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    Clinical Trial Results:
    An Open-Label Extension of Study HGT-SAN-055 (NCT01155778) Evaluating Long Term Safety and Clinical Outcomes of Intrathecal Administration of rhHNS in Subjects with Sanfilippo Syndrome Type A (MPS IIIA)

    Summary
    EudraCT number
    		 2010-021348-16
    Trial protocol
    		 GB   NL  
    Global end of trial date
    12 Apr 2019

    Results information
    Results version number
    		 v2(current)
    This version publication date
    14 Jun 2020
    First version publication date
    21 Sep 2019
    Other versions
    		 v1
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    HGT-SAN-067
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01299727
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Shire
    Sponsor organisation address
    300 Shire Way, Lexington, United States, MA 02421
    Public contact
    Study Director, Shire, 1 866-8425335, ClinicalTransparency@shire.com
    Scientific contact
    Study Director, Shire, 1 866-8425335, ClinicalTransparency@shire.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-001634-PIP01-14
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Interim
    Date of interim/final analysis
    12 Apr 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    12 Apr 2019
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to collect long-term safety and tolerability data in subjects with Sanfilippo Syndrome Type A (mucopolysaccharidosis [MPS] IIIA) who received HGT-1410 via a surgically implanted intrathecal drug delivery device (IDDD) in study HGT-SAN-055 (2009-015984-15) and elected to continue therapy in this study.
    Protection of trial subjects
    The study was conducted in accordance with Good Clinical Practice (GCP) as described in the Code of United States Federal Regulations Title 21 Parts 50, 56, and 312; the International Council for Harmonisation (ICH) GCP guidelines; and the ethical principles described in the Declaration of Helsinki.
    Background therapy
    		 All subjects who were enrolled in Study HGT-SAN-055 (2009-015984-15) through Week 26 and completed the end of study (EOS) evaluations were eligible for enrollment in this open-label extension study.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Mar 2011
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety
    Long term follow-up duration
    		 3 Years
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 6
    Country: Number of subjects enrolled
    Netherlands: 6
    Worldwide total number of subjects
    12
    EEA total number of subjects
    12
    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)
    7
    Adolescents (12-17 years)
    3
    Adults (18-64 years)
    2
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was conducted at 2 study centers in the Netherlands and United Kingdom between 01 March 2011 (first subject first visit) and 12 April 2019 (last subject last visit).

    Pre-assignment
    Screening details
    		 A total of 12 subjects were enrolled in the extension study, with 4 subjects were included in each of the 3 dose groups. Out of them, 10 subjects completed the treatment period of the study.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 HGT-1410/rhHNS 10 mg
    Arm description
    		 Subjects received HGT-1410/Recombinant human heparan N-sulfatase (rhHNS) 10 milligram (mg) for every 4 weeks (Q4W) via an intrathecal drug delivery device (IDDD).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Recombinant human heparan N-sulfatase (rhHNS)
    Investigational medicinal product code
    HGT-1410
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intrathecal use
    Dosage and administration details
    Subjects received HGT-1410/rhHNS via an intrathecal drug delivery device.

    Arm title
    		 HGT-1410/rhHNS 45 mg
    Arm description
    		 Subjects received HGT-1410/rhHNS 45 mg for Q4W via IDDD.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Recombinant human heparan N-sulfatase (rhHNS)
    Investigational medicinal product code
    HGT-1410
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intrathecal use
    Dosage and administration details
    Subjects received HGT-1410/rhHNS via an intrathecal drug delivery device.

    Arm title
    		 HGT-1410/rhHNS 90 mg
    Arm description
    		 Subjects received HGT-1410/rhHNS 90 mg for Q4W via IDDD.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Recombinant human heparan N-sulfatase (rhHNS)
    Investigational medicinal product code
    HGT-1410
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intrathecal use
    Dosage and administration details
    Subjects received HGT-1410/rhHNS via an intrathecal drug delivery device.

    Number of subjects in period 1
    		HGT-1410/rhHNS 10 mg HGT-1410/rhHNS 45 mg HGT-1410/rhHNS 90 mg
    Started
    4
    4
    4
    Completed
    0
    0
    0
    Not completed
    4
    4
    4
         Consent withdrawn by subject
    1
    -
    1
         Subjects Who Completed the Treatment Period
    3
    4
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    HGT-1410/rhHNS 10 mg
    Reporting group description
    		 Subjects received HGT-1410/Recombinant human heparan N-sulfatase (rhHNS) 10 milligram (mg) for every 4 weeks (Q4W) via an intrathecal drug delivery device (IDDD).

    Reporting group title
    HGT-1410/rhHNS 45 mg
    Reporting group description
    		 Subjects received HGT-1410/rhHNS 45 mg for Q4W via IDDD.

    Reporting group title
    HGT-1410/rhHNS 90 mg
    Reporting group description
    		 Subjects received HGT-1410/rhHNS 90 mg for Q4W via IDDD.

    Reporting group values
    		 HGT-1410/rhHNS 10 mg HGT-1410/rhHNS 45 mg HGT-1410/rhHNS 90 mg Total
    Number of subjects
    		 4 4 4
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 9.145 ( 4.6956 ) 9.070 ( 9.7916 ) 10.638 ( 8.6645 ) -
    Gender categorical
    Units:
        Male
    		 3 2 3 8
        Female
    		 1 2 1 4
    Race
    Units: Subjects
        American Indian or Alaskan Native
    		 0 0 0 0
        Asian
    		 0 1 1 2
        Black or African American
    		 0 0 0 0
        Native Hawaiian or other Pacific Islander
    		 0 0 0 0
        White
    		 4 3 3 10
        Other
    		 0 0 0 0
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 0 0 0 0
        Not Hispanic or Latino
    		 4 4 4 12

    End points

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    End points reporting groups
    Reporting group title
    HGT-1410/rhHNS 10 mg
    Reporting group description
    		 Subjects received HGT-1410/Recombinant human heparan N-sulfatase (rhHNS) 10 milligram (mg) for every 4 weeks (Q4W) via an intrathecal drug delivery device (IDDD).

    Reporting group title
    HGT-1410/rhHNS 45 mg
    Reporting group description
    		 Subjects received HGT-1410/rhHNS 45 mg for Q4W via IDDD.

    Reporting group title
    HGT-1410/rhHNS 90 mg
    Reporting group description
    		 Subjects received HGT-1410/rhHNS 90 mg for Q4W via IDDD.

    Primary: Number of Subjects With Treatment Emergent Adverse Events (TEAEs) And Treatment Emergent Serious Adverse Events (SAE)

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    End point title
    		 Number of Subjects With Treatment Emergent Adverse Events (TEAEs) And Treatment Emergent Serious Adverse Events (SAE) [1]
    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 study drug related. Treatment-emergent Adverse events (TEAEs) were defined as all adverse events (AEs) from the time of the surgery for first IDDD implantation or first dose of HGT-1410 in study HGT-SAN-055 (2009-015984-15) to the data cutoff date, or 30 days after the date of the last dose or 2 weeks after the date of device explant if early termination occurred. TEAEs included subjects with any AE, any drug-related AE, any surgery-related AE, any IDDD-related AE, and any IT administration process-related AE, any SAE, any serious drug-related AE. The safety population consisted of all eligible subjects from Study HGT-SAN-055 (2009-015984-15) who agreed to subjects in the extension study, HGT-SAN-067.
    End point type
    Primary
    End point timeframe
    From start of study drug administration up to follow-up (Month 103)
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive statistics were done, no inferential statistical analyses were performed.
    End point values
    		 HGT-1410/rhHNS 10 mg HGT-1410/rhHNS 45 mg HGT-1410/rhHNS 90 mg
    Number of subjects analysed
    4
    4
    4
    Units: subjects
        Subjects with at least one TEAEs
    4
    4
    4
        Subjects with at least one HGT-1410 related TEAEs
    4
    4
    2
        Subjects with at least one surgery related TEAEs
    4
    4
    3
        Subjects with at least one IDDD related TEAEs
    4
    4
    4
        Subjects with at least IT related TEAEs
    3
    3
    2
        Subjects with at least one serious TEAEs
    4
    4
    3
        Subjects with at least drug related serious TEAEs
    0
    0
    0
    No statistical analyses for this end point

    Primary: Number of Subjects With Treatment-Emergent Adverse Events (TEAEs) Based on Severity

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    End point title
    		 Number of Subjects With Treatment-Emergent Adverse Events (TEAEs) Based on Severity [2]
    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 study drug related. Treatment-emergent Adverse events (TEAEs) were defined as all adverse events (AEs) from the time of the surgery for first IDDD implantation or first dose of HGT-1410 in study HGT-SAN-055 (2009-015984-15) to the data cutoff date, or 30 days after the date of the last dose or 2 weeks after the date of device explant if early termination occurred. Severity of an AE is determined by following definitions: Mild: No limitation of usual activities; Moderate: Some limitation of usual activities; Severe: Inability to carry out usual activities. Analysis was performed based on safety population.
    End point type
    Primary
    End point timeframe
    From start of study drug administration up to follow-up (Month 103)
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive statistics were done, no inferential statistical analyses were performed.
    End point values
    		 HGT-1410/rhHNS 10 mg HGT-1410/rhHNS 45 mg HGT-1410/rhHNS 90 mg
    Number of subjects analysed
    4
    4
    4
    Units: subjects
        Subjects with Mild TEAEs
    4
    4
    4
        Subjects with Moderate TEAEs
    4
    4
    3
        Subjects with Severe TEAEs
    1
    2
    2
    No statistical analyses for this end point

    Primary: Number of Subjects With Clinically Significant Laboratory Abnormalities Reported as TEAEs

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    End point title
    		 Number of Subjects With Clinically Significant Laboratory Abnormalities Reported as TEAEs [3]
    End point description
    Clinical laboratory assessments include hematology, serum chemistry including liver function tests, coagulation urinalysis and cerebrospinal fluid (CSF). The safety population consisted of all eligible subjects from Study HGT-SAN-055 (2009-015984-15) who agreed to subjects in the extension study, HGT-SAN-067.
    End point type
    Primary
    End point timeframe
    From start of study drug administration up to follow-up (Month 103)
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive statistics were done, no inferential statistical analyses were performed.
    End point values
    		 HGT-1410/rhHNS 10 mg HGT-1410/rhHNS 45 mg HGT-1410/rhHNS 90 mg
    Number of subjects analysed
    4
    4
    4
    Units: subjects
        Hematology
    3
    0
    1
        Serum Chemistry
    1
    4
    1
        Urinalysis
    0
    1
    1
        Cerebrospinal fluid (CSF)
    1
    0
    0
    No statistical analyses for this end point

    Primary: Number of Subjects With Clinically Significant Change in Electrocardiogram (ECG) Reported as TEAEs

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    End point title
    		 Number of Subjects With Clinically Significant Change in Electrocardiogram (ECG) Reported as TEAEs [4]
    End point description
    Electrocardiogram (ECG) included an assessment of heart rate, sinus rhythm, atrial or ventricular hypertrophy, PR, QRS, QT, and corrected QT intervals. Any change in ECG assessments which were deemed clinically significant findings and abnormalities were recorded as TEAEs. The safety population consisted of all eligible subjects from Study HGT-SAN-055 (2009-015984-15) who agreed to subjects in the extension study, HGT-SAN-067.
    End point type
    Primary
    End point timeframe
    From start of study drug administration up to follow-up (Month 103)
    Notes
    [4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive statistics were done, no inferential statistical analyses were performed.
    End point values
    		 HGT-1410/rhHNS 10 mg HGT-1410/rhHNS 45 mg HGT-1410/rhHNS 90 mg
    Number of subjects analysed
    4
    4
    4
    Units: subjects
    0
    0
    0
    No statistical analyses for this end point

    Primary: Number of Subjects with Postive Anti-rhHNS Antibody Status in Serum by Recombinant Human Heparan N-Sulfatase (rhHNS)

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    End point title
    		 Number of Subjects with Postive Anti-rhHNS Antibody Status in Serum by Recombinant Human Heparan N-Sulfatase (rhHNS) [5]
    End point description
    Antibody status (i.e, positive or negative) was determined at each assessment time point. Antibody titers were determined for the samples that tested positive for anti-rhHNS antibodies. Subjects with positive Anti-rhHNS antibody status in serum were reported. The safety population consisted of all eligible subjects from Study HGT-SAN-055 (2009-015984-15) who agreed to subjects in the extension study, HGT-SAN-067.
    End point type
    Primary
    End point timeframe
    Month 103
    Notes
    [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive statistics were done, no inferential statistical analyses were performed.
    End point values
    		 HGT-1410/rhHNS 10 mg HGT-1410/rhHNS 45 mg HGT-1410/rhHNS 90 mg
    Number of subjects analysed
    4
    4
    4
    Units: subjects
    0
    0
    0
    No statistical analyses for this end point

    Primary: Number of Subjects with Positive Anti-rhHNS Antibody Status in Cerebrospinal Fluid (CSF) by Recombinant Human Heparan N-Sulfatase (rhHNS)

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    End point title
    		 Number of Subjects with Positive Anti-rhHNS Antibody Status in Cerebrospinal Fluid (CSF) by Recombinant Human Heparan N-Sulfatase (rhHNS) [6]
    End point description
    Antibody status (i.e, positive or negative) was determined at each assessment time point. Antibody titers were determined for the samples that tested positive for anti-rhHNS antibodies. Subjects with positive anti-rhHNS antibody in CSF were reported. The safety population consisted of all eligible subjects from Study HGT-SAN-055 (2009-015984-15) who agreed to subjects in the extension study, HGT-SAN-067.
    End point type
    Primary
    End point timeframe
    Month 103
    Notes
    [6] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive statistics were done, no inferential statistical analyses were performed.
    End point values
    		 HGT-1410/rhHNS 10 mg HGT-1410/rhHNS 45 mg HGT-1410/rhHNS 90 mg
    Number of subjects analysed
    4
    4
    4
    Units: subjects
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Change From Baseline in Bayley Scales of Infant Development Third Edition (BSID III) at Month 103

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    End point title
    		 Change From Baseline in Bayley Scales of Infant Development Third Edition (BSID III) at Month 103
    End point description
    The BSID III was a standard series of measurements used primarily to assess the motor fine and gross, language (receptive and expressive), and cognitive development of infants and toddlers, aged 0-42 months. This measure consisted of a series of developmental play tasks and took between 45 to 60 minutes to administer. Composite scores were derived for cognitive, language, and motor development and scaled to a metric, with a mean of 100, standard deviation of 15. The safety population consisted of all eligible subjects from Study HGT-SAN-055 (2009-015984-15) who agreed to subjects in the extension study, HGT-SAN-067. Here, n = subjects evaluable for specified category for each arm, respectively. Here, '99999' indicates that no data was analyzed for that category as there were no subjects at specified time points. Here, '88888' indicates that the standard deviation was not calculated as only one subject was evaluated.
    End point type
    Secondary
    End point timeframe
    Baseline, Month 103
    End point values
    		 HGT-1410/rhHNS 10 mg HGT-1410/rhHNS 45 mg HGT-1410/rhHNS 90 mg
    Number of subjects analysed
    4
    4
    4
    Units: units on a scale
    arithmetic mean (standard deviation)
        Cognitive: Baseline (n=1,3,2)
    19.00 ( 88888 )
    23.33 ( 12.097 )
    21.50 ( 0.707 )
        Cognitive: Change at Month 103 (n=0,0,1)
    99999 ( 99999 )
    99999 ( 99999 )
    3.0 ( 88888 )
        Receptive: Baseline (n=1,3,2)
    17.00 ( 88888 )
    24.00 ( 16.093 )
    17.50 ( 2.121 )
        Receptive: Change at Month 103 (n=0,0,1)
    99999 ( 99999 )
    99999 ( 99999 )
    0.00 ( 88888 )
        Expressive: Baseline (n=1,3,2)
    22.00 ( 88888 )
    26.00 ( 13.528 )
    22.50 ( 0.707 )
        Expressive: Change at Month 103 (n=0,0,1)
    99999 ( 99999 )
    99999 ( 99999 )
    0.00 ( 88888 )
        Fine Motor: Baseline (n=1,3,2)
    25.00 ( 88888 )
    27.67 ( 12.423 )
    23.50 ( 2.121 )
        Fine Motor: Change at Month 103 (n=0,0,1)
    99999 ( 99999 )
    99999 ( 99999 )
    0.00 ( 88888 )
        Gross Motor: Baseline (n=1,3,2)
    21.00 ( 88888 )
    26.67 ( 13.868 )
    35.50 ( 9.192 )
        Gross Motor: Change at Month 103 (n=0,0,1)
    99999 ( 99999 )
    99999 ( 99999 )
    -21.00 ( 88888 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in Bayley Scales of Infant Development Third Edition (BSID III)/Kaufman Assessment Battery for Children Second Edition (KABC II) Age-Equivalent Scores at Month 103

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    End point title
    		 Change From Baseline in Bayley Scales of Infant Development Third Edition (BSID III)/Kaufman Assessment Battery for Children Second Edition (KABC II) Age-Equivalent Scores at Month 103
    End point description
    BSID-III was used to assess the motor (fine and gross), language (receptive and expressive), and cognitive development of infants and toddlers. KABC-II was an individually administered measure of the processing and reasoning abilities of children and adolescents between the ages of 3 and 18 years and is an alternative to BSID-III. Raw scores of successfully completed items were converted to developmental age-equivalent scores as well as composite scores .The global scales on the KABC-II each have a mean or average score of 100 and a standard deviation of 15. Analysis was performed based on safety population. Here, n = subjects evaluable for specified category for each arm, respectively. Here, '99999' indicates that no data was analyzed for that category as there were no subjects at specified time points. Here, '88888' indicates that the standard deviation was not calculated as only one subject was evaluated.
    End point type
    Secondary
    End point timeframe
    Baseline, Month 103
    End point values
    		 HGT-1410/rhHNS 10 mg HGT-1410/rhHNS 45 mg HGT-1410/rhHNS 90 mg
    Number of subjects analysed
    4
    4
    4
    Units: units on a scale
    arithmetic mean (standard deviation)
        Baseline (n=2,4,4)
    66.00 ( 66.468 )
    35.17 ( 21.678 )
    60.90 ( 60.210 )
        Change at Month 103 (n=0,0,1)
    99999 ( 99999 )
    99999 ( 99999 )
    3.00 ( 88888 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in Developmental Quotient (DQ) Using Bayley Scales of Infant Development Third Edition (BSID III) and Kaufman Assessment Battery for Children Second Edition (KABC II) at Month 103

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    End point title
    		 Change From Baseline in Developmental Quotient (DQ) Using Bayley Scales of Infant Development Third Edition (BSID III) and Kaufman Assessment Battery for Children Second Edition (KABC II) at Month 103
    End point description
    BSID-III was used to assess the motor (fine and gross), language (receptive and expressive), and cognitive development of infants and toddlers. This measure consists of a series of developmental play tasks. Raw scores of successfully completed items are converted to scale scores and to composite scores. Composite scores were derived for cognitive, language, and motor development and scaled to a metric, with a mean of 100, standard deviation of 15. Higher scores are indicative of decreased development. KABC-II was an individually administered measure of the processing and reasoning abilities of children and adolescents between the ages of 3 and 18 years and is an alternative to BSID-III. BSID-III DQ score was based on the Cognitive domain. Analysis was performed based on safety population. Here, n = subjects evaluable for specified category for each arm, respectively. Here, '99999' indicates that no data was analyzed for that category as there were no subjects at specified time points.
    End point type
    Secondary
    End point timeframe
    Baseline, Month 103
    End point values
    		 HGT-1410/rhHNS 10 mg HGT-1410/rhHNS 45 mg HGT-1410/rhHNS 90 mg
    Number of subjects analysed
    4
    4
    4
    Units: units on a scale
    arithmetic mean (standard deviation)
        Baseline (n= 2,4,4)
    51.91 ( 27.292 )
    43.24 ( 23.112 )
    51.87 ( 36.095 )
        Change at Month 103 (n= 0,0,1)
    99999 ( 99999 )
    99999 ( 99999 )
    -10.96 ( 88888 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in Vineland Adaptive Behavioral Scales Second Edition (VABS-II) at Month 103

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    End point title
    		 Change From Baseline in Vineland Adaptive Behavioral Scales Second Edition (VABS-II) at Month 103
    End point description
    VABS-II measures adaptive behaviors, including the ability to cope with environmental changes, to learn new everyday skills, and to demonstrate independence. It is an instrument that supports the diagnosis of intellectual and developmental disabilities in subjects. This test measures 5 key domains: communication, daily living skills, socialization, motor skills, and the adaptive behavior composite. The raw scores was converted to domain standard scores (mean 100, SD 15). Higher scores indicate undesirable behavior. The safety population consisted of all eligible subjects from Study HGT-SAN-055 (2009-015984-15) who agreed to subjects in the extension study, HGT-SAN-067. Here, n = subjects evaluable for specified category for each arm, respectively. Here, '99999' indicates that no data was analyzed for that category as there were no subjects at specified time points. Here, '88888' indicates that the standard deviation was not calculated as only one subject was evaluated.
    End point type
    Secondary
    End point timeframe
    Baseline, Month 103
    End point values
    		 HGT-1410/rhHNS 10 mg HGT-1410/rhHNS 45 mg HGT-1410/rhHNS 90 mg
    Number of subjects analysed
    4
    4
    4
    Units: units on a scale
    arithmetic mean (standard deviation)
        Adaptive Behavior: Baseline (n= 4,4,4)
    63.3 ( 14.61 )
    59.0 ( 26.96 )
    59.5 ( 29.77 )
        Adaptive Behavior:Change at Month 103 (n= 1,0,1)
    -18.0 ( 88888 )
    99999 ( 99999 )
    -20.0 ( 88888 )
        Communication: Baseline (n= 4, 4, 4)
    68.3 ( 19.03 )
    57.5 ( 25.94 )
    60.3 ( 30.86 )
        Communication: Change at Month 103 (n= 1,0,1)
    -27.0 ( 88888 )
    99999 ( 99999 )
    -20.0 ( 88888 )
        Daily Living: Baseline (n= 4,4,4)
    62.5 ( 15.52 )
    62.3 ( 27.58 )
    60.0 ( 30.00 )
        Daily Living: Change at Month 103 (n= 1,0,1)
    -19.0 ( 88888 )
    99999 ( 99999 )
    -34.0 ( 88888 )
        Socialization: Baseline (n= 4,4,3)
    64.3 ( 12.50 )
    65.5 ( 32.42 )
    58.7 ( 35.92 )
        Socialization: Change at Month 103 (n= 1,0,0)
    -15.0 ( 88888 )
    99999 ( 99999 )
    0 ( 88888 )
        Motor Skills: Baseline (n= 3,3,2)
    82.7 ( 29.77 )
    76.3 ( 5.69 )
    72.5 ( 12.02 )
        Motor Skills: Change at Month 103 (n= 1,0,1)
    -18.0 ( 88888 )
    99999 ( 99999 )
    -14.0 ( 88888 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in Cerebrospinal Fluid (CSF) Total Heparan Sulfate Levels at Month 103

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    End point title
    		 Change From Baseline in Cerebrospinal Fluid (CSF) Total Heparan Sulfate Levels at Month 103
    End point description
    Change from baseline in CSF total heparan sulfate at month 103 were recorded. The safety population consisted of all eligible subjects from Study HGT-SAN-055 (2009-015984-15) who agreed to subjects in the extension study, HGT-SAN-067. Here, n = subjects evaluable for specified category for each arm, respectively. Here, '99999' indicates that no data was analyzed for that category as there were no subjects at specified time points. Here, '88888' indicates that the standard deviation was not calculated as only one subject was evaluated.
    End point type
    Secondary
    End point timeframe
    Baseline, Month 103
    End point values
    		 HGT-1410/rhHNS 10 mg HGT-1410/rhHNS 45 mg HGT-1410/rhHNS 90 mg
    Number of subjects analysed
    4
    4
    4
    Units: micrometer (μm)
    arithmetic mean (standard deviation)
        Baseline (n= 4,4,4)
    5.775 ( 3.465 )
    4.710 ( 2.968 )
    3.795 ( 1.611 )
        Change at Month 103 (n= 1,0,0)
    -4.010 ( 88888 )
    99999 ( 99999 )
    99999 ( 99999 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in Urine Glycosaminoglycan (GAG) Levels at Month 103

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    End point title
    		 Change From Baseline in Urine Glycosaminoglycan (GAG) Levels at Month 103
    End point description
    Change from baseline in Urine GAG at month 103 were recorded. The safety population consisted of all eligible subjects from Study HGT-SAN-055 (2009-015984-15) who agreed to subjects in the extension study, HGT-SAN-067. Here, '99999' indicates that no data was analyzed for that outcome as the trial was prematurely terminated.
    End point type
    Secondary
    End point timeframe
    Baseline, Month 103
    End point values
    		 HGT-1410/rhHNS 10 mg HGT-1410/rhHNS 45 mg HGT-1410/rhHNS 90 mg
    Number of subjects analysed
    4
    4
    4
    Units: microgram per milliliter (µg/mL)
        arithmetic mean (standard deviation)
    99999 ( 99999 )
    99999 ( 99999 )
    99999 ( 99999 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in Brain Magnetic Resonance Imaging (MRI) at Month 103

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    End point title
    		 Change From Baseline in Brain Magnetic Resonance Imaging (MRI) at Month 103
    End point description
    Brain MRI was measured for grey matter volume (GMV), white matter volume (WMV) and Intracranial cerebrospinal fluid Volume (ICSFV). Change from baseline in brain MRI at Month 103 were reported. The safety population consisted of all eligible subjects from Study HGT-SAN-055 (2009-015984-15) who agreed to subjects in the extension study, HGT-SAN-067. Here, n = subjects evaluable for specified category for each arm, respectively. Here, '99999' indicates that no data was analyzed for that category as there were no subjects at specified time points. Here, '88888' indicates that the standard deviation was not calculated as only one subject was evaluated.
    End point type
    Secondary
    End point timeframe
    Baseline, Month 103
    End point values
    		 HGT-1410/rhHNS 10 mg HGT-1410/rhHNS 45 mg HGT-1410/rhHNS 90 mg
    Number of subjects analysed
    4
    4
    4
    Units: milliliter (mL)
    arithmetic mean (standard deviation)
        GMV: Baseline (n= 4,4,4)
    550.50 ( 111.043 )
    534.25 ( 117.291 )
    600.28 ( 67.884 )
        GMV: Change at Month 103 (n= 1,0,0)
    -99.49 ( 88888 )
    99999 ( 99999 )
    99999 ( 99999 )
        WMV: Baseline (n= 4,4,4)
    403.72 ( 105.575 )
    348.28 ( 76.854 )
    442.45 ( 79.814 )
        WMV: Change at Month 103 (n= 1,0,0)
    -33.19 ( 88888 )
    99999 ( 99999 )
    99999 ( 99999 )
        ICSFV: Baseline (n= 4,4,4)
    26.152 ( 9.2975 )
    22.904 ( 20.8459 )
    20.925 ( 15.9681 )
        ICSFV: Change at Month 103 (n= 1,0,0)
    18.753 ( 88888 )
    99999 ( 99999 )
    99999 ( 99999 )
    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 drug administration up to follow-up (Month 103)
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    13.1
    Reporting groups
    Reporting group title
    HGT-1410/rhHNS-10 mg
    Reporting group description
    		 Subjects received HGT-1410/Recombinant human heparan N-sulfatase (rhHNS) 10 mg for every 4 weeks (Q4W) via an intrathecal drug delivery device (IDDD).

    Reporting group title
    HGT-1410/rhHNS-45 mg
    Reporting group description
    		 Subjects received HGT-1410/rhHNS 45 mg for Q4W via IDDD.

    Reporting group title
    HGT-1410/rhHNS-90 mg
    Reporting group description
    		 Subjects received HGT-1410/rhHNS 90 mg for Q4W via IDDD.

    Serious adverse events
    		 HGT-1410/rhHNS-10 mg HGT-1410/rhHNS-45 mg HGT-1410/rhHNS-90 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 4 (100.00%)
    4 / 4 (100.00%)
    3 / 4 (75.00%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Investigations
    CSF white blood cell count increased
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Accidental overdose
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Wound dehiscence
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Surgical and medical procedures
    Medical device change
         subjects affected / exposed
    3 / 4 (75.00%)
    3 / 4 (75.00%)
    1 / 4 (25.00%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 5
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Medical device removal
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Intracranial hypotension
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Leukocytosis
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Device breakage
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Device component issue
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Device failure
         subjects affected / exposed
    2 / 4 (50.00%)
    4 / 4 (100.00%)
    2 / 4 (50.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 6
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Device leakage
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Device material issue
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Auricular pseudocyst
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Central nervous system infection
         subjects affected / exposed
    2 / 4 (50.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Epstein-Barr virus infection
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Implant site infection
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Meningitis
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Postoperative wound infection
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 HGT-1410/rhHNS-10 mg HGT-1410/rhHNS-45 mg HGT-1410/rhHNS-90 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    4 / 4 (100.00%)
    4 / 4 (100.00%)
    4 / 4 (100.00%)
    Vascular disorders
    Haematoma
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    2
    1
    Hypertension
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Pallor
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Surgical and medical procedures
    Infection prophylaxis
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Medical device removal
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    2 / 4 (50.00%)
         occurrences all number
    1
    0
    2
    General disorders and administration site conditions
    Administration site pain
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Catheter site erythema
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    2
    0
    Catheter site haemorrhage
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Catheter site inflammation
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    7
    0
    0
    Catheter site pain
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Chills
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    2
    0
    Complication of device insertion
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Complication of device removal
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Device breakage
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Device failure
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    3
    0
    Device leakage
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Fatigue
         subjects affected / exposed
    1 / 4 (25.00%)
    2 / 4 (50.00%)
    1 / 4 (25.00%)
         occurrences all number
    4
    3
    1
    Feeling hot
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Gait disturbance
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Implant site effusion
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Implant site swelling
         subjects affected / exposed
    2 / 4 (50.00%)
    3 / 4 (75.00%)
    2 / 4 (50.00%)
         occurrences all number
    4
    7
    3
    Influenza like illness
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    1
    Irritability
         subjects affected / exposed
    3 / 4 (75.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    4
    0
    2
    Local swelling
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Malaise
         subjects affected / exposed
    2 / 4 (50.00%)
    1 / 4 (25.00%)
    1 / 4 (25.00%)
         occurrences all number
    17
    2
    7
    Medical device complication
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    1
    Oedema peripheral
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Pain
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    1
    0
    Pyrexia
         subjects affected / exposed
    4 / 4 (100.00%)
    3 / 4 (75.00%)
    3 / 4 (75.00%)
         occurrences all number
    18
    31
    5
    Immune system disorders
    Allergy to arthropod bite
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    3
    0
    5
    Hypersensitivity
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    1
    0
    2
    Seasonal allergy
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    1
    0
    Social circumstances
    Activities of daily living impaired
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Reproductive system and breast disorders
    Dysmenorrhoea
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    3
    0
    0
    Labia enlarged
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Penile adhesion
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    1
    Penile erythema
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Uterine haemorrhage
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Choking
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Cough
         subjects affected / exposed
    4 / 4 (100.00%)
    1 / 4 (25.00%)
    2 / 4 (50.00%)
         occurrences all number
    6
    2
    2
    Epistaxis
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 4 (25.00%)
    1 / 4 (25.00%)
         occurrences all number
    10
    1
    7
    Hyperventilation
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    2
    Nasal congestion
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Oropharyngeal pain
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    2 / 4 (50.00%)
         occurrences all number
    0
    0
    2
    Pharyngeal erythema
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Rhinorrhoea
         subjects affected / exposed
    3 / 4 (75.00%)
    2 / 4 (50.00%)
    2 / 4 (50.00%)
         occurrences all number
    6
    5
    3
    Psychiatric disorders
    Abnormal behaviour
         subjects affected / exposed
    0 / 4 (0.00%)
    2 / 4 (50.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    3
    1
    Anxiety
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    3 / 4 (75.00%)
         occurrences all number
    0
    0
    3
    Conversion disorder
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    2
    0
    0
    Depressed mood
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    1
    0
    1
    Insomnia
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 4 (25.00%)
    1 / 4 (25.00%)
         occurrences all number
    1
    1
    1
    Intentional self-injury
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Obsessive-compulsive disorder
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Restlessness
         subjects affected / exposed
    2 / 4 (50.00%)
    1 / 4 (25.00%)
    1 / 4 (25.00%)
         occurrences all number
    3
    2
    1
    Sleep disorder
         subjects affected / exposed
    2 / 4 (50.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
         occurrences all number
    6
    1
    0
    Stereotypy
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Investigations
    Blood bicarbonate decreased
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Blood creatine phosphokinase increased
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    2
    Blood uric acid increased
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    1
    Body temperature increased
         subjects affected / exposed
    1 / 4 (25.00%)
    2 / 4 (50.00%)
    2 / 4 (50.00%)
         occurrences all number
    2
    5
    2
    CSF protein increased
         subjects affected / exposed
    1 / 4 (25.00%)
    2 / 4 (50.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    2
    0
    CSF white blood cell count increased
         subjects affected / exposed
    2 / 4 (50.00%)
    3 / 4 (75.00%)
    0 / 4 (0.00%)
         occurrences all number
    4
    3
    0
    Haematocrit decreased
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Haemoglobin decreased
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    2
    0
    Lymphocyte count increased
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    1
    0
    1
    Mean cell haemoglobin decreased
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Mean cell volume decreased
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    2
    0
    Monocyte count decreased
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Neutrophil count decreased
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    1
    Norovirus test positive
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Red blood cells CSF positive
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    3
    0
    Serum ferritin decreased
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    2
    0
    Weight decreased
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    White blood cell count increased
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Injury, poisoning and procedural complications
    Arthropod bite
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Contusion
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Drug toxicity
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Excoriation
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Fall
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 4 (25.00%)
    2 / 4 (50.00%)
         occurrences all number
    7
    1
    4
    Feeding tube complication
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    2
    0
    0
    Head injury
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 4 (25.00%)
    1 / 4 (25.00%)
         occurrences all number
    1
    1
    1
    Nail injury
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    1
    Open wound
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    1
    Post procedural discomfort
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Procedural headache
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    1
    Procedural nausea
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Procedural pain
         subjects affected / exposed
    3 / 4 (75.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    3
    0
    1
    Procedural site reaction
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Procedural vomiting
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Scratch
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Skin laceration
         subjects affected / exposed
    1 / 4 (25.00%)
    2 / 4 (50.00%)
    1 / 4 (25.00%)
         occurrences all number
    1
    2
    1
    Thermal burn
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Congenital, familial and genetic disorders
    Thalassaemia trait
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Cardiac disorders
    Mitral valve incompetence
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Nervous system disorders
    Akathisia
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Balance disorder
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    2
    0
    0
    Bulbar palsy
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Cauda equina syndrome
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    7
    Cognitive disorder
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Crying
         subjects affected / exposed
    2 / 4 (50.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    3
    0
    0
    Dizziness
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Drooling
         subjects affected / exposed
    2 / 4 (50.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    3
    0
    0
    Dyskinesia
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    3
    0
    0
    Head titubation
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Headache
         subjects affected / exposed
    2 / 4 (50.00%)
    1 / 4 (25.00%)
    1 / 4 (25.00%)
         occurrences all number
    13
    6
    91
    Hyperreflexia
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Hypertonia
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Intracranial hypotension
         subjects affected / exposed
    0 / 4 (0.00%)
    2 / 4 (50.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    3
    0
    Memory impairment
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Motor dysfunction
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Nervous system disorder
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Paraesthesia
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 4 (25.00%)
    2 / 4 (50.00%)
         occurrences all number
    12
    12
    10
    Presyncope
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    1
    Psychomotor hyperactivity
         subjects affected / exposed
    0 / 4 (0.00%)
    2 / 4 (50.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    3
    1
    Syncope
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Eosinophilia
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Lymphadenopathy
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Ear and labyrinth disorders
    Ear canal erythema
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    1
    Ear pain
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    3
    Middle ear effusion
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    1
    Otorrhoea
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    1
    Tympanic membrane disorder
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Tympanic membrane hyperaemia
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    2
    0
    Tympanic membrane perforation
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    1
    Eye disorders
    Lacrimation increased
         subjects affected / exposed
    2 / 4 (50.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    2
    0
    0
    Myopia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    1
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    1
    0
    1
    Abnormal faeces
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Constipation
         subjects affected / exposed
    2 / 4 (50.00%)
    2 / 4 (50.00%)
    2 / 4 (50.00%)
         occurrences all number
    8
    2
    6
    Defaecation urgency
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    2
    0
    1
    Diarrhoea
         subjects affected / exposed
    3 / 4 (75.00%)
    3 / 4 (75.00%)
    1 / 4 (25.00%)
         occurrences all number
    10
    10
    1
    Dysphagia
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    2
    0
    0
    Eructation
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Faeces discoloured
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    1
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    1
    0
    Mouth ulceration
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    2 / 4 (50.00%)
         occurrences all number
    0
    0
    2
    Nausea
         subjects affected / exposed
    2 / 4 (50.00%)
    1 / 4 (25.00%)
    1 / 4 (25.00%)
         occurrences all number
    2
    1
    2
    Regurgitation
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    1
    0
    Retching
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Salivary hypersecretion
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Vomiting
         subjects affected / exposed
    3 / 4 (75.00%)
    3 / 4 (75.00%)
    3 / 4 (75.00%)
         occurrences all number
    16
    23
    3
    Skin and subcutaneous tissue disorders
    Dermatitis
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Dermatitis allergic
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    1
    Dermatitis diaper
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Dry skin
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    2
    Eczema
         subjects affected / exposed
    2 / 4 (50.00%)
    1 / 4 (25.00%)
    1 / 4 (25.00%)
         occurrences all number
    3
    1
    2
    Erythema
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    3
    0
    Hyperkeratosis
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Onycholysis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    1
    Pruritus
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    1
    0
    Pruritus generalised
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Rash
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 4 (25.00%)
    1 / 4 (25.00%)
         occurrences all number
    2
    1
    1
    Rash macular
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Rosacea
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Scar
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    1
    Skin chapped
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    1
    Renal and urinary disorders
    Enuresis
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Incontinence
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Micturition urgency
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 4 (25.00%)
    1 / 4 (25.00%)
         occurrences all number
    5
    4
    14
    Urinary incontinence
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    1
    0
    1
    Musculoskeletal and connective tissue disorders
    Acquired claw toe
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Back pain
         subjects affected / exposed
    0 / 4 (0.00%)
    2 / 4 (50.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    3
    2
    Growing pains
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    1
    Intervertebral disc protrusion
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    2
    Joint swelling
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Mobility decreased
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Musculoskeletal stiffness
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    2
    0
    1
    Myalgia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    1
    Pain in extremity
         subjects affected / exposed
    1 / 4 (25.00%)
    2 / 4 (50.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    2
    0
    Scoliosis
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Synovial cyst
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Toe walking
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Trigger finger
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    3
    0
    0
    Weight bearing difficulty
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Infections and infestations
    Abscess oral
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    1
    Bronchitis
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Candida nappy rash
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Catheter site infection
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    6
    0
    0
    Cellulitis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    1
    Central nervous system infection
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Ear infection
         subjects affected / exposed
    1 / 4 (25.00%)
    2 / 4 (50.00%)
    2 / 4 (50.00%)
         occurrences all number
    1
    3
    12
    Enterobiasis
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Fungal infection
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
         occurrences all number
    2
    1
    0
    Gastroenteritis
         subjects affected / exposed
    2 / 4 (50.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    4
    0
    0
    Helminthic infection
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Impetigo
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    2
    0
    1
    Influenza
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    2
    0
    2
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    1
    Nasopharyngitis
         subjects affected / exposed
    2 / 4 (50.00%)
    3 / 4 (75.00%)
    2 / 4 (50.00%)
         occurrences all number
    7
    7
    4
    Onychomycosis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    2
    Oral candidiasis
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Oral herpes
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    2
    Otitis externa
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    4
    Otitis media
         subjects affected / exposed
    0 / 4 (0.00%)
    2 / 4 (50.00%)
    2 / 4 (50.00%)
         occurrences all number
    0
    2
    3
    Otitis media acute
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    3
    0
    0
    Pharyngitis
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Pneumonia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    1
    Post procedural infection
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Postoperative wound infection
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 4 (25.00%)
    1 / 4 (25.00%)
         occurrences all number
    2
    1
    3
    Proteus infection
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Rhinitis
         subjects affected / exposed
    4 / 4 (100.00%)
    2 / 4 (50.00%)
    3 / 4 (75.00%)
         occurrences all number
    6
    16
    5
    Staphylococcal infection
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    2
    0
    Tinea pedis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    1
    Tonsillitis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    1
    Upper respiratory tract infection
         subjects affected / exposed
    3 / 4 (75.00%)
    1 / 4 (25.00%)
    1 / 4 (25.00%)
         occurrences all number
    3
    2
    1
    Urinary tract infection
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 4 (25.00%)
    1 / 4 (25.00%)
         occurrences all number
    2
    1
    1
    Varicella
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    1
    Viral infection
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    2
    Viral rash
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Viral upper respiratory tract infection
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    1
    Wound infection staphylococcal
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Metabolism and nutrition disorders
    Hyperphagia
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Iron deficiency
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Polydipsia
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    27 Jan 2011
    The study duration was clarified to be 4 years.
    13 Jan 2012
    The protocol was revised to change the dose and regimen administered to subjects in Group 3, the dose was changed from 45 mg every 2 weeks to 90 mg Q4W. This change was made to ensure consistency with the revised HGT-SAN-055 study protocol and allowed subjects to continue to receive the same dose in this extension study as they did in the original study.
    28 Aug 2012
    The protocol HGT-SAN-067 was revised to update the study drug description to reflect a change in formulation. Other changes included: clarification of the timing of the neurological examination on days of study drug administration; clarification that full neurodevelopmental testing included VABS-II.
    03 May 2013
    The protocol was amended to include language to indicate that subjects in the lowest dose group (10 mg Q4W) were to have the dose increased to that of the mid-dose, i.e, 45 mg at the first visit following the full approval of this protocol. A decline in the primary pharmacodynamic parameter, CSF HS, was observed in data collected during the 6-month study, HGT-SAN-055. This response to therapy was exhibited at all dose levels; however, the greatest impact was at the 2 higher dose levels. An effect on CSF HS demonstrated in vivo activity of HGT-1410 in the target anatomical compartment and is thought to have central importance in mediating the potential therapeutic benefit of HGT-1410; The protocol was also amended to reduce the number of hours a subject was monitored at the site after administration of HGT-1410 from 8 hours to 4 hours. The monitoring time after each administration of HGT-1410 was reconsidered based on experience with IT administration of HGT-1410, a lack of injection associated safety issues occurring between 4 and 8 hours after administration.
    17 Jan 2014
    The protocol was amended to remove the requirement for subjects to have a WBC count greater than 100 cubic millimeters in CSF just prior to dosing. It was believed that sufficient experience with HGT-1410 existed so that it was safe to proceed with dosing without waiting for CSF clinical laboratory results. This also reduced the time that a needle was in the device port, thus reducing the risk of introducing infection.
    10 Jul 2014
    The protocol was amended to extend the study and provide treatment with HGT-1410 for an additional 24 months (to Month 79 from start of Study HGT-SAN-055); the frequency of hematology, serum chemistry, and urinalysis assessments and the frequency of ECGs were reduced to every 3 months and the frequency of urine and plasma HS and anti-rhHNS assessments was changed to every 6 months within this extended period.
    08 Feb 2016
    The main purpose of this amendment was to extend the study and provide treatment with HGT-1410 for an additional 24 months (to Month 103 from start of Study HGT-SAN-055), and the addition of local (satellite) sites to reduce the burden imposed by monthly travel.
    01 Feb 2017
    Subjects who did not have the IDDD removed at the end of the treatment period were to continue to be observed during a safety follow-up period with visits every 6 months to evaluate subject safety of the device up to an additional 3 years or until the device is removed in the last subject.

    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.
    The study was terminated as pre-specified efficacy criteria were not met. Data was not presented for efficacy parameters: ABR, Children’s Sleep Habits Rating Scale, Infant Toddler QoL Questionnaire, SBRS.
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    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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