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    Clinical Trial Results:
    Multicentre, Randomised, Investigator-blind, Intra-individual, Active and Vehicle Controlled study, Comparing Metvix Natural Daylight Photodynamic Therapy versus Metvix Conventional Photodynamic Therapy in Subjects with Actinic Keratosis

    Summary
    EudraCT number
    		 2013-000973-54
    Trial protocol
    		 SE   DE   NL   ES  
    Global end of trial date
    06 Jan 2014

    Results information
    Results version number
    		 v1(current)
    This version publication date
    11 Mar 2021
    First version publication date
    11 Mar 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    RD.03.SRE.29112
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01821391
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Galderma R&D
    Sponsor organisation address
    2400 route des colles, Biot, France, 06410
    Public contact
    CTA Coordinator, Galderma R&D, 33 493-95-70-85, cta.coordinator@galderma.com
    Scientific contact
    CTA Coordinator, Galderma R&D, 33 493-95-70-85, cta.coordinator@galderma.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
    06 Jan 2014
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    06 Jan 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective of the study was to show the non-inferior efficacy of Metvix natural daylight photodynamic therapy (NDL-PDT) versus Metvix conventional photodynamic therapy (c-PDT) in subjects with mild and/or moderate actinic keratosis (AK) at Week 12.
    Protection of trial subjects
    This study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and that are consistent with Good Clinical Practice and applicable regulatory requirements.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    25 Jul 2013
    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
    France: 40
    Country: Number of subjects enrolled
    Germany: 43
    Country: Number of subjects enrolled
    Netherlands: 12
    Country: Number of subjects enrolled
    Spain: 24
    Country: Number of subjects enrolled
    Sweden: 12
    Worldwide total number of subjects
    131
    EEA total number of subjects
    131
    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)
    21
    From 65 to 84 years
    110
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 This study was conducted at 18 sites in 5 countries between 25 July 2013 to 06 January 2014.

    Pre-assignment
    Screening details
    		 A total of 131 subjects were randomized and 130 completed the study.

    Period 1
    Period 1 title
    Baseline Period (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Single blind
    Roles blinded
    		 Investigator [1]

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Group 1
    Arm description
    		 Subjects applied single dose of Metvix cream topically followed by NDL-PDT (test treatment) on one half-face/scalp and on the contra-lateral side of face/scalp applied Metvix cream topically followed by c-PDT (active comparator) on Day 0 (Baseline).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Metvix natural daylight photodynamic therapy (Metvix NDL-PDT)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Cream
    Routes of administration
    Topical use
    Dosage and administration details
    Subjects applied topically a single dose of Metvix cream followed by NDL-PDT on Day 0 (Baseline).

    Investigational medicinal product name
    Metvix conventional photodynamic therapy (Metvix c-PDT)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Cream
    Routes of administration
    Topical use
    Dosage and administration details
    Subjects applied topically a single dose of Metvix cream followed by C-PDT on Day 0 (Baseline).

    Arm title
    		 Group 2
    Arm description
    		 Subjects applied a single dose of Metvix cream topically followed by NDL-PDT (test treatment) on one half-face/scalp and on the contra-lateral side of face/scalp applied Metvix vehicle cream (placebo) followed by c-PDT on Day 0 (Baseline).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Metvix natural daylight photodynamic therapy (Metvix NDL-PDT)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Cream
    Routes of administration
    Topical use
    Dosage and administration details
    Subjects applied topically a single dose of Metvix cream followed by NDL-PDT on Day 0 (Baseline).

    Investigational medicinal product name
    Metvix vehicle cream (placebo) conventional photodynamic therapy (c-PDT)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Cream
    Routes of administration
    Topical use
    Dosage and administration details
    Subjects applied topically a single dose of Metvix vehicle cream followed by C-PDT on Day 0 (Baseline).

    Notes
    [1] - The roles blinded appear inconsistent with a simple blinded trial.
    Justification: This is an investigator blinded study.
    Number of subjects in period 1
    		Group 1 Group 2
    Started
    108
    23
    Completed
    107
    23
    Not completed
    1
    0
         Adverse Events
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Group 1
    Reporting group description
    		 Subjects applied single dose of Metvix cream topically followed by NDL-PDT (test treatment) on one half-face/scalp and on the contra-lateral side of face/scalp applied Metvix cream topically followed by c-PDT (active comparator) on Day 0 (Baseline).

    Reporting group title
    Group 2
    Reporting group description
    		 Subjects applied a single dose of Metvix cream topically followed by NDL-PDT (test treatment) on one half-face/scalp and on the contra-lateral side of face/scalp applied Metvix vehicle cream (placebo) followed by c-PDT on Day 0 (Baseline).

    Reporting group values
    		 Group 1 Group 2 Total
    Number of subjects
    		 108 23 131
    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)
    		 19 2 21
        From 65-84 years
    		 89 21 110
        85 years and over
    		 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 72.8 ± 9.9 73.9 ± 7.9 -
    Gender categorical
    Units: Subjects
        Female
    		 9 1 10
        Male
    		 99 22 121
    Race
    Units: Subjects
        Caucasian
    		 108 22 130
        Other
    		 0 1 1
    Phototype
    Units: Subjects
        Phototype I
    		 10 1 11
        Phototype II
    		 69 17 86
        Phototype III
    		 24 3 27
        Phototype IV
    		 5 2 7

    End points

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    End points reporting groups
    Reporting group title
    Group 1
    Reporting group description
    		 Subjects applied single dose of Metvix cream topically followed by NDL-PDT (test treatment) on one half-face/scalp and on the contra-lateral side of face/scalp applied Metvix cream topically followed by c-PDT (active comparator) on Day 0 (Baseline).

    Reporting group title
    Group 2
    Reporting group description
    		 Subjects applied a single dose of Metvix cream topically followed by NDL-PDT (test treatment) on one half-face/scalp and on the contra-lateral side of face/scalp applied Metvix vehicle cream (placebo) followed by c-PDT on Day 0 (Baseline).

    Subject analysis set title
    Group I: Metvix NDL-PDT
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Subjects applied topically a single dose of Metvix cream followed by NDL-PDT on Day 0 (Baseline).

    Subject analysis set title
    Group I: Metvix c-PDT
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Subjects applied topically a single dose of Metvix cream followed by C-PDT on Day 0 (Baseline).

    Subject analysis set title
    Group II: Metvix NDL-PDT
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Subjects applied topically a single dose of Metvix cream followed by NDL-PDT on Day 0 (Baseline).

    Subject analysis set title
    Group II: Metvix c-PDT Vehicle
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Subjects applied topically a single dose of Metvix cream followed by vehicle C-PDT on Day 0 (Baseline).

    Primary: Percentage (%) Change from Baseline in Total Lesion Complete Response at Week 12 in Group 1

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    End point title
    		 Percentage (%) Change from Baseline in Total Lesion Complete Response at Week 12 in Group 1
    End point description
    The lesion complete response rate was defined as the percentage of pre-existing and treated lesions at Baseline that were assessed as clear (complete disappearance of the lesion, visually and by palpation) at Week 12. New lesions or the lesions in non-complete response were not not considered in the lesion response assessment. Intent-to-treat (ITT) population included entire population enrolled and randomized. ITT analysis imputed missing data using a worst case approach and considered the lesions with missed lesion response assessment as not responded (ITT/Worst-case) lesions. Here, the "N" number of subjects analyzed signifies subjects who were evaluable for this endpoint.
    End point type
    Primary
    End point timeframe
    Week 12
    End point values
    		 Group I: Metvix NDL-PDT Group I: Metvix c-PDT
    Number of subjects analysed
    108
    108
    Units: % change from baseline
        arithmetic mean (standard deviation)
    68.4 ± 27.7
    71.5 ± 27.6
    Statistical analysis title
    		 Total lesion response at week 12 in GROUP 1
    Comparison groups
    Group I: Metvix c-PDT v Group I: Metvix NDL-PDT
    Number of subjects included in analysis
    216
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2665
    Method
    		 Paired Student's t test
    Confidence interval

    Primary: Percentage Change from Baseline in Total Lesion Complete Response at Week 12 in Group 2

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    End point title
    		 Percentage Change from Baseline in Total Lesion Complete Response at Week 12 in Group 2
    End point description
    The lesion complete response rate was defined as the percentage of pre-existing and treated lesions at Baseline that were assessed as clear (complete disappearance of the lesion, visually and by palpation) at Week 12. New lesions or the lesions in non-complete response were not not considered in the lesion response assessment. Intent-to-treat (ITT) population included entire population enrolled and randomized. ITT analysis imputed missing data using a worst case approach and considered the lesions with missed lesion response assessment as not responded (ITT/Worst-case) lesions. Here, the "N" number of subjects analyzed signifies subjects who were evaluable for this endpoint.
    End point type
    Primary
    End point timeframe
    Week 12
    End point values
    		 Group II: Metvix NDL-PDT Group II: Metvix c-PDT Vehicle
    Number of subjects analysed
    23
    23
    Units: % change from baseline
        arithmetic mean (standard deviation)
    78.3 ± 18.0
    61.2 ± 25.7
    Statistical analysis title
    		 Total lesion response at week 12 in GROUP 2
    Comparison groups
    Group II: Metvix c-PDT Vehicle v Group II: Metvix NDL-PDT
    Number of subjects included in analysis
    46
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.005
    Method
    		 Paired Student's t test
    Confidence interval

    Primary: Change from Baseline in Self-Assessed Maximal Pain at Week 12

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    End point title
    		 Change from Baseline in Self-Assessed Maximal Pain at Week 12 [1]
    End point description
    Change from baseline in maximal pain of both Group 1 and Group 2 at week 12 were reported. After the treatment procedure on each side had been completed, the subject assessed the maximal pain felt during the duration of the light exposure (assessment after NDL-PDT illumination first, and then assessment after c-PDT lamp illumination). The pain sensation was assessed on an 11-point numeric rating scale, where 0 was no pain at all, and 10 was extreme pain. Analysis was performed on safety population (all subjects treated [APT] population) was defined as comprising the ITT population subjects who were administered the study treatment.
    End point type
    Primary
    End point timeframe
    Baseline, Week 12
    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: Statistical analysis was only performed within the group and not comparatively.
    End point values
    		 Group 1 Group 2
    Number of subjects analysed
    108
    23
    Units: Score on scale
        arithmetic mean (standard deviation)
    -3.8 ± 2.7
    0.3 ± 2.3
    No statistical analyses for this end point

    Secondary: Percentage Change from Baseline in Mild Lesion Response at Week 12 in Group 1

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    End point title
    		 Percentage Change from Baseline in Mild Lesion Response at Week 12 in Group 1
    End point description
    ITT population included entire population enrolled and randomized. ITT analysis imputed missing data using a worst case approach and considered the lesions with missed lesion response assessment as not responded (ITT/Worst-case) lesions. Here, the number of subjects analyzed signifies subjects who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12
    End point values
    		 Group I: Metvix NDL-PDT Group I: Metvix c-PDT
    Number of subjects analysed
    92
    91
    Units: % change from baseline
        arithmetic mean (standard deviation)
    71.0 ± 31.9
    71.7 ± 32.3
    No statistical analyses for this end point

    Secondary: Percentage Change from Baseline in Mild Lesion Response at Week 12 in Group 2

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    End point title
    		 Percentage Change from Baseline in Mild Lesion Response at Week 12 in Group 2
    End point description
    ITT population included entire population enrolled and randomized. ITT analysis imputed missing data using a worst case approach and considered the lesions with missed lesion response assessment as not responded (ITT/Worst-case) lesions. Here, the number of subjects analyzed signifies subjects who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12
    End point values
    		 Group II: Metvix NDL-PDT Group II: Metvix c-PDT Vehicle
    Number of subjects analysed
    19
    20
    Units: % change from baseline
        arithmetic mean (standard deviation)
    79.6 ± 21.1
    66.4 ± 26.4
    No statistical analyses for this end point

    Secondary: Subject-side Complete Response (CR) Rate at Week 12

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    End point title
    		 Subject-side Complete Response (CR) Rate at Week 12
    End point description
    Subject-side CR rate was defined as the percentage of subjects with all treated lesions at Baseline clear in the corresponding TA at Week 12. ITT population included entire population enrolled and randomized. ITT analysis imputed missing data using a worst case approach and considered the lesions with missed lesion response assessment as not responded (ITT/Worst-case) lesions.
    End point type
    Secondary
    End point timeframe
    Week 12
    End point values
    		 Group 1 Group 2
    Number of subjects analysed
    108
    23
    Units: percentage of subjects
        number (not applicable)
    -8.3
    8.7
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From start of study drug application up to Week 12
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    15.0
    Reporting groups
    Reporting group title
    Metvix NDL-PDT
    Reporting group description
    		 Subjects applied topically a single dose of Metvix cream followed by NDL-PDT on Day 0 (Baseline).

    Reporting group title
    Metvix c-PDT
    Reporting group description
    		 Subjects applied topically a single dose of Metvix cream followed by C-PDT on Day 0 (Baseline).

    Reporting group title
    c-PDT Vehicle
    Reporting group description
    		 Subjects applied topically a single dose of Metvix cream followed by vehicle C-PDT on Day 0 (Baseline).

    Serious adverse events
    		 Metvix NDL-PDT Metvix c-PDT c-PDT Vehicle
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 131 (0.00%)
    0 / 108 (0.00%)
    0 / 23 (0.00%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Metvix NDL-PDT Metvix c-PDT c-PDT Vehicle
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    65 / 131 (49.62%)
    66 / 108 (61.11%)
    7 / 23 (30.43%)
    Injury, poisoning and procedural complications
    Post procedural hemorrhage
         subjects affected / exposed
    5 / 131 (3.82%)
    4 / 108 (3.70%)
    1 / 23 (4.35%)
         occurrences all number
    5
    4
    1
    Vascular disorders
    Haemorrhage
         subjects affected / exposed
    0 / 131 (0.00%)
    1 / 108 (0.93%)
    0 / 23 (0.00%)
         occurrences all number
    0
    1
    0
    Skin and subcutaneous tissue disorders
    Blister
         subjects affected / exposed
    2 / 131 (1.53%)
    1 / 108 (0.93%)
    0 / 23 (0.00%)
         occurrences all number
    2
    1
    0
    Dermatitis
         subjects affected / exposed
    1 / 131 (0.76%)
    1 / 108 (0.93%)
    1 / 23 (4.35%)
         occurrences all number
    1
    1
    1
    Erythema
         subjects affected / exposed
    31 / 131 (23.66%)
    39 / 108 (36.11%)
    4 / 23 (17.39%)
         occurrences all number
    31
    39
    4
    Pain of skin
         subjects affected / exposed
    8 / 131 (6.11%)
    11 / 108 (10.19%)
    0 / 23 (0.00%)
         occurrences all number
    8
    11
    0
    Photosensitivity reaction
         subjects affected / exposed
    10 / 131 (7.63%)
    8 / 108 (7.41%)
    1 / 23 (4.35%)
         occurrences all number
    10
    8
    1
    Pruritus
         subjects affected / exposed
    13 / 131 (9.92%)
    16 / 108 (14.81%)
    1 / 23 (4.35%)
         occurrences all number
    13
    16
    1
    Purpura
         subjects affected / exposed
    1 / 131 (0.76%)
    1 / 108 (0.93%)
    0 / 23 (0.00%)
         occurrences all number
    1
    1
    0
    Scab
         subjects affected / exposed
    12 / 131 (9.16%)
    16 / 108 (14.81%)
    0 / 23 (0.00%)
         occurrences all number
    12
    17
    0
    Skin burning sensation
         subjects affected / exposed
    12 / 131 (9.16%)
    16 / 108 (14.81%)
    0 / 23 (0.00%)
         occurrences all number
    12
    17
    0
    Skin discomfort
         subjects affected / exposed
    1 / 131 (0.76%)
    0 / 108 (0.00%)
    0 / 23 (0.00%)
         occurrences all number
    1
    0
    0
    Skin erosion
         subjects affected / exposed
    0 / 131 (0.00%)
    5 / 108 (4.63%)
    0 / 23 (0.00%)
         occurrences all number
    0
    5
    0
    Skin exfoliation
         subjects affected / exposed
    2 / 131 (1.53%)
    4 / 108 (3.70%)
    1 / 23 (4.35%)
         occurrences all number
    2
    4
    1
    Skin oedema
         subjects affected / exposed
    2 / 131 (1.53%)
    1 / 108 (0.93%)
    0 / 23 (0.00%)
         occurrences all number
    2
    1
    0
    Skin swelling
         subjects affected / exposed
    1 / 131 (0.76%)
    1 / 108 (0.93%)
    0 / 23 (0.00%)
         occurrences all number
    1
    1
    0
    Skin tightness
         subjects affected / exposed
    0 / 131 (0.00%)
    1 / 108 (0.93%)
    0 / 23 (0.00%)
         occurrences all number
    0
    1
    0
    Infections and infestations
    Rash pustular
         subjects affected / exposed
    1 / 131 (0.76%)
    2 / 108 (1.85%)
    0 / 23 (0.00%)
         occurrences all number
    1
    2
    0

    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
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