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    Clinical Trial Results:
    Clinical Study Protocol Safety and efficacy of escalating doses of LEO 43204 applied once daily for two consecutive days on full balding scalp in subjects with actinic keratosis Part 1: A phase 1, multicentre, open-label,dose escalation, 2-week trial Part 2: A phase 2, multicentre, randomised, double-blind, parallel group, vehicle-controlled, 8-week trial

    Due to the EudraCT – Results system being out of service between 31 July 2015 and 12 January 2016, these results have been published in compliance with revised timelines.
    Summary
    EudraCT number
    		 2014-000037-23
    Trial protocol
    		 DE  
    Global end of trial date
    02 Mar 2015

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

    Trial information

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    Trial identification
    Sponsor protocol code
    LP0084-1014
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02100813
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    LEO Pharma A/S
    Sponsor organisation address
    Industriparken 55, Ballerup, Denmark, 2750
    Public contact
    Clinical Trial Disclosure Manager, LEO pharma A/S, +45 4494 5888, ctr.disclosure@leo-pharma.com
    Scientific contact
    Clinical Trial Disclosure Manager, LEO pharma A/S, +45 4494 5888, 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
    21 Sep 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    02 Mar 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    02 Mar 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Part 1: To identify the Maximum Tolerated Dose (MTD) of LEO 43204 after once daily treatment for two consecutive days. Part 2: To evaluate efficacy of two doses of LEO 43204 given as once daily treatment for two consecutive days.
    Protection of trial subjects
    NA
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    14 May 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
    Germany: 39
    Country: Number of subjects enrolled
    United States: 181
    Worldwide total number of subjects
    220
    EEA total number of subjects
    39
    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)
    47
    From 65 to 84 years
    163
    85 years and over
    10

    Subject disposition

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    Recruitment
    Recruitment details
    		 65 subjects from 7 centres in the US were enrolled into Part 1 of the trial. First subject was enrolled on 14-May-2014 and the last subject´s last visit (LSLV) was on 12-Aug-2014. 197 subjects from 11 centres in the US and 5 centres in Germany were enrolled into Part 2 of trial. First subject was enrolled on 03-Sep-2014 and LSLV was on 02-Mar-2014

    Pre-assignment
    Screening details
    		 Part 1: 7 subjects were screening failures, 1 was excluded as recruitment goals were met. 57 subjects were included and received trial medication. Part 2: 25 subjects did not meet inclusion/exclusion criteria, 7 voluntary withdrawals, 1 randomisation closed, and 1 lost to follow-up. Thus, 163 subjects were randomised.

    Period 1
    Period 1 title
    Part 1 and Part 2 (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded
    Blinding implementation details
    Treatment in Part 1 was open label. Treatment in Part 2, was double-blinded i.e. the sponsor, the investigator, trial site personnel, and the subject were blinded to the trial medication (treatment with LEO 43204 or vehicle) assigned to each individual subject. The packaging and labelling of the investigational products contained no evidence of their identity. It was not considered possible to differentiate between the investigational products solely by sensory evaluation.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Part 1 - 0.018% cohort
    Arm description
    		 Part 1 - Dose escalation
    Arm type
    		 Experimental

    Investigational medicinal product name
    ingenol disoxate gel 0.018%
    Investigational medicinal product code
    LEO 43204 gel 0.018%
    Other name
    Pharmaceutical forms
    Gel
    Routes of administration
    Topical use
    Dosage and administration details
    Dosage and administration details are applicable for all arms in Part 1 and 2. Once daily for two consecutive days on balding scalp. The applications were done by trained research staff. Treatment area was marked on study transparencies with permanent marker using 3-point landmark technique (e.g. ear, eyebrow, scars, moles, birthmarks, bony landmarks, etc.). This was used to locate the treatment area for subsequent trial visits.

    Arm title
    		 Part 1 - 0.025% cohort
    Arm description
    		 Part 1 - Dose escalation
    Arm type
    		 Experimental

    Investigational medicinal product name
    ingenol disoxate gel 0.025%
    Investigational medicinal product code
    LEO 43204 gel 0.025%
    Other name
    Pharmaceutical forms
    Gel
    Routes of administration
    Topical use
    Dosage and administration details
    For description see 0.018% cohort.

    Arm title
    		 Part 1 - 0.037% cohort
    Arm description
    		 Part 1 - Dose escalation
    Arm type
    		 Experimental

    Investigational medicinal product name
    ingenol disoxate gel 0.037%
    Investigational medicinal product code
    LEO 43204 gel 0.037%
    Other name
    Pharmaceutical forms
    Gel
    Routes of administration
    Topical use
    Dosage and administration details
    For description see 0.018% cohort.

    Arm title
    		 Part 1 - 0.05% cohort
    Arm description
    		 Part 1 - Dose escalation
    Arm type
    		 Experimental

    Investigational medicinal product name
    ingenol disoxate gel 0.5%
    Investigational medicinal product code
    LEO 43204 gel 0.5%
    Other name
    Pharmaceutical forms
    Gel
    Routes of administration
    Topical use
    Dosage and administration details
    For description see 0.018% cohort.

    Arm title
    		 Part 1 - 0.075% cohort
    Arm description
    		 Part 1 - Dose escalation
    Arm type
    		 Experimental

    Investigational medicinal product name
    ingenol disoxate gel 0.075%
    Investigational medicinal product code
    LEO 43204 gel 0.075%
    Other name
    Pharmaceutical forms
    Gel
    Routes of administration
    Topical use
    Dosage and administration details
    For description see 0.018% cohort.

    Arm title
    		 Part 2 - Vehicle
    Arm description
    		 Based on the general tolerability profile observed in Part 1 - Dose escalation, it was decided to move forward with the two doses 0.05% and 0.037% in Part 2. See more information under Part 1 - Primary endpoint.
    Arm type
    		 Placebo

    Investigational medicinal product name
    ingenol disoxate gel vehicle
    Investigational medicinal product code
    LEO 43204 gel vehicle
    Other name
    Pharmaceutical forms
    Gel
    Routes of administration
    Topical use
    Dosage and administration details
    For description see 0.018% cohort.

    Arm title
    		 Part 2 - 0.037%
    Arm description
    		 Based on the general tolerability profile observed in Part 1 - Dose escalation, it was decided to move forward with the two doses 0.05% and 0.037% in Part 2. See more information under Part 1 - Primary endpoint.
    Arm type
    		 Experimental

    Investigational medicinal product name
    ingenol disoxate gel 0.037%
    Investigational medicinal product code
    LEO 43204 gel 0.037%
    Other name
    Pharmaceutical forms
    Gel
    Routes of administration
    Topical use
    Dosage and administration details
    For description see 0.018% cohort.

    Arm title
    		 Part 2 - 0.05%
    Arm description
    		 Based on the general tolerability profile observed in Part 1 - Dose escalation, it was decided to move forward with the two doses 0.05% and 0.037% in Part 2. See more information under Part 1 - Primary endpoint.
    Arm type
    		 Experimental

    Investigational medicinal product name
    ingenol disoxate gel 0.5%
    Investigational medicinal product code
    LEO 43204 gel 0.5%
    Other name
    Pharmaceutical forms
    Gel
    Routes of administration
    Topical use
    Dosage and administration details
    For description see 0.018% cohort.

    Number of subjects in period 1
    		Part 1 - 0.018% cohort Part 1 - 0.025% cohort Part 1 - 0.037% cohort Part 1 - 0.05% cohort Part 1 - 0.075% cohort Part 2 - Vehicle Part 2 - 0.037% Part 2 - 0.05%
    Started
    10
    11
    12
    12
    12
    32
    64
    67
    Completed
    10
    11
    12
    12
    12
    32
    64
    66
    Not completed
    0
    0
    0
    0
    0
    0
    0
    1
         Adverse event, non-fatal
    -
    -
    -
    -
    -
    -
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Part 1 - 0.018% cohort
    Reporting group description
    		 Part 1 - Dose escalation

    Reporting group title
    Part 1 - 0.025% cohort
    Reporting group description
    		 Part 1 - Dose escalation

    Reporting group title
    Part 1 - 0.037% cohort
    Reporting group description
    		 Part 1 - Dose escalation

    Reporting group title
    Part 1 - 0.05% cohort
    Reporting group description
    		 Part 1 - Dose escalation

    Reporting group title
    Part 1 - 0.075% cohort
    Reporting group description
    		 Part 1 - Dose escalation

    Reporting group title
    Part 2 - Vehicle
    Reporting group description
    		 Based on the general tolerability profile observed in Part 1 - Dose escalation, it was decided to move forward with the two doses 0.05% and 0.037% in Part 2. See more information under Part 1 - Primary endpoint.

    Reporting group title
    Part 2 - 0.037%
    Reporting group description
    		 Based on the general tolerability profile observed in Part 1 - Dose escalation, it was decided to move forward with the two doses 0.05% and 0.037% in Part 2. See more information under Part 1 - Primary endpoint.

    Reporting group title
    Part 2 - 0.05%
    Reporting group description
    		 Based on the general tolerability profile observed in Part 1 - Dose escalation, it was decided to move forward with the two doses 0.05% and 0.037% in Part 2. See more information under Part 1 - Primary endpoint.

    Reporting group values
    		 Part 1 - 0.018% cohort Part 1 - 0.025% cohort Part 1 - 0.037% cohort Part 1 - 0.05% cohort Part 1 - 0.075% cohort Part 2 - Vehicle Part 2 - 0.037% Part 2 - 0.05% Total
    Number of subjects
    		 10 11 12 12 12 32 64 67 220
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0 0 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0 0 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0 0 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0 0 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0 0 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0 0 0 0 0 0
        Adults (18-64 years)
    		 2 3 4 4 2 9 9 14 47
        From 65-84 years
    		 7 7 8 8 10 21 52 50 163
        85 years and over
    		 1 1 0 0 0 2 3 3 10
    Gender categorical
    Units: Subjects
        Female
    		 0 0 0 0 0 0 0 0 0
        Male
    		 10 11 12 12 12 32 64 67 220

    End points

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    End points reporting groups
    Reporting group title
    Part 1 - 0.018% cohort
    Reporting group description
    		 Part 1 - Dose escalation

    Reporting group title
    Part 1 - 0.025% cohort
    Reporting group description
    		 Part 1 - Dose escalation

    Reporting group title
    Part 1 - 0.037% cohort
    Reporting group description
    		 Part 1 - Dose escalation

    Reporting group title
    Part 1 - 0.05% cohort
    Reporting group description
    		 Part 1 - Dose escalation

    Reporting group title
    Part 1 - 0.075% cohort
    Reporting group description
    		 Part 1 - Dose escalation

    Reporting group title
    Part 2 - Vehicle
    Reporting group description
    		 Based on the general tolerability profile observed in Part 1 - Dose escalation, it was decided to move forward with the two doses 0.05% and 0.037% in Part 2. See more information under Part 1 - Primary endpoint.

    Reporting group title
    Part 2 - 0.037%
    Reporting group description
    		 Based on the general tolerability profile observed in Part 1 - Dose escalation, it was decided to move forward with the two doses 0.05% and 0.037% in Part 2. See more information under Part 1 - Primary endpoint.

    Reporting group title
    Part 2 - 0.05%
    Reporting group description
    		 Based on the general tolerability profile observed in Part 1 - Dose escalation, it was decided to move forward with the two doses 0.05% and 0.037% in Part 2. See more information under Part 1 - Primary endpoint.

    Primary: Part 1: Identify the maximum tolerated dose (MTD) of LEO 43204 after once daily treatment for 2 consecutive days

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    End point title
    		 Part 1: Identify the maximum tolerated dose (MTD) of LEO 43204 after once daily treatment for 2 consecutive days [1] [2]
    End point description
    The MTD was defined as the highest dose level with less than 4 out of 12 subjects experiencing a dose-limiting toxicity (DLT). DLT is defined as: - Erosion/ulceration Grade 4 on the LSR scale - Other clinically relevant signs or symptoms observed, which the International Co-ordinating Investigator judges to be counted as a DLT.
    End point type
    Primary
    End point timeframe
    Day 1 to Day 8
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No subjects met the predefined criteria for DLT. However, there was a dose dependent increase in the number and severity of AEs. In cohort 0.075%, 3 out of 12 subjects experienced severe application site burning or pain, and 2 of them discontinued treatment. Based on the general tolerability profile observed in this cohort, the dose escalation committee decided to stop dose escalation and appoint 0.075% as the MTD. It was decided to move forward with the two doses 0.05% and 0.037% in Part 2
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: As per trial design, MTD of LEO 43204 after once daily treatment for 2 consecutive days was investigated in Part 1 of the trial.
    End point values
    		 Part 1 - 0.018% cohort Part 1 - 0.025% cohort Part 1 - 0.037% cohort Part 1 - 0.05% cohort Part 1 - 0.075% cohort
    Number of subjects analysed
    10
    11
    12
    12
    12
    Units: subjects
    number (not applicable)
        DLT
    0
    0
    0
    0
    0
    No statistical analyses for this end point

    Primary: Part 2: Percent reduction in AK count from baseline to Week 8

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    End point title
    		 Part 2: Percent reduction in AK count from baseline to Week 8 [3]
    End point description
    End point type
    Primary
    End point timeframe
    Baseline to Week 8
    Notes
    [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: As per trial design, percent reduction in AK count from baseline to Week 8 was investigated in Part 2 of the trial.
    End point values
    		 Part 2 - Vehicle Part 2 - 0.037% Part 2 - 0.05%
    Number of subjects analysed
    32
    64
    67
    Units: percent reduction
        number (confidence interval 95%)
    12.6 (9.5 to 30.3)
    72.7 (66.9 to 77.5)
    78.5 (73.7 to 82.5)
    Statistical analysis title
    		 Reduction in AK count at Week 8
    Statistical analysis description
    Negative binominal regression with log baseline count as offset variable and treatment group and analysis site as factors.
    Comparison groups
    Part 2 - 0.037% v Part 2 - 0.05%
    Number of subjects included in analysis
    131
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Negative binomial regression
    Parameter type
    		 AK count ratio
    Point estimate
    0.31
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.23
         upper limit
    		 0.42
    Statistical analysis title
    		 Reduction in AK count at Week 8
    Statistical analysis description
    Negative binominal regression with log baseline count as offset variable and treatment group and analysis site as factors.
    Comparison groups
    Part 2 - 0.05% v Part 2 - Vehicle
    Number of subjects included in analysis
    99
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Negative binomial regression
    Parameter type
    		 AK count ratio
    Point estimate
    0.25
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.18
         upper limit
    		 0.33
    Statistical analysis title
    		 Reduction in AK count at Week 8
    Statistical analysis description
    Negative binominal regression with log baseline count as offset variable and treatment group and analysis site as factors.
    Comparison groups
    Part 2 - 0.05% v Part 2 - 0.037%
    Number of subjects included in analysis
    131
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.096
    Method
    		 Negative binomial regression
    Parameter type
    		 AK count ratio
    Point estimate
    0.79
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.59
         upper limit
    		 1.04

    Secondary: Part 1: Evaluate safety of LEO 43204 in escalating doses after once daily treatment for 2 consecutive days

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    End point title
    		 Part 1: Evaluate safety of LEO 43204 in escalating doses after once daily treatment for 2 consecutive days [4]
    End point description
    Analysis: All dose cohorts had subjects with AEs, most AEs were related to treatment and relatively few AEs were of severe intensity. The number and intensity of administration site reactions (MedDRA high level group term) increased with increasing dose and all severe administration site reactions were observed in the 0.05% and 0.075% cohorts.
    End point type
    Secondary
    End point timeframe
    Day 1 to end of Part 1 - dose escalation
    Notes
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: As per trial design, safety of LEO 43204 in escalating doses after once daily treatment for 2 consecutive days was investigated in Part 1 of the trial.
    End point values
    		 Part 1 - 0.018% cohort Part 1 - 0.025% cohort Part 1 - 0.037% cohort Part 1 - 0.05% cohort Part 1 - 0.075% cohort
    Number of subjects analysed
    10
    11
    12
    12
    12
    Units: NA
        number (not applicable)
    0
    0
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Part 2: Complete clearance at Week 8

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    End point title
    		 Part 2: Complete clearance at Week 8 [5]
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to Week 8
    Notes
    [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: As per trial design, complete clearance at Week 8 was investigated in Part 2 of the trial.
    End point values
    		 Part 2 - Vehicle Part 2 - 0.037% Part 2 - 0.05%
    Number of subjects analysed
    32
    64
    67
    Units: percent
    number (confidence interval 95%)
        Cleared
    3.1 (0.1 to 16.2)
    21.9 (12.5 to 34)
    29.9 (19.3 to 42.3)
    Statistical analysis title
    		 Complete clearance at Week 8
    Statistical analysis description
    Ratio of clearance rates. Log binomial regression with treatment group as factor and baseline AK count included as covariate.
    Comparison groups
    Part 2 - 0.037% v Part 2 - Vehicle
    Number of subjects included in analysis
    96
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.007
    Method
    		 Log binomial regression
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    7.02
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.53
         upper limit
    		 124
    Statistical analysis title
    		 Complete clearance at Week 8
    Statistical analysis description
    Ratio of clearance rates. Log binomial regression with treatment group as factor and baseline AK count included as covariate.
    Comparison groups
    Part 2 - 0.05% v Part 2 - Vehicle
    Number of subjects included in analysis
    99
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [6]
    P-value
    		 = 0.001
    Method
    		 Log binomial regression
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    8.82
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.99
         upper limit
    		 154.5
    Notes
    [6] - Ratio of clearance rates
    Statistical analysis title
    		 Complete clearance at Week 8
    Statistical analysis description
    Ratio of clearance rates. Log binomial regression with treatment group as factor and baseline AK count included as covariate.
    Comparison groups
    Part 2 - 0.05% v Part 2 - 0.037%
    Number of subjects included in analysis
    131
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.43
    Method
    		 Log binomial regression
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    1.26
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.72
         upper limit
    		 2.31

    Secondary: Part 2: Partial clearance of AKs at Week 8

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    End point title
    		 Part 2: Partial clearance of AKs at Week 8 [7]
    End point description
    Partial clearance of AKs at Week 8 is defined as at least 75% reduction from baseline in AK count.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 8
    Notes
    [7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: As per trial design, partial clearance of AKs at Week 8 was investigated in Part 2 of the trial.
    End point values
    		 Part 2 - Vehicle Part 2 - 0.037% Part 2 - 0.05%
    Number of subjects analysed
    32
    64
    67
    Units: NA
        number (confidence interval 95%)
    6.3 (0.8 to 20.8)
    54.7 (41.77 to 67.2)
    59.7 (47 to 71.5)
    Statistical analysis title
    		 Partial clearance of AKs at Week 8
    Comparison groups
    Part 2 - 0.037% v Part 2 - Vehicle
    Number of subjects included in analysis
    96
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Log binomial regression
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    8.73
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.93
         upper limit
    		 51.66
    Statistical analysis title
    		 Partial clearance of AKs at Week 8
    Comparison groups
    Part 2 - 0.05% v Part 2 - Vehicle
    Number of subjects included in analysis
    99
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Log binomial regression
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    9.55
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 3.22
         upper limit
    		 56.4
    Statistical analysis title
    		 Partial clearance of AKs at Week 8
    Comparison groups
    Part 2 - 0.05% v Part 2 - 0.037%
    Number of subjects included in analysis
    131
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.55
    Method
    		 Log binomial regression
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    1.09
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.81
         upper limit
    		 1.49

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Day 1 to End of trial for both part 1 and part 2
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    15.1
    Reporting groups
    Reporting group title
    Part 1 - 0.018% cohort
    Reporting group description
    		 -

    Reporting group title
    Part 1 - 0.025% cohort
    Reporting group description
    		 -

    Reporting group title
    Part 1 - 0.037% cohort
    Reporting group description
    		 -

    Reporting group title
    Part 1 - 0.05% cohort
    Reporting group description
    		 -

    Reporting group title
    Part 1 - 0.075% cohort
    Reporting group description
    		 -

    Reporting group title
    Part 2 - Vehicle
    Reporting group description
    		 -

    Reporting group title
    Part 2 - 0.037%
    Reporting group description
    		 -

    Reporting group title
    Part 2 - 0.05%
    Reporting group description
    		 -

    Serious adverse events
    		 Part 1 - 0.018% cohort Part 1 - 0.025% cohort Part 1 - 0.037% cohort Part 1 - 0.05% cohort Part 1 - 0.075% cohort Part 2 - Vehicle Part 2 - 0.037% Part 2 - 0.05%
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 32 (0.00%)
    2 / 64 (3.13%)
    3 / 67 (4.48%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Brain neoplasm
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 32 (0.00%)
    0 / 64 (0.00%)
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial flutter
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 32 (0.00%)
    1 / 64 (1.56%)
    0 / 67 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 32 (0.00%)
    0 / 64 (0.00%)
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Convulsion
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 32 (0.00%)
    0 / 64 (0.00%)
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Nephrolithiasis
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 32 (0.00%)
    1 / 64 (1.56%)
    0 / 67 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Pain in extremity
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 32 (0.00%)
    0 / 64 (0.00%)
    1 / 67 (1.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Part 1 - 0.018% cohort Part 1 - 0.025% cohort Part 1 - 0.037% cohort Part 1 - 0.05% cohort Part 1 - 0.075% cohort Part 2 - Vehicle Part 2 - 0.037% Part 2 - 0.05%
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    7 / 10 (70.00%)
    7 / 11 (63.64%)
    12 / 12 (100.00%)
    10 / 12 (83.33%)
    12 / 12 (100.00%)
    4 / 32 (12.50%)
    47 / 64 (73.44%)
    50 / 67 (74.63%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Skin papilloma
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 32 (0.00%)
    1 / 64 (1.56%)
    0 / 67 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Squamous cell carcinoma of skin
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 32 (0.00%)
    1 / 64 (1.56%)
    0 / 67 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Vascular disorders
    Peripheral artery aneurysm
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 32 (0.00%)
    0 / 64 (0.00%)
    1 / 67 (1.49%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    Hypertension
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 32 (0.00%)
    1 / 64 (1.56%)
    0 / 67 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Surgical and medical procedures
    Cholecystectomy
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 32 (0.00%)
    0 / 64 (0.00%)
    1 / 67 (1.49%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    General disorders and administration site conditions
    Application site pruritus
         subjects affected / exposed
    3 / 10 (30.00%)
    3 / 11 (27.27%)
    7 / 12 (58.33%)
    5 / 12 (41.67%)
    9 / 12 (75.00%)
    1 / 32 (3.13%)
    16 / 64 (25.00%)
    18 / 67 (26.87%)
         occurrences all number
    3
    3
    7
    5
    10
    1
    18
    18
    Application site pain
         subjects affected / exposed
    2 / 10 (20.00%)
    4 / 11 (36.36%)
    12 / 12 (100.00%)
    9 / 12 (75.00%)
    12 / 12 (100.00%)
    2 / 32 (6.25%)
    31 / 64 (48.44%)
    38 / 67 (56.72%)
         occurrences all number
    3
    5
    18
    16
    17
    2
    42
    51
    Application site paraesthesia
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
    1 / 32 (3.13%)
    0 / 64 (0.00%)
    1 / 67 (1.49%)
         occurrences all number
    0
    0
    0
    0
    2
    1
    0
    1
    Application site discomfort
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 32 (0.00%)
    1 / 64 (1.56%)
    3 / 67 (4.48%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    1
    3
    Application site discharge
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 32 (0.00%)
    0 / 64 (0.00%)
    1 / 67 (1.49%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    Application site hyperaesthesia
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 32 (0.00%)
    0 / 64 (0.00%)
    1 / 67 (1.49%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    Application site oedema
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 32 (0.00%)
    0 / 64 (0.00%)
    1 / 67 (1.49%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    Fatigue
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    1 / 12 (8.33%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 32 (0.00%)
    0 / 64 (0.00%)
    0 / 67 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    Chills
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 32 (0.00%)
    2 / 64 (3.13%)
    4 / 67 (5.97%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    2
    4
    Asthenia
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 32 (0.00%)
    1 / 64 (1.56%)
    1 / 67 (1.49%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    1
    Feeling abnormal
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 32 (0.00%)
    1 / 64 (1.56%)
    0 / 67 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Pain
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 32 (0.00%)
    1 / 64 (1.56%)
    1 / 67 (1.49%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    1
    Discomfort
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 32 (0.00%)
    0 / 64 (0.00%)
    1 / 67 (1.49%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    Oedema peripheral
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 32 (0.00%)
    0 / 64 (0.00%)
    1 / 67 (1.49%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Oropharyngeal pain
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    1 / 12 (8.33%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 32 (0.00%)
    1 / 64 (1.56%)
    0 / 67 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    1
    0
    Cough
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 32 (0.00%)
    1 / 64 (1.56%)
    1 / 67 (1.49%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    1
    Nasal oedema
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 32 (0.00%)
    1 / 64 (1.56%)
    0 / 67 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Rhinorrhoea
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 32 (0.00%)
    1 / 64 (1.56%)
    0 / 67 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Sinus congestion
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 32 (0.00%)
    1 / 64 (1.56%)
    0 / 67 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    4 / 12 (33.33%)
    0 / 32 (0.00%)
    0 / 64 (0.00%)
    1 / 67 (1.49%)
         occurrences all number
    0
    0
    0
    0
    4
    0
    0
    1
    Sleep disorder
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 32 (0.00%)
    1 / 64 (1.56%)
    2 / 67 (2.99%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    2
    Confusional state
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 32 (0.00%)
    1 / 64 (1.56%)
    0 / 67 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Investigations
    Electrocardiogram abnormal
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 32 (0.00%)
    1 / 64 (1.56%)
    0 / 67 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 32 (0.00%)
    0 / 64 (0.00%)
    1 / 67 (1.49%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 32 (0.00%)
    0 / 64 (0.00%)
    1 / 67 (1.49%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    Electrocardiogram t wave abnormal
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 32 (0.00%)
    0 / 64 (0.00%)
    1 / 67 (1.49%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    Electrocardiogram u-wave abnormality
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 32 (0.00%)
    0 / 64 (0.00%)
    1 / 67 (1.49%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    Blood urine present
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    1 / 32 (3.13%)
    0 / 64 (0.00%)
    0 / 67 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    Injury, poisoning and procedural complications
    Laceration
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
    0 / 32 (0.00%)
    0 / 64 (0.00%)
    0 / 67 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    Head injury
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 32 (0.00%)
    1 / 64 (1.56%)
    0 / 67 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Injury
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 32 (0.00%)
    1 / 64 (1.56%)
    0 / 67 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Procedural pain
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 32 (0.00%)
    1 / 64 (1.56%)
    0 / 67 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Tooth fracture
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 32 (0.00%)
    1 / 64 (1.56%)
    0 / 67 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Accidental exposure
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 32 (0.00%)
    0 / 64 (0.00%)
    1 / 67 (1.49%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    Nervous system disorders
    Tension headache
         subjects affected / exposed
    2 / 10 (20.00%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 32 (0.00%)
    0 / 64 (0.00%)
    0 / 67 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    0
    0
    0
    Headache
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 11 (9.09%)
    2 / 12 (16.67%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
    0 / 32 (0.00%)
    6 / 64 (9.38%)
    5 / 67 (7.46%)
         occurrences all number
    0
    1
    2
    0
    1
    0
    7
    5
    Hyperaesthesia
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 32 (0.00%)
    0 / 64 (0.00%)
    2 / 67 (2.99%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    2
    Convulsion
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 32 (0.00%)
    0 / 64 (0.00%)
    1 / 67 (1.49%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    Blood and lymphatic system disorders
    Lymphadenopathy
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    1 / 12 (8.33%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 32 (0.00%)
    1 / 64 (1.56%)
    0 / 67 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    1
    0
    Ear and labyrinth disorders
    Ear pain
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    1 / 12 (8.33%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 32 (0.00%)
    0 / 64 (0.00%)
    0 / 67 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    Eye disorders
    Periorbital oedema
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 11 (9.09%)
    2 / 12 (16.67%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 32 (0.00%)
    3 / 64 (4.69%)
    4 / 67 (5.97%)
         occurrences all number
    0
    1
    2
    0
    0
    0
    3
    5
    Lacrimation increased
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
    0 / 32 (0.00%)
    0 / 64 (0.00%)
    0 / 67 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    0
    0
    Eyelid oedema
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 32 (0.00%)
    1 / 64 (1.56%)
    0 / 67 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Conjunctivitis
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 32 (0.00%)
    0 / 64 (0.00%)
    1 / 67 (1.49%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    Retinal detachment
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 32 (0.00%)
    0 / 64 (0.00%)
    1 / 67 (1.49%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    Xerophthalmia
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 32 (0.00%)
    0 / 64 (0.00%)
    1 / 67 (1.49%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    1 / 12 (8.33%)
    0 / 32 (0.00%)
    1 / 64 (1.56%)
    0 / 67 (0.00%)
         occurrences all number
    1
    0
    0
    0
    1
    0
    1
    0
    Vomiting
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 32 (0.00%)
    0 / 64 (0.00%)
    0 / 67 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    Toothache
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 32 (0.00%)
    1 / 64 (1.56%)
    0 / 67 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Skin and subcutaneous tissue disorders
    Scar
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 32 (0.00%)
    1 / 64 (1.56%)
    0 / 67 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Circumoral oedema
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 32 (0.00%)
    0 / 64 (0.00%)
    1 / 67 (1.49%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    Skin irritation
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 32 (0.00%)
    0 / 64 (0.00%)
    1 / 67 (1.49%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    Skin lesion
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 32 (0.00%)
    0 / 64 (0.00%)
    1 / 67 (1.49%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 32 (0.00%)
    2 / 64 (3.13%)
    0 / 67 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    2
    0
    Intervertebral disc protrusion
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 32 (0.00%)
    1 / 64 (1.56%)
    0 / 67 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Infections and infestations
    Gastroenteritis
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 11 (9.09%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 32 (0.00%)
    0 / 64 (0.00%)
    0 / 67 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    Hordeolum
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 11 (9.09%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 32 (0.00%)
    0 / 64 (0.00%)
    0 / 67 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    Nasopharyngitis
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    1 / 32 (3.13%)
    2 / 64 (3.13%)
    6 / 67 (8.96%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    2
    6
    Oral herpes
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 32 (0.00%)
    2 / 64 (3.13%)
    0 / 67 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    2
    0
    Herpes zoster
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 32 (0.00%)
    1 / 64 (1.56%)
    0 / 67 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Herpes simplex
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 32 (0.00%)
    0 / 64 (0.00%)
    1 / 67 (1.49%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    Influenza
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 32 (0.00%)
    1 / 64 (1.56%)
    0 / 67 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Onychomycosis
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 32 (0.00%)
    1 / 64 (1.56%)
    0 / 67 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 32 (0.00%)
    1 / 64 (1.56%)
    0 / 67 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Urinary tract infection
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 32 (0.00%)
    1 / 64 (1.56%)
    0 / 67 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Visceral larva migrans
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 32 (0.00%)
    1 / 64 (1.56%)
    0 / 67 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Folliculitis
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    1 / 32 (3.13%)
    0 / 64 (0.00%)
    0 / 67 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    Gastroenteritis viral
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    1 / 32 (3.13%)
    0 / 64 (0.00%)
    0 / 67 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    Metabolism and nutrition disorders
    Hypercholesterolaemia
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 12 (0.00%)
    0 / 32 (0.00%)
    1 / 64 (1.56%)
    0 / 67 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0

    More information

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

    Interruptions (globally)
    Were there any global interruptions to the trial? No

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