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    Clinical Trial Results:
    Comparative Study, intraindividual to evaluate efficacy and safety of the treatment of actinic keratosis with photodinamic therapy between methyl aminolevulinate cream and aminolevulinic acid nanosome gel

    Summary
    EudraCT number
    		 2015-002408-97
    Trial protocol
    		 ES  
    Global end of trial date
    21 Jun 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    28 Jun 2021
    First version publication date
    28 Jun 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    MALvsALA
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02647151
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Carlos Serra - Fundación Instituto Valenciano de Oncología
    Sponsor organisation address
    C/. Profesor Beltrán Baguena, n.º 8 , Valencia, Spain, 46009
    Public contact
    Federico Nepote, Marketing Farmacéutico & Investigación Clinica, 0034 934344412, investigacion@mfar.net
    Scientific contact
    Federico Nepote, Marketing Farmacéutico & Investigación Clinica, 0034 934344412, investigacion@mfar.net
    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
    21 Feb 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    21 Jun 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    21 Jun 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To compare MAL with the new photosensitizer BF-200 ALA in terms of local reaction and tolerability of the QA treatment
    Protection of trial subjects
    All procedures were performed in accordance to Good clinical practice guidelines, the ICH principles for development of clinical research derived from the declaration of Helsinki and its later update fortaleza 2013. This clinical trial was approved by the local competent authorities in Spain and was developed in compliance to the current local regulations in terms of clinical research and data protection. The protocol already includes measures to mitigate risk and protection of subjects.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    03 Aug 2015
    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
    Spain: 22
    Worldwide total number of subjects
    22
    EEA total number of subjects
    22
    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)
    12
    From 65 to 84 years
    10
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 In order to achieve masking of the treatment by the researchers, the initial visit where the patient's data was collected and the treatment area was randomly assigned to each of the photosensitizers, was carried out by a different dermatologist from the one who evaluated the variables of the study

    Period 1
    Period 1 title
    Whole study period (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator
    Blinding implementation details
    In order to achieve masking of the treatment by the researchers, the initial visit where the patient's data was collected and the treatment area was randomly assigned to each of the photosensitizers, was carried out by a different dermatologist from the one who evaluated the variables of the study

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 BF-200 ALA
    Arm description
    		 Treatment was randomly and blindly assigned to a lesion. All patients received both treatment but in different regions. The patients were administered with BF-200 ALA in the allocated region.
    Arm type
    		 Experimental

    Investigational medicinal product name
    BF-200 ALA
    Investigational medicinal product code
    ATC: L01XD04
    Other name
    Ameluz 78 mg/g gel
    Pharmaceutical forms
    Gel
    Routes of administration
    Topical use
    Dosage and administration details
    1 aplication previos to phototherapy. 78 mg/g

    Arm title
    		 MAL cream
    Arm description
    		 Treatment was randomly and blindly assigned to a lesion. All patients received both treatment but in different regions. The patients were administered with MAL in the allocated region.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    MAL
    Investigational medicinal product code
    ATC: L01X D03
    Other name
    Metvix 160 mg/g cream
    Pharmaceutical forms
    Cream
    Routes of administration
    Topical use
    Dosage and administration details
    1 dose administration. 160 mg/g

    Number of subjects in period 1
    		BF-200 ALA MAL cream
    Started
    22
    22
    Completed
    22
    22

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Whole study period
    Reporting group description
    		 -

    Reporting group values
    		 Whole study period Total
    Number of subjects
    		 22 22
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 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)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Patient age at inclusion
    Units: years
        log mean (full range (min-max))
    		 72 (57 to 84) -
    Gender categorical
    Units: Subjects
        Female
    		 1 1
        Male
    		 21 21
    Treatment region
    Body region where the patient was treated. Each patient received both treatments in simetric and similar body regions
    Units: Subjects
        scalp
    		 12 12
        forehead
    		 6 6
        cheek
    		 4 4

    End points

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    End points reporting groups
    Reporting group title
    BF-200 ALA
    Reporting group description
    		 Treatment was randomly and blindly assigned to a lesion. All patients received both treatment but in different regions. The patients were administered with BF-200 ALA in the allocated region.

    Reporting group title
    MAL cream
    Reporting group description
    		 Treatment was randomly and blindly assigned to a lesion. All patients received both treatment but in different regions. The patients were administered with MAL in the allocated region.

    Primary: Immediate local reaction

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    End point title
    		 Immediate local reaction
    End point description
    The immediate local reaction to illumination may include, to a greater or lesser degree, erythema, inflammation, and edema. It will be scored on a scale from 0 to 10 where 0 will be normal skin, without local reaction and 10 a maximum local reaction.
    End point type
    Primary
    End point timeframe
    First visit, treatment administration
    End point values
    		 BF-200 ALA MAL cream
    Number of subjects analysed
    22
    22
    Units: Arbitary unit
        arithmetic mean (standard deviation)
    5.4 ± 1.96
    4.7 ± 1.96
    Statistical analysis title
    		 ANOVA 1 factor
    Comparison groups
    BF-200 ALA v MAL cream
    Number of subjects included in analysis
    44
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.255
    Method
    		 ANOVA
    Confidence interval

    Primary: Late local reaction

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    End point title
    		 Late local reaction
    End point description
    The late local reaction defined by the presence to a greater or lesser degree of erythema, inflammation, edema, scabs and pustules, will also be scored from 0 to 10 where 0 will be normal skin, no local reaction and 10 a maximum local reaction.
    End point type
    Primary
    End point timeframe
    Second visit (day 2-3 after treatment administration)
    End point values
    		 BF-200 ALA MAL cream
    Number of subjects analysed
    22
    22
    Units: Arbitary unit
        arithmetic mean (standard deviation)
    7.4 ± 1.92
    5.9 ± 1.92
    Statistical analysis title
    		 ANOVA 1 factor
    Comparison groups
    BF-200 ALA v MAL cream
    Number of subjects included in analysis
    44
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.049
    Method
    		 ANOVA
    Confidence interval

    Primary: Pain

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    End point title
    		 Pain
    End point description
    Pain experienced by patients is measured using a subjective, 10-cm visual analog scale. The most frequent symptoms are pain and burning sensations on the skin, beginning during lighting or shortly after, and lasting a few hours, usually resolving on the day of treatment. The severity is normally mild to moderate, and rarely, requires a premature interruption of lighting.
    End point type
    Primary
    End point timeframe
    First visit, treatment administration
    End point values
    		 BF-200 ALA MAL cream
    Number of subjects analysed
    22
    22
    Units: Arbitary unit
        arithmetic mean (standard deviation)
    5.2 ± 2.6
    5 ± 2.6
    Statistical analysis title
    		 ANOVA 1 factor
    Comparison groups
    BF-200 ALA v MAL cream
    Number of subjects included in analysis
    44
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.956
    Method
    		 ANOVA
    Confidence interval

    Secondary: Qeratosis lesion number on each patient

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    End point title
    		 Qeratosis lesion number on each patient
    End point description
    extension of the treated lesions
    End point type
    Secondary
    End point timeframe
    Baseline
    End point values
    		 BF-200 ALA MAL cream
    Number of subjects analysed
    22
    22
    Units: number of lesions
        arithmetic mean (standard deviation)
    13.4 ± 4.4
    14.7 ± 4.1
    No statistical analyses for this end point

    Secondary: Fluorescence emission

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    End point title
    		 Fluorescence emission
    End point description
    Fluorescence will be studied with a Wood light lamp immediately before illumination and this can be scored from 0 to 10, where 0 was an absolute absence of fluorescence, 5 a limited and selective fluorescence in the QA lesions and 10 a fluorescence in the entire treatment area where the photosensitizer had been applied .
    End point type
    Secondary
    End point timeframe
    Selection visit
    End point values
    		 BF-200 ALA MAL cream
    Number of subjects analysed
    22
    22
    Units: Arbitary unit
        arithmetic mean (standard deviation)
    6.9 ± 2.01
    5.3 ± 2.01
    Statistical analysis title
    		 1 factor ANOVA
    Statistical analysis description
    Descriptive comparison between two means and SD.
    Comparison groups
    BF-200 ALA v MAL cream
    Number of subjects included in analysis
    44
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.026
    Method
    		 ANOVA
    Confidence interval

    Secondary: Treatment satisfaction

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    End point title
    		 Treatment satisfaction
    End point description
    The patients will be asked about the satisfaction provided by the treatment in each of the areas (benefit obtained in relation to the discomfort and discomfort of the treatment) to obtain an answer in the form of a score from 0 to 10 where 0 is absolutely dissatisfied and 10 Totally satisfied.
    End point type
    Secondary
    End point timeframe
    Visit 3, 30 days after treatment administration
    End point values
    		 BF-200 ALA MAL cream
    Number of subjects analysed
    22
    22
    Units: Arbitary unit
        arithmetic mean (standard deviation)
    7.5 ± 3.8
    7.4 ± 3.8
    Statistical analysis title
    		 ANOVA 1 factor
    Comparison groups
    BF-200 ALA v MAL cream
    Number of subjects included in analysis
    44
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.938
    Method
    		 ANOVA
    Confidence interval

    Secondary: Percentage of resolved Qeratosis lesions (QAs)

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    End point title
    		 Percentage of resolved Qeratosis lesions (QAs)
    End point description
    Percentage of queratosis lesions resolved.
    End point type
    Secondary
    End point timeframe
    visit 3, 30 days after treatment administration
    End point values
    		 BF-200 ALA MAL cream
    Number of subjects analysed
    22
    22
    Units: Number of lesions
        Resolved
    84
    81
        Not resolved
    16
    19
    Statistical analysis title
    		 ANOVA 1 factor
    Comparison groups
    BF-200 ALA v MAL cream
    Number of subjects included in analysis
    44
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.7012
    Method
    		 ANOVA
    Confidence interval

    Secondary: Clinical response to treatment

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    End point title
    		 Clinical response to treatment
    End point description
    The clinical response will be assessed with the help of the initial photograph and the transparent template. Partial response (PR) is defined if ≥75% of the initial AKs are resolved and complete response (CR) if 100% of them are resolved.
    End point type
    Secondary
    End point timeframe
    Visit 3, 30 days after treatment administration
    End point values
    		 BF-200 ALA MAL cream
    Number of subjects analysed
    22
    22
    Units: patients
        Complete response
    13
    11
        Partial response
    5
    7
        No response
    4
    4
    Statistical analysis title
    		 Complete response comparison between arms
    Statistical analysis description
    The percentage of patients with complete response was compared between treatment arms
    Comparison groups
    MAL cream v BF-200 ALA
    Number of subjects included in analysis
    44
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.5448
    Method
    		 ANOVA
    Confidence interval
    Statistical analysis title
    		 Partial response comparison between arms
    Statistical analysis description
    The percentage of patients with partial response among treatment arms was compared
    Comparison groups
    BF-200 ALA v MAL cream
    Number of subjects included in analysis
    44
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.735
    Method
    		 ANOVA
    Confidence interval

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    The sponsor collected adverse events (AEs) up to 30 days after administration of the last dose of study treatment.
    Adverse event reporting additional description
    Patients experienced no adverse events during the 30 days of participation in this trail.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23
    Reporting groups
    Reporting group title
    BF-200 ALA
    Reporting group description
    		 Treatment was randomly and blindly assigned to a lesion. All patients received both treatment but in different regions. The patients were administered with BF-200 ALA in the allocated region.

    Reporting group title
    MAL cream
    Reporting group description
    		 Treatment was randomly and blindly assigned to a lesion. All patients received both treatment but in different regions. The patients were administered with MAL in the allocated region.

    Serious adverse events
    		 BF-200 ALA MAL cream
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 22 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 BF-200 ALA MAL cream
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 22 (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: We confirm there were no Adverse events reported throughout the trial. This is consistent with the type of treatment, the pathology and the study design

    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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