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    Clinical Trial Results:
    Multicenter, randomised, double-blind clinical trial on the efficacy and safety of medicinal products containing Diclofenac in patients with actinic keratosis

    Summary
    EudraCT number
    2014-001621-33
    Trial protocol
    DE  
    Global end of trial date
    25 Jun 2015

    Results information
    Results version number
    v2(current)
    This version publication date
    25 Mar 2017
    First version publication date
    20 Jul 2016
    Other versions
    v1
    Version creation reason
    • Correction of full data set
    Erroneous statement regarding the primary efficacy criterion

    Trial information

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    Trial identification
    Sponsor protocol code
    14-01/AK-Diclo
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    -
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Dermapharm AG
    Sponsor organisation address
    Lil-Dagover-Ring 7, Gruenwald, Germany, 82031
    Public contact
    Head of Clinical Department, Dermapharm AG, 0049 08964186-0,
    Scientific contact
    Head of Clinical Department, Dermapharm AG, 0049 08964186-0,
    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
    18 Nov 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    25 Jun 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    25 Jun 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Evaluation of the efficacy and safety of a new diclofenac 3% gel formulation vs. the originator Solaraze (licensed) vs. vehicle in patients with actinic keratosis.
    Protection of trial subjects
    There were no specific measures necessary.
    Background therapy
    There was no background therapy.
    Evidence for comparator
    The trial aimed to show therapeutic equivalence with regard to the comparator in order to obtain a generic marketing authorization for the test product.
    Actual start date of recruitment
    23 Sep 2014
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Germany: 439
    Worldwide total number of subjects
    439
    EEA total number of subjects
    439
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    66
    From 65 to 84 years
    355
    85 years and over
    18

    Subject disposition

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    Recruitment
    Recruitment details
    all study centers in Germany; first patient first visit: 25 September 2014; last patient last visit: 25 June 2015

    Pre-assignment
    Screening details
    Main criteria for inclusion: Immunocompetent women and men ≥ 18 years of age; Diagnosis of “actinic keratosis”; treatment area of approximately 50 cm² on the face or the scalp; at least 7 delimitable target lesions with the following properties: mild to moderate clinical severity, diameter ≥ 4 mm, not hypertrophic, not massively hyperkeratotic

    Period 1
    Period 1 title
    Observation Period (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Monitor, Data analyst
    Blinding implementation details
    All study preparations were indistinguishable in terms of appearance and were filled in white tubes of identical appearance.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    DicloGel
    Arm description
    Treatment arm with test product
    Arm type
    Experimental

    Investigational medicinal product name
    Diclofenac 3% gel
    Investigational medicinal product code
    D11AX18
    Other name
    Pharmaceutical forms
    Gel
    Routes of administration
    Cutaneous use
    Dosage and administration details
    To be rubbed in slightly on the observation area twice daily (in the morning, in the evening)

    Arm title
    Solaraze
    Arm description
    Treatment arm with reference product
    Arm type
    Active comparator

    Investigational medicinal product name
    Solaraze
    Investigational medicinal product code
    D11AX18
    Other name
    Pharmaceutical forms
    Gel
    Routes of administration
    Cutaneous use
    Dosage and administration details
    To be rubbed in slightly on the observation area twice daily (in the morning, in the evening)

    Arm title
    Vehicle
    Arm description
    Treatment arm with vehicle to test product
    Arm type
    Placebo

    Investigational medicinal product name
    Vehicle
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Gel
    Routes of administration
    Cutaneous use
    Dosage and administration details
    To be rubbed in slightly on the observation area twice daily (in the morning, in the evening)

    Number of subjects in period 1
    DicloGel Solaraze Vehicle
    Started
    146
    147
    146
    Completed
    141
    133
    143
    Not completed
    5
    14
    3
         Technical-logistic reasons
    -
    1
    1
         Physician decision
    -
    1
    -
         Adverse event, serious fatal
    -
    4
    -
         Adverse event, non-fatal
    3
    5
    2
         Consent withdrawn by subject
    2
    2
    -
         Lost to follow-up
    -
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Observation Period
    Reporting group description
    -

    Reporting group values
    Observation Period Total
    Number of subjects
    439 439
    Age categorical
    Units: Subjects
        In utero
    0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0
        Newborns (0-27 days)
    0 0
        Infants and toddlers (28 days-23 months)
    0 0
        Children (2-11 years)
    0 0
        Adolescents (12-17 years)
    0 0
        Adults (18-64 years)
    66 66
        From 65-84 years
    355 355
        85 years and over
    18 18
    Gender categorical
    Units: Subjects
        Female
    68 68
        Male
    371 371
    Subject analysis sets

    Subject analysis set title
    ITT
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    includes all patients of the safety data set who comply with the study diagnosis (according to the associated inclusion criteria) and provide the baseline value and at least one post baseline value under treatment

    Subject analysis set title
    PP
    Subject analysis set type
    Per protocol
    Subject analysis set description
    includes all patients of the ITT data set who do not exhibit any major protocol violations

    Subject analysis set title
    Safety
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    comprises all patients who had administered the study medication at least once

    Subject analysis sets values
    ITT PP Safety
    Number of subjects
    433
    349
    439
    Age categorical
    Units: Subjects
        In utero
    0
    0
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
    0
    0
        Newborns (0-27 days)
    0
    0
    0
        Infants and toddlers (28 days-23 months)
    0
    0
    0
        Children (2-11 years)
    0
    0
    0
        Adolescents (12-17 years)
    0
    0
    0
        Adults (18-64 years)
    65
    61
    66
        From 65-84 years
    351
    276
    355
        85 years and over
    17
    12
    18
    Age continuous
    Units:
        
    ±
    ±
    ±
    Gender categorical
    Units: Subjects
        Female
    67
    56
    68
        Male
    366
    293
    371

    End points

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    End points reporting groups
    Reporting group title
    DicloGel
    Reporting group description
    Treatment arm with test product

    Reporting group title
    Solaraze
    Reporting group description
    Treatment arm with reference product

    Reporting group title
    Vehicle
    Reporting group description
    Treatment arm with vehicle to test product

    Subject analysis set title
    ITT
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    includes all patients of the safety data set who comply with the study diagnosis (according to the associated inclusion criteria) and provide the baseline value and at least one post baseline value under treatment

    Subject analysis set title
    PP
    Subject analysis set type
    Per protocol
    Subject analysis set description
    includes all patients of the ITT data set who do not exhibit any major protocol violations

    Subject analysis set title
    Safety
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    comprises all patients who had administered the study medication at least once

    Primary: Treatment effect

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    End point title
    Treatment effect [1]
    End point description
    Number (percentage) of patients with "clinical success" according to predefined criteria at end of observation period
    End point type
    Primary
    End point timeframe
    Inclusion visit (= start of treatment) and main visit (= 30 days after end of treatment)
    Notes
    [1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The primary goal of this trial was to show therapeutic equivalence of test to reference product. The vehicle arm served as verification of the assay sensitivity. The three end point tests had to be done separately in order to avoid the otherwise necessary adjustment of the significance level.
    End point values
    DicloGel Solaraze PP
    Number of subjects analysed
    112
    111
    223
    Units: Number
    72
    75
    147
    Statistical analysis title
    Analysis of efficacy
    Statistical analysis description
    equivalence test (two-sided) with 95% CI and a pre-defined equivalence interval [-0.20; 0.20]
    Comparison groups
    DicloGel v Solaraze
    Number of subjects included in analysis
    223
    Analysis specification
    Pre-specified
    Analysis type
    equivalence
    Method
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.0328
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.1661
         upper limit
    0.1005

    Other pre-specified: Superiority of Test over Vehicle

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    End point title
    Superiority of Test over Vehicle [2]
    End point description
    Number (percentage) of patients with "clinical success" according to predefined criteria at end of observation period
    End point type
    Other pre-specified
    End point timeframe
    Inclusion visit (= start of treatment) and main visit (= 30 days after end of treatment)
    Notes
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The statistical analysis for this end point served as verification of the assay sensitivity and had to be done individually for each active preparation in accordance with CPMP/EWP/908/99.
    End point values
    DicloGel Vehicle ITT
    Number of subjects analysed
    141
    143
    284
    Units: Number
    83
    43
    126
    Statistical analysis title
    Superiority Test - Placebo
    Comparison groups
    DicloGel v Vehicle
    Number of subjects included in analysis
    284
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Fisher exact
    Confidence interval

    Other pre-specified: Superiority of Reference over Vehicle

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    End point title
    Superiority of Reference over Vehicle [3]
    End point description
    Number (percentage) of patients with "clinical success" according to predefined criteria at end of observation period
    End point type
    Other pre-specified
    End point timeframe
    Inclusion visit (= start of treatment) and main visit (= 30 days after end of treatment)
    Notes
    [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The statistical analysis for this end point served as verification of the assay sensitivity and had to be done individually for each active preparation in accordance with CPMP/EWP/908/99.
    End point values
    Solaraze Vehicle ITT
    Number of subjects analysed
    133
    143
    276
    Units: Number
    83
    43
    126
    Statistical analysis title
    Superiority Comparator - Placebo
    Comparison groups
    Solaraze v Vehicle
    Number of subjects included in analysis
    276
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Fisher exact
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Inclusion visit (start of treatment) to main visit (= 30 days after end of treatment; end of observation period)
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    18.1
    Reporting groups
    Reporting group title
    Vehicle
    Reporting group description
    treatment arm with vehicle (to test product)

    Reporting group title
    Solaraze
    Reporting group description
    treatment arm with reference product

    Reporting group title
    DicloGel
    Reporting group description
    treatment arm with test product

    Serious adverse events
    Vehicle Solaraze DicloGel
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 146 (2.05%)
    5 / 147 (3.40%)
    5 / 146 (3.42%)
         number of deaths (all causes)
    0
    4
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Vascular disorders
    Aortic aneurysm
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 147 (0.68%)
    0 / 146 (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
    Facial bones fracture
         subjects affected / exposed
    0 / 146 (0.00%)
    0 / 147 (0.00%)
    1 / 146 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Road traffic accident
         subjects affected / exposed
    0 / 146 (0.00%)
    0 / 147 (0.00%)
    1 / 146 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Bladder transitional cell carcinoma
         subjects affected / exposed
    0 / 146 (0.00%)
    0 / 147 (0.00%)
    1 / 146 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchial carcinoma
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 147 (0.68%)
    0 / 146 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Colon cancer
         subjects affected / exposed
    1 / 146 (0.68%)
    0 / 147 (0.00%)
    0 / 146 (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
    Cardiac disorders
    Cardiac failure
         subjects affected / exposed
    0 / 146 (0.00%)
    0 / 147 (0.00%)
    1 / 146 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    0 / 146 (0.00%)
    0 / 147 (0.00%)
    2 / 146 (1.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 146 (0.00%)
    0 / 147 (0.00%)
    1 / 146 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Syncope
         subjects affected / exposed
    1 / 146 (0.68%)
    0 / 147 (0.00%)
    2 / 146 (1.37%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cerebral infarction
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 147 (0.68%)
    0 / 146 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Cerebral ischaemia
         subjects affected / exposed
    1 / 146 (0.68%)
    0 / 147 (0.00%)
    0 / 146 (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
    General disorders and administration site conditions
    Sudden cardiac death
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 147 (0.68%)
    0 / 146 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Psychiatric disorders
    Mental disorder
         subjects affected / exposed
    1 / 146 (0.68%)
    0 / 147 (0.00%)
    0 / 146 (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
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    1 / 146 (0.68%)
    1 / 147 (0.68%)
    0 / 146 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0.05%
    Non-serious adverse events
    Vehicle Solaraze DicloGel
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    37 / 146 (25.34%)
    52 / 147 (35.37%)
    54 / 146 (36.99%)
    Vascular disorders
    Varicose vein
         subjects affected / exposed
    1 / 146 (0.68%)
    0 / 147 (0.00%)
    1 / 146 (0.68%)
         occurrences all number
    1
    0
    1
    Lymphoedema
         subjects affected / exposed
    0 / 146 (0.00%)
    0 / 147 (0.00%)
    1 / 146 (0.68%)
         occurrences all number
    0
    0
    1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Skin papilloma
         subjects affected / exposed
    0 / 146 (0.00%)
    0 / 147 (0.00%)
    2 / 146 (1.37%)
         occurrences all number
    0
    0
    2
    Squamous cell carcinoma of the skin
         subjects affected / exposed
    1 / 146 (0.68%)
    1 / 147 (0.68%)
    0 / 146 (0.00%)
         occurrences all number
    1
    1
    0
    Bowen's disease
         subjects affected / exposed
    1 / 146 (0.68%)
    0 / 147 (0.00%)
    0 / 146 (0.00%)
         occurrences all number
    1
    0
    0
    Basal cell carcinoma
         subjects affected / exposed
    0 / 146 (0.00%)
    0 / 147 (0.00%)
    1 / 146 (0.68%)
         occurrences all number
    0
    0
    1
    Keratoacanthoma
         subjects affected / exposed
    0 / 146 (0.00%)
    2 / 147 (1.36%)
    0 / 146 (0.00%)
         occurrences all number
    0
    2
    0
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    0 / 146 (0.00%)
    0 / 147 (0.00%)
    1 / 146 (0.68%)
         occurrences all number
    0
    0
    1
    Atopy
         subjects affected / exposed
    0 / 146 (0.00%)
    0 / 147 (0.00%)
    1 / 146 (0.68%)
         occurrences all number
    0
    0
    1
    General disorders and administration site conditions
    Application site pain
         subjects affected / exposed
    6 / 146 (4.11%)
    6 / 147 (4.08%)
    6 / 146 (4.11%)
         occurrences all number
    6
    6
    6
    Application site erythema
         subjects affected / exposed
    5 / 146 (3.42%)
    15 / 147 (10.20%)
    13 / 146 (8.90%)
         occurrences all number
    5
    15
    13
    Application site eczema
         subjects affected / exposed
    1 / 146 (0.68%)
    3 / 147 (2.04%)
    3 / 146 (2.05%)
         occurrences all number
    1
    3
    3
    Application site exfoliation
         subjects affected / exposed
    4 / 146 (2.74%)
    10 / 147 (6.80%)
    7 / 146 (4.79%)
         occurrences all number
    4
    10
    7
    Application site pruritus
         subjects affected / exposed
    4 / 146 (2.74%)
    7 / 147 (4.76%)
    5 / 146 (3.42%)
         occurrences all number
    4
    7
    5
    Application site haemorrhage
         subjects affected / exposed
    0 / 146 (0.00%)
    0 / 147 (0.00%)
    2 / 146 (1.37%)
         occurrences all number
    0
    0
    2
    Application site erosion
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 147 (0.68%)
    2 / 146 (1.37%)
         occurrences all number
    0
    1
    2
    Application site scab
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 147 (0.68%)
    1 / 146 (0.68%)
         occurrences all number
    0
    1
    1
    Application site pustules
         subjects affected / exposed
    0 / 146 (0.00%)
    0 / 147 (0.00%)
    1 / 146 (0.68%)
         occurrences all number
    0
    0
    1
    Impaired healing
         subjects affected / exposed
    0 / 146 (0.00%)
    0 / 147 (0.00%)
    1 / 146 (0.68%)
         occurrences all number
    0
    0
    1
    Application site inflammation
         subjects affected / exposed
    0 / 146 (0.00%)
    0 / 147 (0.00%)
    1 / 146 (0.68%)
         occurrences all number
    0
    0
    1
    Application site discomfort
         subjects affected / exposed
    2 / 146 (1.37%)
    1 / 147 (0.68%)
    2 / 146 (1.37%)
         occurrences all number
    2
    1
    2
    Application site dysaesthesia
         subjects affected / exposed
    1 / 146 (0.68%)
    0 / 147 (0.00%)
    0 / 146 (0.00%)
         occurrences all number
    1
    0
    0
    Psychiatric disorders
    Sleep disorder
         subjects affected / exposed
    1 / 146 (0.68%)
    0 / 147 (0.00%)
    1 / 146 (0.68%)
         occurrences all number
    1
    0
    1
    Depression
         subjects affected / exposed
    1 / 146 (0.68%)
    0 / 147 (0.00%)
    0 / 146 (0.00%)
         occurrences all number
    1
    0
    0
    Reproductive system and breast disorders
    Benign prostatic hyperplasia
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 147 (0.68%)
    1 / 146 (0.68%)
         occurrences all number
    0
    1
    1
    Prostatitis
         subjects affected / exposed
    1 / 146 (0.68%)
    0 / 147 (0.00%)
    1 / 146 (0.68%)
         occurrences all number
    1
    0
    1
    Injury, poisoning and procedural complications
    Arthropod bite
         subjects affected / exposed
    1 / 146 (0.68%)
    0 / 147 (0.00%)
    0 / 146 (0.00%)
         occurrences all number
    1
    0
    0
    Tendon rupture
         subjects affected / exposed
    1 / 146 (0.68%)
    0 / 147 (0.00%)
    0 / 146 (0.00%)
         occurrences all number
    1
    0
    0
    Limb injury
         subjects affected / exposed
    1 / 146 (0.68%)
    0 / 147 (0.00%)
    1 / 146 (0.68%)
         occurrences all number
    1
    0
    1
    Skin wound
         subjects affected / exposed
    0 / 146 (0.00%)
    0 / 147 (0.00%)
    1 / 146 (0.68%)
         occurrences all number
    0
    0
    1
    Investigations
    Traumatic haematoma
         subjects affected / exposed
    0 / 146 (0.00%)
    0 / 147 (0.00%)
    1 / 146 (0.68%)
         occurrences all number
    0
    0
    1
    Cardiac disorders
    Tachycardia
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 147 (0.68%)
    0 / 146 (0.00%)
         occurrences all number
    0
    1
    0
    Congenital, familial and genetic disorders
    Phimosis
         subjects affected / exposed
    0 / 146 (0.00%)
    0 / 147 (0.00%)
    1 / 146 (0.68%)
         occurrences all number
    0
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    0 / 146 (0.00%)
    2 / 147 (1.36%)
    1 / 146 (0.68%)
         occurrences all number
    0
    2
    1
    Pulmonary oedema
         subjects affected / exposed
    0 / 146 (0.00%)
    0 / 147 (0.00%)
    1 / 146 (0.68%)
         occurrences all number
    0
    0
    1
    Oropharyngeal pain
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 147 (0.68%)
    2 / 146 (1.37%)
         occurrences all number
    0
    1
    2
    Asthma
         subjects affected / exposed
    1 / 146 (0.68%)
    0 / 147 (0.00%)
    0 / 146 (0.00%)
         occurrences all number
    1
    0
    0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    1 / 146 (0.68%)
    0 / 147 (0.00%)
    0 / 146 (0.00%)
         occurrences all number
    1
    0
    0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    0 / 146 (0.00%)
    0 / 147 (0.00%)
    1 / 146 (0.68%)
         occurrences all number
    0
    0
    1
    Headache
         subjects affected / exposed
    1 / 146 (0.68%)
    2 / 147 (1.36%)
    1 / 146 (0.68%)
         occurrences all number
    1
    2
    1
    Carpal tunnel syndrome
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 147 (0.68%)
    0 / 146 (0.00%)
         occurrences all number
    0
    1
    0
    Eye disorders
    Blepharitis
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 147 (0.68%)
    0 / 146 (0.00%)
         occurrences all number
    0
    1
    0
    Eye swelling
         subjects affected / exposed
    0 / 146 (0.00%)
    0 / 147 (0.00%)
    1 / 146 (0.68%)
         occurrences all number
    0
    0
    1
    Eye irritation
         subjects affected / exposed
    0 / 146 (0.00%)
    0 / 147 (0.00%)
    1 / 146 (0.68%)
         occurrences all number
    0
    0
    1
    Keratitis
         subjects affected / exposed
    1 / 146 (0.68%)
    0 / 147 (0.00%)
    0 / 146 (0.00%)
         occurrences all number
    1
    0
    0
    Eyelid erosion
         subjects affected / exposed
    0 / 146 (0.00%)
    0 / 147 (0.00%)
    1 / 146 (0.68%)
         occurrences all number
    0
    0
    1
    Gastrointestinal disorders
    Anal fissure
         subjects affected / exposed
    1 / 146 (0.68%)
    0 / 147 (0.00%)
    1 / 146 (0.68%)
         occurrences all number
    1
    0
    1
    Diarrhoea
         subjects affected / exposed
    1 / 146 (0.68%)
    0 / 147 (0.00%)
    0 / 146 (0.00%)
         occurrences all number
    1
    0
    0
    Abdominal pain
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 147 (0.68%)
    1 / 146 (0.68%)
         occurrences all number
    0
    1
    1
    Gastritis
         subjects affected / exposed
    1 / 146 (0.68%)
    0 / 147 (0.00%)
    0 / 146 (0.00%)
         occurrences all number
    1
    0
    0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 147 (0.68%)
    0 / 146 (0.00%)
         occurrences all number
    0
    1
    0
    Renal and urinary disorders
    Urge incontinence
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 147 (0.68%)
    0 / 146 (0.00%)
         occurrences all number
    0
    1
    0
    Skin and subcutaneous tissue disorders
    Actinic keratosis
    Additional description: not in the treatment/ observation area
         subjects affected / exposed
    0 / 146 (0.00%)
    0 / 147 (0.00%)
    1 / 146 (0.68%)
         occurrences all number
    0
    0
    1
    Eczema
         subjects affected / exposed
    4 / 146 (2.74%)
    4 / 147 (2.72%)
    6 / 146 (4.11%)
         occurrences all number
    4
    4
    6
    Androgenetic alopecia
         subjects affected / exposed
    1 / 146 (0.68%)
    0 / 147 (0.00%)
    3 / 146 (2.05%)
         occurrences all number
    1
    0
    3
    Unguis incarnatus
         subjects affected / exposed
    0 / 146 (0.00%)
    0 / 147 (0.00%)
    1 / 146 (0.68%)
         occurrences all number
    0
    0
    1
    Pruritus
         subjects affected / exposed
    1 / 146 (0.68%)
    2 / 147 (1.36%)
    3 / 146 (2.05%)
         occurrences all number
    1
    2
    3
    Erythema
         subjects affected / exposed
    0 / 146 (0.00%)
    3 / 147 (2.04%)
    3 / 146 (2.05%)
         occurrences all number
    0
    3
    3
    Skin irritation
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 147 (0.68%)
    0 / 146 (0.00%)
         occurrences all number
    0
    1
    0
    Stasis dermatitis
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 147 (0.68%)
    0 / 146 (0.00%)
         occurrences all number
    0
    1
    0
    Hyperkeratosis
         subjects affected / exposed
    0 / 146 (0.00%)
    0 / 147 (0.00%)
    1 / 146 (0.68%)
         occurrences all number
    0
    0
    1
    Dermatitis contact
         subjects affected / exposed
    1 / 146 (0.68%)
    3 / 147 (2.04%)
    1 / 146 (0.68%)
         occurrences all number
    1
    3
    1
    Rosacea
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 147 (0.68%)
    0 / 146 (0.00%)
         occurrences all number
    0
    1
    0
    Urticaria
         subjects affected / exposed
    1 / 146 (0.68%)
    1 / 147 (0.68%)
    0 / 146 (0.00%)
         occurrences all number
    1
    1
    0
    Eczema nummular
         subjects affected / exposed
    0 / 146 (0.00%)
    0 / 147 (0.00%)
    1 / 146 (0.68%)
         occurrences all number
    0
    0
    1
    Hand dermatitis
         subjects affected / exposed
    0 / 146 (0.00%)
    0 / 147 (0.00%)
    1 / 146 (0.68%)
         occurrences all number
    0
    0
    1
    Intertrigo
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 147 (0.68%)
    0 / 146 (0.00%)
         occurrences all number
    0
    1
    0
    Seborrhoeic dermatitis
         subjects affected / exposed
    1 / 146 (0.68%)
    0 / 147 (0.00%)
    0 / 146 (0.00%)
         occurrences all number
    1
    0
    0
    Musculoskeletal and connective tissue disorders
    Muscle spasms
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 147 (0.68%)
    0 / 146 (0.00%)
         occurrences all number
    0
    1
    0
    Back pain
         subjects affected / exposed
    1 / 146 (0.68%)
    1 / 147 (0.68%)
    0 / 146 (0.00%)
         occurrences all number
    1
    1
    0
    Synovial cyst
         subjects affected / exposed
    0 / 146 (0.00%)
    0 / 147 (0.00%)
    1 / 146 (0.68%)
         occurrences all number
    0
    0
    1
    Invertebral disc disorder
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 147 (0.68%)
    0 / 146 (0.00%)
         occurrences all number
    0
    1
    0
    Metabolism and nutrition disorders
    Hyperlipidaemia
         subjects affected / exposed
    0 / 146 (0.00%)
    0 / 147 (0.00%)
    1 / 146 (0.68%)
         occurrences all number
    0
    0
    1
    Hyperuricaemia
         subjects affected / exposed
    0 / 146 (0.00%)
    0 / 147 (0.00%)
    1 / 146 (0.68%)
         occurrences all number
    0
    0
    1
    Hypercholesterolaemia
         subjects affected / exposed
    2 / 146 (1.37%)
    0 / 147 (0.00%)
    1 / 146 (0.68%)
         occurrences all number
    2
    0
    1
    Infections and infestations
    Onychomycosis
         subjects affected / exposed
    0 / 146 (0.00%)
    0 / 147 (0.00%)
    1 / 146 (0.68%)
         occurrences all number
    0
    0
    1
    Upper respiratory tract infection
         subjects affected / exposed
    3 / 146 (2.05%)
    6 / 147 (4.08%)
    5 / 146 (3.42%)
         occurrences all number
    3
    6
    5
    Eczema infected
         subjects affected / exposed
    2 / 146 (1.37%)
    1 / 147 (0.68%)
    2 / 146 (1.37%)
         occurrences all number
    2
    1
    2
    Nasopharyngitis
         subjects affected / exposed
    3 / 146 (2.05%)
    5 / 147 (3.40%)
    6 / 146 (4.11%)
         occurrences all number
    3
    5
    6
    Bronchitis
         subjects affected / exposed
    1 / 146 (0.68%)
    0 / 147 (0.00%)
    1 / 146 (0.68%)
         occurrences all number
    1
    0
    1
    Pyoderma
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 147 (0.68%)
    1 / 146 (0.68%)
         occurrences all number
    0
    1
    1
    Folliculitis
         subjects affected / exposed
    1 / 146 (0.68%)
    1 / 147 (0.68%)
    1 / 146 (0.68%)
         occurrences all number
    1
    1
    1
    Fungal skin infection
         subjects affected / exposed
    0 / 146 (0.00%)
    0 / 147 (0.00%)
    1 / 146 (0.68%)
         occurrences all number
    0
    0
    1
    Conjunctivitis
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 147 (0.68%)
    0 / 146 (0.00%)
         occurrences all number
    0
    1
    0
    Urethritis
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 147 (0.68%)
    0 / 146 (0.00%)
         occurrences all number
    0
    1
    0
    Oesophageal candidiasis
         subjects affected / exposed
    1 / 146 (0.68%)
    0 / 147 (0.00%)
    0 / 146 (0.00%)
         occurrences all number
    1
    0
    0
    Influenza
         subjects affected / exposed
    0 / 146 (0.00%)
    2 / 147 (1.36%)
    0 / 146 (0.00%)
         occurrences all number
    0
    2
    0
    Paronychia
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 147 (0.68%)
    0 / 146 (0.00%)
         occurrences all number
    0
    1
    0
    Rhinitis
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 147 (0.68%)
    0 / 146 (0.00%)
         occurrences all number
    0
    1
    0
    Pulpitis dental
         subjects affected / exposed
    2 / 146 (1.37%)
    0 / 147 (0.00%)
    0 / 146 (0.00%)
         occurrences all number
    3
    0
    0
    Epididymitis ureaplasmal
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 147 (0.68%)
    0 / 146 (0.00%)
         occurrences all number
    0
    1
    0
    Spinal cord abscess
         subjects affected / exposed
    0 / 146 (0.00%)
    1 / 147 (0.68%)
    0 / 146 (0.00%)
         occurrences all number
    0
    1
    0

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? No

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

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