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    Clinical Trial Results:
    Investigations of local skin reactions and safety after combined treatment of basal cell carcinoma using ablative fractional laser and ingenol mebutate - an exloratory, prospective, open-label phase 2a trial.

    Summary
    EudraCT number
    		 2017-002843-14
    Trial protocol
    		 DK  
    Global end of trial date
    18 May 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    08 Mar 2020
    First version publication date
    08 Mar 2020
    Other versions
    Summary report(s)
    		 Abstract

    Trial information

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    Trial identification
    Sponsor protocol code
    0407
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Bispebjerg Hospital
    Sponsor organisation address
    Bispebjerg Bakke23, Copenhagen, Denmark, 2400
    Public contact
    Dermatologisk Afdeling, Bispebjerg hospital, mhaedersdal@dadlnet.dk
    Scientific contact
    Dermatologisk Afdeling, Bispebjerg hospital, 45 22860181, mhaedersdal@dadlnet.dk
    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
    31 Jul 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    18 May 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    18 May 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    1) to investigate local skin reactions and safety of ablative fractional laser (AFXL)-assisted ingenol mebutate treatment of basal cell carcinoma (BCC)
    Protection of trial subjects
    local anaesthesia was performed in the treatment area prior to laser exposure. A manually customized well (Duoderm!, Denmark) demarcated the treatment area to avoid IM-induced LSRs of surrounding healthy skin. Patients were advised to take paracetamol if they experienced pain after the procedure.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    02 Oct 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
    Denmark: 20
    Worldwide total number of subjects
    20
    EEA total number of subjects
    20
    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)
    11
    From 65 to 84 years
    8
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 Patients were recruited from the Department of Dermatology, Bispebjerg Hospital, Copenhagen, Denmark and private dermatological practices in Copenhagen, Denmark.

    Pre-assignment
    Screening details
    		 Patients were screened if they seemed to meet inclusion criteria.

    Pre-assignment period milestones
    Number of subjects started
    		 20
    Number of subjects completed
    		 20

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 One arm
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ingenol mebutate
    Investigational medicinal product code
    Other name
    Picato
    Pharmaceutical forms
    Gel
    Routes of administration
    Cutaneous use
    Dosage and administration details
    Immediately after Ablative Fractional Laser exposure, ingenol meditate was applied to treatment areas in a thick layer in concentrations of 0.015% to scalp and facial areas or 0.05% to nonscalp- non-facial areas. The treatment area was occluded 8 (Tegaderm!, Denmark) for two (0.05%) or 3 days (0.015%). A second treatment was performed at day 29 if residual BCC persisted clinically, as evaluated by OCT or RCM.

    Number of subjects in period 1
    		One arm
    Started
    20
    Completed
    20

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall trial
    Reporting group description
    		 Patients with Fitzpatrick skin type I-III were eligible for the trial if they were a minimum of 18 years old with low-risk, histologically verified superficial or nodular BCC. Low-risk tumours were defined as primary BCCs located outside of the high-risk zone,5 tumours ≤20 mm in face or scalp areas and ≤50 mm in non-face or non-scalp areas. BCCs in the high-risk zone, patients with Gorlin’s syndrome and immunosuppressed patients were excluded from the study

    Reporting group values
    		 Overall trial Total
    Number of subjects
    		 20 20
    Age categorical
    > 18 years
    Units: Subjects
        Adults (18-64 years)
    		 0 0
        From 65-84 years
    		 19 19
        85 years and over
    		 1 1
    Age continuous
    Units: years
        median (inter-quartile range (Q1-Q3))
    		 71 (63 to 75) -
    Gender categorical
    Units: Subjects
        Female
    		 9 9
        Male
    		 11 11
    tumor clearance
    Units: Subjects
        tumor clearance
    		 20 20
    Basal cell carcinomas
    Units: 20
        median (full range (min-max))
    		 20 (20 to 20) -
    Subject analysis sets

    Subject analysis set title
    Tumor clearance
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    At day 90, overall histological clearance rate was 14 of 20 (70%; Table 2). Clearance rates were similar for superficial and nodular BCCs (P = 0.354) and for BCCs treated with 0.015% IM concentration vs. 0.05% concentration (P = 0.141). Clinical clearance rate was 13 of 20 (65%) and further six BCCs appeared clinically reduced. OCT and RCM cure rate was 12 of 20 (60%). Overall agreement between evaluation techniques was substantial (kappa = 0.796, P = 0.0001). Similarly, inter-observer agreement between evaluations of unblinded and blinded evaluators was consistent (kappa > 0.8, P < 0.0001).

    Subject analysis sets values
    		 Tumor clearance
    Number of subjects
    20
    Age categorical
    > 18 years
    Units: Subjects
        Adults (18-64 years)
        From 65-84 years
        85 years and over
    Age continuous
    Units: years
        median (inter-quartile range (Q1-Q3))
    Gender categorical
    Units: Subjects
        Female
    9
        Male
    11
    tumor clearance
    Units: Subjects
        tumor clearance
    20
    Basal cell carcinomas
    Units: 20
        median (full range (min-max))
    0 (0 to 0)

    End points

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    End points reporting groups
    Reporting group title
    One arm
    Reporting group description
    		 -

    Subject analysis set title
    Tumor clearance
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    At day 90, overall histological clearance rate was 14 of 20 (70%; Table 2). Clearance rates were similar for superficial and nodular BCCs (P = 0.354) and for BCCs treated with 0.015% IM concentration vs. 0.05% concentration (P = 0.141). Clinical clearance rate was 13 of 20 (65%) and further six BCCs appeared clinically reduced. OCT and RCM cure rate was 12 of 20 (60%). Overall agreement between evaluation techniques was substantial (kappa = 0.796, P = 0.0001). Similarly, inter-observer agreement between evaluations of unblinded and blinded evaluators was consistent (kappa > 0.8, P < 0.0001).

    Primary: Tumor clearance

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    End point title
    		 Tumor clearance [1]
    End point description
    End point type
    Primary
    End point timeframe
    3 months follow up
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: The study was designed as an exploratory study with no formal statistical sample size calculation. Twenty BCCs of superficial or nodular subtype in twenty subjects were considered sufficient to investigate benefit and risk of the treatment. Non-parametric statistics were used for LSR and cosmesis scores, and changes in blood flow measurements. Descriptive data were presented with medians and interquartile ranges (IQR). Wilcoxon matchedpairs test was used to test differences between test a
    End point values
    		 Tumor clearance
    Number of subjects analysed
    20 [2]
    Units: 14
        Tumor clearance
    14
    Notes
    [2] - Out of 20 patients, 14 BCCs cleared after treatment
    No statistical analyses for this end point

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    Adverse events were reported during the study period from patients
    Adverse event reporting additional description
    AEs were mostly moderate siterelated pain and mild pruritus. Clinical scarring in terms of skin structural and pigmentation changes was observed in majority of cleared patients at day 90 [9/14 (64%)]. Cosmesis was good and scored similarly by physician and patient at day 90 (P = 0.313).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    6
    Reporting groups
    Reporting group title
    Patients
    Reporting group description
    		 -

    Serious adverse events
    		 Patients
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 20 (0.00%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Frequency threshold for reporting non-serious adverse events: 1%
    Non-serious adverse events
    		 Patients
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    0 / 20 (0.00%)
    Notes
    [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported.
    Justification: Patient-reported AEs were mostly moderate siterelated pain and mild pruritus. Clinical scarring in terms of skin structural and pigmentation changes was observed in majority of cleared patients at day 90 [9/14 (64%)]. Cosmesis was good and scored similarly by physician and patient at day 90 (P = 0.313).

    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.
    Limitations of the study included the uncontrolled design, the limited sample size, different numbers of evaluated subtypes, and only 3-month follow-up. OCT assessments of BCC thickness were not included in the protocol, which may be considered

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/31442334
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