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    Clinical Trial Results:
    A Multi-center, Open-Label Extension Study of HGT-1111 (Recombinant Human Arylsulfatase A or rhASA) Treatment in Patients with Late Infantile Metachromatic Leukodystrophy (MLD)

    Summary
    EudraCT number
    		 2008-000084-41
    Trial protocol
    		 DK   FR   IT   BE  
    Global end of trial date
    22 Oct 2010

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

    Trial information

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    Trial identification
    Sponsor protocol code
    HGT-MLD-049
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00681811
    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 Human Genetic Therapies, Inc., +1 781-482-9297, nbarton@shire.com
    Scientific contact
    Norman Barton, Shire Human Genetic Therapies, Inc., +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
    22 Oct 2010
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    22 Oct 2010
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to provide ongoing treatment of HGT-1111 to subjects who completed study HGT-MLD-048 (previously study rhASA-03) (2008-000084-41) until HGT-1111 was commercially available or the study was terminated by the Sponsor, provided no safety concerns emerged.
    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 was followed.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    20 Feb 2008
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Denmark: 11
    Worldwide total number of subjects
    11
    EEA total number of subjects
    11
    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)
    11
    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 metachromatic leukodystrophy (MLD) due to arylsulfatase A (ASA) deficiency were recruited.

    Pre-assignment
    Screening details
    		 All subjects that completed study HGT-MLD-048/rhASA-03 (2007-006345-40) participated in this study.

    Period 1
    Period 1 title
    Overall study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 100 U/kg HGT-1111
    Arm description
    		 Subjects received 100 units per kilogram (U/kg) of HGT-1111 intravenous (IV) infusion every other week.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Recombinant human Arylsulfatase A (rhASA)
    Investigational medicinal product code
    HGT-1111
    Other name
    Metazym
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received 100 U/kg of HGT-1111 IV infusion every other week.

    Arm title
    		 200 U/kg HGT-1111
    Arm description
    		 Subjects received 200 U/kg of HGT-1111 IV infusion every other week.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Recombinant human Arylsulfatase A (rhASA)
    Investigational medicinal product code
    HGT-1111
    Other name
    Metazym
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received 200 U/kg of HGT-1111 IV infusion every other week.

    Number of subjects in period 1
    		100 U/kg HGT-1111 200 U/kg HGT-1111
    Started
    6
    5
    Completed
    3
    1
    Not completed
    3
    4
         Consent withdrawn by subject
    2
    2
         Adverse event, non-fatal
    1
    1
         Non-compliance
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    100 U/kg HGT-1111
    Reporting group description
    		 Subjects received 100 units per kilogram (U/kg) of HGT-1111 intravenous (IV) infusion every other week.

    Reporting group title
    200 U/kg HGT-1111
    Reporting group description
    		 Subjects received 200 U/kg of HGT-1111 IV infusion every other week.

    Reporting group values
    		 100 U/kg HGT-1111 200 U/kg HGT-1111 Total
    Number of subjects
    		 6 5 11
    Age categorical
    Units: Subjects
        Less than equal to (<=) 18 years
    		 6 5 11
        Between 18 and 65 years
    		 0 0 0
        Greater than equal to (>=) 65 years
    		 0 0 0
    Age continuous
    Age at week 54 or week 56 in HGT-MLD-049 (2008-000084-41)
    Units: months
        arithmetic mean (standard deviation)
    		 53.14 ( 10.526 ) 49.99 ( 8.752 ) -
    Gender categorical
    Units: Subjects
        Female
    		 3 3 6
        Male
    		 3 2 5

    End points

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    End points reporting groups
    Reporting group title
    100 U/kg HGT-1111
    Reporting group description
    		 Subjects received 100 units per kilogram (U/kg) of HGT-1111 intravenous (IV) infusion every other week.

    Reporting group title
    200 U/kg HGT-1111
    Reporting group description
    		 Subjects received 200 U/kg of HGT-1111 IV infusion every other week.

    Subject analysis set title
    100 U/kg HGT-1111 (Month 6)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects received 100 U/kg of HGT-1111 intravenous (IV) infusion every other week up to month 6.

    Subject analysis set title
    200 U/kg HGT-1111 (Month 6)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects received 200 U/kg of HGT-1111 IV infusion every other week up to month 6.

    Subject analysis set title
    100 U/kg HGT-1111 (Month 12)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects received 100 U/kg of HGT-1111 IV infusion every other week up to month 12.

    Subject analysis set title
    200 U/kg HGT-1111 (Month 12)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects received 200 U/kg of HGT-1111 IV infusion every other week up to month 12.

    Subject analysis set title
    100 U/kg HGT-1111 (Month 18)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects received 100 U/kg of HGT-1111 IV infusion every other week up to month 18.

    Subject analysis set title
    200 U/kg HGT-1111 (Month 18)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects received 200 U/kg of HGT-1111 IV infusion every other week up to month 18.

    Subject analysis set title
    100 U/kg HGT-1111 (Month 24)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects received 100 U/kg of HGT-1111 IV infusion every other week up to month 24.

    Subject analysis set title
    200 U/kg HGT-1111 (Month 24)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects received 200 U/kg of HGT-1111 IV infusion every other week up to month 24.

    Primary: Days of Exposure to HGT-1111

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    End point title
    		 Days of Exposure to HGT-1111 [1]
    End point description
    End of study defined as until HGT-1111 is commercially available, the subject's participation is discontinued, or the study is terminated by the Sponsor.
    End point type
    Primary
    End point timeframe
    Baseline until end of study
    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: Only descriptive statistics were done, no inferential statistical analyses were performed.
    End point values
    		 100 U/kg HGT-1111 200 U/kg HGT-1111
    Number of subjects analysed
    6
    5
    Units: Days
        arithmetic mean (standard deviation)
    644.7 ( 276.11 )
    544.8 ( 397.27 )
    No statistical analyses for this end point

    Secondary: Level of Cerebrospinal Fluid (CSF) Sulfatide

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    End point title
    		 Level of Cerebrospinal Fluid (CSF) Sulfatide
    End point description
    Level of CSF sulfatide measured at 6-month intervals in HGT-MLD-049 (2008-000084-41). Number of subjects analysed is for subjects who were evaluable for this outcome measure at respective arm. 99999 signifies standard deviation not reported as there was only 1 evaluable subject.
    End point type
    Secondary
    End point timeframe
    Baseline until end of study
    End point values
    		 100 U/kg HGT-1111 (Month 6) 200 U/kg HGT-1111 (Month 6) 100 U/kg HGT-1111 (Month 12) 200 U/kg HGT-1111 (Month 12) 100 U/kg HGT-1111 (Month 18) 200 U/kg HGT-1111 (Month 18) 100 U/kg HGT-1111 (Month 24) 200 U/kg HGT-1111 (Month 24)
    Number of subjects analysed
    5
    4
    5
    3
    3
    3
    1
    2
    Units: nanomole per liter (nmol/L)
        arithmetic mean (standard deviation)
    685 ( 522.79 )
    732.5 ( 545.06 )
    745 ( 525.12 )
    1150 ( 676.39 )
    700 ( 526.78 )
    850 ( 491.81 )
    900 ( 99999 )
    837.5 ( 441.94 )
    No statistical analyses for this end point

    Secondary: Level of White Matter Metabolites

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    End point title
    		 Level of White Matter Metabolites
    End point description
    Level of white matter metabolites [N-acetyl Aspartate (NAA)] measured at 6-month intervals in HGT-MLD-049 (2008-000084-41) No subjects were analysed after Month 18 hence, data not available after Month 18. Number of subjects analysed is for subjects who were evaluable for this outcome measure at respective arm.
    End point type
    Secondary
    End point timeframe
    Baseline until end of study
    End point values
    		 100 U/kg HGT-1111 (Month 6) 200 U/kg HGT-1111 (Month 6) 100 U/kg HGT-1111 (Month 12) 200 U/kg HGT-1111 (Month 12) 100 U/kg HGT-1111 (Month 18) 200 U/kg HGT-1111 (Month 18)
    Number of subjects analysed
    4
    4
    5
    2
    2
    2
    Units: nmol/L
        arithmetic mean (standard deviation)
    0.528 ( 0.176 )
    0.385 ( 0.237 )
    0.598 ( 0.208 )
    0.47 ( 0.198 )
    0.51 ( 0.141 )
    0.805 ( 0.445 )
    No statistical analyses for this end point

    Secondary: Score of Gross Motor Function Measurement (GMFM)

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    End point title
    		 Score of Gross Motor Function Measurement (GMFM)
    End point description
    Gross motor function is measured using GMFM-88 and measured at 6-month intervals in HGT-MLD-049 (2008-000084-41) study. 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). With GMFM score decreases over time, it indicates disease progression. Number of subjects analysed is for subjects who were evaluable for this outcome measure at respective arm.
    End point type
    Secondary
    End point timeframe
    Baseline until end of study
    End point values
    		 100 U/kg HGT-1111 (Month 6) 200 U/kg HGT-1111 (Month 6) 100 U/kg HGT-1111 (Month 12) 200 U/kg HGT-1111 (Month 12) 100 U/kg HGT-1111 (Month 18) 200 U/kg HGT-1111 (Month 18) 100 U/kg HGT-1111 (Month 24) 200 U/kg HGT-1111 (Month 24)
    Number of subjects analysed
    5
    5
    5
    3
    4
    2
    2
    2
    Units: score on the scale
        arithmetic mean (standard deviation)
    16.8 ( 11.3 )
    9.2 ( 11.71 )
    15.6 ( 15.84 )
    8.7 ( 9.29 )
    16.8 ( 13.6 )
    9 ( 5.66 )
    14.5 ( 10.61 )
    13 ( 11.31 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to End of Study (until HGT-1111 is commercially available, the subject's participation is discontinued, or the study is terminated by the Sponsor)
    Adverse event reporting additional description
    All other adverse events (AEs) (>5% reporting frequency) reported here are related to drug administration, all were infusion-related reactions.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    8.1
    Reporting groups
    Reporting group title
    200 U/kg HGT-1111
    Reporting group description
    		 Subjects received 200 U/kg of HGT-1111 IV infusion every other week.

    Reporting group title
    100 U/kg HGT-1111
    Reporting group description
    		 Subjects received 100 U/kg of HGT-1111 IV infusion every other week.

    Serious adverse events
    		 200 U/kg HGT-1111 100 U/kg HGT-1111
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 5 (80.00%)
    2 / 6 (33.33%)
         number of deaths (all causes)
    0
    1
         number of deaths resulting from adverse events
    Nervous system disorders
    Convulsion
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    2 / 5 (40.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 5 (20.00%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Catheter bacteraemia
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis acute
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pseudomonas infection
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pneumonia
         subjects affected / exposed
    2 / 5 (40.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malnutrition
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 6 (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
    		 200 U/kg HGT-1111 100 U/kg HGT-1111
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    5 / 5 (100.00%)
    6 / 6 (100.00%)
    Vascular disorders
    Flushing
         subjects affected / exposed
    3 / 5 (60.00%)
    1 / 6 (16.67%)
         occurrences all number
    8
    1
    Pallor
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    General disorders and administration site conditions
    Disease progression
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Adverse drug reaction
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Generalised oedema
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Pyrexia
         subjects affected / exposed
    4 / 5 (80.00%)
    4 / 6 (66.67%)
         occurrences all number
    4
    16
    Reproductive system and breast disorders
    Phimosis
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Increased bronchial secretion
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Epistaxis
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    Cough
         subjects affected / exposed
    0 / 5 (0.00%)
    3 / 6 (50.00%)
         occurrences all number
    0
    5
    Bronchospasm
         subjects affected / exposed
    2 / 5 (40.00%)
    0 / 6 (0.00%)
         occurrences all number
    2
    0
    Asthma
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Respiratory distress
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Pharyngolaryngeal pain
         subjects affected / exposed
    2 / 5 (40.00%)
    1 / 6 (16.67%)
         occurrences all number
    2
    1
    Psychiatric disorders
    Mental status changes
         subjects affected / exposed
    1 / 5 (20.00%)
    1 / 6 (16.67%)
         occurrences all number
    1
    1
    Sleep disorder
         subjects affected / exposed
    2 / 5 (40.00%)
    0 / 6 (0.00%)
         occurrences all number
    2
    0
    Investigations
    Weight decreased
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    Platelet count increased
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    Heart rate increased
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    Blood iron increased
         subjects affected / exposed
    1 / 5 (20.00%)
    1 / 6 (16.67%)
         occurrences all number
    1
    1
    Blood alkaline phosphatase increased
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    Injury, poisoning and procedural complications
    Feeding tube complication
         subjects affected / exposed
    1 / 5 (20.00%)
    1 / 6 (16.67%)
         occurrences all number
    2
    1
    Joint dislocation
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Nervous system disorders
    Muscle spasticity
         subjects affected / exposed
    2 / 5 (40.00%)
    2 / 6 (33.33%)
         occurrences all number
    3
    5
    Hypotonia
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    Febrile convulsion
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    Epilepsy
         subjects affected / exposed
    2 / 5 (40.00%)
    1 / 6 (16.67%)
         occurrences all number
    3
    1
    Dystonia
         subjects affected / exposed
    1 / 5 (20.00%)
    1 / 6 (16.67%)
         occurrences all number
    2
    1
    Depressed level of consciousness
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    Syncope
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Convulsion
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 6 (0.00%)
         occurrences all number
    3
    0
    Ear and labyrinth disorders
    Ear pain
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    Eye disorders
    Conjunctival oedema
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    Visual acuity reduced
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    Eyelid oedema
         subjects affected / exposed
    0 / 5 (0.00%)
    2 / 6 (33.33%)
         occurrences all number
    0
    2
    Gastrointestinal disorders
    Gastritis
         subjects affected / exposed
    1 / 5 (20.00%)
    2 / 6 (33.33%)
         occurrences all number
    1
    2
    Diarrhoea
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    2
    Constipation
         subjects affected / exposed
    2 / 5 (40.00%)
    1 / 6 (16.67%)
         occurrences all number
    2
    1
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    Vomiting
         subjects affected / exposed
    3 / 5 (60.00%)
    3 / 6 (50.00%)
         occurrences all number
    10
    15
    Toothache
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    Regurgitation of food
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    Reflux gastritis
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    Nausea
         subjects affected / exposed
    3 / 5 (60.00%)
    3 / 6 (50.00%)
         occurrences all number
    3
    9
    Skin and subcutaneous tissue disorders
    Urticaria generalised
         subjects affected / exposed
    2 / 5 (40.00%)
    0 / 6 (0.00%)
         occurrences all number
    4
    0
    Urticaria
         subjects affected / exposed
    2 / 5 (40.00%)
    1 / 6 (16.67%)
         occurrences all number
    11
    13
    Swelling face
         subjects affected / exposed
    1 / 5 (20.00%)
    1 / 6 (16.67%)
         occurrences all number
    1
    4
    Rash
         subjects affected / exposed
    3 / 5 (60.00%)
    2 / 6 (33.33%)
         occurrences all number
    6
    9
    Musculoskeletal and connective tissue disorders
    Muscle spasms
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    3 / 5 (60.00%)
    3 / 6 (50.00%)
         occurrences all number
    4
    4
    Infection
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Herpes simplex
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Gastroenteritis
         subjects affected / exposed
    1 / 5 (20.00%)
    1 / 6 (16.67%)
         occurrences all number
    2
    1
    Eye infection
         subjects affected / exposed
    2 / 5 (40.00%)
    1 / 6 (16.67%)
         occurrences all number
    3
    1
    Ear infection
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    Bronchitis acute
         subjects affected / exposed
    2 / 5 (40.00%)
    1 / 6 (16.67%)
         occurrences all number
    2
    1
    Influenza
         subjects affected / exposed
    1 / 5 (20.00%)
    1 / 6 (16.67%)
         occurrences all number
    2
    2
    Pneumonia
         subjects affected / exposed
    1 / 5 (20.00%)
    1 / 6 (16.67%)
         occurrences all number
    1
    1
    Pharyngitis
         subjects affected / exposed
    2 / 5 (40.00%)
    2 / 6 (33.33%)
         occurrences all number
    4
    5
    Oral candidiasis
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Nasopharyngitis
         subjects affected / exposed
    1 / 5 (20.00%)
    4 / 6 (66.67%)
         occurrences all number
    2
    12
    Lung infection
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    Laryngitis
         subjects affected / exposed
    1 / 5 (20.00%)
    1 / 6 (16.67%)
         occurrences all number
    1
    1
    Rhinitis
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    Scarlet fever
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Sinusitis
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Tooth infection
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    Urinary tract infection
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Varicella
         subjects affected / exposed
    1 / 5 (20.00%)
    1 / 6 (16.67%)
         occurrences all number
    1
    1
    Viral pharyngitis
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    Metabolism and nutrition disorders
    Malnutrition
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    28 Feb 2008
    • Clarifications of financial conditions requested by the Ethics Committee • Language added regarding publication of negative results • Addition of a section on biobank • Clarification of minor study procedures
    09 Feb 2009
    • Change in Sponsor from Metazym to Shire HGT • Change in protocol number from rhASA-05 to HGT-MLD-049 • Change in medical monitor and legal representative • All sponsor contact information was updated to reflect the acquisition of Metazym by Shire Human Genetic Therapies, Inc., on 04 June 2008. • The product name changed from Metazym to Shire product code: HGT-1111. • The title of the study was changed to clarify that the study was an extension study and not a compassionate use study and to reflect the new product name. • Subjects who had safely tolerated their HGT-1111 infusions were given the option of receiving subsequent infusions at an infusion site in their home country, once the necessary approvals were obtained. This amendment adapted the relevant language for the inclusion of those countries. • As the focus of the study was to provide continued access of HGT-1111 treatment to subjects who completed study HGT-MLD-048 (formerly study rhASA-03), a number of assessments were eliminated, including gross motor function classification, concentration of neurofilament protein, glial fibrillary acidic protein, tau protein in cerebrospinal fluid, concentration of serum chitotriosidase, diffuser tensor imaging, Loes score, Somatosensory Evoked Potential (SSEP), and nerve conduction and electromyography. • The frequency of anti-rhASA antibody testing was changed from every other week to every 6 weeks plus week 26. • The frequency of hematology, routine serum chemistry and urinalysis assessments was increased to include assessments every 6 weeks as well as the original 26 week assessment. • The format of the protocol, all introductory text, protocol section numbers, most administrative text and adverse event reporting language were updated to reflect the current standard of care and Shire’s document template and standards. • The concentration of the investigational product was changed from milligram per milliliter (mg/mL) to U/mL.
    19 Feb 2009
    The protocol was amended to clarify that the concentration of investigational medicinal product ((IMP), HGT-1111 for IV infusion) would be as indicated on the label, with dosing instructions included as a package insert with each shipment of IMP.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    22 Oct 2010
    Study got terminated prior to planned completion date due to lack of efficacy.
    -

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    Early termination due to lack of efficacy.
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