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    Clinical Trial Results:
    A phase I/II, open-label, study of intracerebral administration of adeno-associated viral vector containing the human alpha-N-acetylglucosaminidase cDNA in children with Sanfilippo type B syndrome

    Summary
    EudraCT number
    2012-000856-33
    Trial protocol
    FR  
    Global end of trial date
    27 Nov 2019

    Results information
    Results version number
    v1(current)
    This version publication date
    12 Dec 2020
    First version publication date
    12 Dec 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    AMT110-CD-001
    Additional study identifiers
    ISRCTN number
    ISRCTN19853672
    US NCT number
    NCT03300453
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    uniQure biopharma B.V
    Sponsor organisation address
    Paasheuvelweg 25A, Amsterdam, Netherlands, 1105BP
    Public contact
    Elise Destree, Elise Destree, +31 20 240 6000, E.Destree@uniqure.com
    Scientific contact
    Elise Destree, Elise Destree, +31 20 240 6000, E.Destree@uniqure.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
    27 Nov 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    27 Nov 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    27 Nov 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the clinical, radiological, biological tolerance associated to the proposed treatment
    Protection of trial subjects
    Appropriate inclusion and exclusion criteria were applied. An IDMC was appointed to - be informed on the research protocol, informed consent documents and data safety reporting plans and monitoring plan; - review the study performance and safety data and make recommendation(s) to the Sponsor on further study conduct, including: o inclusion of the next patient in the protocol depending on clinical evolution of the already/previously treated subjects at 1 month after the immediate previous one, o continuation of the trial, o termination of the trial, o modification to the trial; by assessing the study progress, safety data and especially SUSARs.
    Background therapy
    The following immunosupressive/anti-inflammatory agents were used: - Modigraf (tacrolimus) - starting at 10 - 15 ng/mL, reducing progressively over the course of the study. - Cellcept (mycophenolate mofetil) - 1200 mg/m2 for 2 weeks pre-surgery and 6 weeks post surgery. - Prednisolone - 1mg/kg - for 10 days, starting on the day of surgery.
    Evidence for comparator
    n/a
    Actual start date of recruitment
    17 Sep 2013
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Safety
    Long term follow-up duration
    66 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    France: 4
    Worldwide total number of subjects
    4
    EEA total number of subjects
    4
    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)
    1
    Children (2-11 years)
    3
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    The study began on 17 September 2013 and 4 patients were enrolled on the study.

    Pre-assignment
    Screening details
    Patients were screened against the eligibility criteria. As the study consisted of a first in human trial, the patient recruitment was sequential.

    Period 1
    Period 1 title
    Initial Phase (Until M12)
    Is this the baseline period?
    Yes
    Allocation method
    Not applicable
    Blinding used
    Not blinded
    Blinding implementation details
    n/a

    Arms
    Arm title
    Human NAGLU gene - initial
    Arm description
    Patients received a one-time treatment with human NAGLU gene
    Arm type
    Experimental

    Investigational medicinal product name
    rAAV2/5-hNaGlu
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intracerebral use
    Dosage and administration details
    Administration of the investigational product (solution for injection) into the brain parenchyma and cerebellum at 8 image-guided tracks (6 cortical white matter, 2 cerebellum), with 2 deposits per track at different depths, in a single neurosurgical session. Each patient received 960 μL of vector suspension at 16 simultaneous vector deposit each containing 2.4x1011 vg (4x1012 vg in total) on Day 0 (study initial phase).

    Number of subjects in period 1
    Human NAGLU gene - initial
    Started
    4
    Completed
    4
    Period 2
    Period 2 title
    Extension Phase 1 (M12 to M30)
    Is this the baseline period?
    No
    Allocation method
    Not applicable
    Blinding used
    Not blinded
    Blinding implementation details
    n/a

    Arms
    Arm title
    Extension Phase 1
    Arm description
    Follow up -Extension Phase 1
    Arm type
    Follow Up

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 2
    Extension Phase 1
    Started
    4
    Completed
    4
    Period 3
    Period 3 title
    Extension Phase 2 (M30 to M66)
    Is this the baseline period?
    No
    Allocation method
    Not applicable
    Blinding used
    Not blinded
    Blinding implementation details
    n/a

    Arms
    Arm title
    Extension Phase 2
    Arm description
    Follow-up - Extension Phase 2
    Arm type
    Follow Up

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 3
    Extension Phase 2
    Started
    4
    Completed
    4

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Human NAGLU gene - initial
    Reporting group description
    Patients received a one-time treatment with human NAGLU gene

    Reporting group values
    Human NAGLU gene - initial Total
    Number of subjects
    4 4
    Age categorical
    Units: Subjects
        In utero
    0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0
        Newborns (0-27 days)
    0 0
        Infants and toddlers (28 days-23 months)
    1 1
        Children (2-11 years)
    3 3
        Adolescents (12-17 years)
    0 0
        Adults (18-64 years)
    0 0
        From 65-84 years
    0 0
        85 years and over
    0 0
    Gender categorical
    Units: Subjects
        Not specified
    4 4

    End points

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    End points reporting groups
    Reporting group title
    Human NAGLU gene - initial
    Reporting group description
    Patients received a one-time treatment with human NAGLU gene
    Reporting group title
    Extension Phase 1
    Reporting group description
    Follow up -Extension Phase 1
    Reporting group title
    Extension Phase 2
    Reporting group description
    Follow-up - Extension Phase 2

    Primary: Adverse Events

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    End point title
    Adverse Events [1]
    End point description
    All AEs identified in the period
    End point type
    Primary
    End point timeframe
    As specified by the period
    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: No statistical tests were performed. All patients received the same treatment. The primary objective was to look at safety.
    End point values
    Human NAGLU gene - initial Extension Phase 1 Extension Phase 2
    Number of subjects analysed
    4
    4
    4
    Units: Number of events
    63
    60
    32
    No statistical analyses for this end point

    Primary: Serious Adverse Events

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    End point title
    Serious Adverse Events [2]
    End point description
    End point type
    Primary
    End point timeframe
    As specified by the period
    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: No statistical tests were performed. All patients received the same treatment. The primary objective was to look at safety.
    End point values
    Human NAGLU gene - initial Extension Phase 1 Extension Phase 2
    Number of subjects analysed
    4
    4
    4
    Units: Number of SAEs
    1
    6
    3
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Assessed throughout study
    Adverse event reporting additional description
    Adverse events were assessed throughout the study. They data was collected in 3 time periods: - Initial Phase (Until M12) - Extension Phase 1 (M12 to M30) - Extension Phase 2 (M30 to M66)
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    18
    Reporting groups
    Reporting group title
    Initial Phase
    Reporting group description
    Adverse events collected in the Initial Phase 1

    Reporting group title
    Extension Period 1
    Reporting group description
    Adverse events collected in Extension Phase 1 (M12 to M30)

    Reporting group title
    Extension Period 2
    Reporting group description
    Adverse events collected in Extension Phase 2 (M30 to M66)

    Serious adverse events
    Initial Phase Extension Period 1 Extension Period 2
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 4 (25.00%)
    2 / 4 (50.00%)
    3 / 4 (75.00%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Nasal polyps
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pneumonia respiratory syncytial viral
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia adenoviral
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Transaminases increased
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastroenteritis
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    2 / 4 (50.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Escherichia pyelonephritis
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Electrolyte imbalance
    Additional description: Hydroelectolytic disorders linked to the bacterial infection
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    Initial Phase Extension Period 1 Extension Period 2
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    4 / 4 (100.00%)
    4 / 4 (100.00%)
    4 / 4 (100.00%)
    Surgical and medical procedures
    Central venous catheterisation
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Adenoidectomy
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Ear tube insertion
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    3 / 4 (75.00%)
    3 / 4 (75.00%)
    2 / 4 (50.00%)
         occurrences all number
    5
    7
    2
    Gait disturbance
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Hyperthermia
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Inflammation
         subjects affected / exposed
    2 / 4 (50.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    2
    0
    0
    Influenza like illness
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    3
    0
    Psychiatric disorders
    Abnormal behaviour
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    1
    Agitation
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    2 / 4 (50.00%)
         occurrences all number
    0
    0
    2
    Sleep disorder
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    1
    Reproductive system and breast disorders
    Balanoposthitis
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Investigations
    Carbon dioxide decreased
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Haematocrit decreased
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Haemoglobin decreased
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Protein total decreased
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Red blood cell count decreased
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Transaminases increased
         subjects affected / exposed
    2 / 4 (50.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    2
    0
    0
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    2 / 4 (50.00%)
         occurrences all number
    0
    0
    2
    Blood alkaline phosphatase increased
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Epstein-Barr virus test positive
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    1
    Carbon dioxide increased
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Immunosuppressant drug level increased
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Magnetic resonance imaging brain abnormal
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Varicella virus test positive
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Vitamin D decreased
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Cardiac disorders
    Left ventricular dysfunction
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Mitral valve incompetence
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Rhinitis
         subjects affected / exposed
    4 / 4 (100.00%)
    1 / 4 (25.00%)
    1 / 4 (25.00%)
         occurrences all number
    9
    1
    2
    Bronchitis
         subjects affected / exposed
    1 / 4 (25.00%)
    2 / 4 (50.00%)
    2 / 4 (50.00%)
         occurrences all number
    1
    3
    4
    Bronchitis chronic
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Cough
         subjects affected / exposed
    0 / 4 (0.00%)
    2 / 4 (50.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    3
    1
    Rhinorrhoea
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 4 (50.00%)
    1 / 4 (25.00%)
    1 / 4 (25.00%)
         occurrences all number
    2
    1
    1
    Iron deficiency anaemia
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Splenomegaly
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    1
    Nervous system disorders
    Cerebellar atrophy
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    1
    Cerebral haemosiderin deposition
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Psychomotor hyperactivity
         subjects affected / exposed
    0 / 4 (0.00%)
    2 / 4 (50.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    2
    0
    Presyncope
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Ear and labyrinth disorders
    Otitis media
         subjects affected / exposed
    2 / 4 (50.00%)
    2 / 4 (50.00%)
    1 / 4 (25.00%)
         occurrences all number
    3
    3
    1
    Nasopharyngitis
         subjects affected / exposed
    1 / 4 (25.00%)
    2 / 4 (50.00%)
    1 / 4 (25.00%)
         occurrences all number
    1
    4
    1
    Tonsillectomy
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    3 / 4 (75.00%)
    3 / 4 (75.00%)
    2 / 4 (50.00%)
         occurrences all number
    6
    6
    2
    Vomiting
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Gastroenteritis
         subjects affected / exposed
    2 / 4 (50.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    3
    0
    0
    Hepatobiliary disorders
    Hepatotoxicity
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Hypertransaminasaemia
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    2
    0
    0
    Skin and subcutaneous tissue disorders
    Dermatitis allergic
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Dermatitis atopic
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    1
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Infections and infestations
    Conjunctivitis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    1
    Ear infection
         subjects affected / exposed
    0 / 4 (0.00%)
    2 / 4 (50.00%)
    3 / 4 (75.00%)
         occurrences all number
    0
    3
    3
    Gastroenteritis viral
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Infectious mononucleosis
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Otitis externa
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    Viral infection
         subjects affected / exposed
    3 / 4 (75.00%)
    2 / 4 (50.00%)
    0 / 4 (0.00%)
         occurrences all number
    3
    2
    0
    Lung disorder
    Additional description: Lung infection
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Varicella
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    Pharyngitis
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    1
    0

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    05 Nov 2013
    Amendment 1: At the request of HCB and transmitted by the ANSM during the clinical and pharmaceutical evaluation of the AEC file, it was asked to specify the procedures for the transfer of the material (catheters) under a PSMII for purging.
    22 May 2014
    Amendment 2: In order to follow up on the 4 patients included in the clinical trial, the period of observation and follow-up of the safety of the test treatment is prolonged until 30 months post-surgery with the continuation of the treatment. immunosuppressive therapy (tacrolimus Modigraf®). This will track the progress of patients' health status and collect additional safety data and samples to meet protocol objectives.
    07 Jan 2016
    Amendment 3: 1) Change of the Promoter of the study. The Institut Pasteur transfers the legal and operational responsibility of this trial to a Dutch biotech company, uniQure biopharma B.V. (Tafelbergweg 51, 1105 BD Amsterdam, the Netherlands). 2) Extension of follow-up of 4 patients included in the 36-month clinical trial. Version 5 of protocol consisted in extending the follow-up of the 4 patients to 18 months post-surgery. With this second phase of extension, the total follow-up of the children will be 5 years, in accordance with the recommendations of the European Medicines Agency on the follow-up of patients administered with a gene therapy (EMEA / CHMP / GTWP / 60436 / 2007). It should be noted that during this second phase of extension, the dose of tacrolimus will continue to be reduced and potentially stopped from month 48 post-surgery, depending on the results of available immunological data. 3) Addition of serologies to Cytomegalovirus (CMV) and Varicella-Zoster Virus (VZV) at visits V23-M12 and V41-M30 when previous serologies are negative (note that these serologies are performed by the center at the same time as the Epstein-Barr virus serology (EBV), the results will be retrospectively collected for the V23-M12 visit that has already been performed for the 4 patients included). 4) Addition of a blood sample (volume = 3 ml) at visit V41-M30 for the analysis of total and neutralizing antibodies against transgene 5) Clarification that any adverse event spontaneously reported by the patient / parents, observed by the investigator as well as any laboratory or radiological abnormalities that occurred during the extension phase should be documented in the CRF and added a section describing the monitoring and reporting of adverse events qualified for special notification (in agreement with EMEA / CHMP / GTWP / 60436/2007)
    09 Jan 2018
    Amendment 4: The purpose of the amendment is to incorporate the tacrolimus tapering and discontinuation plan into the current protocol. This includes addition of a new Appendix which outlines the process, as well as adaptation of the protocol itself to include a new M51 (V48) sample and associated updates. In addition, administrative updates related to personnel and address changes were made, as well as correction of some typographical errors identified in the previous version.

    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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