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    Clinical Trial Results:
    A Phase 1/2 Open-Label Dose-Escalation Study to Evaluate Safety, Tolerability, Pharmacokinetics, and Efficacy of Intracerebroventricular BMN 190 in Patients with Late-Infantile Neuronal Ceroid Lipofuscinosis (CLN2) Disease

    Summary
    EudraCT number
    2012-005430-11
    Trial protocol
    GB   DE   IT  
    Global end of trial date
    30 Nov 2015

    Results information
    Results version number
    v1(current)
    This version publication date
    30 Jun 2019
    First version publication date
    30 Jun 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    190-201
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01907087
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    BioMarin Pharmaceutical Inc.
    Sponsor organisation address
    105 Digital Drive, Novato, CA, United States, 94949
    Public contact
    Clinical Trials Information, BioMarin Pharmacutical Inc. , clinicaltrials@bmrn.com
    Scientific contact
    Clinical Trials Information, BioMarin Pharmacutical Inc. , clinicaltrials@bmrn.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    EMEA-001362-PIP01-12
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    27 Apr 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    30 Nov 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Nov 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objectives of this study include the following: To evaluate safety and tolerability of BMN 190 administered to subjects with CLN2 by an implanted intracerebroventricular (ICV) reservoir and cannula. To evaluate effectiveness using a CLN2-specific rating scale score in comparison with natural history data after 12 months of treatment.
    Protection of trial subjects
    This clinical study was designed, conducted, recorded, and reported in compliance with the principles of Good Clinical Practice (GCP) guidelines. These guidelines are stated in U.S. federal regulations as well as Guidance for Good Clinical Practice, International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    13 Sep 2013
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Safety
    Long term follow-up duration
    6 Months
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 3
    Country: Number of subjects enrolled
    Germany: 12
    Country: Number of subjects enrolled
    Italy: 6
    Country: Number of subjects enrolled
    United States: 3
    Worldwide total number of subjects
    24
    EEA total number of subjects
    21
    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)
    24
    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
    This study was conducted at 5 clinic sites in Germany, Italy, United Kingdom and United States.

    Pre-assignment
    Screening details
    Of the 24 subjects enrolled to study, 23 subjects remained on treatment through the end of the study.

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

    Arms
    Are arms mutually exclusive
    No

    Arm title
    Dose Escalation Period - Cohort 1
    Arm description
    All study subjects administered BMN 190 by continuous Intracerebroventricular (ICV) infusion at 2.5mL/hr for approximately 4hrs every 14 days in the morning after a fast of at least 2hrs. Subjects 1 to 3 (Cohort 1) assigned to the 30mg dose, then escalated to 100mg and 300mg after data review.
    Arm type
    Experimental

    Investigational medicinal product name
    BMN 190
    Investigational medicinal product code
    Other name
    recombinant human tripeptidyl peptidase 1 (rhTPP1)
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intracerebroventricular use
    Dosage and administration details
    All study subjects administered BMN 190 by continuous Intracerebroventricular (ICV) infusion at 2.5 mL/hr for approximately 4hrs every 14 days in the morning after a fast of at least 2hrs. Subjects 1 to 3 (Cohort 1) assigned to the 30mg dose, then escalated to 100mg and 300mg after data review.

    Arm title
    Dose Escalation Period - Cohort 2
    Arm description
    All study subjects administered BMN 190 by continuous Intracerebroventricular (ICV) infusion at 2.5mL/hr for approximately 4hrs every 14 days in the morning after a fast of at least 2hrs. Subjects 4 to 6 (Cohort 2) assigned to the 100mg dose, then escalated to 300mg after data review.
    Arm type
    Experimental

    Investigational medicinal product name
    BMN 190
    Investigational medicinal product code
    Other name
    recombinant human tripeptidyl peptidase 1 (rhTPP1)
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intracerebroventricular use
    Dosage and administration details
    All study subjects administered BMN 190 by continuous Intracerebroventricular (ICV) infusion at 2.5 mL/hr for approximately 4hrs every 14 days in the morning after a fast of at least 2hrs. Subjects 4 to 6 (Cohort 2) assigned to the 100mg dose, then escalated to 300mg after data review.

    Arm title
    Dose Escalation Period - Cohort 3
    Arm description
    All study subjects administered BMN 190 by continuous Intracerebroventricular (ICV) infusion at 2.5mL/hr for approximately 4hrs every 14 days in the morning after a fast of at least 2hrs. Subjects 7 to 10 (Cohort 3) assigned to the 300mg dose.
    Arm type
    Experimental

    Investigational medicinal product name
    BMN 190
    Investigational medicinal product code
    Other name
    recombinant human tripeptidyl peptidase 1 (rhTPP1)
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intracerebroventricular use
    Dosage and administration details
    All study subjects administered BMN 190 by continuous Intracerebroventricular (ICV) infusion at 2.5 mL/hr for approximately 4hrs every 14 days in the morning after a fast of at least 2hrs. Subjects 7 to 10 (Cohort 3) assigned to the 300mg dose.

    Arm title
    Stable Dose Period - Stable Dose Only
    Arm description
    All study subjects administered BMN 190 by continuous Intracerebroventricular (ICV) infusion at 2.5mL/hr for approximately 4hrs every 14 days in the morning after a fast of at least 2hrs. Of 9 subjects from Dose Escalation cohorts rolling over into the 48-week Stable Dose Period with 14 subjects enrolled directly, counting 23 during this Stable Dose Period, all subjects were administered BMN 190 infusions of 300 mg for 48 weeks.
    Arm type
    Experimental

    Investigational medicinal product name
    BMN 190
    Investigational medicinal product code
    Other name
    recombinant human tripeptidyl peptidase 1 (rhTPP1)
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intracerebroventricular use
    Dosage and administration details
    All study subjects administered BMN 190 by continuous Intracerebroventricular (ICV) infusion at 2.5mL/hr for approximately 4hrs every 14 days in the morning after a fast of at least 2hrs. Of 9 subjects from Dose Escalation cohorts rolling over into the 48-week Stable Dose Period with 14 subjects enrolled directly, counting 23 during this Stable Dose Period, all subjects were administered BMN 190 infusions of 300 mg for 48 weeks.

    Number of subjects in period 1
    Dose Escalation Period - Cohort 1 Dose Escalation Period - Cohort 2 Dose Escalation Period - Cohort 3 Stable Dose Period - Stable Dose Only
    Started
    3
    3
    4
    23
    Completed
    3
    3
    3
    23
    Not completed
    0
    0
    1
    0
         Withdrew consent
    -
    -
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    All Participants Intervention
    Reporting group description
    -

    Reporting group values
    All Participants Intervention Total
    Number of subjects
    24 24
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    4.3 ± 1.24 -
    Gender categorical
    Units: Subjects
        Female
    15 15
        Male
    9 9
    Race
    Units: Subjects
        Asian
    1 1
        White
    23 23
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    1 1
        Not Hispanic or Latino
    23 23

    End points

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    End points reporting groups
    Reporting group title
    Dose Escalation Period - Cohort 1
    Reporting group description
    All study subjects administered BMN 190 by continuous Intracerebroventricular (ICV) infusion at 2.5mL/hr for approximately 4hrs every 14 days in the morning after a fast of at least 2hrs. Subjects 1 to 3 (Cohort 1) assigned to the 30mg dose, then escalated to 100mg and 300mg after data review.

    Reporting group title
    Dose Escalation Period - Cohort 2
    Reporting group description
    All study subjects administered BMN 190 by continuous Intracerebroventricular (ICV) infusion at 2.5mL/hr for approximately 4hrs every 14 days in the morning after a fast of at least 2hrs. Subjects 4 to 6 (Cohort 2) assigned to the 100mg dose, then escalated to 300mg after data review.

    Reporting group title
    Dose Escalation Period - Cohort 3
    Reporting group description
    All study subjects administered BMN 190 by continuous Intracerebroventricular (ICV) infusion at 2.5mL/hr for approximately 4hrs every 14 days in the morning after a fast of at least 2hrs. Subjects 7 to 10 (Cohort 3) assigned to the 300mg dose.

    Reporting group title
    Stable Dose Period - Stable Dose Only
    Reporting group description
    All study subjects administered BMN 190 by continuous Intracerebroventricular (ICV) infusion at 2.5mL/hr for approximately 4hrs every 14 days in the morning after a fast of at least 2hrs. Of 9 subjects from Dose Escalation cohorts rolling over into the 48-week Stable Dose Period with 14 subjects enrolled directly, counting 23 during this Stable Dose Period, all subjects were administered BMN 190 infusions of 300 mg for 48 weeks.

    Subject analysis set title
    300 mg BMN 190
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    The intent-to-treat (ITT) population comprises all study subjects who received any amount of study drug and report any efficacy results, excluding one subject who withdrew from the study after a single infusion of study drug. The defined ITT population has 23 enrolled subjects that received > 1 dose of study drug.

    Primary: Motor-Language (ML) Scale Score During 300 mg Dosing Period

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    End point title
    Motor-Language (ML) Scale Score During 300 mg Dosing Period [1]
    End point description
    Intent-to-treat (ITT) population The progression of ceroid lipofuscinosis (CLN2) disease was assessed using adapted motor and language domains of the Hamburg rating scale (ML scale score). Motor and Language are each 0 - 3 point subscales in which 3 represents best function and 0 represents loss of function. The sum of the motor and language scores (ML score, 0-6 points) was used to evaluate the loss of function.
    End point type
    Primary
    End point timeframe
    Baseline, Week 49/Last Assessment
    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 primary endpoint is a responder analysis based on the ITT population: absence of an unreversed two-point decline or score of zero in CLN2 score by Week 48 (Study Day 340 relative to first 300 mg infusion). The study met the primary endpoint with 20 of 23 (87%) subjects responding compared to an expected response rate of 50% (p = 0.0002). A 'response' is defined as the absence of an unreversed two-point decline or score of 0 in the 0-to-6 point CLN2 score at 48 weeks.
    End point values
    300 mg BMN 190
    Number of subjects analysed
    23
    Units: unit on scale
    arithmetic mean (standard deviation)
        Baseline
    3.5 ± 1.20
        Last Recorded Observation
    3.1 ± 1.41
        Change from Baseline to Last Recorded Observation
    -0.4 ± 0.84
    No statistical analyses for this end point

    Secondary: Percentage Change From Baseline of Magnetic Resonance Imaging (MRI) at Week 49 During 300 mg Dosing Period: Whole Brain Volume

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    End point title
    Percentage Change From Baseline of Magnetic Resonance Imaging (MRI) at Week 49 During 300 mg Dosing Period: Whole Brain Volume
    End point description
    ITT Population Percentage changes in whole brain volume from the ITT population for the 300 mg dosing period
    End point type
    Secondary
    End point timeframe
    Baseline, Week 49
    End point values
    300 mg BMN 190
    Number of subjects analysed
    23
    Units: percentage change from baseline
        arithmetic mean (standard deviation)
    -4.4 ± 8.46
    No statistical analyses for this end point

    Secondary: Percentage Change From Baseline of Magnetic Resonance Imaging (MRI) at Week 49 During 300 mg Dosing Period: Volume of Total Grey Matter

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    End point title
    Percentage Change From Baseline of Magnetic Resonance Imaging (MRI) at Week 49 During 300 mg Dosing Period: Volume of Total Grey Matter
    End point description
    ITT Population Percentage changes in volume of total grey matter from the ITT population for the 300 mg dosing period
    End point type
    Secondary
    End point timeframe
    Baseline, Week 49
    End point values
    300 mg BMN 190
    Number of subjects analysed
    23
    Units: Percentage change from baseline
        arithmetic mean (standard deviation)
    -9.7 ± 8.08
    No statistical analyses for this end point

    Secondary: Percentage Change From Baseline of Magnetic Resonance Imaging (MRI) at Week 49 During 300 mg Dosing Period: Total White Matter Volume

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    End point title
    Percentage Change From Baseline of Magnetic Resonance Imaging (MRI) at Week 49 During 300 mg Dosing Period: Total White Matter Volume
    End point description
    ITT Population Percentage changes in total white matter volume from the ITT population for the 300 mg dosing period
    End point type
    Secondary
    End point timeframe
    Baseline, Week 49
    End point values
    300 mg BMN 190
    Number of subjects analysed
    23
    Units: percentage change from baseline
        arithmetic mean (standard deviation)
    -4.2 ± 9.58
    No statistical analyses for this end point

    Secondary: Percentage Change From Baseline of Magnetic Resonance Imaging (MRI) at Week 49 During 300 mg Dosing Period: Volume of Cerebrospinal Fluid

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    End point title
    Percentage Change From Baseline of Magnetic Resonance Imaging (MRI) at Week 49 During 300 mg Dosing Period: Volume of Cerebrospinal Fluid
    End point description
    ITT population Percentage changes in volume of cerebrospinal fluid from the ITT population for the 300 mg dosing period
    End point type
    Secondary
    End point timeframe
    Baseline, Week 49
    End point values
    300 mg BMN 190
    Number of subjects analysed
    23
    Units: percentage change from baseline
        arithmetic mean (standard deviation)
    3.6 ± 15.3
    No statistical analyses for this end point

    Secondary: Percentage Change From Baseline of Magnetic Resonance Imaging (MRI) at Week 49 During 300 mg Dosing Period: Whole Brain Apparent Diffusion Coefficient

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    End point title
    Percentage Change From Baseline of Magnetic Resonance Imaging (MRI) at Week 49 During 300 mg Dosing Period: Whole Brain Apparent Diffusion Coefficient
    End point description
    ITT Population Percentage changes in whole brain apparent diffusion coefficient from the ITT population for the 300 mg dosing period
    End point type
    Secondary
    End point timeframe
    Baseline, Week 49
    End point values
    300 mg BMN 190
    Number of subjects analysed
    23
    Units: Percentage change from baseline
        arithmetic mean (standard deviation)
    0.02 ± 0.023
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to 85 weeks (60 weeks + 6 months safety follow up)
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    18.1
    Reporting groups
    Reporting group title
    Adverse Events
    Reporting group description
    -

    Serious adverse events
    Adverse Events
    Total subjects affected by serious adverse events
         subjects affected / exposed
    16 / 24 (66.67%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Injury, poisoning and procedural complications
    Infusion related reaction
         subjects affected / exposed
    1 / 24 (4.17%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    1 / 24 (4.17%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    Epilepsy
         subjects affected / exposed
    2 / 24 (8.33%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Haemorrhage intracranial
         subjects affected / exposed
    1 / 24 (4.17%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hemiparesis
         subjects affected / exposed
    1 / 24 (4.17%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Motor dysfunction
         subjects affected / exposed
    1 / 24 (4.17%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    2 / 24 (8.33%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    6 / 24 (25.00%)
         occurrences causally related to treatment / all
    8 / 8
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Dental caries
         subjects affected / exposed
    1 / 24 (4.17%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Reproductive system and breast disorders
    Vaginal discharge
         subjects affected / exposed
    1 / 24 (4.17%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Sleep apnoea syndrome
         subjects affected / exposed
    1 / 24 (4.17%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Clostridium difficile colitis
         subjects affected / exposed
    1 / 24 (4.17%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 24 (4.17%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Influenza
         subjects affected / exposed
    1 / 24 (4.17%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pharyngitis
         subjects affected / exposed
    1 / 24 (4.17%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pharyngitis bacterial
         subjects affected / exposed
    2 / 24 (8.33%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 24 (4.17%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Propionibacterium infection
         subjects affected / exposed
    1 / 24 (4.17%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Rhinovirus infection
         subjects affected / exposed
    1 / 24 (4.17%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Viral pharyngitis
         subjects affected / exposed
    1 / 24 (4.17%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Adverse Events
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    24 / 24 (100.00%)
    General disorders and administration site conditions
    Developmental delay
         subjects affected / exposed
    3 / 24 (12.50%)
         occurrences all number
    3
    Feeling jittery
         subjects affected / exposed
    2 / 24 (8.33%)
         occurrences all number
    4
    Gait disturbance
         subjects affected / exposed
    7 / 24 (29.17%)
         occurrences all number
    7
    Needle issue
         subjects affected / exposed
    2 / 24 (8.33%)
         occurrences all number
    2
    Pyrexia
         subjects affected / exposed
    13 / 24 (54.17%)
         occurrences all number
    87
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    4 / 24 (16.67%)
         occurrences all number
    6
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    5 / 24 (20.83%)
         occurrences all number
    8
    Psychiatric disorders
    Abnormal behaviour
         subjects affected / exposed
    3 / 24 (12.50%)
         occurrences all number
    3
    Agitation
         subjects affected / exposed
    2 / 24 (8.33%)
         occurrences all number
    2
    Insomnia
         subjects affected / exposed
    4 / 24 (16.67%)
         occurrences all number
    4
    Irritability
         subjects affected / exposed
    4 / 24 (16.67%)
         occurrences all number
    5
    Sleep disorder
         subjects affected / exposed
    3 / 24 (12.50%)
         occurrences all number
    4
    Investigations
    CSF test abnormal
         subjects affected / exposed
    2 / 24 (8.33%)
         occurrences all number
    2
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    6 / 24 (25.00%)
         occurrences all number
    11
    Head injury
         subjects affected / exposed
    2 / 24 (8.33%)
         occurrences all number
    3
    Laceration
         subjects affected / exposed
    2 / 24 (8.33%)
         occurrences all number
    4
    Procedural pain
         subjects affected / exposed
    2 / 24 (8.33%)
         occurrences all number
    2
    Cardiac disorders
    Bradycardia
         subjects affected / exposed
    2 / 24 (8.33%)
         occurrences all number
    2
    Nervous system disorders
    Atonic seizures
         subjects affected / exposed
    2 / 24 (8.33%)
         occurrences all number
    4
    Drop attacks
         subjects affected / exposed
    2 / 24 (8.33%)
         occurrences all number
    2
    Dystonia
         subjects affected / exposed
    4 / 24 (16.67%)
         occurrences all number
    4
    Epilepsy
         subjects affected / exposed
    11 / 24 (45.83%)
         occurrences all number
    87
    Extensor plantar response
         subjects affected / exposed
    4 / 24 (16.67%)
         occurrences all number
    4
    Generalised tonic-clonic seizure
         subjects affected / exposed
    2 / 24 (8.33%)
         occurrences all number
    3
    Headache
         subjects affected / exposed
    3 / 24 (12.50%)
         occurrences all number
    7
    Hypotonia
         subjects affected / exposed
    2 / 24 (8.33%)
         occurrences all number
    2
    Language disorder
         subjects affected / exposed
    2 / 24 (8.33%)
         occurrences all number
    2
    Myoclonus
         subjects affected / exposed
    7 / 24 (29.17%)
         occurrences all number
    14
    Partial seizures
         subjects affected / exposed
    2 / 24 (8.33%)
         occurrences all number
    3
    Petit mal epilepsy
         subjects affected / exposed
    2 / 24 (8.33%)
         occurrences all number
    2
    Pleocytosis
         subjects affected / exposed
    3 / 24 (12.50%)
         occurrences all number
    3
    Seizure
         subjects affected / exposed
    14 / 24 (58.33%)
         occurrences all number
    110
    Seizure cluster
         subjects affected / exposed
    2 / 24 (8.33%)
         occurrences all number
    4
    Tremor
         subjects affected / exposed
    4 / 24 (16.67%)
         occurrences all number
    4
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 24 (8.33%)
         occurrences all number
    3
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    2 / 24 (8.33%)
         occurrences all number
    4
    Constipation
         subjects affected / exposed
    7 / 24 (29.17%)
         occurrences all number
    10
    Diarrhoea
         subjects affected / exposed
    4 / 24 (16.67%)
         occurrences all number
    5
    Dysphagia
         subjects affected / exposed
    4 / 24 (16.67%)
         occurrences all number
    6
    Toothache
         subjects affected / exposed
    2 / 24 (8.33%)
         occurrences all number
    2
    Vomiting
         subjects affected / exposed
    11 / 24 (45.83%)
         occurrences all number
    20
    Skin and subcutaneous tissue disorders
    Dermatitis contact
         subjects affected / exposed
    2 / 24 (8.33%)
         occurrences all number
    3
    Rash
         subjects affected / exposed
    2 / 24 (8.33%)
         occurrences all number
    3
    Urticaria
         subjects affected / exposed
    2 / 24 (8.33%)
         occurrences all number
    2
    Infections and infestations
    Conjunctivitis
         subjects affected / exposed
    2 / 24 (8.33%)
         occurrences all number
    2
    Gastroenteritis
         subjects affected / exposed
    4 / 24 (16.67%)
         occurrences all number
    4
    Nasopharyngitis
         subjects affected / exposed
    7 / 24 (29.17%)
         occurrences all number
    9
    Oral herpes
         subjects affected / exposed
    2 / 24 (8.33%)
         occurrences all number
    4
    Pharyngitis
         subjects affected / exposed
    5 / 24 (20.83%)
         occurrences all number
    6
    Respiratory tract infection
         subjects affected / exposed
    2 / 24 (8.33%)
         occurrences all number
    2
    Rhinitis
         subjects affected / exposed
    5 / 24 (20.83%)
         occurrences all number
    7
    Tonsillitis
         subjects affected / exposed
    2 / 24 (8.33%)
         occurrences all number
    3
    Upper respiratory tract infection
         subjects affected / exposed
    10 / 24 (41.67%)
         occurrences all number
    17
    Urinary tract infection
         subjects affected / exposed
    2 / 24 (8.33%)
         occurrences all number
    3
    Viral infection
         subjects affected / exposed
    5 / 24 (20.83%)
         occurrences all number
    7
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    2 / 24 (8.33%)
         occurrences all number
    2

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    10 May 2013
    Amendment 1: 1. To permit sufficient study drug clearance, based on nonclinical data, the follow-up visit was changed from 4 weeks to 6 months. 2. To ensure additional precaution for subject safety, during the first dosing cohort, at least 72 hours must have elapsed between the first and second subjects. 3. To require antihistamine pretreatment, it was clarified that an antipyretic medication may not be substituted but may be added, if appropriate. 4. To be consistent with European ethics committee recommendations, subjects 16 years of age or older were excluded from study participation. 5. To add a precautionary measure for this pediatric study population, females of child-bearing potential were excluded from study participation.
    26 Jul 2013
    Amendment 2: 1. Added rationale for investigational drug infusion volume and rate. 2. Added statement regarding subject sedation during infusion at the discretion of the investigator. 3. Added statement regarding monitoring for epileptic seizure during infusion and for interrupting infusion at the discretion of the investigator. 4. For safety variables, removed head circumference assessment and replaced “length” with “height” assessment in complete physical exam. 5. Added statements regarding procedure for evaluating status of ICV access device on a regular basis. Specifically, “Surgical implantation of an ICV access device will take place prior to study drug administration. The investigator will evaluate the patency, location, and skin integrity of the reservoir at each study drug administration. At the discretion of the investigator and/or neurosurgeon, the ICV access device may be replaced during the clinical study.”
    07 Jul 2014
    Amendment 3: 1. The schedule for Magnetic resonance imaging (MRI) during the Stable Dose Period for quantitative analysis was changed be done at four time points: Baseline or Week 1 in the Stable Dose Period, and at Weeks 9, 25, and 49 in the Stable Dose Period. A screening MRI was required prior to ICV access device placement for anatomic localization. If sedation or anesthesia were required for this image sequence, the ICV access device placement would occur in the same period. 2. All adapted CLN2 scale assessments were videotaped at all site visits where the adapted CLN2 scale assessments are done. 3. For the post-implantation, first dose, and dose-escalation visits, subjects were monitored for 48 hours after infusions (with a minimum of 24 hours in the pediatric intensive care unit [PICU], and the remaining time on an inpatient ward). A follow-up phone call was also conducted within 24 hours after inpatient discharge. 4. Planned enrollment in the study was changed from 22 to “approximately 22” subjects. 5. Language was added concerning the collection of device-related adverse events (AEs) prior to the first administration of study drug. 6. Language was added detailing the risks of intracerebroventricular drug administration. 7. It was clarified that all Screening procedures are to be completed ≤ 3 days prior to the ICV access device implant surgery. 8. Baseline total and drug-specific IgE assessment was added.
    08 Aug 2014
    Amendment 4: 1. Device-related AE reporting requirements were amended to include all infusion system components that come into contact with BMN 190. 2. Subjects and their caregivers were given written instructions following ICV placement providing details about signs and symptoms of potential device complications or failure.
    24 Sep 2014
    Amendment 5: 1. Device-related AE reporting requirements were amended to include all infusion system components. 2. Language was clarified that, for Stable Dose Period visits, subjects would be closely monitored in an inpatient setting for up to 48 hours following each infusion, but could be discharged after 24 hours if medically stable and if no safety issues were observed.

    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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