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    Clinical Trial Results:
    Multicentre, randomized, parallel, double-blind, vehicle controlled study to evaluate the efficacy and safety of Actikerall® solution in the field-directed treatment of actinic keratoses grade I to II (field cancerization)

    Summary
    EudraCT number
    		 2014-001171-31
    Trial protocol
    		 DE   GB  
    Global end of trial date
    10 Aug 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    24 Aug 2016
    First version publication date
    24 Aug 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    98605101-1401
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 ADP18998: Project Code, ALM014: CRO Trial Code (TFS)
    Sponsors
    Sponsor organisation name
    Almirall Hermal GmbH
    Sponsor organisation address
    Scholtzstraße 3, Reinbek, Germany, 21465
    Public contact
    Disclosure Central Team, ALMIRALL S.A, R&D@almirall.com
    Scientific contact
    Disclosure Central Team, ALMIRALL S.A, R&D@almirall.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
    10 Aug 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    10 Aug 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    10 Aug 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To determine the efficacy and safety of Actikerall® solution in the field-directed treatment of actinic keratosis grade I to II (field cancerization)
    Protection of trial subjects
    This trial was conducted in accordance with the recommendations guiding physicians in biomedical research involving human subjects adopted by the 18th World Medical Assembly of Helsinki (1964), revised at Tokyo (1975), Venice (1983), Hong-Kong (1989), Somerset West (1996) and Edinburgh (2000), including the Notes of clarification made by the World Medical Assembly of Washington (2002) and Tokyo (2004), and 59th WMA General Assembly, Seoul (2008) as well as in compliance with Good Clinical Practice (ICH GCP guidelines) and local regulations Each Investigator was responsible for conducting the trial in accordance with the procedures described in the Protocol. All personnel involved in the clinical trial were fully informed about the drug and the nature of the trial and were subject to protocol procedures concerning their duties in the trial The Investigator, Clinical Research Organisation, and the Sponsor ensured that all work and services described herein, or incidental to those described herein, were conducted in accordance to the standards of Good Clinical Practice (ICH GCP guidelines), local regulations and European Directive 2001/20/EC and 2005/28/EC as well as local transpositions of such Directives, as applicable At the completion of treatment (or premature discontinuation) subjects were instructed to resume the medication they were taking before starting the clinical trial, or any other as deemed appropriate by the Investigator. Medical care after discharge from the study was provided by the subject's family practitioner or specialist that usually treated his/her condition
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    17 Oct 2014
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 32
    Country: Number of subjects enrolled
    Germany: 134
    Worldwide total number of subjects
    166
    EEA total number of subjects
    166
    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)
    22
    From 65 to 84 years
    141
    85 years and over
    3

    Subject disposition

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    Recruitment
    Recruitment details
    		 This study was conducted in 14 sites from two countries in Europe (10 in Germany and 4 in the UK) First patient visit was October 2014 and final patient visit was August 2015

    Pre-assignment
    Screening details
    		 Screening took place up to 2 weeks prior to treatment. A total of 175 subjects were screened and 166 were randomised into the study; 3 patients were excluded from efficacy/ safety analysis Nine subjects were not randomised (1 did not meet inclusion/exclusion criteria; 8 declined)

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Actikerall
    Arm description
    		 5-fluorouracil/salicylic acid administered daily
    Arm type
    		 Experimental

    Investigational medicinal product name
    Actikerall
    Investigational medicinal product code
    Other name
    5-fluorouracil 0.5%, salicylic acid 10.0%
    Pharmaceutical forms
    Cutaneous solution
    Routes of administration
    Cutaneous use, Topical use
    Dosage and administration details
    Actikerall® solution and its corresponding vehicle formulation was applied once daily (preferably always at the same time) in a total area of skin of 25 cm² with 4-10 clinical lesions located on the subject’s face/forehead or bald scalp and, additionally, at least 3 sub-clinical lesions for the subjects participating in the sub-study The dose regimen could be decreased by the physician from 7 doses/week to 3 doses/week (i.e. Monday, Wednesday and Friday) in case of severe local skin reactions on the test area due to the study drug

    Arm title
    		 Vehicle
    Arm description
    		 Administered once daily
    Arm type
    		 Placebo

    Investigational medicinal product name
    Product
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Cutaneous solution
    Routes of administration
    Topical use , Cutaneous use
    Dosage and administration details
    Actikerall® solution and its corresponding vehicle formulation was applied once daily (preferably always at the same time) in a total area of skin of 25 cm² with 4-10 clinical lesions located on the subject’s face/forehead or bald scalp and, additionally, at least 3 sub-clinical lesions for the subjects participating in the sub-study The dose regimen could be decreased by the physician from 7 doses/week to 3 doses/week (i.e. Monday, Wednesday and Friday) in case of severe local skin reactions on the test area due to the study drug

    Number of subjects in period 1 [1]
    		Actikerall Vehicle
    Started
    108
    55
    Completed
    93
    50
    Not completed
    15
    5
         Consent withdrawn by subject
    12
    2
         Adverse event, non-fatal
    2
    2
         Protocol deviation
    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: 3 patients were excluded from efficacy/ safety analysis

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Actikerall
    Reporting group description
    		 5-fluorouracil/salicylic acid administered daily

    Reporting group title
    Vehicle
    Reporting group description
    		 Administered once daily

    Reporting group values
    		 Actikerall Vehicle Total
    Number of subjects
    		 108 55 163
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 17 5 22
        From 65-84 years
    		 89 49 138
        85 years and over
    		 2 1 3
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 71.8 ± 7.3 72.8 ± 6.9 -
    Gender categorical
    Units: Subjects
        Female
    		 16 4 20
        Male
    		 92 51 143

    End points

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    End points reporting groups
    Reporting group title
    Actikerall
    Reporting group description
    		 5-fluorouracil/salicylic acid administered daily

    Reporting group title
    Vehicle
    Reporting group description
    		 Administered once daily

    Subject analysis set title
    Actikerall RCM substudy
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Reflectance confocal microscopy (RCM) was conducted in a subset of subjects to evaluate efficacy in subclinical actinic keratosis lesions

    Subject analysis set title
    Vehicle RCM substudy
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Reflectance confocal microscopy (RCM) was conducted in a subset of subjects to evaluate efficacy in subclinical actinic keratosis lesions

    Primary: Percentage of subjects with complete clinical clearance of AK lesions in the treatment field at 8 weeks post last treatment

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    End point title
    		 Percentage of subjects with complete clinical clearance of AK lesions in the treatment field at 8 weeks post last treatment
    End point description
    Complete Clinical Clearance was considered when the clearance rate was 100% at the end of study; that is, all the lesions counted at baseline were cleared
    End point type
    Primary
    End point timeframe
    Week 8 post last treatment
    End point values
    		 Actikerall Vehicle
    Number of subjects analysed
    103
    55
    Units: Percentage
        number (confidence interval 95%)
    49.52 (39.62 to 59.45)
    18.18 (9.08 to 30.9)
    Statistical analysis title
    		 Actikerall vs vehicle
    Comparison groups
    Vehicle v Actikerall
    Number of subjects included in analysis
    158
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0006
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    3.892
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.745
         upper limit
    		 8.679

    Secondary: Percentage of subjects with complete clinical clearance of AK lesions in the treatment field at each treatment visit

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    End point title
    		 Percentage of subjects with complete clinical clearance of AK lesions in the treatment field at each treatment visit
    End point description
    End point type
    Secondary
    End point timeframe
    Up to Week 12 of treament
    End point values
    		 Actikerall Vehicle
    Number of subjects analysed
    108
    55
    Units: Percentage
    number (not applicable)
        Week 2
    1.01
    0
        Week 4
    4
    1.85
        Week 6
    8
    9.26
        Week 12
    23.76
    22.22
    No statistical analyses for this end point

    Secondary: Percentage of subjects with partial clearance of AK lesions in the treatment field at each treatment visit and at 8 weeks post last treatment

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    End point title
    		 Percentage of subjects with partial clearance of AK lesions in the treatment field at each treatment visit and at 8 weeks post last treatment
    End point description
    End point type
    Secondary
    End point timeframe
    Up to 8 weeks post last treatment
    End point values
    		 Actikerall Vehicle
    Number of subjects analysed
    108
    55
    Units: Percentage
    number (not applicable)
        Week 2
    1.01
    0
        Week 4
    5
    7.41
        Week 6
    15
    11.11
        Week 12
    40.59
    31.48
        Week 8 post last treatment
    69.52
    34.55
    No statistical analyses for this end point

    Secondary: Percentage change from baseline in the total number of AK lesion count at each treatment visit and at 8 weeks post last treatment

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    End point title
    		 Percentage change from baseline in the total number of AK lesion count at each treatment visit and at 8 weeks post last treatment
    End point description
    End point type
    Secondary
    End point timeframe
    Up to 8 weeks post treatment
    End point values
    		 Actikerall Vehicle
    Number of subjects analysed
    108 [1]
    55 [2]
    Units: percent
    arithmetic mean (standard deviation)
        Baseline
    5.61 ± 1.35
    5.62 ± 1.46
        Week 2
    -5.1 ± 14.85
    -6.36 ± 14.3
        Week 4
    -14.46 ± 27.19
    -16.41 ± 27.02
        Week 6
    -28.19 ± 33.61
    -26.26 ± 34.22
        Week 12
    -52.16 ± 39.07
    -44.67 ± 40.68
        Week 8 post last treatment
    -78.42 ± 29.42
    -47.4 ± 38.61
    Notes
    [1] - n=99 at Week 2; n=100 at Week 4 and 6; n=101 at Week 12; n=105 at Week 8 post last treatment
    [2] - n=54 at Week 2, Week 4, Week 6 and Week 12
    No statistical analyses for this end point

    Secondary: Number of lesions by AK grade severity according to Olsen et al. (0, I, II or III) at baseline and at 8 weeks post-treatment

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    End point title
    		 Number of lesions by AK grade severity according to Olsen et al. (0, I, II or III) at baseline and at 8 weeks post-treatment
    End point description
    0: No AK lesion present, neither visible nor palpable I: Flat, pink maculae without signs of hyperkeratosis and erythema, slight palpability, with AK felt better than seen II: Pink to reddish papules and erythematous plaques with hyperkeratotic surface, moderately thick AK that are easily seen and felt III: Very thick and / or obvious AK
    End point type
    Secondary
    End point timeframe
    Up to 8 weeks post last treatment
    End point values
    		 Actikerall Vehicle
    Number of subjects analysed
    108
    55
    Units: Number of lesion
        Grade 0 (Baseline)
    0
    0
        Grade I (Baseline)
    340
    178
        Grade II (Baseline)
    266
    131
        Grade III (Baseline)
    0
    0
        Grade 0 (Week 8 post last treatment)
    470
    147
        Grade I (Week 8 post last treatment)
    84
    103
        Grade II (Week 8 post last treatment)
    21
    38
        Grade III (Week 8 post last treatment)
    0
    0
    No statistical analyses for this end point

    Secondary: Global assessment of efficacy by the physician (PGA, Physician Global Assessment) at each treatment visit and at 8 weeks post last treatment (Week 2 and 4)

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    End point title
    		 Global assessment of efficacy by the physician (PGA, Physician Global Assessment) at each treatment visit and at 8 weeks post last treatment (Week 2 and 4)
    End point description
    End point type
    Secondary
    End point timeframe
    Up to 8 weeks post treatment
    End point values
    		 Actikerall Vehicle
    Number of subjects analysed
    108
    55
    Units: Number of patients
        Very good (Week 2)
    1
    0
        Good (Week 2)
    46
    33
        Moderate (Week 2)
    41
    6
        Minimal (Week 2)
    13
    9
        None (Week 2)
    3
    6
        Very good (Week 4)
    4
    1
        Good (Week 4)
    48
    37
        Moderate (Week 4)
    36
    4
        Minimal (Week 4)
    5
    7
        None (Week 4)
    2
    4
    No statistical analyses for this end point

    Secondary: Global assessment of efficacy by the physician (PGA, Physician Global Assessment) at each treatment visit and at 8 weeks post last treatment (Week 6 and 12)

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    End point title
    		 Global assessment of efficacy by the physician (PGA, Physician Global Assessment) at each treatment visit and at 8 weeks post last treatment (Week 6 and 12)
    End point description
    End point type
    Secondary
    End point timeframe
    Up to 8 weeks post last treatment
    End point values
    		 Actikerall Vehicle
    Number of subjects analysed
    108
    55
    Units: Number of patients
        Very good (Week 6)
    6
    3
        Good (Week 6)
    55
    32
        Moderate (Week 6)
    29
    8
        Minimal (Week 6)
    4
    3
        None (Week 6)
    1
    4
        Very good (Week 12)
    21
    11
        Good (Week 12)
    47
    26
        Moderate (Week 12)
    22
    6
        Minimal (Week 12)
    3
    3
        None (Week 12)
    0
    5
    No statistical analyses for this end point

    Secondary: Global assessment of efficacy by the physician (PGA, Physician Global Assessment) at each treatment visit and at 8 weeks post last treatment (Week 8 post last treatment)

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    End point title
    		 Global assessment of efficacy by the physician (PGA, Physician Global Assessment) at each treatment visit and at 8 weeks post last treatment (Week 8 post last treatment)
    End point description
    End point type
    Secondary
    End point timeframe
    Up to 8 weeks post last treatment
    End point values
    		 Actikerall Vehicle
    Number of subjects analysed
    108
    55
    Units: Number of patients
        Very good (Week 8 post last treatment)
    46
    8
        Good (Week 8 post last treatment)
    46
    32
        Moderate (Week 8 post last treatment)
    6
    8
        Minimal (Week 8 post last treatment)
    2
    1
        None (Week 8 post last treatment)
    2
    4
    No statistical analyses for this end point

    Secondary: Change from baseline in total score and individual domains of the DLQI questionnaire after 12 weeks of treatment and at 8 weeks post last treatment (Daily Activities, Leisure, Personal Relationships)

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    End point title
    		 Change from baseline in total score and individual domains of the DLQI questionnaire after 12 weeks of treatment and at 8 weeks post last treatment (Daily Activities, Leisure, Personal Relationships)
    End point description
    The DLQI consists of ten items and covers six domains including 'symptoms and feelings', 'daily activities', 'leisure', 'work and school', 'personal relationships' and 'treatment'. Responses are 'not at all', 'a little', 'a lot', and 'very much', with corresponding scores of 0, 1, 2, and 3, respectively. A total score is calculated by summing the score of all items, resulting in a maximum score of 30 and a minimum score of 0. Scale scores are calculated for each domain. Higher scores indicate more impairment
    End point type
    Secondary
    End point timeframe
    Up to 8 weeks post last treatment
    End point values
    		 Actikerall Vehicle
    Number of subjects analysed
    108
    55
    Units: Score
    arithmetic mean (standard deviation)
        Daily activities (baseline)
    0.21 ± 0.74
    0.16 ± 0.54
        Daily activities (Week 12)
    0.12 ± 0.61
    -0.04 ± 0.34
        Daily activities (Week 8 post last treatment)
    -0.05 ± 0.59
    0.17 ± 0.77
        Leisure (baseline)
    0.15 ± 0.47
    0.27 ± 0.87
        Leisure (Week 12)
    0.15 ± 0.65
    -0.12 ± 0.82
        Leisure (Week 8 post last treatment)
    -0.01 ± 0.48
    -0.06 ± 0.56
        Personal relationships (baseline)
    0.14 ± 0.46
    0.11 ± 0.46
        Personal relationships (Week 12)
    0.01 ± 0.48
    -0.08 ± 0.39
        Personal relationships (Wk 8 post last treatment)
    -0.08 ± 0.39
    0 ± 0.34
    No statistical analyses for this end point

    Secondary: Change from baseline in total score and individual domains of the DLQI questionnaire after 12 weeks of treatment and at 8 weeks post last treatment (Symptoms and Feelings, Treatment, Work and School)

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    End point title
    		 Change from baseline in total score and individual domains of the DLQI questionnaire after 12 weeks of treatment and at 8 weeks post last treatment (Symptoms and Feelings, Treatment, Work and School)
    End point description
    The DLQI consists of ten items and covers six domains including 'symptoms and feelings', 'daily activities', 'leisure', 'work and school', 'personal relationships' and 'treatment'. Responses are 'not at all', 'a little', 'a lot', and 'very much', with corresponding scores of 0, 1, 2, and 3, respectively. A total score is calculated by summing the score of all items, resulting in a maximum score of 30 and a minimum score of 0. Scale scores are calculated for each domain. Higher scores indicate more impairment
    End point type
    Secondary
    End point timeframe
    Up to 8 weeks post last treatment
    End point values
    		 Actikerall Vehicle
    Number of subjects analysed
    108
    55
    Units: Score
    arithmetic mean (standard deviation)
        Symptoms and feelings (baseline)
    0.92 ± 0.91
    1.11 ± 1.18
        Symptoms and feelings (Week 12)
    0.25 ± 1.33
    -0.31 ± 0.86
        Symptoms and feelings (Week 8 post last treatment)
    -0.44 ± 1.15
    -0.44 ± 1.02
        Treatment (baseline)
    0.06 ± 0.25
    0.07 ± 0.33
        Treatment (Week 12)
    0.09 ± 0.38
    0.16 ± 0.5
        Treatment (Week 8 post last treatment)
    0 ± 0.42
    -0.02 ± 0.24
        Work and school (baseline)
    0.04 ± 0.3
    0.04 ± 0.19
        Work and school (Week 12)
    0 ± 0.15
    -0.02 ± 0.25
        Work and school (Week 8 post last treatment)
    -0.03 ± 0.33
    0.08 ± 0.51
    No statistical analyses for this end point

    Secondary: Change from baseline in total score and individual domains of the DLQI questionnaire after 12 weeks of treatment and at 8 weeks post last treatment (Total Score)

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    End point title
    		 Change from baseline in total score and individual domains of the DLQI questionnaire after 12 weeks of treatment and at 8 weeks post last treatment (Total Score)
    End point description
    The DLQI consists of ten items and covers six domains including 'symptoms and feelings', 'daily activities', 'leisure', 'work and school', 'personal relationships' and 'treatment'. Responses are 'not at all', 'a little', 'a lot', and 'very much', with corresponding scores of 0, 1, 2, and 3, respectively. A total score is calculated by summing the score of all items, resulting in a maximum score of 30 and a minimum score of 0. Scale scores are calculated for each domain. Higher scores indicate more impairment
    End point type
    Secondary
    End point timeframe
    Up to 8 weeks post last treatment
    End point values
    		 Actikerall Vehicle
    Number of subjects analysed
    108
    55
    Units: Score
    arithmetic mean (standard deviation)
        Baseline
    1.52 ± 2.08
    1.76 ± 2.93
        Week 12
    0.62 ± 2.23
    -0.41 ± 1.76
        Week 8 post last treatment
    -0.61 ± 2.05
    -0.26 ± 1.85
    No statistical analyses for this end point

    Secondary: Percentage change from baseline in the selected subclinical AK lesions counts after 4, 6 and 12 weeks of treatment and 8 weeks post last treatment

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    End point title
    		 Percentage change from baseline in the selected subclinical AK lesions counts after 4, 6 and 12 weeks of treatment and 8 weeks post last treatment
    End point description
    Subclinical lesions were assessed with reflectance confocal microscopy (RCM)
    End point type
    Secondary
    End point timeframe
    Up to 8 weeks post last treatment
    End point values
    		 Actikerall RCM substudy Vehicle RCM substudy
    Number of subjects analysed
    17
    10
    Units: Number of lesions
    arithmetic mean (standard deviation)
        Baseline
    3 ± 0
    3 ± 0
        Week 4
    -10.42 ± 20.07
    -3.7 ± 11.11
        Week 6
    -22.92 ± 37.94
    -18.52 ± 37.68
        Week 12
    -66.67 ± 43.89
    -40.74 ± 49.38
        Week 8 post last treatment
    -89.58 ± 15.96
    -46.67 ± 50.18
    No statistical analyses for this end point

    Secondary: Individual domains (effectiveness, side effects, convenience and overall satisfaction) of the TSQM at 8 weeks post last treatment

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    End point title
    		 Individual domains (effectiveness, side effects, convenience and overall satisfaction) of the TSQM at 8 weeks post last treatment
    End point description
    Treatment Satisfaction Questionnaire for Medication (version 1.4) consists of 14 items divided in three specific scales (Effectiveness, Side effects and Convenience) and one global satisfaction scale (Global) TSQM Scale scores range from 0 to 100
    End point type
    Secondary
    End point timeframe
    Up to 8 weeks post treatment
    End point values
    		 Actikerall Vehicle
    Number of subjects analysed
    101 [3]
    53 [4]
    Units: Score
    arithmetic mean (standard deviation)
        TSQM Convenience
    70.93 ± 20.96
    71.58 ± 21.29
        TSQM Effectiveness
    70.93 ± 22.88
    59.43 ± 27.55
        TSQM Side Effects
    92.31 ± 15.54
    96.23 ± 11.39
        TSQM Overall Satisfaction
    69.11 ± 23.05
    56.03 ± 26.62
    Notes
    [3] - n=99 for TSQM Effectiveness and n=100 for TSQM Side Effects
    [4] - n=52 for TSQM Convenience
    No statistical analyses for this end point

    Secondary: Percentage of subjects for which the clearance of one pre-defined representative actinic keratosis clinical lesion is confirmed by means of RCM 8 weeks post-treatment.

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    End point title
    		 Percentage of subjects for which the clearance of one pre-defined representative actinic keratosis clinical lesion is confirmed by means of RCM 8 weeks post-treatment.
    End point description
    Subclinical lesions were assessed with reflectance confocal microscopy (RCM)
    End point type
    Secondary
    End point timeframe
    Up to 8 weeks post treatment
    End point values
    		 Actikerall RCM substudy Vehicle RCM substudy
    Number of subjects analysed
    17
    10
    Units: Percentage of patients
    number (not applicable)
        Week 4
    0
    0
        Week 6
    12.5
    11.11
        Week 12
    56.25
    33.33
        Week 8 post last treatment
    68.75
    40
    No statistical analyses for this end point

    Secondary: AK lesions assessments by RCM at baseline (only one clinical preselected lesion)

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    End point title
    		 AK lesions assessments by RCM at baseline (only one clinical preselected lesion)
    End point description
    Subclinical lesions were assessed with reflectance confocal microscopy (RCM)
    End point type
    Secondary
    End point timeframe
    Up to 8 weeks post last treatment
    End point values
    		 Actikerall RCM substudy Vehicle RCM substudy
    Number of subjects analysed
    17
    10
    Units: Percentage of patients
    number (not applicable)
        Architectural disarray
    100
    100
        Keratinocyte atypia
    100
    100
        Parakeratosis
    100
    100
        Pleomorphism
    100
    100
        Single detached keratinocytes
    64.7
    60
        Solar elastosis
    58.8
    50
        Superficial scale
    64.7
    10
    No statistical analyses for this end point

    Secondary: AK lesions assessments by RCM at Week 8 post last treatment (only one clinical preselected lesion)

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    End point title
    		 AK lesions assessments by RCM at Week 8 post last treatment (only one clinical preselected lesion)
    End point description
    Subclinical lesions were assessed with reflectance confocal microscopy (RCM)
    End point type
    Secondary
    End point timeframe
    Up to 8 weeks post last treatment
    End point values
    		 Actikerall RCM substudy Vehicle RCM substudy
    Number of subjects analysed
    17
    10
    Units: Percentage of patients
    number (not applicable)
        Architectural disarray
    12.5
    55.6
        Keratinocyte atypia
    25
    66.7
        Parakeratosis
    12.5
    77.8
        Pleomorphism
    31.3
    66.7
        Single detached keratinocytes
    12.5
    66.7
        Solar elastosis
    37.5
    55.6
        Superficial scale
    12.5
    55.6
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to Day 140 ±5 (Week 20 or Week 8 post-treatment)
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.1
    Reporting groups
    Reporting group title
    Actikerall
    Reporting group description
    		 -

    Reporting group title
    Vehicle
    Reporting group description
    		 -

    Serious adverse events
    		 Actikerall Vehicle
    Total subjects affected by serious adverse events
         subjects affected / exposed
    6 / 108 (5.56%)
    3 / 55 (5.45%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Bladder neoplasm
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric cancer
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 55 (1.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sick sinus syndrome
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Polypectomy
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Benign prostatic hyperplasia
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal colic
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 55 (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
    Spinal osteoarthritis
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 55 (1.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cystitis bacterial
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 55 (1.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Actikerall Vehicle
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    105 / 108 (97.22%)
    42 / 55 (76.36%)
    General disorders and administration site conditions
    Application site erythema
         subjects affected / exposed
    96 / 108 (88.89%)
    29 / 55 (52.73%)
         occurrences all number
    103
    35
    Application site pain
         subjects affected / exposed
    75 / 108 (69.44%)
    23 / 55 (41.82%)
         occurrences all number
    102
    31
    Application site irritation
         subjects affected / exposed
    64 / 108 (59.26%)
    15 / 55 (27.27%)
         occurrences all number
    70
    19
    Application site scab
         subjects affected / exposed
    63 / 108 (58.33%)
    12 / 55 (21.82%)
         occurrences all number
    69
    15
    Application site inflammation
         subjects affected / exposed
    60 / 108 (55.56%)
    15 / 55 (27.27%)
         occurrences all number
    67
    15
    Application site erosion
         subjects affected / exposed
    46 / 108 (42.59%)
    6 / 55 (10.91%)
         occurrences all number
    55
    7
    Application site pruritus
         subjects affected / exposed
    36 / 108 (33.33%)
    16 / 55 (29.09%)
         occurrences all number
    39
    17
    Application site dermatitis
         subjects affected / exposed
    34 / 108 (31.48%)
    3 / 55 (5.45%)
         occurrences all number
    38
    4
    Application site haemorrhage
         subjects affected / exposed
    26 / 108 (24.07%)
    3 / 55 (5.45%)
         occurrences all number
    30
    4
    Application site oedema
         subjects affected / exposed
    17 / 108 (15.74%)
    0 / 55 (0.00%)
         occurrences all number
    18
    0
    Application site exfoliation
         subjects affected / exposed
    6 / 108 (5.56%)
    3 / 55 (5.45%)
         occurrences all number
    6
    4
    Respiratory, thoracic and mediastinal disorders
    Nasopharyngitis
         subjects affected / exposed
    12 / 108 (11.11%)
    2 / 55 (3.64%)
         occurrences all number
    12
    2
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 108 (0.00%)
    3 / 55 (5.45%)
         occurrences all number
    0
    3

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    01 Sep 2014
    Per the MHRA’s request, the following modifications were made: the study drug should be discontinued in case withdrawal criteria were met brivudine, sorivudine and analogues had to be explicitly mentioned as prohibited medication in the Protocol since, according to the approved SmPC, Actikerall must not have been used in conjunction with these agents highly effective methods of birth control were to be used not only two months before the Screening visit but also throughout the trial During the local implementation of the substantial amendment in Germany (2nd October 2014), the text of exclusion criteria #12 was modified to clarify that the “8 weeks prior to Visit 1” referred to the last study drug application that happened in the previous trial regardless of the duration of the follow-up period. This modification was consistent with the exclusion criteria requiring the wash-out specified for investigational drugs was 8 weeks

    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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