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    Clinical Trial Results:
    Incidence of squamous cell carcinoma and other skin neoplasia in subjects with actinic keratosis treated with ingenol disoxate gel 0.018% or 0.037%, or vehicle. A phase 3 trial to compare the incidence of SCC and other skin neoplasia on skin areas treated with ingenol disoxate gel or vehicle gel for actinic keratosis on face and chest or scalp.

    Summary
    EudraCT number
    2017-000228-85
    Trial protocol
    GB   DE   ES  
    Global end of trial date
    12 Mar 2018

    Results information
    Results version number
    v1(current)
    This version publication date
    03 Apr 2019
    First version publication date
    03 Apr 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    LP0084-1369
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT03115476
    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, LEO Pharma A/S, +45 44945888, disclosure@leo-pharma.com
    Scientific contact
    Clinical Trial Disclosure, LEO Pharma A/S, +45 44945888, 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
    27 Aug 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    12 Mar 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    12 Mar 2018
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To compare the incidence of squamous cell carcinoma after treatment with ingenol disoxate gel and vehicle gel
    Protection of trial subjects
    This 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 the amendment from Somerset West, South Africa, October 1996. All subjects received written and verbal information concerning the clinical trial. Subjects were asked to consent that their personal data were recorded, collected, processed and could be transferred to other countries in accordance with any national legislation regulating privacy and data protection.
    Background therapy
    none
    Evidence for comparator
    This trial was an extension trial. The subjects who qualified for this trial had previously been enrolled in LEO trials LP0084-1193, -1194, -1195, or - 1196 (main trial) in which a treatment area was defined and treatment applied. The trial subjects did not receive investigational medicinal product during the trial
    Actual start date of recruitment
    28 Apr 2017
    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
    Spain: 23
    Country: Number of subjects enrolled
    United Kingdom: 37
    Country: Number of subjects enrolled
    France: 12
    Country: Number of subjects enrolled
    Germany: 61
    Country: Number of subjects enrolled
    United States: 272
    Country: Number of subjects enrolled
    Canada: 158
    Worldwide total number of subjects
    563
    EEA total number of subjects
    133
    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)
    155
    From 65 to 84 years
    391
    85 years and over
    17

    Subject disposition

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    Recruitment
    Recruitment details
    Eligibility criteria: The subject has been treated in one of the trials LP0084-1193, -1194, -1195, or -1196 (main trials) and has been evaluated at Visit 11 of that trial. The following countries participated: Canada, Germany, Spain, France, UK, and US

    Pre-assignment
    Screening details
    In the main trials 1234 subjects were randomised and applied study drug. Less than half of the subjects continued into this trial: 82 from LP0084 -1193, 186 from trial -1194, 163 from -1195, and 132 from -1196. 3 subjects discontinued the trial due to death unrelated to trial treatment. The trial was terminated by sponsor decision.

    Period 1
    Period 1 title
    From V2 (Day1) in main trial
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Monitor, Data analyst, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Ingenol disoxate gel 0.018%
    Arm description
    Subjects who had been treated with ingenol disoxate gel 0.018% on face or chest in the main trial
    Arm type
    Experimental

    Investigational medicinal product name
    Ingenol disoxate gel 0.018%
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Gel
    Routes of administration
    Topical use
    Dosage and administration details
    This trial was an extension trial. The subjects who qualified for this trial had previously been enrolled in LEO trials LP0084-1193, -1194, -1195, or - 1196 (main trial) in which a treatment area was defined and treatment applied. The trial subjects did not receive investigational medicinal product during this trial

    Arm title
    Ingenol disoxate gel 0.037%
    Arm description
    Subjects who had been treated with ingenol disoxate 0.037% on the scalp in the main trial
    Arm type
    Experimental

    Investigational medicinal product name
    Ingenol disoxate gel 0.037%
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Gel
    Routes of administration
    Topical use
    Dosage and administration details
    This trial was an extension trial. The subjects who qualified for this trial had previously been enrolled in LEO trials LP0084-1193, -1194, -1195, or - 1196 (main trial) in which a treatment area was defined and treatment applied. The trial subjects did not receive investigational medicinal product during this trial

    Arm title
    Vehicle gel
    Arm description
    vehicle gel (to ingenol disoxate gel) that contained no active ingredients
    Arm type
    Placebo

    Investigational medicinal product name
    Vehicle gel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Gel
    Routes of administration
    Topical use
    Dosage and administration details
    This trial was an extension trial. The subjects who qualified for this trial had previously been enrolled in LEO trials LP0084-1193, -1194, -1195, or - 1196 (main trial) in which a treatment area was defined and treatment applied. The trial subjects did not receive investigational medicinal product during this trial

    Number of subjects in period 1
    Ingenol disoxate gel 0.018% Ingenol disoxate gel 0.037% Vehicle gel
    Started
    407
    418
    409
    Completed
    377
    393
    316
    Not completed
    30
    25
    93
         Protocol deviation
    1
    -
    2
         not known
    -
    3
    10
         Lack of efficacy
    1
    1
    6
         Adverse event, serious fatal
    -
    -
    2
         Adverse event, non-fatal
    1
    -
    2
         unacceptable local skin reaction
    1
    -
    -
         Consent withdrawn by subject
    20
    11
    54
         Lost to follow-up
    6
    10
    17
    Period 2
    Period 2 title
    LP0084-1369 trial period
    Is this the baseline period?
    Yes [1]
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Monitor, Data analyst, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Ingenol disoxate gel 0.018%
    Arm description
    -
    Arm type
    Experimental

    Investigational medicinal product name
    Ingenol disoxate gel 0.018%
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Gel
    Routes of administration
    Topical use
    Dosage and administration details
    This trial was an extension trial. The subjects who qualified for this trial had previously been enrolled in LEO trials LP0084-1193, -1194, -1195, or - 1196 (main trial) in which a treatment area was defined and treatment applied. The trial subjects did not receive investigational medicinal product during the trial

    Arm title
    Ingenol disoxate gel 0.037%
    Arm description
    -
    Arm type
    Experimental

    Investigational medicinal product name
    Ingenol disoxate gel 0.037%
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Gel
    Routes of administration
    Topical use
    Dosage and administration details
    This trial was an extension trial. The subjects who qualified for this trial had previously been enrolled in LEO trials LP0084-1193, -1194, -1195, or - 1196 (main trial) in which a treatment area was defined and treatment applied. The trial subjects did not receive investigational medicinal product during the trial

    Arm title
    Vehicle gel
    Arm description
    -
    Arm type
    Placebo

    Investigational medicinal product name
    Vehicle gel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Gel
    Routes of administration
    Topical use
    Dosage and administration details
    This trial was an extension trial. The subjects who qualified for this trial had previously been enrolled in LEO trials LP0084-1193, -1194, -1195, or - 1196 (main trial) in which a treatment area was defined and treatment applied. The trial subjects did not receive investigational medicinal product during the trial

    Notes
    [1] - Period 1 is not the baseline period. It is expected that period 1 will be the baseline period.
    Justification: The full analysis set comprise 1234 randomised subjects from the 4 main trials (LP0084-1193, -1194, -1195, or - 1196) who applied investigational medicinal product (This is period 1). Of these subjects, 563 subjects continued into trial LP0084-1369. This would be period 2 i.e the LP0084-1369 trial period which is the baseline period for the present trial
    Number of subjects in period 2 [2]
    Ingenol disoxate gel 0.018% Ingenol disoxate gel 0.037% Vehicle gel
    Started
    191
    210
    162
    Completed
    0
    0
    0
    Not completed
    191
    210
    162
         death untrelated to AE in the treatment area
    1
    -
    2
         trial terminated by sponsor
    190
    210
    160
    Notes
    [2] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: The full analysis set comprise 1234 randomised subjects from the 4 main trials (LP0084-1193, -1194, -1195, or - 1196) who applied investigational medicinal product. Of these subjects, 563 subjects continued into trial LP0084-1369

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    LP0084-1369 trial period
    Reporting group description
    -

    Reporting group values
    LP0084-1369 trial period Total
    Number of subjects
    563 563
    Age categorical
    1234 subjects in the full analysis set (subjects who applied IMP in the main trials)
    Units: Subjects
        Adults (18-64 years)
    155 155
        From 65-84 years
    391 391
        85 years and over
    17 17
    Gender categorical
    1234 subjects in the full analysis set (subjects who applied IMP in the main trials)
    Units: Subjects
        Female
    97 97
        Male
    466 466
    Subject analysis sets

    Subject analysis set title
    Trial period
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    The trial period is from the first visit in trial LP0084-1369 until the end of the trial. 1234 subjects where randomised and applied investigational medicinal product in the 4 main trials and were included in the full analysis set. All subjects in the full analysis set were included in the safety analysis set.

    Subject analysis sets values
    Trial period
    Number of subjects
    563
    Age categorical
    1234 subjects in the full analysis set (subjects who applied IMP in the main trials)
    Units: Subjects
        Adults (18-64 years)
    358
        From 65-84 years
    828
        85 years and over
    48
    Age continuous
    563 subjects from the first visit in trial LP0084-1369 until the end of the trial
    Units:
        
    ±
    Gender categorical
    1234 subjects in the full analysis set (subjects who applied IMP in the main trials)
    Units: Subjects
        Female
    212
        Male
    1022

    End points

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    End points reporting groups
    Reporting group title
    Ingenol disoxate gel 0.018%
    Reporting group description
    Subjects who had been treated with ingenol disoxate gel 0.018% on face or chest in the main trial

    Reporting group title
    Ingenol disoxate gel 0.037%
    Reporting group description
    Subjects who had been treated with ingenol disoxate 0.037% on the scalp in the main trial

    Reporting group title
    Vehicle gel
    Reporting group description
    vehicle gel (to ingenol disoxate gel) that contained no active ingredients
    Reporting group title
    Ingenol disoxate gel 0.018%
    Reporting group description
    -

    Reporting group title
    Ingenol disoxate gel 0.037%
    Reporting group description
    -

    Reporting group title
    Vehicle gel
    Reporting group description
    -

    Subject analysis set title
    Trial period
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    The trial period is from the first visit in trial LP0084-1369 until the end of the trial. 1234 subjects where randomised and applied investigational medicinal product in the 4 main trials and were included in the full analysis set. All subjects in the full analysis set were included in the safety analysis set.

    Primary: Time to first squamous cell carcinoma (SCC) in the treatment area

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    End point title
    Time to first squamous cell carcinoma (SCC) in the treatment area
    End point description
    Time to first squamous cell carcinoma (SCC) in the treatment area. Relative difference between groups (ingenol disoxate vs vehicle) expressed as hazard ratio. The indicated measured values are the observed incidence rates of the SCC in the treatment area which form the basis of the statistical analysis of the time to event analysis
    End point type
    Primary
    End point timeframe
    From Visit 2 to first SCC in the treatment area, up to 24 months
    End point values
    Ingenol disoxate gel 0.018% Ingenol disoxate gel 0.037% Vehicle gel
    Number of subjects analysed
    191 [1]
    210 [2]
    162 [3]
    Units: Incidencerate per 100 patient years
        number (confidence interval 95%)
    2.77 (1.55 to 4.57)
    0.88 (0.28 to 2.04)
    1.26 (0.46 to 2.74)
    Notes
    [1] - actual number of subjects analysed is 407: subjects in the period from Visit 2 in the main trial
    [2] - actual number of subjects analysed is 418: subjects in the period from Visit 2 in the main trial
    [3] - actual number of subjects analysed is 409: subjects in the period from Visit 2 in the main trial
    Statistical analysis title
    likelihood ratio test
    Statistical analysis description
    Relative difference between groups (ingenol disoxate vs vehicle) expressed as hazard ratio
    Comparison groups
    Ingenol disoxate gel 0.018% v Ingenol disoxate gel 0.037% v Vehicle gel
    Number of subjects included in analysis
    563
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.43 [4]
    Method
    likelyhood ratio test
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1.43
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.61
         upper limit
    3.9
    Notes
    [4] - ingenol disoxate vs vehicle

    Secondary: Time to first SCC or other skin neoplasia in the treatment area

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    End point title
    Time to first SCC or other skin neoplasia in the treatment area
    End point description
    To compare the incidence of SCC or other skin neoplasia after treatment with ingenol disoxate gel and vehicle gel. The indicated measured values are the observed incidence rates of the SCC in the treatment area which form the basis of the statistical analysis of the time to event analysis
    End point type
    Secondary
    End point timeframe
    From Visit 2 to first SCC or other skin neoplasia in the treatment area, up to 24 months
    End point values
    Ingenol disoxate gel 0.018% Ingenol disoxate gel 0.037% Vehicle gel
    Number of subjects analysed
    162 [5]
    210 [6]
    162 [7]
    Units: Incidencerate per 100 patient years
        number (confidence interval 95%)
    10.24 (7.65 to 13.4)
    2.84 (1.62 to 4.61)
    3.19 (1.79 to 5.26)
    Notes
    [5] - actual number of subjects analysed is 407: subjects in the period from Visit 2 in the main trial
    [6] - actual number of subjects analysed is 418: subjects in the period from Visit 2 in the main trial
    [7] - actual number of subjects analysed is 409: subjects in the period from Visit 2 in the main trial
    Statistical analysis title
    likelihood ratio test
    Statistical analysis description
    relative difference between treatment groups (ingenol disoxate gel vs vehicle) expressed as hazard ratio, full analysis set
    Comparison groups
    Ingenol disoxate gel 0.037% v Ingenol disoxate gel 0.018% v Vehicle gel
    Number of subjects included in analysis
    534
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.01 [8]
    Method
    likelyhood ratio test
    Parameter type
    Hazard ratio
    Point estimate
    1.99
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.17
         upper limit
    3.62
    Notes
    [8] - Ingenol disoxate vs vehicle

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    The trial period: from first visit in this trial until the end of the trial
    Adverse event reporting additional description
    Safety information is based on actual treatment' i.e. the treatment that was administered to the patient. This differed from 'planned treatment' (wich was used for the Participant Flow). Only events in the treatment area were collected (SAEs outside treatment area only collected if deemed related by the investigator to the study drug)
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    18.1
    Reporting groups
    Reporting group title
    Ingenol disoxate gel 0.018%
    Reporting group description
    Subjects who had been treated with ingenol disoxate gel 0.018% on face or chest in the main trial

    Reporting group title
    Ingenol disoxate gel 0.037%
    Reporting group description
    Subjects who had been treated with ingenol disoxate 0.037% on the scalp in the main trial

    Reporting group title
    Vehicle gel
    Reporting group description
    vehicle gel to ingenol disoxate gel

    Serious adverse events
    Ingenol disoxate gel 0.018% Ingenol disoxate gel 0.037% Vehicle gel
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 211 (0.47%)
    0 / 161 (0.00%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Malignant melanoma
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 211 (0.47%)
    0 / 161 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    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
    Ingenol disoxate gel 0.018% Ingenol disoxate gel 0.037% Vehicle gel
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    16 / 191 (8.38%)
    6 / 211 (2.84%)
    10 / 161 (6.21%)
    Injury, poisoning and procedural complications
    Inflammation of wound
         subjects affected / exposed
    1 / 191 (0.52%)
    0 / 211 (0.00%)
    0 / 161 (0.00%)
         occurrences all number
    1
    0
    0
    Skin abrasion
         subjects affected / exposed
    0 / 191 (0.00%)
    1 / 211 (0.47%)
    0 / 161 (0.00%)
         occurrences all number
    0
    1
    0
    Scar
         subjects affected / exposed
    1 / 191 (0.52%)
    0 / 211 (0.00%)
    0 / 161 (0.00%)
         occurrences all number
    1
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Squamous cell carcinoma of skin
         subjects affected / exposed
    2 / 191 (1.05%)
    0 / 211 (0.00%)
    3 / 161 (1.86%)
         occurrences all number
    2
    0
    3
    Basal cell carcinoma
         subjects affected / exposed
    4 / 191 (2.09%)
    0 / 211 (0.00%)
    0 / 161 (0.00%)
         occurrences all number
    4
    0
    0
    Bowen's disease
         subjects affected / exposed
    3 / 191 (1.57%)
    0 / 211 (0.00%)
    1 / 161 (0.62%)
         occurrences all number
    3
    0
    1
    General disorders and administration site conditions
    Application site scar
         subjects affected / exposed
    8 / 191 (4.19%)
    5 / 211 (2.37%)
    7 / 161 (4.35%)
         occurrences all number
    8
    5
    7
    Application site papules
         subjects affected / exposed
    1 / 191 (0.52%)
    0 / 211 (0.00%)
    0 / 161 (0.00%)
         occurrences all number
    1
    0
    0
    Skin and subcutaneous tissue disorders
    Rosacea
         subjects affected / exposed
    1 / 191 (0.52%)
    0 / 211 (0.00%)
    0 / 161 (0.00%)
         occurrences all number
    1
    0
    0

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    27 Jul 2017
    The reason for the amendment is to change the definition of the full analysis set to include all randomised subjects from the main trials

    Interruptions (globally)

    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    12 Mar 2018
    The trial was terminated early by a sponsor decision to close the development program
    -

    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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