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    Clinical Trial Results:
    A Phase I/II, Randomized, Safety and Ascending Dose Ranging Study of Intrathecal Idursulfase-IT administered in conjunction with intravenous Elaprase in Pediatric Patients with Hunter Syndrome and Cognitive Impairment

    Summary
    EudraCT number
    2010-020048-36
    Trial protocol
    GB  
    Global end of trial date
    29 Oct 2012

    Results information
    Results version number
    v1(current)
    This version publication date
    21 Sep 2019
    First version publication date
    01 Jan 2015
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    HGT-HIT-045
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT00920647
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Shire Human Genetic Therapies, Inc.
    Sponsor organisation address
    300 Shire Way, Lexington, United States, 02421
    Public contact
    Medical Information, Shire Human Genetic Therapies, 001 866-888-0660 ext.2 , US_ShireHGT_Medicalinformation@shire.com
    Scientific contact
    Medical Information, Shire Human Genetic Therapies, 001 866-888-0660 ext.2 , US_ShireHGT_Medicalinformation@shire.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    17 Jul 2013
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    29 Oct 2012
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To determine the safety and tolerability of ascending doses of idursulfase-IT administered via a surgically implanted intrathecal drug delivery device (IDDD) once monthly for 6 months in pediatric patients with Hunter syndrome who have cognitive impairment and who have previously received and tolerated a minimum of 6 months of treatment with Elaprase® (idursulfase for intravenous administration)
    Protection of trial subjects
    This study was conducted in compliance with the United States (US) Food and Drug Administration (FDA) Institutional Review Board (IRB) regulations in 21 Code of Federal Regulations (CFR) 56 and the International Conference on Harmonisation (ICH) Good Clinical Practice (GCP) guidelines. Cautious dose escalation and rigorous safety monitoring by a DSMB were implemented to ensure patient safety throughout this clinical study.
    Background therapy
    All patients, regardless of randomization, received a weekly infusion of Elaprase [0.5 milligram/kilogram, intravenously (IV)].
    Evidence for comparator
    -
    Actual start date of recruitment
    18 Nov 2009
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Safety
    Long term follow-up duration
    30 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United States: 11
    Country: Number of subjects enrolled
    United Kingdom: 5
    Worldwide total number of subjects
    16
    EEA total number of subjects
    5
    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)
    16
    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
    Participants took part in the study at 2 investigational sites from 18 November 2009 to 29 October 2012.

    Pre-assignment
    Screening details
    Screening of all patients occurred between 0 and 60 days prior to randomization.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Control
    Arm description
    Three dose cohorts were planned. Within each dose cohort, patients were randomized to 1 of 2 treatment options: treatment with study drug or no treatment with 4 treated patients per dose group and a total of 4 untreated patients (1-2 untreated patients were assigned in each dose cohort). Untreated patients did not undergo surgical placement of an intrathecal drug delivery device (IDDD) and did not receive Idursulfase-Intrathecal (IT).
    Arm type
    No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    Idursulfase IT (1 mg)
    Arm description
    The original design of the study was to test the dose levels of 10, 30 and 100 mg. This was based on a calculation of a minimally effective dose around 10 mg, with subsequent dose levels being chosen as increasing half-log steps. During the conduct of the study; however, it became clear that the 10 mg dose elicited a strong pharmacodynamic response, as measured by a dramatic and sustained drop in the cerebrospinal fluid (CSF) glycosaminoglycan (GAG) levels. This indicated the need to explore a lower level as a minimally effective dose level, leading to the introduction of the 1 mg group; replacing the planned 100 mg group. Enrollment of patients in this dose cohort commenced after the last patient had been enrolled in 30 mg dose cohort. Four patients were enrolled in the 1 mg dose cohort, underwent surgical placement of an IDDD, and received 1 mg idursulfase as an IT injection via the IDDD once per month (ie, every 28 days) for 6 months.
    Arm type
    Experimental

    Investigational medicinal product name
    Idursulfase
    Investigational medicinal product code
    Other name
    HGT-2310
    Pharmaceutical forms
    Injection
    Routes of administration
    Intrathecal use
    Dosage and administration details
    Injected monthly using an intrathecal drug delivery device (IDDD; PORT-A-CATH® II Low Profile™ Intrathecal Implantable Access System)

    Arm title
    Idursulfase IT (10 mg)
    Arm description
    Four patients were enrolled in the 10 mg dose cohort, underwent surgical placement of an IDDD, and received 10 mg idursulfase as an IT injection via the IDDD once per month (ie, every 28 days) for 6 months.
    Arm type
    Experimental

    Investigational medicinal product name
    Idursulfase
    Investigational medicinal product code
    Other name
    HGT-2310
    Pharmaceutical forms
    Injection
    Routes of administration
    Intrathecal use
    Dosage and administration details
    Injected monthly using an intrathecal drug delivery device (IDDD; PORT-A-CATH® II Low Profile™ Intrathecal Implantable Access System)

    Arm title
    Idursulfase IT (30 mg)
    Arm description
    Four patients were enrolled in the 30 mg dose cohort, underwent surgical placement of an IDDD, and received 30 mg idursulfase as an IT injection via the IDDD once per month (ie, every 28 days) for 6 months.
    Arm type
    Experimental

    Investigational medicinal product name
    Idursulfase
    Investigational medicinal product code
    Other name
    HGT-2310
    Pharmaceutical forms
    Injection
    Routes of administration
    Intrathecal use
    Dosage and administration details
    Injected monthly using an intrathecal drug delivery device (IDDD; PORT-A-CATH® II Low Profile™ Intrathecal Implantable Access System)

    Number of subjects in period 1
    Control Idursulfase IT (1 mg) Idursulfase IT (10 mg) Idursulfase IT (30 mg)
    Started
    4
    4
    4
    4
    Completed
    4
    4
    4
    4

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Control
    Reporting group description
    Three dose cohorts were planned. Within each dose cohort, patients were randomized to 1 of 2 treatment options: treatment with study drug or no treatment with 4 treated patients per dose group and a total of 4 untreated patients (1-2 untreated patients were assigned in each dose cohort). Untreated patients did not undergo surgical placement of an intrathecal drug delivery device (IDDD) and did not receive Idursulfase-Intrathecal (IT).

    Reporting group title
    Idursulfase IT (1 mg)
    Reporting group description
    The original design of the study was to test the dose levels of 10, 30 and 100 mg. This was based on a calculation of a minimally effective dose around 10 mg, with subsequent dose levels being chosen as increasing half-log steps. During the conduct of the study; however, it became clear that the 10 mg dose elicited a strong pharmacodynamic response, as measured by a dramatic and sustained drop in the cerebrospinal fluid (CSF) glycosaminoglycan (GAG) levels. This indicated the need to explore a lower level as a minimally effective dose level, leading to the introduction of the 1 mg group; replacing the planned 100 mg group. Enrollment of patients in this dose cohort commenced after the last patient had been enrolled in 30 mg dose cohort. Four patients were enrolled in the 1 mg dose cohort, underwent surgical placement of an IDDD, and received 1 mg idursulfase as an IT injection via the IDDD once per month (ie, every 28 days) for 6 months.

    Reporting group title
    Idursulfase IT (10 mg)
    Reporting group description
    Four patients were enrolled in the 10 mg dose cohort, underwent surgical placement of an IDDD, and received 10 mg idursulfase as an IT injection via the IDDD once per month (ie, every 28 days) for 6 months.

    Reporting group title
    Idursulfase IT (30 mg)
    Reporting group description
    Four patients were enrolled in the 30 mg dose cohort, underwent surgical placement of an IDDD, and received 30 mg idursulfase as an IT injection via the IDDD once per month (ie, every 28 days) for 6 months.

    Reporting group values
    Control Idursulfase IT (1 mg) Idursulfase IT (10 mg) Idursulfase IT (30 mg) Total
    Number of subjects
    4 4 4 4 16
    Age categorical
    Units: Subjects
        In utero
    0 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0 0 0 0
        Newborns (0-27 days)
    0 0 0 0 0
        Infants and toddlers (28 days-23 months)
    0 0 0 0 0
        Children (2-11 years)
    4 4 4 4 16
        Adolescents (12-17 years)
    0 0 0 0 0
        Adults (18-64 years)
    0 0 0 0 0
        From 65-84 years
    0 0 0 0 0
        85 years and over
    0 0 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    8.64 ± 2.462 5.61 ± 1.799 4.34 ± 0.829 6.91 ± 1.678 -
    Gender categorical
    Units: Subjects
        Female
    0 0 0 0 0
        Male
    4 4 4 4 16
    Region of Enrollment
    Units: Subjects
        United States
    3 2 4 2 11
        United Kingdom
    1 2 0 2 5

    End points

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    End points reporting groups
    Reporting group title
    Control
    Reporting group description
    Three dose cohorts were planned. Within each dose cohort, patients were randomized to 1 of 2 treatment options: treatment with study drug or no treatment with 4 treated patients per dose group and a total of 4 untreated patients (1-2 untreated patients were assigned in each dose cohort). Untreated patients did not undergo surgical placement of an intrathecal drug delivery device (IDDD) and did not receive Idursulfase-Intrathecal (IT).

    Reporting group title
    Idursulfase IT (1 mg)
    Reporting group description
    The original design of the study was to test the dose levels of 10, 30 and 100 mg. This was based on a calculation of a minimally effective dose around 10 mg, with subsequent dose levels being chosen as increasing half-log steps. During the conduct of the study; however, it became clear that the 10 mg dose elicited a strong pharmacodynamic response, as measured by a dramatic and sustained drop in the cerebrospinal fluid (CSF) glycosaminoglycan (GAG) levels. This indicated the need to explore a lower level as a minimally effective dose level, leading to the introduction of the 1 mg group; replacing the planned 100 mg group. Enrollment of patients in this dose cohort commenced after the last patient had been enrolled in 30 mg dose cohort. Four patients were enrolled in the 1 mg dose cohort, underwent surgical placement of an IDDD, and received 1 mg idursulfase as an IT injection via the IDDD once per month (ie, every 28 days) for 6 months.

    Reporting group title
    Idursulfase IT (10 mg)
    Reporting group description
    Four patients were enrolled in the 10 mg dose cohort, underwent surgical placement of an IDDD, and received 10 mg idursulfase as an IT injection via the IDDD once per month (ie, every 28 days) for 6 months.

    Reporting group title
    Idursulfase IT (30 mg)
    Reporting group description
    Four patients were enrolled in the 30 mg dose cohort, underwent surgical placement of an IDDD, and received 30 mg idursulfase as an IT injection via the IDDD once per month (ie, every 28 days) for 6 months.

    Primary: Number of Serious Adverse Events (SAE)

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    End point title
    Number of Serious Adverse Events (SAE) [1]
    End point description
    End point type
    Primary
    End point timeframe
    6 months
    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: The statistical methodology supporting the trial focused on descriptive methods given the early phase and objectives of the trial (primarily evaluation of safety). Summary tables tabulated the mean, standard deviation (SD) or standard error, 95% confidence intervals (CI) for the mean, median, minimum, and maximum values for continuous variables and the number and percentage of patients for categorical variables; a missing category was added as needed.
    End point values
    Control Idursulfase IT (1 mg) Idursulfase IT (10 mg) Idursulfase IT (30 mg)
    Number of subjects analysed
    4
    4
    4
    4
    Units: events
    0
    8
    3
    3
    No statistical analyses for this end point

    Primary: Number of Treatment Emergent Adverse Events (AE)

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    End point title
    Number of Treatment Emergent Adverse Events (AE) [2]
    End point description
    ITT patient population
    End point type
    Primary
    End point timeframe
    Baseline to Week 23
    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: The statistical methodology supporting the trial focused on descriptive methods given the early phase and objectives of the trial (primarily evaluation of safety). Summary tables tabulated the mean, standard deviation (SD) or standard error, 95% confidence intervals (CI) for the mean, median, minimum, and maximum values for continuous variables and the number and percentage of patients for categorical variables; a missing category was added as needed.
    End point values
    Control Idursulfase IT (1 mg) Idursulfase IT (10 mg) Idursulfase IT (30 mg)
    Number of subjects analysed
    4
    4
    4
    4
    Units: events
    23
    147
    116
    104
    No statistical analyses for this end point

    Primary: Safety: Changes in Cerebrospinal Fluid (CSF) White Blood Cells (WBC)

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    End point title
    Safety: Changes in Cerebrospinal Fluid (CSF) White Blood Cells (WBC) [3]
    End point description
    White blood cell count in CSF was monitored throughout the study as a way of assessing any potential inflammation of the meninges induced by idursulfase-IT.
    End point type
    Primary
    End point timeframe
    6 months
    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: The statistical methodology supporting the trial focused on descriptive methods given the early phase and objectives of the trial (primarily evaluation of safety). Summary tables tabulated the mean, standard deviation (SD) or standard error, 95% confidence intervals (CI) for the mean, median, minimum, and maximum values for continuous variables and the number and percentage of patients for categorical variables; a missing category was added as needed.
    End point values
    Control Idursulfase IT (1 mg) Idursulfase IT (10 mg) Idursulfase IT (30 mg)
    Number of subjects analysed
    4
    4
    4
    4
    Units: events
    0
    3
    1
    2
    No statistical analyses for this end point

    Primary: Safety: Development of Anti-idursulfase Antibodies (CSF)

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    End point title
    Safety: Development of Anti-idursulfase Antibodies (CSF) [4]
    End point description
    Reflects development of anti-idursulfase antibodies post baseline
    End point type
    Primary
    End point timeframe
    6 months
    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: The statistical methodology supporting the trial focused on descriptive methods given the early phase and objectives of the trial (primarily evaluation of safety). Summary tables tabulated the mean, standard deviation (SD) or standard error, 95% confidence intervals (CI) for the mean, median, minimum, and maximum values for continuous variables and the number and percentage of patients for categorical variables; a missing category was added as needed.
    End point values
    Control Idursulfase IT (1 mg) Idursulfase IT (10 mg) Idursulfase IT (30 mg)
    Number of subjects analysed
    4
    4
    4
    4
    Units: subjects
    0
    0
    0
    0
    No statistical analyses for this end point

    Primary: Safety: Development of Anti-idursulfase Antibodies (Serum)

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    End point title
    Safety: Development of Anti-idursulfase Antibodies (Serum) [5]
    End point description
    End point type
    Primary
    End point timeframe
    6 months
    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: The statistical methodology supporting the trial focused on descriptive methods given the early phase and objectives of the trial (primarily evaluation of safety). Summary tables tabulated the mean, standard deviation (SD) or standard error, 95% confidence intervals (CI) for the mean, median, minimum, and maximum values for continuous variables and the number and percentage of patients for categorical variables; a missing category was added as needed.
    End point values
    Control Idursulfase IT (1 mg) Idursulfase IT (10 mg) Idursulfase IT (30 mg)
    Number of subjects analysed
    4
    4
    4
    4
    Units: subjects
    1
    0
    0
    0
    No statistical analyses for this end point

    Primary: Clinically Significant Electrocardiogram (ECG) Findings at Any Time During the Study

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    End point title
    Clinically Significant Electrocardiogram (ECG) Findings at Any Time During the Study [6]
    End point description
    ECG parameters included: heart rate, sinus rhythm, atrial/ventricular hypertrophy, PR, QRS, QT, and QTc intervals.
    End point type
    Primary
    End point timeframe
    6 months
    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: The statistical methodology supporting the trial focused on descriptive methods given the early phase and objectives of the trial (primarily evaluation of safety). Summary tables tabulated the mean, standard deviation (SD) or standard error, 95% confidence intervals (CI) for the mean, median, minimum, and maximum values for continuous variables and the number and percentage of patients for categorical variables; a missing category was added as needed.
    End point values
    Control Idursulfase IT (1 mg) Idursulfase IT (10 mg) Idursulfase IT (30 mg)
    Number of subjects analysed
    4
    4
    4
    4
    Units: subjects
    0
    0
    1
    0
    No statistical analyses for this end point

    Secondary: Change from Baseline in CSF Glycosaminoglycans (GAGs)

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    End point title
    Change from Baseline in CSF Glycosaminoglycans (GAGs)
    End point description
    Percent change from Baseline to Week 27.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 27
    End point values
    Control Idursulfase IT (1 mg) Idursulfase IT (10 mg) Idursulfase IT (30 mg)
    Number of subjects analysed
    4
    4
    4
    4
    Units: Percent change
        arithmetic mean (standard error)
    6.68 ± 6.301
    -79.03 ± 5.167
    -90.3 ± 2.917
    -88.87 ± 1.035
    No statistical analyses for this end point

    Secondary: Level of Idursulfase in the CSF Compartment Resulting From Monthly Idursulfase IT Administrations

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    End point title
    Level of Idursulfase in the CSF Compartment Resulting From Monthly Idursulfase IT Administrations [7]
    End point description
    Samples collected from patients treated at doses of 1 mg and 30 mg, as well as the control group, were below the lower limit of detection of the bioanalytical method (3.13 nanogram/millilitre).
    End point type
    Secondary
    End point timeframe
    Week 27 (end of study)
    Notes
    [7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Subjects in the control group did not receive Idursulfase-IT, so the concentration of CSF Idursulfase could not be measured in these patients. Samples collected from subjects in the 1 mg group and the 30 mg group were below the lower limit of detection of the bioanalytical method (3.13 ng/mL).
    End point values
    Idursulfase IT (10 mg)
    Number of subjects analysed
    4
    Units: nanogram/millilitre
        arithmetic mean (standard deviation)
    6.74 ± 12.02
    No statistical analyses for this end point

    Secondary: Concentration of Idursulfase in the Serum After a Single Administration in Conjunction With Elaprase

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    End point title
    Concentration of Idursulfase in the Serum After a Single Administration in Conjunction With Elaprase [8]
    End point description
    Values below lower limit of quantitation (LLOQ) are listed as 0.
    End point type
    Secondary
    End point timeframe
    Week 3
    Notes
    [8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Subjects in the control group did not receive Idursulfase-IT, so the concentration of serum Idursulfase could not be measured in these patients. Data were not available for the calculations in the patients of 1 mg Idursulfase-IT group at Week 3.
    End point values
    Idursulfase IT (10 mg) Idursulfase IT (30 mg)
    Number of subjects analysed
    4
    3
    Units: minutes*nanogram/millilitre
        arithmetic mean (standard deviation)
    140022 ± 45479
    228840 ± 37909
    No statistical analyses for this end point

    Secondary: Concentration of Idursulfase in Serum After Repeated Doses of Intrathecal Idursulfase-IT Given in Conjunction With Elaprase

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    End point title
    Concentration of Idursulfase in Serum After Repeated Doses of Intrathecal Idursulfase-IT Given in Conjunction With Elaprase [9]
    End point description
    End point type
    Secondary
    End point timeframe
    Week 23
    Notes
    [9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Subjects in the control group did not receive Idursulfase-IT, so the concentration of serum Idursulfase could not be measured in these patients.
    End point values
    Idursulfase IT (1 mg) Idursulfase IT (10 mg) Idursulfase IT (30 mg)
    Number of subjects analysed
    1
    4
    4
    Units: min*ng/mL
        arithmetic mean (standard deviation)
    31481 ± 0
    150544 ± 43871
    174247 ± 49795
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in Urinary GAGs

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    End point title
    Percent Change From Baseline in Urinary GAGs
    End point description
    Percent change from Baseline to Week 27.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 27
    End point values
    Control Idursulfase IT (1 mg) Idursulfase IT (10 mg) Idursulfase IT (30 mg)
    Number of subjects analysed
    4
    4
    4
    4
    Units: Percent change
        arithmetic mean (standard error)
    -7.67 ± 20.82
    37.83 ± 27.971
    -22.38 ± 4.84
    29.7 ± 13.7
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Time of informed consent until 30 days after the patient's end of study visit.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    12.0
    Reporting groups
    Reporting group title
    Control
    Reporting group description
    Untreated patients

    Reporting group title
    Idursulfase Intrathecal (IT) (1 mg)
    Reporting group description
    -

    Reporting group title
    Idursulfase IT (10 mg)
    Reporting group description
    -

    Reporting group title
    Idursulfase IT (30 mg)
    Reporting group description
    -

    Serious adverse events
    Control Idursulfase Intrathecal (IT) (1 mg) Idursulfase IT (10 mg) Idursulfase IT (30 mg)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 4 (0.00%)
    3 / 4 (75.00%)
    2 / 4 (50.00%)
    2 / 4 (50.00%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Injury, poisoning and procedural complications
    Device dislocation
    Additional description: Untreated control patients did not have the IDDD implanted.
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Complication of device insertion
    Additional description: Untreated control patients did not have the IDDD implanted.
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Device breakage
    Additional description: Untreated control patients did not have the IDDD implanted.
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Device connection issue
    Additional description: Untreated control patients did not have the IDDD implanted.
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Device failure
    Additional description: Untreated control patients did not have the IDDD implanted.
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Device malfunction
    Additional description: Untreated control patients did not have the IDDD implanted.
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Wound dehiscence
    Additional description: Untreated control patients did not have the IDDD implanted.
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Implant site infection
    Additional description: Untreated control patients did not have the intrathecal drug delivery device (IDDD) implanted.
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    2 / 4 (50.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Control Idursulfase Intrathecal (IT) (1 mg) Idursulfase IT (10 mg) Idursulfase IT (30 mg)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    4 / 4 (100.00%)
    4 / 4 (100.00%)
    4 / 4 (100.00%)
    4 / 4 (100.00%)
    Vascular disorders
    Blood pressure fluctuation
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    2 / 4 (50.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    3
    0
    Flushing
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    2 / 4 (50.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    4
    0
    Haematoma
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    1
    Hypotension
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Surgical and medical procedures
    Tooth extraction
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Immune system disorders
    Seasonal allergy
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    General disorders and administration site conditions
    Catheter related complication
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    1 / 4 (25.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    1
    2
    Catheter site erythema
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Catheter site haematoma
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Extravasation
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Fatigue
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    1
    0
    0
    1
    Implant site effusion
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Implant site erythema
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Implant site scar
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Implant site swelling
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    2
    1
    Infusion site extravasation
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    2
    Oedema peripheral
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    1
    Pyrexia
         subjects affected / exposed
    0 / 4 (0.00%)
    2 / 4 (50.00%)
    0 / 4 (0.00%)
    2 / 4 (50.00%)
         occurrences all number
    0
    4
    0
    3
    Psychiatric disorders
    Abnormal behaviour
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    1
    Aggression
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    3
    0
    0
    Agitation
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Anxiety
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    1
    Insomnia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    1
    Personality change
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Staring
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Injury, poisoning and procedural complications
    Agitation postoperative
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Arthropod bite
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    0
    1
    Burns first degree
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Contusion
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    2 / 4 (50.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Device malfunction
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Drug delivery system malfunction
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Excoriation
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    2
    1
    Medical device complication
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Procedural complication
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Procedural pain
         subjects affected / exposed
    3 / 4 (75.00%)
    4 / 4 (100.00%)
    4 / 4 (100.00%)
    2 / 4 (50.00%)
         occurrences all number
    3
    5
    7
    2
    Procedural site reaction
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    2 / 4 (50.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Scratch
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Skin laceration
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    1
    Suture related complication
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    1
    Thermal burn
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    1
    Traumatic lumbar puncture
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Investigations
    Activated partial thromboplastin time prolonged
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    1
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Blood calcium decreased
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    1
    Blood chloride increased
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    1
    0
    0
    1
    Blood phosphorus decreased
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    1
    Blood pressure decreased
         subjects affected / exposed
    0 / 4 (0.00%)
    2 / 4 (50.00%)
    2 / 4 (50.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    4
    5
    0
    Blood pressure diastolic decreased
         subjects affected / exposed
    0 / 4 (0.00%)
    2 / 4 (50.00%)
    3 / 4 (75.00%)
    2 / 4 (50.00%)
         occurrences all number
    0
    6
    9
    10
    Blood pressure diastolic increased
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 4 (25.00%)
    1 / 4 (25.00%)
    1 / 4 (25.00%)
         occurrences all number
    1
    1
    2
    5
    Blood pressure increased
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    2
    0
    Blood pressure systolic decreased
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    2 / 4 (50.00%)
    2 / 4 (50.00%)
         occurrences all number
    0
    7
    3
    6
    Blood pressure systolic increased
         subjects affected / exposed
    1 / 4 (25.00%)
    2 / 4 (50.00%)
    2 / 4 (50.00%)
    2 / 4 (50.00%)
         occurrences all number
    1
    10
    5
    8
    Blood thyroid stimulating hormone decreased
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    1
    1
    Blood thyroid stimulating hormone increased
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Blood triglycerides increased
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Body temperature decreased
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    1 / 4 (25.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    3
    1
    1
    Body temperature increased
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    1
    0
    CSF cell count increased
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    1 / 4 (25.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    2
    1
    2
    CSF glucose decreased
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    2 / 4 (50.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    2
    0
    CSF protein increased
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    1 / 4 (25.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    2
    1
    2
    CSF white blood cell count increased
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Cardiac murmur
         subjects affected / exposed
    0 / 4 (0.00%)
    2 / 4 (50.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    2
    0
    2
    Electrocardiogram QT prolonged
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Haematocrit decreased
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Haemoglobin decreased
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Heart rate decreased
         subjects affected / exposed
    1 / 4 (25.00%)
    2 / 4 (50.00%)
    1 / 4 (25.00%)
    1 / 4 (25.00%)
         occurrences all number
    1
    8
    2
    1
    Heart sounds abnormal
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Mean cell volume abnormal
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Neutrophil count decreased
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Oxygen saturation decreased
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    PCO2 decreased
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    1
    Protein total decreased
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    2 / 4 (50.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    5
    1
    Red blood cell count decreased
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Red blood cells CSF positive
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    0
    1
    Respiratory rate decreased
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Respiratory rate increased
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Thyroxine decreased
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Vitamin D decreased
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Cardiac disorders
    Atrioventricular block first degree
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    1
    Cyanosis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    1
    Left atrial hypertrophy
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Left ventricular hypertrophy
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Mitral valve incompetence
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Mitral valve prolapse
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Tachycardia
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Congenital, familial and genetic disorders
    Bicuspid aortic valve
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Aspiration
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    1
    Choking
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Cough
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    3
    Epistaxis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    1
    Hypoxia
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Nasal congestion
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    3
    0
    1
    Oropharyngeal pain
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Productive cough
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Rhinorrhoea
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Sneezing
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    1
    Stridor
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Upper respiratory tract congestion
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    0
    1
    Eosinophilia
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Lymphadenopathy
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    1
    Microcytosis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Nervous system disorders
    Carpal tunnel syndrome
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    1
    Clonus
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    2 / 4 (50.00%)
         occurrences all number
    0
    2
    0
    5
    Dyskinesia
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Headache
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    3 / 4 (75.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    3
    0
    Hyperreflexia
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    0
    1
    Psychomotor hyperactivity
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    2
    1
    Pyramidal tract syndrome
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    0
    1
    Sensory integrative dysfunction
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Syncope
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Eye disorders
    Ocular hyperaemia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Ear and labyrinth disorders
    Ear pain
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Middle ear effusion
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Motion sickness
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Otorrhoea
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    2 / 4 (50.00%)
    2 / 4 (50.00%)
         occurrences all number
    0
    2
    2
    2
    Tympanic membrane disorder
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    1
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Constipation
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    1
    Diarrhoea
         subjects affected / exposed
    0 / 4 (0.00%)
    2 / 4 (50.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    4
    2
    0
    Dysphagia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    1
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Nausea
         subjects affected / exposed
    0 / 4 (0.00%)
    2 / 4 (50.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Umbilical hernia
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Vomiting
         subjects affected / exposed
    1 / 4 (25.00%)
    2 / 4 (50.00%)
    3 / 4 (75.00%)
    1 / 4 (25.00%)
         occurrences all number
    1
    6
    7
    1
    Renal and urinary disorders
    Urinary incontinence
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Skin and subcutaneous tissue disorders
    Dermatitis diaper
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Dry skin
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Eczema
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Erythema
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    1 / 4 (25.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    1
    1
    Pruritus
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Rash
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    2 / 4 (50.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Swelling face
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Urticaria
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Neck pain
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Pain in extremity
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Scoliosis
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Tendon disorder
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Toe walking
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Dehydration
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Pica
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Infections and infestations
    Anorectal infection
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Ear infection
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Eye infection
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Gastrointestinal infection
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Herpes zoster
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Implant site infection
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    1
    Otitis media
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    2 / 4 (50.00%)
         occurrences all number
    0
    1
    0
    2
    Rhinitis
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 4 (25.00%)
    3 / 4 (75.00%)
    3 / 4 (75.00%)
    4 / 4 (100.00%)
         occurrences all number
    1
    3
    3
    5
    Urinary tract infection
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    01 Feb 2008
    Clarify information and text related to: • Safety-related stopping rules (such that if any patient experienced a study drug-related, life-threatening [Grade 4] AE or death, or if 2 or more patients experienced a Grade 3 AE considered possibly or probably related to study drug by the sponsor, then the site would be instructed to halt idursulfase-IT administration to all patients).
    25 Jul 2008
    • Allow for surgical insertion of the IDDD (PORT-A-CATH device); • Allow for the addition of 4 patients to participate in screening, baseline, and end of study procedures, but not to receive the IDDD or study drug; • Clarify information and text related to: • Safety-related stopping rules (such that if any patient experienced a study drug-related, life-threatening [Grade 4] AE or death, or if 2 or more patients experienced a Grade 3 AE considered possibly or probably related to study drug by the sponsor, then the site would be instructed to halt idursulfase-IT administration to all patients). • Updating and reformatting of references.
    29 Oct 2008
    • Incorporated an independent review by a DSMB • Allow for proteomic marker testing in plasma and CSF • Clarify information and text related to: • The removal of the abbreviation I2S for the drug product idursulfase • The definition of infusion-related reactions and SAE reporting
    21 Jan 2009
    • Clarify information and text related to: • Secondary endpoints (minor change in text); • Inclusion criteria (added an alternate way to show evidence of early stage Hunter syndrome-related CNS involvement, specifically if the patient is assessed to be between 2 and 3 standard deviations below the mean overall IQ of the healthy population); • Study procedures (clarification of study visit dates, change in text for hearing assessments, addition of X-ray to confirm placement of the device, addition of text regarding neurological screening assessments performed on Day 7); • Clarify that the safety analysis population is to include all enrolled patients; • Include information about an extension study.
    08 Jul 2009
    • Clarify information and text related to: • Removal of redundant text from inclusion criterion 3b; • Removal of the IDDD in patients who discontinue participation in the study; • CSF sampling and measurement of opening pressure; • Study procedures (components of physical examinations, timing of vision and hearing assessment, serum chemistry assessments, urinary GAG assessments, auditory brainstem response, surgical implantation of the IDDD [suture removal, removal of a nonfunctional device], performance of X-ray, timing of neurological assessments, neurodevelopmental/behavioral assessments.)
    21 Oct 2009
    • Clarify information and text related to: • Dose escalation guidelines (role of DSMB); • Inclusion criterion 1b (add documented mutation of iduronate-2 sulfatase gene as part of eligibility for the trial); • Inclusion criteria 3 (relating to increase in the acceptable range of IQ values – changed from “between 2 and 3 standard deviations below the mean” to “from 2 to 3.5 standard deviations below the mean” • Study procedures (timing of serum chemistry assessments, BRIEF neurobehavioral assessment, removal of local postoperative neurological examination at week 2); • Update to Medical Monitor’s contact information.
    23 Mar 2010
    • Clarify information and text related to: • Inclusion criteria (increase the acceptable IQ range and description of cognitive impairment in terms of IQ score: an IQ between 77 and 47 (corresponding to a level between 1.5 and 3.5 standard deviations below the mean overall IQ of the healthy population) • Exclusion criteria (revision of IQ criteria consistent with change to inclusion criterion above, minor change to clarify that opening CSF pressure upon lumbar puncture may not exceed 30.0 cm H20); • Study procedures (revise timing of baseline assessments to precede enrollment/randomization and to be completed in conjunction with confirmatory screening assessments, revise the naming of study visits, institute a delay between randomization and the initial study week for untreated patients to align elapsed time on study with that of treated patients, institute an interim safety follow-up telephone contact for untreated patients, increase the allowable window for the screening visit neurodevelopmental assessments); • Corrections or clarifications to terminologies. • Revise safety objectives of the study to emphasize that the study’s primary objective and respective endpoint is the investigation of the safety and tolerability of idursulfase-IT; • Allow for more than one main clinical site; • Clarify communication between the medical monitor and investigator(s) of reviewed patient safety data.
    07 Jun 2010
    • Clarify information and text related to: • Feed back from the clinical site regarding the labels describing timing of the study periods and study assessments. The study assessment weeks were modified to revert numbering and titles of study weeks to that described in Amendment 6; • Study procedures (clarify timing of randomization (Day 0), eliminate Day 2 neurological exam, correct timing of the brief neurodevelopmental assessment; • Revise text requiring that all deaths during the study be reported to the IEC/IRB. Expedited reports of study drug-related deaths are to be provided to the IRB; however, reporting of nonrelated deaths is not required by IEC/IRB, and the statement that details reporting unrelated deaths was stricken from the protocol.
    16 Aug 2010
    • Clarify information and text related to: • Inclusion criteria modified to include: • Pediatric patients from 3 to 17 years of age, inclusive, with Hunter syndrome who have cognitive impairment defined as a measurable IQ of 77 or less • Flexibility in the protocol language such that potentially eligible patients with inadequate cognitive status for full neurodevelopmental testing may still be acceptable for participation in the study; • Study procedures (addition of the BSID-III to the protocol as an alternative to the DASII) • Text was added describing the classification of AEs with respect to study drug, study drug administration device, and associated procedures. • Introductory text was updated with currently available information concerning the safety profiles of idursulfase-IT and Elaprase derived from the current edition of the Idursulfase-IT Investigator’s Brochure. • Minor edits and/or corrections were made to more closely align in-text descriptions of study procedures with tabulations and footnotes in the Schedules of Study Procedures.
    09 Feb 2011
    • Clarify information and text related to: • The period of time for conduct of screening assessments was extended from 30 days to 60 days; • The timing of patient enrollment during the dose escalation process was modified such that the third and fourth patients within a dose group could both be enrolled upon confirmation of safety following administration of the first dose of study drug to the second patient (previous versions of the protocol required that dosing of the fourth patient be delayed until the third patient had received the first dose of study drug).
    26 Apr 2011
    • Clarify information and text related to: • The timing of vital sign and urine GAG assessments for treated patients; • Updated safety information concerning idursulfase-IT and Elaprase from ongoing studies; • Introduce an additional dose group (Group 4) of 4 patients to receive 6 monthly doses of idursulfase–IT at a revised lowest planned dose level (1 mg) to be administered during the study. The addition of this new dose group was intended to explore the lower end of the dose-response relationship.
    20 Jul 2011
    • Clarify information and text related to: • Operational aspects of the study, most notably, adjustments to the timing of PK evaluations; • Updated safety information concerning IDDD and an appendix intended to assist in investigation and management in the event of a mechanical IDDD failure; • Clarify that the 2 no-treatment patients originally intended for the 100 mg cohort would instead be randomized as part of the 1 mg cohort.
    10 Apr 2012
    • To eliminate evaluation of idursulfase-IT at the highest initially planned dose level of 100 mg • Clarify information and text related to: • Operational aspects of the study, including clarifications to the timing of pre-treatment urine sample and PK blood sample collection, allowance of a time window for vital signs collection • To include up-to-date nonclinical and clinical safety data derived from the annual update of the Idursulfase-IT Investigator’s Brochure (data cutoff date 19 January 2012) • To remove information specific to the Smith’s Medical IDDD in relation to investigation and management of device failures • To define the Intent-to-Treat (ITT) analysis population as all randomized patients.

    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.
    Untreated control subjects were not implanted with an IDDD. Concentration of idursulfase in all CSF samples post single dose of idursulfase-IT were below the lower limit of quantitation of the bioanalytical method; therefore no results are reported.
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