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    Clinical Trial Results:
    A Multicenter, Randomized, Double-Blind, Parallel, Vehicle-Controlled Study to Evaluate the Efficacy And Safety of P-3058 10% Nail Solution in the Treatment of Onychomycosis

    Summary
    EudraCT number
    		 2015-000561-31
    Trial protocol
    		 HU   LV   BG   SE   DE   SK   BE   PL   CZ   LT   GR   IS  
    Global end of trial date
    17 Sep 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    04 Oct 2019
    First version publication date
    04 Oct 2019
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    PM1331
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02549001
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Almirall S.A.
    Sponsor organisation address
    Via Senago 42D, Lugano, Switzerland, CH-6912
    Public contact
    Álvaro Rodríguez Carrasco, International Clinical Trial Manager, Global Clinical Operations – R&D , Almirall S.A., +34 933128993, alvaro.rodriguez@almirall.com
    Scientific contact
    Álvaro Rodríguez Carrasco, International Clinical Trial Manager, Global Clinical Operations – R&D , Almirall S.A., +34 933128993, alvaro.rodriguez@almirall.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    02 Jul 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    17 Sep 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To establish the efficacy and safety of P-3058 (terbinafine 10 percent [%] nail solution) administered once daily for the first 4 weeks and once weekly for the remaining 44 weeks for an overall period of 48 weeks, in comparison to its vehicle in a double-blinded manner. With amendment 1 of the protocol, implemented prior to the randomization of any patient , an open label third arm was added to descriptively compare the efficacy of P-3058 also to that of an active comparator (amorolfine 5%) applied topically once weekly for 48 weeks.
    Protection of trial subjects
    The subjects were informed by the Investigator of all the aspects including nature and purpose, participation conditions, and the risks and benefits of study, before undertaking any study-related procedure. This study was conducted in compliance with the study protocol, the recommendations on biomedical research on human subjects of the Declaration of Helsinki, International Conference of Harmonization – Good Clinical Practice (ICH-GCP) Guidelines, and all applicable national laws and regulations. Signed written informed consent form and privacy authorizations were obtained from all subjects. The subjects were also informed that complete confidentiality would be maintained concerning their identity.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    20 Aug 2015
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Poland: 123
    Country: Number of subjects enrolled
    Slovakia: 17
    Country: Number of subjects enrolled
    Sweden: 127
    Country: Number of subjects enrolled
    Belgium: 5
    Country: Number of subjects enrolled
    Bulgaria: 89
    Country: Number of subjects enrolled
    Czech Republic: 105
    Country: Number of subjects enrolled
    Germany: 197
    Country: Number of subjects enrolled
    Greece: 3
    Country: Number of subjects enrolled
    Hungary: 41
    Country: Number of subjects enrolled
    Iceland: 8
    Country: Number of subjects enrolled
    Latvia: 157
    Country: Number of subjects enrolled
    Lithuania: 33
    Country: Number of subjects enrolled
    Russian Federation: 48
    Worldwide total number of subjects
    953
    EEA total number of subjects
    905
    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)
    1
    Adults (18-64 years)
    603
    From 65 to 84 years
    342
    85 years and over
    7

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was conducted from 20 August 2015 to 17 September 2018 at 114 sites in 13 countries. A total of 953 subjects who met all of the inclusion criteria and none of the exclusion criteria were enrolled and randomised in three arms to receive treatment with P-3058 10%, Vehicle, and Amorolfine, in a ratio of 3:3:1.

    Pre-assignment
    Screening details
    		 Screening and randomisation were performed based on positive potassium hydroxide (KOH) microscopy and mycology results (percentage of the affected target nail area and positive culture for dermatophyte[s] or positive mixed dermatophyte[s]/Candida).

    Period 1
    Period 1 title
    Overall (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Carer
    Blinding implementation details
    This study was conducted with a double-blind, vehicle-controlled design for P-3058 and Vehicle as the vehicle was identical in appearance and indistinguishable from the active treatment to minimize any potential bias. However, Amorolfine was applied in an open label manner due to difference in its product characteristics when compared to P-3058 and Vehicle. Unblinding was performed only in an emergency situation when a medical treatment was required or to assure the safety of the trial subjects.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 P-3058 10%
    Arm description
    		 Subjects applied P-3058 10% nail solution topically, once daily for first 4 weeks and then once weekly for the remaining 44 weeks on all dry nails with suspected onychomycosis.
    Arm type
    		 Experimental

    Investigational medicinal product name
    P-3058 10% nail solution
    Investigational medicinal product code
    Other name
    P-3058 nail solution with 10% terbinafine
    Pharmaceutical forms
    Medicated nail lacquer
    Routes of administration
    Topical use
    Dosage and administration details
    Subjects administered topical nail solution on dry nails, once daily for the first 4 weeks, then once weekly for an additional 44 weeks.

    Arm title
    		 Vehicle
    Arm description
    		 Subjects applied Vehicle of the P-3058 10% nail solution topically, once daily for the first 4 weeks and then once weekly for the remaining 44 weeks on all dry nails with suspected onychomycosis.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Vehicle
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Medicated nail lacquer
    Routes of administration
    Topical use
    Dosage and administration details
    Subjects administered topical nail solution (identical in appearance and indistinguishable from P-3058) on dry nails, once daily for the first 4 weeks, then once weekly for an additional 44 weeks.

    Arm title
    		 Amorolfine
    Arm description
    		 Subjects applied Amorolfine topically, once weekly for 48 weeks on all dry nails with suspected onychomycosis.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Amorolfine nail lacquer 50mg/ml
    Investigational medicinal product code
    Other name
    Loceryl®
    Pharmaceutical forms
    Medicated nail lacquer
    Routes of administration
    Topical use
    Dosage and administration details
    Subjects administered topical nail lacquer on dry nails, once weekly for 48 weeks.

    Number of subjects in period 1
    		P-3058 10% Vehicle Amorolfine
    Started
    406
    410
    137
    Completed
    349
    353
    120
    Not completed
    57
    57
    17
         Consent withdrawn by subject
    25
    32
    9
         Adverse event, non-fatal
    4
    1
    -
         Protocol violation
    4
    2
    -
         Non-compliant
    4
    1
    -
         Other
    -
    2
    -
         Lost to follow-up
    19
    17
    8
         Relevant deterioration of treated nails
    1
    2
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    P-3058 10%
    Reporting group description
    		 Subjects applied P-3058 10% nail solution topically, once daily for first 4 weeks and then once weekly for the remaining 44 weeks on all dry nails with suspected onychomycosis.

    Reporting group title
    Vehicle
    Reporting group description
    		 Subjects applied Vehicle of the P-3058 10% nail solution topically, once daily for the first 4 weeks and then once weekly for the remaining 44 weeks on all dry nails with suspected onychomycosis.

    Reporting group title
    Amorolfine
    Reporting group description
    		 Subjects applied Amorolfine topically, once weekly for 48 weeks on all dry nails with suspected onychomycosis.

    Reporting group values
    		 P-3058 10% Vehicle Amorolfine Total
    Number of subjects
    		 406 410 137 953
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 58.99 ( 12.65 ) 59.19 ( 13.06 ) 58.19 ( 12.72 ) -
    Gender categorical
    Units: Subjects
        Female
    		 180 157 52 389
        Male
    		 226 253 85 564
    Race
    Units: Subjects
        White
    		 405 407 137 949
        Black or African American
    		 0 1 0 1
        Asian
    		 0 1 0 1
        American Indian or Alaska Native
    		 0 1 0 1
        Other
    		 1 0 0 1
    Percent of affected target big toenail
    Units: Percentage
        arithmetic mean (standard deviation)
    		 34.72 ( 9.92 ) 34.82 ( 10.14 ) 35.23 ( 10.11 ) -
    Total number of affected toenails
    Units: number
        arithmetic mean (standard deviation)
    		 4.81 ( 2.90 ) 4.65 ( 2.81 ) 4.96 ( 2.73 ) -

    End points

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    End points reporting groups
    Reporting group title
    P-3058 10%
    Reporting group description
    		 Subjects applied P-3058 10% nail solution topically, once daily for first 4 weeks and then once weekly for the remaining 44 weeks on all dry nails with suspected onychomycosis.

    Reporting group title
    Vehicle
    Reporting group description
    		 Subjects applied Vehicle of the P-3058 10% nail solution topically, once daily for the first 4 weeks and then once weekly for the remaining 44 weeks on all dry nails with suspected onychomycosis.

    Reporting group title
    Amorolfine
    Reporting group description
    		 Subjects applied Amorolfine topically, once weekly for 48 weeks on all dry nails with suspected onychomycosis.

    Primary: Percentage of Subjects With Complete Cure Rate of Onychomycosis Disease at Week 60

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    End point title
    		 Percentage of Subjects With Complete Cure Rate of Onychomycosis Disease at Week 60
    End point description
    Complete cure rate at week 60, was defined as a composite of negative potassium hydroxide (KOH) microscopy, negative culture for dermatophytes, and no residual clinical involvement (nail totally clear) of the target big toenail. The complete cure rate was analysed using the logistic regression models with factor for treatment. Analysis was performed on intention-to-treat (ITT) population which included all subjects randomised and dispensed study medication, using the last observation carried forward (LOCF) approach for missing values (i.e., missing values were replaced by the last non-missing, post-baseline value).
    End point type
    Primary
    End point timeframe
    Week 60
    End point values
    		 P-3058 10% Vehicle Amorolfine
    Number of subjects analysed
    406
    410
    137
    Units: percentage of subjects
    number (not applicable)
        Success rate
    5.67
    2.20
    2.92
        Failure rate
    94.33
    97.80
    97.08
    Statistical analysis title
    		 P-3058 10% versus Vehicle
    Comparison groups
    Vehicle v P-3058 10%
    Number of subjects included in analysis
    816
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0138 [1]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    2.68
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.22
         upper limit
    		 5.86
    Notes
    [1] - p-value less than (<) 0.05 was considered statistically significant.
    Statistical analysis title
    		 P-3058 10% versus Amorolfine
    Comparison groups
    P-3058 10% v Amorolfine
    Number of subjects included in analysis
    543
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2095 [2]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.68
         upper limit
    		 5.88
    Notes
    [2] - p-value <0.05 was considered statistically significant.

    Secondary: Percentage of Subjects With Responder Rate of Onychomycosis at Week 60

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    End point title
    		 Percentage of Subjects With Responder Rate of Onychomycosis at Week 60
    End point description
    Responder rate at Week 60, was defined as a composite of negative KOH microscopy and negative culture for dermatophytes and less than equal to (<=) 10% residual involvement of the target toenail. The responder rate was analysed using the logistic regression models with factor for treatment and missing values for the components were replaced by the last non-missing value. Analysis was performed on ITT population.
    End point type
    Secondary
    End point timeframe
    Week 60
    End point values
    		 P-3058 10% Vehicle Amorolfine
    Number of subjects analysed
    406
    410
    137
    Units: Percentage of subjects
    number (not applicable)
        Success rate
    6.65
    3.41
    3.65
        Failure rate
    93.35
    96.59
    96.35
    Statistical analysis title
    		 P-3058 10% versus Vehicle
    Comparison groups
    P-3058 10% v Vehicle
    Number of subjects included in analysis
    816
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0377 [3]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    2.02
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.04
         upper limit
    		 3.9
    Notes
    [3] - p-value <0.05 was considered statistically significant.
    Statistical analysis title
    		 P-3058 10% versus Amorolfine
    Comparison groups
    P-3058 10% v Amorolfine
    Number of subjects included in analysis
    543
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.204 [4]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.88
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.71
         upper limit
    		 4.98
    Notes
    [4] - p-value <0.05 was considered statistically significant.

    Secondary: Percentage of Subjects With Mycological Cure Rate of Onychomycosis at Week 60

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    End point title
    		 Percentage of Subjects With Mycological Cure Rate of Onychomycosis at Week 60
    End point description
    Mycological cure rate at Week 60, was defined as a composite of negative KOH microscopy and negative culture for dermatophytes of the target toenail. The mycological Cure rate was analysed using the logistic regression models with factor for treatment and missing values for the components were replaced by the last non-missing value. Analysis was performed on ITT population.
    End point type
    Secondary
    End point timeframe
    Week 60
    End point values
    		 P-3058 10% Vehicle Amorolfine
    Number of subjects analysed
    406
    410
    137
    Units: percentage of subjects
    number (not applicable)
        Success rate
    20.44
    12.20
    18.98
        Failure rate
    79.56
    87.80
    81.02
    Statistical analysis title
    		 P-3058 10% versus Vehicle
    Comparison groups
    P-3058 10% v Vehicle
    Number of subjects included in analysis
    816
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0016 [5]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.85
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.26
         upper limit
    		 2.71
    Notes
    [5] - p-value <0.05 was considered statistically significant.
    Statistical analysis title
    		 P-3058 10% versus Amorolfine
    Comparison groups
    P-3058 10% v Amorolfine
    Number of subjects included in analysis
    543
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7113 [6]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.67
         upper limit
    		 1.79
    Notes
    [6] - p-value <0.05 was considered statistically significant.

    Secondary: Number of Subjects With Any Adverse Events (AEs) From Baseline (Week 0) to Week 60/Discontinuation Visit

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    End point title
    		 Number of Subjects With Any Adverse Events (AEs) From Baseline (Week 0) to Week 60/Discontinuation Visit
    End point description
    An AE is defined as "any untoward medical event in a patient or clinical investigation subject administered any dose of a pharmaceutical product and which does not necessarily have to have a causal relationship with the use of the product. Number of subjects with treatment-emergent adverse events (TEAEs), i.e. those AEs with an onset date after at least treatment initiation) and the non-treatment emergent adverse events (non-TEAEs), i.e. AEs with onset date between signed informed consent form and treatment initiation) that occurred during the study were assessed for safety of study drug. Analysis was done on safety population which included all randomised subjects who receive at least one dose of the study drug.
    End point type
    Secondary
    End point timeframe
    Baseline (Week 0) to Week 60/Discontinuation Visit
    End point values
    		 P-3058 10% Vehicle Amorolfine
    Number of subjects analysed
    406
    407
    137
    Units: number of subjects
        Subjects with any non-TEAEs
    21
    29
    7
        Subjects with any TEAEs
    170
    190
    63
        Subjects with serious TEAEs
    21
    22
    9
        Subjects with TEAEs leading to discontinuation
    4
    1
    0
        Subjects with fatal AEs
    2
    0
    0
    No statistical analyses for this end point

    Secondary: Number of Subjects With Local Tolerability From Baseline (Week 0) to Week 60/Discontinuation visit

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    End point title
    		 Number of Subjects With Local Tolerability From Baseline (Week 0) to Week 60/Discontinuation visit
    End point description
    The overall safety of study drug from Baseline to Week 60/Discontinuation visit was assessed through local tolerability score. Local tolerability at the application site was assessed to rate the severity of any periungual irritation from Week 4 to Week 60 (study end-point), or at discontinuation visit, through a severity score for skin irritation. The dermal response score ranges from 0 (no evidence of irritation) to 7 (strong reaction spreading beyond test site), and the score of other effects ranges from A (slight glazed appearance) to G (small petechial erosions or scabs); where higher scores (7 and G) indicated more severe condition. Here, "Discont.' represents 'Discontinuation visit'. Analysis was done of safety population.
    End point type
    Secondary
    End point timeframe
    Baseline (Week 0) to Week 60; Discontinuation visit
    End point values
    		 P-3058 10% Vehicle Amorolfine
    Number of subjects analysed
    406 [7]
    407 [8]
    137 [9]
    Units: number of subjects
        Week 4, Skin irritation evidence- No
    386
    395
    129
        Week 4, Skin irritation evidence- Yes
    16
    8
    7
        Week 12, Skin irritation evidence- No
    380
    383
    126
        Week 12, Skin irritation evidence- Yes
    7
    12
    6
        Week 12, Skin irritation evidence- Missing
    0
    0
    1
        Week 24, Skin irritation evidence- No
    368
    378
    128
        Week 24, Skin irritation evidence- Yes
    6
    6
    3
        Week 24, Skin irritation evidence- Missing
    1
    0
    0
        Week 36, Skin irritation evidence- No
    364
    368
    127
        Week 36, Skin irritation evidence- Yes
    4
    3
    1
        Week 36, Skin irritation evidence- Missing
    0
    1
    0
        Week 48, Skin irritation evidence- No
    358
    356
    123
        Week 48, Skin irritation evidence- Yes
    1
    5
    2
        Week 48, Skin irritation evidence- Missing
    0
    1
    1
        Week 60, Skin irritation evidence- No
    350
    349
    118
        Week 60, Skin irritation evidence- Yes
    1
    1
    2
        Week 60, Skin irritation evidence- Missing
    0
    1
    0
        Discont. Visit, Skin irritation evidence- No
    21
    19
    7
        Discont. Visit, Skin irritation evidence- Yes
    1
    0
    0
        Discont. Visit, Skin irritation evidence- Missing
    3
    8
    1
    Notes
    [7] - No. of subjects analysed-Weeks4,12,24,36,48,60,Discont. were 402,387,375,368,359,351,25;respectively
    [8] - No. of subjects analysed-Weeks4,12,24,36,48,60,Discont. were 403,395,384,372,362,351,27;respectively
    [9] - No. of subjects analysed- Weeks4,12,24,36,48,60,Discont. were 136,133,131,128,126,120,8;respectively
    No statistical analyses for this end point

    Other pre-specified: Percentage of Subjects With Modified Cure Rate of Onychomycosis at Week 60

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    End point title
    		 Percentage of Subjects With Modified Cure Rate of Onychomycosis at Week 60
    End point description
    Modified cure rate at Week 60, was defined as negative culture for dermatophytes and no residual clinical involvement (nail totally clear) of the target toenail. The modified Cure rate was analysed using the logistic regression models with factor for treatment and missing values for the components were replaced by the last non-missing value. Analysis was performed on ITT population.
    End point type
    Other pre-specified
    End point timeframe
    Week 60
    End point values
    		 P-3058 10% Vehicle Amorolfine
    Number of subjects analysed
    406
    410
    137
    Units: percentage of subjects
    number (not applicable)
        Success rate
    10.34
    6.83
    3.65
        Failure rate
    89.66
    93.17
    96.35
    Statistical analysis title
    		 P-3058 10% versus Vehicle
    Comparison groups
    P-3058 10% v Vehicle
    Number of subjects included in analysis
    816
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0749 [10]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.57
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.96
         upper limit
    		 2.59
    Notes
    [10] - p-value <0.05 was considered statistically significant.
    Statistical analysis title
    		 P-3058 10% versus Amorolfine
    Comparison groups
    P-3058 10% v Amorolfine
    Number of subjects included in analysis
    543
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0213 [11]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    3.05
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.18
         upper limit
    		 7.86
    Notes
    [11] - p-value <0.05 was considered statistically significant.

    Other pre-specified: Percentage of Subjects With Modified Responder Rate of Onychomycosis at Week 60

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    End point title
    		 Percentage of Subjects With Modified Responder Rate of Onychomycosis at Week 60
    End point description
    Modified responder rate at Week 60, was defined as composite of negative culture for dermatophytes and <=10% residual involvement of the target big toenail. This rate was analysed using the logistic regression models with factor for treatment and missing values for the components were replaced by the last non-missing value. Analysis was done on ITT population.
    End point type
    Other pre-specified
    End point timeframe
    Week 60
    End point values
    		 P-3058 10% Vehicle Amorolfine
    Number of subjects analysed
    406
    410
    137
    Units: percentage of subjects
    number (not applicable)
        Success rate
    14.04
    9.76
    5.11
        Failure rate
    85.96
    90.24
    94.89
    Statistical analysis title
    		 P-3058 10% versus Vehicle
    Statistical analysis description
    The comparisons between treatment groups at Week 60 were based on odds ratio calculated from a logistic model with factor for treatment. Missing values for the components were replaced by the last non-missing value (LOCF) and the Modified responder rate is computed on the LOCF values.
    Comparison groups
    Vehicle v P-3058 10%
    Number of subjects included in analysis
    816
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.06 [12]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.51
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.98
         upper limit
    		 2.32
    Notes
    [12] - p-value <0.05 was considered statistically significant.
    Statistical analysis title
    		 P-3058 10% versus Amorolfine
    Statistical analysis description
    The comparisons between treatment groups at Week 60 were based on odds ratio calculated from a logistic model with factor for treatment. Missing values for the components were replaced by the last non-missing value (LOCF) and the Modified responder rate is computed on the LOCF values.
    Comparison groups
    P-3058 10% v Amorolfine
    Number of subjects included in analysis
    543
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0073 [13]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    3.03
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.35
         upper limit
    		 6.82
    Notes
    [13] - p-value <0.05 was considered statistically significant.

    Other pre-specified: Percentage of Subjects With Negative Culture for Dermatophyte at Weeks 4, 12, 24, 36, 48, and 60

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    End point title
    		 Percentage of Subjects With Negative Culture for Dermatophyte at Weeks 4, 12, 24, 36, 48, and 60
    End point description
    Rate of negative culture for dermatophytes of the target toenail at each visit. The number and percentage of subjects with negative or positive culture for dermatophytes were assessed using the LOCF approach . The rate of negative culture was analysed using the logistic regression models with factor for treatment. Analysis was done on ITT population.
    End point type
    Other pre-specified
    End point timeframe
    Weeks 4, 12, 24, 36, 48, 60
    End point values
    		 P-3058 10% Vehicle Amorolfine
    Number of subjects analysed
    406
    410
    137
    Units: percentage of subjects
    number (not applicable)
        Week 4
    96.80
    47.07
    97.08
        Week 12
    98.03
    48.78
    99.27
        Week 24
    97.78
    45.37
    98.54
        Week 36
    97.29
    46.10
    97.08
        Week 48
    96.06
    51.46
    95.62
        Week 60
    86.70
    51.46
    67.15
    Statistical analysis title
    		 P-3058 10% versus Vehicle
    Statistical analysis description
    The comparisons between treatment groups at Week 60 were based on odds ratio calculated from a logistic model with factor for treatment, since the model with factors for treatment, study site, and treatment-by-site interaction did not converge. Missing values were replaced by the last non-missing value (LOCF).
    Comparison groups
    P-3058 10% v Vehicle
    Number of subjects included in analysis
    816
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [14]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    6.15
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 4.35
         upper limit
    		 8.69
    Notes
    [14] - p-value <0.05 was considered statistically significant.
    Statistical analysis title
    		 P-3058 10% versus Amorolfine
    Statistical analysis description
    The comparisons between treatment groups at Week 60 were based on odds ratio calculated from a logistic model with factor for treatment, since the model with factors for treatment, study site, and treatment-by-site interaction did not converge. Missing values were replaced by the last non-missing value (LOCF).
    Comparison groups
    P-3058 10% v Amorolfine
    Number of subjects included in analysis
    543
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [15]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    3.19
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.02
         upper limit
    		 5.04
    Notes
    [15] - p-value <0.05 was considered statistically significant.

    Other pre-specified: Change From Baseline (Week 0) of Domain Scores of Onychomycosis Quality of Life Questionnaire For Toenails at Week 60

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    End point title
    		 Change From Baseline (Week 0) of Domain Scores of Onychomycosis Quality of Life Questionnaire For Toenails at Week 60
    End point description
    The Onychomycosis quality of life (ONYCHO) questionnaire consists of 17 questions, assessing social problems, emotional state, and the burden of symptoms. There are 5 possible responses to each question, which are rated as follows: 1 point - 'Not at all'; 2 points - 'Yes, but this is not bothersome'; 3 points - 'Yes, this is somewhat bothersome'; 4 points - 'Yes, this is very bothersome'; 5 points - 'Yes, this is extremely bothersome'. These raw scores to items within each problem group were added to a total and a mean was calculated. All scores were transformed into a 0-100 scale where 0 represented worst score and 100 best score, that is, 0 representing 5 points - (Yes, this is extremely bothersome) (worst), 25 representing 4 points (Yes, this is very bothersome), 50 representing 3 points (Yes, this is somewhat bothersome), 75 representing 2 points (Yes, but this is not bothersome), and 100 represent 1 point (Not at all) (best). Analysis was done on ITT population.
    End point type
    Other pre-specified
    End point timeframe
    Baseline (Week 0); Week 60
    End point values
    		 P-3058 10% Vehicle Amorolfine
    Number of subjects analysed
    406
    410
    137
    Units: score on a scale
    least squares mean (standard error)
        Social problems
    4.97 ( 1.31 )
    5.15 ( 1.30 )
    5.23 ( 2.31 )
        Emotional state
    6.27 ( 0.99 )
    6.04 ( 0.99 )
    8.96 ( 1.75 )
        Burden of symptoms
    6.79 ( 1.08 )
    6.34 ( 1.08 )
    12.68 ( 1.91 )
    Statistical analysis title
    		 Social problems: P-3058 10% versus Vehicle
    Statistical analysis description
    Statistical analysis of the ONYCHO questionnaire by domain change from baseline was reported at Week 60 and were based on ANCOVA model with baseline value as covariate, treatment group, site and treatment-by-site interaction as factors.
    Comparison groups
    P-3058 10% v Vehicle
    Number of subjects included in analysis
    816
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.9947 [16]
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [16] - p-value <0.05 was considered statistically significant.
    Statistical analysis title
    		 Social problems: P-3058 10% versus Amorolfine
    Statistical analysis description
    Statistical analysis of the ONYCHO questionnaire by domain change from baseline was reported at Week 60 and were based on ANCOVA model with baseline value as covariate, treatment group, site and treatment-by-site interaction as factors.
    Comparison groups
    P-3058 10% v Amorolfine
    Number of subjects included in analysis
    543
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.9948 [17]
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [17] - p-value <0.05 was considered statistically significant.
    Statistical analysis title
    		 Emotional state: P-3058 10% versus Vehicle
    Statistical analysis description
    Statistical analysis of the ONYCHO questionnaire by domain change from baseline was reported at Week 60 and were based on ANCOVA model with baseline value as covariate, treatment group, site and treatment-by-site interaction as factors.
    Comparison groups
    P-3058 10% v Vehicle
    Number of subjects included in analysis
    816
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.9862 [18]
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [18] - p-value <0.05 was considered statistically significant.
    Statistical analysis title
    		 Emotional state: P-3058 10% versus Amorolfine
    Statistical analysis description
    Statistical analysis of the ONYCHO questionnaire by domain change from baseline was reported at Week 60 and were based on ANCOVA model with baseline value as covariate, treatment group, site and treatment-by-site interaction as factors.
    Comparison groups
    P-3058 10% v Amorolfine
    Number of subjects included in analysis
    543
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3736 [19]
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [19] - p-value <0.05 was considered statistically significant.
    Statistical analysis title
    		 Burden of symptoms: P-3058 10% versus Vehicle
    Statistical analysis description
    Statistical analysis of the ONYCHO questionnaire by domain change from baseline was reported at Week 60 and were based on ANCOVA model with baseline value as covariate, treatment group, site and treatment-by-site interaction as factors.
    Comparison groups
    P-3058 10% v Vehicle
    Number of subjects included in analysis
    816
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.9528 [20]
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [20] - p-value <0.05 was considered statistically significant.
    Statistical analysis title
    		 Burden of symptoms: P-3058 10% versus Amorolfine
    Statistical analysis description
    Statistical analysis of the ONYCHO questionnaire by domain change from baseline was reported at Week 60 and were based on ANCOVA model with baseline value as covariate, treatment group, site and treatment-by-site interaction as factors.
    Comparison groups
    P-3058 10% v Amorolfine
    Number of subjects included in analysis
    543
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.02 [21]
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [21] - p-value <0.05 was considered statistically significant.

    Other pre-specified: Percentage of Subjects Who Represent Therapy Acceptability at Week 48 - Observed Data

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    End point title
    		 Percentage of Subjects Who Represent Therapy Acceptability at Week 48 - Observed Data
    End point description
    Therapy acceptability was reported at different level of acceptability of therapy which were classified into 1 - poor, 2 - moderate, 3 - good, 4 - very good, and 5 - not evaluated, summarized at Week 48 by treatment, considering the observed data approach. Analysis was done on ITT population. Here, 'number of subjects analysed' = subjects with the available data for the specified treatment arm.
    End point type
    Other pre-specified
    End point timeframe
    Week 48 (End of treatment)
    End point values
    		 P-3058 10% Vehicle Amorolfine
    Number of subjects analysed
    383
    389
    132
    Units: percentage of subjects
    number (not applicable)
        Score 1 - Poor
    15.14
    20.05
    16.67
        Score 2 - Moderate
    27.42
    23.65
    25.00
        Score 3 - Good
    27.94
    31.62
    28.79
        Score 4 - Very Good
    27.68
    23.14
    29.55
        Score 5 - Not Evaluated
    1.83
    1.54
    0.00
    No statistical analyses for this end point

    Other pre-specified: Percentage of Subjects Who Represent Therapy Acceptability at Week 48 - Worst Case

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    End point title
    		 Percentage of Subjects Who Represent Therapy Acceptability at Week 48 - Worst Case
    End point description
    Therapy acceptability according to a worst-case approach (i.e. missing values/not evaluated scores were replaced with the worst score) where summarized at Week 48, by treatment and were classified according to subjects acceptance of study therapy as 1 - poor, 2 - moderate, 3 - good, and 4 - very good. Analysis was done on ITT population.
    End point type
    Other pre-specified
    End point timeframe
    Week 48
    End point values
    		 P-3058 10% Vehicle Amorolfine
    Number of subjects analysed
    406
    410
    137
    Units: percentage of subjects
    number (not applicable)
        Score 1 - Poor
    21.67
    25.61
    19.71
        Score 2 - Moderate
    25.86
    22.44
    24.09
        Score 3 - Good
    26.35
    30.00
    27.74
        Score 4 - Very good
    26.11
    21.95
    28.47
    No statistical analyses for this end point

    Other pre-specified: Percent Change From Baseline (Week 0) in Involved Target Nail Area to Week 60 - Observed Data

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    End point title
    		 Percent Change From Baseline (Week 0) in Involved Target Nail Area to Week 60 - Observed Data
    End point description
    The affected area of the target big toenail (%) as measured on the digital photographs by the imaging company was classified into three categories, i.e. 0%, <=10% but greater than (>) 0%, and >10% at each post screening visit. Analysis was done on ITT population.
    End point type
    Other pre-specified
    End point timeframe
    Baseline (Week 0); Weeks 12, 24, 36, 48, 60
    End point values
    		 P-3058 10% Vehicle Amorolfine
    Number of subjects analysed
    406
    410
    137
    Units: Involved Target nail Area (%)
    arithmetic mean (standard deviation)
        Week 12 (n=368, 381, 125)
    -4.38 ( 13.81 )
    -4.72 ( 12.48 )
    -3.96 ( 12.85 )
        Week 24 (n=353, 366, 129)
    -4.91 ( 15.52 )
    -4.32 ( 14.37 )
    -5.79 ( 14.51 )
        Week 36 (n=353, 356, 126)
    -5.97 ( 17.43 )
    -4.83 ( 15.38 )
    -6.50 ( 14.94 )
        Week 48 (n=350, 350, 123)
    -5.95 ( 18.34 )
    -5.67 ( 15.57 )
    -5.86 ( 15.89 )
        Week 60 (n=326, 339, 114)
    -5.31 ( 18.61 )
    -5.20 ( 17.58 )
    -4.91 ( 17.85 )
        Discontinued visit (n=20, 15, 7)
    -0.24 ( 16.89 )
    3.83 ( 18.88 )
    -13.74 ( 16.21 )
    No statistical analyses for this end point

    Other pre-specified: Percentage of Subjects With No Residual Clinical Involvement (Nail Totally Clear) of the Target Toenail at Weeks 12, 24, 36, 48, and 60

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    End point title
    		 Percentage of Subjects With No Residual Clinical Involvement (Nail Totally Clear) of the Target Toenail at Weeks 12, 24, 36, 48, and 60
    End point description
    Rates of no residual clinical involvement (nail totally clear) of the target toenail assessment ensured that the diseased target nail area equal to (=) 0%. This rate was analysed using the logistic regression models with factor for treatment and LOCF approach, by visit. Analysis was done on ITT population.
    End point type
    Other pre-specified
    End point timeframe
    Weeks 12, 24, 36, 48, 60
    End point values
    		 P-3058 10% Vehicle Amorolfine
    Number of subjects analysed
    406 [22]
    410 [23]
    137 [24]
    Units: percentage of subjects
    number (not applicable)
        Week 12 - No
    97.54
    98.29
    100.00
        Week 12 - Yes
    2.46
    1.71
    0.00
        Week 24 - No
    95.57
    96.83
    97.81
        Week 24 - Yes
    4.43
    3.17
    2.19
        Week 36 - No
    91.63
    95.37
    97.81
        Week 36 - Yes
    8.37
    4.63
    2.19
        Week 48 - No
    90.15
    91.95
    94.89
        Week 48 - Yes
    9.85
    8.05
    5.11
        Week 60 - No
    89.66
    91.46
    95.62
        Week 60 - Yes
    10.34
    8.54
    4.38
    Notes
    [22] - Subjects evaluable at Weeks 12, 24, 36, 48, and 60 were 396, 388, 372, 366, and 364; respectively.
    [23] - Subjects evaluable at Weeks 12, 24, 36, 48, and 60 were 403, 397, 391, 377, and 375; respectively.
    [24] - Subjects evaluable at Weeks 12, 24, 36, 48, and 60 were 137, 134, 134, 130, and 131; respectively.
    Statistical analysis title
    		 P-3058 10% versus Vehicle
    Statistical analysis description
    The comparisons between treatment groups at Week 60 were based on odds ratio calculated from a logistic model with factor for treatment, since the model with factors for treatment, study site, and treatment-by-site interaction did not converge. Missing values were replaced by the LOCF.
    Comparison groups
    P-3058 10% v Vehicle
    Number of subjects included in analysis
    816
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3777 [25]
    Method
    		 Wald Chi-square
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.24
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.77
         upper limit
    		 1.98
    Notes
    [25] - p-value <0.05 was considered statistically significant.
    Statistical analysis title
    		 P-3058 10% versus Amorolfine
    Statistical analysis description
    The comparisons between treatment groups at Week 60 were based on odds ratio calculated from a logistic model with factor for treatment, since the model with factors for treatment, study site, and treatment-by-site interaction did not converge. Missing values were replaced by the last non-missing value (LOCF).
    Comparison groups
    P-3058 10% v Amorolfine
    Number of subjects included in analysis
    543
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [26]
    P-value
    		 = 0.0393
    Method
    		 Wald Chi-square
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    2.52
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.05
         upper limit
    		 6.06
    Notes
    [26] - p-value <0.05 was considered statistically significant.

    Other pre-specified: Dermatological Assessment - Percentage of Subjects With Number of Toenails (5,8,9,&10) and Fingernails (6,7,9,&10) Present at Weeks 4, 12, 36, 48, and 60 - Observed Data

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    End point title
    		 Dermatological Assessment - Percentage of Subjects With Number of Toenails (5,8,9,&10) and Fingernails (6,7,9,&10) Present at Weeks 4, 12, 36, 48, and 60 - Observed Data
    End point description
    Dermatological assessments was defined to be assessed through percentage of subjects with right or left target big toenail, percentage of affected area of the target big toenail (according to the Investigator’s clinical evaluation), number of toenails/fingernails present per subject (as categorical term), number of toenails/fingernails with suspected onychomycosis per subject (as categorical term) and location of toenails with suspected onychomycosis are summarized by treatment. The data for this end point reported number of toenails present per subject. Analysis was done on ITT population.
    End point type
    Other pre-specified
    End point timeframe
    Weeks 4, 12, 36, 48, 60; Discontinuation visit
    End point values
    		 P-3058 10% Vehicle Amorolfine
    Number of subjects analysed
    406
    410
    137
    Units: percentage of subjects
    number (not applicable)
        Week 4, Number of toenails=5
    0.00
    0.25
    0.00
        Week 4, Number of toenails=8
    0.00
    0.25
    0.00
        Week 4, Number of toenails=9
    0.00
    0.25
    0.00
        Week 4, Number of toenails=10
    100.00
    99.26
    100.00
        Week 12, Number of toenails=5
    0.00
    0.25
    0.00
        Week 12, Number of toenails=8
    0.00
    0.25
    0.00
        Week 12, Number of toenails=9
    0.00
    0.51
    0.00
        Week 12, Number of toenails=10
    100.00
    98.99
    100.00
        Week 24, Number of toenails=5
    0.00
    0.26
    0.00
        Week 24, Number of toenails=8
    0.00
    0.26
    0.00
        Week 24, Number of toenails=9
    0.00
    0.26
    0.00
        Week 24, Number of toenails=10
    100.00
    99.22
    100.00
        Week 36, Number of toenails=5
    0.00
    0.27
    0.00
        Week 36, Number of toenails=8
    0.00
    0.27
    0.00
        Week 36, Number of toenails=9
    0.00
    0.27
    0.00
        Week 36, Number of toenails=10
    100.00
    99.20
    100.00
        Week 48, Number of toenails=5
    0.00
    0.28
    0.00
        Week 48, Number of toenails=8
    0.00
    0.28
    0.00
        Week 48, Number of toenails=9
    0.00
    0.28
    0.00
        Week 48, Number of toenails=10
    100.00
    99.17
    100.00
        Week 60, Number of toenails=5
    0.00
    0.28
    0.00
        Week 60, Number of toenails=8
    0.00
    0.28
    0.00
        Week 60, Number of toenails=9
    0.00
    0.28
    0.00
        Week 60, Number of toenails=10
    100.00
    99.15
    100.00
        Discontinuation Visit, Number of toenails=9
    0.00
    5.26
    0.00
        Discontinuation Visit, Number of toenails=10
    100.00
    94.74
    100.00
        Week 4, Number of fingernails=6
    0.00
    0.00
    0.74
        Week 4, Number of fingernails=7
    0.00
    0.00
    0.74
        Week 4, Number of fingernails=9
    0.50
    0.49
    0.00
        Week 4, Number of fingernails=10
    99.50
    99.51
    98.53
        Week 12, Number of fingernails=6
    0.00
    0.00
    0.76
        Week 12, Number of fingernails=7
    0.00
    0.00
    0.76
        Week 12, Number of fingernails=9
    0.52
    0.51
    0.00
        Week 12, Number of fingernails=10
    99.48
    99.49
    98.48
        Week 24, Number of fingernails=6
    0.00
    0.00
    0.76
        Week 24, Number of fingernails=7
    0.00
    0.00
    0.76
        Week 24, Number of fingernails=9
    0.54
    0.52
    0.00
        Week 24, Number of fingernails=10
    99.46
    99.48
    98.47
        Week 36, Number of fingernails=6
    0.00
    0.00
    0.78
        Week 36, Number of fingernails=7
    0.00
    0.00
    0.78
        Week 36, Number of fingernails=9
    0.55
    0.54
    0.00
        Week 36, Number of fingernails=10
    99.45
    99.46
    98.44
        Week 48, Number of fingernails=6
    0.00
    0.00
    0.80
        Week 48, Number of fingernails=7
    0.00
    0.00
    0.80
        Week 48, Number of fingernails=9
    0.56
    0.55
    0.00
        Week 48, Number of fingernails=10
    99.44
    99.45
    98.40
        Week 60, Number of fingernails=6
    0.00
    0.00
    0.83
        Week 60, Number of fingernails=7
    0.00
    0.00
    0.83
        Week 60, Number of fingernails=9
    0.57
    0.57
    0.00
        Week 60, Number of fingernails=10
    99.43
    99.43
    98.33
        Discontinuation Visit, Number of fingernails=10
    100.00
    100.00
    100.00
    No statistical analyses for this end point

    Other pre-specified: Dermatological Assessment - Percentage of Subjects With Number of Nails With Suspected Onychomycosis (0 to 10) Present at Weeks 4, 12, 36, 48, 60, and Discontinuation Visit - Observed Data

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    End point title
    		 Dermatological Assessment - Percentage of Subjects With Number of Nails With Suspected Onychomycosis (0 to 10) Present at Weeks 4, 12, 36, 48, 60, and Discontinuation Visit - Observed Data
    End point description
    Dermatological assessments was defined to be assessed through percentage of subjects with right or left target big toenail, percentage of affected area of the target big toenail (according to the Investigator’s clinical evaluation), number of toenails/fingernails present per subject (as categorical term), number of toenails/fingernails with suspected onychomycosis per subject (as categorical term) and location of toenails/fingernails with suspected onychomycosis are summarized by treatment. The data for this end point reported total number of toenails with suspected onychomycosis. Here, 'Discont.Visit' represents Discontinuation Visit. Analysis was done on ITT population.
    End point type
    Other pre-specified
    End point timeframe
    Weeks 4, 12, 36, 48, 60; Discontinuation visit
    End point values
    		 P-3058 10% Vehicle Amorolfine
    Number of subjects analysed
    406
    410
    137
    Units: percentage of subjects
    number (not applicable)
        Week 4, Total number of suspected toenails=1
    9.00
    8.64
    5.88
        Week 4, Total number of suspected toenails=2
    22.00
    22.22
    21.32
        Week 4, Total number of suspected toenails=3
    12.00
    8.89
    8.09
        Week 4, Total number of suspected toenails=4
    7.25
    14.32
    17.65
        Week 4, Total number of suspected toenails=5
    10.50
    9.88
    7.35
        Week 4, Total number of suspected toenails=6
    9.50
    9.63
    13.97
        Week 4, Total number of suspected toenails=7
    7.00
    6.42
    5.88
        Week 4, Total number of suspected toenails=8
    7.75
    6.91
    7.35
        Week 4, Total number of suspected toenails=9
    4.25
    2.47
    2.94
        Week 4, Total number of suspected toenails=10
    10.75
    10.62
    9.56
        Week 12, Total number of suspected toenails=0
    1.04
    0.76
    0.76
        Week 12, Total number of suspected toenails=1
    8.83
    8.84
    4.55
        Week 12, Total number of suspected toenails=2
    21.82
    22.47
    21.21
        Week 12, Total number of suspected toenails=3
    11.69
    8.08
    9.85
        Week 12, Total number of suspected toenails=4
    8.31
    14.39
    18.18
        Week 12, Total number of suspected toenails=5
    8.83
    9.85
    6.82
        Week 12, Total number of suspected toenails=6
    9.87
    9.34
    12.12
        Week 12, Total number of suspected toenails=7
    6.75
    6.31
    6.06
        Week 12, Total number of suspected toenails=8
    7.01
    7.58
    7.58
        Week 12, Total number of suspected toenails=9
    5.19
    2.27
    3.79
        Week 12, Total number of suspected toenails=10
    10.65
    10.10
    9.09
        Week 24, Total number of suspected toenails=0
    1.88
    1.55
    1.53
        Week 24, Total number of suspected toenails=1
    11.29
    9.84
    5.34
        Week 24, Total number of suspected toenails=2
    19.35
    20.98
    20.61
        Week 24, Total number of suspected toenails=3
    11.29
    10.88
    10.69
        Week 24, Total number of suspected toenails=4
    8.60
    14.77
    16.79
        Week 24, Total number of suspected toenails=5
    8.87
    9.07
    5.34
        Week 24, Total number of suspected toenails=6
    9.68
    8.03
    15.27
        Week 24, Total number of suspected toenails=7
    6.72
    5.70
    5.34
        Week 24, Total number of suspected toenails=8
    7.53
    8.03
    9.16
        Week 24, Total number of suspected toenails=9
    2.69
    2.07
    2.29
        Week 24, Total number of suspected toenails=10
    12.10
    9.07
    7.63
        Week 36, Total number of suspected toenails=0
    4.10
    2.95
    2.34
        Week 36, Total number of suspected toenails=1
    10.66
    10.72
    6.25
        Week 36, Total number of suspected toenails=2
    18.31
    21.18
    18.75
        Week 36, Total number of suspected toenails=3
    11.75
    10.19
    10.16
        Week 36, Total number of suspected toenails=4
    9.56
    12.87
    19.53
        Week 36, Total number of suspected toenails=5
    9.02
    9.92
    7.81
        Week 36, Total number of suspected toenails=6
    8.74
    7.51
    10.16
        Week 36, Total number of suspected toenails=7
    5.46
    5.63
    3.91
        Week 36, Total number of suspected toenails=8
    7.38
    7.51
    10.16
        Week 36, Total number of suspected toenails=9
    3.28
    2.68
    2.34
        Week 36, Total number of suspected toenails=10
    11.75
    8.85
    8.59
        Week 48, Total number of suspected toenails=0
    5.88
    4.68
    2.40
        Week 48, Total number of suspected toenails=1
    10.36
    11.57
    8.00
        Week 48, Total number of suspected toenails=2
    21.57
    19.28
    24.00
        Week 48, Total number of suspected toenails=3
    9.80
    10.74
    10.40
        Week 48, Total number of suspected toenails=4
    10.08
    13.22
    17.60
        Week 48, Total number of suspected toenails=5
    8.40
    9.64
    4.00
        Week 48, Total number of suspected toenails=6
    9.24
    7.71
    8.80
        Week 48, Total number of suspected toenails=7
    6.44
    5.51
    6.40
        Week 48, Total number of suspected toenails=8
    5.04
    7.16
    8.80
        Week 48, Total number of suspected toenails=9
    2.52
    1.93
    2.40
        Week 48, Total number of suspected toenails=10
    10.64
    8.54
    7.20
        Week 60, Total number of suspected toenails=0
    8.31
    5.70
    2.50
        Week 60, Total number of suspected toenails=1
    12.32
    12.54
    9.17
        Week 60, Total number of suspected toenails=2
    20.06
    19.37
    25.83
        Week 60, Total number of suspected toenails=3
    9.46
    9.69
    5.00
        Week 60, Total number of suspected toenails=4
    11.46
    13.96
    20.83
        Week 60, Total number of suspected toenails=5
    6.88
    7.41
    9.17
        Week 60, Total number of suspected toenails=6
    8.88
    9.12
    7.50
        Week 60, Total number of suspected toenails=7
    4.87
    7.98
    2.50
        Week 60, Total number of suspected toenails=8
    5.16
    4.84
    8.33
        Week 60, Total number of suspected toenails=9
    2.58
    1.42
    1.67
        Week 60, Total number of suspected toenails=10
    10.03
    7.98
    7.50
        Discont.Visit,Total number of suspected toenails=0
    0.00
    0.00
    14.29
        Discont.Visit,Total number of suspected toenails=1
    9.09
    5.26
    0.00
        Discont.Visit,Total number of suspected toenails=2
    22.73
    10.53
    14.29
        Discont.Visit,Total number of suspected toenails=3
    18.18
    21.05
    14.29
        Discont.Visit,Total number of suspected toenails=4
    4.55
    10.53
    14.29
        Discont.Visit,Total number of suspected toenails=5
    4.55
    21.05
    0.00
        Discont.Visit,Total number of suspected toenails=7
    9.09
    5.26
    28.57
        Discont.Visit,Total number of suspected toenails=8
    18.18
    5.26
    14.29
        Discont.Visit,Total number of suspected toenails=9
    4.55
    10.53
    0.00
        Discont.Visit,Total number of suspected toenail=10
    9.09
    10.53
    0.00
        Week 4, Total number of suspected fingernails=0
    94.00
    91.60
    93.38
        Week 4, Total number of suspected fingernails=1
    3.75
    5.19
    2.94
        Week 4, Total number of suspected fingernails=2
    2.00
    2.72
    2.94
        Week 4, Total number of suspected fingernails=3
    0.00
    0.00
    0.74
        Week 4, Total number of suspected fingernails=4
    0.00
    0.25
    0.00
        Week 4, Total number of suspected fingernails=5
    0.25
    0.25
    0.00
        Week 12, Total number of suspected fingernails=0
    94.03
    92.17
    93.18
        Week 12, Total number of suspected fingernails=1
    3.64
    5.05
    3.79
        Week 12, Total number of suspected fingernails=2
    2.08
    2.53
    2.27
        Week 12, Total number of suspected fingernails=3
    0.00
    0.00
    0.76
        Week 12, Total number of suspected fingernails=5
    0.26
    0.25
    0.00
        Week 24, Total number of suspected fingernails=0
    94.35
    92.75
    93.13
        Week 24, Total number of suspected fingernails=1
    3.49
    4.15
    3.82
        Week 24, Total number of suspected fingernails=2
    1.88
    2.59
    2.29
        Week 24, Total number of suspected fingernails=3
    0.00
    0.26
    0.76
        Week 24, Total number of suspected fingernails=5
    0.27
    0.26
    0.00
        Week 36, Total number of suspected fingernails=0
    96.17
    93.57
    94.53
        Week 36, Total number of suspected fingernails=1
    2.46
    3.49
    3.13
        Week 36, Total number of suspected fingernails=2
    1.09
    2.41
    1.56
        Week 36, Total number of suspected fingernails=3
    0.00
    0.27
    0.78
        Week 36, Total number of suspected fingernails=5
    0.27
    0.27
    0.00
        Week 48, Total number of suspected fingernails=0
    97.20
    93.94
    95.20
        Week 48, Total number of suspected fingernails=1
    1.96
    3.86
    4.00
        Week 48, Total number of suspected fingernails=2
    0.56
    1.65
    0.80
        Week 48, Total number of suspected fingernails=3
    0.00
    0.28
    0.00
        Week 48, Total number of suspected fingernails=5
    0.28
    0.28
    0.00
        Week 60, Total number of suspected fingernails=0
    98.85
    96.58
    98.33
        Week 60, Total number of suspected fingernails=1
    0.57
    2.28
    1.67
        Week 60, Total number of suspected fingernails=2
    0.29
    1.14
    0.00
        Week 60, Total number of suspected fingernails=5
    0.29
    0.00
    0.00
        Discont.Visit,Total number suspected fingernails=0
    95.45
    100.00
    100.00
        Discont.Visit,Total number suspected fingernails=3
    4.55
    0.00
    0.00
    No statistical analyses for this end point

    Other pre-specified: Dermatological Assessment - Percentage of Subjects With Location of Toenails (Right and Left Foot) and Fingernails (Right and Left Hand) With Suspected Onychomycosis, Present at Weeks 4, 12, 36, 48, 60, and Discontinuation Visit - Observed Data

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    End point title
    		 Dermatological Assessment - Percentage of Subjects With Location of Toenails (Right and Left Foot) and Fingernails (Right and Left Hand) With Suspected Onychomycosis, Present at Weeks 4, 12, 36, 48, 60, and Discontinuation Visit - Observed Data
    End point description
    Dermatological assessments was defined to be assessed through percentage of subjects with right or left target big toenail, percentage of affected area of the target big toenail (according to the Investigator’s clinical evaluation), number of toenails/fingernails present per subject (as categorical term), number of toenails/fingernails with suspected onychomycosis per subject (as categorical term) and location of toenails/fingernails with suspected onychomycosis are summarized by treatment. The data for this end point reported location of toenails in right and left foot and fingernails in right and left hand, with suspected onychomycosis. Analysis was done on ITT population.
    End point type
    Other pre-specified
    End point timeframe
    Weeks 4, 12, 36, 48, 60; Discontinuation Visit
    End point values
    		 P-3058 10% Vehicle Amorolfine
    Number of subjects analysed
    406
    410
    137
    Units: percentage of subjects
    number (not applicable)
        Week 4, Right foot- 1st toenail
    88.50
    90.62
    87.50
        Week 4, Right foot- 2nd toenail
    35.50
    33.58
    39.71
        Week 4, Right foot- 3rd toenail
    30.00
    32.35
    32.35
        Week 4, Right foot- 4th toenail
    35.00
    35.31
    37.50
        Week 4, Right foot- 5th toenail
    50.25
    48.64
    52.94
        Week 4, Left foot- 1st toenail
    90.00
    88.64
    88.24
        Week 4, Left foot- 2nd toenail
    35.50
    33.58
    33.82
        Week 4, Left foot- 3rd toenail
    35.00
    30.37
    32.35
        Week 4, Left foot- 4th toenail
    35.00
    32.35
    30.88
        Week 4, Left foot- 5th toenail
    49.50
    47.41
    50.74
        Week 12, Right foot- 1st toenail
    87.53
    89.17
    88.72
        Week 12, Right foot- 2nd toenail
    36.36
    33.50
    37.59
        Week 12, Right foot- 3rd toenail
    29.61
    32.24
    32.33
        Week 12, Right foot- 4th toenail
    34.29
    35.26
    37.59
        Week 12, Right foot- 5th toenail
    50.65
    48.61
    49.62
        Week 12, Left foot- 1st toenail
    87.79
    87.91
    87.22
        Week 12, Left foot- 2nd toenail
    35.84
    30.73
    31.58
        Week 12, Left foot- 3rd toenail
    33.51
    30.48
    32.33
        Week 12, Left foot- 4th toenail
    35.58
    31.99
    33.08
        Week 12, Left foot- 5th toenail
    49.61
    46.10
    50.38
        Week 24, Right foot- 1st toenail
    85.25
    88.08
    89.31
        Week 24, Right foot- 2nd toenail
    35.39
    31.09
    32.82
        Week 24, Right foot- 3rd toenail
    29.49
    30.57
    32.82
        Week 24, Right foot- 4th toenail
    35.39
    32.64
    41.22
        Week 24, Right foot- 5th toenail
    49.06
    47.67
    49.62
        Week 24, Left foot- 1st toenail
    86.86
    87.31
    86.26
        Week 24, Left foot- 2nd toenail
    34.58
    29.02
    28.24
        Week 24, Left foot- 3rd toenail
    32.98
    27.98
    31.30
        Week 24, Left foot- 4th toenail
    35.12
    31.61
    31.30
        Week 24, Left foot- 5th toenail
    47.72
    44.56
    48.85
        Week 36, Right foot- 1st toenail
    83.88
    85.29
    89.06
        Week 36, Right foot- 2nd toenail
    34.43
    31.28
    33.59
        Week 36, Right foot- 3rd toenail
    28.69
    29.95
    30.47
        Week 36, Right foot- 4th toenail
    34.70
    32.35
    39.84
        Week 36, Right foot- 5th toenail
    47.27
    45.72
    50.00
        Week 36, Left foot- 1st toenail
    85.25
    86.36
    84.38
        Week 36, Left foot- 2nd toenail
    33.88
    29.14
    27.34
        Week 36, Left foot- 3rd toenail
    30.87
    25.94
    32.81
        Week 36, Left foot- 4th toenail
    36.61
    29.68
    33.59
        Week 36, Left foot- 5th toenail
    46.99
    44.92
    46.88
        Week 48, Right foot- 1st toenail
    82.63
    84.07
    86.51
        Week 48, Right foot- 2nd toenail
    31.65
    31.32
    32.54
        Week 48, Right foot- 3rd toenail
    27.17
    27.20
    26.19
        Week 48, Right foot- 4th toenail
    30.81
    29.95
    35.71
        Week 48, Right foot- 5th toenail
    45.38
    45.05
    43.65
        Week 48, Left foot- 1st toenail
    82.91
    83.24
    83.33
        Week 48, Left foot- 2nd toenail
    30.53
    29.12
    25.40
        Week 48, Left foot- 3rd toenail
    27.17
    23.90
    27.78
        Week 48, Left foot- 4th toenail
    32.77
    28.30
    31.75
        Week 48, Left foot- 5th toenail
    44.26
    45.05
    42.86
        Week 60, Right foot- 1st toenail
    78.51
    82.72
    85.83
        Week 60, Right foot- 2nd toenail
    30.09
    29.18
    30.83
        Week 60, Right foot- 3rd toenail
    26.36
    24.08
    25.00
        Week 60, Right foot- 4th toenail
    29.80
    29.75
    36.67
        Week 60, Right foot- 5th toenail
    41.83
    45.04
    46.67
        Week 60, Left foot- 1st toenail
    78.80
    81.30
    81.67
        Week 60, Left foot- 2nd toenail
    28.37
    27.48
    23.33
        Week 60, Left foot- 3rd toenail
    26.65
    22.38
    23.33
        Week 60, Left foot- 4th toenail
    30.09
    26.63
    30.00
        Week 60, Left foot- 5th toenail
    42.69
    44.19
    40.83
        Discontinuation Visit, Right foot- 1st toenail
    74.07
    57.14
    50.00
        Discontinuation Visit, Right foot- 2nd toenail
    25.93
    25.00
    12.50
        Discontinuation Visit, Right foot- 3rd toenail
    22.22
    28.57
    37.50
        Discontinuation Visit, Right foot- 4th toenail
    33.33
    32.14
    37.50
        Discontinuation Visit, Right foot- 5th toenail
    44.44
    39.29
    50.00
        Discontinuation Visit, Left foot- 1st toenail
    77.78
    57.14
    75.00
        Discontinuation Visit, Left foot- 2nd toenail
    22.22
    21.43
    25.00
        Discontinuation Visit, Left foot- 3rd toenail
    22.22
    32.14
    37.50
        Discontinuation Visit, Left foot- 4th toenail
    33.33
    25.00
    25.00
        Discontinuation Visit, Left foot- 5th toenail
    44.44
    32.14
    37.50
        Week 4, Right hand- 1st fingernail
    1.75
    4.94
    2.94
        Week 4, Right hand- 2nd fingernail
    1.50
    1.48
    0.74
        Week 4, Right hand- 3rd fingernail
    0.50
    1.23
    1.47
        Week 4, Right hand- 4th fingernail
    0.00
    0.49
    1.47
        Week 4, Right hand- 5th fingernail
    0.00
    0.74
    0.00
        Week 4, Left hand- 1st fingernail
    2.25
    1.48
    3.68
        Week 4, Left hand- 2nd fingernail
    0.75
    0.99
    0.00
        Week 4, Left hand- 3rd fingernail
    0.50
    0.99
    0.74
        Week 4, Left hand- 4th fingernail
    1.25
    0.25
    0.00
        Week 4, Left hand- 5th fingernail
    0.50
    0.25
    0.00
        Week 12, Right hand- 1st fingernail
    1.82
    4.53
    3.76
        Week 12, Right hand- 2nd fingernail
    1.30
    1.51
    0.75
        Week 12, Right hand- 3rd fingernail
    0.52
    1.01
    0.75
        Week 12, Right hand- 4th fingernail
    0.00
    0.50
    0.00
        Week 12, Right hand- 5th fingernail
    0.00
    0.50
    0.00
        Week 12, Left hand- 1st fingernail
    2.08
    1.51
    3.76
        Week 12, Left hand- 2nd fingernail
    0.78
    1.01
    0.00
        Week 12, Left hand- 3rd fingernail
    0.52
    0.76
    0.75
        Week 12, Left hand- 4th fingernail
    1.30
    0.00
    0.75
        Week 12, Left hand- 5th fingernail
    0.78
    0.00
    0.00
        Week 24, Right hand- 1st fingernail
    1.61
    4.40
    3.82
        Week 24, Right hand- 2nd fingernail
    1.34
    1.30
    0.76
        Week 24, Right hand- 3rd fingernail
    0.54
    1.04
    0.76
        Week 24, Right hand- 4th fingernail
    0.00
    0.52
    0.76
        Week 24, Right hand- 5th fingernail
    0.00
    0.78
    0.00
        Week 24, Left hand- 1st fingernail
    2.14
    1.55
    3.82
        Week 24, Left hand- 2nd fingernail
    0.80
    1.30
    0.00
        Week 24, Left hand- 3rd fingernail
    0.54
    0.52
    0.76
        Week 24, Left hand- 4th fingernail
    1.07
    0.00
    0.00
        Week 24, Left hand- 5th fingernail
    0.54
    0.00
    0.00
        Week 36, Right hand- 1st fingernail
    0.82
    4.01
    2.34
        Week 36, Right hand- 2nd fingernail
    1.09
    1.07
    0.78
        Week 36, Right hand- 3rd fingernail
    0.55
    0.80
    0.78
        Week 36, Right hand- 4th fingernail
    0.00
    0.53
    0.78
        Week 36, Right hand- 5th fingernail
    0.00
    0.80
    0.00
        Week 36, Left hand- 1st fingernail
    1.09
    1.87
    3.13
        Week 36, Left hand- 2nd fingernail
    0.55
    0.80
    0.00
        Week 36, Left hand- 3rd fingernail
    0.27
    0.53
    0.78
        Week 36, Left hand- 4th fingernail
    1.09
    0.00
    0.00
        Week 36, Left hand- 5th fingernail
    0.55
    0.00
    0.00
        Week 48, Right hand- 1st fingernail
    0.00
    3.57
    1.59
        Week 48, Right hand- 2nd fingernail
    1.12
    1.65
    0.79
        Week 48, Right hand- 3rd fingernail
    0.28
    0.82
    0.79
        Week 48, Right hand- 4th fingernail
    0.00
    0.55
    0.00
        Week 48, Right hand- 5th fingernail
    0.00
    0.82
    0.00
        Week 48, Left hand- 1st fingernail
    1.12
    1.37
    2.38
        Week 48, Left hand- 2nd fingernail
    0.28
    0.27
    0.00
        Week 48, Left hand- 3rd fingernail
    0.28
    0.27
    0.00
        Week 48, Left hand- 4th fingernail
    0.84
    0.00
    0.00
        Week 48, Left hand- 5th fingernail
    0.56
    0.00
    0.00
        Week 60, Right hand- 1st fingernail
    0.00
    2.55
    0.83
        Week 60, Right hand- 2nd fingernail
    0.29
    0.57
    0.00
        Week 60, Right hand- 5th fingernail
    0.00
    0.28
    0.00
        Week 60, Left hand- 1st fingernail
    0.29
    0.28
    0.83
        Week 60, Left hand- 2nd fingernail
    0.29
    0.57
    0.00
        Week 60, Left hand- 3rd fingernail
    0.29
    0.28
    0.00
        Week 60, Left hand- 4th fingernail
    0.86
    0.00
    0.00
        Week 60, Left hand- 5th fingernail
    0.57
    0.00
    0.00
        Discontinuation Visit, Right hand- 1st fingernail
    3.70
    0.00
    0.00
        Discontinuation Visit, Left hand- 1st fingernail
    3.70
    0.00
    0.00
        Discontinuation Visit, Left hand- 2nd fingernail
    3.70
    0.00
    0.00
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From Baseline (Week 0) up to Week 60/Discontinuation visit
    Adverse event reporting additional description
    All AEs (TEAEs, non-TEAEs, and serious AEs) which occurred during the study period were recorded. TEAE was defined as those AE with an onset date after at least treatment initiation and non-TEAE was defined as AE with onset date between signed informed consent form and treatment initiation, during study. Analysis was performed on Safety population.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.0
    Reporting groups
    Reporting group title
    P-3058 10%
    Reporting group description
    		 Subjects applied P-3058 10% nail solution topically, once daily for first 4 weeks and then once weekly for the remaining 44 weeks on all dry nails with suspected onychomycosis.

    Reporting group title
    Vehicle
    Reporting group description
    		 Subjects applied Vehicle of the P-3058 10% nail solution topically, once daily for the first 4 weeks and then once weekly for the remaining 44 weeks on all dry nails with suspected onychomycosis.

    Reporting group title
    Amorolfine
    Reporting group description
    		 Subjects applied Amorolfine topically, once weekly for 48 weeks on all dry nails with suspected onychomycosis.

    Serious adverse events
    		 P-3058 10% Vehicle Amorolfine
    Total subjects affected by serious adverse events
         subjects affected / exposed
    21 / 406 (5.17%)
    22 / 407 (5.41%)
    9 / 137 (6.57%)
         number of deaths (all causes)
    2
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal cell carcinoma
         subjects affected / exposed
    0 / 406 (0.00%)
    1 / 407 (0.25%)
    0 / 137 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Breast cancer
         subjects affected / exposed
    1 / 406 (0.25%)
    0 / 407 (0.00%)
    0 / 137 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastric cancer
         subjects affected / exposed
    0 / 406 (0.00%)
    0 / 407 (0.00%)
    1 / 137 (0.73%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Malignant melanoma
         subjects affected / exposed
    1 / 406 (0.25%)
    0 / 407 (0.00%)
    0 / 137 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancreatic carcinoma
         subjects affected / exposed
    1 / 406 (0.25%)
    0 / 407 (0.00%)
    0 / 137 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Prostate cancer
         subjects affected / exposed
    1 / 406 (0.25%)
    0 / 407 (0.00%)
    0 / 137 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Prostate cancer recurrent
         subjects affected / exposed
    0 / 406 (0.00%)
    0 / 407 (0.00%)
    1 / 137 (0.73%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Surgical and medical procedures
    Catheter management
         subjects affected / exposed
    0 / 406 (0.00%)
    0 / 407 (0.00%)
    1 / 137 (0.73%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hysterectomy
         subjects affected / exposed
    1 / 406 (0.25%)
    0 / 407 (0.00%)
    0 / 137 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Knee arthroplasty
         subjects affected / exposed
    1 / 406 (0.25%)
    0 / 407 (0.00%)
    0 / 137 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nasal septal operation
         subjects affected / exposed
    0 / 406 (0.00%)
    1 / 407 (0.25%)
    0 / 137 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oophorectomy
         subjects affected / exposed
    1 / 406 (0.25%)
    0 / 407 (0.00%)
    0 / 137 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pelvic floor repair
         subjects affected / exposed
    1 / 406 (0.25%)
    0 / 407 (0.00%)
    0 / 137 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tonsillectomy
         subjects affected / exposed
    0 / 406 (0.00%)
    1 / 407 (0.25%)
    0 / 137 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vitrectomy
         subjects affected / exposed
    1 / 406 (0.25%)
    0 / 407 (0.00%)
    0 / 137 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Ovarian disorder
         subjects affected / exposed
    1 / 406 (0.25%)
    0 / 407 (0.00%)
    0 / 137 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Sleep apnoea syndrome
         subjects affected / exposed
    1 / 406 (0.25%)
    0 / 407 (0.00%)
    0 / 137 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Prostatic specific antigen increased
         subjects affected / exposed
    0 / 406 (0.00%)
    1 / 407 (0.25%)
    0 / 137 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Ankle fracture
         subjects affected / exposed
    0 / 406 (0.00%)
    1 / 407 (0.25%)
    0 / 137 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cervical vertebral fracture
         subjects affected / exposed
    1 / 406 (0.25%)
    0 / 407 (0.00%)
    0 / 137 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Humerus fracture
         subjects affected / exposed
    0 / 406 (0.00%)
    1 / 407 (0.25%)
    0 / 137 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intestinal anastomosis complication
         subjects affected / exposed
    0 / 406 (0.00%)
    1 / 407 (0.25%)
    0 / 137 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Joint dislocation
         subjects affected / exposed
    1 / 406 (0.25%)
    0 / 407 (0.00%)
    0 / 137 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Joint injury
         subjects affected / exposed
    1 / 406 (0.25%)
    0 / 407 (0.00%)
    0 / 137 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ligament rupture
         subjects affected / exposed
    1 / 406 (0.25%)
    0 / 407 (0.00%)
    0 / 137 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lumbar vertebral fracture
         subjects affected / exposed
    0 / 406 (0.00%)
    1 / 407 (0.25%)
    0 / 137 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tendon rupture
         subjects affected / exposed
    1 / 406 (0.25%)
    1 / 407 (0.25%)
    0 / 137 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thermal burn
         subjects affected / exposed
    0 / 406 (0.00%)
    1 / 407 (0.25%)
    0 / 137 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Wound
         subjects affected / exposed
    0 / 406 (0.00%)
    0 / 407 (0.00%)
    1 / 137 (0.73%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Arrhythmia
         subjects affected / exposed
    0 / 406 (0.00%)
    1 / 407 (0.25%)
    0 / 137 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    0 / 406 (0.00%)
    1 / 407 (0.25%)
    2 / 137 (1.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    0 / 406 (0.00%)
    2 / 407 (0.49%)
    0 / 137 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebrovascular accident
         subjects affected / exposed
    2 / 406 (0.49%)
    0 / 407 (0.00%)
    0 / 137 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Encephalopathy
         subjects affected / exposed
    1 / 406 (0.25%)
    0 / 407 (0.00%)
    0 / 137 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neuropathy peripheral
         subjects affected / exposed
    1 / 406 (0.25%)
    0 / 407 (0.00%)
    0 / 137 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Polyneuropathy chronic
         subjects affected / exposed
    0 / 406 (0.00%)
    1 / 407 (0.25%)
    0 / 137 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    1 / 406 (0.25%)
    1 / 407 (0.25%)
    1 / 137 (0.73%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Colitis
         subjects affected / exposed
    2 / 406 (0.49%)
    0 / 407 (0.00%)
    0 / 137 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Food poisoning
         subjects affected / exposed
    0 / 406 (0.00%)
    0 / 407 (0.00%)
    1 / 137 (0.73%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastric ulcer haemorrhage
         subjects affected / exposed
    0 / 406 (0.00%)
    1 / 407 (0.25%)
    0 / 137 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal inflammation
         subjects affected / exposed
    1 / 406 (0.25%)
    0 / 407 (0.00%)
    0 / 137 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    1 / 406 (0.25%)
    0 / 407 (0.00%)
    0 / 137 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peptic ulcer perforation
         subjects affected / exposed
    0 / 406 (0.00%)
    1 / 407 (0.25%)
    0 / 137 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Chronic kidney disease
         subjects affected / exposed
    0 / 406 (0.00%)
    1 / 407 (0.25%)
    0 / 137 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    0 / 406 (0.00%)
    1 / 407 (0.25%)
    0 / 137 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    1 / 406 (0.25%)
    0 / 407 (0.00%)
    0 / 137 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Intervertebral disc protrusion
         subjects affected / exposed
    1 / 406 (0.25%)
    1 / 407 (0.25%)
    0 / 137 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lumbar spinal stenosis
         subjects affected / exposed
    0 / 406 (0.00%)
    1 / 407 (0.25%)
    0 / 137 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    0 / 406 (0.00%)
    0 / 407 (0.00%)
    1 / 137 (0.73%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spinal pain
         subjects affected / exposed
    0 / 406 (0.00%)
    1 / 407 (0.25%)
    0 / 137 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Erysipelas
         subjects affected / exposed
    0 / 406 (0.00%)
    1 / 407 (0.25%)
    0 / 137 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 406 (0.00%)
    0 / 407 (0.00%)
    1 / 137 (0.73%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Viral rash
         subjects affected / exposed
    1 / 406 (0.25%)
    0 / 407 (0.00%)
    0 / 137 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Type 2 diabetes mellitus
         subjects affected / exposed
    1 / 406 (0.25%)
    0 / 407 (0.00%)
    0 / 137 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 P-3058 10% Vehicle Amorolfine
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    166 / 406 (40.89%)
    187 / 407 (45.95%)
    62 / 137 (45.26%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal cell carcinoma
         subjects affected / exposed
    0 / 406 (0.00%)
    3 / 407 (0.74%)
    0 / 137 (0.00%)
         occurrences all number
    0
    3
    0
    Breast cancer
         subjects affected / exposed
    1 / 406 (0.25%)
    0 / 407 (0.00%)
    0 / 137 (0.00%)
         occurrences all number
    1
    0
    0
    Haemangioma
         subjects affected / exposed
    0 / 406 (0.00%)
    1 / 407 (0.25%)
    0 / 137 (0.00%)
         occurrences all number
    0
    1
    0
    Haemangioma of liver
         subjects affected / exposed
    0 / 406 (0.00%)
    1 / 407 (0.25%)
    0 / 137 (0.00%)
         occurrences all number
    0
    1
    0
    Malignant melanoma
         subjects affected / exposed
    0 / 406 (0.00%)
    0 / 407 (0.00%)
    1 / 137 (0.73%)
         occurrences all number
    0
    0
    1
    Pancreatic carcinoma
         subjects affected / exposed
    0 / 406 (0.00%)
    1 / 407 (0.25%)
    0 / 137 (0.00%)
         occurrences all number
    0
    1
    0
    Prostate cancer
         subjects affected / exposed
    0 / 406 (0.00%)
    0 / 407 (0.00%)
    2 / 137 (1.46%)
         occurrences all number
    0
    0
    2
    Skin papilloma
         subjects affected / exposed
    2 / 406 (0.49%)
    1 / 407 (0.25%)
    2 / 137 (1.46%)
         occurrences all number
    3
    1
    2
    Thyroid neoplasm
         subjects affected / exposed
    1 / 406 (0.25%)
    0 / 407 (0.00%)
    0 / 137 (0.00%)
         occurrences all number
    1
    0
    0
    Vascular disorders
    Haematoma
         subjects affected / exposed
    1 / 406 (0.25%)
    1 / 407 (0.25%)
    0 / 137 (0.00%)
         occurrences all number
    1
    1
    0
    Haemorrhage
         subjects affected / exposed
    1 / 406 (0.25%)
    0 / 407 (0.00%)
    0 / 137 (0.00%)
         occurrences all number
    1
    0
    0
    Hot flush
         subjects affected / exposed
    1 / 406 (0.25%)
    0 / 407 (0.00%)
    0 / 137 (0.00%)
         occurrences all number
    1
    0
    0
    Hypertension
         subjects affected / exposed
    8 / 406 (1.97%)
    14 / 407 (3.44%)
    4 / 137 (2.92%)
         occurrences all number
    8
    14
    4
    Hypertensive crisis
         subjects affected / exposed
    1 / 406 (0.25%)
    3 / 407 (0.74%)
    0 / 137 (0.00%)
         occurrences all number
    1
    3
    0
    Peripheral venous disease
         subjects affected / exposed
    1 / 406 (0.25%)
    0 / 407 (0.00%)
    0 / 137 (0.00%)
         occurrences all number
    1
    0
    0
    Phlebitis
         subjects affected / exposed
    0 / 406 (0.00%)
    0 / 407 (0.00%)
    1 / 137 (0.73%)
         occurrences all number
    0
    0
    1
    Phlebitis superficial
         subjects affected / exposed
    0 / 406 (0.00%)
    1 / 407 (0.25%)
    0 / 137 (0.00%)
         occurrences all number
    0
    1
    0
    Thrombosis
         subjects affected / exposed
    0 / 406 (0.00%)
    1 / 407 (0.25%)
    0 / 137 (0.00%)
         occurrences all number
    0
    1
    0
    Varicose vein
         subjects affected / exposed
    1 / 406 (0.25%)
    1 / 407 (0.25%)
    0 / 137 (0.00%)
         occurrences all number
    1
    1
    0
    Surgical and medical procedures
    Blepharoplasty
         subjects affected / exposed
    0 / 406 (0.00%)
    1 / 407 (0.25%)
    0 / 137 (0.00%)
         occurrences all number
    0
    1
    0
    Cataract operation
         subjects affected / exposed
    1 / 406 (0.25%)
    0 / 407 (0.00%)
    0 / 137 (0.00%)
         occurrences all number
    2
    0
    0
    Cholecystectomy
         subjects affected / exposed
    0 / 406 (0.00%)
    1 / 407 (0.25%)
    0 / 137 (0.00%)
         occurrences all number
    0
    1
    0
    Neoplasm prophylaxis
         subjects affected / exposed
    1 / 406 (0.25%)
    0 / 407 (0.00%)
    0 / 137 (0.00%)
         occurrences all number
    1
    0
    0
    Shoulder operation
         subjects affected / exposed
    0 / 406 (0.00%)
    0 / 407 (0.00%)
    1 / 137 (0.73%)
         occurrences all number
    0
    0
    1
    Skin neoplasm excision
         subjects affected / exposed
    1 / 406 (0.25%)
    1 / 407 (0.25%)
    1 / 137 (0.73%)
         occurrences all number
    1
    1
    1
    Toe operation
         subjects affected / exposed
    1 / 406 (0.25%)
    0 / 407 (0.00%)
    0 / 137 (0.00%)
         occurrences all number
    1
    0
    0
    Tooth extraction
         subjects affected / exposed
    1 / 406 (0.25%)
    1 / 407 (0.25%)
    1 / 137 (0.73%)
         occurrences all number
    1
    1
    1
    Tooth repair
         subjects affected / exposed
    0 / 406 (0.00%)
    1 / 407 (0.25%)
    0 / 137 (0.00%)
         occurrences all number
    0
    1
    0
    Varicose vein operation
         subjects affected / exposed
    0 / 406 (0.00%)
    0 / 407 (0.00%)
    1 / 137 (0.73%)
         occurrences all number
    0
    0
    1
    Pregnancy, puerperium and perinatal conditions
    Pregnancy
         subjects affected / exposed
    0 / 406 (0.00%)
    1 / 407 (0.25%)
    0 / 137 (0.00%)
         occurrences all number
    0
    1
    0
    General disorders and administration site conditions
    Application site pain
         subjects affected / exposed
    2 / 406 (0.49%)
    0 / 407 (0.00%)
    0 / 137 (0.00%)
         occurrences all number
    2
    0
    0
    Asthenia
         subjects affected / exposed
    1 / 406 (0.25%)
    0 / 407 (0.00%)
    0 / 137 (0.00%)
         occurrences all number
    1
    0
    0
    Chest discomfort
         subjects affected / exposed
    1 / 406 (0.25%)
    1 / 407 (0.25%)
    0 / 137 (0.00%)
         occurrences all number
    1
    1
    0
    Chest pain
         subjects affected / exposed
    0 / 406 (0.00%)
    1 / 407 (0.25%)
    0 / 137 (0.00%)
         occurrences all number
    0
    3
    0
    Chills
         subjects affected / exposed
    1 / 406 (0.25%)
    0 / 407 (0.00%)
    0 / 137 (0.00%)
         occurrences all number
    3
    0
    0
    Fatigue
         subjects affected / exposed
    5 / 406 (1.23%)
    5 / 407 (1.23%)
    0 / 137 (0.00%)
         occurrences all number
    8
    5
    0
    Impaired healing
         subjects affected / exposed
    0 / 406 (0.00%)
    1 / 407 (0.25%)
    0 / 137 (0.00%)
         occurrences all number
    0
    1
    0
    Influenza like illness
         subjects affected / exposed
    0 / 406 (0.00%)
    2 / 407 (0.49%)
    1 / 137 (0.73%)
         occurrences all number
    0
    2
    1
    Malaise
         subjects affected / exposed
    1 / 406 (0.25%)
    0 / 407 (0.00%)
    0 / 137 (0.00%)
         occurrences all number
    1
    0
    0
    Oedema peripheral
         subjects affected / exposed
    0 / 406 (0.00%)
    1 / 407 (0.25%)
    0 / 137 (0.00%)
         occurrences all number
    0
    1
    0
    Pain
         subjects affected / exposed
    0 / 406 (0.00%)
    1 / 407 (0.25%)
    0 / 137 (0.00%)
         occurrences all number
    0
    1
    0
    Pyrexia
         subjects affected / exposed
    3 / 406 (0.74%)
    2 / 407 (0.49%)
    1 / 137 (0.73%)
         occurrences all number
    4
    2
    1
    Immune system disorders
    Seasonal allergy
         subjects affected / exposed
    0 / 406 (0.00%)
    0 / 407 (0.00%)
    1 / 137 (0.73%)
         occurrences all number
    0
    0
    1
    Social circumstances
    Family stress
         subjects affected / exposed
    0 / 406 (0.00%)
    0 / 407 (0.00%)
    1 / 137 (0.73%)
         occurrences all number
    0
    0
    1
    Reproductive system and breast disorders
    Benign prostatic hyperplasia
         subjects affected / exposed
    1 / 406 (0.25%)
    1 / 407 (0.25%)
    1 / 137 (0.73%)
         occurrences all number
    1
    1
    1
    Dysmenorrhoea
         subjects affected / exposed
    2 / 406 (0.49%)
    0 / 407 (0.00%)
    0 / 137 (0.00%)
         occurrences all number
    6
    0
    0
    Uterine disorder
         subjects affected / exposed
    0 / 406 (0.00%)
    0 / 407 (0.00%)
    1 / 137 (0.73%)
         occurrences all number
    0
    0
    1
    Uterine polyp
         subjects affected / exposed
    1 / 406 (0.25%)
    0 / 407 (0.00%)
    0 / 137 (0.00%)
         occurrences all number
    1
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    1 / 406 (0.25%)
    0 / 407 (0.00%)
    0 / 137 (0.00%)
         occurrences all number
    2
    0
    0
    Asthma
         subjects affected / exposed
    0 / 406 (0.00%)
    1 / 407 (0.25%)
    1 / 137 (0.73%)
         occurrences all number
    0
    1
    1
    Cough
         subjects affected / exposed
    2 / 406 (0.49%)
    5 / 407 (1.23%)
    2 / 137 (1.46%)
         occurrences all number
    2
    5
    2
    Dyspnoea
         subjects affected / exposed
    1 / 406 (0.25%)
    0 / 407 (0.00%)
    0 / 137 (0.00%)
         occurrences all number
    1
    0
    0
    Oropharyngeal pain
         subjects affected / exposed
    1 / 406 (0.25%)
    3 / 407 (0.74%)
    2 / 137 (1.46%)
         occurrences all number
    2
    3
    2
    Rhinitis allergic
         subjects affected / exposed
    1 / 406 (0.25%)
    2 / 407 (0.49%)
    0 / 137 (0.00%)
         occurrences all number
    1
    2
    0
    Rhinorrhoea
         subjects affected / exposed
    1 / 406 (0.25%)
    0 / 407 (0.00%)
    0 / 137 (0.00%)
         occurrences all number
    1
    0
    0
    Sleep apnoea syndrome
         subjects affected / exposed
    0 / 406 (0.00%)
    1 / 407 (0.25%)
    0 / 137 (0.00%)
         occurrences all number
    0
    1
    0
    Upper respiratory tract inflammation
         subjects affected / exposed
    1 / 406 (0.25%)
    0 / 407 (0.00%)
    0 / 137 (0.00%)
         occurrences all number
    1
    0
    0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    1 / 406 (0.25%)
    0 / 407 (0.00%)
    0 / 137 (0.00%)
         occurrences all number
    1
    0
    0
    Depressed mood
         subjects affected / exposed
    0 / 406 (0.00%)
    0 / 407 (0.00%)
    1 / 137 (0.73%)
         occurrences all number
    0
    0
    1
    Depression
         subjects affected / exposed
    3 / 406 (0.74%)
    0 / 407 (0.00%)
    0 / 137 (0.00%)
         occurrences all number
    4
    0
    0
    Drug dependence
         subjects affected / exposed
    0 / 406 (0.00%)
    1 / 407 (0.25%)
    0 / 137 (0.00%)
         occurrences all number
    0
    1
    0
    Insomnia
         subjects affected / exposed
    2 / 406 (0.49%)
    1 / 407 (0.25%)
    1 / 137 (0.73%)
         occurrences all number
    2
    2
    1
    Loss of libido
         subjects affected / exposed
    0 / 406 (0.00%)
    1 / 407 (0.25%)
    0 / 137 (0.00%)
         occurrences all number
    0
    1
    0
    Sleep disorder
         subjects affected / exposed
    1 / 406 (0.25%)
    0 / 407 (0.00%)
    0 / 137 (0.00%)
         occurrences all number
    1
    0
    0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    1 / 406 (0.25%)
    0 / 407 (0.00%)
    0 / 137 (0.00%)
         occurrences all number
    1
    0
    0
    Gallbladder polyp
         subjects affected / exposed
    1 / 406 (0.25%)
    0 / 407 (0.00%)
    0 / 137 (0.00%)
         occurrences all number
    1
    0
    0
    Hepatic function abnormal
         subjects affected / exposed
    0 / 406 (0.00%)
    0 / 407 (0.00%)
    1 / 137 (0.73%)
         occurrences all number
    0
    0
    1
    Hepatic steatosis
         subjects affected / exposed
    1 / 406 (0.25%)
    0 / 407 (0.00%)
    0 / 137 (0.00%)
         occurrences all number
    1
    0
    0
    Hyperbilirubinaemia
         subjects affected / exposed
    1 / 406 (0.25%)
    1 / 407 (0.25%)
    0 / 137 (0.00%)
         occurrences all number
    1
    1
    0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    5 / 406 (1.23%)
    4 / 407 (0.98%)
    0 / 137 (0.00%)
         occurrences all number
    5
    4
    0
    Aspartate aminotransferase increased
         subjects affected / exposed
    4 / 406 (0.99%)
    0 / 407 (0.00%)
    0 / 137 (0.00%)
         occurrences all number
    4
    0
    0
    Bilirubin conjugated increased
         subjects affected / exposed
    1 / 406 (0.25%)
    0 / 407 (0.00%)
    0 / 137 (0.00%)
         occurrences all number
    1
    0
    0
    Blood cholesterol increased
         subjects affected / exposed
    1 / 406 (0.25%)
    1 / 407 (0.25%)
    0 / 137 (0.00%)
         occurrences all number
    1
    1
    0
    Blood creatinine increased
         subjects affected / exposed
    1 / 406 (0.25%)
    1 / 407 (0.25%)
    0 / 137 (0.00%)
         occurrences all number
    1
    1
    0
    Blood glucose abnormal
         subjects affected / exposed
    0 / 406 (0.00%)
    0 / 407 (0.00%)
    1 / 137 (0.73%)
         occurrences all number
    0
    0
    1
    Blood glucose increased
         subjects affected / exposed
    6 / 406 (1.48%)
    5 / 407 (1.23%)
    0 / 137 (0.00%)
         occurrences all number
    7
    5
    0
    Blood potassium increased
         subjects affected / exposed
    1 / 406 (0.25%)
    2 / 407 (0.49%)
    0 / 137 (0.00%)
         occurrences all number
    1
    2
    0
    Blood pressure increased
         subjects affected / exposed
    0 / 406 (0.00%)
    1 / 407 (0.25%)
    1 / 137 (0.73%)
         occurrences all number
    0
    2
    1
    Blood uric acid increased
         subjects affected / exposed
    1 / 406 (0.25%)
    2 / 407 (0.49%)
    0 / 137 (0.00%)
         occurrences all number
    1
    2
    0
    Cardiac murmur
         subjects affected / exposed
    1 / 406 (0.25%)
    0 / 407 (0.00%)
    0 / 137 (0.00%)
         occurrences all number
    1
    0
    0
    Crystal urine present
         subjects affected / exposed
    1 / 406 (0.25%)
    0 / 407 (0.00%)
    0 / 137 (0.00%)
         occurrences all number
    1
    0
    0
    Eosinophil count increased
         subjects affected / exposed
    1 / 406 (0.25%)
    2 / 407 (0.49%)
    0 / 137 (0.00%)
         occurrences all number
    1
    2
    0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    10 / 406 (2.46%)
    4 / 407 (0.98%)
    1 / 137 (0.73%)
         occurrences all number
    12
    4
    1
    Haemoglobin urine
         subjects affected / exposed
    2 / 406 (0.49%)
    0 / 407 (0.00%)
    0 / 137 (0.00%)
         occurrences all number
    2
    0
    0
    Haemoglobin urine present
         subjects affected / exposed
    1 / 406 (0.25%)
    1 / 407 (0.25%)
    0 / 137 (0.00%)
         occurrences all number
    1
    1
    0
    Hepatic enzyme increased
         subjects affected / exposed
    1 / 406 (0.25%)
    4 / 407 (0.98%)
    1 / 137 (0.73%)
         occurrences all number
    1
    4
    1
    Liver function test abnormal
         subjects affected / exposed
    1 / 406 (0.25%)
    0 / 407 (0.00%)
    0 / 137 (0.00%)
         occurrences all number
    1
    0
    0
    Lymphocyte count decreased
         subjects affected / exposed
    0 / 406 (0.00%)
    1 / 407 (0.25%)
    0 / 137 (0.00%)
         occurrences all number
    0
    1
    0
    Monocyte count increased
         subjects affected / exposed
    0 / 406 (0.00%)
    1 / 407 (0.25%)
    0 / 137 (0.00%)
         occurrences all number
    0
    1
    0
    Neutrophil count increased
         subjects affected / exposed
    0 / 406 (0.00%)
    1 / 407 (0.25%)
    0 / 137 (0.00%)
         occurrences all number
    0
    1
    0
    Platelet count decreased
         subjects affected / exposed
    0 / 406 (0.00%)
    1 / 407 (0.25%)
    0 / 137 (0.00%)
         occurrences all number
    0
    1
    0
    Protein urine present
         subjects affected / exposed
    1 / 406 (0.25%)
    0 / 407 (0.00%)
    0 / 137 (0.00%)
         occurrences all number
    1
    0
    0
    Red blood cells urine positive
         subjects affected / exposed
    0 / 406 (0.00%)
    0 / 407 (0.00%)
    1 / 137 (0.73%)
         occurrences all number
    0
    0
    1
    Urine analysis abnormal
         subjects affected / exposed
    1 / 406 (0.25%)
    0 / 407 (0.00%)
    0 / 137 (0.00%)
         occurrences all number
    1
    0
    0
    Weight decreased
         subjects affected / exposed
    0 / 406 (0.00%)
    1 / 407 (0.25%)
    0 / 137 (0.00%)
         occurrences all number
    0
    1
    0
    White blood cell count decreased
         subjects affected / exposed
    0 / 406 (0.00%)
    0 / 407 (0.00%)
    1 / 137 (0.73%)
         occurrences all number
    0
    0
    1
    White blood cell count increased
         subjects affected / exposed
    1 / 406 (0.25%)
    0 / 407 (0.00%)
    0 / 137 (0.00%)
         occurrences all number
    1
    0
    0
    White blood cells urine positive
         subjects affected / exposed
    2 / 406 (0.49%)
    1 / 407 (0.25%)
    1 / 137 (0.73%)
         occurrences all number
    2
    1
    1
    Injury, poisoning and procedural complications
    Arthropod bite
         subjects affected / exposed
    0 / 406 (0.00%)
    1 / 407 (0.25%)
    0 / 137 (0.00%)
         occurrences all number
    0
    1
    0
    Arthropod sting
         subjects affected / exposed
    0 / 406 (0.00%)
    1 / 407 (0.25%)
    0 / 137 (0.00%)
         occurrences all number
    0
    1
    0
    Contusion
         subjects affected / exposed
    2 / 406 (0.49%)
    2 / 407 (0.49%)
    0 / 137 (0.00%)
         occurrences all number
    2
    2
    0
    Epicondylitis
         subjects affected / exposed
    0 / 406 (0.00%)
    1 / 407 (0.25%)
    0 / 137 (0.00%)
         occurrences all number
    0
    1
    0
    Face injury
         subjects affected / exposed
    1 / 406 (0.25%)
    0 / 407 (0.00%)
    0 / 137 (0.00%)
         occurrences all number
    1
    0
    0
    Fall
         subjects affected / exposed
    1 / 406 (0.25%)
    2 / 407 (0.49%)
    0 / 137 (0.00%)
         occurrences all number
    1
    2
    0
    Frostbite
         subjects affected / exposed
    1 / 406 (0.25%)
    0 / 407 (0.00%)
    0 / 137 (0.00%)
         occurrences all number
    1
    0
    0
    Hand fracture
         subjects affected / exposed
    0 / 406 (0.00%)
    1 / 407 (0.25%)
    0 / 137 (0.00%)
         occurrences all number
    0
    1
    0
    Joint dislocation
         subjects affected / exposed
    1 / 406 (0.25%)
    0 / 407 (0.00%)
    1 / 137 (0.73%)
         occurrences all number
    1
    0
    1
    Joint injury
         subjects affected / exposed
    0 / 406 (0.00%)
    1 / 407 (0.25%)
    1 / 137 (0.73%)
         occurrences all number
    0
    1
    1
    Laceration
         subjects affected / exposed
    0 / 406 (0.00%)
    1 / 407 (0.25%)
    0 / 137 (0.00%)
         occurrences all number
    0
    1
    0
    Ligament rupture
         subjects affected / exposed
    0 / 406 (0.00%)
    1 / 407 (0.25%)
    0 / 137 (0.00%)
         occurrences all number
    0
    1
    0
    Limb injury
         subjects affected / exposed
    2 / 406 (0.49%)
    2 / 407 (0.49%)
    0 / 137 (0.00%)
         occurrences all number
    2
    2
    0
    Muscle rupture
         subjects affected / exposed
    0 / 406 (0.00%)
    1 / 407 (0.25%)
    0 / 137 (0.00%)
         occurrences all number
    0
    1
    0
    Muscle strain
         subjects affected / exposed
    1 / 406 (0.25%)
    2 / 407 (0.49%)
    1 / 137 (0.73%)
         occurrences all number
    1
    2
    1
    Nail injury
         subjects affected / exposed
    2 / 406 (0.49%)
    6 / 407 (1.47%)
    1 / 137 (0.73%)
         occurrences all number
    2
    7
    1
    Procedural pain
         subjects affected / exposed
    0 / 406 (0.00%)
    1 / 407 (0.25%)
    0 / 137 (0.00%)
         occurrences all number
    0
    1
    0
    Rib fracture
         subjects affected / exposed
    1 / 406 (0.25%)
    0 / 407 (0.00%)
    0 / 137 (0.00%)
         occurrences all number
    1
    0
    0
    Sunburn
         subjects affected / exposed
    0 / 406 (0.00%)
    0 / 407 (0.00%)
    1 / 137 (0.73%)
         occurrences all number
    0
    0
    1
    Traumatic haematoma
         subjects affected / exposed
    1 / 406 (0.25%)
    1 / 407 (0.25%)
    1 / 137 (0.73%)
         occurrences all number
    1
    1
    1
    Cardiac disorders
    Angina pectoris
         subjects affected / exposed
    0 / 406 (0.00%)
    0 / 407 (0.00%)
    1 / 137 (0.73%)
         occurrences all number
    0
    0
    1
    Arrhythmia
         subjects affected / exposed
    0 / 406 (0.00%)
    2 / 407 (0.49%)
    0 / 137 (0.00%)
         occurrences all number
    0
    2
    0
    Atrial fibrillation
         subjects affected / exposed
    1 / 406 (0.25%)
    0 / 407 (0.00%)
    0 / 137 (0.00%)
         occurrences all number
    1
    0
    0
    Cardiac failure
         subjects affected / exposed
    1 / 406 (0.25%)
    1 / 407 (0.25%)
    0 / 137 (0.00%)
         occurrences all number
    1
    1
    0
    Cardiac failure chronic
         subjects affected / exposed
    0 / 406 (0.00%)
    0 / 407 (0.00%)
    1 / 137 (0.73%)
         occurrences all number
    0
    0
    1
    Extrasystoles
         subjects affected / exposed
    0 / 406 (0.00%)
    1 / 407 (0.25%)
    0 / 137 (0.00%)
         occurrences all number
    0
    1
    0
    Hypertensive cardiomyopathy
         subjects affected / exposed
    1 / 406 (0.25%)
    0 / 407 (0.00%)
    0 / 137 (0.00%)
         occurrences all number
    1
    0
    0
    Ventricular extrasystoles
         subjects affected / exposed
    0 / 406 (0.00%)
    1 / 407 (0.25%)
    0 / 137 (0.00%)
         occurrences all number
    0
    1
    0
    Nervous system disorders
    Cerebral arteriosclerosis
         subjects affected / exposed
    1 / 406 (0.25%)
    0 / 407 (0.00%)
    0 / 137 (0.00%)
         occurrences all number
    1
    0
    0
    Cerebral ischaemia
         subjects affected / exposed
    1 / 406 (0.25%)
    0 / 407 (0.00%)
    0 / 137 (0.00%)
         occurrences all number
    1
    0
    0
    Cervical radiculopathy
         subjects affected / exposed
    0 / 406 (0.00%)
    2 / 407 (0.49%)
    0 / 137 (0.00%)
         occurrences all number
    0
    2
    0
    Dizziness
         subjects affected / exposed
    2 / 406 (0.49%)
    6 / 407 (1.47%)
    1 / 137 (0.73%)
         occurrences all number
    2
    6
    1
    Dysgeusia
         subjects affected / exposed
    1 / 406 (0.25%)
    2 / 407 (0.49%)
    1 / 137 (0.73%)
         occurrences all number
    1
    2
    1
    Epilepsy
         subjects affected / exposed
    1 / 406 (0.25%)
    0 / 407 (0.00%)
    0 / 137 (0.00%)
         occurrences all number
    1
    0
    0
    Essential tremor
         subjects affected / exposed
    1 / 406 (0.25%)
    0 / 407 (0.00%)
    0 / 137 (0.00%)
         occurrences all number
    1
    0
    0
    Headache
         subjects affected / exposed
    19 / 406 (4.68%)
    18 / 407 (4.42%)
    5 / 137 (3.65%)
         occurrences all number
    28
    31
    6
    Migraine
         subjects affected / exposed
    1 / 406 (0.25%)
    1 / 407 (0.25%)
    0 / 137 (0.00%)
         occurrences all number
    2
    2
    0
    Migraine with aura
         subjects affected / exposed
    0 / 406 (0.00%)
    1 / 407 (0.25%)
    0 / 137 (0.00%)
         occurrences all number
    0
    1
    0
    Neuralgia
         subjects affected / exposed
    0 / 406 (0.00%)
    1 / 407 (0.25%)
    0 / 137 (0.00%)
         occurrences all number
    0
    1
    0
    Neuritis
         subjects affected / exposed
    1 / 406 (0.25%)
    0 / 407 (0.00%)
    0 / 137 (0.00%)
         occurrences all number
    1
    0
    0
    Parkinsonism
         subjects affected / exposed
    1 / 406 (0.25%)
    0 / 407 (0.00%)
    0 / 137 (0.00%)
         occurrences all number
    1
    0
    0
    Polyneuropathy
         subjects affected / exposed
    0 / 406 (0.00%)
    1 / 407 (0.25%)
    0 / 137 (0.00%)
         occurrences all number
    0
    1
    0
    Radiculitis
         subjects affected / exposed
    0 / 406 (0.00%)
    0 / 407 (0.00%)
    1 / 137 (0.73%)
         occurrences all number
    0
    0
    1
    Restless legs syndrome
         subjects affected / exposed
    1 / 406 (0.25%)
    0 / 407 (0.00%)
    0 / 137 (0.00%)
         occurrences all number
    1
    0
    0
    Sciatica
         subjects affected / exposed
    1 / 406 (0.25%)
    2 / 407 (0.49%)
    0 / 137 (0.00%)
         occurrences all number
    1
    2
    0
    Transient ischaemic attack
         subjects affected / exposed
    0 / 406 (0.00%)
    1 / 407 (0.25%)
    0 / 137 (0.00%)
         occurrences all number
    0
    1
    0
    Tremor
         subjects affected / exposed
    1 / 406 (0.25%)
    1 / 407 (0.25%)
    0 / 137 (0.00%)
         occurrences all number
    1
    1
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 406 (0.25%)
    2 / 407 (0.49%)
    0 / 137 (0.00%)
         occurrences all number
    1
    2
    0
    Eosinophilia
         subjects affected / exposed
    1 / 406 (0.25%)
    0 / 407 (0.00%)
    0 / 137 (0.00%)
         occurrences all number
    2
    0
    0
    Haemorrhagic anaemia
         subjects affected / exposed
    0 / 406 (0.00%)
    1 / 407 (0.25%)
    0 / 137 (0.00%)
         occurrences all number
    0
    1
    0
    Leukocytosis
         subjects affected / exposed
    0 / 406 (0.00%)
    1 / 407 (0.25%)
    0 / 137 (0.00%)
         occurrences all number
    0
    1
    0
    Leukopenia
         subjects affected / exposed
    1 / 406 (0.25%)
    2 / 407 (0.49%)
    0 / 137 (0.00%)
         occurrences all number
    1
    2
    0
    Lymph node pain
         subjects affected / exposed
    1 / 406 (0.25%)
    0 / 407 (0.00%)
    0 / 137 (0.00%)
         occurrences all number
    1
    0
    0
    Lymphadenopathy
         subjects affected / exposed
    1 / 406 (0.25%)
    0 / 407 (0.00%)
    0 / 137 (0.00%)
         occurrences all number
    1
    0
    0
    Lymphopenia
         subjects affected / exposed
    0 / 406 (0.00%)
    1 / 407 (0.25%)
    0 / 137 (0.00%)
         occurrences all number
    0
    1
    0
    Neutropenia
         subjects affected / exposed
    0 / 406 (0.00%)
    1 / 407 (0.25%)
    0 / 137 (0.00%)
         occurrences all number
    0
    1
    0
    Polycythaemia
         subjects affected / exposed
    0 / 406 (0.00%)
    1 / 407 (0.25%)
    0 / 137 (0.00%)
         occurrences all number
    0
    1
    0
    Thrombocytosis
         subjects affected / exposed
    0 / 406 (0.00%)
    1 / 407 (0.25%)
    0 / 137 (0.00%)
         occurrences all number
    0
    1
    0
    Ear and labyrinth disorders
    Ear pain
         subjects affected / exposed
    0 / 406 (0.00%)
    1 / 407 (0.25%)
    0 / 137 (0.00%)
         occurrences all number
    0
    1
    0
    Ear pruritus
         subjects affected / exposed
    0 / 406 (0.00%)
    1 / 407 (0.25%)
    0 / 137 (0.00%)
         occurrences all number
    0
    1
    0
    Hypoacusis
         subjects affected / exposed
    1 / 406 (0.25%)
    0 / 407 (0.00%)
    0 / 137 (0.00%)
         occurrences all number
    1
    0
    0
    Tinnitus
         subjects affected / exposed
    2 / 406 (0.49%)
    1 / 407 (0.25%)
    0 / 137 (0.00%)
         occurrences all number
    2
    1
    0
    Vertigo positional
         subjects affected / exposed
    1 / 406 (0.25%)
    0 / 407 (0.00%)
    0 / 137 (0.00%)
         occurrences all number
    1
    0
    0
    Eye disorders
    Cataract
         subjects affected / exposed
    1 / 406 (0.25%)
    0 / 407 (0.00%)
    0 / 137 (0.00%)
         occurrences all number
    1
    0
    0
    Chalazion
         subjects affected / exposed
    0 / 406 (0.00%)
    0 / 407 (0.00%)
    1 / 137 (0.73%)
         occurrences all number
    0
    0
    1
    Conjunctivitis allergic
         subjects affected / exposed
    1 / 406 (0.25%)
    0 / 407 (0.00%)
    0 / 137 (0.00%)
         occurrences all number
    1
    0
    0
    Erythema of eyelid
         subjects affected / exposed
    1 / 406 (0.25%)
    0 / 407 (0.00%)
    1 / 137 (0.73%)
         occurrences all number
    1
    0
    1
    Eye oedema
         subjects affected / exposed
    0 / 406 (0.00%)
    1 / 407 (0.25%)
    0 / 137 (0.00%)
         occurrences all number
    0
    1
    0
    Eye pruritus
         subjects affected / exposed
    0 / 406 (0.00%)
    1 / 407 (0.25%)
    0 / 137 (0.00%)
         occurrences all number
    0
    1
    0
    Eyelid oedema
         subjects affected / exposed
    0 / 406 (0.00%)
    0 / 407 (0.00%)
    1 / 137 (0.73%)
         occurrences all number
    0
    0
    1
    Eyelid rash
         subjects affected / exposed
    0 / 406 (0.00%)
    1 / 407 (0.25%)
    0 / 137 (0.00%)
         occurrences all number
    0
    1
    0
    Retinal haemorrhage
         subjects affected / exposed
    0 / 406 (0.00%)
    1 / 407 (0.25%)
    0 / 137 (0.00%)
         occurrences all number
    0
    1
    0
    Vision blurred
         subjects affected / exposed
    0 / 406 (0.00%)
    1 / 407 (0.25%)
    0 / 137 (0.00%)
         occurrences all number
    0
    1
    0
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    0 / 406 (0.00%)
    0 / 407 (0.00%)
    1 / 137 (0.73%)
         occurrences all number
    0
    0
    1
    Abdominal distension
         subjects affected / exposed
    0 / 406 (0.00%)
    0 / 407 (0.00%)
    1 / 137 (0.73%)
         occurrences all number
    0
    0
    1
    Abdominal pain
         subjects affected / exposed
    3 / 406 (0.74%)
    2 / 407 (0.49%)
    1 / 137 (0.73%)
         occurrences all number
    3
    2
    1
    Abdominal pain lower
         subjects affected / exposed
    0 / 406 (0.00%)
    1 / 407 (0.25%)
    0 / 137 (0.00%)
         occurrences all number
    0
    1
    0
    Abdominal pain upper
         subjects affected / exposed
    7 / 406 (1.72%)
    1 / 407 (0.25%)
    2 / 137 (1.46%)
         occurrences all number
    7
    1
    2
    Abdominal tenderness
         subjects affected / exposed
    1 / 406 (0.25%)
    0 / 407 (0.00%)
    0 / 137 (0.00%)
         occurrences all number
    1
    0
    0
    Cheilitis
         subjects affected / exposed
    0 / 406 (0.00%)
    1 / 407 (0.25%)
    0 / 137 (0.00%)
         occurrences all number
    0
    1
    0
    Constipation
         subjects affected / exposed
    0 / 406 (0.00%)
    1 / 407 (0.25%)
    0 / 137 (0.00%)
         occurrences all number
    0
    1
    0
    Dental caries
         subjects affected / exposed
    0 / 406 (0.00%)
    0 / 407 (0.00%)
    1 / 137 (0.73%)
         occurrences all number
    0
    0
    1
    Diarrhoea
         subjects affected / exposed
    5 / 406 (1.23%)
    5 / 407 (1.23%)
    1 / 137 (0.73%)
         occurrences all number
    5
    6
    1
    Diverticulum
         subjects affected / exposed
    1 / 406 (0.25%)
    0 / 407 (0.00%)
    0 / 137 (0.00%)
         occurrences all number
    1
    0
    0
    Diverticulum intestinal
         subjects affected / exposed
    0 / 406 (0.00%)
    1 / 407 (0.25%)
    0 / 137 (0.00%)
         occurrences all number
    0
    1
    0
    Dyspepsia
         subjects affected / exposed
    2 / 406 (0.49%)
    0 / 407 (0.00%)
    1 / 137 (0.73%)
         occurrences all number
    2
    0
    1
    Dysphagia
         subjects affected / exposed
    1 / 406 (0.25%)
    0 / 407 (0.00%)
    0 / 137 (0.00%)
         occurrences all number
    1
    0
    0
    Faecal incontinence
         subjects affected / exposed
    0 / 406 (0.00%)
    1 / 407 (0.25%)
    0 / 137 (0.00%)
         occurrences all number
    0
    1
    0
    Faeces discoloured
         subjects affected / exposed
    1 / 406 (0.25%)
    0 / 407 (0.00%)
    0 / 137 (0.00%)
         occurrences all number
    2
    0
    0
    Faeces pale
         subjects affected / exposed
    1 / 406 (0.25%)
    0 / 407 (0.00%)
    0 / 137 (0.00%)
         occurrences all number
    1
    0
    0
    Flatulence
         subjects affected / exposed
    1 / 406 (0.25%)
    0 / 407 (0.00%)
    0 / 137 (0.00%)
         occurrences all number
    1
    0
    0
    Frequent bowel movements
         subjects affected / exposed
    0 / 406 (0.00%)
    1 / 407 (0.25%)
    0 / 137 (0.00%)
         occurrences all number
    0
    1
    0
    Gastric disorder
         subjects affected / exposed
    1 / 406 (0.25%)
    0 / 407 (0.00%)
    0 / 137 (0.00%)
         occurrences all number
    1
    0
    0
    Gastritis
         subjects affected / exposed
    1 / 406 (0.25%)
    0 / 407 (0.00%)
    0 / 137 (0.00%)
         occurrences all number
    1
    0
    0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    2 / 406 (0.49%)
    0 / 407 (0.00%)
    1 / 137 (0.73%)
         occurrences all number
    2
    0
    1
    Haematochezia
         subjects affected / exposed
    2 / 406 (0.49%)
    0 / 407 (0.00%)
    0 / 137 (0.00%)
         occurrences all number
    2
    0
    0
    Haemorrhoids
         subjects affected / exposed
    1 / 406 (0.25%)
    0 / 407 (0.00%)
    0 / 137 (0.00%)
         occurrences all number
    1
    0
    0
    Hyperchlorhydria
         subjects affected / exposed
    0 / 406 (0.00%)
    1 / 407 (0.25%)
    0 / 137 (0.00%)
         occurrences all number
    0
    3
    0
    Inguinal hernia
         subjects affected / exposed
    0 / 406 (0.00%)
    1 / 407 (0.25%)
    0 / 137 (0.00%)
         occurrences all number
    0
    1
    0
    Irritable bowel syndrome
         subjects affected / exposed
    1 / 406 (0.25%)
    0 / 407 (0.00%)
    0 / 137 (0.00%)
         occurrences all number
    1
    0
    0
    Nausea
         subjects affected / exposed
    2 / 406 (0.49%)
    1 / 407 (0.25%)
    1 / 137 (0.73%)
         occurrences all number
    2
    1
    1
    Pancreatitis chronic
         subjects affected / exposed
    1 / 406 (0.25%)
    0 / 407 (0.00%)
    0 / 137 (0.00%)
         occurrences all number
    1
    0
    0
    Periodontal disease
         subjects affected / exposed
    0 / 406 (0.00%)
    1 / 407 (0.25%)
    0 / 137 (0.00%)
         occurrences all number
    0
    1
    0
    Proctitis
         subjects affected / exposed
    0 / 406 (0.00%)
    1 / 407 (0.25%)
    0 / 137 (0.00%)
         occurrences all number
    0
    1
    0
    Toothache
         subjects affected / exposed
    2 / 406 (0.49%)
    4 / 407 (0.98%)
    2 / 137 (1.46%)
         occurrences all number
    2
    7
    3
    Vomiting
         subjects affected / exposed
    2 / 406 (0.49%)
    1 / 407 (0.25%)
    0 / 137 (0.00%)
         occurrences all number
    2
    1
    0
    Skin and subcutaneous tissue disorders
    Actinic keratosis
         subjects affected / exposed
    0 / 406 (0.00%)
    1 / 407 (0.25%)
    0 / 137 (0.00%)
         occurrences all number
    0
    1
    0
    Dermatitis contact
         subjects affected / exposed
    0 / 406 (0.00%)
    1 / 407 (0.25%)
    1 / 137 (0.73%)
         occurrences all number
    0
    1
    1
    Diabetic ulcer
         subjects affected / exposed
    0 / 406 (0.00%)
    1 / 407 (0.25%)
    0 / 137 (0.00%)
         occurrences all number
    0
    2
    0
    Dry skin
         subjects affected / exposed
    0 / 406 (0.00%)
    2 / 407 (0.49%)
    0 / 137 (0.00%)
         occurrences all number
    0
    2
    0
    Dyshidrotic eczema
         subjects affected / exposed
    0 / 406 (0.00%)
    0 / 407 (0.00%)
    1 / 137 (0.73%)
         occurrences all number
    0
    0
    1
    Eczema
         subjects affected / exposed
    4 / 406 (0.99%)
    2 / 407 (0.49%)
    0 / 137 (0.00%)
         occurrences all number
    4
    2
    0
    Eczema nummular
         subjects affected / exposed
    0 / 406 (0.00%)
    1 / 407 (0.25%)
    0 / 137 (0.00%)
         occurrences all number
    0
    1
    0
    Erythema
         subjects affected / exposed
    4 / 406 (0.99%)
    4 / 407 (0.98%)
    1 / 137 (0.73%)
         occurrences all number
    5
    4
    1
    Hyperkeratosis
         subjects affected / exposed
    1 / 406 (0.25%)
    1 / 407 (0.25%)
    0 / 137 (0.00%)
         occurrences all number
    1
    1
    0
    Nail bed bleeding
         subjects affected / exposed
    1 / 406 (0.25%)
    0 / 407 (0.00%)
    0 / 137 (0.00%)
         occurrences all number
    1
    0
    0
    Nail disorder
         subjects affected / exposed
    2 / 406 (0.49%)
    3 / 407 (0.74%)
    1 / 137 (0.73%)
         occurrences all number
    2
    3
    2
    Onychalgia
         subjects affected / exposed
    0 / 406 (0.00%)
    1 / 407 (0.25%)
    0 / 137 (0.00%)
         occurrences all number
    0
    1
    0
    Onychoclasis
         subjects affected / exposed
    0 / 406 (0.00%)
    0 / 407 (0.00%)
    1 / 137 (0.73%)
         occurrences all number
    0
    0
    1
    Onychomadesis
         subjects affected / exposed
    0 / 406 (0.00%)
    1 / 407 (0.25%)
    0 / 137 (0.00%)
         occurrences all number
    0
    1
    0
    Pityriasis rosea
         subjects affected / exposed
    0 / 406 (0.00%)
    1 / 407 (0.25%)
    0 / 137 (0.00%)
         occurrences all number
    0
    1
    0
    Pruritus
         subjects affected / exposed
    1 / 406 (0.25%)
    3 / 407 (0.74%)
    1 / 137 (0.73%)
         occurrences all number
    1
    3
    1
    Psoriasis
         subjects affected / exposed
    0 / 406 (0.00%)
    1 / 407 (0.25%)
    0 / 137 (0.00%)
         occurrences all number
    0
    1
    0
    Rash
         subjects affected / exposed
    2 / 406 (0.49%)
    2 / 407 (0.49%)
    2 / 137 (1.46%)
         occurrences all number
    2
    4
    2
    Seborrhoeic dermatitis
         subjects affected / exposed
    0 / 406 (0.00%)
    2 / 407 (0.49%)
    0 / 137 (0.00%)
         occurrences all number
    0
    2
    0
    Skin burning sensation
         subjects affected / exposed
    0 / 406 (0.00%)
    0 / 407 (0.00%)
    1 / 137 (0.73%)
         occurrences all number
    0
    0
    1
    Skin disorder
         subjects affected / exposed
    0 / 406 (0.00%)
    1 / 407 (0.25%)
    0 / 137 (0.00%)
         occurrences all number
    0
    1
    0
    Skin exfoliation
         subjects affected / exposed
    0 / 406 (0.00%)
    1 / 407 (0.25%)
    0 / 137 (0.00%)
         occurrences all number
    0
    1
    0
    Skin irritation
         subjects affected / exposed
    2 / 406 (0.49%)
    1 / 407 (0.25%)
    0 / 137 (0.00%)
         occurrences all number
    2
    2
    0
    Skin lesion
         subjects affected / exposed
    0 / 406 (0.00%)
    0 / 407 (0.00%)
    1 / 137 (0.73%)
         occurrences all number
    0
    0
    1
    Urticaria
         subjects affected / exposed
    0 / 406 (0.00%)
    1 / 407 (0.25%)
    1 / 137 (0.73%)
         occurrences all number
    0
    1
    1
    Renal and urinary disorders
    Bladder discomfort
         subjects affected / exposed
    1 / 406 (0.25%)
    0 / 407 (0.00%)
    0 / 137 (0.00%)
         occurrences all number
    1
    0
    0
    Calculus urinary
         subjects affected / exposed
    1 / 406 (0.25%)
    1 / 407 (0.25%)
    0 / 137 (0.00%)
         occurrences all number
    1
    2
    0
    Chromaturia
         subjects affected / exposed
    1 / 406 (0.25%)
    0 / 407 (0.00%)
    0 / 137 (0.00%)
         occurrences all number
    1
    0
    0
    Chronic kidney disease
         subjects affected / exposed
    0 / 406 (0.00%)
    1 / 407 (0.25%)
    0 / 137 (0.00%)
         occurrences all number
    0
    1
    0
    Glycosuria
         subjects affected / exposed
    0 / 406 (0.00%)
    1 / 407 (0.25%)
    0 / 137 (0.00%)
         occurrences all number
    0
    1
    0
    Haematuria
         subjects affected / exposed
    1 / 406 (0.25%)
    1 / 407 (0.25%)
    0 / 137 (0.00%)
         occurrences all number
    1
    1
    0
    Haemoglobinuria
         subjects affected / exposed
    1 / 406 (0.25%)
    0 / 407 (0.00%)
    0 / 137 (0.00%)
         occurrences all number
    1
    0
    0
    Hyperoxaluria
         subjects affected / exposed
    0 / 406 (0.00%)
    1 / 407 (0.25%)
    0 / 137 (0.00%)
         occurrences all number
    0
    1
    0
    Micturition urgency
         subjects affected / exposed
    1 / 406 (0.25%)
    0 / 407 (0.00%)
    0 / 137 (0.00%)
         occurrences all number
    1
    0
    0
    Nephrolithiasis
         subjects affected / exposed
    0 / 406 (0.00%)
    0 / 407 (0.00%)
    1 / 137 (0.73%)
         occurrences all number
    0
    0
    1
    Proteinuria
         subjects affected / exposed
    0 / 406 (0.00%)
    1 / 407 (0.25%)
    0 / 137 (0.00%)
         occurrences all number
    0
    1
    0
    Renal cyst
         subjects affected / exposed
    0 / 406 (0.00%)
    1 / 407 (0.25%)
    0 / 137 (0.00%)
         occurrences all number
    0
    1
    0
    Urinary tract inflammation
         subjects affected / exposed
    0 / 406 (0.00%)
    0 / 407 (0.00%)
    1 / 137 (0.73%)
         occurrences all number
    0
    0
    2
    Endocrine disorders
    Androgen deficiency
         subjects affected / exposed
    1 / 406 (0.25%)
    0 / 407 (0.00%)
    0 / 137 (0.00%)
         occurrences all number
    1
    0
    0
    Musculoskeletal and connective tissue disorders
    Acquired foramen magnum stenosis
         subjects affected / exposed
    1 / 406 (0.25%)
    0 / 407 (0.00%)
    0 / 137 (0.00%)
         occurrences all number
    1
    0
    0
    Arthralgia
         subjects affected / exposed
    8 / 406 (1.97%)
    4 / 407 (0.98%)
    2 / 137 (1.46%)
         occurrences all number
    8
    5
    3
    Arthritis
         subjects affected / exposed
    1 / 406 (0.25%)
    0 / 407 (0.00%)
    0 / 137 (0.00%)
         occurrences all number
    2
    0
    0
    Back pain
         subjects affected / exposed
    10 / 406 (2.46%)
    13 / 407 (3.19%)
    5 / 137 (3.65%)
         occurrences all number
    16
    13
    6
    Bursitis
         subjects affected / exposed
    3 / 406 (0.74%)
    0 / 407 (0.00%)
    1 / 137 (0.73%)
         occurrences all number
    4
    0
    1
    Chondropathy
         subjects affected / exposed
    0 / 406 (0.00%)
    1 / 407 (0.25%)
    0 / 137 (0.00%)
         occurrences all number
    0
    1
    0
    Exostosis
         subjects affected / exposed
    0 / 406 (0.00%)
    0 / 407 (0.00%)
    1 / 137 (0.73%)
         occurrences all number
    0
    0
    1
    Fibromyalgia
         subjects affected / exposed
    0 / 406 (0.00%)
    1 / 407 (0.25%)
    0 / 137 (0.00%)
         occurrences all number
    0
    1
    0
    Gouty arthritis
         subjects affected / exposed
    0 / 406 (0.00%)
    1 / 407 (0.25%)
    0 / 137 (0.00%)
         occurrences all number
    0
    1
    0
    Intervertebral disc protrusion
         subjects affected / exposed
    0 / 406 (0.00%)
    3 / 407 (0.74%)
    0 / 137 (0.00%)
         occurrences all number
    0
    3
    0
    Muscle spasms
         subjects affected / exposed
    1 / 406 (0.25%)
    1 / 407 (0.25%)
    0 / 137 (0.00%)
         occurrences all number
    1
    1
    0
    Musculoskeletal pain
         subjects affected / exposed
    4 / 406 (0.99%)
    1 / 407 (0.25%)
    2 / 137 (1.46%)
         occurrences all number
    5
    3
    2
    Musculoskeletal stiffness
         subjects affected / exposed
    1 / 406 (0.25%)
    0 / 407 (0.00%)
    0 / 137 (0.00%)
         occurrences all number
    1
    0
    0
    Myositis
         subjects affected / exposed
    0 / 406 (0.00%)
    1 / 407 (0.25%)
    0 / 137 (0.00%)
         occurrences all number
    0
    1
    0
    Neck pain
         subjects affected / exposed
    1 / 406 (0.25%)
    1 / 407 (0.25%)
    0 / 137 (0.00%)
         occurrences all number
    1
    1
    0
    Osteoarthritis
         subjects affected / exposed
    3 / 406 (0.74%)
    1 / 407 (0.25%)
    2 / 137 (1.46%)
         occurrences all number
    3
    1
    2
    Pain in extremity
         subjects affected / exposed
    5 / 406 (1.23%)
    3 / 407 (0.74%)
    0 / 137 (0.00%)
         occurrences all number
    8
    3
    0
    Periarthritis
         subjects affected / exposed
    0 / 406 (0.00%)
    1 / 407 (0.25%)
    0 / 137 (0.00%)
         occurrences all number
    0
    1
    0
    Plantar fasciitis
         subjects affected / exposed
    0 / 406 (0.00%)
    0 / 407 (0.00%)
    1 / 137 (0.73%)
         occurrences all number
    0
    0
    1
    Scoliosis
         subjects affected / exposed
    1 / 406 (0.25%)
    0 / 407 (0.00%)
    0 / 137 (0.00%)
         occurrences all number
    0
    0
    0
    Spinal osteoarthritis
         subjects affected / exposed
    1 / 406 (0.25%)
    2 / 407 (0.49%)
    0 / 137 (0.00%)
         occurrences all number
    2
    2
    0
    Spinal pain
         subjects affected / exposed
    0 / 406 (0.00%)
    1 / 407 (0.25%)
    0 / 137 (0.00%)
         occurrences all number
    0
    1
    0
    Tendonitis
         subjects affected / exposed
    1 / 406 (0.25%)
    1 / 407 (0.25%)
    0 / 137 (0.00%)
         occurrences all number
    2
    1
    0
    Torticollis
         subjects affected / exposed
    0 / 406 (0.00%)
    0 / 407 (0.00%)
    1 / 137 (0.73%)
         occurrences all number
    0
    0
    1
    Trigger finger
         subjects affected / exposed
    1 / 406 (0.25%)
    0 / 407 (0.00%)
    0 / 137 (0.00%)
         occurrences all number
    1
    0
    0
    Infections and infestations
    Abscess jaw
         subjects affected / exposed
    0 / 406 (0.00%)
    1 / 407 (0.25%)
    0 / 137 (0.00%)
         occurrences all number
    0
    1
    0
    Acute tonsillitis
         subjects affected / exposed
    1 / 406 (0.25%)
    0 / 407 (0.00%)
    0 / 137 (0.00%)
         occurrences all number
    1
    0
    0
    Borrelia infection
         subjects affected / exposed
    2 / 406 (0.49%)
    0 / 407 (0.00%)
    0 / 137 (0.00%)
         occurrences all number
    2
    0
    0
    Bronchitis
         subjects affected / exposed
    11 / 406 (2.71%)
    8 / 407 (1.97%)
    4 / 137 (2.92%)
         occurrences all number
    11
    8
    4
    Cellulitis
         subjects affected / exposed
    0 / 406 (0.00%)
    1 / 407 (0.25%)
    0 / 137 (0.00%)
         occurrences all number
    0
    1
    0
    Conjunctivitis
         subjects affected / exposed
    0 / 406 (0.00%)
    3 / 407 (0.74%)
    1 / 137 (0.73%)
         occurrences all number
    0
    3
    1
    Cystitis
         subjects affected / exposed
    2 / 406 (0.49%)
    4 / 407 (0.98%)
    0 / 137 (0.00%)
         occurrences all number
    2
    4
    0
    Dacryocanaliculitis
         subjects affected / exposed
    0 / 406 (0.00%)
    1 / 407 (0.25%)
    0 / 137 (0.00%)
         occurrences all number
    0
    1
    0
    Diverticulitis
         subjects affected / exposed
    1 / 406 (0.25%)
    0 / 407 (0.00%)
    0 / 137 (0.00%)
         occurrences all number
    1
    0
    0
    Ear infection
         subjects affected / exposed
    1 / 406 (0.25%)
    1 / 407 (0.25%)
    0 / 137 (0.00%)
         occurrences all number
    1
    1
    0
    Erysipelas
         subjects affected / exposed
    0 / 406 (0.00%)
    1 / 407 (0.25%)
    0 / 137 (0.00%)
         occurrences all number
    0
    1
    0
    Gastroenteritis
         subjects affected / exposed
    4 / 406 (0.99%)
    2 / 407 (0.49%)
    0 / 137 (0.00%)
         occurrences all number
    4
    2
    0
    Gastroenteritis norovirus
         subjects affected / exposed
    0 / 406 (0.00%)
    0 / 407 (0.00%)
    1 / 137 (0.73%)
         occurrences all number
    0
    0
    1
    Gastroenteritis viral
         subjects affected / exposed
    1 / 406 (0.25%)
    1 / 407 (0.25%)
    0 / 137 (0.00%)
         occurrences all number
    1
    1
    0
    Gastrointestinal infection
         subjects affected / exposed
    1 / 406 (0.25%)
    0 / 407 (0.00%)
    0 / 137 (0.00%)
         occurrences all number
    1
    0
    0
    Helicobacter infection
         subjects affected / exposed
    0 / 406 (0.00%)
    1 / 407 (0.25%)
    0 / 137 (0.00%)
         occurrences all number
    0
    1
    0
    Herpes simplex
         subjects affected / exposed
    0 / 406 (0.00%)
    1 / 407 (0.25%)
    2 / 137 (1.46%)
         occurrences all number
    0
    1
    2
    Herpes zoster
         subjects affected / exposed
    2 / 406 (0.49%)
    0 / 407 (0.00%)
    1 / 137 (0.73%)
         occurrences all number
    2
    0
    1
    Hordeolum
         subjects affected / exposed
    0 / 406 (0.00%)
    0 / 407 (0.00%)
    1 / 137 (0.73%)
         occurrences all number
    0
    0
    1
    Impetigo
         subjects affected / exposed
    0 / 406 (0.00%)
    0 / 407 (0.00%)
    1 / 137 (0.73%)
         occurrences all number
    0
    0
    1
    Infected bites
         subjects affected / exposed
    1 / 406 (0.25%)
    0 / 407 (0.00%)
    0 / 137 (0.00%)
         occurrences all number
    1
    0
    0
    Infection
         subjects affected / exposed
    0 / 406 (0.00%)
    1 / 407 (0.25%)
    1 / 137 (0.73%)
         occurrences all number
    0
    1
    1
    Influenza
         subjects affected / exposed
    5 / 406 (1.23%)
    11 / 407 (2.70%)
    1 / 137 (0.73%)
         occurrences all number
    5
    13
    1
    Laryngitis
         subjects affected / exposed
    1 / 406 (0.25%)
    0 / 407 (0.00%)
    0 / 137 (0.00%)
         occurrences all number
    1
    0
    0
    Nasopharyngitis
         subjects affected / exposed
    39 / 406 (9.61%)
    38 / 407 (9.34%)
    13 / 137 (9.49%)
         occurrences all number
    48
    49
    15
    Onychomycosis
         subjects affected / exposed
    0 / 406 (0.00%)
    1 / 407 (0.25%)
    0 / 137 (0.00%)
         occurrences all number
    0
    1
    0
    Oral herpes
         subjects affected / exposed
    1 / 406 (0.25%)
    0 / 407 (0.00%)
    0 / 137 (0.00%)
         occurrences all number
    1
    0
    0
    Oral infection
         subjects affected / exposed
    1 / 406 (0.25%)
    0 / 407 (0.00%)
    0 / 137 (0.00%)
         occurrences all number
    1
    0
    0
    Paronychia
         subjects affected / exposed
    0 / 406 (0.00%)
    1 / 407 (0.25%)
    0 / 137 (0.00%)
         occurrences all number
    0
    1
    0
    Peritonsillitis
         subjects affected / exposed
    0 / 406 (0.00%)
    1 / 407 (0.25%)
    0 / 137 (0.00%)
         occurrences all number
    0
    1
    0
    Pharyngitis
         subjects affected / exposed
    4 / 406 (0.99%)
    1 / 407 (0.25%)
    0 / 137 (0.00%)
         occurrences all number
    4
    1
    0
    Pneumonia
         subjects affected / exposed
    0 / 406 (0.00%)
    1 / 407 (0.25%)
    0 / 137 (0.00%)
         occurrences all number
    0
    1
    0
    Pulpitis dental
         subjects affected / exposed
    1 / 406 (0.25%)
    1 / 407 (0.25%)
    0 / 137 (0.00%)
         occurrences all number
    1
    1
    0
    Respiratory tract infection
         subjects affected / exposed
    1 / 406 (0.25%)
    1 / 407 (0.25%)
    1 / 137 (0.73%)
         occurrences all number
    1
    1
    1
    Rhinitis
         subjects affected / exposed
    3 / 406 (0.74%)
    0 / 407 (0.00%)
    2 / 137 (1.46%)
         occurrences all number
    4
    0
    2
    Sepsis
         subjects affected / exposed
    0 / 406 (0.00%)
    0 / 407 (0.00%)
    1 / 137 (0.73%)
         occurrences all number
    0
    0
    1
    Sinusitis
         subjects affected / exposed
    3 / 406 (0.74%)
    3 / 407 (0.74%)
    0 / 137 (0.00%)
         occurrences all number
    3
    4
    0
    Skin candida
         subjects affected / exposed
    0 / 406 (0.00%)
    1 / 407 (0.25%)
    0 / 137 (0.00%)
         occurrences all number
    0
    1
    0
    Tinea cruris
         subjects affected / exposed
    0 / 406 (0.00%)
    1 / 407 (0.25%)
    0 / 137 (0.00%)
         occurrences all number
    0
    1
    0
    Tinea infection
         subjects affected / exposed
    0 / 406 (0.00%)
    2 / 407 (0.49%)
    0 / 137 (0.00%)
         occurrences all number
    0
    2
    0
    Tinea pedis
         subjects affected / exposed
    0 / 406 (0.00%)
    8 / 407 (1.97%)
    0 / 137 (0.00%)
         occurrences all number
    0
    8
    0
    Tinea versicolour
         subjects affected / exposed
    0 / 406 (0.00%)
    0 / 407 (0.00%)
    1 / 137 (0.73%)
         occurrences all number
    0
    0
    1
    Tonsillitis
         subjects affected / exposed
    0 / 406 (0.00%)
    1 / 407 (0.25%)
    0 / 137 (0.00%)
         occurrences all number
    0
    1
    0
    Tooth infection
         subjects affected / exposed
    1 / 406 (0.25%)
    1 / 407 (0.25%)
    0 / 137 (0.00%)
         occurrences all number
    1
    1
    0
    Tracheitis
         subjects affected / exposed
    0 / 406 (0.00%)
    0 / 407 (0.00%)
    1 / 137 (0.73%)
         occurrences all number
    0
    0
    1
    Upper respiratory tract infection
         subjects affected / exposed
    4 / 406 (0.99%)
    3 / 407 (0.74%)
    1 / 137 (0.73%)
         occurrences all number
    4
    3
    1
    Urinary tract infection
         subjects affected / exposed
    5 / 406 (1.23%)
    3 / 407 (0.74%)
    1 / 137 (0.73%)
         occurrences all number
    6
    4
    2
    Vaginal infection
         subjects affected / exposed
    1 / 406 (0.25%)
    0 / 407 (0.00%)
    0 / 137 (0.00%)
         occurrences all number
    1
    0
    0
    Viral infection
         subjects affected / exposed
    1 / 406 (0.25%)
    0 / 407 (0.00%)
    0 / 137 (0.00%)
         occurrences all number
    1
    0
    0
    Viral pharyngitis
         subjects affected / exposed
    0 / 406 (0.00%)
    1 / 407 (0.25%)
    0 / 137 (0.00%)
         occurrences all number
    0
    1
    0
    Vulvovaginal candidiasis
         subjects affected / exposed
    0 / 406 (0.00%)
    1 / 407 (0.25%)
    0 / 137 (0.00%)
         occurrences all number
    0
    1
    0
    Metabolism and nutrition disorders
    Appetite disorder
         subjects affected / exposed
    0 / 406 (0.00%)
    1 / 407 (0.25%)
    0 / 137 (0.00%)
         occurrences all number
    0
    1
    0
    Dehydration
         subjects affected / exposed
    0 / 406 (0.00%)
    1 / 407 (0.25%)
    0 / 137 (0.00%)
         occurrences all number
    0
    1
    0
    Diabetes mellitus
         subjects affected / exposed
    0 / 406 (0.00%)
    1 / 407 (0.25%)
    1 / 137 (0.73%)
         occurrences all number
    0
    1
    1
    Folate deficiency
         subjects affected / exposed
    1 / 406 (0.25%)
    0 / 407 (0.00%)
    0 / 137 (0.00%)
         occurrences all number
    1
    0
    0
    Glucose tolerance impaired
         subjects affected / exposed
    0 / 406 (0.00%)
    0 / 407 (0.00%)
    1 / 137 (0.73%)
         occurrences all number
    0
    0
    1
    Gout
         subjects affected / exposed
    2 / 406 (0.49%)
    0 / 407 (0.00%)
    1 / 137 (0.73%)
         occurrences all number
    2
    0
    1
    Hypercholesterolaemia
         subjects affected / exposed
    0 / 406 (0.00%)
    1 / 407 (0.25%)
    0 / 137 (0.00%)
         occurrences all number
    0
    1
    0
    Hyperglycaemia
         subjects affected / exposed
    0 / 406 (0.00%)
    1 / 407 (0.25%)
    1 / 137 (0.73%)
         occurrences all number
    0
    2
    1
    Hyperkalaemia
         subjects affected / exposed
    0 / 406 (0.00%)
    1 / 407 (0.25%)
    1 / 137 (0.73%)
         occurrences all number
    0
    1
    1
    Hyperlipidaemia
         subjects affected / exposed
    0 / 406 (0.00%)
    0 / 407 (0.00%)
    1 / 137 (0.73%)
         occurrences all number
    0
    0
    1
    Hyperuricaemia
         subjects affected / exposed
    0 / 406 (0.00%)
    2 / 407 (0.49%)
    0 / 137 (0.00%)
         occurrences all number
    0
    2
    0
    Hypokalaemia
         subjects affected / exposed
    0 / 406 (0.00%)
    2 / 407 (0.49%)
    0 / 137 (0.00%)
         occurrences all number
    0
    2
    0
    Type 2 diabetes mellitus
         subjects affected / exposed
    0 / 406 (0.00%)
    4 / 407 (0.98%)
    1 / 137 (0.73%)
         occurrences all number
    0
    4
    1
    Vitamin B12 deficiency
         subjects affected / exposed
    2 / 406 (0.49%)
    0 / 407 (0.00%)
    0 / 137 (0.00%)
         occurrences all number
    2
    0
    0
    Vitamin D deficiency
         subjects affected / exposed
    0 / 406 (0.00%)
    1 / 407 (0.25%)
    0 / 137 (0.00%)
         occurrences all number
    0
    1
    0

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    26 May 2015
    Amendment 2 presented change in the study design with the addition of the open-label amorolfine arm.
    18 Nov 2015
    Amendment 3 presented inclusion criteria (age) no longer presents an upper age limit: "Subjects aged 12 years and older of any race."
    11 Apr 2016
    Amendment 4 presented the addition of re-screening procedures. The wording of the analysis populations and serious adverse event sections were also improved.
    22 Mar 2017
    Amendment 5 presented the removal of sample drawing intended to assess the presence of terbinafine in plasma. Additional details about the sensitivity analyses for handling missing data, the combination of small centres for the analysis of primary and secondary efficacy endpoints, the trial termination and data collection and validation were included. The negative culture rate for dermatophytes of the target nail at Week 60 was reclassified as a supportive efficacy endpoint, instead of a key secondary efficacy endpoint, the inclusion of a multiplicity adjustment among the key secondary endpoints using the Holm-Bonferroni method, an additional week (from 1 to 2 weeks) for repeating mycology tests at screening, a timeframe for study documents retention and a Quality Assurance section. Unblinding procedures and subjects numbering were specified as detailed in separate documents archived in the Trial Master File. The following changes were applied prior to database lock: 1) Negative culture rate for dermatophytes of the target toenail was displayed at all study visits. 2) Additional supportive efficacy endpoints: -Since the initial definition of complete cure was considered too stringent to reflect the true benefit of onychomycosis treatment in general practice, particularly since hyphae seen on microscopy may in reality no longer be viable, and may therefore limit the use of newer topical agents in mild-to moderate disease, the absence of clinical signs following an adequate washout period, coupled with negative culture, with or without negative microscopy, was considered a suitable indicator of onychomycosis cure. For this reason, two additional modified supportive endpoints were added:- Modified cure rate at Week 60 and Modified responder rate at Week 60.

    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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