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    Clinical Trial Results:
    Efficacy and Safety of LEO 43204 in Field Treatment of Actinic Keratosis on Face or Chest including 12-month follow-up Part 1: 3-day treatment period including an 8-week follow-up period Part 2: extended 12-month follow-up period A phase 3, multi-centre, randomised, parallel group, double-blind, vehicle-controlled trial

    Summary
    EudraCT number
    		 2015-002450-12
    Trial protocol
    		 DE   IT  
    Global end of trial date
    10 Aug 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    16 Sep 2018
    First version publication date
    16 Sep 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    LP0084-1194
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02549339
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    LEO Pharma A/S
    Sponsor organisation address
    Industriparken 55, Ballerup, Denmark, 2750
    Public contact
    Clinical Disclosure Specialist, LEO Pharma A/S, +45 44945888, disclosure@leo-pharma.com
    Scientific contact
    Clinical Disclosure Specialist, LEO Pharma A/S, +45 44945888, disclosure@leo-pharma.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
    27 Feb 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    10 Aug 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    10 Aug 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To confirm the efficacy of LEO 43204 gel (0.018% for face/chest) in actinic keratosis (AK) when applied topically once daily for 3 consecutive days as field treatment
    Protection of trial subjects
    This clinical trial was conducted in accordance with the revision current at the start of the trial of the World Medical Association’s Declaration of Helsinki – Ethical Principles for Medical Research Involving Human Subjects. All subjects received written and verbal information concerning the clinical trial. This information emphasised that participation in the clinical trial was voluntary and that the subject could withdraw from the clinical trial at any time and for any reason. All subjects were given an opportunity to ask questions and were given sufficient time to consider before consenting.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    20 Nov 2015
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 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
    Spain: 21
    Country: Number of subjects enrolled
    Germany: 36
    Country: Number of subjects enrolled
    Italy: 18
    Country: Number of subjects enrolled
    United States: 158
    Country: Number of subjects enrolled
    Canada: 73
    Worldwide total number of subjects
    306
    EEA total number of subjects
    75
    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)
    101
    From 65 to 84 years
    196
    85 years and over
    9

    Subject disposition

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    Recruitment
    Recruitment details
    		 Subjects were followed for 8 weeks following the first application of investigational medicinal product (IMP) at Day 1 (3-day treatment period including an 8-week follow-up period) and for an additional 12 months following Week 8 (extended 12-month follow-up period).

    Pre-assignment
    Screening details
    		 383 subjects were enrolled, 74 were screening failures, and 309 subjects were randomised. Only 306 of the randomised subjects were treated with investigational medicinal product (IMP), the number of subjects treated is reflected as the number of subjects started in the first period.

    Period 1
    Period 1 title
    3-day Treatment and 8-week Follow-up
    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
    		 LEO 43204 0.018% Gel - Treatment Period Including Follow-up
    Arm description
    		 Treatment with LEO 43204 0.018% gel once daily for 3 consecutive days applied on full face or within a contiguous area of approximately 250 cm2 on the chest.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    LEO 43204
    Investigational medicinal product code
    Other name
    Ingenol disoxate
    Pharmaceutical forms
    Gel
    Routes of administration
    Topical use
    Dosage and administration details
    Ingenol disoxate 0.018% gel applied topically on full face or within a contiguous area of approximately 250 cm2 on the chest once daily for 3 consecutive days.

    Arm title
    		 Vehicle Gel - Treatment Period Including Follow-up
    Arm description
    		 Treatment with vehicle gel once daily for 3 consecutive days applied on full face or within a contiguous area of approximately 250 cm2 on the chest.
    Arm type
    		 Placebo

    Investigational medicinal product name
    LEO 43204 Vehicle Gel
    Investigational medicinal product code
    Other name
    Placebo
    Pharmaceutical forms
    Gel
    Routes of administration
    Topical use
    Dosage and administration details
    Vehicle gel applied topically on full face or within a contiguous area of approximately 250 cm2 on the chest once daily for 3 consecutive days.

    Number of subjects in period 1
    		LEO 43204 0.018% Gel - Treatment Period Including Follow-up Vehicle Gel - Treatment Period Including Follow-up
    Started
    202
    104
    Completed
    201
    99
    Not completed
    1
    5
         Consent withdrawn by subject
    -
    3
         Lost to follow-up
    -
    2
         Protocol deviation
    1
    -
    Period 2
    Period 2 title
    12-month Follow-up
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 LEO 43204 0.018% Gel - Extended Follow-up
    Arm description
    		 Treatment with LEO 43204 0.018% gel once daily for 3 consecutive days applied on full face or within a contiguous area of approximately 250 cm2 on the chest.
    Arm type
    		 Experimental

    Investigational medicinal product name
    LEO 43204
    Investigational medicinal product code
    Other name
    Ingenol disoxate
    Pharmaceutical forms
    Gel
    Routes of administration
    Topical use
    Dosage and administration details
    Ingenol disoxate 0.018% gel applied topically on full face or within a contiguous area of approximately 250 cm2 on the chest once daily for 3 consecutive days.

    Arm title
    		 Vehicle Gel - Extended Follow-up
    Arm description
    		 Treatment with vehicle gel once daily for 3 consecutive days applied on full face or within a contiguous area of approximately 250 cm2 on the chest.
    Arm type
    		 Placebo

    Investigational medicinal product name
    LEO 43204 Vehicle Gel
    Investigational medicinal product code
    Other name
    Placebo
    Pharmaceutical forms
    Gel
    Routes of administration
    Topical use
    Dosage and administration details
    Vehicle gel applied topically on full face or within a contiguous area of approximately 250 cm2 on the chest once daily for 3 consecutive days.

    Number of subjects in period 2 [1]
    		LEO 43204 0.018% Gel - Extended Follow-up Vehicle Gel - Extended Follow-up
    Started
    201
    98
    Completed
    192
    87
    Not completed
    9
    11
         Consent withdrawn by subject
    8
    3
         Other
    -
    3
         Lost to follow-up
    1
    3
         Lack of efficacy
    -
    2
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: Of the 300 subjects who completed the 3-day treatment and 8-week follow-up period, 1 subject in the vehicle group was not included in the 12-month Follow-up period because they withdrew after Week 8.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    LEO 43204 0.018% Gel - Treatment Period Including Follow-up
    Reporting group description
    		 Treatment with LEO 43204 0.018% gel once daily for 3 consecutive days applied on full face or within a contiguous area of approximately 250 cm2 on the chest.

    Reporting group title
    Vehicle Gel - Treatment Period Including Follow-up
    Reporting group description
    		 Treatment with vehicle gel once daily for 3 consecutive days applied on full face or within a contiguous area of approximately 250 cm2 on the chest.

    Reporting group values
    		 LEO 43204 0.018% Gel - Treatment Period Including Follow-up Vehicle Gel - Treatment Period Including Follow-up Total
    Number of subjects
    		 202 104 306
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 63 38 101
        From 65-84 years
    		 131 65 196
        85 years and over
    		 8 1 9
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 69.1 ± 9.2 66.3 ± 9.1 -
    Gender categorical
    Units: Subjects
        Female
    		 65 41 106
        Male
    		 137 63 200

    End points

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    End points reporting groups
    Reporting group title
    LEO 43204 0.018% Gel - Treatment Period Including Follow-up
    Reporting group description
    		 Treatment with LEO 43204 0.018% gel once daily for 3 consecutive days applied on full face or within a contiguous area of approximately 250 cm2 on the chest.

    Reporting group title
    Vehicle Gel - Treatment Period Including Follow-up
    Reporting group description
    		 Treatment with vehicle gel once daily for 3 consecutive days applied on full face or within a contiguous area of approximately 250 cm2 on the chest.
    Reporting group title
    LEO 43204 0.018% Gel - Extended Follow-up
    Reporting group description
    		 Treatment with LEO 43204 0.018% gel once daily for 3 consecutive days applied on full face or within a contiguous area of approximately 250 cm2 on the chest.

    Reporting group title
    Vehicle Gel - Extended Follow-up
    Reporting group description
    		 Treatment with vehicle gel once daily for 3 consecutive days applied on full face or within a contiguous area of approximately 250 cm2 on the chest.

    Primary: Complete Clearance of Actinic Keratosis (AK)

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    End point title
    		 Complete Clearance of Actinic Keratosis (AK)
    End point description
    The number of clinically visible actinic keratosis lesions (AKs) identified in the treatment area was recorded at Day 1, Week 4, and Week 8. Complete clearance was defined as no clinically visible AKs in the treatment area. The table shows the percentage of mean number of subjects across imputations with complete clearance.
    End point type
    Primary
    End point timeframe
    At Week 8
    End point values
    		 LEO 43204 0.018% Gel - Treatment Period Including Follow-up Vehicle Gel - Treatment Period Including Follow-up
    Number of subjects analysed
    202
    104
    Units: percentage of subjects
        number (confidence interval 95%)
    20.4 (14.9 to 26.0)
    2.9 (-0.3 to 6.1)
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Mantel-Haenszel estimate (0.018% relative to vehicle), adjusted for pooled sites.
    Comparison groups
    LEO 43204 0.018% Gel - Treatment Period Including Follow-up v Vehicle Gel - Treatment Period Including Follow-up
    Number of subjects included in analysis
    306
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.001
    Method
    		 Mantel-Haenszel
    Parameter type
    		 Ratio of clearance rates
    Point estimate
    7.57
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.26
         upper limit
    		 25.31

    Secondary: Partial Clearance (Multiple Imputation)

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    End point title
    		 Partial Clearance (Multiple Imputation)
    End point description
    The number of clinically visible AKs identified in the treatment area was recorded at Day 1, Week 4, and Week 8. Partial clearance was defined as at least 75% reduction from baseline in the number of clinically visible AKs in the treatment area.
    End point type
    Secondary
    End point timeframe
    At Week 8
    End point values
    		 LEO 43204 0.018% Gel - Treatment Period Including Follow-up Vehicle Gel - Treatment Period Including Follow-up
    Number of subjects analysed
    202
    104
    Units: percentage of subjects
        number (confidence interval 95%)
    60.3 (53.5 to 67.1)
    10.7 (4.7 to 16.7)
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    The p-values for secondary endpoints have been corrected by the Holm-Bonferroni method to account for multiplicity. The prespecified multiplicity adjustment by the Holm-Bonferroni method requires the ordering of the p-values for the secondary endpoints by size. Mantel-Haenszel estimate (0.018% relative to vehicle), adjusted for pooled sites.
    Comparison groups
    Vehicle Gel - Treatment Period Including Follow-up v LEO 43204 0.018% Gel - Treatment Period Including Follow-up
    Number of subjects included in analysis
    306
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Mantel-Haenszel
    Parameter type
    		 Ratio of clearance rates
    Point estimate
    5.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 3.3
         upper limit
    		 10.54

    Secondary: Partial Clearance (Multiple Imputation)

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    End point title
    		 Partial Clearance (Multiple Imputation)
    End point description
    The number of clinically visible AKs identified in the treatment area was recorded at Day 1, Week 4, and Week 8. Partial clearance was defined as at least 75% reduction from baseline in the number of clinically visible AKs in the treatment area. The table shows the percentage of mean number of subjects across imputations with complete clearance.
    End point type
    Secondary
    End point timeframe
    At Week 4
    End point values
    		 LEO 43204 0.018% Gel - Treatment Period Including Follow-up Vehicle Gel - Treatment Period Including Follow-up
    Number of subjects analysed
    202
    104
    Units: percentage of subjects
        number (confidence interval 95%)
    61.1 (54.4 to 67.8)
    10.8 (4.8 to 16.9)
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    The p-values for secondary endpoints have been corrected by the Holm-Bonferroni method to account for multiplicity. The prespecified multiplicity adjustment by the Holm-Bonferroni method requires the ordering of the p-values for the secondary endpoints by size. Mantel-Haenszel estimate (0.018% relative to vehicle), adjusted for pooled sites.
    Comparison groups
    LEO 43204 0.018% Gel - Treatment Period Including Follow-up v Vehicle Gel - Treatment Period Including Follow-up
    Number of subjects included in analysis
    306
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Mantel-Haenszel
    Parameter type
    		 Ratio of clearance rates
    Point estimate
    5.75
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 3.24
         upper limit
    		 10.2

    Secondary: Percent Reduction in AK Count in the Treatment Area Compared to Baseline

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    End point title
    		 Percent Reduction in AK Count in the Treatment Area Compared to Baseline
    End point description
    End point type
    Secondary
    End point timeframe
    At Week 8
    End point values
    		 LEO 43204 0.018% Gel - Treatment Period Including Follow-up Vehicle Gel - Treatment Period Including Follow-up
    Number of subjects analysed
    202
    104
    Units: percentage of reduction
        number (confidence interval 95%)
    74.8 (71.8 to 77.4)
    15.0 (3.4 to 25.2)
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    The p-values for secondary endpoints have been corrected by the Holm-Bonferroni method to account for multiplicity. The prespecified multiplicity adjustment by the Holm-Bonferroni method requires the ordering of the p-values for the secondary endpoints by size.
    Comparison groups
    LEO 43204 0.018% Gel - Treatment Period Including Follow-up v Vehicle Gel - Treatment Period Including Follow-up
    Number of subjects included in analysis
    306
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [1]
    Method
    		 Mantel-Haenszel
    Parameter type
    		 Week 8 AK count ratio
    Point estimate
    0.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.25
         upper limit
    		 0.35
    Notes
    [1] - Negative binominal regression with treatment group and pooled site as factors and log baseline count as offset variable.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Treatment period including follow-up (from Day 1 to Week 8) and extended follow-up (from Week 8 up to Month 14)
    Adverse event reporting additional description
    Different adverse events within the same preferred term and system organ class and involving the same subject have been counted as one. A single subject could appear in multiple classes. Adverse events presented in the table are investigator-reported terms.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.1
    Reporting groups
    Reporting group title
    LEO 43204 0.018% Gel - Treatment Period Including Follow-up
    Reporting group description
    		 Treatment once daily for 3 days with LEO 43204 0.018% gel

    Reporting group title
    Vehicle Gel - Treatment Period Including Follow-up
    Reporting group description
    		 Treatment once daily for 3 days with vehicle gel

    Reporting group title
    LEO 43204 0.018% Gel - Extended Follow-up
    Reporting group description
    		 -

    Reporting group title
    Vehicle Gel - Extended Follow-up
    Reporting group description
    		 Treatment once daily for 3 days Vehicle gel

    Serious adverse events
    		 LEO 43204 0.018% Gel - Treatment Period Including Follow-up Vehicle Gel - Treatment Period Including Follow-up LEO 43204 0.018% Gel - Extended Follow-up Vehicle Gel - Extended Follow-up
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 202 (0.00%)
    0 / 104 (0.00%)
    1 / 201 (0.50%)
    0 / 98 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Squamous cell carcinoma of skin
    Additional description: The event was classified as serious because the participant was hospitalized.
         subjects affected / exposed
    0 / 202 (0.00%)
    0 / 104 (0.00%)
    1 / 201 (0.50%)
    0 / 98 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 LEO 43204 0.018% Gel - Treatment Period Including Follow-up Vehicle Gel - Treatment Period Including Follow-up LEO 43204 0.018% Gel - Extended Follow-up Vehicle Gel - Extended Follow-up
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    136 / 202 (67.33%)
    32 / 104 (30.77%)
    35 / 201 (17.41%)
    14 / 98 (14.29%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal cell carcinoma
         subjects affected / exposed
    5 / 202 (2.48%)
    3 / 104 (2.88%)
    9 / 201 (4.48%)
    1 / 98 (1.02%)
         occurrences all number
    5
    3
    9
    1
    Squamous cell carcinoma of skin
         subjects affected / exposed
    5 / 202 (2.48%)
    0 / 104 (0.00%)
    6 / 201 (2.99%)
    3 / 98 (3.06%)
         occurrences all number
    5
    0
    6
    3
    Bowen's disease
         subjects affected / exposed
    1 / 202 (0.50%)
    2 / 104 (1.92%)
    10 / 201 (4.98%)
    2 / 98 (2.04%)
         occurrences all number
    1
    2
    10
    2
    Seborrhoeic keratosis
         subjects affected / exposed
    0 / 202 (0.00%)
    0 / 104 (0.00%)
    0 / 201 (0.00%)
    2 / 98 (2.04%)
         occurrences all number
    0
    0
    0
    2
    Malignant melanoma
         subjects affected / exposed
    0 / 202 (0.00%)
    0 / 104 (0.00%)
    1 / 201 (0.50%)
    0 / 98 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 202 (0.00%)
    1 / 104 (0.96%)
    0 / 201 (0.00%)
    0 / 98 (0.00%)
         occurrences all number
    0
    1
    0
    0
    General disorders and administration site conditions
    Application site pain
         subjects affected / exposed
    113 / 202 (55.94%)
    5 / 104 (4.81%)
    0 / 201 (0.00%)
    0 / 98 (0.00%)
         occurrences all number
    113
    5
    0
    0
    Application site pruritus
         subjects affected / exposed
    63 / 202 (31.19%)
    5 / 104 (4.81%)
    0 / 201 (0.00%)
    1 / 98 (1.02%)
         occurrences all number
    63
    5
    0
    1
    Application site discomfort
         subjects affected / exposed
    9 / 202 (4.46%)
    3 / 104 (2.88%)
    0 / 201 (0.00%)
    0 / 98 (0.00%)
         occurrences all number
    9
    3
    0
    0
    Application site warmth
         subjects affected / exposed
    3 / 202 (1.49%)
    1 / 104 (0.96%)
    0 / 201 (0.00%)
    0 / 98 (0.00%)
         occurrences all number
    3
    1
    0
    0
    Application site paraesthesia
         subjects affected / exposed
    2 / 202 (0.99%)
    1 / 104 (0.96%)
    0 / 201 (0.00%)
    0 / 98 (0.00%)
         occurrences all number
    2
    1
    0
    0
    Chills
         subjects affected / exposed
    3 / 202 (1.49%)
    0 / 104 (0.00%)
    0 / 201 (0.00%)
    0 / 98 (0.00%)
         occurrences all number
    3
    0
    0
    0
    Pain
         subjects affected / exposed
    1 / 202 (0.50%)
    1 / 104 (0.96%)
    0 / 201 (0.00%)
    0 / 98 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Application site dryness
         subjects affected / exposed
    1 / 202 (0.50%)
    0 / 104 (0.00%)
    0 / 201 (0.00%)
    0 / 98 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Application site haematoma
         subjects affected / exposed
    0 / 202 (0.00%)
    1 / 104 (0.96%)
    0 / 201 (0.00%)
    0 / 98 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Application site laceration
         subjects affected / exposed
    0 / 202 (0.00%)
    1 / 104 (0.96%)
    0 / 201 (0.00%)
    0 / 98 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Application site nodule
         subjects affected / exposed
    1 / 202 (0.50%)
    0 / 104 (0.00%)
    0 / 201 (0.00%)
    0 / 98 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Chest discomfort
         subjects affected / exposed
    1 / 202 (0.50%)
    0 / 104 (0.00%)
    0 / 201 (0.00%)
    0 / 98 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Facial pain
         subjects affected / exposed
    1 / 202 (0.50%)
    0 / 104 (0.00%)
    0 / 201 (0.00%)
    0 / 98 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Hangover
         subjects affected / exposed
    1 / 202 (0.50%)
    0 / 104 (0.00%)
    0 / 201 (0.00%)
    0 / 98 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Pyrexia
         subjects affected / exposed
    0 / 202 (0.00%)
    1 / 104 (0.96%)
    0 / 201 (0.00%)
    0 / 98 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Application site scar
         subjects affected / exposed
    0 / 202 (0.00%)
    0 / 104 (0.00%)
    3 / 201 (1.49%)
    3 / 98 (3.06%)
         occurrences all number
    0
    0
    3
    3
    Application site discolouration
         subjects affected / exposed
    0 / 202 (0.00%)
    0 / 104 (0.00%)
    1 / 201 (0.50%)
    1 / 98 (1.02%)
         occurrences all number
    0
    0
    1
    1
    Application site dermatitis
         subjects affected / exposed
    0 / 202 (0.00%)
    0 / 104 (0.00%)
    1 / 201 (0.50%)
    0 / 98 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Application site macule
         subjects affected / exposed
    0 / 202 (0.00%)
    0 / 104 (0.00%)
    0 / 201 (0.00%)
    1 / 98 (1.02%)
         occurrences all number
    0
    0
    0
    1
    Reproductive system and breast disorders
    Prostatitis
         subjects affected / exposed
    2 / 202 (0.99%)
    0 / 104 (0.00%)
    0 / 201 (0.00%)
    0 / 98 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Prostatomegaly
         subjects affected / exposed
    0 / 202 (0.00%)
    1 / 104 (0.96%)
    0 / 201 (0.00%)
    0 / 98 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Sinus congestion
         subjects affected / exposed
    0 / 202 (0.00%)
    2 / 104 (1.92%)
    0 / 201 (0.00%)
    0 / 98 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Asthma
         subjects affected / exposed
    0 / 202 (0.00%)
    1 / 104 (0.96%)
    0 / 201 (0.00%)
    0 / 98 (0.00%)
         occurrences all number
    202
    1
    0
    0
    Cough
         subjects affected / exposed
    1 / 202 (0.50%)
    0 / 104 (0.00%)
    0 / 201 (0.00%)
    0 / 98 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Dysphonia
         subjects affected / exposed
    1 / 202 (0.50%)
    0 / 104 (0.00%)
    0 / 201 (0.00%)
    0 / 98 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Epistaxis
         subjects affected / exposed
    1 / 202 (0.50%)
    0 / 104 (0.00%)
    0 / 201 (0.00%)
    0 / 98 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    3 / 202 (1.49%)
    0 / 104 (0.00%)
    0 / 201 (0.00%)
    0 / 98 (0.00%)
         occurrences all number
    3
    0
    0
    0
    Anxiety
         subjects affected / exposed
    1 / 202 (0.50%)
    0 / 104 (0.00%)
    0 / 201 (0.00%)
    0 / 98 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Depression
         subjects affected / exposed
    1 / 202 (0.50%)
    0 / 104 (0.00%)
    0 / 201 (0.00%)
    0 / 98 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Sleep disorder
         subjects affected / exposed
    1 / 202 (0.50%)
    0 / 104 (0.00%)
    0 / 201 (0.00%)
    0 / 98 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Investigations
    Blood creatinine increased
         subjects affected / exposed
    1 / 202 (0.50%)
    0 / 104 (0.00%)
    0 / 201 (0.00%)
    0 / 98 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Liver function test abnormal
         subjects affected / exposed
    1 / 202 (0.50%)
    0 / 104 (0.00%)
    0 / 201 (0.00%)
    0 / 98 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Injury, poisoning and procedural complications
    Laceration
         subjects affected / exposed
    4 / 202 (1.98%)
    0 / 104 (0.00%)
    0 / 201 (0.00%)
    0 / 98 (0.00%)
         occurrences all number
    4
    0
    0
    0
    Fall
         subjects affected / exposed
    1 / 202 (0.50%)
    1 / 104 (0.96%)
    0 / 201 (0.00%)
    0 / 98 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Ligament sprain
         subjects affected / exposed
    1 / 202 (0.50%)
    1 / 104 (0.96%)
    0 / 201 (0.00%)
    0 / 98 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Skin abrasion
         subjects affected / exposed
    1 / 202 (0.50%)
    1 / 104 (0.96%)
    0 / 201 (0.00%)
    0 / 98 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Accidental exposure to product
         subjects affected / exposed
    1 / 202 (0.50%)
    0 / 104 (0.00%)
    0 / 201 (0.00%)
    0 / 98 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Arthropod bite
         subjects affected / exposed
    0 / 202 (0.00%)
    1 / 104 (0.96%)
    0 / 201 (0.00%)
    0 / 98 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Concussion
         subjects affected / exposed
    0 / 202 (0.00%)
    1 / 104 (0.96%)
    0 / 201 (0.00%)
    0 / 98 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Face injury
         subjects affected / exposed
    1 / 202 (0.50%)
    0 / 104 (0.00%)
    0 / 201 (0.00%)
    0 / 98 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Muscle strain
         subjects affected / exposed
    0 / 202 (0.00%)
    1 / 104 (0.96%)
    0 / 201 (0.00%)
    0 / 98 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Periorbital haematoma
         subjects affected / exposed
    0 / 202 (0.00%)
    1 / 104 (0.96%)
    0 / 201 (0.00%)
    0 / 98 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Sunburn
         subjects affected / exposed
    0 / 202 (0.00%)
    1 / 104 (0.96%)
    0 / 201 (0.00%)
    0 / 98 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Scar
         subjects affected / exposed
    0 / 202 (0.00%)
    0 / 104 (0.00%)
    0 / 201 (0.00%)
    1 / 98 (1.02%)
         occurrences all number
    0
    0
    0
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    12 / 202 (5.94%)
    0 / 104 (0.00%)
    0 / 201 (0.00%)
    0 / 98 (0.00%)
         occurrences all number
    12
    0
    0
    0
    Anosmia
         subjects affected / exposed
    1 / 202 (0.50%)
    0 / 104 (0.00%)
    0 / 201 (0.00%)
    0 / 98 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Sciatica
         subjects affected / exposed
    1 / 202 (0.50%)
    0 / 104 (0.00%)
    0 / 201 (0.00%)
    0 / 98 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Tension headache
         subjects affected / exposed
    1 / 202 (0.50%)
    0 / 104 (0.00%)
    0 / 201 (0.00%)
    0 / 98 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Eye disorders
    Periorbital oedema
         subjects affected / exposed
    8 / 202 (3.96%)
    0 / 104 (0.00%)
    0 / 201 (0.00%)
    0 / 98 (0.00%)
         occurrences all number
    8
    0
    0
    0
    Eye irritation
         subjects affected / exposed
    4 / 202 (1.98%)
    1 / 104 (0.96%)
    0 / 201 (0.00%)
    0 / 98 (0.00%)
         occurrences all number
    4
    1
    0
    0
    Lacrimation increased
         subjects affected / exposed
    2 / 202 (0.99%)
    1 / 104 (0.96%)
    0 / 201 (0.00%)
    0 / 98 (0.00%)
         occurrences all number
    2
    1
    0
    0
    Eye pain
         subjects affected / exposed
    2 / 202 (0.99%)
    0 / 104 (0.00%)
    0 / 201 (0.00%)
    0 / 98 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Conjunctival haemorrhage
         subjects affected / exposed
    0 / 202 (0.00%)
    1 / 104 (0.96%)
    0 / 201 (0.00%)
    0 / 98 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Dry eye
         subjects affected / exposed
    1 / 202 (0.50%)
    0 / 104 (0.00%)
    0 / 201 (0.00%)
    0 / 98 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Eczema eyelids
         subjects affected / exposed
    1 / 202 (0.50%)
    0 / 104 (0.00%)
    0 / 201 (0.00%)
    0 / 98 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Eyelid oedema
         subjects affected / exposed
    1 / 202 (0.50%)
    0 / 104 (0.00%)
    0 / 201 (0.00%)
    0 / 98 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Eyelid pain
         subjects affected / exposed
    1 / 202 (0.50%)
    0 / 104 (0.00%)
    0 / 201 (0.00%)
    0 / 98 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Photophobia
         subjects affected / exposed
    1 / 202 (0.50%)
    0 / 104 (0.00%)
    0 / 201 (0.00%)
    0 / 98 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Vision blurred
         subjects affected / exposed
    1 / 202 (0.50%)
    0 / 104 (0.00%)
    0 / 201 (0.00%)
    0 / 98 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    2 / 202 (0.99%)
    0 / 104 (0.00%)
    0 / 201 (0.00%)
    0 / 98 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Vomiting
         subjects affected / exposed
    2 / 202 (0.99%)
    0 / 104 (0.00%)
    0 / 201 (0.00%)
    0 / 98 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Rectal polyp
         subjects affected / exposed
    1 / 202 (0.50%)
    0 / 104 (0.00%)
    0 / 201 (0.00%)
    0 / 98 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Skin and subcutaneous tissue disorders
    Ingrowing nail
         subjects affected / exposed
    0 / 202 (0.00%)
    1 / 104 (0.96%)
    0 / 201 (0.00%)
    0 / 98 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Intertrigo
         subjects affected / exposed
    1 / 202 (0.50%)
    0 / 104 (0.00%)
    0 / 201 (0.00%)
    0 / 98 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Post inflammatory pigmentation change
         subjects affected / exposed
    0 / 202 (0.00%)
    1 / 104 (0.96%)
    4 / 201 (1.99%)
    1 / 98 (1.02%)
         occurrences all number
    0
    1
    4
    1
    Seborrhoeic dermatitis
         subjects affected / exposed
    0 / 202 (0.00%)
    0 / 104 (0.00%)
    3 / 201 (1.49%)
    0 / 98 (0.00%)
         occurrences all number
    0
    0
    3
    0
    Hypertrophic scar
         subjects affected / exposed
    0 / 202 (0.00%)
    0 / 104 (0.00%)
    2 / 201 (1.00%)
    0 / 98 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Papule
         subjects affected / exposed
    0 / 202 (0.00%)
    0 / 104 (0.00%)
    1 / 201 (0.50%)
    0 / 98 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Rosacea
         subjects affected / exposed
    0 / 202 (0.00%)
    0 / 104 (0.00%)
    1 / 201 (0.50%)
    0 / 98 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 202 (0.50%)
    2 / 104 (1.92%)
    0 / 201 (0.00%)
    0 / 98 (0.00%)
         occurrences all number
    1
    2
    0
    0
    Rotator cuff syndrome
         subjects affected / exposed
    1 / 202 (0.50%)
    1 / 104 (0.96%)
    0 / 201 (0.00%)
    0 / 98 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Exostosis
         subjects affected / exposed
    0 / 202 (0.00%)
    1 / 104 (0.96%)
    0 / 201 (0.00%)
    0 / 98 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Muscular weakness
         subjects affected / exposed
    0 / 202 (0.00%)
    1 / 104 (0.96%)
    0 / 201 (0.00%)
    0 / 98 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Musculoskeletal chest pain
         subjects affected / exposed
    1 / 202 (0.50%)
    0 / 104 (0.00%)
    0 / 201 (0.00%)
    0 / 98 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Myalgia
         subjects affected / exposed
    1 / 202 (0.50%)
    0 / 104 (0.00%)
    0 / 201 (0.00%)
    0 / 98 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Osteoarthritis
         subjects affected / exposed
    0 / 202 (0.00%)
    1 / 104 (0.96%)
    0 / 201 (0.00%)
    0 / 98 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    6 / 202 (2.97%)
    1 / 104 (0.96%)
    0 / 201 (0.00%)
    0 / 98 (0.00%)
         occurrences all number
    6
    1
    0
    0
    Nasopharyngitis
         subjects affected / exposed
    3 / 202 (1.49%)
    1 / 104 (0.96%)
    0 / 201 (0.00%)
    0 / 98 (0.00%)
         occurrences all number
    3
    1
    0
    0
    Rhinitis
         subjects affected / exposed
    3 / 202 (1.49%)
    0 / 104 (0.00%)
    0 / 201 (0.00%)
    0 / 98 (0.00%)
         occurrences all number
    3
    0
    0
    0
    Herpes simplex
         subjects affected / exposed
    2 / 202 (0.99%)
    0 / 104 (0.00%)
    1 / 201 (0.50%)
    1 / 98 (1.02%)
         occurrences all number
    2
    0
    1
    1
    Application site infection
         subjects affected / exposed
    1 / 202 (0.50%)
    0 / 104 (0.00%)
    0 / 201 (0.00%)
    0 / 98 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Cellulitis
         subjects affected / exposed
    1 / 202 (0.50%)
    0 / 104 (0.00%)
    0 / 201 (0.00%)
    0 / 98 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Conjunctivitis
         subjects affected / exposed
    1 / 202 (0.50%)
    0 / 104 (0.00%)
    0 / 201 (0.00%)
    0 / 98 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Folliculitis
         subjects affected / exposed
    0 / 202 (0.00%)
    1 / 104 (0.96%)
    0 / 201 (0.00%)
    0 / 98 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Furuncle
         subjects affected / exposed
    0 / 202 (0.00%)
    1 / 104 (0.96%)
    0 / 201 (0.00%)
    0 / 98 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Influenza
         subjects affected / exposed
    1 / 202 (0.50%)
    0 / 104 (0.00%)
    0 / 201 (0.00%)
    0 / 98 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Sinusitis
         subjects affected / exposed
    1 / 202 (0.50%)
    0 / 104 (0.00%)
    0 / 201 (0.00%)
    0 / 98 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Postoperative wound infection
         subjects affected / exposed
    0 / 202 (0.00%)
    0 / 104 (0.00%)
    1 / 201 (0.50%)
    0 / 98 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Metabolism and nutrition disorders
    Hyperglycaemia
         subjects affected / exposed
    1 / 202 (0.50%)
    0 / 104 (0.00%)
    0 / 201 (0.00%)
    0 / 98 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Hyperkalaemia
         subjects affected / exposed
    1 / 202 (0.50%)
    0 / 104 (0.00%)
    0 / 201 (0.00%)
    0 / 98 (0.00%)
         occurrences all number
    1
    0
    0
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    04 Mar 2016
    The protocol was updated to specify the method (an interactive web response system) for ensuring that the trial enrolled a minimum of 15% and a maximum of 25% of chest-treated subjects. The amendment also clarified which medications were allowed and prohibited during the extended follow-up period: lesion-directed laser treatment was added to the allowed medications, and Actikerall, even as lesion-directed treatment, and laser treatment as field treatment were prohibited. The remaining changes in the amendment were either administrative changes or matters that needed further clarification.

    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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