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    Clinical Trial Results:
    Efficacy and safety of ingenol mebutate gel 0.015% compared to diclofenac sodium gel 3% in subjects with actinic keratoses on the face or scalp.

    Summary
    EudraCT number
    2014-003218-98
    Trial protocol
    DE   GB   ES  
    Global end of trial date
    10 Jun 2016

    Results information
    Results version number
    v1(current)
    This version publication date
    25 Jun 2017
    First version publication date
    25 Jun 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    LP0041-1120
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02406014
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    LEO Pharma A/S
    Sponsor organisation address
    Industriparken 55, Ballerup, Denmark, 2750
    Public contact
    Clinical Trial Disclosure Specialist, LEO Pharma A/S, +45 4494 5888, disclosure@leo-pharma.com
    Scientific contact
    Clinical Trial Disclosure Specialist, LEO Pharma A/S, +45 4494 5888, disclosure@leo-pharma.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    15 Dec 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    10 Jun 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    10 Jun 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To compare the efficacy of daily application for 3 consecutive days of ingenol mebutate gel 0.015% with the efficacy of diclofenac sodium gel 3% for 90 days in subjects with AK on the face or scalp.
    Protection of trial subjects
    The clinical trial was conducted to conform to the principles of the Declaration of Helsinki as adopted by the 18th World Medical Association General Assembly, 1964, and subsequent amendments. All subjects received written and verbal information concerning the clinical trial. This information emphasised that participation in the clinical trial was voluntary and that the subject could withdraw from the clinical trial at any time and for any reason. All subjects were given an opportunity to ask questions and were given sufficient time to consider before consenting.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    21 Apr 2015
    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
    Spain: 100
    Country: Number of subjects enrolled
    United Kingdom: 150
    Country: Number of subjects enrolled
    Germany: 252
    Worldwide total number of subjects
    502
    EEA total number of subjects
    502
    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)
    57
    From 65 to 84 years
    409
    85 years and over
    36

    Subject disposition

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    Recruitment
    Recruitment details
    A total of 511 subjects were enrolled, of which 502 subjects were randomised (255 subjects to ingenol mebutate and 247 subjects to diclofenac sodium). The subjects were enrolled in a total of 33 sites in 3 countries Germany (14 sites), Spain (7 sites) and the United Kingdom (12 sites).

    Pre-assignment
    Screening details
    Inclusion criteria: Subjects with 4 to 8 clinically typical, visible and discrete AKs within a contiguous 25 cm² treatment area on the face or scalp.

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Not blinded
    Blinding implementation details
    Not applicable as this is an open-label trial. The (sub) investigators were blinded at the time the aktinic keratosis (AK) assessments and count were performed.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    ingenol mebutate 0.015%
    Arm description
    -
    Arm type
    Experimental

    Investigational medicinal product name
    Picato®
    Investigational medicinal product code
    Other name
    ingenol mebutate gel 0.015%
    Pharmaceutical forms
    Gel
    Routes of administration
    Topical use
    Dosage and administration details
    At Day 1 selected treatment areas (STA) were identified and marked by the investigator. At Week 8 for the ingenol mebutate group, subjects who presented existing AKs or newly emergent AKs in the STA started a second treatment course with ingenol mebutate gel 0.015% (treatment area already marked). The subjects were instructed to apply the IMPs according to the respective SmPCs.

    Arm title
    diclofenac sodium 3%
    Arm description
    -
    Arm type
    Active comparator

    Investigational medicinal product name
    Solaraze®
    Investigational medicinal product code
    Other name
    diclofenac sodium gel 3%
    Pharmaceutical forms
    Gel
    Routes of administration
    Topical use
    Dosage and administration details
    The subjects were instructed to apply the IMPs according to the respective SmPCs.

    Number of subjects in period 1
    ingenol mebutate 0.015% diclofenac sodium 3%
    Started
    255
    247
    Completed
    233
    211
    Not completed
    22
    36
         Investigator decision
    -
    1
         Death
    -
    2
         Protocol deviation
    2
    2
         Other
    -
    2
         Adverse event, non-fatal
    7
    15
         Consent withdrawn by subject
    11
    11
         Lost to follow-up
    2
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    ingenol mebutate 0.015%
    Reporting group description
    -

    Reporting group title
    diclofenac sodium 3%
    Reporting group description
    -

    Reporting group values
    ingenol mebutate 0.015% diclofenac sodium 3% Total
    Number of subjects
    255 247 502
    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)
    32 25 57
        From 65-84 years
    202 207 409
        85 years and over
    21 15 36
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    74.1 ± 8.2 73.6 ± 8.4 -
    Gender categorical
    Units: Subjects
        Female
    39 35 74
        Male
    216 212 428

    End points

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    End points reporting groups
    Reporting group title
    ingenol mebutate 0.015%
    Reporting group description
    -

    Reporting group title
    diclofenac sodium 3%
    Reporting group description
    -

    Primary: Complete clearance at Week 8 (ingenol mebutate) versus Week 17 (diclofenac sodium)

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    End point title
    Complete clearance at Week 8 (ingenol mebutate) versus Week 17 (diclofenac sodium)
    End point description
    End point type
    Primary
    End point timeframe
    Day 1 to Week 8 (ingenol mebutate) Day 1 to Week 17 (diclofenac sodium)
    End point values
    ingenol mebutate 0.015% diclofenac sodium 3%
    Number of subjects analysed
    255
    247
    Units: Subjects
        Cleared
    88
    58
        Not cleared
    167
    189
    Statistical analysis title
    Complete clearance
    Comparison groups
    ingenol mebutate 0.015% v diclofenac sodium 3%
    Number of subjects included in analysis
    502
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.006 [1]
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.79
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.18
         upper limit
    2.71
    Notes
    [1] - Logistic regression with factors treatment and anatomical location and site as random effect.

    Secondary: Complete clearance after last treatment course

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    End point title
    Complete clearance after last treatment course
    End point description
    Last treatment course is defined as: Ingenol mebutate arm: subjects receiving only one treatment course evaluated at Week 8, subjects receiving two treatment courses evaluated at Week 17.
    End point type
    Secondary
    End point timeframe
    Day 1 to Week 8 or Week 17 (ingenol mebutate) Day 1 to Week 17 (diclofenac sodium)
    End point values
    ingenol mebutate 0.015% diclofenac sodium 3%
    Number of subjects analysed
    255
    247
    Units: Subjects
        Cleared
    136
    58
        Not cleared
    119
    189
    Statistical analysis title
    Complete clearance after last treatment course
    Comparison groups
    ingenol mebutate 0.015% v diclofenac sodium 3%
    Number of subjects included in analysis
    502
    Analysis specification
    Pre-specified
    Analysis type
    superiority [2]
    P-value
    < 0.001
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    4.36
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    2.86
         upper limit
    6.64
    Notes
    [2] - Odds of complete clearance (Ingenol mebutate relative to Diclofenac sodium), logistic regression with factors treatment and anatomical location and site as random effect

    Secondary: Complete clearance at Week 17

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    End point title
    Complete clearance at Week 17
    End point description
    The complete clearance at Week 17 for ingenol mebutate and diclofenac sodium.
    End point type
    Secondary
    End point timeframe
    Day 1 to Week 17
    End point values
    ingenol mebutate 0.015% diclofenac sodium 3%
    Number of subjects analysed
    255
    247
    Units: Subjects
        Cleared
    115
    58
        Not cleared
    140
    189
    Statistical analysis title
    Complete clearance at Week 17
    Comparison groups
    ingenol mebutate 0.015% v diclofenac sodium 3%
    Number of subjects included in analysis
    502
    Analysis specification
    Pre-specified
    Analysis type
    superiority [3]
    P-value
    < 0.001
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    3.04
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    2
         upper limit
    4.62
    Notes
    [3] - Odds of complete clearance (Ingenol mebutate relative to Diclofenac sodium), logistic regression with factors treatment and anatomical location and site as random effect.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From signing of Informed Consent Form til End of Trial.
    Adverse event reporting additional description
    The reported adverse events include events reported both inside and outside of treatment area.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    15.1
    Reporting groups
    Reporting group title
    Picato®
    Reporting group description
    -

    Reporting group title
    Solaraze®
    Reporting group description
    -

    Serious adverse events
    Picato® Solaraze®
    Total subjects affected by serious adverse events
         subjects affected / exposed
    9 / 247 (3.64%)
    10 / 234 (4.27%)
         number of deaths (all causes)
    0
    2
         number of deaths resulting from adverse events
    0
    0
    Vascular disorders
    Granulomatosis with polyangiitis
         subjects affected / exposed
    0 / 247 (0.00%)
    1 / 234 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Orthostatic hypotension
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 234 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Spinal fracture
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 234 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tendon rupture
         subjects affected / exposed
    0 / 247 (0.00%)
    1 / 234 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Cholecystectomy
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 234 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Acute myeloid leukaemia
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 234 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    B-cell lymphoma
         subjects affected / exposed
    0 / 247 (0.00%)
    1 / 234 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bile duct cancer
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 234 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bowen's disease
         subjects affected / exposed
    0 / 247 (0.00%)
    1 / 234 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous cell carcinoma of skin
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 234 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    0 / 247 (0.00%)
    2 / 234 (0.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 247 (0.00%)
    2 / 234 (0.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Coronary artery stenosis
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 234 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Carotid artery stenosis
         subjects affected / exposed
    0 / 247 (0.00%)
    1 / 234 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dementia Alzheimer's type
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 234 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Glomerulonephritis membranous
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 234 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nephrotic syndrome
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 234 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Bile duct obstruction
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 234 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Diverticulitis
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 234 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 234 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 247 (0.40%)
    0 / 234 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 247 (0.00%)
    1 / 234 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 2%
    Non-serious adverse events
    Picato® Solaraze®
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    118 / 247 (47.77%)
    90 / 234 (38.46%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal cell carcinoma
         subjects affected / exposed
    7 / 247 (2.83%)
    3 / 234 (1.28%)
         occurrences all number
    8
    3
    Squamous cell carcinoma of skin
         subjects affected / exposed
    5 / 247 (2.02%)
    0 / 234 (0.00%)
         occurrences all number
    5
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    5 / 247 (2.02%)
    1 / 234 (0.43%)
         occurrences all number
    5
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    6 / 247 (2.43%)
    2 / 234 (0.85%)
         occurrences all number
    7
    2
    General disorders and administration site conditions
    Application site erythema
         subjects affected / exposed
    47 / 247 (19.03%)
    27 / 234 (11.54%)
         occurrences all number
    55
    29
    Application site scab
         subjects affected / exposed
    20 / 247 (8.10%)
    6 / 234 (2.56%)
         occurrences all number
    21
    7
    Application site pain
         subjects affected / exposed
    16 / 247 (6.48%)
    8 / 234 (3.42%)
         occurrences all number
    16
    9
    Application site vesicles
         subjects affected / exposed
    11 / 247 (4.45%)
    3 / 234 (1.28%)
         occurrences all number
    13
    3
    Application site pruritus
         subjects affected / exposed
    5 / 247 (2.02%)
    11 / 234 (4.70%)
         occurrences all number
    7
    12
    Application site exfoliation
         subjects affected / exposed
    6 / 247 (2.43%)
    11 / 234 (4.70%)
         occurrences all number
    6
    12
    Application site oedema
         subjects affected / exposed
    7 / 247 (2.83%)
    4 / 234 (1.71%)
         occurrences all number
    7
    4
    Application site dermatitis
         subjects affected / exposed
    0 / 247 (0.00%)
    5 / 234 (2.14%)
         occurrences all number
    0
    5

    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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