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    Clinical Trial Results:
    Phase I, Open-Label, Dose Comparison Study of AVXS-101 for Sitting But Non-ambulatory Patients With Spinal Muscular Atrophy

    Summary
    EudraCT number
    		 2020-003678-28
    Trial protocol
    		 Outside EU/EEA  
    Global end of trial date
    18 Nov 2021

    Results information
    Results version number
    		 v2(current)
    This version publication date
    07 Sep 2022
    First version publication date
    29 May 2022
    Other versions
    		 v1
    Version creation reason
    • Correction of full data set
    Update to adverse event time frame.

    Trial information

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    Trial identification
    Sponsor protocol code
    AVXS-101-CL-102
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Novartis Gene Therapies EU Limited
    Sponsor organisation address
    2275 Half Day Road, Bannockburn, IL, United States, 60015
    Public contact
    EMEA Medical Information, Novartis Gene Therapies, Inc., +353 (1) 556-2364, medinfoemea.gtx@novartis.com
    Scientific contact
    EMEA Medical Information, Novartis Gene Therapies, Inc., +353 (1) 556-2364, medinfoemea.gtx@novartis.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-002168-PIP01-17
    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 Nov 2021
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    18 Nov 2021
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The primary safety objective was to assess the safety and tolerability of intrathecal administration of AVXS-101 by the incidence and severity of adverse events (AEs) while determining the optimal dose of AVXS-101 that demonstrates acceptable safety administered by intrathecal injection. Safety and efficacy were assessed independently for each age cohort. The primary efficacy objective, by age group was as follows: • Participants ≥6 months and <24 months of age at time of dosing: To determine the proportion of participants achieving the ability to stand without support for at least 3 seconds (Bayley Scales of Infant and Toddler Development [BSID] – Gross Motor [GM] Subtest Item #40). • Participants ≥24 months and <60 months of age at time of dosing: To determine the change from baseline in Hammersmith Functional Motor Scale - Expanded (HFMSE).
    Protection of trial subjects
    The study was conducted according to International Council for Harmonisation (ICH) Guideline for Good Clinical Practice (GCP) that have their origin in the Declaration of Helsinki.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    14 Dec 2017
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy
    Long term follow-up duration
    		 15 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United States: 32
    Worldwide total number of subjects
    32
    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)
    20
    Children (2-11 years)
    12
    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
    		 A total of 32 participants took part in the trial at 11 sites in the United States between December 2017 and May 2021.

    Pre-assignment
    Screening details
    		 A total of 38 participants were screened, of which 6 were screen failures and 32 were enrolled and received study drug.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Cohort 1: 6.0E13 Vector Genomes (vg) - Age 6 to <24 Months
    Arm description
    		 Participants aged 6 to <24 months at time of AVXS-101 dosing received a single dose of AVXS-101 on Day 1 of the overall study. Participants also received daily doses of prophylactic oral prednisolone starting at a dose of 1 mg/kg/day from 1 day prior to AVXS-101 injection until at least 30 days post-injection at which point the prednisolone dose could be tapered downwards. At week 9, prednisolone could be discontinued.
    Arm type
    		 Experimental

    Investigational medicinal product name
    AVXS-101
    Investigational medicinal product code
    Other name
    Onasemnogene abeparvovec
    Pharmaceutical forms
    Injection
    Routes of administration
    Intrathecal use
    Dosage and administration details
    AVXS-101 was administered as an intrathecal injection at a dose of 6.0E13 vg.

    Arm title
    		 Cohort 2: 1.2E14 vg - Age 6 to <24 Months
    Arm description
    		 Participants aged 6 to <24 months at time of AVXS-101 dosing received a single dose of AVXS-101 on Day 1 of the overall study. Participants also received daily doses of prophylactic oral prednisolone starting at a dose of 1 mg/kg/day from 1 day prior to AVXS-101 injection until at least 30 days post-injection at which point the prednisolone dose could be tapered downwards. At week 9, prednisolone could be discontinued.
    Arm type
    		 Experimental

    Investigational medicinal product name
    AVXS-101
    Investigational medicinal product code
    Other name
    Onasemnogene abeparvovec
    Pharmaceutical forms
    Injection
    Routes of administration
    Intrathecal use
    Dosage and administration details
    AVXS-101 was administered as an intrathecal injection at a dose of 1.2E14 vg.

    Arm title
    		 Cohort 2: 1.2E14 vg - Age 24 to <60 Months
    Arm description
    		 Participants aged 24 to <60 months at time of AVXS-101 dosing received a single dose of AVXS-101 on Day 1 of the overall study. Participants also received daily doses of prophylactic oral prednisolone starting at a dose of 1 mg/kg/day from 1 day prior to AVXS-101 injection until at least 30 days post-injection at which point the prednisolone dose could be tapered downwards. At week 9, prednisolone could be discontinued.
    Arm type
    		 Experimental

    Investigational medicinal product name
    AVXS-101
    Investigational medicinal product code
    Other name
    Onasemnogene abeparvovec
    Pharmaceutical forms
    Injection
    Routes of administration
    Intrathecal use
    Dosage and administration details
    AVXS-101 was administered as an intrathecal injection at a dose of 1.2E14 vg.

    Arm title
    		 Cohort 3: 2.4E14 vg - Age 6 to <24 Months
    Arm description
    		 Participants aged 6 to <24 months at time of AVXS-101 dosing received a single dose of AVXS-101 on Day 1 of the overall study. Participants also received daily doses of prophylactic oral prednisolone starting at a dose of 1 mg/kg/day from 1 day prior to AVXS-101 injection until at least 30 days post-injection at which point the prednisolone dose could be tapered downwards. At week 9, prednisolone could be discontinued.
    Arm type
    		 Experimental

    Investigational medicinal product name
    AVXS-101
    Investigational medicinal product code
    Other name
    Onasemnogene abeparvovec
    Pharmaceutical forms
    Injection
    Routes of administration
    Intrathecal use
    Dosage and administration details
    AVXS-101 was administered as an intrathecal injection at a dose of 2.4E14 vg.

    Number of subjects in period 1
    		Cohort 1: 6.0E13 Vector Genomes (vg) - Age 6 to <24 Months Cohort 2: 1.2E14 vg - Age 6 to <24 Months Cohort 2: 1.2E14 vg - Age 24 to <60 Months Cohort 3: 2.4E14 vg - Age 6 to <24 Months
    Started
    3
    13
    12
    4
    Received AVXS-101
    3
    13
    12
    4
    Completed
    3
    13
    12
    4

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Cohort 1: 6.0E13 Vector Genomes (vg) - Age 6 to <24 Months
    Reporting group description
    		 Participants aged 6 to <24 months at time of AVXS-101 dosing received a single dose of AVXS-101 on Day 1 of the overall study. Participants also received daily doses of prophylactic oral prednisolone starting at a dose of 1 mg/kg/day from 1 day prior to AVXS-101 injection until at least 30 days post-injection at which point the prednisolone dose could be tapered downwards. At week 9, prednisolone could be discontinued.

    Reporting group title
    Cohort 2: 1.2E14 vg - Age 6 to <24 Months
    Reporting group description
    		 Participants aged 6 to <24 months at time of AVXS-101 dosing received a single dose of AVXS-101 on Day 1 of the overall study. Participants also received daily doses of prophylactic oral prednisolone starting at a dose of 1 mg/kg/day from 1 day prior to AVXS-101 injection until at least 30 days post-injection at which point the prednisolone dose could be tapered downwards. At week 9, prednisolone could be discontinued.

    Reporting group title
    Cohort 2: 1.2E14 vg - Age 24 to <60 Months
    Reporting group description
    		 Participants aged 24 to <60 months at time of AVXS-101 dosing received a single dose of AVXS-101 on Day 1 of the overall study. Participants also received daily doses of prophylactic oral prednisolone starting at a dose of 1 mg/kg/day from 1 day prior to AVXS-101 injection until at least 30 days post-injection at which point the prednisolone dose could be tapered downwards. At week 9, prednisolone could be discontinued.

    Reporting group title
    Cohort 3: 2.4E14 vg - Age 6 to <24 Months
    Reporting group description
    		 Participants aged 6 to <24 months at time of AVXS-101 dosing received a single dose of AVXS-101 on Day 1 of the overall study. Participants also received daily doses of prophylactic oral prednisolone starting at a dose of 1 mg/kg/day from 1 day prior to AVXS-101 injection until at least 30 days post-injection at which point the prednisolone dose could be tapered downwards. At week 9, prednisolone could be discontinued.

    Reporting group values
    		 Cohort 1: 6.0E13 Vector Genomes (vg) - Age 6 to <24 Months Cohort 2: 1.2E14 vg - Age 6 to <24 Months Cohort 2: 1.2E14 vg - Age 24 to <60 Months Cohort 3: 2.4E14 vg - Age 6 to <24 Months Total
    Number of subjects
    		 3 13 12 4 32
    Age categorical
    Units: Subjects
        Infants and toddlers (28 days-23 months)
    		 3 13 0 4 20
        Children (2-11 years)
    		 0 0 12 0 12
    Age continuous
    Units: months
        arithmetic mean (standard deviation)
    		 17.2 ( 4.1 ) 16.7 ( 4.5 ) 37.5 ( 10.6 ) 16.9 ( 5.6 ) -
    Gender categorical
    Units: Subjects
        Female
    		 2 6 6 0 14
        Male
    		 1 7 6 4 18
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 2 3 0 0 5
        Not Hispanic or Latino
    		 1 10 12 4 27
        Unknown or Not Reported
    		 0 0 0 0 0
    Race/Ethnicity
    Units: Subjects
        White
    		 2 10 8 3 23
        Asian
    		 0 1 4 1 6
        Other
    		 0 1 0 0 1
        Multiple
    		 1 1 0 0 2

    End points

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    End points reporting groups
    Reporting group title
    Cohort 1: 6.0E13 Vector Genomes (vg) - Age 6 to <24 Months
    Reporting group description
    		 Participants aged 6 to <24 months at time of AVXS-101 dosing received a single dose of AVXS-101 on Day 1 of the overall study. Participants also received daily doses of prophylactic oral prednisolone starting at a dose of 1 mg/kg/day from 1 day prior to AVXS-101 injection until at least 30 days post-injection at which point the prednisolone dose could be tapered downwards. At week 9, prednisolone could be discontinued.

    Reporting group title
    Cohort 2: 1.2E14 vg - Age 6 to <24 Months
    Reporting group description
    		 Participants aged 6 to <24 months at time of AVXS-101 dosing received a single dose of AVXS-101 on Day 1 of the overall study. Participants also received daily doses of prophylactic oral prednisolone starting at a dose of 1 mg/kg/day from 1 day prior to AVXS-101 injection until at least 30 days post-injection at which point the prednisolone dose could be tapered downwards. At week 9, prednisolone could be discontinued.

    Reporting group title
    Cohort 2: 1.2E14 vg - Age 24 to <60 Months
    Reporting group description
    		 Participants aged 24 to <60 months at time of AVXS-101 dosing received a single dose of AVXS-101 on Day 1 of the overall study. Participants also received daily doses of prophylactic oral prednisolone starting at a dose of 1 mg/kg/day from 1 day prior to AVXS-101 injection until at least 30 days post-injection at which point the prednisolone dose could be tapered downwards. At week 9, prednisolone could be discontinued.

    Reporting group title
    Cohort 3: 2.4E14 vg - Age 6 to <24 Months
    Reporting group description
    		 Participants aged 6 to <24 months at time of AVXS-101 dosing received a single dose of AVXS-101 on Day 1 of the overall study. Participants also received daily doses of prophylactic oral prednisolone starting at a dose of 1 mg/kg/day from 1 day prior to AVXS-101 injection until at least 30 days post-injection at which point the prednisolone dose could be tapered downwards. At week 9, prednisolone could be discontinued.

    Subject analysis set title
    PNCR (Historical Control)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants in historical control Pediatric Neuromuscular Clinical Research (PNCR) cohort received uniform standard of care treatment. Participants visited the study site at baseline and at 2, 4, 6, 9, 12 months and every 6 months thereafter.

    Primary: Age 6 to <24 Months Only: Number of Participants Who Achieved the Ability to Stand Alone

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    End point title
    		 Age 6 to <24 Months Only: Number of Participants Who Achieved the Ability to Stand Alone [1] [2]
    End point description
    Defined by the BSID GM subtest performance criteria number 40, confirmed by video recording, as a participant who stands alone for at least 3 seconds unsupported. Intent-to-Treat (ITT) Set which included all enrolled participants who were given an AVXS-101 intrathecal injection. Participants were analyzed according to the assigned dose.
    End point type
    Primary
    End point timeframe
    From Day 1 up to 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: Pre-specified comparative statistical analysis is reported in the applicable 'Other prespecified' endpoint.
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Data were only planned to be collected for participants aged 6 to <24 months.
    End point values
    		 Cohort 1: 6.0E13 Vector Genomes (vg) - Age 6 to <24 Months Cohort 2: 1.2E14 vg - Age 6 to <24 Months Cohort 3: 2.4E14 vg - Age 6 to <24 Months
    Number of subjects analysed
    3
    13
    4
    Units: participants
        Able to Stand Alone
    1
    1
    0
        Unable to Stand Alone
    2
    12
    4
    No statistical analyses for this end point

    Primary: Age 24 to <60 Months Only: Change from Baseline in HFMSE Score at Month 12

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    End point title
    		 Age 24 to <60 Months Only: Change from Baseline in HFMSE Score at Month 12 [3] [4]
    End point description
    The HFMSE contained 33 items which were scored on a scale of 0-2 with a total achievable score ranging from 0, if all activities are failed, to 66, if all the activities are achieved. A positive change from baseline indicates a better outcome. ITT Set which included all enrolled participants who were given an AVXS-101 intrathecal injection. Participants were analyzed according to the assigned dose.
    End point type
    Primary
    End point timeframe
    Baseline and 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: Pre-specified comparative statistical analysis is reported in the applicable 'Other prespecified' endpoint.
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Data were only planned to be collected for participants aged 24 to <60 months.
    End point values
    		 Cohort 2: 1.2E14 vg - Age 24 to <60 Months
    Number of subjects analysed
    12
    Units: score on a scale
        least squares mean (confidence interval 95%)
    6.0 (3.7 to 8.3)
    No statistical analyses for this end point

    Primary: Number of Participants Who Experienced a Treatment-emergent Adverse Event (TEAE)

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    End point title
    		 Number of Participants Who Experienced a Treatment-emergent Adverse Event (TEAE) [5]
    End point description
    A TEAE was defined as any event that began or worsened in severity on or after the administration of AVXS-101 through the last study visit. Evaluation of TEAEs included the number of participants with at least one: • TEAE • Serious TEAE • TEAE related to AVXS-101 • TEAE with Common Terminology Criteria for Adverse Events (CTCAE) grade ≥ 3 (grade 3 = severe or medically significant to grade 5 = death related to TEAE) Safety Analysis Set which included all participants given an AVXS-101 intrathecal injection. Participants were analyzed according to actual dose received.
    End point type
    Primary
    End point timeframe
    Adverse events were collected from the single dose of study treatment until the end of study visit (12 months for Cohort 1 and 2 and 15 months for Cohort 3)
    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: No comparative statistical analysis was planned for this endpoint.
    End point values
    		 Cohort 1: 6.0E13 Vector Genomes (vg) - Age 6 to <24 Months Cohort 2: 1.2E14 vg - Age 6 to <24 Months Cohort 2: 1.2E14 vg - Age 24 to <60 Months Cohort 3: 2.4E14 vg - Age 6 to <24 Months
    Number of subjects analysed
    3
    13
    12
    4
    Units: participants
        TEAE
    3
    13
    12
    4
        Serious TEAE
    1
    2
    4
    0
        TEAE Related to AVXS-101
    0
    7
    4
    1
        TEAE with CTCAE Grade ≥ 3
    1
    4
    4
    0
    No statistical analyses for this end point

    Secondary: Number of Participants Who Achieved the Ability to Walk Alone

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    End point title
    		 Number of Participants Who Achieved the Ability to Walk Alone
    End point description
    Defined by the BSID GM subtest performance criteria number 43, confirmed by video recording, as a participant who takes 5 coordinated independent steps. ITT Set which included all enrolled participants who were given an AVXS-101 intrathecal injection. Participants were analyzed according to the assigned dose.
    End point type
    Secondary
    End point timeframe
    From Day 1 up to Month 12
    End point values
    		 Cohort 1: 6.0E13 Vector Genomes (vg) - Age 6 to <24 Months Cohort 2: 1.2E14 vg - Age 6 to <24 Months Cohort 2: 1.2E14 vg - Age 24 to <60 Months Cohort 3: 2.4E14 vg - Age 6 to <24 Months
    Number of subjects analysed
    3
    13
    12
    4
    Units: participants
        Able to Walk Alone
    0
    1
    0
    0
        Unable to Walk Alone
    3
    12
    12
    4
    No statistical analyses for this end point

    Secondary: Average Number of Hours Per Day of Non-invasive Ventilatory Support

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    End point title
    		 Average Number of Hours Per Day of Non-invasive Ventilatory Support
    End point description
    Participants were assessed by a pulmonologist and may have been fitted with a non-invasive positive pressure ventilatory (e.g., Bilevel Positive Airway Pressure BiPAP) at the discretion of the pulmonologist and/or investigator. The number of hours per day of non-invasive ventilatory support was captured continuously by the device. Data were only collected in participants requiring BiPAP support. 99999 = no data are available. 9999 = Only 1 participant had available data so standard deviation could not be calculated.
    End point type
    Secondary
    End point timeframe
    Months 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12
    End point values
    		 Cohort 1: 6.0E13 Vector Genomes (vg) - Age 6 to <24 Months Cohort 2: 1.2E14 vg - Age 6 to <24 Months Cohort 2: 1.2E14 vg - Age 24 to <60 Months Cohort 3: 2.4E14 vg - Age 6 to <24 Months
    Number of subjects analysed
    0 [6]
    1 [7]
    1
    0 [8]
    Units: hours/day
    arithmetic mean (standard deviation)
        Month 2
    ( )
    99999 ( 9999 )
    10.530 ( 9999 )
    ( )
        Month 3
    ( )
    99999 ( 9999 )
    2.930 ( 9999 )
    ( )
        Month 4
    ( )
    0.000 ( 9999 )
    5.860 ( 9999 )
    ( )
        Month 5
    ( )
    0.000 ( 9999 )
    4.610 ( 9999 )
    ( )
        Month 6
    ( )
    2.590 ( 9999 )
    4.490 ( 9999 )
    ( )
        Month 7
    ( )
    4.550 ( 9999 )
    7.490 ( 9999 )
    ( )
        Month 8
    ( )
    7.170 ( 9999 )
    8.290 ( 9999 )
    ( )
        Month 9
    ( )
    8.690 ( 9999 )
    7.690 ( 9999 )
    ( )
        Month 10
    ( )
    10.320 ( 9999 )
    9.900 ( 9999 )
    ( )
        Month 11
    ( )
    14.050 ( 9999 )
    3.460 ( 9999 )
    ( )
        Month 12
    ( )
    10.120 ( 9999 )
    0.040 ( 9999 )
    ( )
    Notes
    [6] - No participants required BiPAP support in this arm.
    [7] - Months 2 and 3 N = 0
    [8] - No participants required BiPAP support in this arm.
    No statistical analyses for this end point

    Other pre-specified: Age 6 to <24 Months Only: Number of Participants Who Achieved the Ability to Stand Alone Versus the Population-matched Natural History Pediatric Neuromuscular Clinical Research Network (PNCR) Control Study

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    End point title
    		 Age 6 to <24 Months Only: Number of Participants Who Achieved the Ability to Stand Alone Versus the Population-matched Natural History Pediatric Neuromuscular Clinical Research Network (PNCR) Control Study [9]
    End point description
    Defined by the BSID GM subtest performance criteria number 40, confirmed by video recording, as a participant who stands alone for at least 3 seconds unsupported. ITT Set which included all enrolled participants who were given an AVXS-101 intrathecal injection. Participants were analyzed according to the assigned dose. The PNCR population included all participants with 3 copies of survival of motor neuron 2 (SMN2) with biallelic survival or motor neuron 1 (SMN1) mutations, symptom onset <12 months of age, diagnosis <24 months of age, no standing, no walking, and assessments at ≥24 months and <60 months of age (baseline).
    End point type
    Other pre-specified
    End point timeframe
    From Day 1 up to Month 12
    Notes
    [9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Data were only planned to be collected for participants aged 6 to <24 months.
    End point values
    		 Cohort 1: 6.0E13 Vector Genomes (vg) - Age 6 to <24 Months Cohort 2: 1.2E14 vg - Age 6 to <24 Months Cohort 3: 2.4E14 vg - Age 6 to <24 Months PNCR (Historical Control)
    Number of subjects analysed
    3
    13
    4
    51
    Units: participants
        Able to Stand Alone
    1
    1
    0
    7
        Unable to Stand Alone
    2
    12
    4
    44
    Statistical analysis title
    		 Cohort 2: 1.2E14 vg - Age 6 to <24 Months vs PNCR
    Statistical analysis description
    Difference in the percentage of participants who achieved the ability to stand alone.
    Comparison groups
    Cohort 2: 1.2E14 vg - Age 6 to <24 Months v PNCR (Historical Control)
    Number of subjects included in analysis
    64
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.9999
    Method
    		 Fisher exact
    Parameter type
    		 Difference in Percent
    Point estimate
    -6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -21.8
         upper limit
    		 22.8

    Other pre-specified: Age 24 to <60 Months Only: Change from Baseline in HFMSE Score Versus the Population-matched Natural History PNCR Control Study at Month 12

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    End point title
    		 Age 24 to <60 Months Only: Change from Baseline in HFMSE Score Versus the Population-matched Natural History PNCR Control Study at Month 12 [10]
    End point description
    The HFMSE contained 33 items which were scored on a scale of 0-2 with a total achievable score ranging from 0, if all activities are failed, to 66, if all the activities are achieved. A positive change from baseline indicates a better outcome. ITT Set which included all enrolled participants who were given an AVXS-101 intrathecal injection. Participants were analyzed according to the assigned dose. The PNCR population included all participants who met the criteria of having SMA Types 2 or 3, 3 copies of SMN2, symptom onset before 12 months of age, diagnosis before 24 months of age, unable to stand or walk at enrollment (baseline visit), received a HFMSE evaluation between 24 and 60 months of age (“baseline”), and a follow-up evaluation (Hammersmith Functional Motor Scale [HFMS] or HFMSE) performed between 12 and 14 months following that baseline evaluation.
    End point type
    Other pre-specified
    End point timeframe
    Baseline and Month 12
    Notes
    [10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Data were only planned to be collected for participants aged 24 to <60 months.
    End point values
    		 Cohort 2: 1.2E14 vg - Age 24 to <60 Months PNCR (Historical Control)
    Number of subjects analysed
    12
    9
    Units: score on a scale
        least squares mean (confidence interval 95%)
    6.0 (3.7 to 8.3)
    0.5 (-2.2 to 3.2)
    Statistical analysis title
    		 Cohort 2: 1.2E14 vg - Age 24 to <60 Months vs PNCR
    Comparison groups
    Cohort 2: 1.2E14 vg - Age 24 to <60 Months v PNCR (Historical Control)
    Number of subjects included in analysis
    21
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0027
    Method
    		 Mixed-Model Repeat Measure
    Parameter type
    		 Difference between Least Squares Mean
    Point estimate
    5.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.9
         upper limit
    		 9

    Other pre-specified: Number of Participants Who Achieved the Ability to Walk Alone Versus the Population-matched Natural History PNCR Control Study

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    End point title
    		 Number of Participants Who Achieved the Ability to Walk Alone Versus the Population-matched Natural History PNCR Control Study
    End point description
    Defined by the BSID GM subtest performance criteria number 43, confirmed by video recording, as a participant who takes 5 coordinated independent steps. ITT Set which included all enrolled participants who were given an AVXS-101 intrathecal injection. Participants were analyzed according to the assigned dose. The PNCR population included all participants with 3 copies of SMN2 with biallelic SMN1 mutations, symptom onset <12 months of age, diagnosis <24 months of age, no standing, no walking, and assessments at ≥24 months and <60 months of age (baseline).
    End point type
    Other pre-specified
    End point timeframe
    From Day 1 up to Month 12
    End point values
    		 Cohort 1: 6.0E13 Vector Genomes (vg) - Age 6 to <24 Months Cohort 2: 1.2E14 vg - Age 6 to <24 Months Cohort 2: 1.2E14 vg - Age 24 to <60 Months Cohort 3: 2.4E14 vg - Age 6 to <24 Months PNCR (Historical Control)
    Number of subjects analysed
    3
    13
    12
    4
    51
    Units: participants
        Able to Walk Alone
    0
    1
    0
    0
    5
        Unable to Walk Alone
    3
    12
    12
    4
    46
    Statistical analysis title
    		 Cohort 2: 1.2E14 vg - Age 6 to <24 Months vs PNCR
    Statistical analysis description
    Difference in the percentage of participants who achieved the ability to walk alone.
    Comparison groups
    Cohort 2: 1.2E14 vg - Age 6 to <24 Months v PNCR (Historical Control)
    Number of subjects included in analysis
    64
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.9999
    Method
    		 Fisher exact
    Parameter type
    		 Percentage Difference
    Point estimate
    -2.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -17.2
         upper limit
    		 27

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were collected from the single dose of study treatment until the end of study visit (12 months for Cohort 1 and 2 and 15 months for Cohort 3)
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23.0
    Reporting groups
    Reporting group title
    Cohort 2: 1.2E14 vg - Age 6 to <24 Months
    Reporting group description
    		 Participants aged 6 to <24 months at time of AVXS-101 dosing received a single dose of AVXS-101 on Day 1 of the overall study. Participants also received daily doses of prophylactic oral prednisolone starting at a dose of 1 mg/kg/day from 1 day prior to AVXS-101 injection until at least 30 days post-injection at which point the prednisolone dose could be tapered downwards. At week 9, prednisolone could be discontinued.

    Reporting group title
    Cohort 1: 6.0E13 Vector Genomes (vg) - Age 6 to <24 Months
    Reporting group description
    		 Participants aged 6 to <24 months at time of AVXS-101 dosing received a single dose of AVXS-101 on Day 1 of the overall study. Participants also received daily doses of prophylactic oral prednisolone starting at a dose of 1 mg/kg/day from 1 day prior to AVXS-101 injection until at least 30 days post-injection at which point the prednisolone dose could be tapered downwards. At week 9, prednisolone could be discontinued.

    Reporting group title
    Cohort 2: 1.2E14 vg - Age 24 to <60 Months
    Reporting group description
    		 Participants aged 24 to <60 months at time of AVXS-101 dosing received a single dose of AVXS-101 on Day 1 of the overall study. Participants also received daily doses of prophylactic oral prednisolone starting at a dose of 1 mg/kg/day from 1 day prior to AVXS-101 injection until at least 30 days post-injection at which point the prednisolone dose could be tapered downwards. At week 9, prednisolone could be discontinued.

    Reporting group title
    Cohort 3: 2.4E14 vg - Age 6 to <24 Months
    Reporting group description
    		 Participants aged 6 to <24 months at time of AVXS-101 dosing received a single dose of AVXS-101 on Day 1 of the overall study. Participants also received daily doses of prophylactic oral prednisolone starting at a dose of 1 mg/kg/day from 1 day prior to AVXS-101 injection until at least 30 days post-injection at which point the prednisolone dose could be tapered downwards. At week 9, prednisolone could be discontinued.

    Serious adverse events
    		 Cohort 2: 1.2E14 vg - Age 6 to <24 Months Cohort 1: 6.0E13 Vector Genomes (vg) - Age 6 to <24 Months Cohort 2: 1.2E14 vg - Age 24 to <60 Months Cohort 3: 2.4E14 vg - Age 6 to <24 Months
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 13 (15.38%)
    1 / 3 (33.33%)
    4 / 12 (33.33%)
    0 / 4 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Investigations
    Blood alkaline phosphatase increased
         subjects affected / exposed
    1 / 13 (7.69%)
    1 / 3 (33.33%)
    0 / 12 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 3 (0.00%)
    0 / 12 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 3 (0.00%)
    0 / 12 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 3 (0.00%)
    1 / 12 (8.33%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Asthma
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 3 (0.00%)
    1 / 12 (8.33%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 3 (33.33%)
    0 / 12 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 3 (0.00%)
    1 / 12 (8.33%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 3 (0.00%)
    1 / 12 (8.33%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 3 (0.00%)
    1 / 12 (8.33%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia respiratory syncytial viral
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 3 (0.00%)
    1 / 12 (8.33%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory tract infection viral
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 3 (0.00%)
    1 / 12 (8.33%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rhinovirus infection
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 3 (0.00%)
    1 / 12 (8.33%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Cohort 2: 1.2E14 vg - Age 6 to <24 Months Cohort 1: 6.0E13 Vector Genomes (vg) - Age 6 to <24 Months Cohort 2: 1.2E14 vg - Age 24 to <60 Months Cohort 3: 2.4E14 vg - Age 6 to <24 Months
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    13 / 13 (100.00%)
    3 / 3 (100.00%)
    12 / 12 (100.00%)
    4 / 4 (100.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Acrochordon
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 3 (0.00%)
    1 / 12 (8.33%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    3 / 13 (23.08%)
    0 / 3 (0.00%)
    0 / 12 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    3
    0
    0
    0
    Hypotension
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 3 (33.33%)
    1 / 12 (8.33%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Aortic dilatation
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 3 (0.00%)
    0 / 12 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Flushing
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 3 (0.00%)
    0 / 12 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    6 / 13 (46.15%)
    3 / 3 (100.00%)
    7 / 12 (58.33%)
    2 / 4 (50.00%)
         occurrences all number
    9
    3
    8
    2
    Application site irritation
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 3 (0.00%)
    0 / 12 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Infusion site bruising
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 3 (33.33%)
    0 / 12 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Immune system disorders
    Seasonal allergy
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 3 (0.00%)
    1 / 12 (8.33%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    1
    1
    Hypersensitivity
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 3 (33.33%)
    0 / 12 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Reproductive system and breast disorders
    Balanoposthitis
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 3 (0.00%)
    0 / 12 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    3 / 13 (23.08%)
    0 / 3 (0.00%)
    7 / 12 (58.33%)
    1 / 4 (25.00%)
         occurrences all number
    5
    0
    15
    2
    Nasal congestion
         subjects affected / exposed
    2 / 13 (15.38%)
    1 / 3 (33.33%)
    2 / 12 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    2
    1
    4
    0
    Rhinorrhoea
         subjects affected / exposed
    2 / 13 (15.38%)
    0 / 3 (0.00%)
    2 / 12 (16.67%)
    1 / 4 (25.00%)
         occurrences all number
    2
    0
    2
    1
    Upper respiratory tract congestion
         subjects affected / exposed
    2 / 13 (15.38%)
    0 / 3 (0.00%)
    1 / 12 (8.33%)
    0 / 4 (0.00%)
         occurrences all number
    3
    0
    1
    0
    Respiration abnormal
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 3 (0.00%)
    1 / 12 (8.33%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Sleep apnoea syndrome
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 3 (0.00%)
    1 / 12 (8.33%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Atelectasis
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 3 (0.00%)
    1 / 12 (8.33%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Choking
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 3 (0.00%)
    1 / 12 (8.33%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Hypoxia
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 3 (0.00%)
    0 / 12 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Respiratory tract congestion
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 3 (0.00%)
    0 / 12 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Rhonchi
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 3 (0.00%)
    1 / 12 (8.33%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Psychiatric disorders
    Irritability
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 3 (0.00%)
    0 / 12 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Sleep terror
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 3 (33.33%)
    0 / 12 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Investigations
    Blood alkaline phosphatase increased
         subjects affected / exposed
    2 / 13 (15.38%)
    0 / 3 (0.00%)
    0 / 12 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    2
    0
    0
    1
    Activated partial thromboplastin time prolonged
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 3 (0.00%)
    0 / 12 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 3 (0.00%)
    1 / 12 (8.33%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Blood creatine phosphokinase MB increased
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 3 (0.00%)
    1 / 12 (8.33%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Blood iron decreased
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 3 (0.00%)
    0 / 12 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Blood lead increased
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 3 (0.00%)
    1 / 12 (8.33%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Blood pressure diastolic increased
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 3 (0.00%)
    0 / 12 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Cardiac murmur
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 3 (0.00%)
    0 / 12 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Carnitine decreased
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 3 (0.00%)
    1 / 12 (8.33%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Crystal urine present
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 3 (33.33%)
    0 / 12 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Electrocardiogram QT prolonged
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 3 (0.00%)
    0 / 12 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Eosinophil count increased
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 3 (0.00%)
    0 / 12 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Neutrophil count increased
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 3 (0.00%)
    1 / 12 (8.33%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Norovirus test positive
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 3 (0.00%)
    0 / 12 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    1
    Respirovirus test positive
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 3 (0.00%)
    0 / 12 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Injury, poisoning and procedural complications
    Arthropod bite
         subjects affected / exposed
    3 / 13 (23.08%)
    0 / 3 (0.00%)
    0 / 12 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    3
    0
    0
    0
    Contusion
         subjects affected / exposed
    2 / 13 (15.38%)
    0 / 3 (0.00%)
    0 / 12 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Skin abrasion
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 3 (0.00%)
    2 / 12 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Fall
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 3 (0.00%)
    1 / 12 (8.33%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Congenital, familial and genetic disorders
    Pectus carinatum
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 3 (0.00%)
    0 / 12 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Pectus excavatum
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 3 (0.00%)
    0 / 12 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Cardiac disorders
    Tachycardia
         subjects affected / exposed
    2 / 13 (15.38%)
    0 / 3 (0.00%)
    2 / 12 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    3
    0
    2
    0
    Mitral valve incompetence
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 3 (0.00%)
    1 / 12 (8.33%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Sinus tachycardia
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 3 (0.00%)
    1 / 12 (8.33%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Cardiomegaly
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 3 (0.00%)
    1 / 12 (8.33%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Pericardial effusion
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 3 (0.00%)
    0 / 12 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Pulmonary valve incompetence
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 3 (0.00%)
    1 / 12 (8.33%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 3 (0.00%)
    1 / 12 (8.33%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Language disorder
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 3 (0.00%)
    0 / 12 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Migraine
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 3 (0.00%)
    1 / 12 (8.33%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Muscle contractions involuntary
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 3 (0.00%)
    0 / 12 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Tremor
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 3 (33.33%)
    0 / 12 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Blood and lymphatic system disorders
    Lymphadenopathy
         subjects affected / exposed
    2 / 13 (15.38%)
    0 / 3 (0.00%)
    1 / 12 (8.33%)
    0 / 4 (0.00%)
         occurrences all number
    2
    0
    1
    0
    Leukopenia
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 3 (0.00%)
    0 / 12 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Ear and labyrinth disorders
    Ear discomfort
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 3 (0.00%)
    1 / 12 (8.33%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Motion sickness
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 3 (0.00%)
    1 / 12 (8.33%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    5 / 13 (38.46%)
    0 / 3 (0.00%)
    3 / 12 (25.00%)
    2 / 4 (50.00%)
         occurrences all number
    11
    0
    5
    2
    Constipation
         subjects affected / exposed
    2 / 13 (15.38%)
    0 / 3 (0.00%)
    3 / 12 (25.00%)
    2 / 4 (50.00%)
         occurrences all number
    2
    0
    5
    2
    Teething
         subjects affected / exposed
    2 / 13 (15.38%)
    1 / 3 (33.33%)
    0 / 12 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    2
    1
    0
    1
    Abdominal pain
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 3 (0.00%)
    1 / 12 (8.33%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Anal fissure
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 3 (0.00%)
    0 / 12 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Dental caries
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 3 (0.00%)
    1 / 12 (8.33%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Diarrhoea
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 3 (0.00%)
    0 / 12 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Dysphagia
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 3 (0.00%)
    0 / 12 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    1
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 3 (0.00%)
    0 / 12 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Haematochezia
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 3 (0.00%)
    0 / 12 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Tooth resorption
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 3 (0.00%)
    0 / 12 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Hepatobiliary disorders
    Hepatomegaly
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 3 (0.00%)
    0 / 12 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    2 / 13 (15.38%)
    1 / 3 (33.33%)
    3 / 12 (25.00%)
    0 / 4 (0.00%)
         occurrences all number
    2
    1
    4
    0
    Dermatitis diaper
         subjects affected / exposed
    2 / 13 (15.38%)
    1 / 3 (33.33%)
    0 / 12 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    2
    1
    0
    1
    Eczema
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 3 (0.00%)
    1 / 12 (8.33%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    2
    0
    Erythema
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 3 (0.00%)
    1 / 12 (8.33%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Alopecia
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 3 (0.00%)
    0 / 12 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Blister
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 3 (0.00%)
    0 / 12 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Dermatitis contact
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 3 (0.00%)
    0 / 12 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Dry skin
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 3 (0.00%)
    1 / 12 (8.33%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Hair growth abnormal
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 3 (0.00%)
    1 / 12 (8.33%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Papule
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 3 (0.00%)
    1 / 12 (8.33%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Perioral dermatitis
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 3 (0.00%)
    1 / 12 (8.33%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Skin irritation
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 3 (0.00%)
    1 / 12 (8.33%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Urticaria
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 3 (0.00%)
    1 / 12 (8.33%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Endocrine disorders
    Cushingoid
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 3 (0.00%)
    1 / 12 (8.33%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Musculoskeletal and connective tissue disorders
    Scoliosis
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 3 (0.00%)
    4 / 12 (33.33%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    4
    0
    Joint contracture
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 3 (0.00%)
    2 / 12 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    3
    0
    Kyphosis
         subjects affected / exposed
    2 / 13 (15.38%)
    0 / 3 (0.00%)
    0 / 12 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Limb asymmetry
         subjects affected / exposed
    1 / 13 (7.69%)
    1 / 3 (33.33%)
    0 / 12 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Pain in extremity
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 3 (0.00%)
    2 / 12 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Arthralgia
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 3 (0.00%)
    1 / 12 (8.33%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Back pain
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 3 (0.00%)
    0 / 12 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Joint stiffness
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 3 (0.00%)
    0 / 12 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Knee deformity
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 3 (33.33%)
    0 / 12 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Kyphoscoliosis
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 3 (0.00%)
    1 / 12 (8.33%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Mastication disorder
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 3 (0.00%)
    1 / 12 (8.33%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Muscle contracture
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 3 (0.00%)
    0 / 12 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    1
    Muscle tightness
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 3 (0.00%)
    0 / 12 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    4
    0
    0
    0
    Soft tissue swelling
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 3 (0.00%)
    1 / 12 (8.33%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Tendinous contracture
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 3 (0.00%)
    1 / 12 (8.33%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Tendon discomfort
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 3 (0.00%)
    0 / 12 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    10 / 13 (76.92%)
    2 / 3 (66.67%)
    5 / 12 (41.67%)
    3 / 4 (75.00%)
         occurrences all number
    22
    3
    12
    5
    Nasopharyngitis
         subjects affected / exposed
    3 / 13 (23.08%)
    0 / 3 (0.00%)
    2 / 12 (16.67%)
    1 / 4 (25.00%)
         occurrences all number
    4
    0
    3
    1
    Otitis media
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 3 (33.33%)
    3 / 12 (25.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    2
    3
    0
    Viral infection
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 3 (0.00%)
    1 / 12 (8.33%)
    1 / 4 (25.00%)
         occurrences all number
    1
    0
    1
    2
    Conjunctivitis
         subjects affected / exposed
    2 / 13 (15.38%)
    0 / 3 (0.00%)
    0 / 12 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Ear infection
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 3 (0.00%)
    1 / 12 (8.33%)
    0 / 4 (0.00%)
         occurrences all number
    2
    0
    1
    0
    Pneumonia
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 3 (33.33%)
    1 / 12 (8.33%)
    0 / 4 (0.00%)
         occurrences all number
    0
    2
    1
    0
    Bacteriuria
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 3 (0.00%)
    1 / 12 (8.33%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Coxsackie viral infection
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 3 (0.00%)
    0 / 12 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    1
    Croup infectious
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 3 (0.00%)
    0 / 12 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    1
    Furuncle
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 3 (0.00%)
    0 / 12 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Gastroenteritis
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 3 (0.00%)
    1 / 12 (8.33%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Gastroenteritis viral
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 3 (0.00%)
    0 / 12 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    1
    Metapneumovirus infection
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 3 (33.33%)
    0 / 12 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Parainfluenzae virus infection
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 3 (0.00%)
    1 / 12 (8.33%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Pharyngitis
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 3 (0.00%)
    1 / 12 (8.33%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Pharyngitis streptococcal
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 3 (0.00%)
    0 / 12 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Respiratory tract infection viral
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 3 (0.00%)
    1 / 12 (8.33%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Rhinovirus infection
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 3 (0.00%)
    1 / 12 (8.33%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Viral pharyngitis
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 3 (0.00%)
    0 / 12 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Viral rash
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 3 (0.00%)
    0 / 12 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Viral upper respiratory tract infection
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 3 (0.00%)
    1 / 12 (8.33%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Metabolism and nutrition disorders
    Weight gain poor
         subjects affected / exposed
    3 / 13 (23.08%)
    0 / 3 (0.00%)
    0 / 12 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    3
    0
    0
    0
    Dehydration
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 3 (0.00%)
    2 / 12 (16.67%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Decreased appetite
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 3 (0.00%)
    0 / 12 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Feeding disorder
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 3 (0.00%)
    1 / 12 (8.33%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Malnutrition
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 3 (0.00%)
    0 / 12 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Metabolic acidosis
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 3 (0.00%)
    1 / 12 (8.33%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Vitamin D deficiency
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 3 (0.00%)
    0 / 12 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    11 Aug 2016
    The following updates were made: ● Study design, inclusion/exclusion criteria, safety criteria for discontinuation, and schedule of assessment were updated.
    17 Feb 2017
    The following updates were made: ● Study was re-designed as open-label-label, with a broader age range of participants ● Multiple revisions to reflect change to open-label study design ● Specify non-ambulatory participants ● Revised primary, secondary, and exploratory objectives ● 1-year follow up instead of 2 years ● Added nusinersen information to Background ● Revisions to study drug packaging, labeling, storage, preparation, administration, accountability, handling and disposal ● Clarification for assessment of motor milestones ● Revisions to sample size calculation, and primary, secondary, and additional efficacy endpoints
    29 Mar 2017
    The following updates were made: ● Clarified age requirements and expectation for respiratory syncytial virus vaccination ● Excluded participants with gene mutations rather than homozygous deletions ● Increased dose
    11 Dec 2017
    The following updates were made: ● Specified lower age requirement for the lower age cohort and monitoring of the cardiac enzyme creatine kinase-MB (CK-MB) ● Allowed for high altitude pulse oximetry measurements ● Defined Intent-to-Treat and Enrolled sets
    18 Oct 2018
    The following updates were made: ● Added Dose C and additional changes to reflect dose escalation and study design ● Increased number of participants enrolled based on addition of Dose C ● Added minimum age requirement for the lower age cohort ● Included monitoring of cardiac enzyme CK-MB and Troponin I, and added additional cardiac monitoring ● Updated Good Laboratory Practices (GLP) toxicology data ● Minor clarifications to Schedule of Assessments ● Added measurement of head circumference
    17 Jun 2019
    The following updates were made: ● Added more stringent eligibility criteria for liver function tests and additional visits for monitoring liver function, following an acute liver failure case reported in the US Managed Access Program ● Added benefit/risk language, information on liver failure case, and description of recent adverse events ● Added liver function criteria to prednisolone taper and discontinuation ● Added completed first-in-human trial data ● Revised and reorganized Schedule of Assessments; added Day 44 and Day 72 visits and further clarification on data monitoring committee (DMC) scheduling ● Updated participant withdrawal and discontinuation criteria ● Added a supportive efficacy analysis
    26 Feb 2020
    This amendment was finalized during the partial clinical hold and submitted to the Food and Drug Administration (FDA) but not to local institutional review boards (IRBs), and the amendment was not implemented by the investigator sites. The following updates were made: ● Updates to facilitate detection of clinical symptoms and signs suggestive of ganglionopathy. ● The introduction of the age-appropriate sensory testing as part of the neurological examination, had been implemented for ongoing participants, via an Urgent Safety Measure on 25-Oct-2019. The addition of Sensory Nerve Action Potential (SNAP) at Screening, Day 30 and Month 6, and assessment of neopterin levels at every visit was to apply only to new participants, of which none were enrolled under this amendment.

    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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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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