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    Clinical Trial Results:
    A Single Center, Open-Label, Non-Randomized, Uncontrolled, Multiple-Dose, Dose Escalation Study of the Safety, Pharmacokinetics, Efficacy and Long Term Safety of HGT-1111 (Recombinant Human Arylsulfatase A [rhASA, Metazym]) for the Treatment of Patients with Late Infantile Metachromatic Leukodystrophy (MLD)

    Summary
    EudraCT number
    2007-006345-40
    Trial protocol
    DK  
    Global end of trial date
    25 Sep 2008

    Results information
    Results version number
    v1(current)
    This version publication date
    04 Sep 2018
    First version publication date
    13 May 2015
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    HGT-MLD-048/rhASA-03
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT00633139
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Shire
    Sponsor organisation address
    300 Shire Way, Lexington, Massachusetts, United States, 02421
    Public contact
    Norman Barton, Shire , +1 781-482-9297, nbarton@shire.com
    Scientific contact
    Norman Barton, Shire , +1 781-482-9297, nbarton@shire.com
    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
    25 Sep 2008
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    25 Sep 2008
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The overall objective was to evaluate the long-term safety, efficacy and pharmacokinetics (PK) of recombinant human arylsulfatase A (rhASA) (HGT-1111) treatment in subjects with late infantile Metachromatic Leukodystrophy (MLD) and to determine the minimum effective dose.
    Protection of trial subjects
    This study conformed to the standards of conduct for clinical studies as set forth in the Declaration of Helsinki and the legal regulations in Denmark. International Conference on Harmonization (ICH) guidelines for good clinical practices (GCP) was followed. After written approval from the Independent Ethics Committee (IEC) and competent authority has been obtained, the Investigator obtained informed consent from the subject’s legally acceptable representative.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    22 Jan 2007
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Denmark: 13
    Worldwide total number of subjects
    13
    EEA total number of subjects
    13
    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)
    13
    Adolescents (12-17 years)
    0
    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
    Children with an established diagnosis of late infantile metachromatic leukodystrophy (MLD) due to arylsulfatase A (ASA) deficiency were recruited.

    Pre-assignment
    Screening details
    All subjects that completed study rhASA-01 (2006-005341-11) except 1 subject who did not complete (at week 18) the rhASA-01 (2006-005341-11) participated in rhASA-03 (2007-006345-40).

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Cohort 1
    Arm description
    Subjects received a single dose of rhASA at 25 units per kilogram (U/kg) intravenous (IV) infusion in rhASA-01 (2006-005341-11) study. Thereafter a repeated dose of rhASA at 50 U/kg, over 30 minutes was administered every other week up to Week 52.
    Arm type
    Experimental

    Investigational medicinal product name
    Recombinant human Arylsulfatase A (rhASA)
    Investigational medicinal product code
    HGT-1111
    Other name
    Metazym
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received a single dose of rhASA at 25 U/kg IV infusion in rhASA-01 (2006-005341-11) study. Thereafter a repeated dose of rhASA at 50 U/kg, over 30 minutes was administered every other week up to Week 52.

    Arm title
    Cohort 2
    Arm description
    Subjects received a repeated dose of rhASA at 100 U/kg IV infusion over 30 minutes was administered every other week up to Week 52.
    Arm type
    Experimental

    Investigational medicinal product name
    Recombinant human Arylsulfatase A (rhASA)
    Investigational medicinal product code
    HGT-1111
    Other name
    Metazym
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received a repeated dose of rhASA at 100 U/kg IV infusion over 30 minutes was administered every other week up to Week 52.

    Arm title
    Cohort 3
    Arm description
    Subjects received a repeated dose of rhASA at 200 U/kg IV infusion over 60 minutes was administered every other week up to Week 52.
    Arm type
    Experimental

    Investigational medicinal product name
    Recombinant human Arylsulfatase A (rhASA)
    Investigational medicinal product code
    HGT-1111
    Other name
    Metazym
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received a repeated dose of rhASA at 200 U/kg IV infusion over 60 minutes was administered every other week up to Week 52.

    Number of subjects in period 1
    Cohort 1 Cohort 2 Cohort 3
    Started
    4
    5
    4
    Completed
    4
    4
    3
    Not completed
    0
    1
    1
         Non compliance
    -
    -
    1
         Consent withdrawn by subject
    -
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Cohort 1
    Reporting group description
    Subjects received a single dose of rhASA at 25 units per kilogram (U/kg) intravenous (IV) infusion in rhASA-01 (2006-005341-11) study. Thereafter a repeated dose of rhASA at 50 U/kg, over 30 minutes was administered every other week up to Week 52.

    Reporting group title
    Cohort 2
    Reporting group description
    Subjects received a repeated dose of rhASA at 100 U/kg IV infusion over 30 minutes was administered every other week up to Week 52.

    Reporting group title
    Cohort 3
    Reporting group description
    Subjects received a repeated dose of rhASA at 200 U/kg IV infusion over 60 minutes was administered every other week up to Week 52.

    Reporting group values
    Cohort 1 Cohort 2 Cohort 3 Total
    Number of subjects
    4 5 4 13
    Age categorical
    Units: Subjects
        <=18 years
    4 5 4 13
        Between 18 and 65 years
    0 0 0 0
        >=65 years
    0 0 0 0
    Age continuous
    Units: months
        arithmetic mean (standard deviation)
    36.25 ± 9.32 41.8 ± 10.13 30.75 ± 7.27 -
    Gender categorical
    Units: Subjects
        Female
    2 3 3 8
        Male
    2 2 1 5
    Region of Enrollment
    Units: Subjects
        Denmark
    4 5 4 13

    End points

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    End points reporting groups
    Reporting group title
    Cohort 1
    Reporting group description
    Subjects received a single dose of rhASA at 25 units per kilogram (U/kg) intravenous (IV) infusion in rhASA-01 (2006-005341-11) study. Thereafter a repeated dose of rhASA at 50 U/kg, over 30 minutes was administered every other week up to Week 52.

    Reporting group title
    Cohort 2
    Reporting group description
    Subjects received a repeated dose of rhASA at 100 U/kg IV infusion over 30 minutes was administered every other week up to Week 52.

    Reporting group title
    Cohort 3
    Reporting group description
    Subjects received a repeated dose of rhASA at 200 U/kg IV infusion over 60 minutes was administered every other week up to Week 52.

    Primary: Relative Changes (%) in Gross Motor Function Measurement (GMFM)

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    End point title
    Relative Changes (%) in Gross Motor Function Measurement (GMFM)
    End point description
    Change (percent change) in GMFM is measured from baseline to end of study (Week 52). GMFM is measured using GMFM-88. The GMFM-88 item scores can be summed to calculate a total GMFM-88 score. For each GMFM-88 item, the score is between 0 (minimal) to 3 (maximum). The total GMFM-88 score is between 0 (minimal) to 264 (maximum). Relative changes in GMFM are calculated as percentage change from baseline divided by the age difference in months between first and last visit. The GMFM score decreases over time, which, indicates that the disease worsened over time. Score over time (SOT), data mentioned over arithmetic mean represents the adjusted mean. Intent to Treat (ITT) population included all the subjects in the study.
    End point type
    Primary
    End point timeframe
    Baseline to 52 Weeks
    End point values
    Cohort 1 Cohort 2 Cohort 3
    Number of subjects analysed
    4
    5
    4
    Units: Relative % change in total GMFM-88 SOT
        arithmetic mean (confidence interval 95%)
    -2.98 (-6.08 to 0.12)
    -5.42 (-8.5 to -2.34)
    -5.28 (-8.91 to -1.65)
    Statistical analysis title
    Relative Changes (%) in GMFM
    Comparison groups
    Cohort 1 v Cohort 2 v Cohort 3
    Number of subjects included in analysis
    13
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.4013
    Method
    ANCOVA
    Confidence interval

    Primary: Relative Change in Mullen's Scales of Early Learning

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    End point title
    Relative Change in Mullen's Scales of Early Learning
    End point description
    Changes in Mullen's Scales of Early Learning are measured from baseline to end of study (Week 52) using Mullen's Scales of Early Learning. T scores, percentile ranks, and age equivalents can be computed for the four scales separately (visual reception, fine motor, expressive language, and receptive language). Relative change is calculated as percentage change from baseline divided by the age-difference in months between first and last visit. When Mullen's score decreases over time, it indicates the disease worsened over time. Data mentioned over arithmetic mean represents the adjusted mean. ITT Population.
    End point type
    Primary
    End point timeframe
    52 weeks
    End point values
    Cohort 1 Cohort 2 Cohort 3
    Number of subjects analysed
    4
    5
    4
    Units: Relative % change in Mullen's SOT
        arithmetic mean (confidence interval 95%)
    -2.82 (-6.31 to 0.66)
    -2.97 (-6.47 to 0.54)
    -6.98 (-11.95 to -2.01)
    Statistical analysis title
    Mullen's Scales of Early Learning
    Comparison groups
    Cohort 1 v Cohort 2 v Cohort 3
    Number of subjects included in analysis
    13
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.275
    Method
    ANCOVA
    Confidence interval

    Secondary: Change in Cerebrospinal Fluid (CSF) Sulfatide

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    End point title
    Change in Cerebrospinal Fluid (CSF) Sulfatide
    End point description
    Changes in CSF sulfatide from baseline to end of study (Week 52). Data mentioned over arithmetic mean represents the adjusted mean. ITT Population.
    End point type
    Secondary
    End point timeframe
    52 weeks
    End point values
    Cohort 1 Cohort 2 Cohort 3
    Number of subjects analysed
    4
    5
    4
    Units: %change in CSF sulfatide
        arithmetic mean (confidence interval 95%)
    8.6 (-0.77 to 17.97)
    -1.53 (-8.63 to 5.56)
    -2.77 (-14.35 to 8.81)
    Statistical analysis title
    Change in Cerebrospinal Fluid (CSF) Sulfatide
    Comparison groups
    Cohort 1 v Cohort 2 v Cohort 3
    Number of subjects included in analysis
    13
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1363
    Method
    ANCOVA
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    52 weeks of treatment
    Adverse event reporting additional description
    All other Adverse Events (AEs) (>5% reporting frequency) reported here are either PRB (probable) or DEF (definitely) related to drug administration.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    8.2
    Reporting groups
    Reporting group title
    Cohort 1
    Reporting group description
    Cohort 1: Subjects received a single dose of rhASA at 25 U/kg IV infusion in rhASA-01 (2006-005341-11) study. Thereafter a repeated dose of rhASA at 50 U/kg, over 30 minutes was administered every other week up to Week 52.

    Reporting group title
    Cohort 2
    Reporting group description
    Cohort 2: Subjects received a repeated dose of rhASA at 100 U/kg IV infusion over 30 minutes was administered every other week up to Week 52.

    Reporting group title
    Cohort 3
    Reporting group description
    Cohort 3: Subjects received a repeated dose of rhASA at 200 U/kg IV infusion over 60 minutes was administered every other week up to Week 52.

    Serious adverse events
    Cohort 1 Cohort 2 Cohort 3
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 4 (50.00%)
    2 / 5 (40.00%)
    3 / 4 (75.00%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    Injury, poisoning and procedural complications
    Post procedural vomiting
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 4 (25.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pneumonia aspiration
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 5 (20.00%)
    1 / 4 (25.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Blindness
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 4 (25.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Peritonitis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 4 (25.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 5 (20.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Malnutrition
         subjects affected / exposed
    1 / 4 (25.00%)
    2 / 5 (40.00%)
    2 / 4 (50.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Bronchitis acute
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 5 (0.00%)
    3 / 4 (75.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Cohort 1 Cohort 2 Cohort 3
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    4 / 4 (100.00%)
    5 / 5 (100.00%)
    4 / 4 (100.00%)
    Injury, poisoning and procedural complications
    Feeding tube complication
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 5 (20.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Medical device complication
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    1
    Procedural pain
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 5 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    1
    0
    1
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 5 (20.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Blood alkaline phosphatase increased
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 5 (20.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Blood iron decreased
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Blood iron increased
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 5 (20.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Drug specific antibody present
         subjects affected / exposed
    2 / 4 (50.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    2
    0
    0
    General physical condition abnormal
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 5 (20.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    1
    Haemoglobin decreased
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 5 (20.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    2
    Neutrophil count increased
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 5 (20.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    White blood cell count decreased
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 5 (20.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Congenital, familial and genetic disorders
    Leukodystrophy
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 5 (20.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 5 (20.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    1
    Pharyngeal oedema
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Pharyngolaryngeal pain
         subjects affected / exposed
    2 / 4 (50.00%)
    1 / 5 (20.00%)
    0 / 4 (0.00%)
         occurrences all number
    2
    1
    0
    Nervous system disorders
    Cognitive disorder
         subjects affected / exposed
    2 / 4 (50.00%)
    2 / 5 (40.00%)
    1 / 4 (25.00%)
         occurrences all number
    5
    3
    1
    Convulsion
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    2 / 4 (50.00%)
         occurrences all number
    0
    0
    2
    Hypotonia
         subjects affected / exposed
    2 / 4 (50.00%)
    4 / 5 (80.00%)
    3 / 4 (75.00%)
         occurrences all number
    5
    5
    4
    Muscle spasticity
         subjects affected / exposed
    4 / 4 (100.00%)
    4 / 5 (80.00%)
    1 / 4 (25.00%)
         occurrences all number
    6
    7
    1
    Mutism
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    1
    Speech disorder developmental
         subjects affected / exposed
    1 / 4 (25.00%)
    2 / 5 (40.00%)
    0 / 4 (0.00%)
         occurrences all number
    2
    2
    0
    General disorders and administration site conditions
    Discomfort
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 5 (20.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Infusion related reaction
         subjects affected / exposed
    2 / 4 (50.00%)
    2 / 5 (40.00%)
    3 / 4 (75.00%)
         occurrences all number
    15
    16
    11
    Pyrexia
         subjects affected / exposed
    3 / 4 (75.00%)
    3 / 5 (60.00%)
    3 / 4 (75.00%)
         occurrences all number
    6
    4
    5
    Psychiatric disorders
    Depression
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 5 (20.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Sleep disorder
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    1
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 5 (20.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Constipation
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Diarrhoea
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 5 (20.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    1
    Nausea
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 5 (20.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Flatulence
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 5 (20.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Vomiting
         subjects affected / exposed
    0 / 4 (0.00%)
    2 / 5 (40.00%)
    2 / 4 (50.00%)
         occurrences all number
    0
    3
    4
    Musculoskeletal and connective tissue disorders
    Muscle spasms
         subjects affected / exposed
    1 / 4 (25.00%)
    3 / 5 (60.00%)
    1 / 4 (25.00%)
         occurrences all number
    1
    3
    1
    Infections and infestations
    Acute tonsillitis
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Bronchitis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    1
    Bronchitis acute
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Enterobiasis
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 5 (20.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Herpangina
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Gastroenteritis
         subjects affected / exposed
    3 / 4 (75.00%)
    2 / 5 (40.00%)
    1 / 4 (25.00%)
         occurrences all number
    3
    2
    1
    Influenza
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 5 (20.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Nasopharyngitis
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 5 (20.00%)
    1 / 4 (25.00%)
         occurrences all number
    1
    1
    1
    Otitis media
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    2
    0
    0
    Pneumonia
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 5 (20.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    1
    Postoperative infection
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    1
    Tonsillitis
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 5 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    1
    0
    1
    Urinary tract infection
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Varicella
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 5 (20.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Viral infection
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    21 Feb 2008
    - For the first infusion within each cohort, it will be required not to dose the 4 subjects within each cohort simultaneously. A minimum interval of 60 minutes between each subject will be allowed. -Subjects experiencing a mild infusion-related reaction may be pre-medicated with antihistamine for subsequent infusions. If fever is a component of the reaction, pre-medication with ibuprofen or acetaminophen may be considered. If infusions continue without incidents, then tapering of medications can be considered -Dose Reduction: The subject will discontinue if he/she experiences severe or intolerable reactions defined as: 1) liver (or other) toxicity attributed to rhASA; 2) symptoms suggestive of immune complex disease attributable to rhASA; or 3) unmanageable infusion-associated reaction (IAR), defined as an IAR that does not respond to pretreatment, rate reduction or treatment during the reaction. The final decision to discontinue treatment will be made by Investigator in consultation with Zymenex, and upon recommendation by the data monitoring committee (DMC) /allergic reaction review board (ARRB).

    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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