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    Clinical Trial Results:
    Does 4% 5-fluorouracil pre-treatment improve the efficacy of daylight photodynamic therapy for actinic keratoses – a randomized controlled study

    Summary
    EudraCT number
    		 2021-001586-21
    Trial protocol
    		 DK  
    Global end of trial date
    06 Dec 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    29 Aug 2024
    First version publication date
    29 Aug 2024
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    5FUdPDT78842
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Department of Dermatology, Bispebjerg Hospital
    Sponsor organisation address
    Nielsine Nielsens Vej 9, Copenhagen NV, Denmark, 2400
    Public contact
    Principal investigator, Bispebjerg Hospital, Department of Dermatology, stine.regin.wiegell@regionh.dk
    Scientific contact
    Principal investigator, Bispebjerg Hospital, Department of Dermatology, 0045 30914617, stine.regin.wiegell@regionh.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
    13 Aug 2024
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    05 Dec 2023
    Global end of trial reached?
    Yes
    Global end of trial date
    06 Dec 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The aim of the study is to compare the efficacy of sequential 4% 5-FU and daylight MAL-PDT with daylight MAL-PDT alone in the treatment of multiple actinic keratoses in the face and scalp
    Protection of trial subjects
    This study was conducted in accordance with the ethical principles of the Declaration of Helsinki. Signed informed consent was obtained from all participants prior to entry into the study and the Good Clinical Practice Unit, Copenhagen University, performed external monitoring. The protocol was approved by the Danish Medicine Agency (EudraCT 2021-0015860-21), The Regional Ethics Committee of Region Hovedstaden (H-78842), and the Danish Data Protection Agency.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    27 Oct 2021
    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: 60
    Worldwide total number of subjects
    60
    EEA total number of subjects
    60
    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)
    9
    From 65 to 84 years
    48
    85 years and over
    3

    Subject disposition

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    Recruitment
    Recruitment details
    		 Patients were recruited from October 2021 to November 2022

    Pre-assignment
    Screening details
    		 Patients referred to the Department of Dermatology, Bispebjerg University Hospital, Copenhagen (n=50) or Private Hospital Mølholm, Vejle, Denmark (n=10) for treatment of multiple AKs.

    Pre-assignment period milestones
    Number of subjects started
    		 60
    Number of subjects completed
    		 60

    Period 1
    Period 1 title
    Treatment and follow-up (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 5-FU dPDT
    Arm description
    		 Patients applied 5-FU cream (Tolak® 40 mg/g, Pierre-Fabre Dermatologie, Boulogne, France) twice daily for 7 days. At day 7 MAL patients were treated with MAL-daylight PDT
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tolak
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Cream
    Routes of administration
    Cutaneous use
    Dosage and administration details
    twice daily for 7 days

    Investigational medicinal product name
    Metvix
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Cream
    Routes of administration
    Cutaneous use
    Dosage and administration details
    One treatment with daylight photodynamic therapy

    Arm title
    		 dPDT
    Arm description
    		 At day 7 patients were treated with MAL-dPDT
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Metvix
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Cream
    Routes of administration
    Cutaneous use
    Dosage and administration details
    One treatment with daylight photodynamic therapy

    Number of subjects in period 1
    		5-FU dPDT dPDT
    Started
    60
    60
    Completed
    60
    60

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Treatment and follow-up
    Reporting group description
    		 Inter-individual design, split-face/scalp study

    Reporting group values
    		 Treatment and follow-up Total
    Number of subjects
    		 60 60
    Age categorical
    Units: Subjects
        18-64 years
    		 9 9
        65-84 years
    		 48 48
        85 years and over
    		 3 3
    Age continuous
    Units: years
        arithmetic mean (full range (min-max))
    		 73 (56 to 89) -
    Gender categorical
    Units: Subjects
        Female
    		 6 6
        Male
    		 54 54

    End points

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    End points reporting groups
    Reporting group title
    5-FU dPDT
    Reporting group description
    		 Patients applied 5-FU cream (Tolak® 40 mg/g, Pierre-Fabre Dermatologie, Boulogne, France) twice daily for 7 days. At day 7 MAL patients were treated with MAL-daylight PDT

    Reporting group title
    dPDT
    Reporting group description
    		 At day 7 patients were treated with MAL-dPDT

    Primary: Lesion response rate

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    End point title
    		 Lesion response rate
    End point description
    End point type
    Primary
    End point timeframe
    3-month after treatment
    End point values
    		 5-FU dPDT dPDT
    Number of subjects analysed
    60
    60
    Units: %
    87
    75
    Statistical analysis title
    		 Comparison
    Comparison groups
    5-FU dPDT v dPDT
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    12-months
    Adverse event reporting additional description
    Follow-up
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 None
    Dictionary version
    0
    Reporting groups
    Reporting group title
    5-FU dPDT
    Reporting group description
    		 Patients applied 5-FU cream (Tolak® 40 mg/g, Pierre-Fabre Dermatologie, Boulogne, France) twice daily for 7 days. At day 7 MAL patients were treated with MAL-daylight PDT

    Reporting group title
    dPDT
    Reporting group description
    		 At day 7 patients were treated with MAL-dPDT

    Serious adverse events
    		 5-FU dPDT dPDT
    Total subjects affected by serious adverse events
         subjects affected / exposed
    10 / 60 (16.67%)
    10 / 60 (16.67%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    cancer coli
         subjects affected / exposed
    1 / 60 (1.67%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Hypotension
         subjects affected / exposed
    1 / 60 (1.67%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 60 (1.67%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    2 / 60 (3.33%)
    2 / 60 (3.33%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    aorta valve repair
         subjects affected / exposed
    1 / 60 (1.67%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    2 / 60 (3.33%)
    2 / 60 (3.33%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Aneurysm thrombosis
         subjects affected / exposed
    1 / 60 (1.67%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anemia and melaena
         subjects affected / exposed
    1 / 60 (1.67%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pseudoaneurysm infection
         subjects affected / exposed
    1 / 60 (1.67%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Stomach scan normal
         subjects affected / exposed
    2 / 60 (3.33%)
    2 / 60 (3.33%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspepsia
         subjects affected / exposed
    1 / 60 (1.67%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Polypectomy
         subjects affected / exposed
    1 / 60 (1.67%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    fractured collumna
         subjects affected / exposed
    1 / 60 (1.67%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 1%
    Non-serious adverse events
    		 5-FU dPDT dPDT
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    60 / 60 (100.00%)
    60 / 60 (100.00%)
    Skin and subcutaneous tissue disorders
    Erythema
    alternative assessment type: Non-systematic
         subjects affected / exposed
    60 / 60 (100.00%)
    60 / 60 (100.00%)
         occurrences all number
    60
    60

    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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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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