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    Clinical Trial Results:
    A Single Center, Open-label, Non-randomized, Uncontrolled, Multiple-dose, Dose Escalation Study of the Safety, Pharmacokinetics and Efficacy of Metazym for the Treatment of Patients With Late Infantile Metachromatic Leukodystrophy (MLD)

    Summary
    EudraCT number
    2006-005341-11
    Trial protocol
    DK  
    Global end of trial date
    27 Mar 2008

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

    Trial information

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    Trial identification
    Sponsor protocol code
    rhASA-01
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT00418561
    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?
    Yes
    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
    27 Mar 2008
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    27 Mar 2008
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the safety profile of Metazym and to determine the pharmacokinetic (PK) profile of Metazym in subjects with late infantile metachromatic leukodystrophy (MLD) as measured by recombinant human Arylsulphatase A (rhASA) levels in plasma and Arylsulfatase A (ASA) activity in leukocytes.
    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/Good Clinical Practice (ICH/GCP) guidelines for clinical studies were followed.
    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
    -

    Pre-assignment
    Screening details
    Thirteen subjects participated in the study.

    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
    Single dose of 25 U/kg recombinant human Arylsulphatase A (Metazym, rhASA), thereafter, received repeated doses of 50 U/kg recombinant human Arylsulphatase A, once in every 2 weeks for a period of 26 weeks, as an intravenous (IV) infusion over 30 minutes. Dosage adjustment was done monthly to account for changes in body weight.
    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
    Single dose of 25 U/kg recombinant human Arylsulphatase A (Metazym, rhASA), thereafter, received repeated doses of 50 U/kg recombinant human Arylsulphatase A, once in every 2 weeks for a period of 26 weeks, as an IV infusion over 30 minutes. Dosage adjustment was done monthly to account for changes in body weight.

    Arm title
    Cohort 2
    Arm description
    Repeated doses of 100 U/kg recombinant human Arylsulphatase A (Metazym, rhASA), once in every 2 weeks for a period of 26 weeks, as an IV infusion over 30 minutes. Dosage adjustment was done monthly to account for changes in body weight.
    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
    Repeated doses of 100 U/kg recombinant human Arylsulphatase A (Metazym, rhASA), once in every 2 weeks for a period of 26 weeks, as an IV infusion over 30 minutes. Dosage adjustment was done monthly to account for changes in body weight.

    Arm title
    Cohort 3
    Arm description
    Repeated doses of 200 U/kg recombinant human Arylsulphatase A (Metazym, rhASA), once in every 2 weeks for a period of 26 weeks, as an IV infusion over 60 minutes. Dosage adjustment was done monthly to account for changes in body weight.
    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
    Repeated doses of 200 U/kg recombinant human Arylsulphatase A (Metazym, rhASA), once in every 2 weeks for a period of 26 weeks, as an IV infusion over 60 minutes. Dosage adjustment was done monthly to account for changes in body weight.

    Number of subjects in period 1
    Cohort 1 Cohort 2 Cohort 3
    Started
    4
    5
    4
    Completed
    4
    4
    4
    Not completed
    0
    1
    0
         Subject's (guardian's) decision
    -
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Cohort 1
    Reporting group description
    Single dose of 25 U/kg recombinant human Arylsulphatase A (Metazym, rhASA), thereafter, received repeated doses of 50 U/kg recombinant human Arylsulphatase A, once in every 2 weeks for a period of 26 weeks, as an intravenous (IV) infusion over 30 minutes. Dosage adjustment was done monthly to account for changes in body weight.

    Reporting group title
    Cohort 2
    Reporting group description
    Repeated doses of 100 U/kg recombinant human Arylsulphatase A (Metazym, rhASA), once in every 2 weeks for a period of 26 weeks, as an IV infusion over 30 minutes. Dosage adjustment was done monthly to account for changes in body weight.

    Reporting group title
    Cohort 3
    Reporting group description
    Repeated doses of 200 U/kg recombinant human Arylsulphatase A (Metazym, rhASA), once in every 2 weeks for a period of 26 weeks, as an IV infusion over 60 minutes. Dosage adjustment was done monthly to account for changes in body weight.

    Reporting group values
    Cohort 1 Cohort 2 Cohort 3 Total
    Number of subjects
    4 5 4 13
    Age categorical
    Units: Subjects
    Age Continuous
    Units: months
        arithmetic mean (standard deviation)
    36.25 ± 9.32 41.8 ± 10.13 30.75 ± 7.27 -
    Gender, Male/Female
    Units: Subjects
        Female
    2 3 3 8
        Male
    2 2 1 5

    End points

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    End points reporting groups
    Reporting group title
    Cohort 1
    Reporting group description
    Single dose of 25 U/kg recombinant human Arylsulphatase A (Metazym, rhASA), thereafter, received repeated doses of 50 U/kg recombinant human Arylsulphatase A, once in every 2 weeks for a period of 26 weeks, as an intravenous (IV) infusion over 30 minutes. Dosage adjustment was done monthly to account for changes in body weight.

    Reporting group title
    Cohort 2
    Reporting group description
    Repeated doses of 100 U/kg recombinant human Arylsulphatase A (Metazym, rhASA), once in every 2 weeks for a period of 26 weeks, as an IV infusion over 30 minutes. Dosage adjustment was done monthly to account for changes in body weight.

    Reporting group title
    Cohort 3
    Reporting group description
    Repeated doses of 200 U/kg recombinant human Arylsulphatase A (Metazym, rhASA), once in every 2 weeks for a period of 26 weeks, as an IV infusion over 60 minutes. Dosage adjustment was done monthly to account for changes in body weight.

    Primary: Number of Subjects With Treatment-emergent Adverse Events (TEAEs)

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    End point title
    Number of Subjects With Treatment-emergent Adverse Events (TEAEs) [1]
    End point description
    An adverse event (AE) is any untoward, undesired, unplanned clinical event in the form of signs, symptoms, disease, or laboratory or physiological observations occurring in a subject participating in a clinical study with study drug, regardless of causal relationship. TEAEs were AEs occurred after study drug administration that were absent before treatment or that worsened relative to pre-treatment state, up to Week 28 until evaluation (when last cohort had 26-week evaluation and data management performed within 4 weeks) completed. Intent-to-treat (ITT) population included all subjects who received at least 1 dose of study drug.
    End point type
    Primary
    End point timeframe
    From study drug administration up to Week 28
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive statistics were done, no inferential statistical analyses were performed.
    End point values
    Cohort 1 Cohort 2 Cohort 3
    Number of subjects analysed
    4
    5
    4
    Units: Subjects
        number (not applicable)
    4
    5
    4
    No statistical analyses for this end point

    Primary: Change From Baseline in Gross Motor Function Measure (GMFM) at Week 26

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    End point title
    Change From Baseline in Gross Motor Function Measure (GMFM) at Week 26
    End point description
    GMFM was measured using GMFM-88 item scores and summed to calculate a total GMFM-88 score. For each GMFM-88 item, the score was between 0 (minimal) to 3 (maximum). The total GMFM-88 score was between 0 (minimal) and 264 (maximum). The decrease in GMFM score over time indicates worsening of disease over time. Relative change from baseline at Week 26 was calculated as percentage change from baseline divided by the age-difference in months between first and last visit. Adjusted mean and 95 percent (%) confidence intervals were reported. ITT population.
    End point type
    Primary
    End point timeframe
    Baseline, Week 26
    End point values
    Cohort 1 Cohort 2 Cohort 3
    Number of subjects analysed
    4
    5
    4
    Units: percent (%) change
        arithmetic mean (confidence interval 95%)
    -2.36 (-7.62 to 2.91)
    -8.29 (-13.55 to -3.02)
    -10.9 (-16.17 to -5.64)
    Statistical analysis title
    Statistical analysis 1
    Statistical analysis description
    The comparisons of the three doses were done using analysis of variance (ANOVA) model including the baseline measurement as a covariate.
    Comparison groups
    Cohort 1 v Cohort 2 v Cohort 3
    Number of subjects included in analysis
    13
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.0737 [2]
    Method
    ANOVA
    Confidence interval
    Notes
    [2] - Test for no difference between cohorts.

    Primary: Change From Baseline in Cerebrospinal Fluid (CSF) Sulfatide at Week 26

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    End point title
    Change From Baseline in Cerebrospinal Fluid (CSF) Sulfatide at Week 26
    End point description
    Relative change from baseline at Week 26 was calculated as percentage change from baseline divided by the age-difference in months between first and last visit. Adjusted mean and 95 percent (%) confidence intervals were reported. ITT population.
    End point type
    Primary
    End point timeframe
    Baseline, Week 26
    End point values
    Cohort 1 Cohort 2 Cohort 3
    Number of subjects analysed
    4
    5
    4
    Units: percent (%) change
        arithmetic mean (confidence interval 95%)
    24.55 (0.44 to 48.66)
    -3.77 (-22.33 to 14.8)
    -4.32 (-28.17 to 19.53)
    Statistical analysis title
    Statistical analysis 1
    Statistical analysis description
    The comparisons of the three doses were done using ANOVA model including the baseline measurement as a covariate.
    Comparison groups
    Cohort 1 v Cohort 2 v Cohort 3
    Number of subjects included in analysis
    13
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.1115 [3]
    Method
    ANOVA
    Confidence interval
    Notes
    [3] - Test for no difference between cohorts.

    Primary: Number of Subjects With Shift From Baseline to Week 26 in Sulfatide Levels in Urine

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    End point title
    Number of Subjects With Shift From Baseline to Week 26 in Sulfatide Levels in Urine [4]
    End point description
    Number of subjects with shifts between negative (value=0) and positive (value=1) values in urine sulfatide levels from baseline at Week 26 is reported. ITT population. Here, the number of subjects analyzed are the subjects evaluable for this endpoint.
    End point type
    Primary
    End point timeframe
    Baseline up to Week 26
    Notes
    [4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive statistics were done, no inferential statistical analyses were performed.
    End point values
    Cohort 1 Cohort 2 Cohort 3
    Number of subjects analysed
    3
    2
    2
    Units: Subjects
    number (not applicable)
        Negative(0) to negative(0)
    0
    0
    0
        Negative(0) to positive(1)
    0
    0
    0
        Positive(1) to negative(0)
    0
    0
    0
        Positive(1) to positive(1)
    3
    2
    2
    No statistical analyses for this end point

    Primary: Change From Baseline in Mullen’s Scales of Early Learning at Week 26

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    End point title
    Change From Baseline in Mullen’s Scales of Early Learning at Week 26
    End point description
    Mullen's Scales of Early Learning is used to assess performance and learning ability in young children. The scale consisted of 144 items that had specific scoring criteria for each item. The scores were converted to T-scores with a decrease in score indicating worsening of disease. Relative change from baseline at Week 26 was calculated as percentage change from baseline divided by the age-difference in months between first and last visit. Adjusted mean and 95 percent (%) confidence intervals were reported. ITT population.
    End point type
    Primary
    End point timeframe
    Baseline, Week 26
    End point values
    Cohort 1 Cohort 2 Cohort 3
    Number of subjects analysed
    4
    5
    4
    Units: percent (%) change
        arithmetic mean (confidence interval 95%)
    16.28 (0.72 to 31.84)
    0.26 (-15.49 to 16.02)
    -4.92 (-20.26 to 10.41)
    Statistical analysis title
    Statistical analysis 1
    Statistical analysis description
    The comparisons of the three doses were done using ANOVA model including the baseline measurement as a covariate.
    Comparison groups
    Cohort 1 v Cohort 2 v Cohort 3
    Number of subjects included in analysis
    13
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.1268 [5]
    Method
    ANOVA
    Confidence interval
    Notes
    [5] - Test for no difference between cohorts.

    Primary: Maximum Plasma Drug Concentration (Cmax) of Recombinant Human Arylsulphatase A (rhASA)

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    End point title
    Maximum Plasma Drug Concentration (Cmax) of Recombinant Human Arylsulphatase A (rhASA) [6]
    End point description
    End point type
    Primary
    End point timeframe
    Pre-dose and post-dose at 20, 40, 90 minutes, 3, 6 and 8 hours on Day 0, 40 minutes post-dose at Week 4, Pre-dose and post-dose at 20, 40, 90 minutes, 3, 6 and 8 hours at Week 8
    Notes
    [6] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Due to quick disappearance of rhASA from plasma, rHASA levels were not possible to report.
    End point values
    Cohort 1 Cohort 2 Cohort 3
    Number of subjects analysed
    0 [7]
    0 [8]
    0 [9]
    Units: microgram per liter
        geometric mean (geometric coefficient of variation)
    ±
    ±
    ±
    Notes
    [7] - Due to quick disappearance of rhASA from plasma, rhASA levels were not possible to report.
    [8] - Due to quick disappearance of rhASA from plasma, rhASA levels were not possible to report.
    [9] - Due to quick disappearance of rhASA from plasma, rhASA levels were not possible to report.
    No statistical analyses for this end point

    Primary: Arylsulfatase A (ASA) Activity in Leukocytes

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    End point title
    Arylsulfatase A (ASA) Activity in Leukocytes [10]
    End point description
    End point type
    Primary
    End point timeframe
    Pre-dose and post-dose at 24 hours on Day 0 and at Weeks 8 and 26
    Notes
    [10] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Data could not be reported as the results were presented graphically, as planned.
    End point values
    Cohort 1 Cohort 2 Cohort 3
    Number of subjects analysed
    0 [11]
    0 [12]
    0 [13]
    Units: Not applicable
    Notes
    [11] - Data could not be reported as the results were presented graphically, as planned.
    [12] - Data could not be reported as the results were presented graphically, as planned.
    [13] - Data could not be reported as the results were presented graphically, as planned.
    No statistical analyses for this end point

    Secondary: Change From Baseline in Nerve Conduction Velocity at Week 26

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    End point title
    Change From Baseline in Nerve Conduction Velocity at Week 26
    End point description
    An electrophysiological evaluation using standard electrophysiological and electromyography to measure the speed and extent of nerve conduction and units are expressed in meters per second. '99999' indicate that the data could not be reported since there were no subjects evaluable for SN, Sensory R LM - MC category at Week 26. Abbreviations: MN=Median Nerve; PN=Peroneal Nerve; SN=Sural Nerve; Dig.=Digit; FH=fibular hemimelia; L LM=left lateral medial; R LM=right lateral medial; MC=medial collateral. ITT population. Here, "N" signifies the number of subjects who were evaluable for the respective category.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 26
    End point values
    Cohort 1 Cohort 2 Cohort 3
    Number of subjects analysed
    4
    5
    4
    Units: meters per second
    arithmetic mean (standard deviation)
        MN, Elbow Wrist: Baseline (N=4,5,4)
    20.38 ± 6.99
    25.78 ± 17.72
    15.95 ± 5.68
        MN, Elbow Wrist: Change at Week 26 (N=4,4,4)
    -4 ± 1.1
    2.62 ± 4.42
    -3.65 ± 3.33
        MN, Dig. II Wrist: Baseline (N=3,5,4)
    39.83 ± 7.22
    36.82 ± 16.64
    23.3 ± 11.99
        MN, Dig. II Wrist: Change at Week 26 (N=3,4,4)
    -11.7 ± 5.78
    -0.25 ± 4.39
    -1.33 ± 4.72
        PN, Dig. Ankle FH: Baseline (N=4,4,4)
    20.7 ± 9.08
    32.23 ± 21.41
    14.13 ± 5.92
        PN, Dig. Ankle FH: Change at Week 26 (N=4,3,4)
    -7.85 ± 3.92
    -2.43 ± 1.59
    -2.65 ± 3.61
        SN, Sensory L LM - MC: Baseline (N=4,4,4)
    26.88 ± 9.29
    36.13 ± 20.61
    29.18 ± 15.93
        SN, Sensory L LM - MC: Change at Week 26 (N=3,3,4)
    -5.57 ± 4.18
    3.7 ± 9.79
    -9.33 ± 10.64
        SN, Sensory R LM - MC: Baseline (N=4,4,4)
    31.35 ± 6.46
    34.58 ± 17.74
    27.48 ± 13.91
        SN, Sensory R LM - MC: Change at Week 26 (N=0,0,0)
    99999 ± 99999
    99999 ± 99999
    99999 ± 99999
    No statistical analyses for this end point

    Secondary: Number of Subjects who had Undergone Nerve Biopsy and had a Normal Nerve at Both Baseline and Week 26

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    End point title
    Number of Subjects who had Undergone Nerve Biopsy and had a Normal Nerve at Both Baseline and Week 26
    End point description
    ITT population.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 26
    End point values
    Cohort 1 Cohort 2 Cohort 3
    Number of subjects analysed
    4
    5
    4
    Units: Subjects
    number (not applicable)
        Baseline
    0
    2
    0
        Week 26
    0
    2
    0
    No statistical analyses for this end point

    Secondary: Number of Subjects With Shift From Baseline to Week 26 in Magnetic Resonance Imaging (MRI)-Loes scores

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    End point title
    Number of Subjects With Shift From Baseline to Week 26 in Magnetic Resonance Imaging (MRI)-Loes scores
    End point description
    Loes scoring system is used to grade the demyelinating abnormalities on brain MRI. A total of 17 locations of the brain were scored from 0 (normal appearance) to 2 (dense appearance). The total score ranged from 0 to 34 with a score of 14 or greater being considered severe. Number of participants with any shift of score between 0 to 2 for each of the 17 locations (Parieto Occipital [PO]-Periventricular [P], Central [C], Subcortical [Sc]; Anterior Temporal [AT]-P, C, Sc; Frontal [F]-P, C, Sc; Corpus Callosum [CC]-Splenium [S], Genus [G]; Projection Fibers [PF]-Capsular interna [CI] ant, CI post, Brainstem [B]; Cerebellum [Cb]-Cortex, Atrophy; Basal Ganglia [BG]-BG, Thalamus [T]; Cerebral Atrophy [CA]-CA), are only reported. ITT population. Here, number of subjects analyzed in the Cohort 2 are the subjects evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 26
    End point values
    Cohort 1 Cohort 2 Cohort 3
    Number of subjects analysed
    4
    4
    4
    Units: Subjects
    number (not applicable)
        PO, P: 1 to 2
    1
    0
    1
        PO, P: 2 to 2
    3
    4
    3
        PO, C: 2 to 2
    4
    4
    4
        PO, Sc: 0 to 0
    1
    0
    1
        PO, Sc: 0 to 1
    0
    1
    0
        PO, Sc: 0 to 2
    0
    0
    1
        PO, Sc: 1 to 1
    0
    1
    0
        PO, Sc: 1 to 2
    0
    0
    1
        PO, Sc: 2 to 2
    3
    2
    1
        AT, P: 0 to 2
    1
    0
    0
        AT, P: 1 to 2
    0
    1
    2
        AT, P: 2 to 2
    3
    3
    2
        AT, C: 0 to 2
    1
    0
    0
        AT, C: 1 to 2
    0
    0
    1
        AT, C: 2 to 2
    3
    4
    3
        AT, Sc: 0 to 0
    1
    0
    1
        AT, Sc: 0 to 1
    0
    1
    0
        AT, Sc: 0 to 2
    0
    2
    2
        AT, Sc: 1 to 1
    0
    1
    0
        AT, Sc: 1 to 2
    1
    0
    0
        AT, Sc: 2 to 2
    2
    0
    1
        F, P: 0 to 2
    1
    0
    1
        F, P: 1 to 2
    0
    1
    1
        F, P: 2 to 2
    3
    3
    2
        F, C: 1 to 2
    1
    0
    2
        F, C: 2 to 2
    3
    4
    2
        F, Sc: 0 to 0
    1
    0
    1
        F, Sc: 0 to 2
    0
    2
    2
        F, Sc: 1 to 2
    1
    1
    0
        F, Sc: 2 to 2
    2
    1
    1
        CC, S: 1 to 0
    0
    1
    1
        CC, S: 1 to 2
    1
    0
    0
        CC, S: 2 to 0
    1
    1
    1
        CC, S: 2 to 1
    2
    1
    0
        CC, S: 2 to 2
    0
    1
    2
        CC, G: 0 to 2
    1
    1
    0
        CC, G: 1 to 1
    0
    1
    0
        CC, G: 1 to 2
    0
    0
    2
        CC, G: 2 to 1
    1
    0
    1
        CC, G: 2 to 2
    2
    2
    1
        PF, CI ant: 0 to 0
    2
    3
    4
        PF, CI ant: 0 to 1
    1
    1
    0
        PF, CI ant: 1 to 1
    1
    0
    0
        PF, CI post: 0 to 0
    0
    1
    0
        PF, CI post: 0 to 1
    1
    0
    2
        PF, CI post: 1 to 1
    0
    2
    0
        PF, CI post: 1 to 2
    1
    0
    1
        PF, CI post: 2 to 1
    0
    1
    0
        PF, CI post: 2 to 2
    2
    0
    1
        PF, B: 0 to 0
    1
    0
    1
        PF, B: 0 to 1
    0
    1
    1
        PF, B: 0 to 2
    0
    0
    1
        PF, B: 1 to 0
    0
    1
    0
        PF, B: 1 to 1
    1
    0
    0
        PF, B: 1 to 2
    1
    1
    1
        PF, B: 2 to 2
    1
    1
    0
        Cb, Cortex: 0 to 0
    2
    1
    1
        Cb, Cortex: 0 to 1
    0
    2
    2
        Cb, Cortex: 1 to 1
    2
    1
    1
        Cb, Atrophy: 0 to 0
    1
    1
    3
        Cb, Atrophy: 0 to 1
    1
    1
    0
        Cb, Atrophy: 1 to 1
    2
    2
    1
        Bg, Bg: 0 to 0
    2
    3
    2
        Bg, Bg: 0 to 1
    0
    0
    2
        Bg, Bg: 1 to 0
    0
    1
    0
        Bg, Bg: 1 to 1
    2
    0
    0
        Bg, T: 0 to 0
    2
    3
    3
        Bg, T: 1 to 0
    0
    1
    1
        Bg, T: 1 to 1
    2
    0
    0
        CA, CA: 0 to 0
    1
    0
    2
        CA, CA: 0 to 1
    0
    2
    1
        CA, CA: 1 to 1
    1
    1
    1
        CA, CA: 1 to 2
    2
    1
    0
    No statistical analyses for this end point

    Secondary: Change From Baseline in Paediatric Evaluation of Disability Inventory (PEDI) Scores at Week 26

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    End point title
    Change From Baseline in Paediatric Evaluation of Disability Inventory (PEDI) Scores at Week 26
    End point description
    PEDI is used for the clinical evaluation of functional capabilities, performance and changes in functional skills in children with disabilities. It consisted of 20 items scored on a scale from 0 (total assistance) to 5 (independent). Total score ranged from 0-100 with higher scores indicating better functioning. None, child, rehab, extensive are items in 3 domains (self-care, mobility and social functioning). ITT population. Here, "N" signifies the number of subjects who were evaluable for the respective category.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 26
    End point values
    Cohort 1 Cohort 2 Cohort 3
    Number of subjects analysed
    4
    5
    4
    Units: units on a scale
    arithmetic mean (standard deviation)
        Self-care, None: Baseline (N=4,5,4)
    6.25 ± 0.96
    6 ± 1.41
    4.75 ± 2.06
        Self-care, None: Change at Week 26 (N=4,4,4)
    -0.75 ± 1.5
    -1.5 ± 1.73
    -1.5 ± 1.91
        Self-care, Child: Baseline (N=4,5,4)
    1.75 ± 0.96
    2 ± 1.41
    3.25 ± 2.06
        Self-care, Child: Change at Week 26 (N=4,4,4)
    0.75 ± 1.5
    1.25 ± 1.5
    0.75 ± 2.22
        Self-care, Rehab: Baseline (N=4,5,4)
    0 ± 0
    0 ± 0
    0 ± 0
        Self-care, Rehab: Change at Week 26 (N=4,4,4)
    0 ± 0
    0 ± 0
    0 ± 0
        Self-care, Extensive: Baseline (N=4,5,4)
    0 ± 0
    0.2 ± 0.45
    0 ± 0
        Self-care, Extensive: Change at Week 26 (N=4,4,4)
    0 ± 0
    0.25 ± 0.5
    0.5 ± 0.58
        Mobility, None: Baseline (N=4,5,4)
    4.25 ± 1.89
    3.6 ± 1.14
    5 ± 0.82
        Mobility, None: Change at Week 26 (N=4,4,4)
    -0.75 ± 1.71
    -0.5 ± 1.29
    -1.25 ± 1.71
        Mobility, Child: Baseline (N=4,5,4)
    2.5 ± 1.91
    2.4 ± 1.67
    1.25 ± 1.26
        Mobility, Child: Change at Week 26 (N=4,4,4)
    0 ± 1.41
    0.25 ± 1.26
    -0.5 ± 0.58
        Mobility, Rehab: Baseline (N=4,5,4)
    0 ± 0
    1 ± 1.41
    0.75 ± 0.96
        Mobility, Rehab: Change at Week 26 (N=4,4,4)
    1 ± 0.82
    0.25 ± 0.5
    0.5 ± 1.73
        Mobility, Extensive: Baseline (N=4,5,4)
    0 ± 0
    0 ± 0
    0 ± 0
        Mobility, Extensive: Change at Week 26 (N=4,4,4)
    0 ± 0
    0 ± 0
    1.25 ± 1.5
        Social, None: Baseline (N=4,5,4)
    4.25 ± 0.96
    4.6 ± 0.55
    4.75 ± 0.5
        Social, None: Change at Week 26 (N=4,4,4)
    0.75 ± 0.96
    -0.25 ± 0.5
    0.25 ± 0.5
        Social, Child: Baseline (N=4,5,4)
    1.5 ± 2.38
    0 ± 0
    0.25 ± 0.5
        Social, Child: Change at Week 26 (N=4,4,4)
    -1.5 ± 2.38
    0 ± 0
    -0.25 ± 0.5
        Social, Rehab: Baseline (N=4,5,4)
    0 ± 0
    0.4 ± 0.55
    0 ± 0
        Social, Rehab: Change at Week 26 (N=4,4,4)
    0 ± 0
    0 ± 0
    0 ± 0
        Social, Extensive: Baseline (N=4,5,4)
    0 ± 0
    0 ± 0
    0 ± 0
        Social, Extensive: Change at Week 26 (N=4,4,4)
    0 ± 0
    0.25 ± 0.5
    0 ± 0
    No statistical analyses for this end point

    Other pre-specified: Number of Subjects With Shift From Baseline to Week 26 in Clinical Laboratory Evaluations: Biochemistry

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    End point title
    Number of Subjects With Shift From Baseline to Week 26 in Clinical Laboratory Evaluations: Biochemistry
    End point description
    Number of subjects with at least 1 shift from baseline to Week 26, are reported. Abbreviations: ALT=Alanine transaminase; CK=Creatine kinase; AP=Amyloid P component; LDH=Lactate dehydrogenase. ITT population. Here, number of subjects analyzed in the Cohort 2 are the subjects evaluable for this endpoint.
    End point type
    Other pre-specified
    End point timeframe
    Baseline up to Week 26
    End point values
    Cohort 1 Cohort 2 Cohort 3
    Number of subjects analysed
    4
    4
    4
    Units: Subjects
    number (not applicable)
        ALT-Serum: Low to low
    2
    0
    1
        ALT-Serum: Low to normal
    1
    1
    0
        ALT-Serum: Normal to low
    0
    1
    2
        ALT-Serum: Normal to normal
    0
    1
    1
        ALT-Serum: High to low
    1
    0
    0
        ALT-Serum: High to normal
    0
    1
    0
        Amylase-Serum: Normal to normal
    4
    4
    4
        AP-Serum: Normal to normal
    4
    4
    4
        Calcium-Serum: Normal to normal
    4
    3
    4
        CK-Serum: Normal to normal
    4
    3
    2
        CK-Serum: Normal to high
    0
    1
    0
        CK-Serum: High to normal
    0
    0
    1
        CK-Serum: High to high
    0
    0
    1
        Creatinine-Serum: Normal to normal
    4
    4
    4
        Iron-Serum: Low to normal
    0
    1
    0
        Iron-Serum: Normal to low
    0
    0
    1
        Iron-Serum: Normal to normal
    3
    3
    3
        Iron-Serum: Normal to high
    1
    0
    0
        LDH-Serum: Normal to normal
    3
    4
    4
        LDH-Serum: High to normal
    1
    0
    0
        Magnesium-Serum: Normal to normal
    4
    4
    4
        Phosphate-Serum: Normal to normal
    2
    3
    3
        Phosphate-Serum: Normal to high
    1
    0
    0
        Phosphate-Serum: High to normal
    1
    1
    1
        Potassium-Serum: Normal to normal
    4
    4
    4
        Sodium-Serum: Normal to normal
    4
    3
    4
        Sodium-Serum: High to normal
    0
    1
    0
        T Bilirubin-Serum: Normal to normal
    4
    3
    4
        T Bilirubin-Serum: High to normal
    0
    1
    0
    No statistical analyses for this end point

    Other pre-specified: Number of Subjects With Shift From Baseline to Week 26 in Clinical Laboratory Evaluations: Coagulation

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    End point title
    Number of Subjects With Shift From Baseline to Week 26 in Clinical Laboratory Evaluations: Coagulation
    End point description
    Number of subjects with at least 1 shift from baseline to Week 26 are reported. The shift reported below for Cohort 1 was from low level at baseline to low level at Week 26. ITT population.
    End point type
    Other pre-specified
    End point timeframe
    Baseline up to Week 26
    End point values
    Cohort 1 Cohort 2 Cohort 3
    Number of subjects analysed
    4
    0 [14]
    0 [15]
    Units: Subjects
        number (not applicable)
    4
    Notes
    [14] - No subjects with shift from baseline to Week 26 in coagulation evaluations.
    [15] - No subjects with shift from baseline to Week 26 in coagulation evaluations.
    No statistical analyses for this end point

    Other pre-specified: Number of Subjects With Shift From Baseline to Week 26 in Clinical Laboratory Evaluations: Genotyping

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    End point title
    Number of Subjects With Shift From Baseline to Week 26 in Clinical Laboratory Evaluations: Genotyping
    End point description
    Number of subjects with at least 1 shift from baseline to Week 26 are reported. Abbreviations: CSF=Cerebrospinal fluid; NFP=Neurofilament proteins. ITT population. The number of subjects analyzed in the Cohort 2 are the subjects evaluable for this outcome. Here, "N" signifies the number of subjects who were evaluable for the respective category.
    End point type
    Other pre-specified
    End point timeframe
    Baseline up to Week 26
    End point values
    Cohort 1 Cohort 2 Cohort 3
    Number of subjects analysed
    4
    4
    4
    Units: Subjects
    number (not applicable)
        Albumin CSF: Normal to normal (N=3,4,4)
    0
    2
    0
        Albumin CSF: Normal to high (N=3,4,4)
    1
    0
    0
        Albumin CSF: High to high (N=3,4,4)
    2
    2
    4
        Albumin index: Normal to normal (N=3,4,4)
    0
    1
    0
        Albumin index: High to high (N=3,4,4)
    3
    3
    4
        Albumin Serum: Low to low (N=3,4,4)
    2
    2
    2
        Albumin Serum: Low to normal (N=3,4,4)
    0
    1
    0
        Albumin Serum: Normal to low (N=3,4,4)
    0
    0
    1
        Albumin Serum: Normal to normal (N=3,4,4)
    1
    1
    1
        Chitotriosidase CSF: Low to low (N=4,4,4)
    1
    0
    0
        Chitotriosidase CSF: High to high (N=4,4,4)
    3
    4
    4
        NFP CSF: Normal to high (N=4,4,4)
    1
    0
    0
        NFP CSF: High to high (N=4,4,4)
    3
    4
    4
        Sulfatide CSF: High to high (N=3,4,4)
    3
    4
    4
        Tauprotein CSF: High to low (N=4,4,4)
    0
    1
    0
        Tauprotein CSF: High to high (N=4,4,4)
    4
    3
    4
    No statistical analyses for this end point

    Other pre-specified: Number of Subjects With Shift From Baseline to Week 26 in Clinical Laboratory Evaluations: Hematology

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    End point title
    Number of Subjects With Shift From Baseline to Week 26 in Clinical Laboratory Evaluations: Hematology
    End point description
    Number of subjects with at least 1 shift from baseline to Week 26 are reported. Abbreviations: Abs=Absolute count; ERCS=Erythrocytes; MCHC=Mean corpuscular hemoglobin concentration; MCH=Mean cell hemoglobin. ITT population. The number of subjects analyzed in the Cohort 2 are the subjects evaluable for this outcome. Here, "N" signifies the number of subjects who were evaluable for the respective category.
    End point type
    Other pre-specified
    End point timeframe
    Baseline up to Week 26
    End point values
    Cohort 1 Cohort 2 Cohort 3
    Number of subjects analysed
    4
    4
    4
    Units: Subjects
    number (not applicable)
        Basophils Abs - Blood: Normal to normal (N=4,4,4)
    4
    4
    4
        Eosinophil Abs - Blood: Normal to normal (N=4,4,4)
    4
    4
    4
        ERCS - Blood: Low to low (N=4,4,4)
    1
    0
    0
        ERCS - Blood: Normal to normal (N=4,4,4)
    3
    4
    4
        Haemoglobin - Blood: Low to low (N=4,4,4)
    1
    1
    1
        Haemoglobin - Blood: Low to normal (N=4,4,4)
    1
    0
    1
        Haemoglobin - Blood: Normal to low (N=4,4,4)
    1
    0
    1
        Haemoglobin - Blood: Normal to normal (N=4,4,4)
    1
    3
    1
        Lymphocyte Abs - Blood: Low to low (N=4,4,4)
    0
    1
    0
        Lymphocyte Abs - Blood: Normal to low (N=4,4,4)
    2
    2
    2
        Lymphocyte Abs - Blood: Normal to normal (N=4,4,4)
    2
    1
    2
        MCHC - Blood: Normal to normal (N=4,4,4)
    3
    3
    4
        MCHC - Blood: High to normal (N=4,4,4)
    1
    1
    0
        MCH - Blood: Low to low (N=4,4,4)
    0
    0
    1
        MCH - Blood: Normal to normal (N=4,4,4)
    4
    4
    3
        Monocytes Abs - Blood: Normal to normal (N=4,4,4)
    4
    4
    3
        Monocytes Abs - Blood: High to normal (N=4,4,4)
    0
    0
    1
        Neutropil Abs - Blood: Normal to normal (N=4,4,4)
    4
    4
    3
        Neutropil Abs - Blood: Normal to high (N=4,4,4)
    0
    0
    1
        Thrombocytes - Blood: Normal to low (N=4,3,4)
    1
    0
    1
        Thrombocytes - Blood: Normal to normal (N=4,3,4)
    2
    0
    2
        Thrombocytes - Blood: High to normal (N=4,3,4)
    1
    3
    1
        T Leucocytes - Blood: Low to normal (N=4,4,4)
    0
    0
    1
        T Leucocytes - Blood: Normal to low (N=4,4,4)
    2
    2
    0
        T Leucocytes - Blood: Normal to normal (N=4,4,4)
    2
    2
    3
    No statistical analyses for this end point

    Other pre-specified: Number of Subjects With Abnormal Findings in Urine Analysis

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    End point title
    Number of Subjects With Abnormal Findings in Urine Analysis
    End point description
    The parameters analyzed in urine were albumin/protein, glucose, leucocytes, acetoacetate/ketones, nitrite and pH. Urine analysis findings were considered abnormal as judged by the investigator. ITT population.
    End point type
    Other pre-specified
    End point timeframe
    Baseline up to Week 26
    End point values
    Cohort 1 Cohort 2 Cohort 3
    Number of subjects analysed
    4
    5
    4
    Units: Subjects
        number (not applicable)
    0
    0
    0
    No statistical analyses for this end point

    Other pre-specified: Number of Subjects With Clinically Significant Abnormal Electrocardiogram (ECG) Findings

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    End point title
    Number of Subjects With Clinically Significant Abnormal Electrocardiogram (ECG) Findings
    End point description
    Abnormal ECG findings were considered as clinically significant at the discretion of investigator. ITT population.
    End point type
    Other pre-specified
    End point timeframe
    Baseline up to Week 26
    End point values
    Cohort 1 Cohort 2 Cohort 3
    Number of subjects analysed
    4
    5
    4
    Units: Subjects
        number (not applicable)
    0
    0
    0
    No statistical analyses for this end point

    Other pre-specified: Change From Baseline in Chitotriosidase at Week 26

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    End point title
    Change From Baseline in Chitotriosidase at Week 26
    End point description
    ITT population. Here, "N" signifies the number of subjects who were evaluable for the respective category.
    End point type
    Other pre-specified
    End point timeframe
    Baseline, Week 26
    End point values
    Cohort 1 Cohort 2 Cohort 3
    Number of subjects analysed
    4
    5
    4
    Units: nanomole/hour/milliliter
    arithmetic mean (standard deviation)
        Baseline (N=4, 5, 4)
    924 ± 1431
    1481 ± 1165
    367 ± 179
        Change at Week 26 (N=4, 4, 4)
    -76 ± 393.9
    -228 ± 692.7
    94.75 ± 103.6
    No statistical analyses for this end point

    Other pre-specified: Change From Baseline in Neurofilament Proteins (NFP), Glial Fibrillary Acidic Protein (GFAP) and Tauprotein in Cerebrospinal Fluid (CSF) at Week 26

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    End point title
    Change From Baseline in Neurofilament Proteins (NFP), Glial Fibrillary Acidic Protein (GFAP) and Tauprotein in Cerebrospinal Fluid (CSF) at Week 26
    End point description
    ITT population. Here, "N" signifies the number of subjects who were evaluable for the respective category.
    End point type
    Other pre-specified
    End point timeframe
    Baseline, Week 26
    End point values
    Cohort 1 Cohort 2 Cohort 3
    Number of subjects analysed
    4
    5
    4
    Units: nanogram/milliliter
    arithmetic mean (standard deviation)
        NFP: Baseline (N=4, 5, 4)
    5436 ± 3698
    7848 ± 4510
    12558 ± 3529
        NFP: Change at Week 26 (N=4, 4, 4)
    1134 ± 8098
    -3505 ± 2553
    -4020 ± 9061
        GFAP: Baseline (N=4, 5, 4)
    1758 ± 397.4
    1014 ± 524.3
    1415 ± 625.7
        GFAP: Change at Week 26 (N=4, 4, 4)
    330 ± 380.3
    402.5 ± 460.5
    502.5 ± 285.4
        Tauprotein: Baseline (N=4, 5, 4)
    1148 ± 143.4
    1014 ± 530.9
    1610 ± 543.4
        Tauprotein: Change at Week 26 (N=4, 4, 4)
    -288 ± 692.3
    -273 ± 228.7
    -118 ± 907.6
    No statistical analyses for this end point

    Other pre-specified: Change From Baseline in Amplitude at Week 26

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    End point title
    Change From Baseline in Amplitude at Week 26
    End point description
    '99999' indicate that the data could not be reported since there were no subjects evaluable for SN, Sensory R LM - MC category at Week 26. Abbreviations: MN=Median Nerve; PN=Peroneal Nerve; SN=Sural Nerve; Dig.=Digit; APB=abductor pollicis brevis; EDB=extensor digitorum brevis. ITT population. Here, "N" signifies the number of subjects who were evaluable for the respective category.
    End point type
    Other pre-specified
    End point timeframe
    Baseline, Week 26
    End point values
    Cohort 1 Cohort 2 Cohort 3
    Number of subjects analysed
    4
    5
    4
    Units: millivolts
    arithmetic mean (standard deviation)
        MN, Wrist-APB: Baseline (N=4,5,4)
    5.63 ± 1.73
    7.88 ± 2.2
    4.3 ± 1.05
        MN, Wrist-APB: Change at Week 26 (N=4,4,4)
    0 ± 2.84
    0.65 ± 0.74
    -0.35 ± 1.66
        MN, Elbow-APB: Baseline (N=4,5,4)
    3.85 ± 1.23
    6.34 ± 2.71
    2.65 ± 0.6
        MN, Elbow-APB: Change at Week 26 (N=4,4,4)
    0.15 ± 2.05
    0.33 ± 0.57
    -0.55 ± 0.65
        MN, Dig. II Wrist: Baseline (N=4,5,4)
    2.68 ± 1.3
    11.64 ± 14.89
    1.78 ± 0.83
        MN, Dig. II Wrist: Change at Week 26 (N=4,4,4)
    -0.32 ± 1
    3.53 ± 6.6
    -0.93 ± 0.85
        PN, Ankle EDB: Baseline (N=4,4,4)
    1.85 ± 0.91
    5.4 ± 2.55
    1.3 ± 0.68
        PN, Ankle EDB: Change at Week 26 (N=4,3,4)
    -0.72 ± 1.66
    -0.43 ± 1.56
    0.08 ± 0.96
        PN, FH EDB: Baseline (N=4,4,4)
    2.43 ± 1.8
    4.98 ± 2.95
    0.95 ± 0.74
        PN, FH EDB: Change at Week 26 (N=4,3,4)
    -1.68 ± 2.06
    -0.63 ± 1.46
    0.16 ± 0.75
        SN, Sensory L LM - MC: Baseline (N=4,4,4)
    5.25 ± 6.31
    41.18 ± 51.5
    1.65 ± 2.28
        SN, Sensory L LM - MC: Change at Week 26 (N=4,3,4)
    -2.45 ± 4.18
    0.53 ± 21.75
    -0.78 ± 2.34
        SN, Sensory R LM - MC: Baseline (N=4,4,4)
    5.35 ± 5.45
    50.05 ± 56.13
    1.73 ± 2.01
        SN, Sensory R LM - MC: Change at Week 26 (N=0,0,0)
    99999 ± 99999
    99999 ± 99999
    99999 ± 99999
    No statistical analyses for this end point

    Other pre-specified: Physical Examination Results

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    End point title
    Physical Examination Results
    End point description
    Physical examination included general appearance, skin, head, ears, eyes, nose and throat, lymph nodes, heart, lungs, abdomen, extremities/joints, hip, neurological, mental status and, if appropriate, breasts, external genitalia, pelvic and rectal, and in addition weight, height and head circumference were recorded. ITT population.
    End point type
    Other pre-specified
    End point timeframe
    Baseline up to Week 26
    End point values
    Cohort 1 Cohort 2 Cohort 3
    Number of subjects analysed
    0 [16]
    0 [17]
    0 [18]
    Units: Not applicable
    Notes
    [16] - Results could not be reported since data were collected in subject's listing only as planned.
    [17] - Results could not be reported since data were collected in subject's listing only as planned.
    [18] - Results could not be reported since data were collected in subject's listing only as planned.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From study drug administration up to Week 28 until evaluation (when last cohort had 26-week evaluation and data management performed within 4 weeks)
    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
    Single dose of 25 U/kg recombinant human Arylsulphatase A (Metazym, rhASA), thereafter, received repeated doses of 50 U/kg recombinant human Arylsulphatase A, once in every 2 weeks for a period of 26 weeks, as an intravenous (IV) infusion over 30 minutes. Dosage adjustment was done monthly to account for changes in body weight.

    Reporting group title
    Cohort 2
    Reporting group description
    Repeated doses of 100 U/kg recombinant human Arylsulphatase A (Metazym, rhASA), once in every 2 weeks for a period of 26 weeks, as an IV infusion over 30 minutes. Dosage adjustment was done monthly to account for changes in body weight.

    Reporting group title
    Cohort 3
    Reporting group description
    Repeated doses of 200 U/kg recombinant human Arylsulphatase A (Metazym, rhASA), once in every 2 weeks for a period of 26 weeks, as an IV infusion over 60 minutes. Dosage adjustment was done monthly to account for changes in body weight.

    Serious adverse events
    Cohort 1 Cohort 2 Cohort 3
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 4 (25.00%)
    2 / 5 (40.00%)
    2 / 4 (50.00%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    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
    Metabolism and nutrition disorders
    Malnutrition
         subjects affected / exposed
    0 / 4 (0.00%)
    2 / 5 (40.00%)
    2 / 4 (50.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
         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
    Frequency threshold for reporting non-serious adverse events: 0%
    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%)
    Vascular disorders
    Flushing
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    2
    Pallor
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Injury, poisoning and procedural complications
    Procedural pain
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    1
    Feeding tube complication
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    1
    Device occlusion
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 5 (20.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Investigations
    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
    Hepatic enzyme 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
    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
    Immune system disorders
    Type III immune complex mediated reaction
         subjects affected / exposed
    2 / 4 (50.00%)
    1 / 5 (20.00%)
    2 / 4 (50.00%)
         occurrences all number
    12
    2
    2
    Nervous system disorders
    Muscle spasticity
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    1
    Convulsion
         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
    0 / 4 (0.00%)
    1 / 5 (20.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Mutism
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    1
    Eye disorders
    Blindness
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    1
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    1 / 4 (25.00%)
    3 / 5 (60.00%)
    2 / 4 (50.00%)
         occurrences all number
    1
    6
    3
    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
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    1
    Psychiatric disorders
    Sleep disorder
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    1
    Depression
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 5 (20.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    0 / 4 (0.00%)
    2 / 5 (40.00%)
    2 / 4 (50.00%)
         occurrences all number
    0
    4
    3
    Nausea
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 5 (20.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Diarrhoea
         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
    Abdominal pain upper
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 5 (20.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Pharyngolaryngeal pain
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 5 (20.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    1
    0
    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
    Bronchitis acute
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Tonsillitis
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 5 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    1
    0
    1
    Nasopharyngitis
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 5 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    1
    0
    1
    Influenza
         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
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    1
    Acute tonsillitis
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 5 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Viral 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
    Postoperative infection
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    1
    Otitis media
         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
    13 Apr 2007
    The study was extended to last from 8 weeks to 26 weeks.

    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.
    ASA activity in leukocytes could not be included in EudraCT results format as the results were presented graphically. Due to quick disappearance of rhASA from plasma, rhASA levels were not possible to report.
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