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    Clinical Trial Results:
    A Controlled, Randomized, Two-arm, Open-label, Assessor-blinded, Multicenter Study of Intrathecal Idursulfase-IT Administered in Conjunction with ELAPRASE® in Pediatric Patients with Hunter Syndrome and Early Cognitive Impairment

    Summary
    EudraCT number
    		 2013-002885-38
    Trial protocol
    		 GB   ES   FR  
    Global end of trial date
    28 Sep 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    13 Apr 2018
    First version publication date
    13 Apr 2018
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    HGT-HIT-094
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02055118
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Shire Human Genetic Therapies, Inc
    Sponsor organisation address
    300 Shire Way, Lexington, MA, United States, 02421
    Public contact
    Study Physician, Shire, 1 866-842-5335, clinicaltransparency@shire.com
    Scientific contact
    Study Physician, Shire, 1 866-842-5335, clinicaltransparency@shire.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-000294-PIP02-12
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    28 Sep 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    28 Sep 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    28 Sep 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective of this study was to determine the effect of the treatment regimen in pediatric subjects with Hunter syndrome and early cognitive impairment on the General Conceptual Ability (GCA) score as measured by the Differential Ability Scales, Second Edition (DAS-II), in conjunction with ELAPRASE therapy.
    Protection of trial subjects
    The procedures set out in the study protocol, pertaining to the conduct, evaluation, and documentation of this study, were designed to ensure that the sponsor and investigators abided by GCP as described in 21 CFR Parts 50, 56, and 312 and the ICH GCP Guidelines. Compliance with these regulations and guidelines also constitutes compliance with the ethical principles described in the Declaration of Helsinki and its revisions.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    24 Mar 2014
    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
    Australia: 1
    Country: Number of subjects enrolled
    Canada: 2
    Country: Number of subjects enrolled
    France: 2
    Country: Number of subjects enrolled
    Mexico: 4
    Country: Number of subjects enrolled
    Spain: 5
    Country: Number of subjects enrolled
    United Kingdom: 3
    Country: Number of subjects enrolled
    United States: 32
    Worldwide total number of subjects
    49
    EEA total number of subjects
    10
    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)
    48
    Adolescents (12-17 years)
    1
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Study was conducted at 9 centers in Australia, Canada, France, Mexico, Spain, the United Kingdom and the United States between 24 Mar 2014 (first subject first visit) and 28 Sep 2017 (last subject last visit).

    Pre-assignment
    Screening details
    		 Overall, 103 subjects were screened, of them 54 subjects failed to meet the randomization and remaining 49 subjects were randomized to receive either IT treatment or No IT treatment.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    The assessor was blinded.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 No IT Treatment
    Arm description
    		 Subjects aged 3 to less than (<) 18 years received elaprase therapy intravenously as standard of care for 12 months.
    Arm type
    		 Standard of Care

    Investigational medicinal product name
    Elaprase
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects aged 3 to < 18 years received elaprase therapy intravenously as standard of care for 12 months.

    Arm title
    		 IT Treatment
    Arm description
    		 Subjects aged 3 to < 18 years received intrathecal (IT) injections of 10 milligram (mg) idursulfase-IT once monthly for 12 months through SOPH-A-PORT Mini S intrathecal drug delivery device (IDDD) along with elaprase therapy.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Idursulfase
    Investigational medicinal product code
    SHP609, HGT-2310
    Other name
    Idursulfase-IT
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intrathecal use
    Dosage and administration details
    Subjects aged 3 to < 18 years received IT injections of 10 mg idursulfase-IT once monthly for 12 months through SOPH-A-PORT Mini S IDDD along with elaprase.

    Investigational medicinal product name
    Elaprase
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects aged 3 to < 18 years received elaprase therapy intravenously as standard of care for 12 months.

    Number of subjects in period 1
    		No IT Treatment IT Treatment
    Started
    15
    34
    Completed
    15
    32
    Not completed
    0
    2
         Consent withdrawn by subject
    -
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    No IT Treatment
    Reporting group description
    		 Subjects aged 3 to less than (<) 18 years received elaprase therapy intravenously as standard of care for 12 months.

    Reporting group title
    IT Treatment
    Reporting group description
    		 Subjects aged 3 to < 18 years received intrathecal (IT) injections of 10 milligram (mg) idursulfase-IT once monthly for 12 months through SOPH-A-PORT Mini S intrathecal drug delivery device (IDDD) along with elaprase therapy.

    Reporting group values
    		 No IT Treatment IT Treatment Total
    Number of subjects
    		 15 34
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 5.29 ± 2.624 4.95 ± 1.496 -
    Gender categorical
    Units: Subjects
        Female
    		 0 0 0
        Male
    		 15 34 49
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 5 9 14
        Not Hispanic or Latino
    		 8 25 33
        Unknown or Not Reported
    		 2 0 2
    Race/Ethnicity, Customized
    Units: Subjects
        Race Asian
    		 0 4 4
        Race Black or African American
    		 0 1 1
        Race White
    		 12 23 35
        Race Other
    		 3 6 9

    End points

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    End points reporting groups
    Reporting group title
    No IT Treatment
    Reporting group description
    		 Subjects aged 3 to less than (<) 18 years received elaprase therapy intravenously as standard of care for 12 months.

    Reporting group title
    IT Treatment
    Reporting group description
    		 Subjects aged 3 to < 18 years received intrathecal (IT) injections of 10 milligram (mg) idursulfase-IT once monthly for 12 months through SOPH-A-PORT Mini S intrathecal drug delivery device (IDDD) along with elaprase therapy.

    Primary: Change From Baseline in Differential Ability Scales, Second Edition (DAS-II) General Conceptual Ability (GCA) Standard Score at Week 52

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    End point title
    		 Change From Baseline in Differential Ability Scales, Second Edition (DAS-II) General Conceptual Ability (GCA) Standard Score at Week 52
    End point description
    The DAS-II was used to assess cognitive development in all randomized subjects. The GCA standard score of the DAS-II was used to obtain a general measure of cognitive ability. The GCA score represent a score (mean = 100 and standard deviation of 15) on which higher scores indicate a higher level of cognitive ability. A positive change value indicates improvement in cognitive ability. Intent to treat (ITT) population included all randomized subjects.
    End point type
    Primary
    End point timeframe
    Baseline, Week 52
    End point values
    		 No IT Treatment IT Treatment
    Number of subjects analysed
    15
    29
    Units: Score on a scale
    least squares mean (standard error)
        Score on a scale
    -7.4 ± 4.22
    -4.4 ± 3.14
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    The Mixed model repeated measures included fixed categorical effects for treatment, visit week, treatment by visit week interaction, baseline GCA classification factor (less than or equal to [<=] 70 or >70), baseline age group (<6 years or >=6 years), treatment by baseline GCA classification factor interaction, treatment by baseline age group interaction, interaction between baseline GCA classification factor and baseline age group, genotype, and the baseline GCA score as a continuous covariate.
    Comparison groups
    IT Treatment v No IT Treatment
    Number of subjects included in analysis
    44
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.5669
    Method
    		 Mixed model repeated measures
    Parameter type
    		 Least squares mean
    Point estimate
    3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7.3
         upper limit
    		 13.3
    Variability estimate
    Standard error of the mean
    Dispersion value
    5.12

    Secondary: Change From Baseline in the Vineland Adaptive Behavior Scales, Second Edition (VABS-II) Adaptive Behavior Composite (ABC) Score at Week 52

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    End point title
    		 Change From Baseline in the Vineland Adaptive Behavior Scales, Second Edition (VABS-II) Adaptive Behavior Composite (ABC) Score at Week 52
    End point description
    The VABS-II test measures adaptive behaviors, including the ability to cope with environmental changes, to learn new everyday skills, and to demonstrate independence. This test measures the following 5 key domains: communication, daily living skills, socialization, motor skills, and the adaptive behavior composite (a composite of the other 4 domains). The ABC ranges from 20 to 160 on which higher scores indicate a higher level of adaptive functioning. A positive change value indicates improvement in adaptive functioning. ITT population included all randomized subjects.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 52
    End point values
    		 No IT Treatment IT Treatment
    Number of subjects analysed
    14
    31
    Units: Score on a scale
    least squares mean (standard error)
        Score on a scale
    -5.3 ± 2.55
    -5.0 ± 2.05
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    The Mixed model repeated measures included fixed categorical effects for treatment, visit week, treatment by visit week interaction, baseline GCA classification factor (<= 70 or >70), baseline age group (<6 years or >=6 years), treatment by baseline GCA classification factor interaction, treatment by baseline age group interaction, interaction between baseline GCA classification factor and baseline age group, genotype, and the baseline ABC score as a continuous covariate.
    Comparison groups
    No IT Treatment v IT Treatment
    Number of subjects included in analysis
    45
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.9218
    Method
    		 Mixed model repeated measures
    Parameter type
    		 Least squares mean
    Point estimate
    0.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6
         upper limit
    		 6.6
    Variability estimate
    Standard error of the mean
    Dispersion value
    3.11

    Secondary: Change From Baseline in the Differential Ability Scales, Second Edition (DAS-II) General Conceptual Ability (GCA) Standard Score at Weeks 16, 28 and 40

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    End point title
    		 Change From Baseline in the Differential Ability Scales, Second Edition (DAS-II) General Conceptual Ability (GCA) Standard Score at Weeks 16, 28 and 40
    End point description
    The DAS-II was used to assess cognitive development in all randomized subjects. The GCA standard score of the DAS-II was used to obtain a general measure of cognitive ability. The GCA score represent a score (mean = 100 and standard deviation of 15) on which higher scores indicate a higher level of cognitive ability. A positive change value indicates improvement in cognitive ability. In the below table, "n" signifies subjects who were evaluable for the specified category, respectively. ITT population included all randomized subjects.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 16, Week 28 and Week 40
    End point values
    		 No IT Treatment IT Treatment
    Number of subjects analysed
    15
    34
    Units: Score on a scale
    least squares mean (standard error)
        Week 16 (n=14,30)
    -2.9 ± 3.33
    -0.6 ± 2.54
        Week 28 (n=12,30)
    -6.1 ± 3.34
    -0.3 ± 2.56
        Week 40 (n=15,30)
    -6.4 ± 3.87
    -3.2 ± 2.92
    No statistical analyses for this end point

    Secondary: Change From Baseline in the Vineland Adaptive Behavior Scales, Second Edition (VABS-II) Adaptive Behavior Composite (ABC) Score at Weeks 16, 28 and 40

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    End point title
    		 Change From Baseline in the Vineland Adaptive Behavior Scales, Second Edition (VABS-II) Adaptive Behavior Composite (ABC) Score at Weeks 16, 28 and 40
    End point description
    The VABS-II test measures adaptive behaviors, including the ability to cope with environmental changes, to learn new everyday skills, and to demonstrate independence. This test measures the following 5 key domains: communication, daily living skills, socialization, motor skills, and the adaptive behavior composite (a composite of the other 4 domains). The ABC ranges from 20 to 160 on which higher scores indicate a higher level of adaptive functioning. A positive change value indicates improvement in adaptive functioning. In the below table, "n" signifies subjects who were evaluable for the specified category, respectively. ITT population included all randomized subjects.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 16, Week 28 and Week 40
    End point values
    		 No IT Treatment IT Treatment
    Number of subjects analysed
    15
    34
    Units: Score on a scale
    least squares mean (standard error)
        Week 16 (n=15,31)
    -2.8 ± 2.21
    -3.1 ± 1.86
        Week 28 (n=15,29)
    -1.1 ± 2.45
    -1.8 ± 2.01
        Week 40 (n=14,30)
    -3.3 ± 2.41
    -4.7 ± 1.97
    No statistical analyses for this end point

    Secondary: Change From Baseline in Differential Ability Scales, Second Edition (DAS-II) Cluster Standard Scores at Weeks 16, 28, 40 and 52

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    End point title
    		 Change From Baseline in Differential Ability Scales, Second Edition (DAS-II) Cluster Standard Scores at Weeks 16, 28, 40 and 52
    End point description
    The DAS-II was used to assess cognitive development in all randomized subjects. The cluster score represents a score (mean = 100 and standard deviation of 15) on which higher scores indicate a higher level of cognitive ability. In the below table, "n" signifies subjects who were evaluable for the specified category, respectively. ITT population included all randomized subjects.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 16, Week 28, Week 40 and Week 52
    End point values
    		 No IT Treatment IT Treatment
    Number of subjects analysed
    15
    34
    Units: Score on a scale
    least squares mean (standard error)
        Week 16: Verbal (n=15,32)
    -1.1 ± 3.75
    -6.9 ± 2.81
        Week 16: Nonverbal (n=14,32)
    -6.7 ± 5.06
    2.6 ± 3.82
        Week 16: Spatial (n=11,28)
    -5.6 ± 3.18
    1.9 ± 2.47
        Week 16: Special Nonverbal Composite (n=11,28)
    -7.4 ± 3.95
    -0.7 ± 2.96
        Week 28: Verbal (n=12,30)
    -7.0 ± 4.26
    -5.1 ± 3.10
        Week 28: Nonverbal (n=12,30)
    -8.8 ± 5.41
    0.7 ± 4.06
        Week 28: Spatial (n=9,27)
    -7.8 ± 3.66
    -0.8 ± 2.70
        Week 28: Special Nonverbal Composite) (n=9,27)
    -8.0 ± 4.01
    -1.7 ± 3.00
        Week 40: Verbal (n=15,30)
    -7.3 ± 4.01
    -10.8 ± 3.07
        Week 40: Nonverbal (n=15,30)
    -8.7 ± 5.35
    -2.8 ± 4.09
        Week 40: Spatial (n=11,27)
    -7.3 ± 4.39
    0.6 ± 3.13
        Week 40: Special Nonverbal Composite (n=11,27)
    -9.7 ± 5.51
    -3.1 ± 3.78
        Week 52: Verbal (n=15,30)
    -5.7 ± 4.45
    -9.8 ± 3.31
        Week 52: Nonverbal (n=15,30)
    -11.2 ± 5.61
    -1.5 ± 4.25
        Week 52: Spatial (n=11,26)
    -9.6 ± 4.21
    -4.8 ± 3.04
        Week 52: Special Nonverbal Composite (n=11,26)
    -11.8 ± 5.38
    -5.0 ± 3.74
    No statistical analyses for this end point

    Secondary: Change From Baseline in Vineland Adaptive Behavior Scales, Second Edition (VABS-II) Standard Scores of Other Domains at Weeks 16, 28, 40, 52

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    End point title
    		 Change From Baseline in Vineland Adaptive Behavior Scales, Second Edition (VABS-II) Standard Scores of Other Domains at Weeks 16, 28, 40, 52
    End point description
    The VABS-II test measures adaptive behaviors, including the ability to cope with environmental changes, to learn new everyday skills, and to demonstrate independence. This test measures the following 5 key domains: communication, daily living skills, socialization, motor skills, and the adaptive behavior composite (a composite of the other 4 domains). The standard scores represent a score (mean = 100 and standard deviation of 15) on which higher scores indicate a higher level of cognitive ability. A positive change value indicates improvement in adaptive functioning. Communication, daily living skills, socialization and motor skills domains were reported here. In the below table, "n" signifies subjects who were evaluable for the specified category, respectively. ITT population included all randomized subjects.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 16, Week 28, Week 40, Week 52
    End point values
    		 No IT Treatment IT Treatment
    Number of subjects analysed
    15
    34
    Units: Score on a scale
    least squares mean (standard error)
        Week 16: Communication (n=15,33)
    -2.8 ± 2.65
    -1.7 ± 1.94
        Week 16: Daily Living Skills (n=15,33)
    -3.5 ± 3.11
    -3.5 ± 2.33
        Week 16: Socialization (n=15,32)
    -4.0 ± 2.43
    -2.0 ± 2.05
        Week 16: Motor Skills (n=12,27)
    1.0 ± 2.00
    0.0 ± 1.46
        Week 28: Communication (n=15,30)
    -2.4 ± 2.80
    -0.3 ± 2.08
        Week 28: Daily Living Skills (n=15,30)
    0.1 ± 3.40
    -2.0 ± 2.53
        Week 28: Socialization (n=15,30)
    -0.8 ± 2.37
    -0.2 ± 2.02
        Week 28: Motor Skills (n=12,25)
    -0.2 ± 2.46
    0.7 ± 1.77
        Week 40: Communication (n=14,32)
    -3.5 ± 2.82
    -4.6 ± 2.07
        Week 40: Daily Living Skills (n=15,31)
    -2.0 ± 3.47
    -3.7 ± 2.57
        Week 40: Socialization (n=15,32)
    -4.0 ± 2.65
    -3.8 ± 2.17
        Week 40: Motor Skills (n=12,26)
    -2.2 ± 2.47
    -1.1 ± 1.77
        Week 52: Communication (n=15,32)
    -4.8 ± 2.99
    -5.8 ± 2.18
        Week 52: Daily Living Skills (n=14,32)
    -4.5 ± 3.50
    -4.4 ± 2.57
        Week 52: Socialization (n=15,32)
    -5.8 ± 2.72
    -2.8 ± 2.21
        Week 52: Motor Skills (n=12,26)
    -5.7 ± 2.47
    -1.3 ± 1.77
    No statistical analyses for this end point

    Secondary: Change From Baseline of Age Equivalents for Early Age of Core Subtests of the Differential Ability Scales, Second Edition (DAS-II) at Weeks 16, 28, 40 and 52

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    End point title
    		 Change From Baseline of Age Equivalents for Early Age of Core Subtests of the Differential Ability Scales, Second Edition (DAS-II) at Weeks 16, 28, 40 and 52
    End point description
    The DAS-II was used to assess cognitive development in all randomized subjects. The early years battery is designed for children ages 2 years 6 months through 6 years 11 months. The higher score indicates greater cognitive ability. The subtest score represent a score (mean = 50 and standard deviation of 10) on which higher scores indicate a higher level of cognitive ability. A positive change value indicates improvement in cognitive ability. In the below table, "n" signifies subjects who were evaluable for the specified category, respectively. ITT population who have been evaluated by the DAS-II test for early years were analysed.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 16, Week 28, Week 40 and Week 52
    End point values
    		 No IT Treatment IT Treatment
    Number of subjects analysed
    15
    32
    Units: Score on a scale
    arithmetic mean (standard deviation)
        Week 16: Verbal Comprehension (n=14,29)
    0.05 ± 0.748
    0.03 ± 0.700
        Week 16: Picture Similarities (n=14,29)
    0.00 ± 1.056
    0.48 ± 1.002
        Week 16: Naming Vocabulary (n=14,29)
    0.18 ± 0.432
    -0.02 ± 0.702
        Week 16: Pattern Construction (n=14,27)
    -0.14 ± 0.435
    0.25 ± 0.475
        Week 16: Matrices (n=10,27)
    0.48 ± 2.076
    0.38 ± 1.322
        Week 16: Copying (n=10,27)
    0.05 ± 0.197
    0.10 ± 0.211
        Week 28: Verbal Comprehension (n=11,28)
    -0.16 ± 0.846
    0.39 ± 0.780
        Week 28: Picture Similarities (n=11,28)
    0.39 ± 1.051
    0.43 ± 0.693
        Week 28: Naming Vocabulary (n=11,28)
    0.27 ± 0.325
    0.26 ± 0.870
        Week 28: Pattern Construction (n=11,28)
    -0.18 ± 0.389
    0.29 ± 0.543
        Week 28: Matrices (n=8,25)
    0.78 ± 1.089
    0.51 ± 1.802
        Week 28: Copying (n=8,25)
    0.06 ± 0.291
    0.14 ± 0.361
        Week 40: Verbal Comprehension (n=14,27)
    -0.11 ± 0.783
    0.17 ± 0.519
        Week 40: Picture Similarities (n=14,27)
    0.23 ± 1.277
    0.52 ± 1.081
        Week 40: Naming Vocabulary (n=14,27)
    -0.04 ± 0.950
    0.17 ± 0.721
        Week 40: Pattern Construction (n=14,27)
    -0.02 ± 0.317
    0.43 ± 0.733
        Week 40: Matrices (n=10,24)
    0.15 ± 1.890
    0.45 ± 1.721
        Week 40: Copying (n=10,24)
    0.33 ± 0.472
    0.30 ± 0.556
        Week 52: Verbal Comprehension (n=14,27)
    0.16 ± 1.090
    0.32 ± 0.657
        Week 52: Picture Similarities (n=14,27)
    0.27 ± 1.207
    0.84 ± 1.215
        Week 52: Naming Vocabulary (n=14,27)
    0.16 ± 0.959
    0.34 ± 1.006
        Week 52: Pattern Construction (n=14,27)
    0.02 ± 0.360
    0.31 ± 0.660
        Week 52: Matrices (n=10,24)
    0.00 ± 1.863
    0.64 ± 1.771
        Week 52: Copying (n=10,23)
    0.20 ± 0.438
    0.28 ± 0.502
    No statistical analyses for this end point

    Secondary: Change From Baseline of Age Equivalents for School Age of Core Subtests of the Differential Ability Scales, Second Edition (DAS-II) at Weeks 16, 28, 40 and 52

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    End point title
    		 Change From Baseline of Age Equivalents for School Age of Core Subtests of the Differential Ability Scales, Second Edition (DAS-II) at Weeks 16, 28, 40 and 52
    End point description
    The DAS-II was used to assess cognitive development in all randomized subjects. The school age battery is designed for children ages 7 years 0 months through 17 years 11 months. The higher score indicates greater cognitive ability. The subtest score represent a score (mean = 50 and standard deviation of 10) on which higher scores indicate a higher level of cognitive ability. A positive change value indicates improvement in cognitive ability. In the below table, "n" signifies subjects who were evaluable for the specified category, respectively and "99999" indicates that the standard deviation was not calculated due to less number of subjects. ITT population who have been evaluated by the DAS-II test for school age were analysed.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 16, Week 28, Week 40 and Week 52
    End point values
    		 No IT Treatment IT Treatment
    Number of subjects analysed
    1
    4
    Units: Score on a scale
    arithmetic mean (standard deviation)
        Week 16: Recall of Designs (n=1,2)
    -1.75 ± 99999
    1.00 ± 1.414
        Week 16: Word Definitions (n=1,2)
    1.50 ± 99999
    0.25 ± 0.707
        Week 16: Pattern Construction (n=1,2)
    1.00 ± 99999
    -0.13 ± 0.177
        Week 16: Matrices (n=1,2)
    -0.75 ± 99999
    0.38 ± 2.652
        Week 16: Verbal Similarities (n=1,2)
    0.75 ± 99999
    0.63 ± 0.884
        Week 16: SQR (n=1,2)
    1.17 ± 99999
    0.63 ± 0.884
        Week 28: Recall of Designs (n=1,1)
    -1.00 ± 99999
    0.00 ± 99999
        Week 28: Word Definitions (n=1,1)
    1.50 ± 99999
    -0.25 ± 99999
        Week 28: Pattern Construction (n=1,1)
    1.50 ± 99999
    -1.75 ± 99999
        Week 28: Matrices (n=1,1)
    -2.50 ± 99999
    0.00 ± 99999
        Week 28: Verbal Similarities (n=1,1)
    0.75 ± 99999
    0.00 ± 99999
        Week 28: SQR (n=1,1)
    0.25 ± 99999
    0.75 ± 99999
        Week 40: Recall of Designs (n=1,1)
    -2.00 ± 99999
    0.00 ± 99999
        Week 40: Word Definitions (n=1,1)
    1.50 ± 99999
    -0.25 ± 99999
        Week 40: Pattern Construction (n=1,1)
    1.92 ± 99999
    0.00 ± 99999
        Week 40: Matrices (n=1,1)
    -2.25 ± 99999
    1.25 ± 99999
        Week 40: Verbal Similarities (n=1,1)
    0.75 ± 99999
    1.00 ± 99999
        Week 40: SQR (n=1,1)
    1.17 ± 99999
    1.00 ± 99999
        Week 52: Recall of Designs (n=1,1)
    -2.50 ± 99999
    0.00 ± 99999
        Week 52: Word Definitions (n=1,1)
    1.75 ± 99999
    -0.25 ± 99999
        Week 52: Pattern Construction (n=1,1)
    1.92 ± 99999
    -2.75 ± 99999
        Week 52: Matrices (n=1,1)
    -0.25 ± 99999
    0.00 ± 99999
        Week 52: Verbal Similarities (n=1,1)
    1.17 ± 99999
    0.00 ± 99999
        Week 52: SQR (n=1,1)
    0.67 ± 99999
    1.00 ± 99999
    No statistical analyses for this end point

    Secondary: Change From Baseline of Development Quotients for Early Age of Core Subtests of the Differential Ability Scales, Second Edition (DAS-II) at Weeks 16, 28, 40 and 52

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    End point title
    		 Change From Baseline of Development Quotients for Early Age of Core Subtests of the Differential Ability Scales, Second Edition (DAS-II) at Weeks 16, 28, 40 and 52
    End point description
    The DAS-II was used to assess cognitive development in all randomized subjects. The early years battery is designed for children ages 2 years 6 months through 6 years 11 months. The higher score indicates greater cognitive ability. The subtest score represent a score (mean = 50 and standard deviation of 10) on which higher scores indicate a higher level of cognitive ability. A positive change value indicates improvement in cognitive ability. In the below table, "n" signifies subjects who were evaluable for the specified category, respectively. ITT population who have been evaluated by the DAS-II test for early years were analysed.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 16, Week 28, Week 40 and Week 52
    End point values
    		 No IT Treatment IT Treatment
    Number of subjects analysed
    14
    32
    Units: Score on a scale
    arithmetic mean (standard deviation)
        Week 16: Verbal Comprehension (n=14,29)
    -5.91 ± 13.454
    -4.71 ± 12.990
        Week 16: Picture Similarities (n=14,29)
    -4.91 ± 16.959
    3.41 ± 19.157
        Week 16: Naming Vocabulary (n=14,29)
    -2.09 ± 7.758
    -5.44 ± 11.221
        Week 16: Pattern Construction (n=14,27)
    -7.79 ± 7.339
    -0.43 ± 9.213
        Week 16: Matrices (n=10,27)
    4.60 ± 30.134
    0.57 ± 24.054
        Week 16: Copying (n=10,27)
    -4.59 ± 4.206
    -4.15 ± 4.794
        Week 28: Verbal Comprehension (n=11,28)
    -14.05 ± 16.558
    -1.46 ± 15.790
        Week 28: Picture Similarities (n=11,28)
    -1.89 ± 17.409
    0.03 ± 14.733
        Week 28: Naming Vocabulary (n=11,28)
    -3.78 ± 6.970
    -3.76 ± 18.235
        Week 28: Pattern Construction (n=11,28)
    -11.95 ± 7.039
    -3.09 ± 10.708
        Week 28: Matrices (n=8,25)
    2.96 ± 18.576
    0.45 ± 34.931
        Week 28: Copying (n=8,25)
    -6.88 ± 5.759
    -6.66 ± 7.820
        Week 40: Verbal Comprehension (n=14,27)
    -15.40 ± 17.544
    -8.97 ± 11.618
        Week 40: Picture Similarities (n=14,27)
    -6.86 ± 19.775
    -3.11 ± 20.029
        Week 40: Naming Vocabulary (n=14,27)
    -10.02 ± 13.307
    -8.96 ± 14.427
        Week 40: Pattern Construction (n=14,27)
    -11.56 ± 6.989
    -3.89 ± 13.394
        Week 40: Matrices (n=10,24)
    -7.79 ± 24.750
    -5.73 ± 32.283
        Week 40: Copying (n=10,24)
    -6.15 ± 9.533
    -7.69 ± 11.208
        Week 52: Verbal Comprehension (n=14,27)
    -14.49 ± 22.614
    -8.59 ± 13.473
        Week 52: Picture Similarities (n=14,27)
    -8.32 ± 19.393
    0.56 ± 22.325
        Week 52: Naming Vocabulary (n=14,27)
    -10.29 ± 13.522
    -8.20 ± 18.543
        Week 52: Pattern Construction (n=14,27)
    -13.59 ± 8.232
    -8.49 ± 11.528
        Week 52: Matrices (n=10,24)
    -12.47 ± 23.892
    -5.53 ± 32.584
        Week 52: Copying (n=10,23)
    -10.19 ± 9.608
    -10.34 ± 10.429
    No statistical analyses for this end point

    Secondary: Change From Baseline of Development Quotients for School Age of Core Subtests of the Differential Ability Scales, Second Edition (DAS-II) at Weeks 16, 28, 40 and 52

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    End point title
    		 Change From Baseline of Development Quotients for School Age of Core Subtests of the Differential Ability Scales, Second Edition (DAS-II) at Weeks 16, 28, 40 and 52
    End point description
    The DAS-II was used to assess cognitive development in all randomized subjects. The school age battery is designed for children ages 7 years 0 months through 17 years 11 months. The higher score indicates greater cognitive ability. The subtest score represent a score (mean = 50 and standard deviation of 10) on which higher scores indicate a higher level of cognitive ability. A positive change value indicates improvement in cognitive ability. In the below table, "n" signifies subjects who were evaluable for the specified category, respectively and "99999" indicates that the standard deviation was not calculated due to less number of subjects. ITT population who have been evaluated by the DAS-II test for school age were analysed.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 16, Week 28, Week 40 and Week 52
    End point values
    		 No IT Treatment IT Treatment
    Number of subjects analysed
    1
    4
    Units: Score on a scale
    arithmetic mean (standard deviation)
        Week 16: Recall of Designs (n=1,2)
    -15.10 ± 99999
    9.20 ± 17.395
        Week 16: Word Definitions (n=1,2)
    9.60 ± 99999
    0.00 ± 9.192
        Week 16: Pattern Construction (n=1,2)
    5.70 ± 99999
    -4.85 ± 2.051
        Week 16: Matrices (n=1,2)
    -7.60 ± 99999
    2.40 ± 33.800
        Week 16: Verbal Similarities (n=1,2)
    3.70 ± 99999
    4.65 ± 10.960
        Week 16: SQR (n=1,2)
    6.70 ± 99999
    4.50 ± 10.748
        Week 28: Recall of Designs (n=1,1)
    -10.40 ± 99999
    -4.80 ± 99999
        Week 28: Word Definitions (n=1,1)
    8.70 ± 99999
    -8.20 ± 99999
        Week 28: Pattern Construction (n=1,1)
    8.40 ± 99999
    -26.90 ± 99999
        Week 28: Matrices (n=1,1)
    -21.40 ± 99999
    -3.40 ± 99999
        Week 28: Verbal Similarities (n=1,1)
    2.60 ± 99999
    -4.80 ± 99999
        Week 28: SQR (n=1,1)
    -1.20 ± 99999
    4.40 ± 99999
        Week 40: Recall of Designs (n=1,1)
    -18.70 ± 99999
    -6.50 ± 99999
        Week 40: Word Definitions (n=1,1)
    7.50 ± 99999
    -9.90 ± 99999
        Week 40: Pattern Construction (n=1,1)
    10.20 ± 99999
    -7.20 ± 99999
        Week 40: Matrices (n=1,1)
    -20.50 ± 99999
    10.40 ± 99999
        Week 40: Verbal Similarities (n=1,1)
    1.40 ± 99999
    5.50 ± 99999
        Week 40: SQR (n=1,1)
    4.20 ± 99999
    5.50 ± 99999
        Week 52: Recall of Designs (n=1,1)
    -22.90 ± 99999
    -8.10 ± 99999
        Week 52: Word Definitions (n=1,1)
    8.40 ± 99999
    -11.50 ± 99999
        Week 52: Pattern Construction (n=1,1)
    9.20 ± 99999
    -41.00 ± 99999
        Week 52: Matrices (n=1,1)
    -6.90 ± 99999
    -5.70 ± 99999
        Week 52: Verbal Similarities (n=1,1)
    3.40 ± 99999
    -8.10 ± 99999
        Week 52: SQR (n=1,1)
    -0.40 ± 99999
    3.60 ± 99999
    No statistical analyses for this end point

    Secondary: Change From Baseline of T-scores for Early Age of Core Subtests of the Differential Ability Scale, Second Edition (DAS-II) at Weeks 16, 28, 40 and 52

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    End point title
    		 Change From Baseline of T-scores for Early Age of Core Subtests of the Differential Ability Scale, Second Edition (DAS-II) at Weeks 16, 28, 40 and 52
    End point description
    The DAS-II was used to assess cognitive development in all randomized subjects. The early years battery is designed for children ages 2 years 6 months through 6 years 11 months. The higher score indicates greater cognitive ability. The subtest score represent a score (mean = 50 and standard deviation of 10) on which higher scores indicate a higher level of cognitive ability. A positive change value indicates improvement in cognitive ability. In the below table, "n" signifies subjects who were evaluable for the specified category, respectively. ITT population who have been evaluated by the DAS-II test for early years were analysed.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 16, Week 28, Week 40 and Week 52
    End point values
    		 No IT Treatment IT Treatment
    Number of subjects analysed
    14
    32
    Units: Score on a scale
    arithmetic mean (standard deviation)
        Week 16: Verbal Comprehension (n=14,29)
    -1.7 ± 7.27
    -3.6 ± 9.30
        Week 16: Picture Similarities (n=14,29)
    -2.3 ± 9.62
    2.1 ± 9.10
        Week 16: Naming Vocabulary (n=14,29)
    -0.1 ± 6.01
    -2.4 ± 6.21
        Week 16: Pattern Construction (n=14,27)
    -6.4 ± 6.01
    0.6 ± 8.77
        Week 16: Matrices (n=10,27)
    -4.3 ± 17.73
    0.4 ± 14.65
        Week 16: Copying (n=10,27)
    -2.2 ± 8.48
    -0.5 ± 8.76
        Week 28: Verbal Comprehension (n=11,28)
    -2.2 ± 10.32
    -1.8 ± 11.33
        Week 28: Picture Similarities (n=11,28)
    2.6 ± 7.97
    0.3 ± 6.28
        Week 28: Naming Vocabulary (n=11,28)
    -0.3 ± 4.13
    -2.0 ± 7.79
        Week 28: Pattern Construction (n=11,28)
    -8.9 ± 5.36
    -1.5 ± 9.74
        Week 28: Matrices (n=8,25)
    2.9 ± 6.47
    0.6 ± 16.09
        Week 28: Copying (n=8,25)
    -0.9 ± 6.36
    -1.6 ± 11.26
        Week 40: Verbal Comprehension (n=14,27)
    -4.9 ± 8.21
    -3.4 ± 6.55
        Week 40: Picture Similarities (n=14,27)
    0.1 ± 13.04
    -2.0 ± 9.81
        Week 40: Naming Vocabulary (n=14,27)
    -4.4 ± 9.69
    -3.9 ± 7.54
        Week 40: Pattern Construction (n=14,27)
    -8.7 ± 5.78
    -2.6 ± 11.24
        Week 40: Matrices (n=10,24)
    -7.4 ± 16.87
    -3.2 ± 16.71
        Week 40: Copying (n=10,24)
    -1.8 ± 11.39
    -0.1 ± 12.69
        Week 52: Verbal Comprehension (n=14,27)
    -4.6 ± 11.21
    -4.9 ± 11.10
        Week 52: Picture Similarities (n=14,27)
    -1.7 ± 15.41
    0.3 ± 10.44
        Week 52: Naming Vocabulary (n=14,27)
    -2.7 ± 8.59
    -3.2 ± 8.54
        Week 52: Pattern Construction (n=14,27)
    -10.9 ± 8.03
    -6.1 ± 10.90
        Week 52: Matrices (n=10,24)
    -8.5 ± 15.52
    -0.8 ± 17.00
        Week 52: Copying (n=10,23)
    -4.0 ± 10.68
    -2.4 ± 12.07
    No statistical analyses for this end point

    Secondary: Change From Baseline of T-scores for School Age of Core Subtests of the Differential Ability Scale, Second Edition (DAS-II) at Weeks 16, 28, 40 and 52

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    End point title
    		 Change From Baseline of T-scores for School Age of Core Subtests of the Differential Ability Scale, Second Edition (DAS-II) at Weeks 16, 28, 40 and 52
    End point description
    The DAS-II was used to assess cognitive development in all randomized subjects. The school age battery is designed for children ages 7 years 0 months through 17 years 11 months. The higher score indicates greater cognitive ability. The subtest score represent a score (mean = 50 and standard deviation of 10) on which higher scores indicate a higher level of cognitive ability. A positive change value indicates improvement in cognitive ability. In the below table, "n" signifies subjects who were evaluable for the specified category, respectively and "99999" indicates that the standard deviation was not calculated due to less number of subjects. ITT population who have been evaluated by the DAS-II test for school age were analysed.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 16, Week 28, Week 40 and Week 52
    End point values
    		 No IT Treatment IT Treatment
    Number of subjects analysed
    1
    4
    Units: Score on a scale
    arithmetic mean (standard deviation)
        Week 16: Recall of Designs (n=1,2)
    -10.0 ± 99999
    5.0 ± 12.73
        Week 16: Word Definitions (n=1,2)
    7.0 ± 99999
    -0.5 ± 7.78
        Week 16: Pattern Construction (n=1,2)
    3.0 ± 99999
    -2.0 ± 1.41
        Week 16: Matrices (n=1,2)
    -5.0 ± 99999
    -0.5 ± 12.02
        Week 16: Verbal Similarities (n=1,2)
    4.0 ± 99999
    -4.0 ± 8.49
        Week 16: SQR (n=1,2)
    2.0 ± 99999
    3.0 ± 2.83
        Week 28: Recall of Designs (n=1,1)
    -7.0 ± 99999
    10.0 ± 99999
        Week 28: Word Definitions (n=1,1)
    5.0 ± 99999
    -8.0 ± 99999
        Week 28: Pattern Construction (n=1,1)
    4.0 ± 99999
    -19.0 ± 99999
        Week 28: Matrices (n=1,1)
    -12.0 ± 99999
    -9.0 ± 99999
        Week 28: Verbal Similarities (n=1,1)
    3.0 ± 99999
    -10.0 ± 99999
        Week 28: SQR (n=1,1)
    -2.0 ± 99999
    9.0 ± 99999
        Week 40: Recall of Designs (n=1,1)
    -14.0 ± 99999
    -4.0 ± 99999
        Week 40: Word Definitions (n=1,1)
    5.0 ± 99999
    -16.0 ± 99999
        Week 40: Pattern Construction (n=1,1)
    5.0 ± 99999
    -3.0 ± 99999
        Week 40: Matrices (n=1,1)
    -11.0 ± 99999
    1.0 ± 99999
        Week 40: Verbal Similarities (n=1,1)
    2.0 ± 99999
    1.0 ± 99999
        Week 40: SQR (n=1,1)
    1.0 ± 99999
    10.0 ± 99999
        Week 52: Recall of Designs (n=1,1)
    -17.0 ± 99999
    -4.0 ± 99999
        Week 52: Word Definitions (n=1,1)
    6.0 ± 99999
    -17.0 ± 99999
        Week 52: Pattern Construction (n=1,1)
    4.0 ± 99999
    -30.0 ± 99999
        Week 52: Matrices (n=1,1)
    -4.0 ± 99999
    -5.0 ± 99999
        Week 52: Verbal Similarities (n=1,1)
    5.0 ± 99999
    -10.0 ± 99999
        Week 52: SQR (n=1,1)
    -2.0 ± 99999
    9.0 ± 99999
    No statistical analyses for this end point

    Secondary: Change From Baseline of Age Equivalents Scores of Sub-domains of the Vineland Adaptive Behavior Scales, Second Edition (VABS-II) at Weeks 16, 28, 40 and 52

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    End point title
    		 Change From Baseline of Age Equivalents Scores of Sub-domains of the Vineland Adaptive Behavior Scales, Second Edition (VABS-II) at Weeks 16, 28, 40 and 52
    End point description
    The VABS-II test measures adaptive behaviors, including the ability to cope with environmental changes, to learn new everyday skills, and to demonstrate independence. The standard scores represent a score (mean = 100 and standard deviation of 15) on which higher scores indicate a higher level of cognitive ability. A positive change value indicates improvement in adaptive functioning. In the below table, "IR" indicates interpersonal relationship; "PLT" indicates play and leisure time and "DLS" indicates daily living skills. In the below table, "n" signifies subjects who were evaluable for the specified category, respectively. ITT population included all randomized subjects.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 16, Week 28, Week 40 and Week 52
    End point values
    		 No IT Treatment IT Treatment
    Number of subjects analysed
    15
    34
    Units: Score on a scale
    arithmetic mean (standard deviation)
        Week 16: Communication- Expressive (n=15,33)
    0.09 ± 0.512
    0.12 ± 0.544
        Week 16: Communication- Receptive (n=15,33)
    -0.09 ± 1.020
    -0.32 ± 1.845
        Week 16: Communication- Written (n=15,33)
    0.08 ± 0.406
    0.02 ± 0.572
        Week 16: DLS- Community (n=15,33)
    0.16 ± 0.583
    0.05 ± 0.710
        Week 16: DLS- Domestic (n=15,33)
    0.02 ± 1.477
    -0.09 ± 1.149
        Week 16: DLS- Personal (n=15,33)
    -0.23 ± 0.864
    -0.11 ± 0.599
        Week 16: Socialization- Coping Skills (n=15,32)
    -0.16 ± 0.712
    -0.09 ± 0.792
        Week 16: Socialization- IR (n=15,33)
    -0.09 ± 0.749
    0.04 ± 0.637
        Week 16: Socialization- PLT (n=15,33)
    0.21 ± 0.934
    0.11 ± 0.783
        Week 16: Motor Skills- Fine (n=12,27)
    0.30 ± 0.499
    0.29 ± 0.429
        Week 16: Motor Skills- Gross (n=12,28)
    0.17 ± 0.607
    0.36 ± 0.736
        Week 28: Communication- Expressive (n=15,30)
    0.28 ± 0.669
    0.36 ± 0.806
        Week 28: Communication- Receptive (n=15,30)
    0.83 ± 2.393
    0.44 ± 1.333
        Week 28: Communication- Written (n=15,30)
    0.21 ± 0.663
    0.18 ± 0.525
        Week 28: DLS- Community (n=15,30)
    0.22 ± 0.701
    0.26 ± 0.762
        Week 28: DLS- Domestic (n=15,30)
    0.67 ± 1.481
    0.34 ± 1.326
        Week 28: DLS- Personal (n=15,30)
    0.48 ± 1.260
    0.16 ± 0.544
        Week 28: Socialization- Coping Skills (n=15,30)
    0.29 ± 0.731
    0.27 ± 0.982
        Week 28: Socialization- IR (n=15,30)
    0.07 ± 0.884
    0.43 ± 0.876
        Week 28: Socialization- PLT (n=15,30)
    0.62 ± 0.818
    0.51 ± 1.017
        Week 28: Motor Skills- Fine (n=12,25)
    0.30 ± 0.403
    0.37 ± 0.533
        Week 28: Motor Skills- Gross (n=12,26)
    0.41 ± 0.588
    0.82 ± 1.061
        Week 40: Communication- Expressive (n=15,32)
    0.28 ± 0.679
    0.30 ± 0.764
        Week 40: Communication- Receptive (n=15,32)
    0.80 ± 2.388
    -0.07 ± 2.015
        Week 40: Communication- Written (n=14,32)
    0.30 ± 0.699
    0.00 ± 0.740
        Week 40: DLS- Community (n=15,31)
    0.38 ± 0.640
    0.02 ± 0.760
        Week 40: DLS- Domestic (n=15,32)
    0.72 ± 1.542
    0.39 ± 1.420
        Week 40: DLS- Personal (n=15,32)
    0.18 ± 0.720
    0.29 ± 0.587
        Week 40: Socialization- Coping Skills (n=15,32)
    0.14 ± 1.178
    0.26 ± 1.581
        Week 40: Socialization- IR (n=15,32)
    0.05 ± 0.796
    0.10 ± 0.973
        Week 40: Socialization- PLT (n=15,32)
    0.44 ± 0.808
    0.31 ± 0.921
        Week 40: Motor Skills- Fine (n=12,26)
    0.44 ± 0.453
    0.44 ± 0.640
        Week 40: Motor Skills- Gross (n=12,27)
    0.33 ± 0.662
    0.73 ± 0.990
        Week 52: Communication- Expressive (n=15,32)
    0.32 ± 0.973
    0.34 ± 0.858
        Week 52: Communication- Receptive (n=15,32)
    1.25 ± 2.253
    -0.05 ± 1.953
        Week 52: Communication- Written (n=15,32)
    0.16 ± 0.485
    0.11 ± 0.783
        Week 52: DLS- Community (n=14,32)
    0.36 ± 0.603
    0.30 ± 0.941
        Week 52: DLS- Domestic (n=15,32)
    0.27 ± 1.678
    0.37 ± 1.405
        Week 52: DLS- Personal (n=15,32)
    0.42 ± 0.572
    0.35 ± 0.840
        Week 52: Socialization- Coping Skills (n=15,32)
    0.29 ± 1.211
    0.31 ± 1.189
        Week 52: Socialization- IR (n=15,32)
    0.00 ± 0.752
    0.36 ± 1.005
        Week 52: Socialization- PLT (n=15,32)
    0.67 ± 1.446
    0.45 ± 0.839
        Week 52: Motor Skills- Fine (n=12,26)
    0.38 ± 0.365
    0.58 ± 0.645
        Week 52: Motor Skills- Gross (n=12,27)
    0.25 ± 0.773
    0.93 ± 1.008
    No statistical analyses for this end point

    Secondary: Change From Baseline of Development Quotients of Sub-domains of the Vineland Adaptive Behavior Scales, Second Edition (VABS-II) at Weeks 16, 28, 40 and 52

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    End point title
    		 Change From Baseline of Development Quotients of Sub-domains of the Vineland Adaptive Behavior Scales, Second Edition (VABS-II) at Weeks 16, 28, 40 and 52
    End point description
    The VABS-II test measures adaptive behaviors, including the ability to cope with environmental changes, to learn new everyday skills, and to demonstrate independence. The standard scores represent a score (mean = 100 and standard deviation of 15) on which higher scores indicate a higher level of cognitive ability. A positive change value indicates improvement in adaptive functioning. In the below table, "IR" indicates interpersonal relationship; "PLT" indicates play and leisure time and "DLS" indicates daily living skills. In the below table, "n" signifies subjects who were evaluable for the specified category, respectively. ITT population included all randomized subjects.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 16, Week 28, Week 40 and Week 52
    End point values
    		 No IT Treatment IT Treatment
    Number of subjects analysed
    15
    34
    Units: Score on a scale
    arithmetic mean (standard deviation)
        Week 16: Communication- Expressive (n=15,33)
    -1.09 ± 7.866
    -2.57 ± 11.781
        Week 16: Communication- Receptive (n=15,33)
    -2.58 ± 14.735
    -8.19 ± 26.774
        Week 16: Communication- Written (n=15,33)
    -4.10 ± 8.727
    -5.62 ± 12.554
        Week 16: DLS- Community (n=15,33)
    -0.37 ± 12.814
    -4.48 ± 15.498
        Week 16: DLS- Domestic (n=15,33)
    -2.80 ± 30.338
    -7.18 ± 24.610
        Week 16: DLS- Personal (n=15,33)
    -9.94 ± 21.052
    -6.35 ± 11.185
        Week 16: Socialization- Coping Skills (n=15,32)
    -9.08 ± 14.414
    -6.56 ± 15.923
        Week 16: Socialization- IR (n=15,33)
    -3.87 ± 9.602
    -3.17 ± 14.610
        Week 16: Socialization- PLT (n=15,33)
    1.66 ± 18.903
    -0.64 ± 15.366
        Week 16: Motor Skills- Fine (n=12,27)
    0.48 ± 12.969
    0.00 ± 10.308
        Week 16: Motor Skills- Gross (n=12,28)
    -3.92 ± 15.524
    1.28 ± 15.410
        Week 28: Communication- Expressive (n=15,30)
    -0.23 ± 11.301
    -0.59 ± 14.480
        Week 28: Communication- Receptive (n=15,30)
    3.30 ± 24.423
    0.50 ± 17.058
        Week 28: Communication- Written (n=15,30)
    -5.15 ± 13.510
    -6.54 ± 11.339
        Week 28: DLS- Community (n=15,30)
    -3.07 ± 13.984
    -2.80 ± 15.937
        Week 28: DLS- Domestic (n=15,30)
    6.75 ± 28.703
    -3.37 ± 25.635
        Week 28: DLS- Personal (n=15,30)
    3.41 ± 26.699
    -4.27 ± 12.124
        Week 28: Socialization- Coping Skills (n=15,30)
    -4.88 ± 15.881
    -2.45 ± 19.142
        Week 28: Socialization- IR (n=15,30)
    -2.30 ± 13.889
    2.16 ± 17.844
        Week 28: Socialization- PLT (n=15,30)
    8.17 ± 17.767
    4.49 ± 20.413
        Week 28: Motor Skills- Fine (n=12,25)
    -2.86 ± 9.014
    -2.05 ± 12.124
        Week 28: Motor Skills- Gross (n=12,26)
    -3.05 ± 15.068
    7.78 ± 21.604
        Week 40: Communication- Expressive (n=15,32)
    -2.35 ± 10.521
    -3.74 ± 12.846
        Week 40: Communication- Receptive (n=15,32)
    0.31 ± 22.511
    -8.32 ± 29.716
        Week 40: Communication- Written (n=14,32)
    -5.39 ± 14.066
    -13.31 ± 15.173
        Week 40: DLS- Community (n=15,31)
    -2.29 ± 13.856
    -9.72 ± 15.988
        Week 40: DLS- Domestic (n=15,32)
    4.40 ± 27.464
    -4.53 ± 27.189
        Week 40: DLS- Personal (n=15,32)
    -5.54 ± 14.516
    -4.33 ± 11.630
        Week 40: Socialization- Coping Skills (n=15,32)
    -11.75 ± 18.650
    -7.31 ± 22.758
        Week 40: Socialization- IR (n=15,32)
    -5.47 ± 13.597
    -6.38 ± 18.307
        Week 40: Socialization- PLT (n=15,32)
    1.83 ± 18.194
    -1.20 ± 19.009
        Week 40: Motor Skills- Fine (n=12,26)
    -3.51 ± 10.891
    -4.04 ± 14.407
        Week 40: Motor Skills- Gross (n=12,27)
    -9.01 ± 18.404
    1.75 ± 18.235
        Week 52: Communication- Expressive (n=15,32)
    -4.87 ± 13.094
    -5.22 ± 14.616
        Week 52: Communication- Receptive (n=15,32)
    5.58 ± 18.225
    -10.14 ± 29.190
        Week 52: Communication- Written (n=15,32)
    -11.22 ± 10.973
    -13.90 ± 16.079
        Week 52: DLS- Community (n=14,32)
    -6.46 ± 13.154
    -7.10 ± 18.149
        Week 52: DLS- Domestic (n=15,32)
    -6.81 ± 28.704
    -8.64 ± 27.817
        Week 52: DLS- Personal (n=15,32)
    -3.64 ± 11.626
    -5.79 ± 15.032
        Week 52: Socialization- Coping Skills (n=15,32)
    -11.26 ± 19.505
    -6.54 ± 20.142
        Week 52: Socialization- IR (n=15,32)
    -8.53 ± 12.960
    -4.46 ± 17.892
        Week 52: Socialization- PLT (n=15,32)
    1.95 ± 25.499
    -0.83 ± 15.499
        Week 52: Motor Skills- Fine (n=12,26)
    -8.58 ± 8.790
    -4.67 ± 15.370
        Week 52: Motor Skills- Gross (n=12,27)
    -14.54 ± 21.617
    2.46 ± 18.655
    No statistical analyses for this end point

    Secondary: Change From Baseline of V-Scale Scores of Sub-domains of the Vineland Adaptive Behavior Scales, Second Edition (VABS-II) at Weeks 16, 28, 40 and 52

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    End point title
    		 Change From Baseline of V-Scale Scores of Sub-domains of the Vineland Adaptive Behavior Scales, Second Edition (VABS-II) at Weeks 16, 28, 40 and 52
    End point description
    The VABS-II test measures adaptive behaviors, including the ability to cope with environmental changes, to learn new everyday skills, and to demonstrate independence. This test measures the following 5 key domains: communication, daily living skills, socialization, motor skills, and the adaptive behavior composite (a composite of the other 4 domains). The V-scale scores represent a score (mean = 15 and standard deviation of 3; range: 1-24) on which higher scores indicate a higher level of adaptive functioning. A positive change value indicates improvement in adaptive functioning. In the below table, "IR" indicates interpersonal relationship; "PLT" indicates play and leisure time and "DLS" indicates daily living skills. In the below table, "n" signifies subjects who were evaluable for the specified category, respectively. ITT population included all randomized subjects.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 16, Week 28, Week 40 and Week 52
    End point values
    		 No IT Treatment IT Treatment
    Number of subjects analysed
    15
    34
    Units: Score on a scale
    arithmetic mean (standard deviation)
        Week 16: Communication- Expressive (n=15,33)
    -0.1 ± 1.81
    -0.4 ± 2.05
        Week 16: Communication- Receptive (n=15,33)
    -0.3 ± 1.84
    -0.7 ± 1.85
        Week 16: Communication- Written (n=15,33)
    -0.7 ± 1.83
    -1.1 ± 2.87
        Week 16: DLS- Community (n=15,33)
    -0.3 ± 1.28
    -0.7 ± 2.05
        Week 16: DLS- Domestic (n=15,33)
    -0.3 ± 2.61
    -0.7 ± 1.93
        Week 16: DLS- Personal (n=15,33)
    -1.2 ± 3.23
    -1.2 ± 2.34
        Week 16: Socialization- Coping Skills (n=15,32)
    -0.6 ± 1.80
    -0.4 ± 1.46
        Week 16: Socialization- IR (n=15,33)
    -0.5 ± 1.46
    -0.3 ± 1.55
        Week 16: Socialization- PLT (n=15,33)
    0.2 ± 2.37
    -0.4 ± 1.62
        Week 16: Motor Skills- Fine (n=12,27)
    0.3 ± 1.36
    -0.1 ± 1.33
        Week 16: Motor Skills- Gross (n=12,28)
    -0.3 ± 1.61
    0.0 ± 2.00
        Week 28: Communication- Expressive (n=15,30)
    0.0 ± 2.00
    -0.3 ± 2.20
        Week 28: Communication- Receptive (n=15,30)
    -0.1 ± 2.40
    -0.1 ± 1.17
        Week 28: Communication- Written (n=15,30)
    -0.6 ± 2.41
    -1.2 ± 2.04
        Week 28: DLS- Community (n=15,30)
    -0.7 ± 1.75
    -0.7 ± 1.95
        Week 28: DLS- Domestic (n=15,30)
    0.4 ± 2.75
    -0.4 ± 2.11
        Week 28: DLS- Personal (n=15,30)
    0.6 ± 3.50
    -0.6 ± 2.21
        Week 28: Socialization- Coping Skills (n=15,30)
    0.1 ± 1.51
    -0.2 ± 1.43
        Week 28: Socialization- IR (n=15,30)
    -0.4 ± 1.84
    0.1 ± 1.49
        Week 28: Socialization- PLT (n=15,30)
    1.1 ± 2.03
    0.2 ± 2.04
        Week 28: Motor Skills- Fine (n=12,25)
    -0.3 ± 1.06
    -0.3 ± 1.62
        Week 28: Motor Skills- Gross (n=12,26)
    -0.2 ± 2.33
    0.5 ± 2.06
        Week 40: Communication- Expressive (n=15,32)
    0.0 ± 1.85
    -0.8 ± 1.76
        Week 40: Communication- Receptive (n=15,32)
    -0.2 ± 2.08
    -0.7 ± 2.07
        Week 40: Communication- Written (n=14,32)
    -0.9 ± 2.59
    -2.6 ± 3.05
        Week 40: DLS- Community (n=15,31)
    -0.6 ± 1.59
    -1.6 ± 1.91
        Week 40: DLS- Domestic (n=15,32)
    0.3 ± 2.72
    -0.7 ± 2.66
        Week 40: DLS- Personal (n=15,32)
    -0.6 ± 2.69
    -0.5 ± 2.09
        Week 40: Socialization- Coping Skills (n=15,32)
    -0.6 ± 1.96
    -0.8 ± 1.80
        Week 40: Socialization- IR (n=15,32)
    -0.8 ± 1.70
    -0.9 ± 1.72
        Week 40: Socialization- PLT (n=15,32)
    0.5 ± 2.10
    -0.4 ± 2.24
        Week 40: Motor Skills- Fine (n=12,26)
    -0.3 ± 1.56
    -0.5 ± 1.79
        Week 40: Motor Skills- Gross (n=12,27)
    -0.8 ± 1.90
    -0.1 ± 2.23
        Week 52: Communication- Expressive (n=15,32)
    -0.5 ± 1.88
    -1.0 ± 2.44
        Week 52: Communication- Receptive (n=15,32)
    0.1 ± 2.00
    -0.9 ± 2.08
        Week 52: Communication- Written (n=15,32)
    -2.1 ± 2.09
    -3.0 ± 3.25
        Week 52: DLS- Community (n=14,32)
    -1.5 ± 1.70
    -1.6 ± 2.46
        Week 52: DLS- Domestic (n=15,32)
    -0.5 ± 2.77
    -0.7 ± 2.40
        Week 52: DLS- Personal (n=15,32)
    -0.1 ± 1.85
    -0.9 ± 2.76
        Week 52: Socialization- Coping Skills (n=15,32)
    -0.7 ± 1.80
    -0.5 ± 1.55
        Week 52: Socialization- IR (n=15,32)
    -1.0 ± 1.65
    -0.6 ± 1.81
        Week 52: Socialization- PLT (n=15,32)
    -0.1 ± 3.38
    -0.4 ± 2.00
        Week 52: Motor Skills- Fine (n=12,26)
    -1.1 ± 1.08
    -0.6 ± 2.06
        Week 52: Motor Skills- Gross (n=12,27)
    -1.5 ± 2.07
    -0.1 ± 2.35
    No statistical analyses for this end point

    Secondary: Change From Baseline of V-Scale Scores of Maladaptive Behavior Index and Its Sub-scales at Weeks 16, 28, 40 and 52

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    End point title
    		 Change From Baseline of V-Scale Scores of Maladaptive Behavior Index and Its Sub-scales at Weeks 16, 28, 40 and 52
    End point description
    The VABS-II test measures adaptive behaviors, including the ability to cope with environmental changes, to learn new everyday skills, and to demonstrate independence. Maladaptive behavior index is a composite of the internalizing, externalizing, and other types of undesirable behavior that may interfere with the individual’s adaptive functioning. The V-scale scores represent a score (mean = 15 and standard deviation of 3; range: 1-24) on which higher scores indicate a higher level of cognitive ability. A positive change value indicates improvement in adaptive functioning. In the below table, "MBI " indicates Maladaptive Behavior Index, "n" signifies subjects who were evaluable for the specified category, respectively. ITT population included all randomized subjects.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 16, Week 28, Week 40 and Week 52
    End point values
    		 No IT Treatment IT Treatment
    Number of subjects analysed
    15
    34
    Units: Score on a scale
    arithmetic mean (standard deviation)
        Week 16: MBI (n=12,31)
    0.3 ± 1.14
    -0.2 ± 1.18
        Week 16: MBI- Internalizing (n=14,32)
    0.1 ± 2.37
    -0.3 ± 2.31
        Week 16: MBI- Externalizing (n=13,31)
    0.5 ± 1.71
    0.0 ± 1.53
        Week 28: MBI (n=14,28)
    0.3 ± 0.91
    -0.3 ± 1.27
        Week 28: MBI- Internalizing (n=14,29)
    -0.4 ± 1.60
    -0.8 ± 2.11
        Week 28: MBI- Externalizing (n=14,28)
    0.6 ± 1.34
    -0.1 ± 2.01
        Week 40: MBI (n=14,31)
    -0.5 ± 1.40
    -0.3 ± 1.13
        Week 40: MBI- Internalizing (n=14,31)
    -1.0 ± 2.57
    -0.7 ± 2.98
        Week 40: MBI- Externalizing (n=14,31)
    -0.1 ± 1.64
    -0.1 ± 1.29
        Week 52: MBI (n=14,31)
    -0.5 ± 1.45
    -0.5 ± 1.41
        Week 52: MBI- Internalizing (n=14,31)
    -1.1 ± 1.96
    -0.9 ± 2.72
        Week 52: MBI- Externalizing (n=14,31)
    -0.4 ± 2.27
    -0.2 ± 1.69
    No statistical analyses for this end point

    Secondary: Observed Maladaptive Levels of Maladaptive Behavior Index and Its Sub-scales of Vineland Adaptive Behavior Scales, Second Edition (VABS-II)

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    End point title
    		 Observed Maladaptive Levels of Maladaptive Behavior Index and Its Sub-scales of Vineland Adaptive Behavior Scales, Second Edition (VABS-II)
    End point description
    The VABS-II test measures adaptive behaviors, including the ability to cope with environmental changes, to learn new everyday skills, and to demonstrate independence. Maladaptive behavior index is a composite of the internalizing, externalizing, and other types of undesirable behavior that may interfere with the individual’s adaptive functioning. The V-scale scores represent a score (mean = 15 and standard deviation of 3; range: 1-24) on which higher scores indicate a higher level of cognitive ability. A positive change value indicates improvement in adaptive functioning. In the below table, "MBI " indicates Maladaptive Behavior Index.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 16, Week 28, Week 40 and Week 52
    End point values
    		 No IT Treatment IT Treatment
    Number of subjects analysed
    15
    34
    Units: Subject
        Baseline: MBI- Average
    7
    8
        Baseline: MBI- Elevated
    5
    20
        Baseline: MBI- Clinically Significant
    2
    5
        Baseline: Internalizing- Average
    7
    15
        Baseline: Internalizing- Elevated
    4
    11
        Baseline: Internalizing- Clinically Significant
    3
    7
        Baseline: Externalizing- Average
    8
    11
        Baseline: Externalizing- Elevated
    5
    19
        Baseline: Externalizing- Clinically Significant
    1
    3
        Week 16: MBI- Average
    4
    9
        Week 16: MBI- Elevated
    8
    17
        Week 16: MBI- Clinically Significant
    1
    6
        Week 16: Internalizing- Average
    7
    19
        Week 16: Internalizing- Elevated
    6
    9
        Week 16: Internalizing- Clinically Significant
    2
    5
        Week 16: Externalizing- Average
    7
    13
        Week 16: Externalizing- Elevated
    7
    14
        Week 16: Externalizing- Clinically Significant
    0
    5
        Week 28: MBI- Average
    7
    8
        Week 28: MBI- Elevated
    7
    16
        Week 28: MBI- Clinically Significant
    1
    5
        Week 28: Internalizing- Average
    9
    18
        Week 28: Internalizing- Elevated
    6
    10
        Week 28: Internalizing- Clinically Significant
    0
    2
        Week 28: Externalizing- Average
    10
    11
        Week 28: Externalizing- Elevated
    5
    14
        Week 28: Externalizing- Clinically Significant
    0
    4
        Week 40: MBI- Average
    7
    7
        Week 40: MBI- Elevated
    8
    21
        Week 40: MBI- Clinically Significant
    0
    4
        Week 40: Internalizing- Average
    9
    20
        Week 40: Internalizing- Elevated
    6
    10
        Week 40: Internalizing- Clinically Significant
    0
    2
        Week 40: Externalizing- Average
    9
    12
        Week 40: Externalizing- Elevated
    6
    18
        Week 40: Externalizing- Clinically Significant
    0
    2
        Week 52: MBI- Average
    9
    10
        Week 52: MBI- Elevated
    6
    18
        Week 52: MBI- Clinically Significant
    0
    4
        Week 52: Internalizing- Average
    11
    20
        Week 52: Internalizing- Elevated
    4
    9
        Week 52: Internalizing- Clinically Significant
    0
    3
        Week 52: Externalizing- Average
    10
    15
        Week 52: Externalizing- Elevated
    5
    15
        Week 52: Externalizing- Clinically Significant
    0
    2
    No statistical analyses for this end point

    Secondary: Maximum Observed Drug Concentration (Cmax) of Idursulfase After IT administration

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    End point title
    		 Maximum Observed Drug Concentration (Cmax) of Idursulfase After IT administration [1]
    End point description
    The Cmax of idursulfase after IT administration was reported. In the below table, "n" signifies subjects who were evaluable for the specified category, respectively. Pharmacokinetic (PK) population included all subjects who received investigational product and participated in the scheduled PK studies, and for whom at least 1 post-dose PK blood sample was collected.
    End point type
    Secondary
    End point timeframe
    Pre-dose, 30, 60, 120 minutes, 4, 6, 8, 12, 24, 30 and 36 hour (h) post-dose on Weeks 4, 24, and 48
    Notes
    [1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Pharmacokinetic parameters were evaluated only for subjects who received active study medication.
    End point values
    		 IT Treatment
    Number of subjects analysed
    24
    Units: Nanogram per milliliter (ng/mL)
    arithmetic mean (standard deviation)
        Week 4 (n=24)
    253.44 ± 686.569
        Week 24 (n=22)
    132.87 ± 147.044
        Week 48 (n=22)
    136.15 ± 127.524
    No statistical analyses for this end point

    Secondary: Time to Reach Maximum Drug Concentration (tmax) of Idursulfase After IT administration

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    End point title
    		 Time to Reach Maximum Drug Concentration (tmax) of Idursulfase After IT administration [2]
    End point description
    The tmax of idursulfase after IT administration was reported. In the below table, "n" signifies subjects who were evaluable for the specified category, respectively. PK population included all subjects who received investigational product and participated in the scheduled PK studies, and for whom at least 1 post-dose PK blood sample was collected.
    End point type
    Secondary
    End point timeframe
    Pre-dose, 30, 60, 120 minutes, 4, 6, 8, 12, 24, 30 and 36 hour (h) post-dose on Weeks 4, 24, and 48
    Notes
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Pharmacokinetic parameters were evaluated only for subjects who received active study medication.
    End point values
    		 IT Treatment
    Number of subjects analysed
    24
    Units: Hour (h)
    arithmetic mean (standard deviation)
        Week 4 (n=24)
    10.07 ± 7.217
        Week 24 (n=22)
    10.37 ± 7.302
        Week 48 (n=22)
    10.18 ± 6.609
    No statistical analyses for this end point

    Secondary: Area Under the Concentration Versus Time Curve From Zero From the Time of Dosing to the Last Measurable Concentration (AUC0-t) of Idursulfase After IT Administration

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    End point title
    		 Area Under the Concentration Versus Time Curve From Zero From the Time of Dosing to the Last Measurable Concentration (AUC0-t) of Idursulfase After IT Administration [3]
    End point description
    The AUC0-t of idursulfase after IT administration was reported. In the below table, "n" signifies subjects who were evaluable for the specified category, respectively. PK population included all subjects who received investigational product and participated in the scheduled PK studies, and for whom at least 1 post-dose PK blood sample was collected.
    End point type
    Secondary
    End point timeframe
    Pre-dose, 30, 60, 120 minutes, 4, 6, 8, 12, 24, 30 and 36 hour (h) post-dose on Weeks 4, 24, and 48
    Notes
    [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Pharmacokinetic parameters were evaluated only for subjects who received active study medication.
    End point values
    		 IT Treatment
    Number of subjects analysed
    24
    Units: Nanogram*hour per milliliter (ng*h/mL)
    arithmetic mean (standard deviation)
        Week 4 (n=24)
    2601 ± 5028.0
        Week 24 (n=22)
    2949 ± 4500.4
        Week 48 (n=22)
    2863 ± 3571.6
    No statistical analyses for this end point

    Secondary: Terminal Half-life (t1/2) of Idursulfase After IT Administration

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    End point title
    		 Terminal Half-life (t1/2) of Idursulfase After IT Administration [4]
    End point description
    The t1/2 of idursulfase after IT administration was reported. In the below table, "n" signifies subjects who were evaluable for the specified category, respectively. PK population included all subjects who received investigational product and participated in the scheduled PK studies, and for whom at least 1 post-dose PK blood sample was collected.
    End point type
    Secondary
    End point timeframe
    Pre-dose, 30, 60, 120 minutes, 4, 6, 8, 12, 24, 30 and 36 hour (h) post-dose on Weeks 4, 24, and 48
    Notes
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Pharmacokinetic parameters were evaluated only for subjects who received active study medication.
    End point values
    		 IT Treatment
    Number of subjects analysed
    24
    Units: Hour (h)
    arithmetic mean (standard deviation)
        Week 4 (n=11)
    11.39 ± 4.996
        Week 24 (n=12)
    10.68 ± 2.851
        Week 48 (n=11)
    11.52 ± 4.243
    No statistical analyses for this end point

    Secondary: Total Body Clearance for Extravascular Administration Divided by the Fraction of Dose Absorbed (CL/F) of Idursulfase after IT Administration

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    End point title
    		 Total Body Clearance for Extravascular Administration Divided by the Fraction of Dose Absorbed (CL/F) of Idursulfase after IT Administration [5]
    End point description
    The CL/F of idursulfase after IT administration was reported. In the below table, "n" signifies subjects who were evaluable for the specified category, respectively. PK population included all subjects who received investigational product and participated in the scheduled PK studies, and for whom at least 1 post-dose PK blood sample was collected.
    End point type
    Secondary
    End point timeframe
    Pre-dose, 30, 60, 120 minutes, 4, 6, 8, 12, 24, 30 and 36 hour (h) post-dose on Weeks 4, 24, and 48
    Notes
    [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Pharmacokinetic parameters were evaluated only for subjects who received active study medication.
    End point values
    		 IT Treatment
    Number of subjects analysed
    24
    Units: Liter per hour (L/h)
    arithmetic mean (standard deviation)
        Week 4 (n=11)
    4.82 ± 1.753
        Week 24 (n=12)
    4.54 ± 2.029
        Week 48 (n=11)
    3.94 ± 1.461
    No statistical analyses for this end point

    Secondary: Change From Baseline in the Concentration of Glycosaminoglycans (GAG) in Cerebrospinal Fluid (CSF) at Week 52

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    End point title
    		 Change From Baseline in the Concentration of Glycosaminoglycans (GAG) in Cerebrospinal Fluid (CSF) at Week 52
    End point description
    Change from baseline in the concentration of GAG in CSF was reported. PK population included all subjects who received investigational product and participated in the scheduled PK studies, and for whom at least 1 post-dose PK blood sample was collected.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 52
    End point values
    		 No IT Treatment IT Treatment
    Number of subjects analysed
    14
    30
    Units: Nanogram per milliliter (ng/mL)
        arithmetic mean (standard deviation)
    -124.6 ± 905.08
    -961.8 ± 797.01
    No statistical analyses for this end point

    Secondary: Concentration of Idursulfase in Cerebrospinal Fluid (CSF)

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    End point title
    		 Concentration of Idursulfase in Cerebrospinal Fluid (CSF) [6]
    End point description
    CSF samples were collected via the IDDD or lumbar puncture prior to the injection of Idursulfase-IT. In the below table, "n" signifies subjects who were evaluable for the specified category, respectively and "99999" indicates that the standard deviation was not calculated due to less number of subjects. PK population included all subjects who received investigational product and participated in the scheduled PK studies, and for whom at least 1 post-dose PK blood sample was collected.
    End point type
    Secondary
    End point timeframe
    Pre-dose on Week 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44 and 48
    Notes
    [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Pharmacokinetic parameters were evaluated only for subjects who received active study medication.
    End point values
    		 IT Treatment
    Number of subjects analysed
    33
    Units: ng/mL
    arithmetic mean (standard deviation)
        Week 4 (n=31)
    0 ± 99999
        Week 8 (n=29)
    552.75 ± 2638.000
        Week 12 (n=27)
    520.29 ± 2096.512
        Week 16 (n=27)
    176.87 ± 572.459
        Week 20 (n=29)
    146.66 ± 553.354
        Week 24 (n=29)
    268.72 ± 979.733
        Week 28 (n=28)
    1471.61 ± 5893.839
        Week 32 (n=28)
    141.16 ± 443.484
        Week 36 (n=29)
    521.63 ± 1524.740
        Week 40 (n=29)
    14436.70 ± 75712.900
        Week 44 (n=29)
    1105.46 ± 5331.560
        Week 48 (n=27)
    678.50 ± 3266.592
    No statistical analyses for this end point

    Secondary: Subject Response to Quality of Life EuroQol-5D (EQ-5D) Questionnaire at Week 52

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    End point title
    		 Subject Response to Quality of Life EuroQol-5D (EQ-5D) Questionnaire at Week 52
    End point description
    The EQ-5D provides a descriptive profile and index value for health status. The questionnaire measures 5 dimensions of health status: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. For each dimension, there are 5 levels of response: no problems, slight problems, moderate problems, severe problems, and unable to do/extreme problems. ITT population included all randomized subjects.
    End point type
    Secondary
    End point timeframe
    Week 52
    End point values
    		 No IT Treatment IT Treatment
    Number of subjects analysed
    15
    34
    Units: Subject
        Mobility: No problems
    9
    22
        Mobility: Slight problems
    4
    7
        Mobility: Moderate problems
    1
    1
        Mobility: Severe problems
    0
    0
        Mobility: Unable to do
    0
    0
        Self-care: No problems
    3
    6
        Self-care: Slight problems
    4
    10
        Self-care: Moderate problems
    4
    7
        Self-care: Severe problems
    0
    3
        Self-care: Unable to do
    3
    4
        Usual activities: No problems
    8
    17
        Usual activities: Slight problems
    3
    5
        Usual activities: Moderate problems
    2
    6
        Usual activities: Severe problems
    0
    1
        Usual activities: Unable to do
    1
    1
        Pain/discomfort: No problems
    6
    20
        Pain/discomfort: Slight problems
    8
    7
        Pain/discomfort: Moderate problems
    0
    3
        Pain/discomfort: Severe problems
    0
    0
        Pain/discomfort: Unable to do
    0
    0
        Anxiety/depression: No problems
    11
    22
        Anxiety/depression: Slight problems
    3
    6
        Anxiety/depression: Moderate problems
    0
    1
        Anxiety/depression: Severe problems
    0
    1
        Anxiety/depression: Unable to do
    0
    0
    No statistical analyses for this end point

    Secondary: 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)
    End point description
    An adverse event (AE) was any noxious, pathologic, or unintended change in anatomical, physiologic, or metabolic function as indicated by physical signs, symptoms, or laboratory changes occurring in any phase of a clinical study, whether or not considered investigational product-related. Treatment-emergent AEs for the no IT treatment group were defined as all AEs occurring on or after the date of randomization and at or before the end of the study (EOS) visit. Treatment-emergent AEs for the IT treatment group were defined as all AEs occurring on or after the date of the first IDDD implant surgery or first dose of the investigational product (whichever was earlier) and at or before the EOS visit (+30 days) or 2 weeks after the removal of the last IDDD (whichever was later). Safety population included all randomized subjects with any postrandomization safety assessments, analyzed according to the treatment received.
    End point type
    Secondary
    End point timeframe
    From start of study treatment up to Week 53
    End point values
    		 No IT Treatment IT Treatment
    Number of subjects analysed
    15
    33
    Units: Subject
    14
    33
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From start of study treatment up to Week 53
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    16.1
    Reporting groups
    Reporting group title
    No IT Treatment
    Reporting group description
    		 Subjects aged 3 to less than (<) 18 years received elaprase therapy intravenously as standard of care for 12 months.

    Reporting group title
    IT Treatment
    Reporting group description
    		 Subjects aged 3 to < 18 years received intrathecal (IT) injections of 10 milligram (mg) idursulfase-IT once monthly for 12 months through SOPH-A-PORT Mini S intrathecal drug delivery device (IDDD) along with elaprase therapy.

    Serious adverse events
    		 No IT Treatment IT Treatment
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 15 (13.33%)
    12 / 33 (36.36%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Investigations
    Csf cell count increased
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Procedural nausea
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Procedural pain
         subjects affected / exposed
    0 / 15 (0.00%)
    2 / 33 (6.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Procedural vomiting
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pseudomeningocele
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Hypotension
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebrospinal fluid leakage
         subjects affected / exposed
    0 / 15 (0.00%)
    4 / 33 (12.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device dislocation
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device failure
         subjects affected / exposed
    0 / 15 (0.00%)
    2 / 33 (6.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device kink
         subjects affected / exposed
    0 / 15 (0.00%)
    3 / 33 (9.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypothermia
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inflammation
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 15 (0.00%)
    4 / 33 (12.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular complication associated with device
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Catheter site cellulitis
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound infection
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 No IT Treatment IT Treatment
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    14 / 15 (93.33%)
    33 / 33 (100.00%)
    Vascular disorders
    Diastolic hypertension
         subjects affected / exposed
    1 / 15 (6.67%)
    4 / 33 (12.12%)
         occurrences all number
    1
    7
    Diastolic hypotension
         subjects affected / exposed
    1 / 15 (6.67%)
    4 / 33 (12.12%)
         occurrences all number
    1
    6
    Hypotension
         subjects affected / exposed
    0 / 15 (0.00%)
    3 / 33 (9.09%)
         occurrences all number
    0
    3
    Systolic hypertension
         subjects affected / exposed
    1 / 15 (6.67%)
    4 / 33 (12.12%)
         occurrences all number
    1
    9
    General disorders and administration site conditions
    Catheter site pain
         subjects affected / exposed
    0 / 15 (0.00%)
    2 / 33 (6.06%)
         occurrences all number
    0
    3
    Device breakage
         subjects affected / exposed
    0 / 15 (0.00%)
    2 / 33 (6.06%)
         occurrences all number
    0
    2
    Device occlusion
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 33 (0.00%)
         occurrences all number
    2
    0
    Gait disturbance
         subjects affected / exposed
    0 / 15 (0.00%)
    4 / 33 (12.12%)
         occurrences all number
    0
    4
    Implant site effusion
         subjects affected / exposed
    0 / 15 (0.00%)
    6 / 33 (18.18%)
         occurrences all number
    0
    8
    Implant site pain
         subjects affected / exposed
    0 / 15 (0.00%)
    2 / 33 (6.06%)
         occurrences all number
    0
    2
    Implant site swelling
         subjects affected / exposed
    0 / 15 (0.00%)
    3 / 33 (9.09%)
         occurrences all number
    0
    3
    Irritability
         subjects affected / exposed
    0 / 15 (0.00%)
    4 / 33 (12.12%)
         occurrences all number
    0
    4
    Medical device pain
         subjects affected / exposed
    0 / 15 (0.00%)
    3 / 33 (9.09%)
         occurrences all number
    0
    3
    Pain
         subjects affected / exposed
    0 / 15 (0.00%)
    3 / 33 (9.09%)
         occurrences all number
    0
    3
    Puncture site pain
         subjects affected / exposed
    1 / 15 (6.67%)
    1 / 33 (3.03%)
         occurrences all number
    1
    1
    Pyrexia
         subjects affected / exposed
    7 / 15 (46.67%)
    19 / 33 (57.58%)
         occurrences all number
    10
    39
    Vascular complication associated with device
         subjects affected / exposed
    3 / 15 (20.00%)
    5 / 33 (15.15%)
         occurrences all number
    8
    5
    Immune system disorders
    Allergy to animal
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    Drug hypersensitivity
         subjects affected / exposed
    0 / 15 (0.00%)
    2 / 33 (6.06%)
         occurrences all number
    0
    2
    Respiratory, thoracic and mediastinal disorders
    Atelectasis
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    Cough
         subjects affected / exposed
    4 / 15 (26.67%)
    15 / 33 (45.45%)
         occurrences all number
    4
    33
    Epistaxis
         subjects affected / exposed
    0 / 15 (0.00%)
    3 / 33 (9.09%)
         occurrences all number
    0
    3
    Hiccups
         subjects affected / exposed
    0 / 15 (0.00%)
    2 / 33 (6.06%)
         occurrences all number
    0
    6
    Nasal congestion
         subjects affected / exposed
    3 / 15 (20.00%)
    7 / 33 (21.21%)
         occurrences all number
    4
    10
    Oropharyngeal pain
         subjects affected / exposed
    1 / 15 (6.67%)
    2 / 33 (6.06%)
         occurrences all number
    1
    4
    Rhinorrhoea
         subjects affected / exposed
    1 / 15 (6.67%)
    8 / 33 (24.24%)
         occurrences all number
    1
    10
    Wheezing
         subjects affected / exposed
    0 / 15 (0.00%)
    3 / 33 (9.09%)
         occurrences all number
    0
    5
    Psychiatric disorders
    Abnormal behaviour
         subjects affected / exposed
    0 / 15 (0.00%)
    2 / 33 (6.06%)
         occurrences all number
    0
    2
    Affect lability
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    Aggression
         subjects affected / exposed
    1 / 15 (6.67%)
    4 / 33 (12.12%)
         occurrences all number
    2
    4
    Agitation
         subjects affected / exposed
    0 / 15 (0.00%)
    2 / 33 (6.06%)
         occurrences all number
    0
    2
    Anxiety
         subjects affected / exposed
    0 / 15 (0.00%)
    2 / 33 (6.06%)
         occurrences all number
    0
    2
    Communication disorder
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    Dysphemia
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    Impulsive behaviour
         subjects affected / exposed
    1 / 15 (6.67%)
    1 / 33 (3.03%)
         occurrences all number
    1
    1
    Insomnia
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    Self injurious behaviour
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    Sleep disorder
         subjects affected / exposed
    1 / 15 (6.67%)
    1 / 33 (3.03%)
         occurrences all number
    1
    1
    Social avoidant behaviour
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 15 (6.67%)
    2 / 33 (6.06%)
         occurrences all number
    2
    2
    Albumin csf increased
         subjects affected / exposed
    1 / 15 (6.67%)
    3 / 33 (9.09%)
         occurrences all number
    1
    3
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    Blood calcium decreased
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    Blood pressure diastolic decreased
         subjects affected / exposed
    3 / 15 (20.00%)
    8 / 33 (24.24%)
         occurrences all number
    3
    26
    Blood pressure diastolic increased
         subjects affected / exposed
    2 / 15 (13.33%)
    6 / 33 (18.18%)
         occurrences all number
    2
    10
    Blood pressure increased
         subjects affected / exposed
    2 / 15 (13.33%)
    1 / 33 (3.03%)
         occurrences all number
    2
    1
    Blood pressure systolic decreased
         subjects affected / exposed
    1 / 15 (6.67%)
    7 / 33 (21.21%)
         occurrences all number
    1
    20
    Blood pressure systolic increased
         subjects affected / exposed
    2 / 15 (13.33%)
    7 / 33 (21.21%)
         occurrences all number
    3
    20
    Blood triglycerides increased
         subjects affected / exposed
    1 / 15 (6.67%)
    2 / 33 (6.06%)
         occurrences all number
    2
    2
    Body temperature decreased
         subjects affected / exposed
    0 / 15 (0.00%)
    5 / 33 (15.15%)
         occurrences all number
    0
    6
    Cardiac murmur
         subjects affected / exposed
    1 / 15 (6.67%)
    1 / 33 (3.03%)
         occurrences all number
    1
    1
    Coagulation time prolonged
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    Csf cell count increased
         subjects affected / exposed
    0 / 15 (0.00%)
    4 / 33 (12.12%)
         occurrences all number
    0
    5
    Csf glucose decreased
         subjects affected / exposed
    1 / 15 (6.67%)
    7 / 33 (21.21%)
         occurrences all number
    1
    9
    Csf pressure increased
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    Csf protein increased
         subjects affected / exposed
    2 / 15 (13.33%)
    5 / 33 (15.15%)
         occurrences all number
    2
    6
    Csf white blood cell count increased
         subjects affected / exposed
    0 / 15 (0.00%)
    2 / 33 (6.06%)
         occurrences all number
    0
    2
    Electrocardiogram qt prolonged
         subjects affected / exposed
    0 / 15 (0.00%)
    3 / 33 (9.09%)
         occurrences all number
    0
    4
    Eosinophil count increased
         subjects affected / exposed
    1 / 15 (6.67%)
    5 / 33 (15.15%)
         occurrences all number
    1
    7
    Eosinophil percentage increased
         subjects affected / exposed
    0 / 15 (0.00%)
    2 / 33 (6.06%)
         occurrences all number
    0
    3
    Gamma-Glutamyltransferase increased
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 33 (0.00%)
         occurrences all number
    2
    0
    Haematocrit decreased
         subjects affected / exposed
    0 / 15 (0.00%)
    2 / 33 (6.06%)
         occurrences all number
    0
    3
    Heart rate decreased
         subjects affected / exposed
    3 / 15 (20.00%)
    7 / 33 (21.21%)
         occurrences all number
    5
    25
    Heart rate increased
         subjects affected / exposed
    4 / 15 (26.67%)
    7 / 33 (21.21%)
         occurrences all number
    6
    17
    Lymphocyte count increased
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    Monocyte count increased
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    Neutrophil count increased
         subjects affected / exposed
    1 / 15 (6.67%)
    3 / 33 (9.09%)
         occurrences all number
    1
    3
    Nuclear magnetic resonance imaging abnormal
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    Oxygen saturation decreased
         subjects affected / exposed
    2 / 15 (13.33%)
    4 / 33 (12.12%)
         occurrences all number
    2
    5
    Platelet count decreased
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    Protein total decreased
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    Red blood cell count decreased
         subjects affected / exposed
    0 / 15 (0.00%)
    2 / 33 (6.06%)
         occurrences all number
    0
    3
    Red blood cells csf positive
         subjects affected / exposed
    0 / 15 (0.00%)
    3 / 33 (9.09%)
         occurrences all number
    0
    3
    Respiratory rate decreased
         subjects affected / exposed
    1 / 15 (6.67%)
    2 / 33 (6.06%)
         occurrences all number
    1
    2
    Urine leukocyte esterase positive
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    White blood cell count decreased
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    White blood cell count increased
         subjects affected / exposed
    1 / 15 (6.67%)
    2 / 33 (6.06%)
         occurrences all number
    1
    2
    White blood cells urine positive
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    Injury, poisoning and procedural complications
    Arthropod bite
         subjects affected / exposed
    0 / 15 (0.00%)
    2 / 33 (6.06%)
         occurrences all number
    0
    2
    Contusion
         subjects affected / exposed
    2 / 15 (13.33%)
    1 / 33 (3.03%)
         occurrences all number
    2
    1
    Excoriation
         subjects affected / exposed
    0 / 15 (0.00%)
    3 / 33 (9.09%)
         occurrences all number
    0
    4
    Fall
         subjects affected / exposed
    0 / 15 (0.00%)
    3 / 33 (9.09%)
         occurrences all number
    0
    5
    Head injury
         subjects affected / exposed
    0 / 15 (0.00%)
    2 / 33 (6.06%)
         occurrences all number
    0
    2
    Incision site oedema
         subjects affected / exposed
    0 / 15 (0.00%)
    4 / 33 (12.12%)
         occurrences all number
    0
    4
    Incision site pain
         subjects affected / exposed
    0 / 15 (0.00%)
    2 / 33 (6.06%)
         occurrences all number
    0
    2
    Infusion related reaction
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    Laceration
         subjects affected / exposed
    1 / 15 (6.67%)
    2 / 33 (6.06%)
         occurrences all number
    1
    2
    Procedural hypertension
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    Procedural hypotension
         subjects affected / exposed
    1 / 15 (6.67%)
    3 / 33 (9.09%)
         occurrences all number
    1
    3
    Procedural nausea
         subjects affected / exposed
    0 / 15 (0.00%)
    2 / 33 (6.06%)
         occurrences all number
    0
    2
    Procedural pain
         subjects affected / exposed
    0 / 15 (0.00%)
    14 / 33 (42.42%)
         occurrences all number
    0
    15
    Procedural vomiting
         subjects affected / exposed
    0 / 15 (0.00%)
    4 / 33 (12.12%)
         occurrences all number
    0
    6
    Thermal burn
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    Wound secretion
         subjects affected / exposed
    0 / 15 (0.00%)
    2 / 33 (6.06%)
         occurrences all number
    0
    2
    Cardiac disorders
    Dilatation ventricular
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    Sinus bradycardia
         subjects affected / exposed
    0 / 15 (0.00%)
    2 / 33 (6.06%)
         occurrences all number
    0
    3
    Sinus tachycardia
         subjects affected / exposed
    1 / 15 (6.67%)
    4 / 33 (12.12%)
         occurrences all number
    1
    10
    Tachycardia
         subjects affected / exposed
    0 / 15 (0.00%)
    3 / 33 (9.09%)
         occurrences all number
    0
    4
    Nervous system disorders
    Carpal tunnel syndrome
         subjects affected / exposed
    3 / 15 (20.00%)
    1 / 33 (3.03%)
         occurrences all number
    3
    1
    Cerebrospinal fluid leakage
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    Drooling
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    Headache
         subjects affected / exposed
    1 / 15 (6.67%)
    12 / 33 (36.36%)
         occurrences all number
    1
    23
    Intracranial pressure increased
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    Psychomotor hyperactivity
         subjects affected / exposed
    1 / 15 (6.67%)
    5 / 33 (15.15%)
         occurrences all number
    1
    5
    Subdural effusion
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    Ear and labyrinth disorders
    Motion sickness
         subjects affected / exposed
    0 / 15 (0.00%)
    2 / 33 (6.06%)
         occurrences all number
    0
    2
    Otorrhoea
         subjects affected / exposed
    2 / 15 (13.33%)
    2 / 33 (6.06%)
         occurrences all number
    11
    2
    Eye disorders
    Astigmatism
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    1 / 15 (6.67%)
    1 / 33 (3.03%)
         occurrences all number
    1
    1
    Abdominal pain upper
         subjects affected / exposed
    0 / 15 (0.00%)
    3 / 33 (9.09%)
         occurrences all number
    0
    3
    Constipation
         subjects affected / exposed
    2 / 15 (13.33%)
    4 / 33 (12.12%)
         occurrences all number
    3
    4
    Dental caries
         subjects affected / exposed
    0 / 15 (0.00%)
    4 / 33 (12.12%)
         occurrences all number
    0
    4
    Diarrhoea
         subjects affected / exposed
    2 / 15 (13.33%)
    10 / 33 (30.30%)
         occurrences all number
    2
    20
    Frequent bowel movements
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    Nausea
         subjects affected / exposed
    0 / 15 (0.00%)
    4 / 33 (12.12%)
         occurrences all number
    0
    5
    Swollen tongue
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    Teething
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 33 (0.00%)
         occurrences all number
    2
    0
    Vomiting
         subjects affected / exposed
    3 / 15 (20.00%)
    25 / 33 (75.76%)
         occurrences all number
    4
    72
    Skin and subcutaneous tissue disorders
    Dermatitis allergic
         subjects affected / exposed
    1 / 15 (6.67%)
    1 / 33 (3.03%)
         occurrences all number
    1
    1
    Dermatitis contact
         subjects affected / exposed
    1 / 15 (6.67%)
    2 / 33 (6.06%)
         occurrences all number
    1
    2
    Dermatitis diaper
         subjects affected / exposed
    2 / 15 (13.33%)
    3 / 33 (9.09%)
         occurrences all number
    4
    4
    Dry skin
         subjects affected / exposed
    0 / 15 (0.00%)
    2 / 33 (6.06%)
         occurrences all number
    0
    3
    Rash
         subjects affected / exposed
    1 / 15 (6.67%)
    5 / 33 (15.15%)
         occurrences all number
    2
    5
    Rash erythematous
         subjects affected / exposed
    1 / 15 (6.67%)
    2 / 33 (6.06%)
         occurrences all number
    1
    2
    Rash generalised
         subjects affected / exposed
    1 / 15 (6.67%)
    1 / 33 (3.03%)
         occurrences all number
    1
    1
    Rash maculo-papular
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    Rash papular
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    Red man syndrome
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    Scab
         subjects affected / exposed
    0 / 15 (0.00%)
    2 / 33 (6.06%)
         occurrences all number
    0
    2
    Skin irritation
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    Urticaria
         subjects affected / exposed
    2 / 15 (13.33%)
    1 / 33 (3.03%)
         occurrences all number
    3
    1
    Renal and urinary disorders
    Polyuria
         subjects affected / exposed
    1 / 15 (6.67%)
    1 / 33 (3.03%)
         occurrences all number
    1
    1
    Proteinuria
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 15 (6.67%)
    3 / 33 (9.09%)
         occurrences all number
    1
    3
    Foot deformity
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    Joint range of motion decreased
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    Joint stiffness
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 33 (0.00%)
         occurrences all number
    2
    0
    Knee deformity
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    Muscle tightness
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    Pain in extremity
         subjects affected / exposed
    0 / 15 (0.00%)
    3 / 33 (9.09%)
         occurrences all number
    0
    6
    Toe walking
         subjects affected / exposed
    0 / 15 (0.00%)
    2 / 33 (6.06%)
         occurrences all number
    0
    2
    Trigger finger
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    Infections and infestations
    Atypical pneumonia
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    Ear infection
         subjects affected / exposed
    4 / 15 (26.67%)
    9 / 33 (27.27%)
         occurrences all number
    7
    10
    Ear infection fungal
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    Fungal infection
         subjects affected / exposed
    0 / 15 (0.00%)
    2 / 33 (6.06%)
         occurrences all number
    0
    2
    Gastroenteritis
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    Gastroenteritis viral
         subjects affected / exposed
    1 / 15 (6.67%)
    5 / 33 (15.15%)
         occurrences all number
    2
    6
    Influenza
         subjects affected / exposed
    1 / 15 (6.67%)
    2 / 33 (6.06%)
         occurrences all number
    1
    3
    Localised infection
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    Nasopharyngitis
         subjects affected / exposed
    5 / 15 (33.33%)
    13 / 33 (39.39%)
         occurrences all number
    6
    22
    Otitis media
         subjects affected / exposed
    1 / 15 (6.67%)
    4 / 33 (12.12%)
         occurrences all number
    1
    4
    Otitis media acute
         subjects affected / exposed
    1 / 15 (6.67%)
    1 / 33 (3.03%)
         occurrences all number
    2
    1
    Periodontitis
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    Pharyngitis streptococcal
         subjects affected / exposed
    1 / 15 (6.67%)
    2 / 33 (6.06%)
         occurrences all number
    1
    2
    Respiratory tract infection
         subjects affected / exposed
    1 / 15 (6.67%)
    1 / 33 (3.03%)
         occurrences all number
    1
    2
    Rhinitis
         subjects affected / exposed
    1 / 15 (6.67%)
    3 / 33 (9.09%)
         occurrences all number
    1
    4
    Sinusitis
         subjects affected / exposed
    1 / 15 (6.67%)
    3 / 33 (9.09%)
         occurrences all number
    1
    4
    Tinea infection
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    Tinea pedis
         subjects affected / exposed
    0 / 15 (0.00%)
    2 / 33 (6.06%)
         occurrences all number
    0
    2
    Upper respiratory tract infection
         subjects affected / exposed
    3 / 15 (20.00%)
    11 / 33 (33.33%)
         occurrences all number
    5
    15
    Viral pharyngitis
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    Viral upper respiratory tract infection
         subjects affected / exposed
    1 / 15 (6.67%)
    1 / 33 (3.03%)
         occurrences all number
    1
    1

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    14 Aug 2013
    - Modifications to the study schedules of events, in particular: scheduling of serum antibody sampling every 3 months in both treatment groups of the pivotal study and in the separate substudy, instructions concerning subject genotyping requirements, clarification concerning safety follow-up post IT injection, and introduction of serum and CSF albumin testing to monitor permeability of the blood-brain barrier. - Specification that the Expanded Interview Form of the VABS-II be utilized. - Specification that the DAS-II Early Years (Spanish version) only will be used for assessment of eligible Spanish-speaking subjects who, additionally, must be below 7 years 8 months of age at the time of informed consent. - Adjustment to dosing for subjects below 3 years of age; the dose of idursulfase-IT dose was adjusted based on reference brain weights, and introduction of cognitive eligibility criteria for this subject subgroup. - Increased the required duration of prior Elaprase therapy from 3 to 4 months. - Modification of the planned statistical analysis.
    16 Dec 2013
    - Allowed a limited number of US subjects randomized to the IT treatment arm of the pivotal study to receive monthly IT doses of idursulfase-IT by lumbar puncture prior to FDA authorization of use of the SOPH-A-PORT Mini S device for the purpose of study drug administration. - Made change to determination of cognitive status for inclusion in the separate substudy. Instead of using a standard (composite) score, a developmental quotient (DQ) was used. The DQ has a wider range than the composite score which has a lower boundary at a value of 55.
    09 Feb 2015
    - Adusted the timing of the planned blinded variability assessment to meet the criterion of being conducted “prior to enrollment closure” and not to meet the former criterion of being conducted after approximately one-half of the planned number of subjects (ie, approximately 21 subjects) complete Week 52. - Removed US-specific text, no longer necessary following FDA authorization of investigational use of the SOPH-A-PORT Mini S device, allowing a limited number of US subjects randomized to the IT treatment arm of the pivotal study to receive monthly IT doses of idursulfase-IT by lumbar puncture. - Incorporated FDA input (Advice/Information Request letter of 03 December 2014) concerning the planned statistical analysis, add plans for pharmacokinetic analysis, and made minor corrections/clarifications in the statistical analysis text.
    21 Dec 2015
    - Allowed the enrollment of approximately 48 subjects based on a blinded variability assessment. - Update to the text pertaining to the SOPH-A-PORT Mini S IDDD for consistency with the sponsor’s other protocols utilizing this device for intrathecal drug delivery. - Clarification of aspects of the study schedule pertaining to analysis of CSF and serum samples.
    18 Apr 2016
    - Provided guidance concerning the minimum size of a child to undergo IDDD implantation. - Specified the maximum volume of blood to be collected from a subject by study visit.

    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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