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    Clinical Trial Results:
    A Global Study of a Single, One-Time Dose of AVXS-101 Delivered to Infants with Genetically Diagnosed and Pre-symptomatic Spinal Muscular Atrophy with Multiple Copies of SMN2

    Summary
    EudraCT number
    		 2017-004087-35
    Trial protocol
    		 ES   IT   GB   BE   NL  
    Global end of trial date
    15 Jun 2021

    Results information
    Results version number
    		 v1
    This version publication date
    11 Jan 2022
    First version publication date
    11 Jan 2022
    Other versions
    		 v2

    Trial information

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    Trial identification
    Sponsor protocol code
    AVXS-101-CL-304
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03505099
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 JapicCTI: JapicCTI-184203
    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) 566-2364, medinfoemea.gtx@novartis.com
    Scientific contact
    EMEA Medical Information, Novartis Gene Therapies, Inc., +353 (1) 566-2364, 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
    15 Jun 2021
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    15 Jun 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objectives of the trial were to: • Cohort 1 - Assess the efficacy of AVXS-101 by demonstrating functional independent sitting for at least 30 seconds as defined by the Bayley Scales of Infant and Toddler Development (BSID) gross motor (GM) subtest item number 26 at any visit up to 18 months of age. • Cohort 2 - Assess the efficacy of AVXS-101 based on the proportion of participants achieving the ability to stand without support for at least 3 seconds as defined by BSID GM subtest item number 40 at any visit up to 24 months of age.
    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
    02 Apr 2018
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Efficacy, Safety
    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: 20
    Country: Number of subjects enrolled
    Australia: 4
    Country: Number of subjects enrolled
    Canada: 1
    Country: Number of subjects enrolled
    Japan: 3
    Country: Number of subjects enrolled
    United Kingdom: 1
    Country: Number of subjects enrolled
    Belgium: 1
    Worldwide total number of subjects
    30
    EEA total number of subjects
    1
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    17
    Infants and toddlers (28 days-23 months)
    13
    Children (2-11 years)
    0
    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 44 participants were screened, of which 14 were screen failures and 30 were enrolled and received study drug. A total of 30 participants took part in the trial at 16 sites in the United States, the United Kingdom, Belgium, Canada, Australia and Japan between April 2018 and June 2021.

    Pre-assignment
    Screening details
    		 One participant was initially diagnosed as having 3 copies of survival of motor neuron 2 (SMN2) and was enrolled into Cohort 2, but a re-confirmation test reported post-dose showed 4 copies of SMN2. This participant was excluded from all analysis populations and data is not reported due to privacy concerns.

    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
    		 Cohort 1: Bi-allelic Deletions of SMN1 and 2 Copies of SMN2
    Arm description
    		 Participants with bi-allelic deletions of survival of motor neuron 1 (SMN1) and 2 copies of SMN2 received a single dose of AVXS-101 administered as an intravenous (IV) infusion over 60 minutes on Day 1 of the overall study. Participants also received daily doses of prophylactic oral prednisolone starting at a dose of 1-2 mg/kg/day from 1 day prior to AVXS-101 infusion until at least 30 days post-infusion 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
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    AVXS-101 was administered as an IV infusion over 60 minutes at a dose of 1.1 × 10^14 vg/kg (vector genome per kilogram).

    Arm title
    		 Cohort 2: Bi-allelic Deletions of SMN1 and 3 Copies of SMN2
    Arm description
    		 Participants with bi-allelic deletions of SMN1 and 3 copies of SMN2 received a single dose of AVXS-101 administered as an IV infusion over 60 minutes on Day 1 of the overall study. Participants also received daily doses of prophylactic oral prednisolone starting at a dose of 1-2 mg/kg/day from 1 day prior to AVXS-101 infusion until at least 30 days post-infusion 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
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    AVXS-101 was administered as an IV infusion over 60 minutes at a dose of 1.1 × 10^14 vg/kg.

    Number of subjects in period 1 [1]
    		Cohort 1: Bi-allelic Deletions of SMN1 and 2 Copies of SMN2 Cohort 2: Bi-allelic Deletions of SMN1 and 3 Copies of SMN2
    Started
    14
    15
    Received AVXS-101
    14
    15
    Completed
    14
    15
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: One participant was initially diagnosed as having 3 copies of SMN2 and was enrolled into Cohort 2, but a re-confirmation test reported post-dose showed 4 copies of SMN2. This participant was excluded from all analysis populations and data is not reported due to privacy concerns.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Cohort 1: Bi-allelic Deletions of SMN1 and 2 Copies of SMN2
    Reporting group description
    		 Participants with bi-allelic deletions of survival of motor neuron 1 (SMN1) and 2 copies of SMN2 received a single dose of AVXS-101 administered as an intravenous (IV) infusion over 60 minutes on Day 1 of the overall study. Participants also received daily doses of prophylactic oral prednisolone starting at a dose of 1-2 mg/kg/day from 1 day prior to AVXS-101 infusion until at least 30 days post-infusion at which point the prednisolone dose could be tapered downwards. At week 9, prednisolone could be discontinued.

    Reporting group title
    Cohort 2: Bi-allelic Deletions of SMN1 and 3 Copies of SMN2
    Reporting group description
    		 Participants with bi-allelic deletions of SMN1 and 3 copies of SMN2 received a single dose of AVXS-101 administered as an IV infusion over 60 minutes on Day 1 of the overall study. Participants also received daily doses of prophylactic oral prednisolone starting at a dose of 1-2 mg/kg/day from 1 day prior to AVXS-101 infusion until at least 30 days post-infusion at which point the prednisolone dose could be tapered downwards. At week 9, prednisolone could be discontinued.

    Reporting group values
    		 Cohort 1: Bi-allelic Deletions of SMN1 and 2 Copies of SMN2 Cohort 2: Bi-allelic Deletions of SMN1 and 3 Copies of SMN2 Total
    Number of subjects
    		 14 15 29
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 11 6 17
        Infants and toddlers (28 days-23 months)
    		 3 9 12
        Children (2-11 years)
    		 0 0 0
        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
    Gender categorical
    Units: Subjects
        Female
    		 10 9 19
        Male
    		 4 6 10
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 4 2 6
        Not Hispanic or Latino
    		 10 13 23
        Unknown or Not Reported
    		 0 0 0
    Race
    Units: Subjects
        Asian
    		 2 2 4
        American Indian or Alaska Native
    		 0 1 1
        Black or African American
    		 1 0 1
        White
    		 7 10 17
        Other
    		 4 2 6
    SMN2 gene modifier mutation (c.859G>C)
    Units: Subjects
        SMN2 gene modifier mutation (c.859G>C) Present
    		 0 0 0
        SMN2 gene modifier mutation (c.859G>C) Absent
    		 14 15 29

    End points

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    End points reporting groups
    Reporting group title
    Cohort 1: Bi-allelic Deletions of SMN1 and 2 Copies of SMN2
    Reporting group description
    		 Participants with bi-allelic deletions of survival of motor neuron 1 (SMN1) and 2 copies of SMN2 received a single dose of AVXS-101 administered as an intravenous (IV) infusion over 60 minutes on Day 1 of the overall study. Participants also received daily doses of prophylactic oral prednisolone starting at a dose of 1-2 mg/kg/day from 1 day prior to AVXS-101 infusion until at least 30 days post-infusion at which point the prednisolone dose could be tapered downwards. At week 9, prednisolone could be discontinued.

    Reporting group title
    Cohort 2: Bi-allelic Deletions of SMN1 and 3 Copies of SMN2
    Reporting group description
    		 Participants with bi-allelic deletions of SMN1 and 3 copies of SMN2 received a single dose of AVXS-101 administered as an IV infusion over 60 minutes on Day 1 of the overall study. Participants also received daily doses of prophylactic oral prednisolone starting at a dose of 1-2 mg/kg/day from 1 day prior to AVXS-101 infusion until at least 30 days post-infusion at which point the prednisolone dose could be tapered downwards. At week 9, prednisolone could be discontinued.

    Primary: Cohort 1: Number of Participants Who Achieved Sitting Alone for at Least 30 Seconds

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    End point title
    		 Cohort 1: Number of Participants Who Achieved Sitting Alone for at Least 30 Seconds [1] [2]
    End point description
    Defined by the Bayley Scales of Infant and Toddler Development (BSID) Gross Motor (GM) subtest performance criteria number 26, confirmed by video recording, as a participant who sits for at least 30 seconds without assistance from another person or object. The participant was allowed to use their upper extremities. The analysis population was the Intent-to-Treat (ITT) population (cohort 1) which included all enrolled participants with bi-allelic SMN1 deletions and 2 copies of SMN2 without the SMN2 gene modifier mutation (c.859G>C) who received AVXS-101.
    End point type
    Primary
    End point timeframe
    From Day 1 up to 18 months of age visit
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No comparative statistical analyses were planned for this 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 for this endpoint was only collected for participants in Cohort 1.
    End point values
    		 Cohort 1: Bi-allelic Deletions of SMN1 and 2 Copies of SMN2
    Number of subjects analysed
    14
    Units: Participants
    14
    No statistical analyses for this end point

    Primary: Cohort 2: Cohort 2: Number of Participants Who Achieved Standing Alone for at Least 3 Seconds

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    End point title
    		 Cohort 2: Cohort 2: Number of Participants Who Achieved Standing Alone for at Least 3 Seconds [3] [4]
    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. The analysis population was the ITT population (cohort 2) which included all enrolled participants with bi-allelic SMN1 deletions and 3 copies of SMN2 without the SMN2 gene modifier mutation (c.859G>C) who received AVXS-101.
    End point type
    Primary
    End point timeframe
    From Day 1 up to 24 months of age visit
    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: No comparative statistical analyses were planned for this 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 for this endpoint was only collected for participants in Cohort 2.
    End point values
    		 Cohort 2: Bi-allelic Deletions of SMN1 and 3 Copies of SMN2
    Number of subjects analysed
    15
    Units: Participants
    15
    No statistical analyses for this end point

    Secondary: Cohort 1: Event-free Survival at 14 Months of Age

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    End point title
    		 Cohort 1: Event-free Survival at 14 Months of Age [5]
    End point description
    Event-free survival at 14 months of age was defined as the number of participants who did not die, did not require permanent ventilation and did not withdraw from the study by 14 months of age. The analysis population was the ITT population (cohort 1) which included all enrolled participants with bi-allelic SMN1 deletions and 2 copies of SMN2 without the SMN2 gene modifier mutation (c.859G>C) who received AVXS-101.
    End point type
    Secondary
    End point timeframe
    From Day 1 up to 14 months of age
    Notes
    [5] - 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 for this endpoint was only collected for participants in Cohort 1.
    End point values
    		 Cohort 1: Bi-allelic Deletions of SMN1 and 2 Copies of SMN2
    Number of subjects analysed
    14
    Units: Participants
    14
    No statistical analyses for this end point

    Secondary: Cohort 1: Number of Participants Who Achieved the Ability to Maintain Weight at or Above the Third Percentile Without the Need for Non-Oral or Mechanical Feeding Support

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    End point title
    		 Cohort 1: Number of Participants Who Achieved the Ability to Maintain Weight at or Above the Third Percentile Without the Need for Non-Oral or Mechanical Feeding Support [6]
    End point description
    The ability to maintain weight at or above the third percentile without the need for non-oral or mechanical feeding support was defined by meeting the following criteria at each visit up to 18 months of age: • Did not receive nutrition through mechanical support (i.e., feeding tube) • Maintained weight (≥ third percentile for age and sex as defined by World Health Organization [WHO] guidelines) consistent with the participant’s age at the assessment. The analysis population was the ITT population (cohort 1) which included all enrolled participants with bi-allelic SMN1 deletions and 2 copies of SMN2 without the SMN2 gene modifier mutation (c.859G>C) who received AVXS-101.
    End point type
    Secondary
    End point timeframe
    From Day 1 up to 18 months of age
    Notes
    [6] - 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 for this endpoint was only collected for participants in Cohort 1.
    End point values
    		 Cohort 1: Bi-allelic Deletions of SMN1 and 2 Copies of SMN2
    Number of subjects analysed
    14
    Units: Participants
    13
    No statistical analyses for this end point

    Secondary: Cohort 2: Number of Participants Who Achieved the Ability to Walk Alone

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    End point title
    		 Cohort 2: Number of Participants Who Achieved the Ability to Walk Alone [7]
    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. The analysis population was the ITT population (cohort 2) which included all enrolled participants with bi-allelic SMN1 deletions and 3 copies of SMN2 without the SMN2 gene modifier mutation (c.859G>C) who received AVXS-101.
    End point type
    Secondary
    End point timeframe
    From Day 1 up to 24 months of age visit
    Notes
    [7] - 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 for this endpoint was only collected for participants in Cohort 2.
    End point values
    		 Cohort 2: Bi-allelic Deletions of SMN1 and 3 Copies of SMN2
    Number of subjects analysed
    15
    Units: Participants
    14
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Cohort 1: Treatment-emergent adverse events (TEAEs) were collected from Day 1 up to 18 months of age. Cohort 2: TEAEs were collected from Day 1 up to 24 months of age.
    Adverse event reporting additional description
    Serious adverse events (SAEs) were collected from signing of informed consent to 30 days after the last study visit (up to a maximum of approximately 20 months for Cohort 1 and 26 months for Cohort 2).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23.0
    Reporting groups
    Reporting group title
    Cohort 1: Bi-allelic Deletions of SMN1 and 2 Copies of SMN2
    Reporting group description
    		 Participants with bi-allelic deletions of survival of motor neuron 1 (SMN1) and 2 copies of SMN2 received a single dose of AVXS-101 administered as an intravenous (IV) infusion over 60 minutes on Day 1 of the overall study. Participants also received daily doses of prophylactic oral prednisolone starting at a dose of 1-2 mg/kg/day from 1 day prior to AVXS-101 infusion until at least 30 days post-infusion at which point the prednisolone dose could be tapered downwards. At week 9, prednisolone could be discontinued.

    Reporting group title
    Cohort 2: Bi-allelic Deletions of SMN1 and 3 Copies of SMN2
    Reporting group description
    		 Participants with bi-allelic deletions of SMN1 and 3 copies of SMN2 received a single dose of AVXS-101 administered as an IV infusion over 60 minutes on Day 1 of the overall study. Participants also received daily doses of prophylactic oral prednisolone starting at a dose of 1-2 mg/kg/day from 1 day prior to AVXS-101 infusion until at least 30 days post-infusion at which point the prednisolone dose could be tapered downwards. At week 9, prednisolone could be discontinued.

    Serious adverse events
    		 Cohort 1: Bi-allelic Deletions of SMN1 and 2 Copies of SMN2 Cohort 2: Bi-allelic Deletions of SMN1 and 3 Copies of SMN2
    Total subjects affected by serious adverse events
         subjects affected / exposed
    5 / 14 (35.71%)
    3 / 15 (20.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Nervous system disorders
    Lethargy
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Middle ear effusion
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Inguinal hernia
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Sleep apnoea syndrome
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Croup infectious
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear infection
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pharyngitis
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hypercalcaemia
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Cohort 1: Bi-allelic Deletions of SMN1 and 2 Copies of SMN2 Cohort 2: Bi-allelic Deletions of SMN1 and 3 Copies of SMN2
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    14 / 14 (100.00%)
    15 / 15 (100.00%)
    General disorders and administration site conditions
    Developmental delay 
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    Influenza like illness 
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    Malaise
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    Pyrexia 
         subjects affected / exposed
    7 / 14 (50.00%)
    11 / 15 (73.33%)
         occurrences all number
    7
    18
    Vessel puncture site bruise 
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    Immune system disorders
    Food allergy 
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Cough 
         subjects affected / exposed
    1 / 14 (7.14%)
    4 / 15 (26.67%)
         occurrences all number
    4
    6
    Nasal congestion 
         subjects affected / exposed
    3 / 14 (21.43%)
    2 / 15 (13.33%)
         occurrences all number
    3
    2
    Rhinorrhoea 
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    Sleep apnoea syndrome 
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    Snoring 
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    Upper respiratory tract congestion 
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Psychiatric disorders
    Irritability 
         subjects affected / exposed
    1 / 14 (7.14%)
    1 / 15 (6.67%)
         occurrences all number
    1
    2
    Agitation 
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Investigations
    Alanine aminotransferase increased 
         subjects affected / exposed
    1 / 14 (7.14%)
    3 / 15 (20.00%)
         occurrences all number
    2
    5
    Aspartate aminotransferase increased 
         subjects affected / exposed
    3 / 14 (21.43%)
    4 / 15 (26.67%)
         occurrences all number
    4
    6
    Blood creatine phosphokinase MB increased 
         subjects affected / exposed
    1 / 14 (7.14%)
    2 / 15 (13.33%)
         occurrences all number
    1
    2
    Blood creatine phosphokinase increased 
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    Gamma-glutamyltransferase increased 
         subjects affected / exposed
    1 / 14 (7.14%)
    1 / 15 (6.67%)
         occurrences all number
    1
    1
    Head lag 
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    Platelet count decreased 
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    Platelet count increased 
         subjects affected / exposed
    1 / 14 (7.14%)
    1 / 15 (6.67%)
         occurrences all number
    1
    1
    Troponin increased 
         subjects affected / exposed
    1 / 14 (7.14%)
    2 / 15 (13.33%)
         occurrences all number
    2
    2
    Bacterial test positive 
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    2
    Blood alkaline phosphatase increased 
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Blood calcium increased 
         subjects affected / exposed
    0 / 14 (0.00%)
    2 / 15 (13.33%)
         occurrences all number
    0
    2
    Carbon dioxide decreased 
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Injury, poisoning and procedural complications
    Eye injury 
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    Skin abrasion 
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    Tracheal deviation 
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    Arthropod sting 
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Contusion 
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Eyelid injury 
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Scratch 
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Skin wound 
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Congenital, familial and genetic disorders
    Dacryostenosis congenital 
         subjects affected / exposed
    1 / 14 (7.14%)
    1 / 15 (6.67%)
         occurrences all number
    1
    1
    Hydrocele 
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    Nervous system disorders
    Areflexia 
         subjects affected / exposed
    2 / 14 (14.29%)
    1 / 15 (6.67%)
         occurrences all number
    2
    2
    Hypertonia 
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    Hypokinesia 
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    Hyporeflexia 
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    Hypotonia 
         subjects affected / exposed
    3 / 14 (21.43%)
    2 / 15 (13.33%)
         occurrences all number
    5
    3
    Motor developmental delay 
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    Muscle contractions involuntary 
         subjects affected / exposed
    3 / 14 (21.43%)
    1 / 15 (6.67%)
         occurrences all number
    3
    1
    Tremor 
         subjects affected / exposed
    3 / 14 (21.43%)
    0 / 15 (0.00%)
         occurrences all number
    4
    0
    Febrile convulsion 
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Lethargy 
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Blood and lymphatic system disorders
    Lymphadenopathy 
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    Microcytic anaemia 
         subjects affected / exposed
    1 / 14 (7.14%)
    2 / 15 (13.33%)
         occurrences all number
    1
    3
    Thrombocytopenia 
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    Iron deficiency anaemia 
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Ear and labyrinth disorders
    Middle ear effusion 
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    Ear pain 
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    2
    Eye disorders
    Eye discharge 
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    Chalazion 
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Ocular hyperaemia 
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Gastrointestinal disorders
    Abdominal discomfort 
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    Constipation 
         subjects affected / exposed
    4 / 14 (28.57%)
    1 / 15 (6.67%)
         occurrences all number
    5
    1
    Diarrhoea 
         subjects affected / exposed
    3 / 14 (21.43%)
    4 / 15 (26.67%)
         occurrences all number
    4
    5
    Dysphagia 
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    Gastrooesophageal reflux disease 
         subjects affected / exposed
    3 / 14 (21.43%)
    3 / 15 (20.00%)
         occurrences all number
    3
    4
    Gingival pain 
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 15 (0.00%)
         occurrences all number
    2
    0
    Inguinal hernia 
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    Teething 
         subjects affected / exposed
    2 / 14 (14.29%)
    5 / 15 (33.33%)
         occurrences all number
    2
    6
    Tooth development disorder 
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    Vomiting
         subjects affected / exposed
    3 / 14 (21.43%)
    2 / 15 (13.33%)
         occurrences all number
    3
    2
    Abdominal pain upper 
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Haematemesis 
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Haematochezia 
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Nausea 
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Regurgitation 
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Flatulence 
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    Stomatitis 
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Skin and subcutaneous tissue disorders
    Cafe au lait spots 
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    Eczema 
         subjects affected / exposed
    2 / 14 (14.29%)
    0 / 15 (0.00%)
         occurrences all number
    2
    0
    Rash 
         subjects affected / exposed
    3 / 14 (21.43%)
    2 / 15 (13.33%)
         occurrences all number
    6
    2
    Blister 
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Dermatitis diaper
         subjects affected / exposed
    0 / 14 (0.00%)
    3 / 15 (20.00%)
         occurrences all number
    0
    3
    Eczema infantile 
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Lipohypertrophy 
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Miliaria 
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Pruritus 
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Rash macular
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Renal and urinary disorders
    Nephrocalcinosis 
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    Pyelocaliectasis 
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    Dysuria 
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Endocrine disorders
    Precocious puberty 
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    Cushingoid 
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Musculoskeletal and connective tissue disorders
    Hip deformity 
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    Joint contracture 
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    Kyphosis 
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    Loose body in joint 
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    Pain in extremity 
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Infections and infestations
    Adenovirus infection 
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    COVID-19 
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    Candida infection 
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    Candida nappy rash 
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 15 (0.00%)
         occurrences all number
    2
    0
    Conjunctivitis 
         subjects affected / exposed
    1 / 14 (7.14%)
    1 / 15 (6.67%)
         occurrences all number
    2
    2
    Croup infectious 
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    Ear infection 
         subjects affected / exposed
    2 / 14 (14.29%)
    1 / 15 (6.67%)
         occurrences all number
    3
    3
    Fungal infection 
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    Gastroenteritis viral 
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    Infected bite 
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    Influenza 
         subjects affected / exposed
    2 / 14 (14.29%)
    0 / 15 (0.00%)
         occurrences all number
    2
    0
    Nasopharyngitis 
         subjects affected / exposed
    2 / 14 (14.29%)
    3 / 15 (20.00%)
         occurrences all number
    3
    4
    Otitis media 
         subjects affected / exposed
    1 / 14 (7.14%)
    3 / 15 (20.00%)
         occurrences all number
    1
    6
    Pneumonia 
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    Respiratory tract infection 
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    Respiratory tract infection viral 
         subjects affected / exposed
    1 / 14 (7.14%)
    1 / 15 (6.67%)
         occurrences all number
    1
    2
    Rhinitis 
         subjects affected / exposed
    1 / 14 (7.14%)
    1 / 15 (6.67%)
         occurrences all number
    1
    1
    Rhinovirus infection 
         subjects affected / exposed
    2 / 14 (14.29%)
    0 / 15 (0.00%)
         occurrences all number
    2
    0
    Upper respiratory tract infection 
         subjects affected / exposed
    5 / 14 (35.71%)
    9 / 15 (60.00%)
         occurrences all number
    7
    13
    Viral upper respiratory tract infection 
         subjects affected / exposed
    3 / 14 (21.43%)
    1 / 15 (6.67%)
         occurrences all number
    10
    1
    Bronchitis 
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Exanthema subitum 
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Fungal skin infection 
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Gastroenteritis 
         subjects affected / exposed
    0 / 14 (0.00%)
    2 / 15 (13.33%)
         occurrences all number
    0
    3
    Hand-foot-and-mouth disease 
         subjects affected / exposed
    0 / 14 (0.00%)
    2 / 15 (13.33%)
         occurrences all number
    0
    2
    Otitis media acute 
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Respiratory syncytial virus infection 
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Roseola 
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Urinary tract infection 
         subjects affected / exposed
    0 / 14 (0.00%)
    2 / 15 (13.33%)
         occurrences all number
    0
    2
    Viral infection 
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Metabolism and nutrition disorders
    Failure to thrive 
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    Hypercalcaemia 
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    Hypomagnesaemia 
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 15 (0.00%)
         occurrences all number
    2
    0
    Lactose intolerance 
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Poor feeding infant 
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Weight gain poor 
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    27 Sep 2018
    Global version 2.0 - Amendment 1 Updated to include recent good laboratory practice toxicology data, to provide additional cardiac monitoring for participant safety, to allow laboratory samples to be processed locally in certain instances, and added Japan participant urine, saliva and stool collections for viral shedding analysis. Cohort 3 for participants with 4 copies of SMN2 removed leading to changes in objectives, investigational plan, selection criteria, assessments of efficacy and safety, and statistical analysis. Amendment 1 was not submitted to Institutional Review Board /Independent Ethics Committee or regulatory agencies because Amendment 2 was already planned and was submitted as soon as Global Version 1.0 was approved (in countries where it had been submitted).
    19 Oct 2018
    Global Version 3.0 - Amendment 2 Included the changes outlined above for Amendment 1. In addition, updated to provide a correction to the timing of genetic reconfirmation testing from Month 3 to screening and revisions for consistency across AVXS-101 protocols. Additional cardiac monitoring (24-hour Holter monitoring, electrocardiogram [ECG], and echocardiogram [ECHO]) were added to assure participant safety.
    30 May 2019
    Global Version 4.0 - Amendment 3 Updated to include a new regimen for prophylactic prednisolone and additional visits for liver function test monitoring according to recommendations made by Sponsor following acute liver failure case reported in the United States Managed Access Program. Updates related to additional toxicology biodistribution studies, release of AVXS-101-CL-101 clinical study report. Safety reporting and analysis, and removal of Japan specific assessments which were included in a separate, Japan-specific protocol.
    26 Nov 2019
    Global Version 5.0 - Amendment 4 Updates related to non-clinical recent dorsal root ganglia findings in cynomolgus monkeys to further clarify that detailed age appropriate sensory testing is performed during the neurological component of the physical exam. Adverse events of special interests in the areas of hepatotoxicity, thrombocytopenia, cardiac adverse events, and sensory abnormalities suggestive of ganglionitis were included in this protocol amendment.
    28 Jul 2020
    Global Version 6.0 - Amendment 5 Updates related to potential coronavirus disease 2019 (COVID-19) impact on trial conduct, consistency for definitions of the primary endpoints and exploratory endpoints, central review of videos for efficacy parameters, Safety Reporting timelines and addition Hy's Law Criteria due to request by Belgian Regulatory Authority.

    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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    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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