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    Clinical Trial Results:
    An open, non-controlled, parallel, ascending multiple-dose, multicenter study to assess the safety, tolerability, pharmacokinetics and pharmacodynamics of SOBI003 in pediatric MPS IIIA patients

    Summary
    EudraCT number
    		 2017-002806-10
    Trial protocol
    		 DE   NL  
    Global end of trial date
    25 Oct 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    22 Apr 2023
    First version publication date
    22 Apr 2023
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    SOBI003-001
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03423186
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Swedish Orphan Biovitrum AB
    Sponsor organisation address
    Tomtebodavägen 23A, Stockholm, Sweden, 11276
    Public contact
    Anders Bröijersen MD, Medical Information, Swedish Orphan Biovitrum AB, +46 86972000, medical.info@sobi.com
    Scientific contact
    Anders Bröijersen MD, Medical Information, Swedish Orphan Biovitrum AB, +46 86972000, medical.info@sobi.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-002380-PIP01-18
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    25 Oct 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    25 Oct 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    25 Oct 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to evaluate the safety and tolerability of SOBI003 at different dose levels.
    Protection of trial subjects
    This study was conducted in compliance with the protocol, the International Conference on Harmonization (ICH) Guideline for Good Clinical Practice (GCP), applicable regulatory requirements, and in accordance with the latest revision of the Ethical Principles for Medical Research Involving Human Subjects (the Declaration of Helsinki).
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    19 Jun 2018
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Turkey: 3
    Country: Number of subjects enrolled
    United States: 3
    Worldwide total number of subjects
    6
    EEA total number of subjects
    0
    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)
    2
    Children (2-11 years)
    4
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was conducted in 3 sites from 19 June, 2018 to 25 October, 2019.

    Pre-assignment
    Screening details
    		 A total of 6 participants were enrolled and treated with Sobi003 in this study.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Experimental: SOBI003 3 mg/kg
    Arm description
    		 Subject received a dose level of SOBI003 3 milligrams per kilogram (mg/kg) intravenous (IV) infusion once weekly for 24 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    SOBI003
    Investigational medicinal product code
    Other name
    Modified recombinant human sulphamidase
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subject received SOBI003 3 mg/kg IV infusion once weekly over a period of time of 4 hours using a central access venous port.

    Arm title
    		 Experimental: SOBI003 10 mg/kg
    Arm description
    		 Subject received a dose level of SOBI003 10 mg/kg IV infusion once weekly for 24 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    SOBI003
    Investigational medicinal product code
    Other name
    Modified recombinant human sulphamidase
    Pharmaceutical forms
    Concentrate for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subject received SOBI003 10 mg/kg IV infusion once weekly over a period of time of 4 hours using a central access venous port.

    Number of subjects in period 1
    		Experimental: SOBI003 3 mg/kg Experimental: SOBI003 10 mg/kg
    Started
    3
    3
    Completed
    3
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Experimental: SOBI003 3 mg/kg
    Reporting group description
    		 Subject received a dose level of SOBI003 3 milligrams per kilogram (mg/kg) intravenous (IV) infusion once weekly for 24 weeks.

    Reporting group title
    Experimental: SOBI003 10 mg/kg
    Reporting group description
    		 Subject received a dose level of SOBI003 10 mg/kg IV infusion once weekly for 24 weeks.

    Reporting group values
    		 Experimental: SOBI003 3 mg/kg Experimental: SOBI003 10 mg/kg Total
    Number of subjects
    		 3 3 6
    Age categorical
    Units: Subjects
    Age continuous
    Age at day of first infusion (months).
    Units: months
        arithmetic mean (standard deviation)
    		 46.3 ( 24.2 ) 29.0 ( 12.2 ) -
    Gender categorical
    Units: Subjects
        Female
    		 1 1 2
        Male
    		 2 2 4
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0
        Asian
    		 0 0 0
        Native Hawaiian or Other Pacific Islander
    		 0 0 0
        Black or African American
    		 0 0 0
        White
    		 3 3 6
        More than one race
    		 0 0 0
        Unknown or Not Reported
    		 0 0 0
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 0 0 0
        Not Hispanic or Latino
    		 3 3 6
        Unknown or Not Reported
    		 0 0 0

    End points

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    End points reporting groups
    Reporting group title
    Experimental: SOBI003 3 mg/kg
    Reporting group description
    		 Subject received a dose level of SOBI003 3 milligrams per kilogram (mg/kg) intravenous (IV) infusion once weekly for 24 weeks.

    Reporting group title
    Experimental: SOBI003 10 mg/kg
    Reporting group description
    		 Subject received a dose level of SOBI003 10 mg/kg IV infusion once weekly for 24 weeks.

    Primary: Safety as Measured by Adverse Events Frequencies (by Type and Severity)

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    End point title
    		 Safety as Measured by Adverse Events Frequencies (by Type and Severity) [1]
    End point description
    Number of adverse events, by type and severity, from start of infusion up to 24 weeks. Safety analysis set was the primary analysis set and consists of all subjects who received at least 1 dose of IMP.
    End point type
    Primary
    End point timeframe
    From start of first infusion up to Week 24
    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 performed; no inferential statistical analyses were performed.
    End point values
    		 Experimental: SOBI003 3 mg/kg Experimental: SOBI003 10 mg/kg
    Number of subjects analysed
    3
    3
    Units: Number of events
    number (not applicable)
        Any adverse event
    53
    128
        Any non-treatment emergent serious adverse event
    0
    1
        Any treatment emergent adverse event (TEAE)
    53
    124
        Any non-serious TEAE
    52
    121
        Any serious TEAE
    1
    3
        Any serious drug-related TEAE
    0
    0
        Any TEAE leading to study or treatment withdrawal
    0
    0
        Drug-related TEAE leading to treatment withdrawal
    0
    0
        Any serious TEAE leading to treatment withdrawal
    0
    0
        Any TEAE leading to death
    0
    0
        Any Infusion related Reaction
    0
    0
    No statistical analyses for this end point

    Secondary: The Observed Serum Concentration Immediately Before the Start of Infusion of SOBI003

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    End point title
    		 The Observed Serum Concentration Immediately Before the Start of Infusion of SOBI003
    End point description
    The observed serum concentration immediately before the start of infusion of SOBI003 (CPre-dose).The table report number of available pharmacokinetic (PK) samples. Here, “n” signifies to subjects who are evaluable at given timepoints and “-99999” was used as a space filler which states that median or minimum or maximum data was not computed as the value was less than lower limit of quantification (LLOQ). PK analysis set consists of all subjects where at least 1 SOBI003 dose had been administered correctly and where SOBI003 serum or Cerebrospinal fluid (CSF) concentration data was available without any protocol deviation interfering with these results.
    End point type
    Secondary
    End point timeframe
    Weeks 1, 2, 3, 4, 8, 12, and 24
    End point values
    		 Experimental: SOBI003 3 mg/kg Experimental: SOBI003 10 mg/kg
    Number of subjects analysed
    3
    3
    Units: nanogram per milliliter (ng/mL)
    median (full range (min-max))
        At Week 1 (n=3,3)
    -99999 (-99999 to 99999)
    -99999 (-99999 to 99999)
        At week 2(n=3,3)
    58.4 (33.0 to 62.2)
    109.0 (85.7 to 137.0)
        At Week 3 (n=2,2)
    68.85 (55.2 to 82.5)
    135.5 (114.0 to 157.0)
        At Week 4 (n=3,3)
    71.4 (-99999 to 97.7)
    49.8 (31.4 to 603.0)
        At Week 8 (n=3,2)
    -99999 (-99999 to 27.0)
    25.5 (-99999 to 51)
        At Week 12 (n=2,3)
    33.75 (26.6 to 40.9)
    -99999 (-99999 to 10.3)
        At Week 24 (n=3,3)
    -99999 (-99999 to 99999)
    16.4 (-99999 to 90.0)
    No statistical analyses for this end point

    Secondary: The Observed Serum Concentration at the End of Infusion of SOBI003

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    End point title
    		 The Observed Serum Concentration at the End of Infusion of SOBI003
    End point description
    The observed serum concentration at the end of infusion of SOBI003 (CEnd of inf). The table report number of available PK samples. Here, “n” signifies to subjects who are evaluable at given timepoints. PK analysis set consists of all subjects where at least 1 SOBI003 dose had been administered correctly and where SOBI003 serum or CSF concentration data was available without any protocol deviation interfering with these results.
    End point type
    Secondary
    End point timeframe
    Weeks 1, 2, 3, 4, 8, 12, and 24
    End point values
    		 Experimental: SOBI003 3 mg/kg Experimental: SOBI003 10 mg/kg
    Number of subjects analysed
    3
    3
    Units: ng/mL
    arithmetic mean (full range (min-max))
        At Week 1 (n=3,3)
    33800 (29500 to 36400)
    87500 (75300 to 114000)
        At Week 2 (n=2,2)
    34950 (33300 to 36600)
    108200 (99400 to 117000)
        At Week 3 (n=2,2)
    36750 (31300 to 42200)
    82700 (73300 to 92100)
        At Week 4 (n=3,3)
    35700 (16200 to 36600)
    77400 (71800 to 102000)
        At Week 8 (n=3,3)
    20800 (65.5 to 36600)
    50900 (33300 to 68600)
        At Week 12 (n=3,3)
    30500 (32.5 to 36700)
    56900 (56100 to 71000)
        At Week 24 (n=3,3)
    17500 (47.5 to 35400)
    93500 (69700 to 103000)
    No statistical analyses for this end point

    Secondary: The Time of the End of the Infusion of SOBI003

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    End point title
    		 The Time of the End of the Infusion of SOBI003
    End point description
    The time of the end of infusion of SOBI003 (tEnd of inf). The table report number of available PK samples. Here, “n” signifies to subjects who are evaluable at given timepoints. PK analysis set consists of all subjects where at least 1 SOBI003 dose had been administered correctly and where SOBI003 serum or CSF concentration data was available without any protocol deviation interfering with these results.
    End point type
    Secondary
    End point timeframe
    Weeks 1, 2, 3, 4, 8, 12, and 24
    End point values
    		 Experimental: SOBI003 3 mg/kg Experimental: SOBI003 10 mg/kg
    Number of subjects analysed
    3
    3
    Units: Hours
    median (full range (min-max))
        At Week 1 (n=3,3)
    4.57 (4.27 to 4.62)
    4.33 (4.02 to 4.33)
        At Week 2 (n=2,2)
    4.565 (4.30 to 4.83)
    4.245 (4.07 to 4.42)
        At Week 3 (n=2,2)
    4.28 (4.13 to 4.43)
    4.1 (3.98 to 4.22)
        At Week 4 (n=3,3)
    4.28 (4.05 to 4.50)
    4.42 (4.27 to 4.90)
        At Week 8 (n=3,2)
    4.85 (4.42 to 6.58)
    8.17 (8.17 to 8.17)
        At Week 12 (n=3,3)
    4.23 (4.10 to 6.42)
    6.83 (5.08 to 7.03)
        At Week 24 (n=3,3)
    4.45 (4.08 to 4.53)
    4.75 (4.47 to 5.57)
    No statistical analyses for this end point

    Secondary: The Maximum Observed Serum Concentration of SOBI003

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    End point title
    		 The Maximum Observed Serum Concentration of SOBI003
    End point description
    The Maximum Observed Serum Concentration of SOBI003 (Cmax). Samples were taken centrally and/or peripherally. The table report number of available PK samples. PK analysis set consists of all subjects where at least 1 SOBI003 dose had been administered correctly and where SOBI003 serum or CSF concentration data was available without any protocol deviation interfering with these results.
    End point type
    Secondary
    End point timeframe
    0, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96 hours post-dose on Weeks 1, 4, 12, and 24
    End point values
    		 Experimental: SOBI003 3 mg/kg Experimental: SOBI003 10 mg/kg
    Number of subjects analysed
    3
    3
    Units: ng/mL
    median (full range (min-max))
        At Week 1
    33800 (29500 to 36400)
    87500 (75300 to 114000)
        At Week 4
    35700 (16200 to 36600)
    77400 (71800 to 102000)
        At Week 12
    30500 (32.5 to 36700)
    56900 (56100 to 71000)
        At Week 24
    17500 (47.5 to 35400)
    93500 (69700 to 103000)
    No statistical analyses for this end point

    Secondary: The Time at Which the Maximum Serum Concentration of SOBI003 is Observed

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    End point title
    		 The Time at Which the Maximum Serum Concentration of SOBI003 is Observed
    End point description
    The time after start of infusion at which the maximum serum concentration is observed (tmax). The table report number of available PK samples. PK analysis set consists of all subjects where at least 1 SOBI003 dose had been administered correctly and where SOBI003 serum or CSF concentration data was available without any protocol deviation interfering with these results.
    End point type
    Secondary
    End point timeframe
    Weeks 1, 4, 12, and 24
    End point values
    		 Experimental: SOBI003 3 mg/kg Experimental: SOBI003 10 mg/kg
    Number of subjects analysed
    3
    3
    Units: hours
    median (full range (min-max))
        At Week 1
    4.57 (4.27 to 4.62)
    4.33 (4.02 to 4.33)
        At Week 4
    4.28 (4.05 to 4.50)
    4.42 (4.27 to 4.90)
        At Week 12
    4.23 (4.10 to 6.42)
    6.83 (5.08 to 7.03)
        At Week 24
    4.45 (4.08 to 4.53)
    4.75 (4.47 to 5.57)
    No statistical analyses for this end point

    Secondary: The Minimum Observed Serum Concentration of SOBI003

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    End point title
    		 The Minimum Observed Serum Concentration of SOBI003
    End point description
    The minimum observed serum concentration of SOBI003 (CTrough). The table report number of available PK samples. Here “-99999 and 999” was used as a space filler which states that median or minimum or maximum data was not computed as the value was less than LLOQ. PK analysis set consists of all subjects where at least 1 SOBI003 dose had been administered correctly and where SOBI003 serum or CSF concentration data was available without any protocol deviation interfering with these results.
    End point type
    Secondary
    End point timeframe
    Weeks 1, 4, 12, and 24
    End point values
    		 Experimental: SOBI003 3 mg/kg Experimental: SOBI003 10 mg/kg
    Number of subjects analysed
    3
    3
    Units: ng/ml
    median (full range (min-max))
        At Week 1
    -99999 (-99999 to 2010)
    -99999 (-99999 to 99999)
        At Week 4
    28.9 (-99999 to 61.3)
    115 (20.8 to 7730)
        At Week 12
    26.2 (17.0 to 32.5)
    -99999 (-99999 to 29.7)
        At Week 24
    44.8 (-99999 to 47.5)
    999 (14.6 to 9010)
    No statistical analyses for this end point

    Secondary: Clearance (CL)

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    End point title
    		 Clearance (CL)
    End point description
    Clearance of SOBI003. Here,“number of subjects analysed” signifies subjects who were evaluable for this endpoint. PK analysis set consists of all subjects where at least 1 SOBI003 dose had been administered correctly and where SOBI003 serum or CSF concentration data was available without any protocol deviation interfering with these results.
    End point type
    Secondary
    End point timeframe
    Weeks 1, 4, 12, and 24
    End point values
    		 Experimental: SOBI003 3 mg/kg Experimental: SOBI003 10 mg/kg
    Number of subjects analysed
    2
    2
    Units: milliliter per hour perkilogram(mL/h/kg)
    median (full range (min-max))
        At Week 1
    10.4 (9.7 to 11.1)
    12.8 (12.0 to 13.6)
        At Week 4
    8.1 (8.0 to 8.2)
    12.75 (12.4 to 13.1)
        At Week 12
    9.5 (7.8 to 11.2)
    13.45 (12.1 to 14.8)
        At Week 24
    19.5 (10.2 to 28.8)
    10.4 (9.9 to 10.9)
    No statistical analyses for this end point

    Secondary: Area Under the Serum Concentration-time Curve From Time 0 to 168 Hours

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    End point title
    		 Area Under the Serum Concentration-time Curve From Time 0 to 168 Hours
    End point description
    Area under the serum concentration-time curve from time 0 to 168 hours (AUC 0-168h).The table report number of available PK samples. Here, “n” signifies to subjects who were evaluable for this endpoint. PK analysis set consists of all subjects where at least 1 SOBI003 dose had been administered correctly and where SOBI003 serum or CSF concentration data was available without any protocol deviation interfering with these results.
    End point type
    Secondary
    End point timeframe
    0,1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, 168 hours post-dose on Weeks 1, 4, 12, and 24
    End point values
    		 Experimental: SOBI003 3 mg/kg Experimental: SOBI003 10 mg/kg
    Number of subjects analysed
    3
    3
    Units: Hour*nanogram per milliliter (h*ng/mL)
    median (full range (min-max))
        At Week 1 (n=2,3)
    290044.5 (275152 to 304937)
    834411 (737687 to 2492658)
        At Week 4 (n=2,2)
    369915.5 (365435 to 374396)
    789106.5 (761760 to 816453)
        At Week 12 (n=2,2)
    324999.5 (267722 to 382277)
    749864 (674188 to 828540)
        At Week 24 (n=2,2)
    198973 (104009 to 293937)
    961516.5 (915941 to 1007092)
    No statistical analyses for this end point

    Secondary: Half-life

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    End point title
    		 Half-life
    End point description
    The half-life of SOBI003 in serum (T1/2). The table report number of available PK samples. Here, “number of subjects analysed” signifies subjects who were evaluable for this endpoint. PK analysis set consists of all participants where at least 1 SOBI003 dose had been administered correctly and where SOBI003 serum or CSF concentration data was available without any protocol deviation interfering with these results.
    End point type
    Secondary
    End point timeframe
    Weeks 1, 4, 12, and 24
    End point values
    		 Experimental: SOBI003 3 mg/kg Experimental: SOBI003 10 mg/kg
    Number of subjects analysed
    2
    2
    Units: Hours
    median (full range (min-max))
        At Week 1
    19.8 (5.4 to 34.2)
    22.75 (5.8 to 39.7)
        At Week 4
    34.3 (29.7 to 38.9)
    7.65 (6.3 to 9.0)
        At Week 12
    40.95 (34.4 to 47.5)
    10.75 (8.8 to 12.7)
        At Week 24
    20.85 (9.3 to 32.4)
    15.95 (6.0 to 25.9)
    No statistical analyses for this end point

    Secondary: SOBI003 Concentration in Cerebrospinal Fluid

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    End point title
    		 SOBI003 Concentration in Cerebrospinal Fluid
    End point description
    SOBI003 concentration in cerebrospinal fluid. Here, “n” signifies to subjects who are evaluable at given timepoints and “-99999” was used as a space filler which states that median or minimum or maximum data was not computed as the value was less than LLOQ. PK analysis set consists of all participants where at least 1 SOBI003 dose had been administered correctly and where SOBI003 serum or CSF concentration data was available without any protocol deviation interfering with these results.
    End point type
    Secondary
    End point timeframe
    Weeks 12 and 24
    End point values
    		 Experimental: SOBI003 3 mg/kg Experimental: SOBI003 10 mg/kg
    Number of subjects analysed
    3
    3
    Units: Milligram per liter (mg/L)
    median (full range (min-max))
        At Week 12 (n=3,1)
    -99999 (-99999 to 99999)
    17.8 (17.8 to 17.8)
        At Week 24 (n=3,3)
    -99999 (-99999 to 99999)
    47.2 (12.2 to 64.6)
    No statistical analyses for this end point

    Secondary: Number of Subjects Having Anti-drug Antibodies in Serum

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    End point title
    		 Number of Subjects Having Anti-drug Antibodies in Serum
    End point description
    Number of subjects in each dose group having anti-drug antibodies in serum. Immunogenicity set consists of those subjects in the safety analysis set who had sufficient blood samples taken for ADA testing at Baseline and at least 1 post-dose time point.
    End point type
    Secondary
    End point timeframe
    Weeks 2, 4, 8, 12 and 24
    End point values
    		 Experimental: SOBI003 3 mg/kg Experimental: SOBI003 10 mg/kg
    Number of subjects analysed
    3
    3
    Units: Subjects
        At Week 2
    1
    1
        At Week 4
    2
    3
        At Week 8
    3
    3
        At Week 12
    3
    3
        At Week 24
    3
    3
    No statistical analyses for this end point

    Secondary: Percentage of Subjects Having Anti-drug Antibodies in Cerebrospinal Fluid

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    End point title
    		 Percentage of Subjects Having Anti-drug Antibodies in Cerebrospinal Fluid
    End point description
    Percentage of subjects having anti-drug antibodies in cerebrospinal fluid. Immunogenicity set consists of those subjects in the safety analysis set who had sufficient blood samples taken for ADA testing at Baseline and at least 1 post-dose time point.
    End point type
    Secondary
    End point timeframe
    Weeks 12 and 24
    End point values
    		 Experimental: SOBI003 3 mg/kg Experimental: SOBI003 10 mg/kg
    Number of subjects analysed
    3
    3
    Units: Percentage of Subjects
    number (not applicable)
        At Week 12
    33.3
    66.7
        At Week 24
    66.7
    100
    No statistical analyses for this end point

    Secondary: Change From Baseline in Heparan Sulfate Levels in Cerebrospinal Fluid

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    End point title
    		 Change From Baseline in Heparan Sulfate Levels in Cerebrospinal Fluid
    End point description
    Change from baseline, in percent, of Heparan Sulfate levels in cerebrospinal fluid. Safety analysis set was the primary analysis set and consists of all subjects who received at least 1 dose of IMP.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 12, and 24
    End point values
    		 Experimental: SOBI003 3 mg/kg Experimental: SOBI003 10 mg/kg
    Number of subjects analysed
    3
    3
    Units: percent change
    median (full range (min-max))
        At Week 12
    -5.4 (-33.0 to 7.7)
    -52.8 (-64.6 to -28.4)
        At Week 24
    -17.5 (-26.5 to 14.7)
    -50.9 (-59.4 to 21.2)
    No statistical analyses for this end point

    Secondary: Change From Baseline in Heparan Sulfate Levels in Serum

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    End point title
    		 Change From Baseline in Heparan Sulfate Levels in Serum
    End point description
    Change from baseline in Heparan sulfate levels in serum. Safety analysis set was the primary analysis set and consists of all subjects who received at least 1 dose of IMP.
    End point type
    Secondary
    End point timeframe
    Weeks 2, 3, 4, 8, 12 and 24
    End point values
    		 Experimental: SOBI003 3 mg/kg Experimental: SOBI003 10 mg/kg
    Number of subjects analysed
    3
    3
    Units: mg/L
    median (full range (min-max))
        At Week 2
    -1.8070 (-1.891 to -0.660)
    -1.7460 (-3.409 to -1.705)
        At Week 3
    -1.22 (-2.006 to -0.220)
    -1.9190 (-3.576 to -1.856)
        At Week 4
    -1.9040 (-2.083 to -1.850)
    -1.9229 (-3.770 to -1.268)
        At Week 8
    -2.1030 (-2.210 to -1.615)
    -1.8290 (-3.730 to -1.772)
        At Week 12
    -1.8170 (-2.131 to -1.597)
    -1.8340 (-3.729 to -1.722)
        At Week 24
    -1.7480 (-2.207 to -1.657)
    -1.8310 (-3.722 to -1.818)
    No statistical analyses for this end point

    Secondary: Change From Baseline in Heparan Sulfate Levels in Urine

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    End point title
    		 Change From Baseline in Heparan Sulfate Levels in Urine
    End point description
    Change from baseline in Heparan sulfate levels in urine. Safety analysis set was the primary analysis set and consists of all subjects who received at least 1 dose of IMP.
    End point type
    Secondary
    End point timeframe
    Weeks 2, 3, 4, 8, 12 and 24
    End point values
    		 Experimental: SOBI003 3 mg/kg Experimental: SOBI003 10 mg/kg
    Number of subjects analysed
    3
    3
    Units: g/mol
    median (full range (min-max))
        At Week 2
    -421.98 (-557.33 to -258.1)
    -695.9 (-698.03 to -348.05)
        At Week 3
    -494.67 (-592.1 to -390.0)
    -597.4 (-618.8 to -309.3)
        At Week 4
    -498.53 (-575.8 to -422.79)
    -503.465 (-672.17 to -334.76)
        At Week 8
    -474.7 (-542.22 to -460.95)
    -666.81 (-672.42 to -341.70)
        At Week 12
    -534.1 (-540.71 to -442.33)
    -640.2 (-668.83 to -326.13)
        At Week 24
    -421.98 (-557.33 to -258.1)
    -695.9 (-698.03 to -348.05)
    No statistical analyses for this end point

    Secondary: Change From Baseline in Neurocognitive Development Quotient

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    End point title
    		 Change From Baseline in Neurocognitive Development Quotient
    End point description
    Quotient between age equivalent score and age, 0 - 100, where high values are desirable. The age equivalent score represents the age of the typical and normal individual who would achieve the same result as the one who was tested. The age equivalent scores are assessed by the Bayley Scales of Infant and Toddler Development®, third edition cognitive subtest or the Kaufman Assessment Battery for Children, Second edition. The Bayley Scales of Infant and Toddler Development-Third Edition is an individually administered test designed to assess developmental functioning of infants and toddlers. The Bayley-III assesses development in five areas: cognitive, language, motor, social-emotional, and adaptive behavior. The Kaufman Assessment Battery for Children (K-ABC) is a clinical instrument for assessing cognitive development. Full analysis set consists of all subjects who had a baseline assessment and at least 1 post-baseline assessment of any secondary or exploratory assessment.
    End point type
    Secondary
    End point timeframe
    Week 24
    End point values
    		 Experimental: SOBI003 3 mg/kg Experimental: SOBI003 10 mg/kg
    Number of subjects analysed
    3
    3
    Units: Unitless
    median (full range (min-max))
        At Week 24
    -8.7 (-11.2 to -4.9)
    -15.68 (-53.3 to 4.1)
    No statistical analyses for this end point

    Secondary: Change From Baseline in Age-equivalence Score

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    End point title
    		 Change From Baseline in Age-equivalence Score
    End point description
    The age equivalent score represents the age in months of the typical and normal individual who would achieve the same result as the one who was tested. The age equivalent scores are assessed by the Bayley Scales of Infant and Toddler Development®, third edition cognitive subtest or the Kaufman Assessment Battery for Children, Second edition. The Bayley Scales of Infant and Toddler Development-Third Edition is an individually administered test designed to assess developmental functioning of infants and toddlers. The Bayley-III assesses development in five areas: cognitive, language, motor, social-emotional, and adaptive behavior. The Kaufman Assessment Battery for Children (K-ABC) is a clinical instrument for assessing cognitive development. PK analysis set consists of all subjects where at least 1 SOBI003 dose had been administered correctly and where SOBI003 serum or CSF concentration data was available without any protocol deviation interfering with these results.
    End point type
    Secondary
    End point timeframe
    Week 24
    End point values
    		 Experimental: SOBI003 3 mg/kg Experimental: SOBI003 10 mg/kg
    Number of subjects analysed
    3
    3
    Units: Months
    median (full range (min-max))
        At Week 24
    -1.0 (-4 to 1)
    -3.0 (-6 to 6)
    No statistical analyses for this end point

    Secondary: Change From Baseline in Age-equivalence Score as Assessed by VABS-II

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    End point title
    		 Change From Baseline in Age-equivalence Score as Assessed by VABS-II
    End point description
    The age equivalent score represents the age in months of the typical and normal individual who would achieve the same result as the one who was tested. The age equivalent scores are assessed by Vineland™ Adaptive Behavior Scales, Expanded Interview Form, Second edition (VABS-II). The Vineland is designed to measure adaptive behavior of individuals from birth to age 90. The Vineland-II contains 5 domains each with 2-3 subdomains. The main domains are Communication, Daily Living Skills, Socialization, Motor Skills, and Maladaptive Behavior. Full analysis set consists of all subjects who had a baseline assessment and at least 1 post-baseline assessment of any secondary or exploratory assessment.
    End point type
    Secondary
    End point timeframe
    Week 24
    End point values
    		 Experimental: SOBI003 3 mg/kg Experimental: SOBI003 10 mg/kg
    Number of subjects analysed
    3
    3
    Units: Months
    median (full range (min-max))
        At week 24
    1.0 (-9 to 2)
    0.0 (-3 to 24)
    No statistical analyses for this end point

    Secondary: Change From Baseline in Gray Matter Volume

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    End point title
    		 Change From Baseline in Gray Matter Volume
    End point description
    Grey matter contains most of the brain's neuronal cell bodies. The grey matter includes regions of the brain involved in muscle control, and sensory perception such as seeing and hearing, memory, emotions, speech, decision making, and self-control. The gray matter volume will be measured by volumetric magnetic resonance imaging (MRI). Full analysis set consists of all subjects who had a baseline assessment and at least 1 post-baseline assessment of any secondary or exploratory assessment.
    End point type
    Secondary
    End point timeframe
    Week 24
    End point values
    		 Experimental: SOBI003 3 mg/kg Experimental: SOBI003 10 mg/kg
    Number of subjects analysed
    3
    3
    Units: milliliter (mL)
    median (full range (min-max))
        At Week 24
    10.858 (-6.22 to 42.27)
    39.129 (-33.28 to 111.53)
    No statistical analyses for this end point

    Secondary: Change From Baseline in Pediatric Quality of Life Inventory (PedsQL™) Total Score

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    End point title
    		 Change From Baseline in Pediatric Quality of Life Inventory (PedsQL™) Total Score
    End point description
    Pediatric Quality of Life Inventory (PedsQL™) is a modular approach to measuring health-related quality of life (HRQOL) in healthy children and adolescents and those with acute and chronic health conditions. Lower scores indicate better functioning. Min score = 0, and max score = 144. Here,“number of subjects analysed” signifies subjects who were evaluable for this endpoint.Full analysis set consists of all subjects who had a baseline assessment and at least 1 post-baseline assessment of any secondary or exploratory assessment.
    End point type
    Secondary
    End point timeframe
    Week 24
    End point values
    		 Experimental: SOBI003 3 mg/kg Experimental: SOBI003 10 mg/kg
    Number of subjects analysed
    3
    2
    Units: Units on a scale
    arithmetic mean (standard deviation)
        At week 24
    -9.3 ( 15.52 )
    -7.3 ( 14.9 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in PedsQL™ Family Impact Module Total Score

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    End point title
    		 Change From Baseline in PedsQL™ Family Impact Module Total Score
    End point description
    Pediatric Quality of Life Inventory (PedsQL™) is a modular approach to measuring health-related quality of life in healthy children and adolescents and those with acute and chronic health conditions. The measure includes a scale, from where the categorical score "4", "3", "2", "1", and "0" was reversed and linearly transformed to a 0-100 scale to 4=0, 3=25, 2=50, 1=75 and 0=100, where 100 = minimum and 0 = maximum. The Total Score is the sum of all 36 items in the test divided by the number of items answered. Higher scores indicate better functioning. Here,“number of subjects analysed” signifies subjects who were evaluable for this endpoint. Full analysis set consists of all subjects who had a baseline assessment and at least 1 post-baseline assessment of any secondary or exploratory assessment.
    End point type
    Secondary
    End point timeframe
    At Week 24
    End point values
    		 Experimental: SOBI003 3 mg/kg Experimental: SOBI003 10 mg/kg
    Number of subjects analysed
    3
    2
    Units: Units on a scale
    arithmetic mean (standard deviation)
        At Week 24
    -9.77 ( 19.05 )
    1.3 ( 3.11 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    The period for recording adverse events, including Serious Adverse Events (SAEs), began upon receiving the first dose of SOBI003 and ended at completion of the week 24 visit.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.1
    Reporting groups
    Reporting group title
    Experimental: SOBI003 3 mg/kg
    Reporting group description
    		 Subject received a dose level of SOBI003 3 mg/kg IV infusion once weekly for 24 weeks.

    Reporting group title
    Experimental: SOBI003 10 mg/kg
    Reporting group description
    		 Subject received a dose level of SOBI003 10 mg/kg IV infusion once weekly for 24 weeks.

    Serious adverse events
    		 Experimental: SOBI003 3 mg/kg Experimental: SOBI003 10 mg/kg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 3 (33.33%)
    1 / 3 (33.33%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Device related infestations
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocarditis
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
         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 / 3 (0.00%)
    1 / 3 (33.33%)
         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
    		 Experimental: SOBI003 3 mg/kg Experimental: SOBI003 10 mg/kg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    3 / 3 (100.00%)
    3 / 3 (100.00%)
    Vascular disorders
    Hyperaemia
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    General disorders and administration site conditions
    Medical device site haemorrhage
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    Application site irritation
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    1
    Pyrexia
         subjects affected / exposed
    0 / 3 (0.00%)
    3 / 3 (100.00%)
         occurrences all number
    0
    5
    Social circumstances
    Vascular device user
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    1 / 3 (33.33%)
    1 / 3 (33.33%)
         occurrences all number
    1
    2
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    Restlessness
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 3 (66.67%)
         occurrences all number
    0
    3
    Product issues
    Device damage
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
         occurrences all number
    2
    0
    Device malfunction
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    Device dislocation
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    1
    Investigations
    Activated partial thromboplastin time prolonged
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    3
    Blood fibrinogen increased
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    2
    Blood pressure diastolic increased
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    1
    Blood pressure systolic increased
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    1
    C-reactive protein increased
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    2
    CSF glucose decreased
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    1
    CSF protein increased
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    1
    Eosinophil count increased
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    2
    Haemoglobin increased
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    1
    Monocyte count decreased
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    1
    Neutrophil count increased
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    1
    Oxygen saturation decreased
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    5
    Platelet count decreased
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    1
    Red blood cell count increased
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    1
    White blood cell count increased
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    2
    Injury, poisoning and procedural complications
    Vascular access site occlusion
         subjects affected / exposed
    1 / 3 (33.33%)
    2 / 3 (66.67%)
         occurrences all number
    4
    5
    Arthropod bite
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    1
    Contusion
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    1
    Fall
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    2
    Lip injury
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    1
    Skin abrasion
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    1
    Vascular access complication
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    1
    Cardiac disorders
    Tachycardia
         subjects affected / exposed
    1 / 3 (33.33%)
    3 / 3 (100.00%)
         occurrences all number
    13
    15
    Aortic valve thickening
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    1
    Nervous system disorders
    Tremor
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 3 (33.33%)
    2 / 3 (66.67%)
         occurrences all number
    1
    4
    Clonus
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    1
    Blood and lymphatic system disorders
    Iron deficiency anaemia
         subjects affected / exposed
    1 / 3 (33.33%)
    1 / 3 (33.33%)
         occurrences all number
    1
    1
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    1 / 3 (33.33%)
    3 / 3 (100.00%)
         occurrences all number
    2
    10
    Abdominal pain upper
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    1
    Abnormal faeces
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    1
    Diarrhoea
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    6
    Faeces discoloured
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    1
    Nausea
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    1
    Skin and subcutaneous tissue disorders
    Urticaria
         subjects affected / exposed
    2 / 3 (66.67%)
    3 / 3 (100.00%)
         occurrences all number
    4
    13
    Dermatitis diaper
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    3
    Erythema
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    4
    Hyperhidrosis
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    1
    Rash
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    2
    Rash erythematous
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    1
    Infections and infestations
    Conjunctivitis
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    Gastroenteritis
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
         occurrences all number
    2
    0
    Upper respiratory tract infection
         subjects affected / exposed
    3 / 3 (100.00%)
    2 / 3 (66.67%)
         occurrences all number
    7
    3
    Viral infection
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    Otitis media acute
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    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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