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    Clinical Trial Results:
    A Clinical Trial for Treatment of Aromatic L-Amino Acid Decarboxylase (AADC) Deficiency Using AAV2-hAADC - An Expansion

    Summary
    EudraCT number
    		 2019-003072-39
    Trial protocol
    		 Outside EU/EEA  
    Global end of trial date
    24 Jan 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    01 Sep 2022
    First version publication date
    01 Sep 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    NTUH-AADC-011
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02926066
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    National Taiwan University Hospital
    Sponsor organisation address
    7 Chung Shan South Road, Taipei City, Taiwan, 10002
    Public contact
    Yin-Hsiu Chien, National Taiwan University Hospital, Department of Pediatrics and Medical Genetics, 886 2 23123456 71937,
    Scientific contact
    Yin-Hsiu Chien, National Taiwan University Hospital, Department of Pediatrics and Medical Genetics, 886 2 23123456 71937,
    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
    19 May 2022
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    24 Jan 2022
    Global end of trial reached?
    Yes
    Global end of trial date
    24 Jan 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    This study evaluated the safety and efficacy of eladocagene exuparvovec in AADC-deficient participants who were not enrolled into the Phase 1/2 trial (AADC-010). This study was designed to extend the experience in this gene therapy and to slightly increase the dosage in participants younger than 3 years old.
    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
    09 Nov 2016
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Efficacy, Ethical reason, Scientific research, Safety
    Long term follow-up duration
    		 13 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Taiwan: 12
    Worldwide total number of subjects
    12
    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)
    6
    Children (2-11 years)
    6
    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
    		 Individuals with a confirmed diagnosis of AADC deficiency between the ages of 2 and 6 at time of surgery were eligible to participate in the study.

    Pre-assignment
    Screening details
    		 A total of 12 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
    Are arms mutually exclusive
    Yes

    Arm title
    		 Eladocagene Exuparvovec 1.8×10^11 vg
    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.

    Arm title
    		 Eladocagene Exuparvovec 2.4×10^11 vg
    Arm description
    		 Participants received eladocagene exuparvovec administered during a single operative session at a dose of 0.6×10^11 vg and a volume of 80 μL per site to 4 sites (2 per putamen), for a total dose of 2.4×10^11 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 1.8×10^11 vg Eladocagene Exuparvovec 2.4×10^11 vg
    Started
    3
    9
    Completed
    3
    9

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Eladocagene Exuparvovec 1.8×10^11 vg
    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 title
    Eladocagene Exuparvovec 2.4×10^11 vg
    Reporting group description
    		 Participants received eladocagene exuparvovec administered during a single operative session at a dose of 0.6×10^11 vg and a volume of 80 μL per site to 4 sites (2 per putamen), for a total dose of 2.4×10^11 vg and a total volume of 320 μL.

    Reporting group values
    		 Eladocagene Exuparvovec 1.8×10^11 vg Eladocagene Exuparvovec 2.4×10^11 vg Total
    Number of subjects
    		 3 9 12
    Age Categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 6 6
        Children (2-11 years)
    		 3 3 6
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 0 0 0
        From 65-84 years
    		 0 0 0
        85 years and over
    		 0 0 0
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 55.0 ( 13.23 ) 23.3 ( 3.32 ) -
    Gender Categorical
    Units: Subjects
        Female
    		 1 3 4
        Male
    		 2 6 8
    Subject analysis sets

    Subject analysis set title
    Overall
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All participants treated with eladocagene exuparvovec.

    Subject analysis sets values
    		 Overall
    Number of subjects
    12
    Age Categorical
    Units: Subjects
        In utero
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
        Newborns (0-27 days)
    0
        Infants and toddlers (28 days-23 months)
    6
        Children (2-11 years)
    6
        Adolescents (12-17 years)
    0
        Adults (18-64 years)
    0
        From 65-84 years
    0
        85 years and over
    0
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    31.3 ( 15.65 )
    Gender Categorical
    Units: Subjects
        Female
    4
        Male
    8

    End points

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    End points reporting groups
    Reporting group title
    Eladocagene Exuparvovec 1.8×10^11 vg
    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 title
    Eladocagene Exuparvovec 2.4×10^11 vg
    Reporting group description
    		 Participants received eladocagene exuparvovec administered during a single operative session at a dose of 0.6×10^11 vg and a volume of 80 μL per site to 4 sites (2 per putamen), for a total dose of 2.4×10^11 vg and a total volume of 320 μL.

    Subject analysis set title
    Overall
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All participants treated with eladocagene exuparvovec.

    Primary: Proportion of Participants Achieving Key Motor Milestones at Month 12, Assessed Using the Peabody Developmental Motor Scale, Second Edition (PDMS-2)

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    End point title
    		 Proportion of Participants Achieving Key Motor Milestones at Month 12, Assessed Using the Peabody Developmental Motor Scale, Second Edition (PDMS-2) [1]
    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 key motor milestones used to define the natural history of participants with AADC deficiency. Skill items were 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, numeric score of “2” was translated into mastery of the milestone, indicating that the child achieved the milestone; score of “1” translated into demonstrating emerging skill, and was often indicative of eventually mastering the milestone; score of “0,” “or unscored” equated to “fail,” and therefore the participant did not achieve the milestone. Intent-to-treat (ITT) population included all enrolled participants.
    End point type
    Primary
    End point timeframe
    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: As per statistical analysis plan, no statistical analysis was conducted.
    End point values
    		 Eladocagene Exuparvovec 1.8×10^11 vg Eladocagene Exuparvovec 2.4×10^11 vg Overall
    Number of subjects analysed
    3
    7 [2]
    10
    Units: proportion of participants
    number (confidence interval 95%)
        Achieved full head control (score of 2)
    0.3333 (0.0084 to 0.9057)
    0.8571 (0.4213 to 0.9964)
    0.7000 (0.3475 to 0.9333)
        Achieved sitting unassisted (score of 2)
    0.0000 (0.0000 to 0.7076)
    0.4286 (0.0990 to 0.8159)
    0.3000 (0.0667 to 0.6525)
        Achieved standing with support (score of 2)
    0.0000 (0.0000 to 0.7076)
    0.0000 (0.0000 to 0.4096)
    0.0000 (0.0000 to 0.3085)
        Achieved walking with assistance (score of 2)
    0.0000 (0.0000 to 0.7076)
    0.0000 (0.0000 to 0.4096)
    0.0000 (0.0000 to 0.3085)
    Notes
    [2] - Only 7 of the 9 enrolled participants were assessed at Month 12.
    No statistical analyses for this end point

    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 [3]
    End point description
    The presence of neurotransmitter metabolite HVA (the metabolite of dopamine) was measured in cerebrospinal fluid (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
    [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: As per statistical analysis plan, no statistical analysis was conducted.
    End point values
    		 Eladocagene Exuparvovec 1.8×10^11 vg Eladocagene Exuparvovec 2.4×10^11 vg Overall
    Number of subjects analysed
    3
    7 [4]
    10
    Units: nmol/L
    arithmetic mean (standard deviation)
        Baseline
    16.17 ( 17.58 )
    16.44 ( 16.16 )
    16.38 ( 15.69 )
        Change from Baseline
    15.17 ( 3.88 )
    25.07 ( 16.16 )
    22.10 ( 14.16 )
    Notes
    [4] - Only 7 of the 9 enrolled participants were assessed at Month 12.
    No statistical analyses for this end point

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

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    End point title
    		 Change From Baseline in Neurotransmitter Metabolite 5-Hydroxyindoleacetic Acid (5-HIAA) in Cerebrospinal Fluid (CSF) at Month 12 [5]
    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
    [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: As per statistical analysis plan, no statistical analysis was conducted.
    End point values
    		 Eladocagene Exuparvovec 1.8×10^11 vg Eladocagene Exuparvovec 2.4×10^11 vg Overall
    Number of subjects analysed
    3
    7 [6]
    10
    Units: nmol/L
    arithmetic mean (standard deviation)
        Baseline
    15.17 ( 10.98 )
    7.33 ( 6.03 )
    9.29 ( 7.81 )
        Change from Baseline
    -12.67 ( 10.98 )
    0.86 ( 8.54 )
    -3.20 ( 10.87 )
    Notes
    [6] - Only 7 of the 9 enrolled participants were assessed at Month 12.
    No statistical analyses for this end point

    Primary: Proportion of Participants who Achieved an Increase of at Least 10-Points From Baseline in 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 PDMS-2 Total Score at Month 12 [7]
    End point description
    The PDMS-2 is a validated instrument used to measure motor skills and developmental milestone achievement in infants and children. The PDMS-2 total score is calculated by summing the scores for the 249 items; each skill item was assessed as a simple, 3-level scoring system: 0 = the skill is not met, 1 = the skill is emerging and shows a clear resemblance to mastery of the skill item, and 2 = the child has mastered the motor skill. PDMS2-Total score ranges from 0 to 498. 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
    [7] - 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: As per statistical analysis plan, no statistical analysis was conducted.
    End point values
    		 Eladocagene Exuparvovec 1.8×10^11 vg Eladocagene Exuparvovec 2.4×10^11 vg Overall
    Number of subjects analysed
    3
    7 [8]
    10
    Units: proportion of participants
        number (not applicable)
    1.00
    1.00
    1.00
    Notes
    [8] - Only 7 of the 9 enrolled participants were assessed at Month 12.
    No statistical analyses for this end point

    Secondary: Change From Baseline in PDMS-2 Total Score at Month 12

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    End point title
    		 Change From Baseline in PDMS-2 Total Score at Month 12
    End point description
    The PDMS-2 is a validated instrument used to measure motor skills and developmental milestone achievement in infants and children. The PDMS-2 total score is calculated by summing the scores for the 249 items; each skill item was assessed as a simple, 3-level scoring system: 0 = the skill is not met, 1 = the skill is emerging and shows a clear resemblance to mastery of the skill item, and 2 = the child has mastered the motor skill. PDMS2-Total score ranges from 0 to 498. An increase from baseline indicates 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 12
    End point values
    		 Eladocagene Exuparvovec 1.8×10^11 vg Eladocagene Exuparvovec 2.4×10^11 vg Overall
    Number of subjects analysed
    3
    7 [9]
    10
    Units: units on a scale
    arithmetic mean (standard deviation)
        Baseline
    14.67 ( 10.02 )
    19.00 ( 14.96 )
    17.92 ( 13.59 )
        Change from Baseline
    61.33 ( 37.07 )
    101.29 ( 29.15 )
    89.30 ( 35.28 )
    Notes
    [9] - Only 7 of the 9 enrolled participants were assessed at Month 12.
    No statistical analyses for this end point

    Secondary: Change From Baseline in Alberta Infant Motor Scale (AIMS) Total Score at Month 12

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    End point title
    		 Change From Baseline in Alberta Infant Motor Scale (AIMS) Total Score at Month 12
    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 12
    End point values
    		 Eladocagene Exuparvovec 1.8×10^11 vg Eladocagene Exuparvovec 2.4×10^11 vg Overall
    Number of subjects analysed
    3
    7 [10]
    10
    Units: units on a scale
    arithmetic mean (standard deviation)
        Baseline
    4.00 ( 3.46 )
    2.56 ( 1.13 )
    2.92 ( 1.88 )
        Change from Baseline
    13.67 ( 12.50 )
    23.57 ( 6.27 )
    20.60 ( 9.16 )
    Notes
    [10] - Only 7 of the 9 enrolled participants were assessed at Month 12.
    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 12

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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 12
    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 a higher score indicated stronger skills and abilities and lower scores indicated 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 12
    End point values
    		 Eladocagene Exuparvovec 1.8×10^11 vg Eladocagene Exuparvovec 2.4×10^11 vg Overall
    Number of subjects analysed
    3
    7 [11]
    10
    Units: units on a scale
    arithmetic mean (standard deviation)
        Baseline
    35.00 ( 4.36 )
    34.56 ( 7.40 )
    34.67 ( 6.58 )
        Change from Baseline
    10.00 ( 5.57 )
    21.57 ( 3.36 )
    18.10 ( 6.76 )
    Notes
    [11] - Only 7 of the 9 enrolled participants were assessed at Month 12.
    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 13
    End point values
    		 Eladocagene Exuparvovec 1.8×10^11 vg Eladocagene Exuparvovec 2.4×10^11 vg Overall
    Number of subjects analysed
    3
    9
    12
    Units: participants
    0
    0
    0
    No statistical analyses for this end point

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

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    End point title
    		 Number of Participants With Craniotomy-induced 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 13
    End point values
    		 Eladocagene Exuparvovec 1.8×10^11 vg Eladocagene Exuparvovec 2.4×10^11 vg Overall
    Number of subjects analysed
    3
    9
    12
    Units: participants
    0
    0
    0
    No statistical analyses for this end point

    Post-hoc: 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
    Post-hoc
    End point timeframe
    Baseline, Month 12
    End point values
    		 Eladocagene Exuparvovec 1.8×10^11 vg Eladocagene Exuparvovec 2.4×10^11 vg Overall
    Number of subjects analysed
    3
    7 [12]
    10
    Units: kilograms (kg)
    arithmetic mean (standard deviation)
        Baseline
    11.17 ( 0.91 )
    9.10 ( 1.04 )
    9.62 ( 1.34 )
        Change from Baseline
    1.77 ( 1.14 )
    2.51 ( 1.45 )
    2.29 ( 1.35 )
    Notes
    [12] - Only 7 of the 9 enrolled participants were assessed at Month 12.
    No statistical analyses for this end point

    Post-hoc: Change From Baseline in Putaminal Positron Emission Tomography (PET)-Specific Uptake at Month 12

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    End point title
    		 Change From Baseline in Putaminal Positron Emission Tomography (PET)-Specific Uptake at Month 12
    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-dihydroxyphenylalanine (18F-DOPA), a positron-emitting fluorine-labeled version of levodopa, which is a substrate for AADC. An increase in 18F-DOPA putamen uptake over time demonstrates newly produced dopamine and the presence of functional AADC enzyme. PET 18F-fluorodopa uptake values were used to compute the specific uptake at each time point as follows: specific uptake = ((left putamen-occipital lobe) + (right putamen-occipital lobe))/2 occipital lobe ITT population included all enrolled participants. Here, overall number of participants analyzed = participants evaluable for this endpoint.
    End point type
    Post-hoc
    End point timeframe
    Baseline, Month 12
    End point values
    		 Eladocagene Exuparvovec 1.8×10^11 vg Eladocagene Exuparvovec 2.4×10^11 vg Overall
    Number of subjects analysed
    3
    7 [13]
    10
    Units: specific uptake value
    arithmetic mean (standard deviation)
        Baseline
    0.52 ( 0.05 )
    0.26 ( 0.13 )
    0.32 ( 0.17 )
        Change from Baseline
    -0.03 ( 0.07 )
    0.43 ( 0.27 )
    0.29 ( 0.32 )
    Notes
    [13] - Only 7 of the 9 enrolled participants were assessed at Month 12.
    No statistical analyses for this end point

    Post-hoc: Percentage of Participants Achieving Additional Motor Milestones Assessed Using the PDMS-2

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    End point title
    		 Percentage of Participants Achieving Additional Motor Milestones Assessed Using the PDMS-2
    End point description
    Additional motor milestones of partial head control, sitting with assistance, and crawling were assessed using the PDMS-2. Each motor skill item was assessed as a 3-level scoring system: 0 = the skill is not met, 1 = the skill is emerging and shows a clear resemblance to mastery of the skill item, and 2 = the child has mastered the motor skill. For each additional motor milestones, numeric score of “2” was translated into mastery of the milestone, indicating that the child achieved the milestone; score of “1” translated into demonstrating emerging skill; score of “0,” “or unscored” equated to “fail,” and therefore the participant did not achieve the milestone. ITT population included all enrolled participants. Here, overall number of participants analyzed = participants evaluable for this endpoint.
    End point type
    Post-hoc
    End point timeframe
    Month 12
    End point values
    		 Eladocagene Exuparvovec 1.8×10^11 vg Eladocagene Exuparvovec 2.4×10^11 vg Overall
    Number of subjects analysed
    3
    7 [14]
    10
    Units: percentage of participants
    number (not applicable)
        Achieved partial head control (score of 2)
    33
    71
    60
        Achieved sitting with assistance (score of 2)
    33
    43
    40
        Achieved crawling (score of 2)
    0
    0
    0
    Notes
    [14] - Only 7 of the 9 enrolled participants were assessed at Month 12.
    No statistical analyses for this end point

    Post-hoc: Fine Motor Grasping Total Scores Assessed Using the PDMS-2

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    End point title
    		 Fine Motor Grasping Total Scores Assessed Using the PDMS-2
    End point description
    Based on total scores of the PDMS-2 fine motor skills of grasping rattle sitting on lap, grabbing cube fingers space, grasping pellets, manipulating paper, grasping pellets thumb, and grasping pellets pad. Each skill item was assessed as a simple, 3-level scoring system: 0 = the skill is not met, 1 = the skill is emerging and shows a clear resemblance to mastery of the skill item, and 2 = the child has mastered the motor skill. The total score is determined by the sum of the points of each subscale/item. ITT population included all enrolled participants. Here, overall number of participants analyzed = participants evaluable for this endpoint.
    End point type
    Post-hoc
    End point timeframe
    Month 12
    End point values
    		 Eladocagene Exuparvovec 1.8×10^11 vg Eladocagene Exuparvovec 2.4×10^11 vg Overall
    Number of subjects analysed
    3
    7
    10
    Units: units on a scale
        arithmetic mean (standard deviation)
    6.33 ( 6.028 )
    6.57 ( 3.735 )
    6.50 ( 4.170 )
    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 13
    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 1.8×10^11 vg
    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 title
    Overall
    Reporting group description
    		 All participants treated with eladocagene exuparvovec.

    Reporting group title
    Eladocagene Exuparvovec 2.4×10^11 vg
    Reporting group description
    		 Participants received eladocagene exuparvovec administered during a single operative session at a dose of 0.6×10^11 vg and a volume of 80 μL per site to 4 sites (2 per putamen), for a total dose of 2.4×10^11 vg and a total volume of 320 μL.

    Serious adverse events
    		 Eladocagene Exuparvovec 1.8×10^11 vg Overall Eladocagene Exuparvovec 2.4×10^11 vg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 3 (100.00%)
    12 / 12 (100.00%)
    9 / 9 (100.00%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    Injury, poisoning and procedural complications
    Joint dislocation
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 12 (8.33%)
    1 / 9 (11.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 12 (8.33%)
    1 / 9 (11.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Paranasal sinus inflammation
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 12 (8.33%)
    1 / 9 (11.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 12 (8.33%)
    1 / 9 (11.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory distress
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 12 (8.33%)
    1 / 9 (11.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 12 (8.33%)
    1 / 9 (11.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Bronchiolitis
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 12 (8.33%)
    1 / 9 (11.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 12 (8.33%)
    1 / 9 (11.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Exanthema subitum
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 12 (8.33%)
    1 / 9 (11.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    2 / 3 (66.67%)
    4 / 12 (33.33%)
    2 / 9 (22.22%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Parainfluenzae virus infection
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 12 (8.33%)
    1 / 9 (11.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 3 (33.33%)
    3 / 12 (25.00%)
    2 / 9 (22.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia haemophilus
         subjects affected / exposed
    1 / 3 (33.33%)
    1 / 12 (8.33%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia viral
         subjects affected / exposed
    1 / 3 (33.33%)
    1 / 12 (8.33%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 3 (33.33%)
    2 / 12 (16.67%)
    1 / 9 (11.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 12 (8.33%)
    1 / 9 (11.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    3 / 3 (100.00%)
    5 / 12 (41.67%)
    2 / 9 (22.22%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 5
    0 / 2
         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
    		 Eladocagene Exuparvovec 1.8×10^11 vg Overall Eladocagene Exuparvovec 2.4×10^11 vg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    3 / 3 (100.00%)
    12 / 12 (100.00%)
    9 / 9 (100.00%)
    Vascular disorders
    Haemorrhage
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 12 (8.33%)
    1 / 9 (11.11%)
         occurrences all number
    0
    1
    1
    Cyanosis
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 12 (8.33%)
    1 / 9 (11.11%)
         occurrences all number
    0
    1
    1
    Hypotension
         subjects affected / exposed
    1 / 3 (33.33%)
    7 / 12 (58.33%)
    6 / 9 (66.67%)
         occurrences all number
    1
    7
    6
    Surgical and medical procedures
    Tooth extraction
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 12 (8.33%)
    1 / 9 (11.11%)
         occurrences all number
    0
    1
    1
    General disorders and administration site conditions
    Swelling
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 12 (8.33%)
    1 / 9 (11.11%)
         occurrences all number
    0
    1
    1
    Pyrexia
         subjects affected / exposed
    3 / 3 (100.00%)
    12 / 12 (100.00%)
    9 / 9 (100.00%)
         occurrences all number
    7
    20
    13
    Hypothermia
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 12 (16.67%)
    2 / 9 (22.22%)
         occurrences all number
    0
    2
    2
    Respiratory, thoracic and mediastinal disorders
    Atelectasis
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 12 (8.33%)
    1 / 9 (11.11%)
         occurrences all number
    0
    1
    1
    Choking
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 12 (16.67%)
    2 / 9 (22.22%)
         occurrences all number
    0
    2
    2
    Cough
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 12 (8.33%)
    1 / 9 (11.11%)
         occurrences all number
    0
    1
    1
    Dyspnoea
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 12 (8.33%)
    1 / 9 (11.11%)
         occurrences all number
    0
    1
    1
    Pneumothorax
         subjects affected / exposed
    1 / 3 (33.33%)
    1 / 12 (8.33%)
    0 / 9 (0.00%)
         occurrences all number
    1
    1
    0
    Nasal obstruction
         subjects affected / exposed
    1 / 3 (33.33%)
    2 / 12 (16.67%)
    1 / 9 (11.11%)
         occurrences all number
    1
    2
    1
    Rhinorrhoea
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 12 (8.33%)
    1 / 9 (11.11%)
         occurrences all number
    0
    1
    1
    Rhinitis allergic
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 12 (8.33%)
    1 / 9 (11.11%)
         occurrences all number
    0
    1
    1
    Rales
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 12 (8.33%)
    1 / 9 (11.11%)
         occurrences all number
    0
    1
    1
    Use of accessory respiratory muscles
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 12 (8.33%)
    1 / 9 (11.11%)
         occurrences all number
    0
    1
    1
    Snoring
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 12 (8.33%)
    1 / 9 (11.11%)
         occurrences all number
    0
    1
    1
    Psychiatric disorders
    Irritability
         subjects affected / exposed
    0 / 3 (0.00%)
    3 / 12 (25.00%)
    3 / 9 (33.33%)
         occurrences all number
    0
    3
    3
    Investigations
    Breath sounds abnormal
         subjects affected / exposed
    2 / 3 (66.67%)
    9 / 12 (75.00%)
    7 / 9 (77.78%)
         occurrences all number
    5
    17
    12
    Viral test positive
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 12 (8.33%)
    1 / 9 (11.11%)
         occurrences all number
    0
    1
    1
    Oxygen saturation decreased
         subjects affected / exposed
    1 / 3 (33.33%)
    1 / 12 (8.33%)
    0 / 9 (0.00%)
         occurrences all number
    1
    1
    0
    Haemoglobin decreased
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 12 (8.33%)
    1 / 9 (11.11%)
         occurrences all number
    0
    1
    1
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 12 (8.33%)
    1 / 9 (11.11%)
         occurrences all number
    0
    1
    1
    Endotracheal intubation complication
         subjects affected / exposed
    1 / 3 (33.33%)
    1 / 12 (8.33%)
    0 / 9 (0.00%)
         occurrences all number
    1
    1
    0
    Pneumocephalus
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 12 (8.33%)
    1 / 9 (11.11%)
         occurrences all number
    0
    1
    1
    Thermal burn
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 12 (8.33%)
    1 / 9 (11.11%)
         occurrences all number
    0
    1
    1
    Tooth avulsion
         subjects affected / exposed
    1 / 3 (33.33%)
    1 / 12 (8.33%)
    0 / 9 (0.00%)
         occurrences all number
    1
    1
    0
    Transfusion reaction
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 12 (8.33%)
    1 / 9 (11.11%)
         occurrences all number
    0
    1
    1
    Wound complication
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 12 (8.33%)
    1 / 9 (11.11%)
         occurrences all number
    0
    1
    1
    Wound
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 12 (8.33%)
    1 / 9 (11.11%)
         occurrences all number
    0
    1
    1
    Congenital, familial and genetic disorders
    Developmental hip dysplasia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 12 (8.33%)
    1 / 9 (11.11%)
         occurrences all number
    0
    1
    1
    Laryngomalacia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 12 (8.33%)
    1 / 9 (11.11%)
         occurrences all number
    0
    1
    1
    Cardiac disorders
    Bradycardia
         subjects affected / exposed
    1 / 3 (33.33%)
    2 / 12 (16.67%)
    1 / 9 (11.11%)
         occurrences all number
    1
    3
    2
    Nervous system disorders
    Dyskinesia
         subjects affected / exposed
    3 / 3 (100.00%)
    8 / 12 (66.67%)
    5 / 9 (55.56%)
         occurrences all number
    3
    8
    5
    Dystonia
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 12 (16.67%)
    2 / 9 (22.22%)
         occurrences all number
    0
    2
    2
    Irregular sleep phase
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 12 (8.33%)
    1 / 9 (11.11%)
         occurrences all number
    0
    1
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    4 / 12 (33.33%)
    4 / 9 (44.44%)
         occurrences all number
    0
    4
    4
    Eosinophilia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 12 (8.33%)
    1 / 9 (11.11%)
         occurrences all number
    0
    1
    1
    Eye disorders
    Ocular hyperaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 12 (8.33%)
    1 / 9 (11.11%)
         occurrences all number
    0
    1
    1
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 12 (16.67%)
    2 / 9 (22.22%)
         occurrences all number
    0
    2
    2
    Dental caries
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 12 (8.33%)
    1 / 9 (11.11%)
         occurrences all number
    0
    1
    1
    Diarrhoea
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 12 (16.67%)
    2 / 9 (22.22%)
         occurrences all number
    0
    3
    3
    Faecaloma
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 12 (8.33%)
    1 / 9 (11.11%)
         occurrences all number
    0
    1
    1
    Flatulence
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 12 (8.33%)
    1 / 9 (11.11%)
         occurrences all number
    0
    1
    1
    Gingival bleeding
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 12 (8.33%)
    1 / 9 (11.11%)
         occurrences all number
    0
    1
    1
    Haematochezia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 12 (8.33%)
    1 / 9 (11.11%)
         occurrences all number
    0
    1
    1
    Mouth ulceration
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 12 (16.67%)
    2 / 9 (22.22%)
         occurrences all number
    0
    3
    3
    Regurgitation
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 12 (8.33%)
    1 / 9 (11.11%)
         occurrences all number
    0
    1
    1
    Stress ulcer
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 12 (8.33%)
    1 / 9 (11.11%)
         occurrences all number
    0
    1
    1
    Vomiting
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 12 (8.33%)
    1 / 9 (11.11%)
         occurrences all number
    0
    1
    1
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    2 / 3 (66.67%)
    5 / 12 (41.67%)
    3 / 9 (33.33%)
         occurrences all number
    2
    6
    4
    Skin and subcutaneous tissue disorders
    Decubitus ulcer
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 12 (16.67%)
    2 / 9 (22.22%)
         occurrences all number
    0
    2
    2
    Dermatitis diaper
         subjects affected / exposed
    1 / 3 (33.33%)
    3 / 12 (25.00%)
    2 / 9 (22.22%)
         occurrences all number
    1
    3
    2
    Eczema
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 12 (16.67%)
    2 / 9 (22.22%)
         occurrences all number
    0
    2
    2
    Rash
         subjects affected / exposed
    1 / 3 (33.33%)
    3 / 12 (25.00%)
    2 / 9 (22.22%)
         occurrences all number
    1
    3
    2
    Musculoskeletal and connective tissue disorders
    Joint range of motion decreased
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 12 (8.33%)
    1 / 9 (11.11%)
         occurrences all number
    0
    1
    1
    Infections and infestations
    Gastroenteritis
         subjects affected / exposed
    0 / 3 (0.00%)
    3 / 12 (25.00%)
    3 / 9 (33.33%)
         occurrences all number
    0
    3
    3
    Conjunctivitis
         subjects affected / exposed
    1 / 3 (33.33%)
    2 / 12 (16.67%)
    1 / 9 (11.11%)
         occurrences all number
    1
    2
    1
    Bronchitis
         subjects affected / exposed
    1 / 3 (33.33%)
    1 / 12 (8.33%)
    0 / 9 (0.00%)
         occurrences all number
    1
    1
    0
    Gingivitis
         subjects affected / exposed
    1 / 3 (33.33%)
    4 / 12 (33.33%)
    3 / 9 (33.33%)
         occurrences all number
    1
    4
    3
    Norovirus infection
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 12 (8.33%)
    1 / 9 (11.11%)
         occurrences all number
    0
    1
    1
    Otitis media
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 12 (8.33%)
    1 / 9 (11.11%)
         occurrences all number
    0
    1
    1
    Pneumonia
         subjects affected / exposed
    1 / 3 (33.33%)
    4 / 12 (33.33%)
    3 / 9 (33.33%)
         occurrences all number
    1
    5
    4
    Pneumonia mycoplasmal
         subjects affected / exposed
    1 / 3 (33.33%)
    1 / 12 (8.33%)
    0 / 9 (0.00%)
         occurrences all number
    1
    1
    0
    Upper respiratory tract infection
         subjects affected / exposed
    2 / 3 (66.67%)
    9 / 12 (75.00%)
    7 / 9 (77.78%)
         occurrences all number
    4
    14
    10
    Metabolism and nutrition disorders
    Hypokalaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 12 (8.33%)
    1 / 9 (11.11%)
         occurrences all number
    0
    1
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    19 Dec 2016
    - Information regarding the status of Studies AADC-CU/1601 and AADC-010 was updated. - Inclusion criteria were revised to specify that the participant was to be over 2 years old or have a skull thick enough for surgery and be under 6 years old prior to treatment with study drug. - Exclusion criteria were revised to specify that prohibition of taking any medications that may have affected the clinical trial does not apply to those drugs used at specified duration as mentioned in the protocol. - Timing of visits that required hospitalization was specified. - Eligible age of participants to receive 1.8 x 10^11 vg was changed from ‘≥3 years’ to ‘>3 years’ - Text regarding analysis of CSF fluid for L-3, 4-dihydroxyphenylalanine, 3-O-methyldopa, dopamine and serotonin was removed. - The assessments of motor function and development (PDMS-2, AIMS and Bayley-III) were described in more detail. - Items and schedules of treatment and examinations were updated for the screening, baseline examination, dosing day, 7-day post-treatment and 3-, 6-, 9-, and 12-month post-treatment time points. The table displaying the schedule of study procedures was also updated accordingly. A table of vital signs was added. - Specified for participants withdrawing from the trial (early termination), an overall evaluation with test items at 12 months would be required. - List of principal and sub-investigators was updated. - Time point of the magnetic resonance imaging performed post-treatment was specified to be 7 days (±7 days) post-surgery. - Number of participants in clinical trials to date for which gene therapy-induced dyskinesia was observed was updated from 8 to 18 participants. - Number of expected participants to be recruited was changed from 5 to 6 throughout where applicable. - Duration of the trial was updated to 14 months, including 28 days for pre-operative baseline examinations and 13 months for post-operative observations, throughout where applicable.
    16 May 2017
    - The period for recording oculogyric crises was changed from 28 days before gene therapy to the third month after gene therapy (previously 12 months post gene therapy). - The sponsor was updated from N/A to the National Taiwan University Hospital.
    26 Jul 2017
    - The aim of the trial was updated to include a slight increase in dose. - The number of participants expected to be recruited was updated to 10. - Enrollment of participants was allocated to 2 cohorts: cohort 1 (6 who were already treated or had their surgery date scheduled) and cohort 2 (4 planned to be treated with the 2.4 x 10^11 vg dose). For cohort 1, a summary of cases and a summary of post-gene therapy dyskinesia were included. - It was specified that either of 2 doses (1.8 x 10^11 vg or 2.4 x 10^11 vg) were administered in this study. - The text was updated to include 10 participants. • The duration for recording episodes of oculogyric crises was updated to: 28 days pre-surgery to 3 months post-surgery in-text and in the ‘Summary of items and schedules of treatment and examination’ table - Information about the long-term follow-up program after 12 months post-surgery was added. - Information about the Safety Committee was updated, including specifying that an external statistician would be included, and that the committee would meet once every 6 months to review adverse event reports related to significant events.
    25 Feb 2020
    - The text was updated to include 12 participants in the study.

    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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