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    Clinical Trial Results:
    A Phase 1/2 Clinical Trial for Treatment of Aromatic L-Amino Acid Decarboxylase (AADC) Deficiency Using AAV2-hAADC (Eladocagene Exuparvovec)

    Summary
    EudraCT number
    2019-003032-23
    Trial protocol
    Outside EU/EEA  
    Global end of trial date
    18 Dec 2020

    Results information
    Results version number
    v1(current)
    This version publication date
    31 Aug 2022
    First version publication date
    31 Aug 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    AADC-010
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01395641
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    National Taiwan University
    Sponsor organisation address
    7 Chung Shan South Road, Taipei City, Taiwan, 10002
    Public contact
    Wuh-Liang Hwu, National Taiwan University, 886 223123456 71938,
    Scientific contact
    Wuh-Liang Hwu, National Taiwan University, 886 223123456 71938,
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    EMEA-002435-PIP01-18
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    18 Dec 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    18 Dec 2020
    Global end of trial reached?
    Yes
    Global end of trial date
    18 Dec 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objectives of this trial were to understand if the expression of human aromatic L-amino acid decarboxylase (hAADC) gene transferred by adeno-associated viral vector, serotype 2 (AAV2) vector may facilitate the conversion from L3,4-dihydroxyphenylalanine (L-DOPA) to dopamine to improve the motor function of participants; and to ensure the safety of hAADC gene transfer by AAV2 vector for children with AADC deficiency.
    Protection of trial subjects
    This study was conducted in full accordance with the International Council for Harmonisation (ICH), Good Clinical Practice (GCP), Consolidated Guideline (E6), and any applicable national and local laws and regulations.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    08 Aug 2014
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Safety
    Long term follow-up duration
    5 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Taiwan: 10
    Worldwide total number of subjects
    10
    EEA total number of subjects
    0
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    1
    Children (2-11 years)
    9
    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
    -

    Pre-assignment
    Screening details
    A total of 10 participants were enrolled and treated in the study.

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

    Arms
    Arm title
    Eladocagene Exuparvovec
    Arm description
    Participants received eladocagene exuparvovec administered during a single operative session at a dose of 0.45×10^11 viral genomes (vg) and a volume of 80 microliters (μL) per site to 4 sites (2 per putamen), for a total dose of 1.8×10^11 vg and a total volume of 320 μL.
    Arm type
    Experimental

    Investigational medicinal product name
    Eladocagene Exuparvovec
    Investigational medicinal product code
    Other name
    AAV2-hAADC
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intracerebral use
    Dosage and administration details
    Eladocagene exuparvovec gene therapy was administered in a single operative session using an established stereotactic neurosurgical procedure at a fixed dose.

    Number of subjects in period 1
    Eladocagene Exuparvovec
    Started
    10
    Received gene therapy
    10
    Completed
    9
    Not completed
    1
         Death from Encephalitis due to Influenza B
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Eladocagene Exuparvovec
    Reporting group description
    Participants received eladocagene exuparvovec administered during a single operative session at a dose of 0.45×10^11 viral genomes (vg) and a volume of 80 microliters (μL) per site to 4 sites (2 per putamen), for a total dose of 1.8×10^11 vg and a total volume of 320 μL.

    Reporting group values
    Eladocagene Exuparvovec Total
    Number of subjects
    10 10
    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)
    9 9
        Adolescents (12-17 years)
    0 0
        Adults (18-64 years)
    0 0
        From 65-84 years
    0 0
        85 years and over
    0 0
    Age Continuous
    Units: months
        arithmetic mean (standard deviation)
    52.5 ( 30.84 ) -
    Gender Categorical
    Units: Subjects
        Female
    5 5
        Male
    5 5
    Neurotransmitter Metabolite Homovanillic Acid (HVA)
    Units: nanomoles (nmol)/liter (L)
        arithmetic mean (standard deviation)
    5.65 ( 7.95 ) -
    Neurotransmitter Metabolite 5-Hydroxyindoleacetic Acid (5-HIAA)
    Units: nmol/L
        arithmetic mean (standard deviation)
    3.10 ( 1.29 ) -

    End points

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    End points reporting groups
    Reporting group title
    Eladocagene Exuparvovec
    Reporting group description
    Participants received eladocagene exuparvovec administered during a single operative session at a dose of 0.45×10^11 viral genomes (vg) and a volume of 80 microliters (μL) per site to 4 sites (2 per putamen), for a total dose of 1.8×10^11 vg and a total volume of 320 μL.

    Primary: Change From Baseline in Neurotransmitter Metabolite Homovanillic Acid (HVA) in Cerebrospinal Fluid at Month 12

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    End point title
    Change From Baseline in Neurotransmitter Metabolite Homovanillic Acid (HVA) in Cerebrospinal Fluid at Month 12 [1]
    End point description
    The presence of neurotransmitter metabolite HVA (the metabolite of dopamine) was measured in cerebrospinal fluid (CSF). Intent-to-treat (ITT) population included all enrolled participants. Here, overall number of participants analyzed = participants evaluable for this endpoint.
    End point type
    Primary
    End point timeframe
    Baseline, Month 12
    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: Statistical analysis was not planned for this endpoint.
    End point values
    Eladocagene Exuparvovec
    Number of subjects analysed
    9
    Units: nmol/L
        arithmetic mean (standard deviation)
    26.56 ( 21.57 )
    No statistical analyses for this end point

    Primary: Change From Baseline in Neurotransmitter Metabolite 5-Hydroxyindoleacetic Acid (5-HIAA) in Cerebrospinal Fluid at Month 12

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    End point title
    Change From Baseline in Neurotransmitter Metabolite 5-Hydroxyindoleacetic Acid (5-HIAA) in Cerebrospinal Fluid at Month 12 [2]
    End point description
    The presence of neurotransmitter metabolite 5-HIAA (the metabolite of serotonin) was measured in CSF. ITT population included all enrolled participants. Here, overall number of participants analyzed = participants evaluable for this endpoint.
    End point type
    Primary
    End point timeframe
    Baseline, Month 12
    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: Statistical analysis was not planned for this endpoint.
    End point values
    Eladocagene Exuparvovec
    Number of subjects analysed
    9
    Units: nmol/L
        arithmetic mean (standard deviation)
    6.56 ( 12.72 )
    No statistical analyses for this end point

    Primary: Proportion of Participants who Achieved an Increase of at least 10-Points From Baseline in Peabody Developmental Motor Scale, Second Edition (PDMS-2) Total Score at Month 12

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    End point title
    Proportion of Participants who Achieved an Increase of at least 10-Points From Baseline in Peabody Developmental Motor Scale, Second Edition (PDMS-2) Total Score at Month 12 [3]
    End point description
    The PDMS-2 is a standardized, norm-referenced test, which includes gross motor and fine motor domains. All items of the PDMS-2 are scored on a 3-point scale (0 to 2): 0 is assigned when the child cannot perform the item or when the attempts do not meet the criteria of the item; 1 is assigned when the attempts do not meet for successful performance, but the behavior is emerging; and 2 indicates that the behavior is emerging, and the criterion for successful performance is fully met. The total score is the sum of all of the subscale scores (stationary, locomotion, object manipulation, grasping, visual-motor integration, and reflexes [the latter was not assessed in this population]) and varies based on age. The total score ranges from 0 to 482, where higher scores indicating more advanced motor function. ITT population included all enrolled participants. Here, overall number of participants analyzed = participants evaluable for this endpoint.
    End point type
    Primary
    End point timeframe
    Month 12
    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: Statistical analysis was not planned for this endpoint.
    End point values
    Eladocagene Exuparvovec
    Number of subjects analysed
    9
    Units: proportion of participants
        number (not applicable)
    1.00
    No statistical analyses for this end point

    Primary: Percentage of Participants who Achieved the Key Motor Milestones at Month 60

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    End point title
    Percentage of Participants who Achieved the Key Motor Milestones at Month 60 [4]
    End point description
    PDMS-2 motor skill items assess key motor milestones of 1) full head control (Stationary Item 10), 2) sitting unassisted (Stationary Item 14), 3) standing with support (Locomotion Item 28), and 4) walking with assistance (Locomotion Item 34), as these were the key motor milestones used to define the natural history of participants with AADC deficiency. Each skill item was assessed as a 3-level scoring system: 0 = skill is not met, 1 = skill is emerging and shows a clear resemblance to mastery, and 2 = child has mastered the motor skill. For each of the 4 key motor milestones, the numeric score of “2” was translated into mastery of the milestone, indicating that the child achieved the milestone; a score of “1” translated into demonstrating emerging skill, and was often indicative of eventually mastering the milestone; a numeric score of “0,” “or unscored” equated to “fail,” and therefore the participant did not achieve the milestone. ITT population included all enrolled participants.
    End point type
    Primary
    End point timeframe
    Month 60
    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: Statistical analysis was not planned for this endpoint.
    End point values
    Eladocagene Exuparvovec
    Number of subjects analysed
    10
    Units: percentage of participants
    number (not applicable)
        Full head control
    70.0
        Sitting unassisted
    60.0
        Standing with support
    30.0
        Walking with assistance
    20.0
    No statistical analyses for this end point

    Secondary: Number of Participants With Intracranial Bleeding That Required Surgical Treatment

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    End point title
    Number of Participants With Intracranial Bleeding That Required Surgical Treatment
    End point description
    Safety analysis set included all treated participants
    End point type
    Secondary
    End point timeframe
    Baseline up to Month 60
    End point values
    Eladocagene Exuparvovec
    Number of subjects analysed
    10
    Units: participants
    0
    No statistical analyses for this end point

    Secondary: Number of Participants With Craniotomy-induced Cerebrospinal Fluid (CSF) Exudation (CSF Leaks)

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    End point title
    Number of Participants With Craniotomy-induced Cerebrospinal Fluid (CSF) Exudation (CSF Leaks)
    End point description
    Safety analysis set included all treated participants.
    End point type
    Secondary
    End point timeframe
    Baseline up to Month 60
    End point values
    Eladocagene Exuparvovec
    Number of subjects analysed
    10
    Units: participants
    2
    No statistical analyses for this end point

    Secondary: Number of Participants With Adverse Events (AEs) Potentially Associated With Post-surgical Hyperactivity

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    End point title
    Number of Participants With Adverse Events (AEs) Potentially Associated With Post-surgical Hyperactivity
    End point description
    AEs potentially associated with post-surgical hyperactivity included dyskinesia, diarrhoea, initial insomnia, and salivary hypersecretion. Safety analysis set included all treated participants
    End point type
    Secondary
    End point timeframe
    Baseline up to Month 60
    End point values
    Eladocagene Exuparvovec
    Number of subjects analysed
    10
    Units: participants
        Dyskinesia
    10
        Diarrhoea
    7
        Initial insomnia
    4
        Salivary hypersecretion
    2
    No statistical analyses for this end point

    Secondary: Number of Participants With Treatment-Emergent Adverse Events (TEAEs)

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    End point title
    Number of Participants With Treatment-Emergent Adverse Events (TEAEs)
    End point description
    An adverse event (AE) was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. TEAEs are those AEs with an onset on or after the surgery start time; AEs with a missing onset date were considered treatment emergent. AEs included both SAEs and non-serious AEs. A summary of other non-serious AEs and all SAEs, regardless of causality is located in the 'Reported AE section'. Safety analysis set included all treated participants.
    End point type
    Secondary
    End point timeframe
    Baseline up to Month 60
    End point values
    Eladocagene Exuparvovec
    Number of subjects analysed
    10
    Units: participants
    10
    No statistical analyses for this end point

    Secondary: Change From Baseline in Body Weight at Month 12

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    End point title
    Change From Baseline in Body Weight at Month 12
    End point description
    ITT population included all enrolled participants. Here, overall number of participants analyzed = participants evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Month 12
    End point values
    Eladocagene Exuparvovec
    Number of subjects analysed
    9
    Units: kilograms (kg)
        arithmetic mean (standard deviation)
    3.39 ( 2.05 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in Putaminal Positron Emission Tomography (PET)-Specific Uptake at Month 60

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    End point title
    Change From Baseline in Putaminal Positron Emission Tomography (PET)-Specific Uptake at Month 60
    End point description
    Expression and activity of the AADC enzyme in the putamen was assessed by PET imaging using L-6-[18F] fluoro-3,4-dihydroxyphenylalnine (18F-DOPA), a positron-emitting fluorine-labeled version of levodopa, which is a substrate for AADC. The 18F-DOPA is administered intravenously, crosses the blood-brain barrier, and is taken up by the presynaptic nigrostriatal dopaminergic neurons in the putamen and converted by AADC to dopamine. Therefore, increased 18F-DOPA putamen uptake over time objectively demonstrates newly produced dopamine and the presence of functional AADC enzyme. ITT population included all enrolled participants. Here, overall number of participants analyzed = participants evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Month 60
    End point values
    Eladocagene Exuparvovec
    Number of subjects analysed
    8
    Units: millicurie (mCi)
        arithmetic mean (standard deviation)
    0.46 ( 0.17 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in PDMS-2 Total Score at Month 60

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    End point title
    Change From Baseline in PDMS-2 Total Score at Month 60
    End point description
    The PDMS-2 is a standardized, norm-referenced test, which includes gross motor and fine motor domains. All items of the PDMS-2 are scored on a 3-point scale (0 to 2): 0 is assigned when the child cannot perform the item or when the attempts do not meet the criteria of the item; 1 is assigned when the attempts do not meet for successful performance, but the behavior is emerging; and 2 indicates that the behavior is emerging, and the criterion for successful performance is fully met. The total score is the sum of all of the subscale scores (stationary, locomotion, object manipulation, grasping, visual-motor integration, and reflexes [the latter was not assessed in this population]) and varies based on age. The total score ranges from 0 to 482, where higher scores indicating more advanced motor function. ITT population included all enrolled participants. Here, overall number of participants analyzed = participants evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Month 60
    End point values
    Eladocagene Exuparvovec
    Number of subjects analysed
    8
    Units: units on a scale
        arithmetic mean (standard deviation)
    122.13 ( 77.21 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in Bayley Scale of Infant and Toddler Development, Third Edition [Bayley-III]) Total Score at Month 60

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    End point title
    Change From Baseline in Bayley Scale of Infant and Toddler Development, Third Edition [Bayley-III]) Total Score at Month 60
    End point description
    The Bayley-III has 5 main subscales: Cognitive Scale, Language Scale (expressive and receptive), Motor Scale, Social Emotional Scale, and Adaptive Behavior Scale. The Cognitive Scale includes items such as attention to familiar and unfamiliar objects, looking for a fallen object, and pretend play. The Language Scale includes understanding and expression of language, for example, recognition of objects and people, following directions, and naming objects and pictures. The study only used the cognitive scales and language scales for evaluation, and Bayley-III “total” score (refers to the sum of the Cognition, Expressive Communication, and Receptive Communication subscales) ranges from 40 to 160, where higher score indicated stronger skills and abilities and lower scores indicate possible delay/deficit. ITT population included all enrolled participants. Here, overall number of participants analyzed = participants evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Month 60
    End point values
    Eladocagene Exuparvovec
    Number of subjects analysed
    8
    Units: units on a scale
        arithmetic mean (standard deviation)
    39.75 ( 20.01 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in Alberta Infant Motor Scale (AIMS) Total Score at Month 60

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    End point title
    Change From Baseline in Alberta Infant Motor Scale (AIMS) Total Score at Month 60
    End point description
    The AIMS is a validated, 58-item observational measure that assesses the sequential development of motor milestones. Each item is scored as “observed” or “not observed,” and a point is given for each observed item. The AIMS total score is calculated by summing the scores for the 58 items, with a range of scores from 0 to 58. Higher scores indicate more advanced motor function. Each of the 58 items consists of an artist’s drawing and a photograph of a young child performing a particular movement. The AIMS scale requires minimal handling of the child and assesses the child’s movement in 4 positions: prone, supine, sitting, and standing. ITT population included all enrolled participants. Here, overall number of participants analyzed = participants evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Month 60
    End point values
    Eladocagene Exuparvovec
    Number of subjects analysed
    8
    Units: units on a scale
        arithmetic mean (standard deviation)
    25.88 ( 18.65 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline up to Month 60
    Adverse event reporting additional description
    Safety analysis set included all treated participants.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    24.0
    Reporting groups
    Reporting group title
    Eladocagene Exuparvovec
    Reporting group description
    Participants received eladocagene exuparvovec administered during a single operative session at a dose of 0.45×10^11 viral genomes (vg) and a volume of 80 microliters (μL) per site to 4 sites (2 per putamen), for a total dose of 1.8×10^11 vg and a total volume of 320 μL.

    Serious adverse events
    Eladocagene Exuparvovec
    Total subjects affected by serious adverse events
         subjects affected / exposed
    8 / 10 (80.00%)
         number of deaths (all causes)
    1
         number of deaths resulting from adverse events
    Congenital, familial and genetic disorders
    Developmental hip dysplasia
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Polydactyly
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Vascular disorders
    Hypovolaemic shock
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    3 / 10 (30.00%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Inguinal hernia
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Sleep apnoea syndrome
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Acute sinusitis
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Encephalitis influenzal
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    3 / 10 (30.00%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Pneumonia influenzal
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumonia
         subjects affected / exposed
    5 / 10 (50.00%)
         occurrences causally related to treatment / all
    0 / 12
         deaths causally related to treatment / all
    0 / 0
    Post procedural pneumonia
         subjects affected / exposed
    2 / 10 (20.00%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Septic shock
         subjects affected / exposed
    2 / 10 (20.00%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    2 / 10 (20.00%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    Eladocagene Exuparvovec
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    10 / 10 (100.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Cholesteatoma
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences all number
    1
    Vascular disorders
    Cyanosis
         subjects affected / exposed
    2 / 10 (20.00%)
         occurrences all number
    2
    Hypotension
         subjects affected / exposed
    4 / 10 (40.00%)
         occurrences all number
    4
    Pallor
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences all number
    1
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    10 / 10 (100.00%)
         occurrences all number
    15
    Peripheral swelling
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences all number
    1
    Oedema
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences all number
    1
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences all number
    1
    Reproductive system and breast disorders
    Genital erythema
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences all number
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences all number
    3
    Tonsillar hypertrophy
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences all number
    1
    Hypoxia
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences all number
    1
    Psychiatric disorders
    Initial insomnia
         subjects affected / exposed
    4 / 10 (40.00%)
         occurrences all number
    5
    Investigations
    Breath sounds abnormal
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences all number
    1
    Oxygen saturation decreased
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences all number
    1
    Injury, poisoning and procedural complications
    Thermal burn
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences all number
    1
    Tooth fracture
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences all number
    1
    Congenital, familial and genetic disorders
    Developmental hip dysplasia
         subjects affected / exposed
    2 / 10 (20.00%)
         occurrences all number
    2
    Testotoxicosis
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences all number
    1
    Cardiac disorders
    Bradycardia
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences all number
    1
    Sinus bradycardia
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences all number
    1
    Nervous system disorders
    Cerebrospinal fluid leakage
         subjects affected / exposed
    2 / 10 (20.00%)
         occurrences all number
    2
    Seizure
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences all number
    1
    Loss of consciousness
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences all number
    1
    Vocal cord paralysis
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences all number
    2
    Dyskinesia
         subjects affected / exposed
    10 / 10 (100.00%)
         occurrences all number
    18
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences all number
    1
    Ear and labyrinth disorders
    Allergic otitis media
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences all number
    1
    Eye disorders
    Eyelid disorder
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences all number
    1
    Astigmatism
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences all number
    1
    Ocular hyperaemia
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences all number
    1
    Gastrointestinal disorders
    Dental caries
         subjects affected / exposed
    2 / 10 (20.00%)
         occurrences all number
    2
    Diarrhoea
         subjects affected / exposed
    5 / 10 (50.00%)
         occurrences all number
    9
    Enteritis
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences all number
    1
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences all number
    1
    Mouth ulceration
         subjects affected / exposed
    3 / 10 (30.00%)
         occurrences all number
    3
    Oral mucosa erosion
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences all number
    1
    Salivary hypersecretion
         subjects affected / exposed
    2 / 10 (20.00%)
         occurrences all number
    2
    Stress ulcer
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences all number
    1
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    4 / 10 (40.00%)
         occurrences all number
    7
    Vomiting
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences all number
    1
    Skin and subcutaneous tissue disorders
    Decubitus ulcer
         subjects affected / exposed
    2 / 10 (20.00%)
         occurrences all number
    2
    Dermatitis
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences all number
    1
    Dermatitis contact
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences all number
    1
    Eczema
         subjects affected / exposed
    2 / 10 (20.00%)
         occurrences all number
    2
    Endocrine disorders
    Precocious puberty
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences all number
    1
    Musculoskeletal and connective tissue disorders
    Lordosis
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences all number
    1
    Scoliosis
         subjects affected / exposed
    5 / 10 (50.00%)
         occurrences all number
    5
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    2 / 10 (20.00%)
         occurrences all number
    2
    Bronchiolitis
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences all number
    1
    Acute sinusitis
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences all number
    1
    Nasopharyngitis
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences all number
    1
    Gastroenteritis
         subjects affected / exposed
    4 / 10 (40.00%)
         occurrences all number
    4
    Gingivitis
         subjects affected / exposed
    3 / 10 (30.00%)
         occurrences all number
    3
    Influenza
         subjects affected / exposed
    2 / 10 (20.00%)
         occurrences all number
    2
    Pneumonia
         subjects affected / exposed
    3 / 10 (30.00%)
         occurrences all number
    5
    Pneumonia influenzal
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences all number
    1
    Otitis media acute
         subjects affected / exposed
    2 / 10 (20.00%)
         occurrences all number
    2
    Upper respiratory tract infection
         subjects affected / exposed
    5 / 10 (50.00%)
         occurrences all number
    12
    Viral rash
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences all number
    1
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences all number
    1
    Feeding disorder
         subjects affected / exposed
    3 / 10 (30.00%)
         occurrences all number
    3
    Hypoglycaemia
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences all number
    2
    Hypokalaemia
         subjects affected / exposed
    3 / 10 (30.00%)
         occurrences all number
    3

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    30 Nov 2014
    • Updated background information for AADC deficiency in Taiwan; • Updated treatment information for AADC deficiency with citation of recent articles; • Expanded the description of the mechanism of action of PD; • Added preclinical study results; • Added description of infusion of AADC vector; • Specified the number of post-study visits and associated procedures; • Removed details of by-visit procedures as they are present in the summary of items and schedules of treatment and examinations; • Added a subsection describing dosage and infusion of viral vector; • Added a subsection on allowable concomitant medications; • Added a new section describing the expected duration of the study; • Added a new section header for classifying the radiologic and functional assessments to be used for postsurgical evaluation; • Added subsection on treatment and examination procedures to be performed at each stage of the study; • New section added to provide timing of standardized rehabilitation therapy; • Modified the endpoints to evaluate neurotransmitter metabolites and assess PDMS-2 score; • Modified the secondary endpoints to add evaluation of craniotomy-induced CSF exudation and effect on feeding and need for nasogastric tube as well as adding collection of severity information for adverse events; • New section added to describe the preparation of AAV2-hAADC viral vector and genome titers; • Included a summary of AAV2-hAADC toxicity in rats; • New section added to hypothesize the anticipated outcomes of the study; • New section header added along with introductory paragraph describing the collection of information on AEs, TEAEs, and SAEs; • Added description for management of severe symptoms; • Added description on risks of study evaluation, including respiratory risk, use of anesthesia, and lumbar puncture; • Added statements summarizing the damage and insurance compensation and withdrawal from the study;
    23 May 2019
    Updated information on subinvestigators.

    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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