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    Clinical Trial Results:
    A randomised trial of the European and American Osteosarcoma Study group to optimize treatment strategies for resectable osteosarcoma based on histological response to pre-operative chemotherapy

    Summary
    EudraCT number
    2004-000242-20
    Trial protocol
    FI   NO   BE   IE   AT   CZ   GB  
    Global end of trial date
    31 Dec 2018

    Results information
    Results version number
    v1(current)
    This version publication date
    05 Sep 2020
    First version publication date
    05 Sep 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    EURAMOS 1
    Additional study identifiers
    ISRCTN number
    ISRCTN67613327
    US NCT number
    NCT00134030
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Medical Research Council
    Sponsor organisation address
    90 High Holborn, London, United Kingdom, WC1V 6LJ
    Public contact
    EURAMOS trial team, MRC CTU at UCL, mrcctu.euramos@ucl.ac.uk
    Scientific contact
    EURAMOS trial team, MRC CTU at UCL, mrcctu.euramos@ucl.ac.uk
    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
    30 Nov 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    18 Nov 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    31 Dec 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The principal aim of this study is to find out whether giving extra treatment for osteosarcoma in addition to the standard 3-drug chemotherapy, methotrexate, doxorubicin and cisplatin (MAP), will improve the overall results for patients. Initially, all patients will receive two cycles of pre-operative MAP. After the tumour has been removed by surgery, it will be assessed for histological response: good response is defined as less than 10% viable tumour, poor response is defined as 10% or more viable tumour. The primary objectives of the trial are: 1. To investigate whether the addition of extra chemotherapy agents (ifosfamide and etoposide) to their post-operative chemotherapy improves event-free survival in patients who have a poor response to pre-operative chemotherapy 2. To investigate whether maintenance therapy (interferon alfa) following chemotherapy improves event-free survival in patients who have a good response to pre-operative chemotherapy.
    Protection of trial subjects
    Patients provided informed consent prior to entering the trial. All patients were followed and treated by qualified clinicians and surgeons in specialised teams.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    24 Aug 2005
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Safety, Efficacy, Scientific research
    Long term follow-up duration
    5 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Sweden: 33
    Country: Number of subjects enrolled
    Switzerland: 25
    Country: Number of subjects enrolled
    United Kingdom: 166
    Country: Number of subjects enrolled
    United States: 543
    Country: Number of subjects enrolled
    Australia: 13
    Country: Number of subjects enrolled
    Austria: 20
    Country: Number of subjects enrolled
    Belgium: 44
    Country: Number of subjects enrolled
    Canada: 47
    Country: Number of subjects enrolled
    Czech Republic: 6
    Country: Number of subjects enrolled
    Denmark: 12
    Country: Number of subjects enrolled
    Finland: 3
    Country: Number of subjects enrolled
    Germany: 298
    Country: Number of subjects enrolled
    Hungary: 19
    Country: Number of subjects enrolled
    Ireland: 1
    Country: Number of subjects enrolled
    Netherlands: 65
    Country: Number of subjects enrolled
    New Zealand: 5
    Country: Number of subjects enrolled
    Norway: 34
    Worldwide total number of subjects
    1334
    EEA total number of subjects
    701
    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)
    322
    Adolescents (12-17 years)
    740
    Adults (18-64 years)
    272
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    -

    Pre-assignment period milestones
    Number of subjects started
    2260 [1]
    Number of subjects completed
    1334

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    Late histology: 83
    Reason: Number of subjects
    Wrong pre-op chemotherapy: 56
    Reason: Number of subjects
    Disease progression: 130
    Reason: Number of subjects
    Not recovered from pre-op treatment: 22
    Reason: Number of subjects
    Incomplete surgery: 40
    Reason: Number of subjects
    Could not randomised in time: 14
    Reason: Number of subjects
    Patient <5 years (good response): 6
    Reason: Number of subjects
    Physician decision: 10
    Reason: Number of subjects
    Consent withdrawn by subject: 403
    Reason: Number of subjects
    Uncertain response: 2
    Reason: Number of subjects
    Histological response unknown: 160
    Notes
    [1] - The number of subjects reported to have started the pre-assignment period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: The number enrolled is the number of patients randomised. In the pre-assignment period, patients were registered to assess response.
    Period 1
    Period 1 title
    Main 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
    MAP-GR
    Arm description
    Methotrexate, Doxorubicin and Cisplatin. Control arm for patients with good response after surgery (<10% viable tumour)
    Arm type
    Active comparator

    Investigational medicinal product name
    Methotrexate
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    12000 mg/m2, given in weeks 4, 5, 9, 10, 15, 16, 20, 21, 24, 25, 28, 29. Weeks 4-10 are pre-randomisation.

    Investigational medicinal product name
    Doxorubicin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    75 mg/m2, given in weeks 1, 6, 12, 17, 22, and 26. Weeks 1 and 6 are pre-randomisation.

    Investigational medicinal product name
    Cisplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    120 mg/m2, given in weeks 1, 6, 12, 17. Weeks 1 and 6 are pre-randomisation.

    Arm title
    MAPifn
    Arm description
    Methotrexate, Doxorubicin, Cisplatin plus pegylated interferon. Experimental arm for patients with good response after surgery (<10% viable tumour).
    Arm type
    Experimental

    Investigational medicinal product name
    Doxorubicin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    75 mg/m2, given in weeks 1, 6, 12, 17, 22, 26. Weeks 1 and 6 are pre-randomisation.

    Investigational medicinal product name
    Methotrexate
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    12000 mg/m2, given in weeks 4, 5, 9, 10, 15, 16, 20, 21, 24, 25, 28, 29. Weeks 4-10 are pre-randomisation.

    Investigational medicinal product name
    Cisplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    120 mg/m2, given in weeks 1, 6, 12, 17. Weeks 1 and 6 are pre-randomisation.

    Investigational medicinal product name
    Pegylated interferon
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Weekly from week 30 (or recovery from toxicity from MAP) until week 104. 0.5-1.0 microgram/kg s.c. once weekly.

    Arm title
    MAP-PR
    Arm description
    Methotrexate, Doxorubicin and Cisplatin. Control arm for patients with poor response after surgery (>10% viable tumour).
    Arm type
    Active comparator

    Investigational medicinal product name
    Methotrexate
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    12000 mg/m2, given in weeks 4, 5, 9, 10, 15, 16, 20, 21, 24, 25, 28, 29. Weeks 4-10 are pre-randomisation.

    Investigational medicinal product name
    Doxorubicin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    75 mg/m2, given in weeks 1, 6, 12, 17, 22, 26. Weeks 1 and 6 are pre-randomisation.

    Investigational medicinal product name
    Cisplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    120 mg/m2, given in weeks 1, 6, 12, 17. Weeks 1 and 6 are pre-randomisation.

    Arm title
    MAPIE
    Arm description
    Methotrexate, Doxorubicin, Cisplatin, plus ifosfamide and etoposide. Experimental arm for patients with poor response after surgery (>10% viable tumour).
    Arm type
    Experimental

    Investigational medicinal product name
    Methotrexate
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    12000 mg/m2, given in weeks 4, 5, 9, 10, 15, 19, 23, 27, 31, 35, 39, 40. Weeks 4-10 are pre-randomisation.

    Investigational medicinal product name
    Doxorubicin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    75 mg/m2, given in weeks 1, 6, 12, 20, 28, 36. Weeks 1 and 6 are pre-randomisation.

    Investigational medicinal product name
    Cisplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    120 mg/m2, given in weeks 1, 6, 12, 28. Weeks 1 and 6 are pre-randomisation.

    Investigational medicinal product name
    Ifosfamide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    14 g/m2, given in weeks 16, 24, 32. 9 g/m2 given in weeks 20 and 36.

    Investigational medicinal product name
    Etoposide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    500 mg/m2, given in weeks 16, 24, 32.

    Number of subjects in period 1
    MAP-GR MAPifn MAP-PR MAPIE
    Started
    359
    357
    310
    308
    Completed
    359
    357
    310
    308

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    MAP-GR
    Reporting group description
    Methotrexate, Doxorubicin and Cisplatin. Control arm for patients with good response after surgery (<10% viable tumour)

    Reporting group title
    MAPifn
    Reporting group description
    Methotrexate, Doxorubicin, Cisplatin plus pegylated interferon. Experimental arm for patients with good response after surgery (<10% viable tumour).

    Reporting group title
    MAP-PR
    Reporting group description
    Methotrexate, Doxorubicin and Cisplatin. Control arm for patients with poor response after surgery (>10% viable tumour).

    Reporting group title
    MAPIE
    Reporting group description
    Methotrexate, Doxorubicin, Cisplatin, plus ifosfamide and etoposide. Experimental arm for patients with poor response after surgery (>10% viable tumour).

    Reporting group values
    MAP-GR MAPifn MAP-PR MAPIE Total
    Number of subjects
    359 357 310 308 1334
    Age categorical
    Units: Subjects
        In utero
    0 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0 0 0 0
        Newborns (0-27 days)
    0 0 0 0 0
        Infants and toddlers (28 days-23 months)
    0 0 0 0 0
        Children (2-11 years)
    94 77 85 66 322
        Adolescents (12-17 years)
    206 218 142 174 740
        Adults (18-64 years)
    59 62 83 68 272
        From 65-84 years
    0 0 0 0 0
        85 years and over
    0 0 0 0 0
    Age continuous
    Units: years
        median (inter-quartile range (Q1-Q3))
    14 (11 to 16) 14 (12 to 16) 15 (11 to 18) 15 (12 to 17) -
    Gender categorical
    Units: Subjects
        Female
    148 147 136 117 548
        Male
    211 210 174 191 786
    Site of tumour
    Units: Subjects
        Femur
    179 191 154 166 690
        Tibia
    113 102 75 76 366
        Fibula
    14 20 17 13 64
        Humerus
    36 33 39 27 135
        Radius
    5 5 4 6 20
        Ulna
    2 0 2 1 5
        Scapula/clavicle
    2 1 3 2 8
        Pelvis/sacrum
    5 5 8 11 29
        Rib
    3 0 3 3 9
        Other
    0 0 5 3 8
    Location of tumour on the bone
    Units: Subjects
        Proximal
    156 150 114 109 529
        Diapysis
    13 12 11 12 48
        Distal
    180 189 166 168 703
        N/A (not long bone)
    10 6 19 19 54
    Pathological fracture at diagnosis
    Units: Subjects
        No
    321 308 276 270 1175
        Yes
    37 49 34 35 155
        Data missing
    1 0 0 3 4
    Lung metastases
    Units: Subjects
        No/possible
    324 321 272 280 1197
        Yes
    35 36 38 28 137
    Histological classification
    Units: Subjects
        Conventional
    320 322 288 289 1219
        Telangiectatic
    25 20 11 6 62
        Small cell
    2 1 3 2 8
        High-grade surface
    3 5 5 6 19
        Other
    4 2 0 1 7
        Data missing
    5 7 3 4 19

    End points

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    End points reporting groups
    Reporting group title
    MAP-GR
    Reporting group description
    Methotrexate, Doxorubicin and Cisplatin. Control arm for patients with good response after surgery (<10% viable tumour)

    Reporting group title
    MAPifn
    Reporting group description
    Methotrexate, Doxorubicin, Cisplatin plus pegylated interferon. Experimental arm for patients with good response after surgery (<10% viable tumour).

    Reporting group title
    MAP-PR
    Reporting group description
    Methotrexate, Doxorubicin and Cisplatin. Control arm for patients with poor response after surgery (>10% viable tumour).

    Reporting group title
    MAPIE
    Reporting group description
    Methotrexate, Doxorubicin, Cisplatin, plus ifosfamide and etoposide. Experimental arm for patients with poor response after surgery (>10% viable tumour).

    Primary: Event-free survival at 3 years (primary analysis)

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    End point title
    Event-free survival at 3 years (primary analysis)
    End point description
    Event-free survival is the time from randomisation until the first occurrence of local recurrence, new metastatic disease, progression of primary metastatic disease, secondary malignancy, or death. Patients without an even were censored at the date of last contact. These results are from the primary analyses, published in 2016 (poor response groups) and 2015 (good response group).
    End point type
    Primary
    End point timeframe
    Event rate at 3 years
    End point values
    MAP-GR MAPifn MAP-PR MAPIE
    Number of subjects analysed
    359
    357
    310
    308
    Units: Percentage
        number (confidence interval 95%)
    74 (69 to 79)
    77 (72 to 81)
    55 (49 to 60)
    53 (47 to 59)
    Statistical analysis title
    Good response group EFS
    Statistical analysis description
    Hazard ratio comparing event-free survival for patients with a good response after surgery.
    Comparison groups
    MAP-GR v MAPifn
    Number of subjects included in analysis
    716
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.214
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.83
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.61
         upper limit
    1.12
    Statistical analysis title
    Poor response group EFS
    Statistical analysis description
    Hazard ratio comparing event-free survival for patients with a poor response after surgery.
    Comparison groups
    MAP-PR v MAPIE
    Number of subjects included in analysis
    618
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.86
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.98
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.78
         upper limit
    1.23

    Secondary: RMST (primary analysis)

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    End point title
    RMST (primary analysis) [1]
    End point description
    For the poor response group, there was evidence of non-proportional hazards, so secondary analysis was performed using restricted mean survival.
    End point type
    Secondary
    End point timeframe
    RMST over 6 years from randomisation.
    Notes
    [1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This analysis is only in the cohort of poor responders.
    End point values
    MAP-PR MAPIE
    Number of subjects analysed
    310
    308
    Units: Months
        number (confidence interval 95%)
    43.3 (40.1 to 46.4)
    44.1 (41.1 to 47.1)
    Statistical analysis title
    Poor response group EFS (RMST)
    Statistical analysis description
    Difference in RMST for poor response group (MAPIE - MAP-PR).
    Comparison groups
    MAPIE v MAP-PR
    Number of subjects included in analysis
    618
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.69
    Method
    t-test, 2-sided
    Parameter type
    Mean difference (final values)
    Point estimate
    0.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.3
         upper limit
    4.9

    Secondary: Event-free survival at 5 years (long-term analysis)

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    End point title
    Event-free survival at 5 years (long-term analysis)
    End point description
    Event-free survival is the time from randomisation until the first occurrence of local recurrence, new metastatic disease, progression of primary metastatic disease, secondary malignancy, or death. Patients without an even were censored at the date of last contact. These results are from the long-term analysis, first presented at CTOS in November 2019.
    End point type
    Secondary
    End point timeframe
    Event-free survival rate at 5 years
    End point values
    MAP-GR MAPifn MAP-PR MAPIE
    Number of subjects analysed
    359
    357
    310
    308
    Units: percent
        number (confidence interval 95%)
    69 (65 to 74)
    74 (70 to 80)
    50 (45 to 55)
    46 (41 to 52)
    Statistical analysis title
    Good response group EFS
    Comparison groups
    MAPifn v MAP-GR
    Number of subjects included in analysis
    716
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.212
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.84
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.64
         upper limit
    1.1
    Statistical analysis title
    Poor response group EFS
    Comparison groups
    MAP-PR v MAPIE
    Number of subjects included in analysis
    618
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.993
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.81
         upper limit
    1.24

    Secondary: Overall survival at 5 years (long-term analysis)

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    End point title
    Overall survival at 5 years (long-term analysis)
    End point description
    Overall survival defined as time from randomisation until death from any cause, with patients censored at date of last follow-up. Results of long-term analysis, first presented at CTOS conference in November 2019.
    End point type
    Secondary
    End point timeframe
    Overall survival at 5 years
    End point values
    MAP-GR MAPifn MAP-PR MAPIE
    Number of subjects analysed
    359
    357
    310
    308
    Units: percent
        number (confidence interval 95%)
    84 (80 to 88)
    84 (81 to 88)
    68 (63 to 73)
    68 (63 to 73)
    Statistical analysis title
    Good response group OS
    Comparison groups
    MAP-GR v MAPifn
    Number of subjects included in analysis
    716
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.804
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.96
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.69
         upper limit
    1.33
    Statistical analysis title
    Poor response group OS
    Comparison groups
    MAP-PR v MAPIE
    Number of subjects included in analysis
    618
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.674
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1.06
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.81
         upper limit
    1.39

    Secondary: RMST (long-term EFS analysis)

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    End point title
    RMST (long-term EFS analysis) [2]
    End point description
    For the poor response group, there was evidence of non-proportional hazards, so secondary analysis was performed using restricted mean survival.
    End point type
    Secondary
    End point timeframe
    Randomisation to 11 years
    Notes
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This analysis is only in the cohort of poor responders.
    End point values
    MAP-PR MAPIE
    Number of subjects analysed
    310
    308
    Units: months
        arithmetic mean (confidence interval 95%)
    69.1 (62.9 to 75.2)
    71.2 (64.9 to 77.4)
    Statistical analysis title
    Poor response group EFS (RMST, long-term analysis)
    Comparison groups
    MAP-PR v MAPIE
    Number of subjects included in analysis
    618
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.667
    Method
    Difference in RMST
    Parameter type
    Mean difference (final values)
    Point estimate
    -2.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -11.8
         upper limit
    7.5

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    From randomisation until 30 days after last protocol treatment.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    22.1
    Reporting groups
    Reporting group title
    MAP-GR
    Reporting group description
    Methotrexate, Doxorubicin and Cisplatin. Control arm for patients with good response after surgery (<10% viable tumour)

    Reporting group title
    MAPifn
    Reporting group description
    Methotrexate, Doxorubicin, Cisplatin plus pegylated interferon. Experimental arm for patients with good response after surgery (<10% viable tumour).

    Reporting group title
    MAP-PR
    Reporting group description
    Methotrexate, Doxorubicin and Cisplatin. Control arm for patients with poor response after surgery (>10% viable tumour).

    Reporting group title
    MAPIE
    Reporting group description
    Methotrexate, Doxorubicin, Cisplatin, plus ifosfamide and etoposide. Experimental arm for patients with poor response after surgery (>10% viable tumour).

    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: Toxicity was collected through SAEs, data on non serious adverse events are not available.
    Serious adverse events
    MAP-GR MAPifn MAP-PR MAPIE
    Total subjects affected by serious adverse events
         subjects affected / exposed
    49 / 359 (13.65%)
    76 / 357 (21.29%)
    36 / 310 (11.61%)
    43 / 308 (13.96%)
         number of deaths (all causes)
    57
    57
    101
    92
         number of deaths resulting from adverse events
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    1 / 359 (0.28%)
    0 / 357 (0.00%)
    0 / 310 (0.00%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    0 / 359 (0.00%)
    0 / 357 (0.00%)
    0 / 310 (0.00%)
    1 / 308 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Jugular vein thrombosis
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 357 (0.28%)
    0 / 310 (0.00%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pelvic venous thrombosis
         subjects affected / exposed
    1 / 359 (0.28%)
    0 / 357 (0.00%)
    0 / 310 (0.00%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peripheral artery dissection
         subjects affected / exposed
    1 / 359 (0.28%)
    0 / 357 (0.00%)
    0 / 310 (0.00%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Acute myeloid leukaemia
         subjects affected / exposed
    1 / 359 (0.28%)
    0 / 357 (0.00%)
    0 / 310 (0.00%)
    2 / 308 (0.65%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ewing's sarcoma
         subjects affected / exposed
    0 / 359 (0.00%)
    0 / 357 (0.00%)
    0 / 310 (0.00%)
    1 / 308 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myelodysplastic syndrome
         subjects affected / exposed
    0 / 359 (0.00%)
    0 / 357 (0.00%)
    1 / 310 (0.32%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Papillary thyroid cancer
         subjects affected / exposed
    0 / 359 (0.00%)
    0 / 357 (0.00%)
    0 / 310 (0.00%)
    1 / 308 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal cell carcinoma stage I
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 357 (0.28%)
    0 / 310 (0.00%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Anaphylactic reaction
         subjects affected / exposed
    0 / 359 (0.00%)
    0 / 357 (0.00%)
    0 / 310 (0.00%)
    1 / 308 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemophagocytic lymphohistiocytosis
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 357 (0.28%)
    0 / 310 (0.00%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypersensitivity
         subjects affected / exposed
    0 / 359 (0.00%)
    0 / 357 (0.00%)
    0 / 310 (0.00%)
    1 / 308 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chills
         subjects affected / exposed
    1 / 359 (0.28%)
    0 / 357 (0.00%)
    0 / 310 (0.00%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Complication associated with device
         subjects affected / exposed
    1 / 359 (0.28%)
    0 / 357 (0.00%)
    0 / 310 (0.00%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Impaired healing
         subjects affected / exposed
    1 / 359 (0.28%)
    0 / 357 (0.00%)
    0 / 310 (0.00%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infusion site erythema
         subjects affected / exposed
    0 / 359 (0.00%)
    0 / 357 (0.00%)
    1 / 310 (0.32%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infusion site thrombosis
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 357 (0.28%)
    0 / 310 (0.00%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mucosal inflammation
         subjects affected / exposed
    3 / 359 (0.84%)
    2 / 357 (0.56%)
    6 / 310 (1.94%)
    3 / 308 (0.97%)
         occurrences causally related to treatment / all
    3 / 3
    2 / 2
    7 / 7
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    4 / 359 (1.11%)
    3 / 357 (0.84%)
    2 / 310 (0.65%)
    2 / 308 (0.65%)
         occurrences causally related to treatment / all
    6 / 7
    4 / 5
    2 / 2
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Abnormal behaviour
         subjects affected / exposed
    0 / 359 (0.00%)
    0 / 357 (0.00%)
    0 / 310 (0.00%)
    1 / 308 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Depressed mood
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 357 (0.28%)
    0 / 310 (0.00%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mania
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 357 (0.28%)
    0 / 310 (0.00%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Suicide attempt
         subjects affected / exposed
    1 / 359 (0.28%)
    0 / 357 (0.00%)
    0 / 310 (0.00%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Femoral neck fracture
         subjects affected / exposed
    0 / 359 (0.00%)
    0 / 357 (0.00%)
    0 / 310 (0.00%)
    1 / 308 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 357 (0.28%)
    0 / 310 (0.00%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Periprosthetic fracture
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 357 (0.28%)
    0 / 310 (0.00%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Postoperative wound complication
         subjects affected / exposed
    1 / 359 (0.28%)
    0 / 357 (0.00%)
    0 / 310 (0.00%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Radius fracture
         subjects affected / exposed
    1 / 359 (0.28%)
    0 / 357 (0.00%)
    0 / 310 (0.00%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tibia fracture
         subjects affected / exposed
    2 / 359 (0.56%)
    2 / 357 (0.56%)
    0 / 310 (0.00%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Toxicity to various agents
         subjects affected / exposed
    0 / 359 (0.00%)
    0 / 357 (0.00%)
    0 / 310 (0.00%)
    1 / 308 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper limb fracture
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 357 (0.28%)
    0 / 310 (0.00%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 359 (0.28%)
    0 / 357 (0.00%)
    0 / 310 (0.00%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood creatinine increased
         subjects affected / exposed
    1 / 359 (0.28%)
    1 / 357 (0.28%)
    0 / 310 (0.00%)
    1 / 308 (0.32%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chemotherapeutic drug level increased
         subjects affected / exposed
    2 / 359 (0.56%)
    0 / 357 (0.00%)
    0 / 310 (0.00%)
    1 / 308 (0.32%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Drug clearance decreased
         subjects affected / exposed
    2 / 359 (0.56%)
    0 / 357 (0.00%)
    0 / 310 (0.00%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Influenza B virus test positive
         subjects affected / exposed
    1 / 359 (0.28%)
    0 / 357 (0.00%)
    0 / 310 (0.00%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neutrophil count decreased
         subjects affected / exposed
    0 / 359 (0.00%)
    0 / 357 (0.00%)
    1 / 310 (0.32%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Platelet count decreased
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 357 (0.28%)
    0 / 310 (0.00%)
    1 / 308 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Transaminases increased
         subjects affected / exposed
    0 / 359 (0.00%)
    0 / 357 (0.00%)
    0 / 310 (0.00%)
    1 / 308 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    White blood cell count decreased
         subjects affected / exposed
    0 / 359 (0.00%)
    0 / 357 (0.00%)
    0 / 310 (0.00%)
    1 / 308 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute left ventricular failure
         subjects affected / exposed
    1 / 359 (0.28%)
    0 / 357 (0.00%)
    0 / 310 (0.00%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    Atrial thrombosis
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 357 (0.28%)
    0 / 310 (0.00%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 357 (0.28%)
    0 / 310 (0.00%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    0 / 359 (0.00%)
    2 / 357 (0.56%)
    0 / 310 (0.00%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiomyopathy
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 357 (0.28%)
    0 / 310 (0.00%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiovascular insufficiency
         subjects affected / exposed
    1 / 359 (0.28%)
    0 / 357 (0.00%)
    0 / 310 (0.00%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Congestive cardiomyopathy
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 357 (0.28%)
    0 / 310 (0.00%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Left ventricular dysfunction
         subjects affected / exposed
    1 / 359 (0.28%)
    2 / 357 (0.56%)
    1 / 310 (0.32%)
    2 / 308 (0.65%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    Left ventricular failure
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 357 (0.28%)
    0 / 310 (0.00%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myocarditis
         subjects affected / exposed
    0 / 359 (0.00%)
    0 / 357 (0.00%)
    1 / 310 (0.32%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 357 (0.28%)
    0 / 310 (0.00%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tachycardia
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 357 (0.28%)
    0 / 310 (0.00%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ventricular dysfunction
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 357 (0.28%)
    0 / 310 (0.00%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ventricular fibrillation
         subjects affected / exposed
    0 / 359 (0.00%)
    0 / 357 (0.00%)
    1 / 310 (0.32%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory distress syndrome
         subjects affected / exposed
    1 / 359 (0.28%)
    0 / 357 (0.00%)
    0 / 310 (0.00%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 357 (0.28%)
    1 / 310 (0.32%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    1 / 359 (0.28%)
    0 / 357 (0.00%)
    0 / 310 (0.00%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypersensitivity pneumonitis
         subjects affected / exposed
    0 / 359 (0.00%)
    0 / 357 (0.00%)
    1 / 310 (0.32%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    0 / 359 (0.00%)
    2 / 357 (0.56%)
    0 / 310 (0.00%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pleurisy
         subjects affected / exposed
    0 / 359 (0.00%)
    0 / 357 (0.00%)
    1 / 310 (0.32%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 359 (0.28%)
    2 / 357 (0.56%)
    1 / 310 (0.32%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Febrile neutropenia
         subjects affected / exposed
    7 / 359 (1.95%)
    5 / 357 (1.40%)
    3 / 310 (0.97%)
    10 / 308 (3.25%)
         occurrences causally related to treatment / all
    11 / 11
    6 / 6
    4 / 4
    17 / 17
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    1 / 359 (0.28%)
    0 / 357 (0.00%)
    0 / 310 (0.00%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    1 / 359 (0.28%)
    1 / 357 (0.28%)
    0 / 310 (0.00%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Anosmia
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 357 (0.28%)
    0 / 310 (0.00%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebral artery embolism
         subjects affected / exposed
    1 / 359 (0.28%)
    0 / 357 (0.00%)
    0 / 310 (0.00%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cytotoxic oedema
         subjects affected / exposed
    0 / 359 (0.00%)
    0 / 357 (0.00%)
    1 / 310 (0.32%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Disturbance in attention
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 357 (0.28%)
    0 / 310 (0.00%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dystonia
         subjects affected / exposed
    0 / 359 (0.00%)
    0 / 357 (0.00%)
    1 / 310 (0.32%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Encephalopathy
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 357 (0.28%)
    1 / 310 (0.32%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Generalised tonic-clonic seizure
         subjects affected / exposed
    2 / 359 (0.56%)
    0 / 357 (0.00%)
    0 / 310 (0.00%)
    1 / 308 (0.32%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hemiparesis
         subjects affected / exposed
    1 / 359 (0.28%)
    2 / 357 (0.56%)
    1 / 310 (0.32%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hemiplegia
         subjects affected / exposed
    1 / 359 (0.28%)
    0 / 357 (0.00%)
    0 / 310 (0.00%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Leukoencephalopathy
         subjects affected / exposed
    1 / 359 (0.28%)
    0 / 357 (0.00%)
    0 / 310 (0.00%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Monoparesis
         subjects affected / exposed
    0 / 359 (0.00%)
    0 / 357 (0.00%)
    1 / 310 (0.32%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Presyncope
         subjects affected / exposed
    0 / 359 (0.00%)
    0 / 357 (0.00%)
    1 / 310 (0.32%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    1 / 359 (0.28%)
    1 / 357 (0.28%)
    1 / 310 (0.32%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Stupor
         subjects affected / exposed
    0 / 359 (0.00%)
    0 / 357 (0.00%)
    0 / 310 (0.00%)
    1 / 308 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Toxic encephalopathy
         subjects affected / exposed
    1 / 359 (0.28%)
    0 / 357 (0.00%)
    0 / 310 (0.00%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Optic neuropathy
         subjects affected / exposed
    0 / 359 (0.00%)
    0 / 357 (0.00%)
    1 / 310 (0.32%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Deafness bilateral
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 357 (0.28%)
    1 / 310 (0.32%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 359 (0.28%)
    2 / 357 (0.56%)
    0 / 310 (0.00%)
    1 / 308 (0.32%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anal fistula
         subjects affected / exposed
    0 / 359 (0.00%)
    0 / 357 (0.00%)
    0 / 310 (0.00%)
    1 / 308 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anal ulcer
         subjects affected / exposed
    1 / 359 (0.28%)
    0 / 357 (0.00%)
    0 / 310 (0.00%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    0 / 359 (0.00%)
    0 / 357 (0.00%)
    2 / 310 (0.65%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    0 / 359 (0.00%)
    0 / 357 (0.00%)
    1 / 310 (0.32%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mouth ulceration
         subjects affected / exposed
    0 / 359 (0.00%)
    0 / 357 (0.00%)
    1 / 310 (0.32%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 359 (0.28%)
    1 / 357 (0.28%)
    0 / 310 (0.00%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 357 (0.28%)
    0 / 310 (0.00%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    0 / 359 (0.00%)
    0 / 357 (0.00%)
    1 / 310 (0.32%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Stomatitis
         subjects affected / exposed
    3 / 359 (0.84%)
    1 / 357 (0.28%)
    0 / 310 (0.00%)
    1 / 308 (0.32%)
         occurrences causally related to treatment / all
    3 / 3
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    3 / 359 (0.84%)
    1 / 357 (0.28%)
    0 / 310 (0.00%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 359 (0.00%)
    0 / 357 (0.00%)
    2 / 310 (0.65%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nephropathy toxic
         subjects affected / exposed
    1 / 359 (0.28%)
    2 / 357 (0.56%)
    0 / 310 (0.00%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    1 / 359 (0.28%)
    0 / 357 (0.00%)
    0 / 310 (0.00%)
    1 / 308 (0.32%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal impairment
         subjects affected / exposed
    1 / 359 (0.28%)
    0 / 357 (0.00%)
    0 / 310 (0.00%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatotoxicity
         subjects affected / exposed
    0 / 359 (0.00%)
    0 / 357 (0.00%)
    0 / 310 (0.00%)
    1 / 308 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Liver disorder
         subjects affected / exposed
    0 / 359 (0.00%)
    0 / 357 (0.00%)
    0 / 310 (0.00%)
    1 / 308 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Venoocclusive liver disease
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 357 (0.28%)
    0 / 310 (0.00%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Rash erythematous
         subjects affected / exposed
    0 / 359 (0.00%)
    0 / 357 (0.00%)
    1 / 310 (0.32%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urticaria
         subjects affected / exposed
    0 / 359 (0.00%)
    0 / 357 (0.00%)
    1 / 310 (0.32%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Product issues
    Device dislocation
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 357 (0.28%)
    0 / 310 (0.00%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Device failure
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 357 (0.28%)
    0 / 310 (0.00%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thrombosis in device
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 357 (0.28%)
    0 / 310 (0.00%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Bone infarction
         subjects affected / exposed
    0 / 359 (0.00%)
    0 / 357 (0.00%)
    1 / 310 (0.32%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bone pain
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 357 (0.28%)
    0 / 310 (0.00%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Joint swelling
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 357 (0.28%)
    0 / 310 (0.00%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Osteoporotic fracture
         subjects affected / exposed
    1 / 359 (0.28%)
    0 / 357 (0.00%)
    0 / 310 (0.00%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pathological fracture
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 357 (0.28%)
    0 / 310 (0.00%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Autoimmune thyroiditis
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 357 (0.28%)
    0 / 310 (0.00%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Basedow's disease
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 357 (0.28%)
    0 / 310 (0.00%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Inappropriate antidiuretic hormone secretion
         subjects affected / exposed
    0 / 359 (0.00%)
    0 / 357 (0.00%)
    1 / 310 (0.32%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thyroiditis
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 357 (0.28%)
    0 / 310 (0.00%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    1 / 359 (0.28%)
    0 / 357 (0.00%)
    0 / 310 (0.00%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Abscess limb
         subjects affected / exposed
    0 / 359 (0.00%)
    0 / 357 (0.00%)
    1 / 310 (0.32%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anal abscess
         subjects affected / exposed
    0 / 359 (0.00%)
    2 / 357 (0.56%)
    0 / 310 (0.00%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    1 / 359 (0.28%)
    2 / 357 (0.56%)
    0 / 310 (0.00%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Arthritis bacterial
         subjects affected / exposed
    0 / 359 (0.00%)
    2 / 357 (0.56%)
    0 / 310 (0.00%)
    1 / 308 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bacterial sepsis
         subjects affected / exposed
    0 / 359 (0.00%)
    0 / 357 (0.00%)
    0 / 310 (0.00%)
    1 / 308 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchopulmonary aspergillosis
         subjects affected / exposed
    0 / 359 (0.00%)
    0 / 357 (0.00%)
    1 / 310 (0.32%)
    1 / 308 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Catheter site infection
         subjects affected / exposed
    1 / 359 (0.28%)
    0 / 357 (0.00%)
    0 / 310 (0.00%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    2 / 359 (0.56%)
    1 / 357 (0.28%)
    0 / 310 (0.00%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Clostridium difficile infection
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 357 (0.28%)
    0 / 310 (0.00%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    3 / 359 (0.84%)
    6 / 357 (1.68%)
    3 / 310 (0.97%)
    1 / 308 (0.32%)
         occurrences causally related to treatment / all
    2 / 3
    6 / 7
    2 / 3
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Device related sepsis
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 357 (0.28%)
    0 / 310 (0.00%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ecthyma
         subjects affected / exposed
    0 / 359 (0.00%)
    0 / 357 (0.00%)
    0 / 310 (0.00%)
    1 / 308 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    1 / 359 (0.28%)
    0 / 357 (0.00%)
    0 / 310 (0.00%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Escherichia sepsis
         subjects affected / exposed
    0 / 359 (0.00%)
    0 / 357 (0.00%)
    0 / 310 (0.00%)
    1 / 308 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Febrile infection
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 357 (0.28%)
    0 / 310 (0.00%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 357 (0.28%)
    0 / 310 (0.00%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    H1N1 influenza
         subjects affected / exposed
    0 / 359 (0.00%)
    0 / 357 (0.00%)
    0 / 310 (0.00%)
    1 / 308 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Herpes simplex
         subjects affected / exposed
    0 / 359 (0.00%)
    0 / 357 (0.00%)
    1 / 310 (0.32%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    0 / 359 (0.00%)
    0 / 357 (0.00%)
    0 / 310 (0.00%)
    1 / 308 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Implant site cellulitis
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 357 (0.28%)
    0 / 310 (0.00%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Incision site abscess
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 357 (0.28%)
    0 / 310 (0.00%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neutropenic infection
         subjects affected / exposed
    0 / 359 (0.00%)
    2 / 357 (0.56%)
    0 / 310 (0.00%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neutropenic sepsis
         subjects affected / exposed
    0 / 359 (0.00%)
    2 / 357 (0.56%)
    2 / 310 (0.65%)
    1 / 308 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    0 / 359 (0.00%)
    0 / 357 (0.00%)
    0 / 310 (0.00%)
    1 / 308 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 359 (0.28%)
    0 / 357 (0.00%)
    0 / 310 (0.00%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Postoperative wound infection
         subjects affected / exposed
    0 / 359 (0.00%)
    0 / 357 (0.00%)
    2 / 310 (0.65%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pseudomonal sepsis
         subjects affected / exposed
    0 / 359 (0.00%)
    0 / 357 (0.00%)
    1 / 310 (0.32%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rash pustular
         subjects affected / exposed
    0 / 359 (0.00%)
    0 / 357 (0.00%)
    0 / 310 (0.00%)
    1 / 308 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    2 / 359 (0.56%)
    1 / 357 (0.28%)
    1 / 310 (0.32%)
    4 / 308 (1.30%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 1
    1 / 1
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    Septic arthritis staphylococcal
         subjects affected / exposed
    0 / 359 (0.00%)
    0 / 357 (0.00%)
    1 / 310 (0.32%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    1 / 359 (0.28%)
    0 / 357 (0.00%)
    0 / 310 (0.00%)
    1 / 308 (0.32%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Staphylococcal infection
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 357 (0.28%)
    0 / 310 (0.00%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Staphylococcal scalded skin syndrome
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 357 (0.28%)
    0 / 310 (0.00%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Staphylococcal sepsis
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 357 (0.28%)
    0 / 310 (0.00%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Staphylococcal skin infection
         subjects affected / exposed
    1 / 359 (0.28%)
    0 / 357 (0.00%)
    0 / 310 (0.00%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Varicella
         subjects affected / exposed
    0 / 359 (0.00%)
    0 / 357 (0.00%)
    1 / 310 (0.32%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular device infection
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 357 (0.28%)
    0 / 310 (0.00%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Wound infection
         subjects affected / exposed
    1 / 359 (0.28%)
    3 / 357 (0.84%)
    0 / 310 (0.00%)
    1 / 308 (0.32%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Wound infection staphylococcal
         subjects affected / exposed
    1 / 359 (0.28%)
    0 / 357 (0.00%)
    0 / 310 (0.00%)
    0 / 308 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    MAP-GR MAPifn MAP-PR MAPIE
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    0 / 359 (0.00%)
    0 / 357 (0.00%)
    0 / 310 (0.00%)
    0 / 308 (0.00%)

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    13 Jan 2009
    Recruitment period extended, with anticipated number of registered patients increase from 1400 to 2000. The target number of randomised patients stayed at 1260.
    08 Sep 2011
    Collection of quality of life data clarified, confirming that patients who don't complete an assessment at 5 weeks can still complete assessments at a later date. Clarification that Dexrazoxane cannot be used in the European Union.
    13 May 2015
    Duration of trial definition amended, to state that long term follow-up will continue for a minimum of 5 years after the final protocol treatment visit for the last patient. The trial will be closed after follow-up of patients is completed and all data queries have been resolved.

    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.
    In the good response patients (randomised to MAP-GR or MAPifn), 128 of 357 MAPifn patiients completed the planned protocol treatment. Among poor response patients (randomised to MAP-PR or MAPie), 42% of registered patients were not randomised.

    Online references

    http://www.ncbi.nlm.nih.gov/pubmed/27569442
    http://www.ncbi.nlm.nih.gov/pubmed/26033801
    http://www.ncbi.nlm.nih.gov/pubmed/25421877
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