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    Clinical Trial Results:
    Ingenol Mebutate Gel, 0.015% Repeat Use for Multiple Actinic Keratoses on Face and Scalp

    Summary
    EudraCT number
    2011-005018-13
    Trial protocol
    GB   DE  
    Global end of trial date
    05 Feb 2014

    Results information
    Results version number
    v1(current)
    This version publication date
    19 Feb 2016
    First version publication date
    22 Jul 2015
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    LP0041-22
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01600014
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    LEO Pharma A/S
    Sponsor organisation address
    Industriparken 55, Ballerup, Denmark,
    Public contact
    Clinical Trial Disclosure Manager, LEO Pharma A/S, +45 44 94 58 88, ctr.disclosure@leo-pharma.com
    Scientific contact
    Clinical Trial Disclosure Manager, LEO Pharma A/S, +45 44 94 58 88, ctr.disclosure@leo-pharma.com
    Sponsor organisation name
    LEO Pharma A/S
    Sponsor organisation address
    Industriparken 55, Ballerup, Denmark,
    Public contact
    Clinical Trial Disclosure Manager, LEO Pharma A/S, +45 44945888, ctr.disclosure@leo-pharma.com
    Scientific contact
    Clinical Trial Disclosure Manager, LEO Pharma A/S, +45 44945888, ctr.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
    05 Feb 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    05 Feb 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    05 Feb 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To demonstrate that ingenol mebutate gel is efficacious in treating AKs present 8 weeks after initial field treatment (field recalcitrant) or emerging in a previously cleared field (field recurrent). Efficacy will be evaluated separately for the two sub-groups of “field recalcitrant” and “field recurrent”.
    Protection of trial subjects
    Not Applicable
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    04 Jun 2012
    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
    France: 115
    Country: Number of subjects enrolled
    United Kingdom: 92
    Country: Number of subjects enrolled
    Germany: 91
    Country: Number of subjects enrolled
    Canada: 91
    Country: Number of subjects enrolled
    Australia: 61
    Worldwide total number of subjects
    450
    EEA total number of subjects
    298
    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)
    86
    From 65 to 84 years
    338
    85 years and over
    26

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    A total of 463 subjects were enrolled in the trial, 13 of whom were screening failures. The remaining 450 subjects were allocated to open-label treatment with ingenol mebutate gel.

    Period 1
    Period 1 title
    Initial treatment and Observation period
    Is this the baseline period?
    Yes
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Arm title
    Ingenol mebutate gel 0.015% - Complete AK clearance at week 8
    Arm description
    -
    Arm type
    Experimental

    Investigational medicinal product name
    Ingenol mebutate 0.015%
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Gel
    Routes of administration
    Cutaneous use
    Dosage and administration details
    Treatment with ingenol mebutate gel 0.015% in the selected treatment area (STA) for 3 consecutive days (Day 1-3)

    Number of subjects in period 1 [1]
    Ingenol mebutate gel 0.015% - Complete AK clearance at week 8
    Started
    450
    Completed
    162
    Not completed
    288
         Other
    27
         Transferred to other arm/group
    203
         Adverse event, non-fatal
    6
         Exclusion criteria emerging during the study
    14
         Site closure due to protocol deviation
    6
         Voluntary (and no other reason)
    24
         Lost to follow-up
    8
    Notes
    [1] - The number of subjects transferring in and out of the arms in the period are not the same. It is expected the net number of transfers in and out of the arms in a period, will be zero.
    Justification: In the first treatment cycle (Day 1 to Week 8), all eligible subjects were to be treated with ingenol mebutate gel, 0.015% in the STA for 3 consecutive days (Day 1-3). At 8 weeks (Day 57) following first application with ingenol mebutate gel subjects not completely cleared in the STA were randomised 2:1 to ingenol mebutate gel or vehicle gel. The first unit dose of trial medication was applied on the same day, corresponding to Day 1 in the second treatment cycle.
    Period 2
    Period 2 title
    Second treatment cycle Week 8-Week 52
    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
    Ingenol mebutate gel 0.015% field recalcitrant subgroup
    Arm description
    -
    Arm type
    Experimental

    Investigational medicinal product name
    Ingenol mebutate 0.015%
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Gel
    Routes of administration
    Cutaneous use
    Dosage and administration details
    Treatment with ingenol mebutate gel 0.015% in the STA for 3 consecutive days (Day 1-3)

    Arm title
    Vehicle gel field recalcitrant subgroup
    Arm description
    -
    Arm type
    Placebo

    Investigational medicinal product name
    Vehicle gel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Gel
    Routes of administration
    Cutaneous use
    Dosage and administration details
    The investigational product was applied once daily for 3 consecutive days in the STA in patients with recalcitrant disease on the face or scalp.

    Number of subjects in period 2 [2]
    Ingenol mebutate gel 0.015% field recalcitrant subgroup Vehicle gel field recalcitrant subgroup
    Started
    92
    49
    Completed
    80
    39
    Not completed
    12
    10
         Death
    1
    2
         Other
    1
    3
         Lack of efficacy
    1
    -
         Exclusion criteria emerging during the study
    1
    1
         Site closure due to protocol deviation
    5
    -
         Voluntary (and no other reason)
    2
    1
         Lost to follow-up
    1
    3
    Notes
    [2] - 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: Second Treatment Cycle (Period of 8 weeks: From either Week 26 or 44): At Day 1 in the second treatment cycle, subjects who were not completely cleared in the STA were randomised 2:1 to treatment with ingenol mebutate gel or vehicle gel. Follow-up Period (Week 16 or 34 to Week 52): The follow-up period was only applicable for subjects who had completed the second treatment cycle (8 weeks after randomisation), and the period continued until trial completion at Week 52.
    Period 3
    Period 3 title
    Second treatment cycle Week 26 or 44-52
    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
    Ingenol mebutate gel 0.015% field recurrent subgroup
    Arm description
    -
    Arm type
    Experimental

    Investigational medicinal product name
    Ingenol mebutate 0.015%
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Gel
    Routes of administration
    Cutaneous use
    Dosage and administration details
    Treatment with ingenol mebutate gel 0.015% in the STA for 3 consecutive days (Day 1-3)

    Arm title
    Vehicle gel field recurrent subgroup
    Arm description
    -
    Arm type
    Placebo

    Investigational medicinal product name
    Vehicle gel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Gel
    Routes of administration
    Cutaneous use
    Dosage and administration details
    The investigational product was applied once daily for 3 consecutive days in the STA in patients with recalcitrant disease on the face or scalp.

    Number of subjects in period 3 [3]
    Ingenol mebutate gel 0.015% field recurrent subgroup Vehicle gel field recurrent subgroup
    Started
    42
    20
    Completed
    39
    20
    Not completed
    3
    0
         Adverse event, non-fatal
    1
    -
         Voluntary (and no other reason)
    1
    -
         Lost to follow-up
    1
    -
    Notes
    [3] - 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: Second Treatment Cycle (Period of 8 weeks: From either Week 26 or 44): At Day 1 in the second treatment cycle, subjects who were not completely cleared in the STA were randomised 2:1 to treatment with ingenol mebutate gel or vehicle gel. Follow-up Period (Week 34 to Week 52): The follow-up period was only applicable for subjects who had completed the second treatment cycle (8 weeks after randomisation), and the period continued until trial completion at Week 52.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Ingenol mebutate gel 0.015% - Complete AK clearance at week 8
    Reporting group description
    -

    Reporting group values
    Ingenol mebutate gel 0.015% - Complete AK clearance at week 8 Total
    Number of subjects
    450 450
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    86 86
        From 65-84 years
    338 338
        85 years and over
    26 26
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    71.7 ± 8.7 -
    Gender categorical
    Units: Subjects
        Female
    53 53
        Male
    397 397

    End points

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    End points reporting groups
    Reporting group title
    Ingenol mebutate gel 0.015% - Complete AK clearance at week 8
    Reporting group description
    -
    Reporting group title
    Ingenol mebutate gel 0.015% field recalcitrant subgroup
    Reporting group description
    -

    Reporting group title
    Vehicle gel field recalcitrant subgroup
    Reporting group description
    -
    Reporting group title
    Ingenol mebutate gel 0.015% field recurrent subgroup
    Reporting group description
    -

    Reporting group title
    Vehicle gel field recurrent subgroup
    Reporting group description
    -

    Primary: Complete clearance of AKs, defined as no clinically visible AKs in the STA, 8 weeks after randomisation

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    End point title
    Complete clearance of AKs, defined as no clinically visible AKs in the STA, 8 weeks after randomisation
    End point description
    End point type
    Primary
    End point timeframe
    8 weeks after randomisation
    End point values
    Ingenol mebutate gel 0.015% field recalcitrant subgroup Vehicle gel field recalcitrant subgroup Ingenol mebutate gel 0.015% field recurrent subgroup Vehicle gel field recurrent subgroup
    Number of subjects analysed
    92
    49
    42
    20
    Units: AK count
    43
    9
    25
    5
    Statistical analysis title
    AK clearance, Week 8 field recalcitrant subgroup
    Statistical analysis description
    Cochran-Mantel-Haenszel ratio of clearance rates (Ingenol mebutate relative to Vehicle) adjusted for anatomical location and country.
    Comparison groups
    Ingenol mebutate gel 0.015% field recalcitrant subgroup v Vehicle gel field recalcitrant subgroup
    Number of subjects included in analysis
    141
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.001 [1]
    Method
    Cochran-Mantel-Haenszel
    Confidence interval
    Notes
    [1] - The complete clearance rate in the field recalcitrant subgroup was statistically significantly higher in the ingenol mebutate group (46.7%) compared to the vehicle group (18.4%).
    Statistical analysis title
    Week 8 field recurrent subgroup
    Statistical analysis description
    Cochran-Mantel-Haenszel ratio of clearance rates (Ingenol mebutate relative to Vehicle) adjusted for anatomical location and week of randomisation.
    Comparison groups
    Ingenol mebutate gel 0.015% field recurrent subgroup v Vehicle gel field recurrent subgroup
    Number of subjects included in analysis
    62
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.013 [2]
    Method
    Cochran-Mantel-Haenszel
    Confidence interval
    Notes
    [2] - The complete clearance rate in the field recurrent subgroup was statistically significantly higher in the ingenol mebutate group (59.5%) compared to the vehicle group (25.0%) (p=0.013).

    Secondary: Complete clearance through to Month 12, defined as no clinically visible AKs and no lesions treated in the STA at any time from last treatment cycle through to Month 12

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    End point title
    Complete clearance through to Month 12, defined as no clinically visible AKs and no lesions treated in the STA at any time from last treatment cycle through to Month 12
    End point description
    The complete clearance through to Month 12 was defined as no clinically visible lesions at any time from the last treatment cycle through to month 12. The analysis was done separately for the field recalcitrant and the field recurrent subgroups. Repeat use regimen: The complete clearance through to Month 12 of the repeat use regimen was defined as no clinically visible lesions at any time from the last treatment cycle through to month 12. The overall estimate of 12 months clearance includes subjects not randomised to a second treatment cycle. Subjects randomised to vehicle were not included in the estimate, instead the subjects randomised to ingenol mebutate were given higher weights to reflect the hypothetical scenario where all subjects were given active treatment during the second treatment cycle. For the full analysis set, depending on the imputation method used, the complete clearance through to Month 12 of the repeat use regimen ranged from 37.8% to 61.6%.
    End point type
    Secondary
    End point timeframe
    The complete clearance through month 12
    End point values
    Ingenol mebutate gel 0.015% field recalcitrant subgroup Vehicle gel field recalcitrant subgroup Ingenol mebutate gel 0.015% field recurrent subgroup Vehicle gel field recurrent subgroup
    Number of subjects analysed
    92
    49
    42
    20
    Units: Number of subjects
    17
    2
    13
    3
    Statistical analysis title
    Clearance Month 12 field recalcitrant, frequency
    Statistical analysis description
    Cochran-Mantel-Haenszel ratio of clearance rates (Ingenol mebutate relative to Vehicle) adjusted for anatomical location and country.
    Comparison groups
    Ingenol mebutate gel 0.015% field recalcitrant subgroup v Vehicle gel field recalcitrant subgroup
    Number of subjects included in analysis
    141
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.016 [3]
    Method
    Cochran-Mantel-Haenszel
    Confidence interval
    Notes
    [3] - The complete clearance rate through to Month 12 in the field recalcitrant subgroup was statistically significantly higher in the ingenol mebutate group (18.5%) compared to the vehicle group (4.1%)
    Statistical analysis title
    Clearance Month 12 field recurrent, frequency
    Comparison groups
    Ingenol mebutate gel 0.015% field recurrent subgroup v Vehicle gel field recurrent subgroup
    Number of subjects included in analysis
    62
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1 [4]
    Method
    Cochran-Mantel-Haenszel
    Confidence interval
    Notes
    [4] - The complete clearance rate through to Month 12 in the field recurrent subgroup was higher in the ingenol mebutate group (31.0%) compared to the vehicle group (15.0%). This difference was not statistically significant (p=0.10).

    Secondary: The change in AK count from randomisation to 8 weeks after randomisation

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    End point title
    The change in AK count from randomisation to 8 weeks after randomisation
    End point description
    The change in AK count from randomisation to 8 weeks after randomisation was determined for the field recalcitrant and the field recurrent subgroups.
    End point type
    Secondary
    End point timeframe
    From randomisation to Week 8
    End point values
    Ingenol mebutate gel 0.015% field recalcitrant subgroup Vehicle gel field recalcitrant subgroup Ingenol mebutate gel 0.015% field recurrent subgroup Vehicle gel field recurrent subgroup
    Number of subjects analysed
    92
    49
    42
    20
    Units: Change in AK count
        arithmetic mean (standard deviation)
    -1.41 ± 1.49
    -0.51 ± 1.65
    -1.52 ± 1.49
    -0.85 ± 0.99
    Statistical analysis title
    Analysis 1
    Statistical analysis description
    Analysed using ANCOVA adjusted for anatomical location, country and AK count at randomisation.
    Comparison groups
    Ingenol mebutate gel 0.015% field recalcitrant subgroup v Vehicle gel field recalcitrant subgroup
    Number of subjects included in analysis
    141
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001 [5]
    Method
    ANCOVA
    Confidence interval
    Notes
    [5] - At 8 weeks after randomisation, using baseline observation carried forward (BOCF) as the imputation method, there was a statistically significant difference in the adjusted mean AK count between the ingenol mebutate and vehicle groups of -0.88.
    Statistical analysis title
    Analysis 2
    Statistical analysis description
    sensitivity analysis using complete cases,
    Comparison groups
    Ingenol mebutate gel 0.015% field recalcitrant subgroup v Vehicle gel field recalcitrant subgroup
    Number of subjects included in analysis
    141
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001 [6]
    Method
    ANCOVA
    Confidence interval
    Notes
    [6] - The difference was -1.01
    Statistical analysis title
    Analysis 3
    Comparison groups
    Ingenol mebutate gel 0.015% field recurrent subgroup v Vehicle gel field recurrent subgroup
    Number of subjects included in analysis
    62
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.008 [7]
    Method
    ANCOVA
    Confidence interval
    Notes
    [7] - At 8 weeks after randomisation, using BOCF as the imputation method, the difference in the adjusted mean AK count between the ingenol mebutate and vehicle groups was -0.69.
    Statistical analysis title
    Analysis 4
    Comparison groups
    Ingenol mebutate gel 0.015% field recurrent subgroup v Vehicle gel field recurrent subgroup
    Number of subjects included in analysis
    62
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.003 [8]
    Method
    ANCOVA
    Confidence interval
    Notes
    [8] - In a sensitivity analysis using complete cases, this difference was -0.77.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All AEs were recorded up to and including Week 8 of the first treatment cycle and second treatment cycle. In the observation period and follow-up period, all AEs within the STA, all SAEs, and all SCC or BCC outside the STA were to be recorded
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    15.1
    Reporting groups
    Reporting group title
    First treatment cycle and observation period
    Reporting group description
    All AEs reported up to Week 8 of the first treatment cycle.

    Reporting group title
    Second treatment cycle and follow-up period
    Reporting group description
    All AEs reported up to Week 8 of the second treatment cycle. During the follow-up period, only the following was to be recorded: all AEs within the selected treatment area, all SAEs, and all occurrences of SCC or BCC outside the selected treatment area.

    Serious adverse events
    First treatment cycle and observation period Second treatment cycle and follow-up period
    Total subjects affected by serious adverse events
         subjects affected / exposed
    19 / 450 (4.22%)
    16 / 203 (7.88%)
         number of deaths (all causes)
    0
    3
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal cell carcinoma
         subjects affected / exposed
    3 / 450 (0.67%)
    3 / 203 (1.48%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Carcinoma in situ of skin
         subjects affected / exposed
    1 / 450 (0.22%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous cell carcinoma
         subjects affected / exposed
    2 / 450 (0.44%)
    2 / 203 (0.99%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Squamous cell carcinoma of skin
         subjects affected / exposed
    0 / 450 (0.00%)
    3 / 203 (1.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Carcinoma in situ
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Basosquamous carcinoma of skin
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphangioma
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasm skin
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bowen's disease
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Keratoacanthoma
         subjects affected / exposed
    1 / 450 (0.22%)
    0 / 203 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prostate cancer
         subjects affected / exposed
    1 / 450 (0.22%)
    0 / 203 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Myocardial infarction
         subjects affected / exposed
    2 / 450 (0.44%)
    0 / 203 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorder
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Lung disorder
         subjects affected / exposed
    1 / 450 (0.22%)
    0 / 203 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Nervous system disorders
    Sciatica
         subjects affected / exposed
    1 / 450 (0.22%)
    0 / 203 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thalamic infarction
         subjects affected / exposed
    1 / 450 (0.22%)
    0 / 203 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    1 / 450 (0.22%)
    0 / 203 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    1 / 450 (0.22%)
    0 / 203 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Oedema peripheral
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Completed suicide
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Gastrointestinal disorders
    Inguinal hernia
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Prostatism
         subjects affected / exposed
    1 / 450 (0.22%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    1 / 450 (0.22%)
    0 / 203 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    0 / 450 (0.00%)
    2 / 203 (0.99%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Aktinic keratosis
         subjects affected / exposed
    0 / 450 (0.00%)
    2 / 203 (0.99%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Polymyalgia rheumatica
         subjects affected / exposed
    1 / 450 (0.22%)
    0 / 203 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arthralgia
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Herpes virus infection
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pyelonephritis
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    0 / 450 (0.00%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 450 (0.22%)
    0 / 203 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 450 (0.22%)
    0 / 203 (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: 2%
    Non-serious adverse events
    First treatment cycle and observation period Second treatment cycle and follow-up period
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    265 / 450 (58.89%)
    105 / 203 (51.72%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal cell carcinoma
         subjects affected / exposed
    46 / 450 (10.22%)
    22 / 203 (10.84%)
         occurrences all number
    67
    43
    Bowen's disease
         subjects affected / exposed
    7 / 450 (1.56%)
    8 / 203 (3.94%)
         occurrences all number
    11
    10
    Squamous cell carcinoma of skin
         subjects affected / exposed
    14 / 450 (3.11%)
    13 / 203 (6.40%)
         occurrences all number
    15
    22
    Seborrhoeic keratosis
         subjects affected / exposed
    10 / 450 (2.22%)
    0 / 203 (0.00%)
         occurrences all number
    15
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    21 / 450 (4.67%)
    0 / 203 (0.00%)
         occurrences all number
    24
    0
    Eye disorders
    Eyelid oedema
         subjects affected / exposed
    17 / 450 (3.78%)
    0 / 203 (0.00%)
         occurrences all number
    18
    0
    Periorbital oedema
         subjects affected / exposed
    15 / 450 (3.33%)
    0 / 203 (0.00%)
         occurrences all number
    16
    0
    General disorders and administration site conditions
    Application site pain
         subjects affected / exposed
    62 / 450 (13.78%)
    15 / 203 (7.39%)
         occurrences all number
    71
    19
    Application site pruritus
         subjects affected / exposed
    20 / 450 (4.44%)
    0 / 203 (0.00%)
         occurrences all number
    20
    0
    Skin and subcutaneous tissue disorders
    Actinic keratosis
         subjects affected / exposed
    60 / 450 (13.33%)
    39 / 203 (19.21%)
         occurrences all number
    87
    67
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    12 / 450 (2.67%)
    0 / 203 (0.00%)
         occurrences all number
    12
    0

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? No

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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