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    Clinical Trial Results:
    Prospective, randomized, controlled, multicenter, two-armed, study comparing daylight photodynamic therapy using MAL with cryosurgery for the treatment and prophylaxis of actinic keratoses in photodamaged skin of the face

    Summary
    EudraCT number
    		 2014-005121-13
    Trial protocol
    		 DE  
    Global end of trial date
    07 May 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    27 May 2022
    First version publication date
    27 May 2022
    Other versions
    Summary report(s)
    		 Abstract

    Trial information

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    Trial identification
    Sponsor protocol code
    Daylight_01
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02736760
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    University Hospital Regensburg
    Sponsor organisation address
    Franz-Josef-Strauss Allee 11, 93042 Regensburg , Germany, 93053
    Public contact
    Klinik für Dermatologie Regensburg , University Hospital Regensburg, 0049 9419449656, sigrid.karrer@ukr.de
    Scientific contact
    Klinik für Dermatologie Regensburg , University Hospital Regensburg, 0049 9419449656, sigrid.karrer@ukr.de
    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
    02 Jun 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    07 May 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    07 May 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary aim of the study is the evaluation of the efficacy of daylight- PDT with MAL in the treatment and prophylaxis of AKs in the face compared to cryosurgery
    Protection of trial subjects
    There were no specific measures
    Background therapy
    		 There was no background therapy
    Evidence for comparator
    		 Cryosurgery was chosen as control instead of a placebo treatment because it would have been unethical to leave AKs untreated for the study duration of 2 years due to their precancerous potential. Since cryosurgery only targets single lesions, no preventive effect in field-cancerized areas can be expected.
    Actual start date of recruitment
    01 Mar 2016
    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: 58
    Worldwide total number of subjects
    58
    EEA total number of subjects
    58
    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)
    29
    From 65 to 84 years
    29
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The first patient entered the study on 3 April 2016, and the last patient finished the study on 7 May 2018.

    Pre-assignment
    Screening details
    		 Consecutive patients who fullfilled inclusion criteria were screened (n=59), 58 patients were randomised. 29 for the intervention group, 29 for the control group. 6 patients withdrew consent during the study. At the end of the study the ITT analysis set was n=55 and the PP analysis set was n = 44 patients

    Pre-assignment period milestones
    Number of subjects started
    		 58
    Number of subjects completed

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 daylight-PDT
    Arm description
    		 MAL application followed by illumination with daylight (daylight-PDT)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Metvix
    Investigational medicinal product code
    L01XD03 (ATC code)
    Other name
    Pharmaceutical forms
    Cream
    Routes of administration
    Cutaneous use
    Dosage and administration details
    10 g, cutaneous use

    Arm title
    		 Kryosurgery
    Arm description
    		 cryosurgery
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Metvix
    Investigational medicinal product code
    L01XD03 (ATC code)
    Other name
    Pharmaceutical forms
    Cream
    Routes of administration
    Cutaneous use
    Dosage and administration details
    10 g, cutaneous use

    Number of subjects in period 1
    		daylight-PDT Kryosurgery
    Started
    29
    29
    Completed
    24
    24
    Not completed
    5
    5
         Adverse event, serious fatal
    2
    -
         Consent withdrawn by subject
    2
    4
         Lost to follow-up
    1
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    daylight-PDT
    Reporting group description
    		 MAL application followed by illumination with daylight (daylight-PDT)

    Reporting group title
    Kryosurgery
    Reporting group description
    		 cryosurgery

    Reporting group values
    		 daylight-PDT Kryosurgery Total
    Number of subjects
    		 29 29 58
    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)
    		 2 4 6
        From 65-84 years
    		 26 25 51
        85 years and over
    		 1 0 1
    Gender categorical
    Units: Subjects
        Female
    		 24 23 47
        Male
    		 5 6 11
    Subject analysis sets

    Subject analysis set title
    ITT
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The intention-to-treat (ITT) collective comprises all patients who were included in the study. According to the ITT principle, all patients are evaluated according to their randomly assigned treatment, regardless of whether they refused or discontinued treatment or whether other protocol violations occurred. Only patients in whom the number of newly occurring AKs was recorded at least once via visits 2 to 6 will be included in the ITT collective.

    Subject analysis set title
    PP
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The per-protocol (PP) collective includes all patients from the ITT collective without serious protocol violations.

    Subject analysis set title
    Safety
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The safety collective includes all patients who received at least one treatment and had at least one post-baseline safety assessment.

    Subject analysis sets values
    		 ITT PP Safety
    Number of subjects
    55
    44
    58
    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)
    6
    5
    6
        From 65-84 years
    48
    39
    51
        85 years and over
    1
    0
    1
    Age continuous
    Units:
        
    ( )
    ( )
    ( )
    Gender categorical
    Units: Subjects
        Female
    45
    34
    47
        Male
    10
    10
    11

    End points

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    End points reporting groups
    Reporting group title
    daylight-PDT
    Reporting group description
    		 MAL application followed by illumination with daylight (daylight-PDT)

    Reporting group title
    Kryosurgery
    Reporting group description
    		 cryosurgery

    Subject analysis set title
    ITT
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The intention-to-treat (ITT) collective comprises all patients who were included in the study. According to the ITT principle, all patients are evaluated according to their randomly assigned treatment, regardless of whether they refused or discontinued treatment or whether other protocol violations occurred. Only patients in whom the number of newly occurring AKs was recorded at least once via visits 2 to 6 will be included in the ITT collective.

    Subject analysis set title
    PP
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The per-protocol (PP) collective includes all patients from the ITT collective without serious protocol violations.

    Subject analysis set title
    Safety
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The safety collective includes all patients who received at least one treatment and had at least one post-baseline safety assessment.

    Primary: Cumulative number of observed AKs at time points 2 to 6

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    End point title
    		 Cumulative number of observed AKs at time points 2 to 6
    End point description
    End point type
    Primary
    End point timeframe
    Assessment of number of lesions: 3, 6, 12, 18, 24 months after baseline.
    End point values
    		 daylight-PDT Kryosurgery ITT PP
    Number of subjects analysed
    29
    26
    55
    44
    Units: AK lesions
    29
    26
    55
    44
    Statistical analysis title
    		 Analysis of primary endpoint
    Comparison groups
    daylight-PDT v Kryosurgery v ITT v PP
    Number of subjects included in analysis
    154
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.183 [1]
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -2.48
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.18
         upper limit
    		 1.21
    Variability estimate
    Standard deviation
    Notes
    [1] - P-value of per protocol analysis set p = 0.542

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline, 3, 6, 12, 18, 24 months
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21
    Reporting groups
    Reporting group title
    Daylight-PDT
    Reporting group description
    		 MAL application followed by illumination with daylight (daylight-PDT)

    Reporting group title
    Cryosurgery
    Reporting group description
    		 cryosurgery

    Serious adverse events
    		 Daylight-PDT Cryosurgery
    Total subjects affected by serious adverse events
         subjects affected / exposed
    5 / 29 (17.24%)
    1 / 29 (3.45%)
         number of deaths (all causes)
    2
    0
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Squamous cell carcinoma
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 29 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Coronary artery disease
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 29 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 29 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Nervous system disorders
    Lacunar infarction
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 29 (3.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Death
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 29 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Eye disorders
    Retinal detachment
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 29 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Benign prostatic hyperplasia
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 29 (3.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Osteoarthritis
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 29 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Daylight-PDT Cryosurgery
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    11 / 29 (37.93%)
    13 / 29 (44.83%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Acanthoma
         subjects affected / exposed
    0 / 29 (0.00%)
    2 / 29 (6.90%)
         occurrences all number
    0
    2
    Acrochordon
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 29 (0.00%)
         occurrences all number
    1
    0
    Basal cell carcinoma
         subjects affected / exposed
    1 / 29 (3.45%)
    2 / 29 (6.90%)
         occurrences all number
    1
    2
    Malignant melanoma
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 29 (3.45%)
         occurrences all number
    0
    1
    Bowen's disease
         subjects affected / exposed
    3 / 29 (10.34%)
    1 / 29 (3.45%)
         occurrences all number
    3
    1
    Dysplastic naevus
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 29 (0.00%)
         occurrences all number
    1
    0
    Haemangioma
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 29 (3.45%)
         occurrences all number
    0
    1
    Keratoacanthoma
         subjects affected / exposed
    2 / 29 (6.90%)
    0 / 29 (0.00%)
         occurrences all number
    2
    0
    Skin papilloma
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 29 (0.00%)
         occurrences all number
    1
    0
    Squamous cell carcinoma
         subjects affected / exposed
    1 / 29 (3.45%)
    2 / 29 (6.90%)
         occurrences all number
    1
    2
    Surgical and medical procedures
    Joint arthroplasty
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 29 (0.00%)
         occurrences all number
    1
    0
    General disorders and administration site conditions
    Ulcer
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 29 (0.00%)
         occurrences all number
    1
    0
    Reproductive system and breast disorders
    Asthma
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 29 (3.45%)
         occurrences all number
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Pulmonary oedema
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 29 (3.45%)
         occurrences all number
    0
    1
    Injury, poisoning and procedural complications
    Post-traumatic neck syndrome
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 29 (3.45%)
         occurrences all number
    0
    1
    Nervous system disorders
    Polyneuropathy
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 29 (3.45%)
         occurrences all number
    0
    1
    Gastrointestinal disorders
    Gastrointestinal pain
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 29 (0.00%)
         occurrences all number
    1
    0
    Hepatobiliary disorders
    Hepatic lesion
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 29 (0.00%)
         occurrences all number
    1
    0
    Skin and subcutaneous tissue disorders
    Decubitus ulcer
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 29 (3.45%)
         occurrences all number
    0
    1
    Eczema
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 29 (0.00%)
         occurrences all number
    1
    0
    Intertrigo
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 29 (0.00%)
         occurrences all number
    1
    0
    Pruritus
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 29 (0.00%)
         occurrences all number
    1
    0
    Seborrhoeic dermatitis
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 29 (0.00%)
         occurrences all number
    1
    0
    Renal and urinary disorders
    Urinary hesitation
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 29 (3.45%)
         occurrences all number
    0
    1
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 29 (3.45%)
         occurrences all number
    0
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 29 (3.45%)
         occurrences all number
    0
    1
    Back pain
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 29 (3.45%)
         occurrences all number
    0
    1
    Synovial cyst
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 29 (3.45%)
         occurrences all number
    0
    1
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 29 (0.00%)
         occurrences all number
    1
    0
    Diverticulitis
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 29 (3.45%)
         occurrences all number
    0
    1
    Infected bite
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 29 (3.45%)
         occurrences all number
    0
    1
    Onychomycosis
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 29 (3.45%)
         occurrences all number
    0
    1
    Pneumonia
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 29 (3.45%)
         occurrences all number
    0
    1
    Postoperative wound infection
         subjects affected / exposed
    1 / 29 (3.45%)
    1 / 29 (3.45%)
         occurrences all number
    1
    1
    Pulpitis dental
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 29 (0.00%)
         occurrences all number
    1
    0
    Body tinea
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 29 (3.45%)
         occurrences all number
    0
    1
    Tinea pedis
         subjects affected / exposed
    0 / 29 (0.00%)
    2 / 29 (6.90%)
         occurrences all number
    0
    2
    Metabolism and nutrition disorders
    Hypercholesterolaemia
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 29 (3.45%)
         occurrences all number
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    10 Oct 2016
    Change of PI and deputy.
    06 Dec 2016
    Change of PI-deputy

    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
    For support, Contact us.
    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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