 ( 15.41 )
    -44.9 ( 42.74 )
    No statistical analyses for this end point

    Other pre-specified: Reduction of total lesion area 3-4 weeks after last PDT compared to baseline

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    End point title
    		 Reduction of total lesion area 3-4 weeks after last PDT compared to baseline
    End point description
    A tertiary efficacy variable was the reduction from baseline in total lesion area per patient assessed 3-4 weeks after last PDT.
    End point type
    Other pre-specified
    End point timeframe
    3-4 weeks after PDT 1 or 3-4 weeks after PDT 2 which might have been necessary because not all lesions were cleared after the first PDT
    End point values
    		 Verum Placebo
    Number of subjects analysed
    55
    32
    Units: percent
        arithmetic mean (standard deviation)
    -88.2 ( 28.44 )
    -32.4 ( 48.45 )
    No statistical analyses for this end point

    Other pre-specified: New lesions in the treated field 12 weeks after PDT 2

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    End point title
    		 New lesions in the treated field 12 weeks after PDT 2
    End point description
    A tertiary efficacy variable was the number of new lesions in the treated field(s) 12 weeks after PDT-2.
    End point type
    Other pre-specified
    End point timeframe
    12 weeks after PDT 2
    End point values
    		 Verum Placebo
    Number of subjects analysed
    21
    29
    Units: subjects
    0
    1
    No statistical analyses for this end point

    Other pre-specified: New lesions in the treated fields 12 weeks after last PDT

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    End point title
    		 New lesions in the treated fields 12 weeks after last PDT
    End point description
    A tertiary efficacy variable was the number of new lesions in the treated field(s) 12 weeks after the last PDT.
    End point type
    Other pre-specified
    End point timeframe
    12 weeks after PDT 1 or 12 weeks after PDT 2 which might have been necessary because not all lesions were cleared after the first PDT
    End point values
    		 Verum Placebo
    Number of subjects analysed
    55
    32
    Units: subjects
    0
    1
    No statistical analyses for this end point

    Other pre-specified: Change in skin quality assessments compared to baseline 12 weeks after last PDT

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    End point title
    		 Change in skin quality assessments compared to baseline 12 weeks after last PDT
    End point description
    Improvements in skin quality - parameter = Skin surface - 12 weeks after the last PDT compared to baseline (with the exclusion of patients who had no problems at baseline, thus making an improvement impossible).
    End point type
    Other pre-specified
    End point timeframe
    12 weeks after PDT 1 or 12 weeks after PDT 2 which might have been necessary because not all lesions were cleared after the first PDT
    End point values
    		 Verum Placebo
    Number of subjects analysed
    46
    25
    Units: percent
        arithmetic mean (confidence interval 95%)
    69.6 (54.2 to 82.3)
    32 (14.9 to 53.5)
    No statistical analyses for this end point

    Other pre-specified: Change in skin quality assessments compared to baseline 12 weeks after last PDT

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    End point title
    		 Change in skin quality assessments compared to baseline 12 weeks after last PDT
    End point description
    Improvements in skin quality - parameter = Hyperpigmentation - 12 weeks after the last PDT compared to baseline (with the exclusion of patients who had no problems at baseline, thus making an improvement impossible).
    End point type
    Other pre-specified
    End point timeframe
    12 weeks after PDT 1 or 12 weeks after PDT 2 which might have been necessary because not all lesions were cleared after the first PDT
    End point values
    		 Verum Placebo
    Number of subjects analysed
    32
    20
    Units: percent
        arithmetic mean (confidence interval 95%)
    43.8 (26.4 to 62.3)
    25 (8.7 to 49.1)
    No statistical analyses for this end point

    Other pre-specified: Change in skin quality assessments compared to baseline 12 weeks after last PDT

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    End point title
    		 Change in skin quality assessments compared to baseline 12 weeks after last PDT
    End point description
    Improvements in skin quality - parameter = Hypopigmentation - 12 weeks after the last PDT compared to baseline (with the exclusion of patients who had no problems at baseline, thus making an improvement impossible).
    End point type
    Other pre-specified
    End point timeframe
    12 weeks after PDT 1 or 12 weeks after PDT 2 which might have been necessary because not all lesions were cleared after the first PDT
    End point values
    		 Verum Placebo
    Number of subjects analysed
    25
    13
    Units: percent
        arithmetic mean (confidence interval 95%)
    44 (24.4 to 65.1)
    15.4 (1.9 to 45.4)
    No statistical analyses for this end point

    Other pre-specified: Change in skin quality assessments compared to baseline 12 weeks after last PDT

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    End point title
    		 Change in skin quality assessments compared to baseline 12 weeks after last PDT
    End point description
    Improvements in skin quality - parameter = Mottled or irregular pigmentation - 12 weeks after the last PDT compared to baseline (with the exclusion of patients who had no problems at baseline, thus making an improvement impossible).
    End point type
    Other pre-specified
    End point timeframe
    12 weeks after PDT 1 or 12 weeks after PDT 2 which might have been necessary because not all lesions were cleared after the first PDT
    End point values
    		 Verum Placebo
    Number of subjects analysed
    26
    15
    Units: percent
        arithmetic mean (confidence interval 95%)
    50 (29.9 to 70.1)
    33.3 (11.8 to 61.6)
    No statistical analyses for this end point

    Other pre-specified: Change in skin quality assessments compared to baseline 12 weeks after last PDT

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    End point title
    		 Change in skin quality assessments compared to baseline 12 weeks after last PDT
    End point description
    Improvements in skin quality - parameter = Degree of scarring - 12 weeks after the last PDT compared to baseline (with the exclusion of patients who had no problems at baseline, thus making an improvement impossible).
    End point type
    Other pre-specified
    End point timeframe
    12 weeks after PDT 1 or 12 weeks after PDT 2 which might have been necessary because not all lesions were cleared after the first PDT
    End point values
    		 Verum Placebo
    Number of subjects analysed
    14
    8
    Units: percent
        arithmetic mean (confidence interval 95%)
    35.7 (12.8 to 64.9)
    12.5 (0.3 to 52.7)
    No statistical analyses for this end point

    Other pre-specified: Change in skin quality assessments compared to baseline 12 weeks after last PDT

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    End point title
    		 Change in skin quality assessments compared to baseline 12 weeks after last PDT
    End point description
    Improvements in skin quality - parameter = Atrophy - 12 weeks after the last PDT compared to baseline (with the exclusion of patients who had no problems at baseline, thus making an improvement impossible).
    End point type
    Other pre-specified
    End point timeframe
    12 weeks after PDT 1 or 12 weeks after PDT 2 which might have been necessary because not all lesions were cleared after the first PDT
    End point values
    		 Verum Placebo
    Number of subjects analysed
    17
    9
    Units: percent
        arithmetic mean (confidence interval 95%)
    47.1 (23 to 72.2)
    0 (0 to 33.6)
    No statistical analyses for this end point

    Other pre-specified: Cosmetic outcome 12 weeks after last PDT

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    End point title
    		 Cosmetic outcome 12 weeks after last PDT
    End point description
    Very good and good cosmetic outcomes 12 weeks after last PDT
    End point type
    Other pre-specified
    End point timeframe
    12 weeks after PDT 1 or 12 weeks after PDT 2 which might have been necessary because not all lesions were cleared after the first PDT
    End point values
    		 Verum: patients with sum score at baseline of 0 to 3 Placebo: patients with sum score at baseline of 0 to 3 Verum: patients with sum score at baseline of 1 to 3 Placebo: patients with sum score at baseline of 1 to 3
    Number of subjects analysed
    54
    29
    48
    26
    Units: percent
        arithmetic mean (confidence interval 95%)
    59.3 (45 to 72.4)
    31 (15.3 to 50.8)
    66.7 (51.6 to 79.6)
    34.6 (17.2 to 55.7)
    No statistical analyses for this end point

    Other pre-specified: Patient satisfaction

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    End point title
    		 Patient satisfaction
    End point description
    Patient satisfaction was assessed at 12 weeks after last PDT (PDT-1 or PDT-2) using a 5-point scale of 0 to 4, where 0= very good, 1=good, 2=satisfactory, 3=unsatisfactory, and 4=impaired.
    End point type
    Other pre-specified
    End point timeframe
    12 weeks after PDT 1 or 12 weeks after PDT 2 which might have been necessary because not all lesions were cleared after the first PDT
    End point values
    		 Verum Placebo
    Number of subjects analysed
    54
    29
    Units: percent
    arithmetic mean (confidence interval 95%)
        Very good
    27.8 (16.5 to 41.6)
    6.9 (0.8 to 22.8)
        Good
    63 (48.7 to 75.7)
    37.9 (20.7 to 57.7)
        Satisfactory
    7.4 (2.1 to 17.9)
    17.2 (5.8 to 35.8)
        Unsatisfactory
    1.9 (0 to 9.9)
    37.9 (20.7 to 57.7)
        Impaired
    0 (0 to 6.6)
    0 (0 to 11.9)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    04-Oct-2013 (first patient signed informed consent) until 03-Sep-2014 (data base lock)
    Adverse event reporting additional description
    AEs expected to occur as local discomfort were reported via patient questionnaires, local skin reaktions expected to occur were to be assessed by the assigned study team, any other AEs were to be reported by the patient or according to the assessment of the investigator.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.0
    Reporting groups
    Reporting group title
    Verum
    Reporting group description
    		 -

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Serious adverse events
    		 Verum Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 55 (3.64%)
    0 / 32 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Injury, poisoning and procedural complications
    Femoral neck fracture
         subjects affected / exposed
    1 / 55 (1.82%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    1 / 55 (1.82%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebrovascular accident
         subjects affected / exposed
    1 / 55 (1.82%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Bursitis
         subjects affected / exposed
    1 / 55 (1.82%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Verum Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    55 / 55 (100.00%)
    22 / 32 (68.75%)
    General disorders and administration site conditions
    Application site pain
         subjects affected / exposed
    53 / 55 (96.36%)
    16 / 32 (50.00%)
         occurrences all number
    162
    30
    Application site erythema
         subjects affected / exposed
    51 / 55 (92.73%)
    11 / 32 (34.38%)
         occurrences all number
    76
    14
    Application site pruritus
         subjects affected / exposed
    21 / 55 (38.18%)
    9 / 32 (28.13%)
         occurrences all number
    25
    10
    Application site scab
         subjects affected / exposed
    20 / 55 (36.36%)
    1 / 32 (3.13%)
         occurrences all number
    26
    1
    Application site exfoliation
         subjects affected / exposed
    17 / 55 (30.91%)
    1 / 32 (3.13%)
         occurrences all number
    21
    1
    Application site oedema
         subjects affected / exposed
    12 / 55 (21.82%)
    1 / 32 (3.13%)
         occurrences all number
    14
    1
    Application site vesicles
         subjects affected / exposed
    6 / 55 (10.91%)
    0 / 32 (0.00%)
         occurrences all number
    6
    0
    Application site discomfort
         subjects affected / exposed
    5 / 55 (9.09%)
    0 / 32 (0.00%)
         occurrences all number
    7
    0
    Application site discharge
         subjects affected / exposed
    3 / 55 (5.45%)
    0 / 32 (0.00%)
         occurrences all number
    5
    0
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    6 / 55 (10.91%)
    0 / 32 (0.00%)
         occurrences all number
    7
    0

    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
    For support, Contact us.
    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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