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    Clinical Trial Results:
    A RANDOMISED, CROSS-OVER, PHASE II STUDY, TO INVESTIGATE THE EFFICACY AND SAFETY OF GLUCARPIDASE FOR ROUTINE USE AFTER HIGH DOSE METHOTREXATE IN PATIENTS WITH BONE SARCOMA

    Summary
    EudraCT number
    2006-003203-40
    Trial protocol
    GB  
    Global end of trial date
    13 Apr 2015

    Results information
    Results version number
    v1(current)
    This version publication date
    15 Jul 2018
    First version publication date
    15 Jul 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    06/085
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    -
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    University College London Joint Research Office
    Sponsor organisation address
    1st Floor Maple House, Suite A 149 Tottenham Court Rd , London, United Kingdom, W1T 7DN
    Public contact
    Prof Jeremy Whelan, University College London Joint research Office, 44 0203447 9346, jeremy.whelan@nhs.net
    Scientific contact
    Prof Jeremy Whelan, University College London Joint Research Office, 44 0203447 9346, jeremy.whelan@nhs.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
    14 Mar 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    13 Apr 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    13 Apr 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To investigate whether glucarpidase rescue after high-dose methotrexate reduces delay to subsequent cycle of chemotherapy due to methotrexate toxicity
    Protection of trial subjects
    Written informed consent taken Safety measures to enable appropriate patient assessment pre-chemotherapy and timely reporting of treatment related adverse reactions/events.
    Background therapy
    MAP chemotherapy (methotrexate, doxorubicin, cisplatin) for high-grade bone osteosarcoma
    Evidence for comparator
    -
    Actual start date of recruitment
    13 Jun 2007
    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
    United Kingdom: 34
    Worldwide total number of subjects
    34
    EEA total number of subjects
    34
    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)
    14
    Adults (18-64 years)
    20
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Patients with osteosarcoma undergoing standard first line chemotherapy -> Enter recruitement dates etc, hoover over 'i' on the right to get the info

    Pre-assignment
    Screening details
    Written informed consent from patient or parent/guardian Diagnosis of high grade osteosarcoma, localised or metastatic or high grade osteosarcoma as a second malignancy or spindle cell sarcoma of bone or relapsed high grade osteosarcoma Age: 5-50 years at registration Ability to comply with study and follow up procedures (WHO performance 0-2)

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    A (M-GluM)
    Arm description
    Cycle 1 methotrexate alone Day 1 and Day 8. Cycle 2 Methotrexate plus glucarpidase Day 1 and Day 8
    Arm type
    No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    B (GluM-M)
    Arm description
    Cycle 1 Methotrexate plus glucarpidase Day 1 and Day 8. Cycle 2 methotrexate alone Day 1 and Day 8.
    Arm type
    Experimental

    Investigational medicinal product name
    Glucarpidase
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate and solvent for suspension for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    50u/kg by slow iv injection

    Number of subjects in period 1 [1]
    A (M-GluM) B (GluM-M)
    Started
    16
    16
    Completed
    14
    16
    Not completed
    2
    0
         Adverse event, non-fatal
    2
    -
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: 2 patients were not randomised
    Period 2
    Period 2 title
    Period 2
    Is this the baseline period?
    No
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    No

    Arm title
    A (M-GluM)
    Arm description
    Glucarpidace plus Methotrexate
    Arm type
    Experimental

    Investigational medicinal product name
    Glucarpidase
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate and solvent for suspension for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    50u/kg by slow iv injection

    Arm title
    B (GluM-M)
    Arm description
    Methotrexate only
    Arm type
    No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    GluM
    Arm description
    Outcomes for patients when on Glucarpidace (aggregated over both periods)
    Arm type
    Experimental

    Investigational medicinal product name
    Glucarpidase
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate and solvent for suspension for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    50u/kg by slow iv injection

    Arm title
    No Glu
    Arm description
    Outcomes for patients when not on Glucarpidace (aggregated over both periods)
    Arm type
    No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 2
    A (M-GluM) B (GluM-M) GluM No Glu
    Started
    14
    16
    29
    29
    Completed
    12
    11
    29
    29
    Not completed
    2
    5
    0
    0
         Progressive Disease
    1
    -
    -
    -
         MTX Toxicity
    1
    5
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    A (M-GluM)
    Reporting group description
    Cycle 1 methotrexate alone Day 1 and Day 8. Cycle 2 Methotrexate plus glucarpidase Day 1 and Day 8

    Reporting group title
    B (GluM-M)
    Reporting group description
    Cycle 1 Methotrexate plus glucarpidase Day 1 and Day 8. Cycle 2 methotrexate alone Day 1 and Day 8.

    Reporting group values
    A (M-GluM) B (GluM-M) Total
    Number of subjects
    16 16 32
    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 1 1
        Adolescents (12-17 years)
    11 9 20
        Adults (18-64 years)
    5 6 11
        From 65-84 years
    0 0 0
        85 years and over
    0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    18.7 ± 22.9 5.2 ± 11.8 -
    Gender categorical
    Units: Subjects
        Female
    3 4 7
        Male
    13 12 25
    Metastases
    Units: Subjects
        Yes
    4 1 5
        No
    12 15 27
    Site
    Units: Subjects
        Extremity
    15 11 26
        Other
    1 5 6
    Histology
    Units: Subjects
        Osteosarcoma
    14 15 29
        Other
    2 1 3

    End points

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    End points reporting groups
    Reporting group title
    A (M-GluM)
    Reporting group description
    Cycle 1 methotrexate alone Day 1 and Day 8. Cycle 2 Methotrexate plus glucarpidase Day 1 and Day 8

    Reporting group title
    B (GluM-M)
    Reporting group description
    Cycle 1 Methotrexate plus glucarpidase Day 1 and Day 8. Cycle 2 methotrexate alone Day 1 and Day 8.
    Reporting group title
    A (M-GluM)
    Reporting group description
    Glucarpidace plus Methotrexate

    Reporting group title
    B (GluM-M)
    Reporting group description
    Methotrexate only

    Reporting group title
    GluM
    Reporting group description
    Outcomes for patients when on Glucarpidace (aggregated over both periods)

    Reporting group title
    No Glu
    Reporting group description
    Outcomes for patients when not on Glucarpidace (aggregated over both periods)

    Subject analysis set title
    Fitness for chemotherapy at day 15
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    The McNemar’s test considers the null hypothesis that the proportions of patients fit for chemotherapy after Glu and no Glu are equal.

    Primary: Fitness for chemotherapy at Day 15 following Glu or no Glu

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    End point title
    Fitness for chemotherapy at Day 15 following Glu or no Glu
    End point description
    End point type
    Primary
    End point timeframe
    Day 15 fitness post chemotherapy
    End point values
    A (M-GluM) B (GluM-M) A (M-GluM) B (GluM-M) GluM No Glu
    Number of subjects analysed
    13
    16
    13
    16
    29
    29
    Units: Yes or No
        Fitness at Day 15
    5
    5
    8
    5
    13
    10
    Statistical analysis title
    Fitness for chemotherapy at Day 15
    Statistical analysis description
    The McNemar’s test considers the null hypothesis that the proportions of patients fit for chemotherapy after Glu and no Glu are equal.
    Comparison groups
    A (M-GluM) v B (GluM-M)
    Number of subjects included in analysis
    29
    Analysis specification
    Pre-specified
    Analysis type
    equivalence [1]
    P-value
    < 0.05
    Method
    Mcnemar
    Confidence interval
    Notes
    [1] - The sample size calculation is based on a McNemar’s test with an assumption that the responses to glucarpidase and folinic acid rescue are independent. With anticipated proportions of responses to standard rescue and glucarpidase+folinic acid of 55% and 90% respectively, the study will require 38 patients to give 80% power at a significance level of 5% and to allow for up to 30% drop-out during the study.The O’Brien and Flemming boundary method will be used for testing significance of effe

    Secondary: Mucositis assessment

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    End point title
    Mucositis assessment
    End point description
    End point type
    Secondary
    End point timeframe
    Assessment at Day 15
    End point values
    GluM No Glu
    Number of subjects analysed
    21
    21
    Units: CTCAE grade
    number (not applicable)
        Mucositis
    4
    9
    No statistical analyses for this end point

    Secondary: Renal toxicity

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    End point title
    Renal toxicity
    End point description
    End point type
    Secondary
    End point timeframe
    DAy 15
    End point values
    GluM No Glu
    Number of subjects analysed
    21
    21
    Units: CTCAE grade
    number (not applicable)
        Renal toxicity
    5
    6
    No statistical analyses for this end point

    Secondary: Neutropenia

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    End point title
    Neutropenia
    End point description
    End point type
    Secondary
    End point timeframe
    Day 15
    End point values
    GluM No Glu
    Number of subjects analysed
    21
    21
    Units: CTCAE grade
    number (not applicable)
        Neutropenia
    1
    1
    No statistical analyses for this end point

    Secondary: Liver toxicity

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    End point title
    Liver toxicity
    End point description
    End point type
    Secondary
    End point timeframe
    Day 15
    End point values
    GluM No Glu
    Number of subjects analysed
    21
    21
    Units: CTCAE grade
    number (not applicable)
        Liver toxicity
    13
    14
    No statistical analyses for this end point

    Secondary: Thromobcytopenia

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    End point title
    Thromobcytopenia
    End point description
    End point type
    Secondary
    End point timeframe
    Day 15
    End point values
    GluM No Glu
    Number of subjects analysed
    21
    21
    Units: CTCAE grade
    number (not applicable)
        Thrombocytopenia
    2
    1
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    AE related to IMP followed up until resolution. AE not related to IMP followed up until the end of the study (Day 21 of cycle 2)
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    CTCAE
    Dictionary version
    3
    Reporting groups
    Reporting group title
    Data analysis
    Reporting group description
    -

    Serious adverse events
    Data analysis
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 32 (0.00%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Frequency threshold for reporting non-serious adverse events: 3%
    Non-serious adverse events
    Data analysis
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    2 / 32 (6.25%)
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    2 / 32 (6.25%)
         occurrences all number
    2
    Metabolism and nutrition disorders
    Hypophosphataemia
         subjects affected / exposed
    1 / 32 (3.13%)
         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
    04 Dec 2006
    Inclusion of new study site and clarifications on administration of care
    17 Apr 2007
    Manufacturer's data amending timing of folinic acid administration post glucarpidase to minimise competition
    08 Sep 2009
    To provide real-time stability data for IMP To provide new safety data for IMP Change of study design to double blind, randomised to unblind, randomised Revision of sample size to allow drop-out rate of 30% Administrative changes to contact details Study solely sponsored by UCL
    03 Nov 2010
    Notification of additional laboratory conducting anti-glucarpidase antibody analysis Change in co-investigator Updated hydration details of methotrexate addition of safety reporting procedures to protocol
    02 Feb 2011
    IMP updated to new batch Updated methotrexate hydration details
    24 May 2012
    ALT and albumin measurement ranges removed from inclusion criteria Platelet count reduced to 75 for inclusion IMP shelf life changed to 4 hours ASR replaced with DSUR Clarifications to reporting of SAEs
    23 Aug 2013
    Change of Chief Investigator title Notification of new Co-investigator New contact details Updated protocol and appendices

    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.
    Results are preliminary and unpublished
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