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    Clinical Trial Results:
    Optical measurement with 5-ALA during surgical resection of brain tumors in children

    Summary
    EudraCT number
    		 2013-005565-40
    Trial protocol
    		 SE  
    Global end of trial date
    28 Oct 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    23 Feb 2020
    First version publication date
    23 Feb 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    OTP-B-Linköping
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Linköping University
    Sponsor organisation address
    Department of Biomedical Engineering, Linköping, Sweden, 581 85
    Public contact
    Linköping University , Department of Biomedical Engineering, 46 13286716, neda.haj.hosseini@liu.se
    Scientific contact
    Linköping University , Department of Biomedical Engineering, 46 13286716, neda.haj.hosseini@liu.se
    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
    07 Feb 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    28 Oct 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    28 Oct 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Improve brain tumour resection in children.
    Protection of trial subjects
    5-ALA induced fluorescence guided brain tumor surgery is well established on adults and 5-ALA is approved by FDA and European and Swedish Medical Product Agencies and adheres Good Manufacturing Practice (GMP). In this study 5-ALA induced fluorescence guided surgery is applied in children. Inclusion and exclusion criteria are clearly described. Before start the patients and two next of kin gave written informed consent. Monitoring and quality control are done to ensure the safety and integrity of the participant subjects, the data quality and that the study is compliant with the current version of the Declaration of Helsinki, ICH GCP, national regulations and scientific integrity. The Sponsor has delegated the monitoring to the CRO at the University, an independent party, who perform on-site monitoring before, during and after the study. The monitoring included source data verification. To enable this, the monitor has been given access to relevant medical records.
    Background therapy
    		 Patients were acutely admitted without any background therapy.
    Evidence for comparator
    		 No comparators.
    Actual start date of recruitment
    03 Oct 2014
    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
    Sweden: 14
    Worldwide total number of subjects
    14
    EEA total number of subjects
    14
    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)
    12
    Adolescents (12-17 years)
    2
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 All subjects were recruited prior to their brain tumor operation within the time period 2014-05-15 to 2018-10-28. 1-4 cases were recruited per year. The trial was kept open until 2019-09-11, but no more subjects were enrolled during this extra year. All subjects came from Sweden.

    Pre-assignment
    Screening details
    		 15 children and their two next of kin (parents) were asked to participate. One child was not included due to inadequate blood values. 14 children aged 4 to 17 years participated after informed written consent from the children and the two parents.

    Pre-assignment period milestones
    Number of subjects started
    		 14
    Number of subjects completed
    		 14

    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
    		 Fluorescence guided surgery
    Arm description
    		 All patients received an oral dose of 5-ALA prior to surgery. Measurements and data collection of fluorescence with a hand held probe and through the neurosurgical blue-light microscope was done during surgery. Biopsies were taken and sent for analysis. At the end of surgery another probe was used for recording of spectra from the skin. Data analysis was done postoperatively.
    Arm type
    		 Neurosurgery

    Investigational medicinal product name
    5-ALA
    Investigational medicinal product code
    L01XD04
    Other name
    5 aminulevulinic acid
    Pharmaceutical forms
    Powder for oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    One oral dose of 20 mg/kg milligram(s)/kilogram

    Number of subjects in period 1
    		Fluorescence guided surgery
    Started
    14
    Completed
    14

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Fluorescence guided surgery
    Reporting group description
    		 All patients received an oral dose of 5-ALA prior to surgery. Measurements and data collection of fluorescence with a hand held probe and through the neurosurgical blue-light microscope was done during surgery. Biopsies were taken and sent for analysis. At the end of surgery another probe was used for recording of spectra from the skin. Data analysis was done postoperatively.

    Reporting group values
    		 Fluorescence guided surgery Total
    Number of subjects
    		 14 14
    Age categorical
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 12 12
        Adolescents (12-17 years)
    		 2 2
        Adults (18-64 years)
    		 0 0
        From 65-84 years
    		 0 0
        85 years and over
    		 0 0
    Gender categorical
    Units: Subjects
        Female
    		 6 6
        Male
    		 8 8

    End points

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    End points reporting groups
    Reporting group title
    Fluorescence guided surgery
    Reporting group description
    		 All patients received an oral dose of 5-ALA prior to surgery. Measurements and data collection of fluorescence with a hand held probe and through the neurosurgical blue-light microscope was done during surgery. Biopsies were taken and sent for analysis. At the end of surgery another probe was used for recording of spectra from the skin. Data analysis was done postoperatively.

    Primary: Tumor fluorescence

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    End point title
    		 Tumor fluorescence [1]
    End point description
    Fluorescence in the neurosurgical microscope was graded as "none", "weak" or "strong". "None" was set to 0 and "weak" and "strong" were set to "1" . Fluorescence measured with the probe was measured as the size of the peak at 635 nm. No peak was set to 0 and peak was set to 1. Probe measurements on the skin was measured as no peak (0) and peak (1). The results were linked to the location in the brain (infratentorial and supratentorial) and to to the histopathology analysis i.e. as high-grade tumour or low-grade tumour. Summary of the result is attached as a pdf-file.
    End point type
    Primary
    End point timeframe
    During surgery
    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: Descriptive data and analysis is used. No hypothesis testing with statistical analysis is motivated.
    End point values
    		 Fluorescence guided surgery
    Number of subjects analysed
    14
    Units: aribitrary
        number (not applicable)
    14
    Attachments
    		 OTP-B
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From inclusion to 3 days post surgery.
    Adverse event reporting additional description
    Hospitalized patient with continuous reporting.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 No dictionary used
    Dictionary version
    0
    Reporting groups
    Reporting group title
    Total data set
    Reporting group description
    		 Tongue swelling after intubation.

    Serious adverse events
    		 Total data set
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 14 (7.14%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Respiratory, thoracic and mediastinal disorders
    Toung swelling during intubation
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Total data set
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    7 / 14 (50.00%)
    Blood and lymphatic system disorders
    Infleunce on heamatology
    Additional description: Result from blood samples (differential count of reticulocyte CRP, leukocyte, thrombocyte, hemoglobin, erythrocyte, MVC, MCHC). Subtile changes probably postoperatively induced.
         subjects affected / exposed
    7 / 14 (50.00%)
         occurrences all number
    1
    Hepatobiliary disorders
    Reduced liver function
    Additional description: Result from blood samples after surgery (ALAT, ASAT, ALP, Bilirubin). Subtile changes probably postoperatively induced.
         subjects affected / exposed
    5 / 14 (35.71%)
         occurrences all number
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    02 Dec 2014
    Exclusion criteria: Blood samples taken before surgery deviates more than +/‐ 10% from reference values Blood samples post surgery deviates from reference values more than +/‐ 10% and longer than 3 days, these are continued to be followed up. Per-oral administration of 5-ALA at least 2 hrs prior to surgery.

    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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