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    Clinical Trial Results:
    Bortezomib (Velcade®): a feasibility and phase II study in childhood relapsed acute lymphoblastic leukemia

    Summary
    EudraCT number
    2009-014037-25
    Trial protocol
    NL   DE   IT   BE   DK   AT  
    Global end of trial date
    21 Oct 2014

    Results information
    Results version number
    v1(current)
    This version publication date
    21 Mar 2018
    First version publication date
    21 Mar 2018
    Other versions
    Summary report(s)
    Summary Bortezomib_CSR

    Trial information

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    Trial identification
    Sponsor protocol code
    ITCC021
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    -
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Erasmus MC
    Sponsor organisation address
    Dr. Molenwaterplein 60, Rotterdam, Netherlands, 3015 GD
    Public contact
    C.M. Zwaan, Erasmus MC, 0031 107036691, c.m.zwaan@erasmusmc.nl
    Scientific contact
    C.M. Zwaan, Erasmus MC, 0031 107036691, c.m.zwaan@erasmusmc.nl
    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
    23 May 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    21 Oct 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    21 Oct 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Determine the antileukemic activity of combination chemotherapy including bortezomib as reinduction therapy in childhood relapsed/refractory ALL
    Protection of trial subjects
    By the Informed consent and voluntary participation in the trial. Surgical interventions take place under anaesthesia.
    Background therapy
    Dexamethasone, vincristine and intrathecal methotrexate
    Evidence for comparator
    All patients will be treated with one cycle of bortezomib, consisting of 4 doses in 2 weeks. However, they will be randomised 1:1 in 2 arms, group A getting“early” bortezomib, starting at day 1 of therapy, and group B getting “late” bortezomib, starting at day 8. Randomization will be stratified for the number of circulating leukemic blasts at inclusion in this study protocol. This design allows demonstrating an additional antileukemic effect of bortezomib when added to dexamethasone, after 1 week of therapy, measured by a reduction in ALL cells in peripheral blood and bone marrow. In addition, this design allows comparing the toxicity of limited (group A) and more extended (group B) overlap of administrations of bortezomib and vincristine.
    Actual start date of recruitment
    08 Oct 2010
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Austria: 1
    Country: Number of subjects enrolled
    Belgium: 1
    Country: Number of subjects enrolled
    France: 6
    Country: Number of subjects enrolled
    Germany: 4
    Country: Number of subjects enrolled
    Italy: 8
    Country: Number of subjects enrolled
    Netherlands: 9
    Worldwide total number of subjects
    29
    EEA total number of subjects
    29
    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)
    4
    Children (2-11 years)
    14
    Adolescents (12-17 years)
    11
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Study initiation date / first subject visit: October 8, 2010 Study completion date / last subject completed: October 21, 2014 29 subjects enrolled; 29 subjects completed and analyzed.

    Pre-assignment
    Screening details
    Screening measures conducted prior to enrollment constitute a standard battery of tests designed to thoroughly examine the potential subject for any medical issues.

    Period 1
    Period 1 title
    overall 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
    Arm A
    Arm description
    Arm A received bortezomib on days 1, 4, 8 and 11
    Arm type
    Active comparator

    Investigational medicinal product name
    Bortezomib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder and solvent for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Per day, 1.3 mg/m2 milligram(s)/square meter

    Arm title
    Arm B
    Arm description
    Arm B received bortezomib on days 8, 11, 15 and 18
    Arm type
    Active comparator

    Investigational medicinal product name
    Bortezomib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder and solvent for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Per day, 1.3 mg/m2 milligram(s)/square meter

    Number of subjects in period 1
    Arm A Arm B
    Started
    14
    15
    Completed
    14
    15

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    overall trial
    Reporting group description
    -

    Reporting group values
    overall trial Total
    Number of subjects
    29 29
    Age categorical
    Age at randomization (years)
    Units: Subjects
        In utero
    0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0
        Newborns (0-27 days)
    0 0
        Infants and toddlers (28 days-23 months)
    4 4
        Children (2-11 years)
    14 14
        Adolescents (12-17 years)
    11 11
        Adults (18-64 years)
    0 0
        From 65-84 years
    0 0
        85 years and over
    0 0
    Age continuous
    Age at randomization (years)
    Units: years
        median (full range (min-max))
    9.8 (1 to 17) -
    Gender categorical
    Units: Subjects
        Female
    12 12
        Male
    17 17
    Relapse type
    Units: Subjects
        2nd/subs relapsed ALL
    16 16
        1st relapsed ALL after allo-SCT
    11 11
        Refractory 1st relapsed ALL
    2 2
    Immunophenotype
    Units: Subjects
        T-ALL
    4 4
        Pro-B ALL
    7 7
        Pre-B ALL
    8 8
        Common-ALL
    10 10
    Subject analysis sets

    Subject analysis set title
    Full analysis
    Subject analysis set type
    Full analysis
    Subject analysis set description
    29 patients with information on response and/or toxicity after cycle 1 enrolled in this study. It coincides with the safety analysis set

    Subject analysis set title
    Full Analysis Set Primary Efficacy
    Subject analysis set type
    Full analysis
    Subject analysis set description
    The Full Analysis Set Primary Efficacy (FAS Primary Efficacy), which included all randomized patients who had a valid absolute PB blast count measurement at day 8 of treatment. This set was used for the primary analysis.

    Subject analysis set title
    Per Protocol Analysis Set Primary Efficacy
    Subject analysis set type
    Per protocol
    Subject analysis set description
    The Per Protocol Analysis Set Primary Efficacy (PPS Primary Efficacy), which was used for the primary analysis, and included all patients in the FAS Primary Efficacy who completed the study and did not have any major protocol deviations.

    Subject analysis set title
    Full Analysis Set Secondary Efficacy, BM day 8
    Subject analysis set type
    Full analysis
    Subject analysis set description
    The Full Analysis Set Secondary Efficacy (FAS Secondary Efficacy), which was used for the analysis of secondary efficacy objectives and, for each endpoint, included all patients who had a valid measurement.

    Subject analysis set title
    Full Analysis Set Secondary Efficacy, BM day 22
    Subject analysis set type
    Full analysis
    Subject analysis set description
    The Full Analysis Set Secondary Efficacy (FAS Secondary Efficacy), which was used for the analysis of secondary efficacy objectives and, for each endpoint, included all patients who had a valid measurement.

    Subject analysis set title
    Full Analysis Set Secondary Efficacy, PB day 22
    Subject analysis set type
    Full analysis
    Subject analysis set description
    The Full Analysis Set Secondary Efficacy (FAS Secondary Efficacy), which was used for the analysis of secondary efficacy objectives and, for each endpoint, included all patients who had a valid measurement.

    Subject analysis set title
    Full analysis set secondary efficacy, day 43
    Subject analysis set type
    Full analysis
    Subject analysis set description
    The Full Analysis Set Secondary Efficacy (FAS Secondary Efficacy), which was used for the analysis of secondary efficacy objectives and, for each endpoint, included all patients who had a valid measurement.

    Subject analysis sets values
    Full analysis Full Analysis Set Primary Efficacy Per Protocol Analysis Set Primary Efficacy Full Analysis Set Secondary Efficacy, BM day 8 Full Analysis Set Secondary Efficacy, BM day 22 Full Analysis Set Secondary Efficacy, PB day 22 Full analysis set secondary efficacy, day 43
    Number of subjects
    29
    26
    24
    27
    24
    19
    8
    Age categorical
    Age at randomization (years)
    Units: Subjects
        In utero
    0
    0
    0
    0
    0
    0
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
    0
    0
    0
    0
    0
    0
        Newborns (0-27 days)
    0
    0
    0
    0
    0
    0
    0
        Infants and toddlers (28 days-23 months)
    4
    3
    2
    3
    3
    2
    1
        Children (2-11 years)
    14
    12
    12
    13
    11
    9
    3
        Adolescents (12-17 years)
    11
    11
    10
    11
    10
    8
    4
        Adults (18-64 years)
    0
    0
    0
    0
    0
    0
    0
        From 65-84 years
    0
    0
    0
    0
    0
    0
    0
        85 years and over
    0
    0
    0
    0
    0
    0
    0
    Age continuous
    Age at randomization (years)
    Units: years
        median (full range (min-max))
    9.8 (1 to 17)
    10.2 (1 to 17)
    10.2 (1 to 17)
    10.0 (1 to 17)
    9.9 (1 to 17)
    9.8 (1 to 17)
    12.4 (1 to 16)
    Gender categorical
    Units: Subjects
        Female
    12
    12
    12
    12
    10
    6
    4
        Male
    17
    14
    12
    15
    14
    13
    4
    Relapse type
    Units: Subjects
        2nd/subs relapsed ALL
    16
    15
    14
    16
    13
    9
    3
        1st relapsed ALL after allo-SCT
    11
    9
    8
    9
    9
    10
    5
        Refractory 1st relapsed ALL
    2
    2
    2
    2
    2
    0
    0
    Immunophenotype
    Units: Subjects
        T-ALL
    4
    4
    4
    4
    4
    4
    1
        Pro-B ALL
    7
    6
    5
    6
    6
    5
    4
        Pre-B ALL
    8
    7
    6
    8
    8
    4
    2
        Common-ALL
    10
    9
    9
    9
    6
    6
    1

    End points

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    End points reporting groups
    Reporting group title
    Arm A
    Reporting group description
    Arm A received bortezomib on days 1, 4, 8 and 11

    Reporting group title
    Arm B
    Reporting group description
    Arm B received bortezomib on days 8, 11, 15 and 18

    Subject analysis set title
    Full analysis
    Subject analysis set type
    Full analysis
    Subject analysis set description
    29 patients with information on response and/or toxicity after cycle 1 enrolled in this study. It coincides with the safety analysis set

    Subject analysis set title
    Full Analysis Set Primary Efficacy
    Subject analysis set type
    Full analysis
    Subject analysis set description
    The Full Analysis Set Primary Efficacy (FAS Primary Efficacy), which included all randomized patients who had a valid absolute PB blast count measurement at day 8 of treatment. This set was used for the primary analysis.

    Subject analysis set title
    Per Protocol Analysis Set Primary Efficacy
    Subject analysis set type
    Per protocol
    Subject analysis set description
    The Per Protocol Analysis Set Primary Efficacy (PPS Primary Efficacy), which was used for the primary analysis, and included all patients in the FAS Primary Efficacy who completed the study and did not have any major protocol deviations.

    Subject analysis set title
    Full Analysis Set Secondary Efficacy, BM day 8
    Subject analysis set type
    Full analysis
    Subject analysis set description
    The Full Analysis Set Secondary Efficacy (FAS Secondary Efficacy), which was used for the analysis of secondary efficacy objectives and, for each endpoint, included all patients who had a valid measurement.

    Subject analysis set title
    Full Analysis Set Secondary Efficacy, BM day 22
    Subject analysis set type
    Full analysis
    Subject analysis set description
    The Full Analysis Set Secondary Efficacy (FAS Secondary Efficacy), which was used for the analysis of secondary efficacy objectives and, for each endpoint, included all patients who had a valid measurement.

    Subject analysis set title
    Full Analysis Set Secondary Efficacy, PB day 22
    Subject analysis set type
    Full analysis
    Subject analysis set description
    The Full Analysis Set Secondary Efficacy (FAS Secondary Efficacy), which was used for the analysis of secondary efficacy objectives and, for each endpoint, included all patients who had a valid measurement.

    Subject analysis set title
    Full analysis set secondary efficacy, day 43
    Subject analysis set type
    Full analysis
    Subject analysis set description
    The Full Analysis Set Secondary Efficacy (FAS Secondary Efficacy), which was used for the analysis of secondary efficacy objectives and, for each endpoint, included all patients who had a valid measurement.

    Primary: Antileukemic activity of bortezomib when added to dexamethasone and vincristine and intrathecal methotrexate, as determined by the absolute peripheral blood (PB) blast count on day 8 of treatment.

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    End point title
    Antileukemic activity of bortezomib when added to dexamethasone and vincristine and intrathecal methotrexate, as determined by the absolute peripheral blood (PB) blast count on day 8 of treatment.
    End point description
    End point type
    Primary
    End point timeframe
    Day 8 of treatment
    End point values
    Arm A Arm B Full Analysis Set Primary Efficacy
    Number of subjects analysed
    12
    14
    26
    Units: Absolute blast count per microliter
        median (full range (min-max))
    465 (2 to 38888)
    774 (4 to 203820)
    732 (2 to 203820)
    Attachments
    Absolute blast count, day 8 (full analysis set)
    Statistical analysis title
    Mann-Whitney U test PB day 8, full analysis set
    Comparison groups
    Arm A v Arm B
    Number of subjects included in analysis
    26
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.4
    Method
    Wilcoxon (Mann-Whitney)
    Parameter type
    Location shift (BTZ early-BTZ late)
    Point estimate
    -177.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3638
         upper limit
    630
    Variability estimate
    Standard error of the mean
    Dispersion value
    1100.02

    Secondary: Antileukemic activity of bortezomib when added to dexamethasone and vincristine and intrathecal methotrexate, as determined by the absolute bone marrow (BM) blast percentage on day 8 of treatment

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    End point title
    Antileukemic activity of bortezomib when added to dexamethasone and vincristine and intrathecal methotrexate, as determined by the absolute bone marrow (BM) blast percentage on day 8 of treatment
    End point description
    End point type
    Secondary
    End point timeframe
    Day 8 of treatment
    End point values
    Arm A Arm B Full Analysis Set Secondary Efficacy, BM day 8
    Number of subjects analysed
    13
    14
    27
    Units: blast percentage
        median (full range (min-max))
    86 (3 to 99)
    79 (1 to 96)
    84 (1 to 99)
    Attachments
    Absolute BM blast percentage, day 8
    Statistical analysis title
    Mann-Whitney U test BM day 8, full analysis set
    Comparison groups
    Arm A v Arm B
    Number of subjects included in analysis
    27
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.21
    Method
    Wilcoxon (Mann-Whitney)
    Parameter type
    Location shift (BTZ early-BTZ late)
    Point estimate
    6
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -5
         upper limit
    24
    Variability estimate
    Standard error of the mean
    Dispersion value
    7.7808

    Secondary: Antileukemic activity of bortezomib when added to demathasone and vincristine and intrathecal methotrexate, as determined by the absolute bone marrow (BM) blast percentage on day 22 of treatment

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    End point title
    Antileukemic activity of bortezomib when added to demathasone and vincristine and intrathecal methotrexate, as determined by the absolute bone marrow (BM) blast percentage on day 22 of treatment
    End point description
    End point type
    Secondary
    End point timeframe
    Day 22 of treatment
    End point values
    Arm A Arm B Full Analysis Set Secondary Efficacy, BM day 22
    Number of subjects analysed
    11
    13
    24
    Units: blast percentage
        median (full range (min-max))
    13 (0 to 95)
    12 (0 to 98)
    12.5 (0 to 98)
    Attachments
    Absolute BM blast percentage, day 22
    Statistical analysis title
    Mann-Whitney U test BM day 22, full analysis set
    Comparison groups
    Arm A v Arm B
    Number of subjects included in analysis
    24
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.95
    Method
    Wilcoxon (Mann-Whitney)
    Parameter type
    Location shift (BTZ early-BTZ late)
    Point estimate
    0
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -17
         upper limit
    59
    Variability estimate
    Standard error of the mean
    Dispersion value
    19.6432

    Secondary: Antileukemic activity of bortezomib when added to dexamethasone and vincristine and intrathecal methotrexate, as determined by the absolute peripheral blood (PB) blast count on day 22 of treatment

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    End point title
    Antileukemic activity of bortezomib when added to dexamethasone and vincristine and intrathecal methotrexate, as determined by the absolute peripheral blood (PB) blast count on day 22 of treatment
    End point description
    End point type
    Secondary
    End point timeframe
    Day 22 of treatment
    End point values
    Arm A Arm B Full Analysis Set Secondary Efficacy, PB day 22
    Number of subjects analysed
    8
    11
    19
    Units: Absolute blast count per microliter
        median (full range (min-max))
    0 (0 to 265)
    7 (0 to 33288)
    0 (0 to 33288)
    Statistical analysis title
    Mann-Whitney U test PB day 22, full analysis set
    Comparison groups
    Arm A v Arm B
    Number of subjects included in analysis
    19
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.23
    Method
    Wilcoxon (Mann-Whitney)
    Parameter type
    Location shift (BTZ early-BTZ late)
    Point estimate
    0
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -130
         upper limit
    0
    Variability estimate
    Standard error of the mean
    Dispersion value
    39.7966

    Secondary: Feasibility of combining bortezomib with dexamethasone and vincristine and intrathecal methotrexate

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    End point title
    Feasibility of combining bortezomib with dexamethasone and vincristine and intrathecal methotrexate
    End point description
    Feasibility of combining bortezomib with dexamethasone and vincristine and intrathecal methotrexate, as determined by the percentage of patients in whom bortezomib had to be dose reduced or withdrawn because of toxicity.
    End point type
    Secondary
    End point timeframe
    All study
    End point values
    Arm A Arm B Full analysis
    Number of subjects analysed
    14
    15
    29
    Units: Number of patients
        Dose-reduced/withdrawn at any cycle
    2
    3
    5
        Not dose-reduced/withdrawn
    12
    12
    24
    No statistical analyses for this end point

    Secondary: Toxicity of bortezomib when combined with dexamethasone and vincristine and intrathecal methotrexate, as determined by the percentage of patients suffering from grade III/IV toxicity in any field

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    End point title
    Toxicity of bortezomib when combined with dexamethasone and vincristine and intrathecal methotrexate, as determined by the percentage of patients suffering from grade III/IV toxicity in any field
    End point description
    End point type
    Secondary
    End point timeframe
    All study
    End point values
    Arm A Arm B Full analysis
    Number of subjects analysed
    14
    15
    29
    Units: Number of patients
        >= grade III/IV toxicity
    14
    15
    29
        < grade III/IV toxicity
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Feasibility of combining a second cycle of bortezomib with combination chemotherapy, its toxicity and antileukemic activity, day 43

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    End point title
    Feasibility of combining a second cycle of bortezomib with combination chemotherapy, its toxicity and antileukemic activity, day 43
    End point description
    Determine the feasibility of combining a second cycle of bortezomib with combination chemotherapy, its toxicity and antileukemic activity, as measured after 6 weeks of therapy by bone marrow, peripheral blood and cerebrospinal fluid
    End point type
    Secondary
    End point timeframe
    Day 43 of treatment
    End point values
    Arm A Arm B Full analysis set secondary efficacy, day 43
    Number of subjects analysed
    3
    5
    8
    Units: Blast percentage
        median (full range (min-max))
    0 (0 to 0)
    1 (0 to 15)
    0 (0 to 15)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    AEs will be collected until 30 days after the administration of the last dose of bortezomib.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    CTCAE
    Dictionary version
    3
    Reporting groups
    Reporting group title
    Arm A (early bortezomib)
    Reporting group description
    -

    Reporting group title
    Arm B (late bortezomib)
    Reporting group description
    -

    Serious adverse events
    Arm A (early bortezomib) Arm B (late bortezomib)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    6 / 14 (42.86%)
    4 / 15 (26.67%)
         number of deaths (all causes)
    11
    13
         number of deaths resulting from adverse events
    5
    2
    Blood and lymphatic system disorders
    Blood/bone marrow other, progression of leukemia
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Febrile neutropenia
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Hemorrhage, CNS
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Neuropathic pain
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Seizure
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    General disorders and administration site conditions
    Death, multi-organ failure
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Death (sudden/NOS)
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Psychiatric disorders
    Psychosis (hallucinations)
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Ileus
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Infections and infestations
    Skin infection
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Infection with grade 3 or 4 neutrophils
         subjects affected / exposed
    0 / 14 (0.00%)
    2 / 15 (13.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    1 / 2
    Infection with neutropenia
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Arm A (early bortezomib) Arm B (late bortezomib)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    14 / 14 (100.00%)
    15 / 15 (100.00%)
    Vascular disorders
    Arterial hypertension
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    3
    Investigations
    ALAT
         subjects affected / exposed
    3 / 14 (21.43%)
    1 / 15 (6.67%)
         occurrences all number
    5
    2
    ALT increase
         subjects affected / exposed
    1 / 14 (7.14%)
    2 / 15 (13.33%)
         occurrences all number
    1
    3
    ALT/GPT transaminase
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    2
    AST increase
         subjects affected / exposed
    1 / 14 (7.14%)
    2 / 15 (13.33%)
         occurrences all number
    1
    4
    GGT increase
         subjects affected / exposed
    1 / 14 (7.14%)
    1 / 15 (6.67%)
         occurrences all number
    2
    2
    Haemorrhage
         subjects affected / exposed
    5 / 14 (35.71%)
    5 / 15 (33.33%)
         occurrences all number
    5
    6
    INR alteration
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    2
    Respiratory, thoracic and mediastinal disorders
    Cough and rhinitis
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    2
    Hypoxia
         subjects affected / exposed
    1 / 14 (7.14%)
    1 / 15 (6.67%)
         occurrences all number
    1
    1
    Blood and lymphatic system disorders
    Anemia
         subjects affected / exposed
    13 / 14 (92.86%)
    14 / 15 (93.33%)
         occurrences all number
    27
    30
    Leukopenia
         subjects affected / exposed
    13 / 14 (92.86%)
    12 / 15 (80.00%)
         occurrences all number
    22
    24
    Neutropenia
         subjects affected / exposed
    14 / 14 (100.00%)
    13 / 15 (86.67%)
         occurrences all number
    25
    28
    Thrombopenia
         subjects affected / exposed
    14 / 14 (100.00%)
    15 / 15 (100.00%)
         occurrences all number
    32
    38
    Nervous system disorders
    Peripheral neuropathy
         subjects affected / exposed
    2 / 14 (14.29%)
    5 / 15 (33.33%)
         occurrences all number
    4
    8
    Tremor
         subjects affected / exposed
    1 / 14 (7.14%)
    1 / 15 (6.67%)
         occurrences all number
    1
    1
    General disorders and administration site conditions
    Edema
         subjects affected / exposed
    2 / 14 (14.29%)
    2 / 15 (13.33%)
         occurrences all number
    2
    3
    Fatigue
         subjects affected / exposed
    8 / 14 (57.14%)
    6 / 15 (40.00%)
         occurrences all number
    12
    9
    Fever
         subjects affected / exposed
    9 / 14 (64.29%)
    9 / 15 (60.00%)
         occurrences all number
    11
    12
    Pain
         subjects affected / exposed
    7 / 14 (50.00%)
    8 / 15 (53.33%)
         occurrences all number
    10
    12
    Gastrointestinal disorders
    Mucositis
         subjects affected / exposed
    1 / 14 (7.14%)
    4 / 15 (26.67%)
         occurrences all number
    2
    5
    Nausea
         subjects affected / exposed
    4 / 14 (28.57%)
    3 / 15 (20.00%)
         occurrences all number
    5
    3
    Vomiting
         subjects affected / exposed
    3 / 14 (21.43%)
    2 / 15 (13.33%)
         occurrences all number
    3
    3
    Renal and urinary disorders
    Renal function failure
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 15 (0.00%)
         occurrences all number
    2
    0
    Hepatobiliary disorders
    Hepatotoxicity
         subjects affected / exposed
    1 / 14 (7.14%)
    1 / 15 (6.67%)
         occurrences all number
    1
    1
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    2 / 14 (14.29%)
    0 / 15 (0.00%)
         occurrences all number
    2
    0
    Ecchymosis and petechias
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    2
    Rash/desquamation
         subjects affected / exposed
    4 / 14 (28.57%)
    3 / 15 (20.00%)
         occurrences all number
    6
    4
    Infections and infestations
    Infection with neutropenia
         subjects affected / exposed
    5 / 14 (35.71%)
    8 / 15 (53.33%)
         occurrences all number
    6
    9

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    18 Dec 2009
    Protocol Amendment 1 (first approved version)
    08 Dec 2010
    clarification total dose vincristine Protocol
    08 Jul 2011
    updated safety and risk paragraph due to new IB ed 14 Velcade

    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.
    Some patients who were not fully eligible in hindsight and slow recruitment.
    The status of studies in GB is no longer updated from 1.1.2021
    For the UK, as from 1.1.2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI
    EU Clinical Trials Register Service Desk: https://servicedesk.ema.europa.eu
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