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    Clinical Trial Results:
    Comparative efficacy and safety of two asparaginase preparations in children with previously untreated acute lymphoblastic leukaemia

    Summary
    EudraCT number
    		 2006-003180-31
    Trial protocol
    		 NL  
    Global end of trial date
    17 Feb 2012

    Results information
    Results version number
    		 v1(current)
    This version publication date
    10 Aug 2016
    First version publication date
    10 Aug 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    MC-ASP.5/ALL
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    medac Gesellschaft für klinische Spezialpräparate mbH
    Sponsor organisation address
    Theaterstraße 6, Wedel, Germany, 22880
    Public contact
    Clinical Trial Disclosure Desk, medac Gesellschaft für klinische Spezialpräparate mbH Theaterstraße 6 22880 Wedel, 0049 04103 8006 0, eudract@medac.de
    Scientific contact
    Medical Expert, medac Gesellschaft für klinische Spezialpräparate mbH Theaterstraße 6 22880 Wedel, 0049 04103 8006 0, med-wiss@medac.de
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-000013-PIP01-07
    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?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    01 Oct 2012
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    17 Feb 2012
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To determine the rate of patients with complete asparagine (ASN) depletion in serum during induction treatment and to demonstrate non-inferiority of rASNase compared to Asparaginase medac with respect to this parameter.
    Protection of trial subjects
    Only pseudonymous collection and storage of patient’s data
    Background therapy
    		 Acute Lymphoblastic Leukaemia (ALL) type chemotherapy
    Evidence for comparator
    		 To demonstrate non-inferiority of rASNase compared to Asparaginase medac
    Actual start date of recruitment
    29 Oct 2008
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Netherlands: 199
    Worldwide total number of subjects
    199
    EEA total number of subjects
    199
    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)
    13
    Children (2-11 years)
    150
    Adolescents (12-17 years)
    36
    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
    		 They fulfilled the criteria to be involved in the study. Parents signed the declaration of consent.

    Pre-assignment
    Screening details
    		 Investigation, laboratory, diagnosis of ALL

    Period 1
    Period 1 title
    Baseline (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Asparaginase medac
    Arm description
    		 Reference-Arm
    Arm type
    		 Experimental

    Investigational medicinal product name
    Aspraginase medac
    Investigational medicinal product code
    MC0904
    Other name
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    During induction treatment patients received eight doses of 5000 U/m² each of Asparaginase medac. In the post induction phase some high risk (HR) patients received additional infusions of 10 000 U/m² Asparaginase medac

    Arm title
    		 rASNase
    Arm description
    		 Test-Arm
    Arm type
    		 Experimental

    Investigational medicinal product name
    Recombinant ASNase
    Investigational medicinal product code
    MC0707
    Other name
    rASNase
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    During induction treatment patients received eight doses of 5000 U/m² each of Recombinant Asparaginase (rASNase). In the post induction phase some high risk (HR) patients received additional infusions of 10 000 U/m² Recombinant Asparaginase

    Number of subjects in period 1
    		Asparaginase medac rASNase
    Started
    101
    98
    Induction phase
    98
    94
    Post-induction phase
    95
    92
    Completed
    88
    84
    Not completed
    13
    14
         Adverse event, serious fatal
    1
    3
         Consent withdrawn by subject
    1
    -
         Physician decision
    7
    6
         Adverse event, non-fatal
    3
    -
         Other
    1
    4
         Protocol deviation
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Asparaginase medac
    Reporting group description
    		 Reference-Arm

    Reporting group title
    rASNase
    Reporting group description
    		 Test-Arm

    Reporting group values
    		 Asparaginase medac rASNase Total
    Number of subjects
    		 101 98 199
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 8 5 13
        Children (2-11 years)
    		 75 75 150
        Adolescents (12-17 years)
    		 18 18 36
        Adults (18-64 years)
    		 0 0 0
        From 65-84 years
    		 0 0 0
        85 years and over
    		 0 0 0
    Age continuous
    Units: years
        median (full range (min-max))
    		 4 (1 to 16) 5 (1 to 17) -
    Gender categorical
    Units: Subjects
        Female
    		 48 44 92
        Male
    		 53 54 107
    Body weight
    Units: kilogram(s)
        median (full range (min-max))
    		 18 (7 to 71) 22 (9 to 90) -
    Body surface area
    Units: square meter
        median (full range (min-max))
    		 0.73 (0.4 to 1.9) 0.85 (0.4 to 2.1) -
    Body height
    Units: cm
        median (full range (min-max))
    		 108 (72 to 191) 118.5 (75 to 185) -

    End points

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    End points reporting groups
    Reporting group title
    Asparaginase medac
    Reporting group description
    		 Reference-Arm

    Reporting group title
    rASNase
    Reporting group description
    		 Test-Arm

    Subject analysis set title
    Full analysis set
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All patients randomized for study participation

    Subject analysis set title
    Per protocol set
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Per-protocol analysis is a comparison of treatment groups that includes only those patients who completed the treatment originally allocated without major protocol deviations.

    Primary: Complete Asparagine Depletion in Serum during induction treatment

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    End point title
    		 Complete Asparagine Depletion in Serum during induction treatment
    End point description
    End point type
    Primary
    End point timeframe
    Induction Phase
    End point values
    		 Asparaginase medac rASNase Full analysis set
    Number of subjects analysed
    101
    98
    199
    Units: Patients
        Yes
    95
    93
    188
        No
    2
    2
    4
        Not Evaluable
    4
    3
    7
    Statistical analysis title
    		 Non-Inferiority of complete Asparagine Depletion
    Comparison groups
    Asparaginase medac v rASNase
    Number of subjects included in analysis
    199
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.0028
    Method
    		 REML estimates
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.25
         upper limit
    		 8.04

    Secondary: Complete Asparagine Depletion in Cerebrospinal fluid on day 33

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    End point title
    		 Complete Asparagine Depletion in Cerebrospinal fluid on day 33
    End point description
    End point type
    Secondary
    End point timeframe
    Induction Phase
    End point values
    		 Asparaginase medac rASNase Full analysis set
    Number of subjects analysed
    101
    98
    199
    Units: Patients
        Yes
    88
    82
    170
        No
    6
    1
    7
        Not Evaluable
    7
    15
    22
    Statistical analysis title
    		 DescriptiveAnlaysis of difference in ASN depletion
    Comparison groups
    Asparaginase medac v rASNase
    Number of subjects included in analysis
    199
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Risk difference (RD)
    Point estimate
    -3.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -13.67
         upper limit
    		 6.58

    Secondary: Trough Levels of Asparaginase Activity in serum

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    End point title
    		 Trough Levels of Asparaginase Activity in serum
    End point description
    End point type
    Secondary
    End point timeframe
    Day 15
    End point values
    		 Asparaginase medac rASNase Full analysis set
    Number of subjects analysed
    99
    92
    191
    Units: Patients
        geometric mean (full range (min-max))
    146.79 (35.36 to 410.61)
    159.77 (28.14 to 524.44)
    152.9 (28.14 to 524.44)
    No statistical analyses for this end point

    Secondary: Trough Levels of Asparaginase Activitiy in serum

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    End point title
    		 Trough Levels of Asparaginase Activitiy in serum
    End point description
    End point type
    Secondary
    End point timeframe
    Day 21
    End point values
    		 Asparaginase medac rASNase Full analysis set
    Number of subjects analysed
    95
    94
    189
    Units: Patients
        geometric mean (full range (min-max))
    153.99 (1.25 to 584.69)
    158.41 (3.69 to 696.33)
    156.17 (1.25 to 696.33)
    No statistical analyses for this end point

    Secondary: Trough Levels of Asparaginase Activity in serum

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    End point title
    		 Trough Levels of Asparaginase Activity in serum
    End point description
    End point type
    Secondary
    End point timeframe
    Day 27
    End point values
    		 Asparaginase medac rASNase Full analysis set
    Number of subjects analysed
    92
    89
    181
    Units: Patients
        geometric mean (full range (min-max))
    177.45 (18.37 to 747.61)
    149.58 (1.25 to 739.53)
    163.15 (1.25 to 747.61)
    No statistical analyses for this end point

    Secondary: Trough Levels of Asparaginase Activity in serum

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    End point title
    		 Trough Levels of Asparaginase Activity in serum
    End point description
    End point type
    Secondary
    End point timeframe
    Day 33
    End point values
    		 Asparaginase medac rASNase Full analysis set
    Number of subjects analysed
    95
    93
    188
    Units: Patients
        geometric mean (full range (min-max))
    153.54 (1.25 to 1980.94)
    127.26 (1.25 to 697.8)
    139.92 (1.25 to 1980.94)
    No statistical analyses for this end point

    Secondary: Complete Remission

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    End point title
    		 Complete Remission
    End point description
    End point type
    Secondary
    End point timeframe
    After induction phase
    End point values
    		 Asparaginase medac rASNase Full analysis set
    Number of subjects analysed
    101
    98
    199
    Units: Patients
        Yes
    97
    90
    187
        No
    2
    2
    4
        Not Evaluable
    2
    6
    8
    Statistical analysis title
    		 Descriptive Anlaysis of complete remission
    Comparison groups
    Asparaginase medac v rASNase
    Number of subjects included in analysis
    199
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Risk difference (RD)
    Point estimate
    -4.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -11.9
         upper limit
    		 2.81

    Secondary: Minimal residual disease

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    End point title
    		 Minimal residual disease
    End point description
    End point type
    Secondary
    End point timeframe
    After induction phase
    End point values
    		 Asparaginase medac rASNase Full analysis set
    Number of subjects analysed
    101
    98
    199
    Units: Patients
        Negative
    32
    29
    61
        Positive
    60
    63
    123
        Not Evaluable
    9
    6
    15
    Statistical analysis title
    		 Descriptive Anlaysis of minimal residual disease
    Comparison groups
    Asparaginase medac v rASNase
    Number of subjects included in analysis
    199
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Risk difference (RD)
    Point estimate
    -2.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -14.97
         upper limit
    		 10.84

    Secondary: Level of glutamic acid in serum Day 15

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    End point title
    		 Level of glutamic acid in serum Day 15
    End point description
    Concentration of glutamic acid in serum on Day 15 of the induction phase
    End point type
    Secondary
    End point timeframe
    Day 15
    End point values
    		 Asparaginase medac rASNase Full analysis set
    Number of subjects analysed
    99
    94
    193
    Units: µmol/L
        median (full range (min-max))
    50.83 (5.36 to 145.8)
    51.93 (5.36 to 182.23)
    51.54 (5.36 to 182.23)
    No statistical analyses for this end point

    Secondary: Level of glutamic acid in serum Day 21

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    End point title
    		 Level of glutamic acid in serum Day 21
    End point description
    Concentration of glutamic acid in serum on Day 21 of the induction phase
    End point type
    Secondary
    End point timeframe
    Day 21
    End point values
    		 Asparaginase medac rASNase Full analysis set
    Number of subjects analysed
    95
    95
    190
    Units: µmol/L
        median (full range (min-max))
    49.85 (5.36 to 431.42)
    53.77 (12.82 to 247.77)
    51.06 (5.36 to 431.42)
    No statistical analyses for this end point

    Secondary: Level of glutamic acid in serum Day 27

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    End point title
    		 Level of glutamic acid in serum Day 27
    End point description
    Concentration of glutamic acid in serum on Day 27 of the induction phase
    End point type
    Secondary
    End point timeframe
    Day 27
    End point values
    		 Asparaginase medac rASNase Full analysis set
    Number of subjects analysed
    93
    89
    182
    Units: µmol/L
        median (full range (min-max))
    58.83 (5.36 to 197.25)
    53.14 (24.25 to 405.92)
    57.22 (5.36 to 405.92)
    No statistical analyses for this end point

    Secondary: Level of glutamic acid in serum Day 33

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    End point title
    		 Level of glutamic acid in serum Day 33
    End point description
    Concentration of glutamic acid in serum on Day 33 of the induction phase
    End point type
    Secondary
    End point timeframe
    Day 33
    End point values
    		 Asparaginase medac rASNase Full analysis set
    Number of subjects analysed
    95
    93
    188
    Units: µmol/L
        median (full range (min-max))
    63 (5.36 to 303.29)
    61.26 (5.36 to 161.42)
    62.47 (5.36 to 303.29)
    No statistical analyses for this end point

    Secondary: Anti-ASNase antibodies in serum

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    End point title
    		 Anti-ASNase antibodies in serum
    End point description
    Anti-ASNase antibodies in serum during repeated administration of ASNase
    End point type
    Secondary
    End point timeframe
    Determined at all time points during induction and post-induction treatment where blood sample collection was performed
    End point values
    		 Asparaginase medac rASNase Full analysis set
    Number of subjects analysed
    101
    97
    198
    Units: Patients
        Positive
    55
    58
    113
        Negative
    46
    38
    84
        NK
    0
    1
    1
    Statistical analysis title
    		 Anti-ASNase antibodies
    Comparison groups
    Asparaginase medac v rASNase
    Number of subjects included in analysis
    198
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 CI based on Chan & Zhung
    Point estimate
    6.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7.52
         upper limit
    		 20.43

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Please refer to protocol.
    Adverse event reporting additional description
    Please refer to protocol. Events coded by CTCAE V3.0, System Organ Classes mapped to CTCAE V4.0.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 CTCAE
    Dictionary version
    4.0
    Reporting groups
    Reporting group title
    ASNase medac
    Reporting group description
    		 -

    Reporting group title
    rASNase
    Reporting group description
    		 -

    Serious adverse events
    		 ASNase medac rASNase
    Total subjects affected by serious adverse events
         subjects affected / exposed
    37 / 101 (36.63%)
    33 / 97 (34.02%)
         number of deaths (all causes)
    1
    3
         number of deaths resulting from adverse events
    0
    3
    Investigations
    Weight loss
         subjects affected / exposed
    1 / 101 (0.99%)
    3 / 97 (3.09%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholesterol
         subjects affected / exposed
    0 / 101 (0.00%)
    1 / 97 (1.03%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    GGT
         subjects affected / exposed
    0 / 101 (0.00%)
    1 / 97 (1.03%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Vascular - Other
         subjects affected / exposed
    4 / 101 (3.96%)
    5 / 97 (5.15%)
         occurrences causally related to treatment / all
    4 / 4
    5 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombosis/thrombus/embolism
         subjects affected / exposed
    1 / 101 (0.99%)
    2 / 97 (2.06%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    CNS hemorrhage
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 97 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Involuntary movement
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 97 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neuropathy-motor
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 97 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain [Head/headache]
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 97 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 97 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Febrile neutropenia
         subjects affected / exposed
    7 / 101 (6.93%)
    9 / 97 (9.28%)
         occurrences causally related to treatment / all
    3 / 7
    5 / 13
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Fever
         subjects affected / exposed
    3 / 101 (2.97%)
    1 / 97 (1.03%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    0 / 101 (0.00%)
    1 / 97 (1.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain [Chest/thorax NOS]
         subjects affected / exposed
    0 / 101 (0.00%)
    1 / 97 (1.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syndromes - Other
         subjects affected / exposed
    0 / 101 (0.00%)
    1 / 97 (1.03%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Gastrointestinal disorders
    Diarrhea
         subjects affected / exposed
    2 / 101 (1.98%)
    1 / 97 (1.03%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mucositis (clinical exam) [Oral cavity]
         subjects affected / exposed
    2 / 101 (1.98%)
    1 / 97 (1.03%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    1 / 101 (0.99%)
    1 / 97 (1.03%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    GI - Other
         subjects affected / exposed
    2 / 101 (1.98%)
    0 / 97 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain [Abdomen NOS]
         subjects affected / exposed
    0 / 101 (0.00%)
    2 / 97 (2.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enteritis
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 97 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Esophagitis
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 97 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 97 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mucositis (clinical exam) [Anus]
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 97 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mucositis (clinical exam) [Small bowel]
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 97 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatits
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 97 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 97 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Liver dysfunction
         subjects affected / exposed
    3 / 101 (2.97%)
    1 / 97 (1.03%)
         occurrences causally related to treatment / all
    3 / 3
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary - Other
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 97 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Airway obstruction [Larynx]
         subjects affected / exposed
    0 / 101 (0.00%)
    1 / 97 (1.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mucositis (clinical exam) [Pharynx]
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 97 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonray - Other
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 97 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Erythema multiforme
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 97 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Obstruction, GU [Ureter]
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 97 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Infection (documented clinically) [Blood]
         subjects affected / exposed
    2 / 101 (1.98%)
    2 / 97 (2.06%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection - Other
         subjects affected / exposed
    3 / 101 (2.97%)
    0 / 97 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Opportunistic infection
         subjects affected / exposed
    1 / 101 (0.99%)
    2 / 97 (2.06%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Infection (documented clinically) [Lung (pneumonia)]
         subjects affected / exposed
    2 / 101 (1.98%)
    0 / 97 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection with normal ANC [Brain+Spinal cord (encephalomyelitis)]
         subjects affected / exposed
    0 / 101 (0.00%)
    2 / 97 (2.06%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Infection (documented clinically) [Skin (cellulitis)]
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 97 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection with normal ANC [Brain (encephalitis, infectious)]
         subjects affected / exposed
    0 / 101 (0.00%)
    1 / 97 (1.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection with normal ANC [Liver]
         subjects affected / exposed
    0 / 101 (0.00%)
    1 / 97 (1.03%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection with normal ANC [Meninges (meningitis)]
         subjects affected / exposed
    0 / 101 (0.00%)
    1 / 97 (1.03%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Diabetes
         subjects affected / exposed
    2 / 101 (1.98%)
    1 / 97 (1.03%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertriglyceridemia
         subjects affected / exposed
    1 / 101 (0.99%)
    2 / 97 (2.06%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    0 / 101 (0.00%)
    2 / 97 (2.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anorexia
         subjects affected / exposed
    1 / 101 (0.99%)
    0 / 97 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 ASNase medac rASNase
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    93 / 101 (92.08%)
    90 / 97 (92.78%)
    Investigations
    Weight loss
         subjects affected / exposed
    3 / 101 (2.97%)
    9 / 97 (9.28%)
         occurrences all number
    4
    10
    Vascular disorders
    Hypertension
         subjects affected / exposed
    9 / 101 (8.91%)
    8 / 97 (8.25%)
         occurrences all number
    11
    9
    Hematoma
         subjects affected / exposed
    4 / 101 (3.96%)
    5 / 97 (5.15%)
         occurrences all number
    5
    5
    Nervous system disorders
    Pain [Head/headache]
         subjects affected / exposed
    13 / 101 (12.87%)
    17 / 97 (17.53%)
         occurrences all number
    14
    17
    Neuropathy-motor
         subjects affected / exposed
    15 / 101 (14.85%)
    14 / 97 (14.43%)
         occurrences all number
    15
    14
    Neuropathy-sensory
         subjects affected / exposed
    11 / 101 (10.89%)
    13 / 97 (13.40%)
         occurrences all number
    12
    14
    Dizziness
         subjects affected / exposed
    2 / 101 (1.98%)
    6 / 97 (6.19%)
         occurrences all number
    2
    8
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    36 / 101 (35.64%)
    34 / 97 (35.05%)
         occurrences all number
    39
    39
    Gastrointestinal disorders
    Diarrhea
         subjects affected / exposed
    21 / 101 (20.79%)
    20 / 97 (20.62%)
         occurrences all number
    21
    23
    Pain [Abdomen NOS]
         subjects affected / exposed
    20 / 101 (19.80%)
    21 / 97 (21.65%)
         occurrences all number
    24
    23
    Vomiting
         subjects affected / exposed
    17 / 101 (16.83%)
    16 / 97 (16.49%)
         occurrences all number
    21
    20
    Constipation
         subjects affected / exposed
    13 / 101 (12.87%)
    13 / 97 (13.40%)
         occurrences all number
    15
    13
    Nausea
         subjects affected / exposed
    11 / 101 (10.89%)
    14 / 97 (14.43%)
         occurrences all number
    12
    17
    Mucositis (clinical exam) [Oral cavity]
         subjects affected / exposed
    9 / 101 (8.91%)
    12 / 97 (12.37%)
         occurrences all number
    11
    12
    Pain [Stomach]
         subjects affected / exposed
    4 / 101 (3.96%)
    8 / 97 (8.25%)
         occurrences all number
    4
    8
    Respiratory, thoracic and mediastinal disorders
    Pain [Throat/pharynx/larynx]
         subjects affected / exposed
    6 / 101 (5.94%)
    6 / 97 (6.19%)
         occurrences all number
    6
    6
    Hemorrhage pulmonary [Nose]
         subjects affected / exposed
    3 / 101 (2.97%)
    6 / 97 (6.19%)
         occurrences all number
    3
    9
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    9 / 101 (8.91%)
    8 / 97 (8.25%)
         occurrences all number
    10
    10
    Dermatology - Other
         subjects affected / exposed
    7 / 101 (6.93%)
    7 / 97 (7.22%)
         occurrences all number
    7
    7
    Petechiae
         subjects affected / exposed
    3 / 101 (2.97%)
    6 / 97 (6.19%)
         occurrences all number
    3
    7
    Psychiatric disorders
    Mood alteration [Agitation]
         subjects affected / exposed
    14 / 101 (13.86%)
    17 / 97 (17.53%)
         occurrences all number
    14
    17
    Insomnia
         subjects affected / exposed
    5 / 101 (4.95%)
    11 / 97 (11.34%)
         occurrences all number
    5
    11
    Musculoskeletal and connective tissue disorders
    Pain [Extremity-limb]
         subjects affected / exposed
    21 / 101 (20.79%)
    11 / 97 (11.34%)
         occurrences all number
    22
    13
    Muscle weakness [Extremity-lower]
         subjects affected / exposed
    12 / 101 (11.88%)
    10 / 97 (10.31%)
         occurrences all number
    12
    10
    Pain [Back]
         subjects affected / exposed
    8 / 101 (7.92%)
    13 / 97 (13.40%)
         occurrences all number
    9
    13
    Pain [Bone]
         subjects affected / exposed
    7 / 101 (6.93%)
    11 / 97 (11.34%)
         occurrences all number
    7
    13
    Pain [Joint]
         subjects affected / exposed
    1 / 101 (0.99%)
    5 / 97 (5.15%)
         occurrences all number
    1
    5
    Infections and infestations
    Infection (documented clinically) [Oral cavity-gums (gingivitis)]
         subjects affected / exposed
    6 / 101 (5.94%)
    8 / 97 (8.25%)
         occurrences all number
    6
    8
    Infection with normal ANC [Oral cavity-gums (gingivitis)]
         subjects affected / exposed
    4 / 101 (3.96%)
    6 / 97 (6.19%)
         occurrences all number
    4
    6
    Metabolism and nutrition disorders
    Anorexia
         subjects affected / exposed
    7 / 101 (6.93%)
    5 / 97 (5.15%)
         occurrences all number
    8
    6

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    13 Jul 2009
    Relevant changes were: • Secondary endpoint was defined more precisely • Study medication: time of infusion was changed to 0.5 to 2.0 hours • Specification statistical data analysis • Specification on timing of blood drawings • Change of sample size and power calculation according to modified PIP • Deletion of the interim analysis • Administrative changes
    14 Dec 2010
    Relevant changes were: • Update of timelines • Update of information according to SPC Asparaginase medac • Minimal Residual Disease (MRD) status to be evaluated centrally in Rotterdam within the DOOG ALL 10 protocol.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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