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    Clinical Trial Results:
    An Open-Label Study to Assess the Efficacy, Safety, Tolerability, and Pharmacokinetics of Multiple Doses of ISIS 396443 Delivered Intrathecally to Subjects With Genetically Diagnosed and Presymptomatic Spinal Muscular Atrophy

    Summary
    EudraCT number
    		 2014-002098-12
    Trial protocol
    		 IT   GB   DE  
    Global end of trial date
    16 Dec 2024

    Results information
    Results version number
    		 v1(current)
    This version publication date
    29 Jun 2025
    First version publication date
    29 Jun 2025
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    232SM201
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02386553
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Biogen
    Sponsor organisation address
    225 Binney Street, Cambridge, Massachusetts, United States, 02142
    Public contact
    Study Medical Director, Biogen, clinicaltrials@biogen.com
    Scientific contact
    Study Medical Director, Biogen, clinicaltrials@biogen.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-001448-PIP01-13
    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
    16 Dec 2024
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    16 Dec 2024
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of the study was to examine the efficacy of multiple doses of ISIS 396443 administered intrathecally in preventing or delaying the need for respiratory intervention or death in infants with genetically diagnosed and presymptomatic spinal muscular atrophy (SMA).
    Protection of trial subjects
    Written informed consent was obtained from each subject’s parent or legal guardian prior to evaluations being performed for eligibility. Adequate time to review the information in the informed consent and ask questions concerning all portions of the conduct of the study was provided. Through the informed consent process, awareness of the purpose of the study, the procedures, the benefits and risks of the study, the discomforts and the precautions taken was made. Any side effects or other health issues occurring during the study were followed up by the study doctor. Subjects were able to stop taking part in the study at any time without giving any reason.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    18 May 2015
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United States: 16
    Country: Number of subjects enrolled
    Italy: 3
    Country: Number of subjects enrolled
    Germany: 1
    Country: Number of subjects enrolled
    Türkiye: 1
    Country: Number of subjects enrolled
    Australia: 1
    Country: Number of subjects enrolled
    Taiwan: 2
    Country: Number of subjects enrolled
    Qatar: 1
    Worldwide total number of subjects
    25
    EEA total number of subjects
    4
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    21
    Infants and toddlers (28 days-23 months)
    4
    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
    		 Participants were enrolled at the investigative sites in Australia, Germany, Italy, Qatar, Taiwan, Turkey and the United States from 18 May 2015 to 17 Dec 2024.

    Pre-assignment
    Screening details
    		 A total of 25 participants diagnosed with Spinal Muscular Atrophy (SMA) were enrolled in the study of which 22 participants completed the study.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 ISIS 396443 2 SMN2 Copies
    Arm description
    		 Participants with 2 survival motor neuron 2 (SMN2) copies received 12 milligrams (mg) nusinersen, intrathecally (IT) on Days 1, 15, 29, 64, 183, 302, 421, 540, 659, 778, 897, 1016, 1135, 1254, 1373, 1492, 1611, 1730, 1849, 1968, 2087, 2206, 2325, 2444, 2563, 2682, and 2801.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Nusinersen
    Investigational medicinal product code
    ISIS 396443
    Other name
    BIIB058, Spinraza™
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intrathecal use
    Dosage and administration details
    Administered as specified in the treatment arm.

    Arm title
    		 ISIS 396443 3 SMN2 Copies
    Arm description
    		 Participants with 3 SMN2 copies received 12 mg nusinersen, IT on Days 1, 15, 29, 64, 183, 302, 421, 540, 659, 778, 897, 1016, 1135, 1254, 1373, 1492, 1611, 1730, 1849, 1968, 2087, 2206, 2325, 2444, 2563, 2682, and 2801.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Nusinersen
    Investigational medicinal product code
    ISIS 396443
    Other name
    BIIB058, Spinraza™
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intrathecal use
    Dosage and administration details
    Administered as specified in the treatment arm.

    Number of subjects in period 1
    		ISIS 396443 2 SMN2 Copies ISIS 396443 3 SMN2 Copies
    Started
    15
    10
    Completed
    13
    9
    Not completed
    2
    1
         Reason Not Specified
    1
    1
         Withdrawal by parent/Guardian
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    ISIS 396443 2 SMN2 Copies
    Reporting group description
    		 Participants with 2 survival motor neuron 2 (SMN2) copies received 12 milligrams (mg) nusinersen, intrathecally (IT) on Days 1, 15, 29, 64, 183, 302, 421, 540, 659, 778, 897, 1016, 1135, 1254, 1373, 1492, 1611, 1730, 1849, 1968, 2087, 2206, 2325, 2444, 2563, 2682, and 2801.

    Reporting group title
    ISIS 396443 3 SMN2 Copies
    Reporting group description
    		 Participants with 3 SMN2 copies received 12 mg nusinersen, IT on Days 1, 15, 29, 64, 183, 302, 421, 540, 659, 778, 897, 1016, 1135, 1254, 1373, 1492, 1611, 1730, 1849, 1968, 2087, 2206, 2325, 2444, 2563, 2682, and 2801.

    Reporting group values
    		 ISIS 396443 2 SMN2 Copies ISIS 396443 3 SMN2 Copies Total
    Number of subjects
    		 15 10
    Age Categorical
    Units: Subjects
    Age continuous
    The Intent-to-treat (ITT) set included all participants who received at least 1 dose of ISIS 396443.
    Units: days
        arithmetic mean (standard deviation)
    		 19.5 ( 9.29 ) 22.3 ( 12.45 ) -
    Gender categorical
    Units: Subjects
        Male
    		 8 4 12
        Female
    		 7 6 13
    Race
    Units: Subjects
        American Indian or Alaska Native
    		 1 0 1
        Asian
    		 1 2 3
        White
    		 8 6 14
        Other
    		 2 1 3
        Not Reported
    		 3 1 4
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 2 0 2
        Not Hispanic or Latino
    		 10 9 19
        Not Reported
    		 3 1 4

    End points

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    End points reporting groups
    Reporting group title
    ISIS 396443 2 SMN2 Copies
    Reporting group description
    		 Participants with 2 survival motor neuron 2 (SMN2) copies received 12 milligrams (mg) nusinersen, intrathecally (IT) on Days 1, 15, 29, 64, 183, 302, 421, 540, 659, 778, 897, 1016, 1135, 1254, 1373, 1492, 1611, 1730, 1849, 1968, 2087, 2206, 2325, 2444, 2563, 2682, and 2801.

    Reporting group title
    ISIS 396443 3 SMN2 Copies
    Reporting group description
    		 Participants with 3 SMN2 copies received 12 mg nusinersen, IT on Days 1, 15, 29, 64, 183, 302, 421, 540, 659, 778, 897, 1016, 1135, 1254, 1373, 1492, 1611, 1730, 1849, 1968, 2087, 2206, 2325, 2444, 2563, 2682, and 2801.

    Primary: Time to Death or Respiratory Intervention

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    End point title
    		 Time to Death or Respiratory Intervention [1]
    End point description
    The time was the age of the participant at the first occurrence of either a respiratory intervention or death. Respiratory intervention was defined as invasive or noninvasive ventilation for ≥6 hours/day continuously for 7 or more days OR tracheostomy. The ITT set included all participants who received at least 1 dose of ISIS 396443. Here, 'number of subjects analysed' signifies the number of participants analysed in this endpoint. 99999 indicates that median and upper range of 95% CI was not estimable due to low number of events of permanent ventilation or death.
    End point type
    Primary
    End point timeframe
    Screening up to Day 2891
    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: Only descriptive analysis was planned to be analysed.
    End point values
    		 ISIS 396443 2 SMN2 Copies ISIS 396443 3 SMN2 Copies
    Number of subjects analysed
    5
    0 [2]
    Units: months
        median (confidence interval 95%)
    99999 (19.1 to 99999)
    ( to )
    Notes
    [2] - 'Number of subjects analysed' signifies the number of participants analysed in this endpoint.
    No statistical analyses for this end point

    Secondary: Proportion of Participants Developing Clinically Manifested Spinal Muscular Atrophy (SMA)

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    End point title
    		 Proportion of Participants Developing Clinically Manifested Spinal Muscular Atrophy (SMA)
    End point description
    A participant was considered having clinically manifested SMA if any of the following occurred: • Age-adjusted weight <5th percentile or decrease of ≥2 major weight growth curve percentiles (3rd, 5th, 10th, 25th, or 50th) or a percutaneous gastric tube placement for nutritional support • Failure to achieve the ability to sit without support • Failure to achieve standing with assistance • Failure to achieve hands-and-knees crawling • Failure to achieve walking with assistance by 24 months of age • Failure to achieve standing alone by 24 months of age • Failure to achieve walking alone by 24 months of age The ITT set included all participants who received at least 1 dose of ISIS 396443.
    End point type
    Secondary
    End point timeframe
    At 13 and 24 months of age
    End point values
    		 ISIS 396443 2 SMN2 Copies ISIS 396443 3 SMN2 Copies
    Number of subjects analysed
    15
    10
    Units: Proportion of participants
    number (confidence interval 95%)
        13 months of age
    0.67 (0.39 to 0.87)
    0.20 (0.04 to 0.56)
        24 months of age
    0.47 (0.22 to 0.73)
    0 (0.00 to 0.34)
    No statistical analyses for this end point

    Secondary: Percentage of Participants Who Attained Motor Milestones Assessed as Part of the Hammersmith Infant Neurological Examination (HINE)

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    End point title
    		 Percentage of Participants Who Attained Motor Milestones Assessed as Part of the Hammersmith Infant Neurological Examination (HINE)
    End point description
    HINE is evaluated in infants between 2-24 months of age. It's a simple, standardized instrument including 26 items assessing different aspects of neurological examinations, such as cranial nerves, posture, movements, tone, and reflexes. In this study, Module 2 of HINE (HINE-2) was assessed, which evaluates 8 developmental milestones (head control, sitting, voluntary grasp, ability to kick, rolling, crawling, standing, and walking) scored on a 3, 4, or 5-point scale, with 0 indicating inability to perform task and score of 2, 3, or 4 indicating full milestone development. Total score is calculated by summing item scores to give maximum possible score of 26. Higher score indicates good neurological function. The ITT set included all participants who received at least 1 dose of ISIS 396443.
    End point type
    Secondary
    End point timeframe
    Day 700
    End point values
    		 ISIS 396443 2 SMN2 Copies ISIS 396443 3 SMN2 Copies
    Number of subjects analysed
    15
    10
    Units: percentage of participants
    number (not applicable)
        Sitting: Stable Sit or Pivots (Rotates)
    100
    100
        Standing: Stands With Support or Stands Unaided
    93
    100
        Standing: Stands Unaided
    73
    100
        Walking: Walks Holding on/Walking Independently
    87
    100
        Walking: Walking Independently
    67
    100
        Head Control: All the Time Maintained Upright
    100
    100
        Voluntary Grasp: Pincer Grasp
    100
    100
        Ability to Kick: Touches Toe
    100
    100
        Rolling: Prone to Supine or Supine to Prone
    100
    100
        Crawling: Crawling on Hands and Knees
    73
    100
    No statistical analyses for this end point

    Secondary: Percentage of Participants Alive

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    End point title
    		 Percentage of Participants Alive
    End point description
    A Kaplan-Meier survival curve was used to estimate the proportion of subjects alive at 13 months and 2, 3, 4, 5, 6, 7, and 8 years of age. The ITT set included all participants who received at least 1 dose of ISIS 396443.
    End point type
    Secondary
    End point timeframe
    At 13 months, and 2, 3, 4, 5, 6, 7 and 8 years of age
    End point values
    		 ISIS 396443 2 SMN2 Copies ISIS 396443 3 SMN2 Copies
    Number of subjects analysed
    15
    10
    Units: percentage of participants
        number (not applicable)
    100
    100
    No statistical analyses for this end point

    Secondary: Percentage of Participants Who Attained Motor Milestones as Assessed by World Health Organization (WHO) Criteria

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    End point title
    		 Percentage of Participants Who Attained Motor Milestones as Assessed by World Health Organization (WHO) Criteria
    End point description
    The WHO motor milestones are a set of six milestones in motor development, all of which would be expected to be attained by 24 months of age in healthy children. The individual milestones are: sitting without support, standing with assistance, hands and knees crawling, walking with assistance, standing alone and walking alone. The ITT set included all participants who received at least 1 dose of ISIS 396443.
    End point type
    Secondary
    End point timeframe
    Baseline up to Day 2891
    End point values
    		 ISIS 396443 2 SMN2 Copies ISIS 396443 3 SMN2 Copies
    Number of subjects analysed
    15
    10
    Units: percentage of participants
    number (not applicable)
        First Sitting Without Support
    100
    100
        First Hands-and-Knees Crawling
    93
    100
        First Standing With Assistance
    100
    100
        First Walking With Assistance
    93
    100
        First Standing Alone
    93
    100
        First Walking Alone
    87
    100
    No statistical analyses for this end point

    Secondary: Change From Baseline in the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) Motor Function Scale

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    End point title
    		 Change From Baseline in the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) Motor Function Scale
    End point description
    CHOP-INTEND test was designed to evaluate the motor skills of infants with significant motor weakness.Participants who were ≥2 years were continued to be assessed until CHOP INTEND maximum score of 64 was achieved.It included 16 items(capturing neck, trunk, and proximal and distal limb strength),nine of which were scored 0, 1, 2, 3, or 4, five were scored as 0,2 or 4, one was scored as 0,1,2 or 4, and one as 0, 2, 3, or 4 with higher scores indicating greater muscle strength and function.Total score was calculated as sum of scores for each item.Total score ranged from 0(worst possible score)and 64(best possible score).Assessments were discontinued once participants achieved maximum score of 64,so number of participants with available data points decreased over time.ITT set included all participants who received at least 1 dose of ISIS 396443.'n' signifies number of participants available for analysis at specified time point.9999 indicates that data was not evaluable at given time point.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 2891
    End point values
    		 ISIS 396443 2 SMN2 Copies ISIS 396443 3 SMN2 Copies
    Number of subjects analysed
    15
    10
    Units: score on a scale
    arithmetic mean (standard deviation)
        Baseline (n= 15, 10)
    47.0 ( 10.04 )
    51.9 ( 6.10 )
        Change at Day 2891 (n= 2, 0)
    29.0 ( 11.31 )
    9999 ( 9999 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in Hammersmith Functional Motor Scale - Expanded (HFMSE)

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    End point title
    		 Change From Baseline in Hammersmith Functional Motor Scale - Expanded (HFMSE)
    End point description
    The HFMSE consists of 33 scored activities used to assess motor function in children with SMA. Participants were asked to do a specific activity (such as rolling) and they were then graded on the quality and execution of that movement on a scale of 0=being unable, 1=performed with some compensation, and 2=unaided. The overall score is the sum of the scores for all activities with a maximum achievable score of 66. Higher scores indicate increased motor function. Baseline was defined as the time of first HFMSE score after Day 700. The ITT set included all participants who received at least 1 dose of ISIS 396443. Here 'n' signifies the number of participants available for analysis at a specified time point. 9999 indicates that data was not evaluable at given time point.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 2160
    End point values
    		 ISIS 396443 2 SMN2 Copies ISIS 396443 3 SMN2 Copies
    Number of subjects analysed
    15
    10
    Units: score on a scale
    arithmetic mean (standard deviation)
        Baseline (n= 15, 10)
    34.5 ( 12.15 )
    46.4 ( 7.44 )
        Change at Day 2160 (n= 10, 6)
    23.5 ( 5.34 )
    9999 ( 9999 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in Weight for Age

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    End point title
    		 Change From Baseline in Weight for Age
    End point description
    The World Health Organization (WHO) child growth standards for participants aged up to 10 years was used to determine the percentiles. WHO Anthro software was used to calculate the percentiles for the given weights of each child. Negative change from baseline indicates low weight for age percentile. The ITT set included all participants who received at least 1 dose of ISIS 396443. Here 'n' signifies the number of participants available for analysis at a specified time point.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 2891
    End point values
    		 ISIS 396443 2 SMN2 Copies ISIS 396443 3 SMN2 Copies
    Number of subjects analysed
    15
    10
    Units: percentile
    arithmetic mean (standard deviation)
        Baseline (n= 15, 10)
    44.04 ( 31.197 )
    34.76 ( 16.054 )
        Change at Day 2891 (n= 13, 9)
    -1.46 ( 48.041 )
    24.49 ( 40.263 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in Weight for Length

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    End point title
    		 Change From Baseline in Weight for Length
    End point description
    The World Health Organization (WHO) child growth standards for participants aged up to 10 years was used to determine the percentiles. WHO Anthro software was used to calculate the percentiles for the given weights of each child. The ITT set included all participants who received at least 1 dose of ISIS 396443. Here 'n' signifies the number of participants available for analysis at a specified time point. 9999 indicates that data was not evaluable at given time point. 999999 indicates that since only one participant was evaluable at Day 2891, the standard deviation (SD) could not be estimated.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 1849
    End point values
    		 ISIS 396443 2 SMN2 Copies ISIS 396443 3 SMN2 Copies
    Number of subjects analysed
    10
    6
    Units: percentile
    arithmetic mean (standard deviation)
        Baseline (n= 10, 6)
    21.63 ( 22.806 )
    45.26 ( 28.039 )
        Change at Day 1849
    38.94 ( 999999 )
    9999 ( 9999 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in Head Circumference

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    End point title
    		 Change From Baseline in Head Circumference
    End point description
    The ITT set included all participants who received at least 1 dose of ISIS 396443. Here 'n' signifies the number of participants available for analysis at a specified time point. 9999 indicates that data was not evaluable at given time point. 999999 indicates that since only one participant was evaluable at Day 2891, the SD could not be estimated.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 2891
    End point values
    		 ISIS 396443 2 SMN2 Copies ISIS 396443 3 SMN2 Copies
    Number of subjects analysed
    15
    10
    Units: centimeter (cm)
    arithmetic mean (standard deviation)
        Baseline (n= 15, 10)
    35.59 ( 2.285 )
    36.11 ( 2.198 )
        Change at Day 2891 (n= 0, 1)
    9999 ( 9999 )
    19.00 ( 999999 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in Chest Circumference

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    End point title
    		 Change From Baseline in Chest Circumference
    End point description
    The ITT set included all participants who received at least 1 dose of ISIS 396443. Here 'n' signifies the number of participants available for analysis at a specified time point. 9999 indicates that data was not evaluable at given time point. 999999 indicates that since only one participant was evaluable at Day 2891, the SD could not be estimated.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 2891
    End point values
    		 ISIS 396443 2 SMN2 Copies ISIS 396443 3 SMN2 Copies
    Number of subjects analysed
    15
    10
    Units: cm
    arithmetic mean (standard deviation)
        Baseline (n= 15, 10)
    34.43 ( 2.724 )
    35.25 ( 2.551 )
        Change at Day 2891 (n= 0, 1)
    9999 ( 9999 )
    28.20 ( 999999 )
    No statistical analyses for this end point

    Secondary: Change from Baseline in Head to Chest Circumference Ratio

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    End point title
    		 Change from Baseline in Head to Chest Circumference Ratio
    End point description
    Negative change from baseline indicates reduction in head-to-chest circumference ratio. The ITT set included all participants who received at least 1 dose of ISIS 396443. Here 'n' signifies the number of participants available for analysis at a specified time point. 9999 indicates that data was not evaluable at given time point. 999999 indicates that since only one participant was evaluable at Day 2891, the SD could not be estimated.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 2891
    End point values
    		 ISIS 396443 2 SMN2 Copies ISIS 396443 3 SMN2 Copies
    Number of subjects analysed
    15
    10
    Units: ratio
    arithmetic mean (standard deviation)
        Baseline (n= 15, 10)
    1.036 ( 0.0537 )
    1.027 ( 0.0595 )
        Change at Day 2891 (n= 0, 1)
    9999 ( 9999 )
    -0.186 ( 999999 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in Arm Circumference

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    End point title
    		 Change From Baseline in Arm Circumference
    End point description
    The ITT set included all participants who received at least 1 dose of ISIS 396443. Here 'n' signifies the number of participants available for analysis at a specified time point. 9999 indicates that data was not evaluable at given time point. 999999 indicates that since only one participant was evaluable at Day 2891, the SD could not be estimated.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 2891
    End point values
    		 ISIS 396443 2 SMN2 Copies ISIS 396443 3 SMN2 Copies
    Number of subjects analysed
    15
    10
    Units: cm
    arithmetic mean (standard deviation)
        Baseline (n= 15, 10)
    10.85 ( 1.251 )
    10.77 ( 1.656 )
        Change at Day 2891 (n= 0, 1)
    9999 ( 9999 )
    9.40 ( 999999 )
    No statistical analyses for this end point

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

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    End point title
    		 Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)
    End point description
    AE was any unfavorable and unintended sign (including an abnormal assessment such as an abnormal laboratory value), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product. An SAE was any untoward medical occurrence that at any dose resulted in death, in the view of the Investigator, placed the participant at immediate risk of death, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, resulted in a birth defect. AE was regarded as treatment-emergent if it was present prior to receiving the first dose of nusinersen in the current study and subsequently worsened in severity or was not present prior to receiving the first dose of nusinersen and subsequently appeared. The ITT set included all participants who received at least 1 dose of ISIS 396443.
    End point type
    Secondary
    End point timeframe
    From first dose of study drug up to end of study (up to 2891 days)
    End point values
    		 ISIS 396443 2 SMN2 Copies ISIS 396443 3 SMN2 Copies
    Number of subjects analysed
    15
    10
    Units: participants
        TEAEs
    15
    10
        SAEs
    10
    4
    No statistical analyses for this end point

    Secondary: Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Hematology Parameters)

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    End point title
    		 Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Hematology Parameters)
    End point description
    Hematology parameters included hemoglobin, hematocrit, erythrocytes, platelets, leukocytes, neutrophils, eosinophils, basophils, lymphocytes, and monocytes count. These parameters were flagged as low, normal, or high relative to parameter’s normal range or as unknown if no result was available. Here, shift to low indicated values that were normal, high or unknown at baseline and shifted to low values postbaseline. Shift to high indicates values that were normal, low or unknown at baseline and shifted to high postbaseline values. The ITT set included all participants who received at least 1 dose of ISIS 396443. Here 'n' signifies the number of participants available for analysis of the specified hematology parameter.
    End point type
    Secondary
    End point timeframe
    Baseline up to Day 2891
    End point values
    		 ISIS 396443 2 SMN2 Copies ISIS 396443 3 SMN2 Copies
    Number of subjects analysed
    15
    10
    Units: participants
        Hemoglobin Shift to Low (n= 13, 10)
    10
    5
        Hemoglobin Shift to High (n= 13, 9)
    3
    4
        Hematocrit Shift to High (n= 11, 10)
    7
    7
        Hematocrit Shift to High (n= 13, 9)
    4
    4
        Erythrocytes Shift to Low (n= 14, 9)
    3
    5
        Erythrocytes Shift to High (n= 13, 9)
    9
    3
        Leukocytes Shift to Low (n= 13, 10)
    5
    6
        Leukocytes Shift to High (n= 15, 9)
    11
    4
        Neutrophils/Leukocytes Shift to Low (n= 9, 4)
    4
    2
        Neutrophils/Leukocytes Shift to High (n= 9, 4)
    4
    0
        Eosinophils/Leukocytes Shift to Low (n= 15, 10)
    0
    0
        Eosinophils/Leukocytes Shift to High (n= 8, 9))
    7
    8
        Basophils/Leukocytes Shift to Low (n= 14, 10)
    0
    0
        Basophils/Leukocytes Shift to High (n= 13, 10)
    10
    9
        Lymphocytes/Leukocytes Shift to Low (15, 10)
    4
    1
        Lymphocytes/Leukocytes Shift to High (n= 6, 4)
    6
    4
        Monocytes/Leukocytes Shift to Low (n= 14, 10)
    11
    7
        Monocytes/Leukocytes Shift to High (n= 12, 6)
    4
    1
        Neutrophils Shift to Low (n= 9, 4)
    2
    1
        Neutrophils Shift to High (n= 9, 4)
    3
    0
        Neutrophils, Segmented Shift to Low (n= 15, 10)
    6
    4
        Neutrophils, Segmented Shift to High (n= 15, 10)
    9
    1
        Eosinophils Shift to Low (n= 15, 10)
    0
    0
        Eosinophils Shift to High (n= 11, 8)
    11
    8
        Basophils Shift to Low (n= 15, 9)
    0
    0
        Basophils Shift to High (n= 14, 10)
    4
    2
        Lymphocytes Shift to Low (n= 15, 10)
    2
    1
        Lymphocytes Shift to High (n= 14, 8)
    11
    8
        Monocytes Shift to Low (n= 15, 10)
    14
    10
        Monocytes Shift to High (n= 14, 6)
    4
    0
        Platelets Shift to Low (n= 15, 10)
    3
    5
        Platelets Shift to High (n= 10, 8)
    9
    7
    No statistical analyses for this end point

    Secondary: Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Blood Chemistry Parameters)

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    End point title
    		 Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Blood Chemistry Parameters)
    End point description
    Blood chemistry parameters included bilirubin (direct and indirect), alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transferase, creatinine, sodium, potassium, chloride, protein, albumin, calcium, phosphate, glucose, cystatin C, creatine kinase. These parameters were flagged as low, normal, or high relative to parameter’s normal range or as unknown if no result was available. Here, shift to low indicated values that were normal, high or unknown at baseline and shifted to low values postbaseline. Shift to high indicates values that were normal, low or unknown at baseline and shifted to high postbaseline values. The ITT set included all participants who received at least 1 dose of ISIS 396443. Here 'n' signifies the number of participants available for analysis of the specified blood chemistry parameter.
    End point type
    Secondary
    End point timeframe
    Baseline up to Day 2891
    End point values
    		 ISIS 396443 2 SMN2 Copies ISIS 396443 3 SMN2 Copies
    Number of subjects analysed
    15
    10
    Units: participants
        Bilirubin Shift to Low (n= 14, 10)
    14
    10
        Bilirubin Shift to High (n= 9, 6)
    2
    1
        Indirect Bilirubin Shift to Low (n= 15, 10)
    0
    0
        Indirect Bilirubin Shift to High (n= 8, 6)
    1
    1
        Direct Bilirubin Shift to Low (n= 14, 10)
    14
    6
        Direct Bilirubin Shift to High (n= 13, 9)
    0
    1
        Alkaline Phosphatase Shift to Low (n= 15, 10)
    3
    0
        Alkaline Phosphatase Shift to High (n= 15, 9)
    2
    5
        Alanine Aminotransferase Shift to Low (n= 15, 10)
    0
    0
        Alanine Aminotransferase Shift to High (n= 14, 7)
    7
    2
        Aspartate Aminotransferase Shift to Low (n=15,10)
    0
    0
        Aspartate Aminotransferase Shift to High (n=14,8)
    6
    2
        Gamma Glutamyl Transferase Shift to Low (n=15,10)
    1
    0
        Gamma Glutamyl Transferase Shift to High(n=15,10)
    1
    0
        Urea Nitrogen Shift to Low (n= 15, 8)
    6
    0
        Urea Nitrogen Shift to High (n= 15, 10)
    0
    2
        Creatinine Shift to Low (n= 11, 7)
    5
    2
        Creatinine Shift to High (n= 15, 10)
    1
    4
        Sodium Shift to Low (n= 13, 10)
    2
    0
        Sodium Shift to High (n= 15, 10)
    0
    1
        Potassium Shift to Low (n= 15, 10)
    0
    1
        Potassium Shift to High (n= 13, 7)
    8
    3
        Chloride Shift to Low (n= 15, 10)
    0
    1
        Chloride Shift to High (n= 15, 10)
    0
    2
        Protein Shift to Low (n= 11, 8)
    2
    5
        Protein Shift to High (n= 15, 10)
    13
    6
        Albumin Shift to Low (n= 15, 9)
    0
    0
        Albumin Shift to High (n= 14, 9)
    10
    8
        Bicarbonate Shift to Low (n= 14, 10)
    8
    7
        Bicarbonate Shift to High (n= 15, 10)
    1
    0
        Calcium Shift to Low (n= 15, 10)
    3
    3
        Calcium Shift to High (n= 10, 9)
    6
    8
        Phosphate Shift to Low (n= 15, 10)
    0
    0
        Phosphate Shift to High (n= 15, 9)
    9
    4
        Glucose Shift to Low (n= 14, 10)
    7
    6
        Glucose Shift to High (n= 12, 8)
    11
    7
        Cystatin C Shift to Low (n= 15, 9)
    6
    4
        Cystatin C Shift to High (n= 15, 9)
    2
    0
        Creatine Kinase Shift to Low (n= 15, 10)
    0
    0
        Creatine Kinase Shift to High (n= 9, 7)
    8
    6
    No statistical analyses for this end point

    Secondary: Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Urinalysis Parameters)

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    End point title
    		 Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Urinalysis Parameters)
    End point description
    Urinalysis included assessments of specific gravity, pH, protein, glucose, ketones, bilirubin, occult blood, erythrocytes, leukocytes, epithelial cells, bacteria, casts and crystals. These parameters were flagged as low, normal, or high relative to parameter's normal range or as unknown if no result was available. Here, shift to low indicated values that were normal, high or unknown at baseline and shifted to low values postbaseline. Shift to high indicates values that were normal, low or unknown at baseline and shifted to high postbaseline values. The ITT set included all participants who received at least 1 dose of ISIS 396443. Here 'n' signifies the number of participants available for analysis of the specified urinalysis parameter.
    End point type
    Secondary
    End point timeframe
    Baseline up to Day 2891
    End point values
    		 ISIS 396443 2 SMN2 Copies ISIS 396443 3 SMN2 Copies
    Number of subjects analysed
    15
    10
    Units: participants
        Specific Gravity Shift to Low (n= 13, 8)
    3
    1
        Specific Gravity Shift to High (n= 15, 10)
    6
    5
        pH Shift to Low (n= 14, 10)
    0
    1
        pH Shift to High (n= 15, 9)
    3
    3
        Protein Shift to High/positive (n= 14, 9)
    13
    8
        Glucose Shift to High/positive (n= 15, 10)
    1
    0
        Ketones Shift to High/positive (n= 15, 10)
    9
    6
        Bilirubin Shift to High/positive (n= 15, 10)
    0
    0
        Occult Blood Shift to High/positive (n= 15, 9)
    4
    2
        Erythrocytes Shift to High/positive (n= 15, 10)
    7
    1
        Leukocytes Shift to High/positive (n= 12, 10)
    5
    4
        Epithelial Cells Shift to High/positive (n= 8, 3)
    5
    0
        Bacteria Shift to High/positive (n= 7, 7)
    7
    6
        Casts Shift to High/positive (n= 3, 3)
    1
    2
        Crystals Shift to High/positive (n= 2, 3)
    1
    2
    No statistical analyses for this end point

    Secondary: Number of Participants With Shifts From Baseline in Coagulation Parameters [Prothrombin Time (PT)]

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    End point title
    		 Number of Participants With Shifts From Baseline in Coagulation Parameters [Prothrombin Time (PT)]
    End point description
    PT was evaluated to assess safety. Shift to high measured change in normal, low and unknown values at baseline to high values postbaseline. The ITT set included all participants who received at least 1 dose of ISIS 396443. Here, 'number of subjects analysed' signifies the number of participants analysed in this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline up to Day 2891
    End point values
    		 ISIS 396443 2 SMN2 Copies ISIS 396443 3 SMN2 Copies
    Number of subjects analysed
    11
    8
    Units: participants
    7
    5
    No statistical analyses for this end point

    Secondary: Number of Participants With Shifts From Baseline in Coagulation Parameters [Activated Partial Thromboplastin Time (aPTT)]

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    End point title
    		 Number of Participants With Shifts From Baseline in Coagulation Parameters [Activated Partial Thromboplastin Time (aPTT)]
    End point description
    aPTT was evaluated to assess safety. Shift to high measured change in normal, low and unknown values at baseline to high values postbaseline. The ITT set included all participants who received at least 1 dose of ISIS 396443. Here, 'number of subjects analysed' signifies the number of participants analysed in this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline up to Day 2891
    End point values
    		 ISIS 396443 2 SMN2 Copies ISIS 396443 3 SMN2 Copies
    Number of subjects analysed
    9
    8
    Units: participants
    4
    2
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Clinically Significant Shifts in Electrocardiograms (ECG) Abnormalities

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    End point title
    		 Percentage of Participants With Clinically Significant Shifts in Electrocardiograms (ECG) Abnormalities
    End point description
    Clinical significance of abnormalities in ECG was determined based on the investigator's discretion. Shift to abnormal indicated values that were normal or unknown at baseline and shifted to abnormal values post-baseline. The ITT set included all participants who received at least 1 dose of ISIS 396443. Here, 'number of subjects analysed' signifies the number of participants analysed in this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline up to Day 2891
    End point values
    		 ISIS 396443 2 SMN2 Copies ISIS 396443 3 SMN2 Copies
    Number of subjects analysed
    12
    8
    Units: percentage of participants
    0
    0
    No statistical analyses for this end point

    Secondary: Change From Baseline in Vital Signs (Temperature)

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    End point title
    		 Change From Baseline in Vital Signs (Temperature)
    End point description
    Negative change from baseline indicates reduction in temperature. The ITT set included all participants who received at least 1 dose of ISIS 396443. Here 'n' signifies the number of participants available for analysis at a specified time point.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 2891
    End point values
    		 ISIS 396443 2 SMN2 Copies ISIS 396443 3 SMN2 Copies
    Number of subjects analysed
    15
    8
    Units: celsius
    arithmetic mean (standard deviation)
        Baseline (n= 15, 10)
    36.7 ( 0.39 )
    36.8 ( 0.44 )
        Change at Day 2891 (n= 14, 9)
    0.0 ( 0.54 )
    -0.1 ( 0.52 )
    No statistical analyses for this end point

    Secondary: Number of Participants With Shifts From Baseline in Coagulation Parameters [International Normalized Ratio (INR)]

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    End point title
    		 Number of Participants With Shifts From Baseline in Coagulation Parameters [International Normalized Ratio (INR)]
    End point description
    INR was evaluated to assess safety. Shift to high measured change in normal, low and unknown values at baseline to high values postbaseline. The ITT set included all participants who received at least 1 dose of ISIS 396443. Here, 'number of subjects analysed' signifies the number of participants analysed in this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline up to Day 2891
    End point values
    		 ISIS 396443 2 SMN2 Copies ISIS 396443 3 SMN2 Copies
    Number of subjects analysed
    11
    7
    Units: participants
    4
    4
    No statistical analyses for this end point

    Secondary: Change From Baseline in Vital Signs [Blood Pressure (BP)]

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    End point title
    		 Change From Baseline in Vital Signs [Blood Pressure (BP)]
    End point description
    The ITT set included all participants who received at least 1 dose of ISIS 396443. Here 'n' signifies the number of participants available for analysis at a specified time point.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 2891
    End point values
    		 ISIS 396443 2 SMN2 Copies ISIS 396443 3 SMN2 Copies
    Number of subjects analysed
    15
    10
    Units: millimeters of mercury (mmHg)
    arithmetic mean (standard deviation)
        Baseline-Systolic BP (n= 15, 10)
    83.4 ( 16.40 )
    88.1 ( 17.84 )
        Change at Day 2891-Systolic BP (n=14,9)
    22.9 ( 15.29 )
    13.6 ( 15.24 )
        Baseline-Diastolic BP (n= 15, 10)
    51.1 ( 17.46 )
    50.8 ( 12.30 )
        Change at Day 2891-Diastolic BP (n=14,9)
    12.8 ( 17.16 )
    11.0 ( 13.07 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in Vital Signs (Heart Rate)

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    End point title
    		 Change From Baseline in Vital Signs (Heart Rate)
    End point description
    Negative change from baseline indicates reduction in heart rate. The ITT set included all participants who received at least 1 dose of ISIS 396443. Here, 'number of subjects analysed' signifies the number of participants analysed in this endpoint. Here 'n' signifies the number of participants available for analysis at a specified time point.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 2891
    End point values
    		 ISIS 396443 2 SMN2 Copies ISIS 396443 3 SMN2 Copies
    Number of subjects analysed
    15
    9
    Units: beats per minute (beats/min)
    arithmetic mean (standard deviation)
        Baseline (n= 15, 9)
    141.5 ( 14.71 )
    154.2 ( 16.55 )
        Change at Day 2891 (n= 14, 8)
    -47.2 ( 20.86 )
    -62.4 ( 25.16 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in Vital Signs (Respiratory Rate)

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    End point title
    		 Change From Baseline in Vital Signs (Respiratory Rate)
    End point description
    Negative change from baseline indicates reduction in respiratory rate. The ITT set included all participants who received at least 1 dose of ISIS 396443. Here 'n' signifies the number of participants available for analysis at a specified time point.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 2891
    End point values
    		 ISIS 396443 2 SMN2 Copies ISIS 396443 3 SMN2 Copies
    Number of subjects analysed
    15
    10
    Units: breaths per minute (breaths/min)
    arithmetic mean (standard deviation)
        Baseline (n= 15, 10)
    42.1 ( 12.17 )
    39.8 ( 13.87 )
        Change at Day 2891 (n= 14, 9)
    -21.0 ( 12.39 )
    -20.6 ( 14.43 )
    No statistical analyses for this end point

    Secondary: Number of Participants With Neurological Examination Abnormalities Reported as AEs

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    End point title
    		 Number of Participants With Neurological Examination Abnormalities Reported as AEs
    End point description
    Participants with abnormalities in neurological examinations recorded as AEs were reported. The ITT set included all participants who received at least 1 dose of ISIS 396443.
    End point type
    Secondary
    End point timeframe
    From first dose of study drug up to end of study (up to 2891 days)
    End point values
    		 ISIS 396443 2 SMN2 Copies ISIS 396443 3 SMN2 Copies
    Number of subjects analysed
    15
    10
    Units: participants
        Muscle contractions involuntary
    8
    1
        Dysarthria
    7
    1
        Tremor
    8
    0
        Hypotonia
    4
    0
        Areflexia
    2
    1
        Facial paresis
    2
    0
        Hyperreflexia
    1
    1
        Myoclonus
    2
    0
        Clonus
    1
    0
        Extensor plantar response
    1
    0
        Peripheral sensory neuropathy
    1
    0
        Unresponsive to stimuli
    1
    0
        Muscular weakness
    9
    1
        Torticollis
    1
    1
        Muscle spasms
    0
    1
        Muscle twitching
    0
    1
        Trismus
    1
    0
        Winged scapula
    1
    0
        Anisocoria
    0
    1
        Heterophoria
    1
    0
        Strabismus
    0
    1
        Vision blurred
    0
    1
        Automatism
    1
    0
    No statistical analyses for this end point

    Secondary: Cerebrospinal fluid (CSF) Concentration of Nusinersen

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    End point title
    		 Cerebrospinal fluid (CSF) Concentration of Nusinersen
    End point description
    The ITT set included all participants who received at least 1 dose of ISIS 396443. Here 'n' signifies the number of participants available for analysis at a specified time point.
    End point type
    Secondary
    End point timeframe
    Predose on Days 1, 15, 29, 64, 183, 302, 421, 540, 659, 778, 897, 1016, 1135, 1254, 1373, 1492, 1611, 1730, 1849, 1968, 2087, 2206, 2325, 2444, 2563, 2682, 2801
    End point values
    		 ISIS 396443 2 SMN2 Copies ISIS 396443 3 SMN2 Copies
    Number of subjects analysed
    15
    10
    Units: nanograms per milliliter (ng/mL)
    geometric mean (geometric coefficient of variation)
        Day 1, Pre-dose (n= 14, 9)
    0.03 ( 0.00 )
    0.03 ( 0.00 )
        Day 15, Pre-dose (n= 14, 10)
    7.52 ( 189.00 )
    10.22 ( 285.47 )
        Day 29, Pre-dose (n= 14, 10)
    23.41 ( 72.04 )
    24.56 ( 85.78 )
        Day 64, Pre-dose (n= 12, 9)
    14.95 ( 58.06 )
    21.33 ( 63.00 )
        Day 183, Pre-dose (n= 14, 9)
    11.66 ( 69.60 )
    13.85 ( 54.32 )
        Day 302, Pre-dose (n= 15, 10)
    11.34 ( 54.67 )
    10.06 ( 27.29 )
        Day 421, Pre-dose (n= 13, 10)
    12.20 ( 66.72 )
    10.53 ( 67.48 )
        Day 540, Pre-dose (n= 15, 9)
    10.23 ( 38.84 )
    9.42 ( 51.04 )
        Day 659, Pre-dose (n= 14, 10)
    11.91 ( 42.32 )
    10.30 ( 38.34 )
        Day 778, Pre-dose (n= 14, 10)
    10.87 ( 54.28 )
    11.77 ( 61.01 )
        Day 897, Pre-dose (n= 15, 10)
    11.03 ( 43.91 )
    10.72 ( 35.90 )
        Day 1016, Pre-dose (n= 15, 9)
    12.06 ( 58.41 )
    10.65 ( 39.34 )
        Day 1135, Pre-dose (n= 15, 10)
    10.49 ( 46.05 )
    10.87 ( 36.62 )
        Day 1254, Pre-dose (n= 15, 9)
    12.88 ( 47.06 )
    11.29 ( 33.29 )
        Day 1373, Pre-dose (n= 14, 10)
    11.94 ( 61.51 )
    10.19 ( 52.12 )
        Day 1492, Pre-dose (n= 14, 8)
    15.04 ( 51.20 )
    12.71 ( 92.23 )
        Day 1611, Pre-dose (n= 13, 8)
    13.46 ( 40.19 )
    13.90 ( 36.31 )
        Day 1730, Pre-dose (n= 9, 9)
    13.63 ( 57.76 )
    15.14 ( 42.12 )
        Day 1849, Pre-dose (n= 11, 9)
    15.14 ( 63.15 )
    14.19 ( 42.87 )
        Day 1968, Pre-dose (n= 10, 8)
    16.52 ( 67.05 )
    17.46 ( 48.67 )
        Day 2087, Pre-dose (n= 12, 10)
    15.57 ( 47.34 )
    17.07 ( 58.91 )
        Day 2206, Pre-dose (n= 13, 9)
    16.95 ( 45.86 )
    17.16 ( 46.34 )
        Day 2325, Pre-dose (n= 12, 8)
    18.27 ( 59.23 )
    20.02 ( 37.41 )
        Day 2444, Pre-dose (n= 13, 9)
    16.92 ( 49.19 )
    17.01 ( 40.87 )
        Day 2563, Pre-dose (n= 12, 9)
    16.74 ( 53.14 )
    13.37 ( 85.72 )
        Day 2682, Pre-dose (n= 11, 9)
    17.42 ( 44.34 )
    16.05 ( 41.83 )
        Day 2801, Pre-dose (n= 13, 9)
    17.44 ( 45.60 )
    17.85 ( 36.35 )
    No statistical analyses for this end point

    Secondary: Plasma Concentration of Nusinersen

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    End point title
    		 Plasma Concentration of Nusinersen
    End point description
    The ITT set included all participants who received at least 1 dose of ISIS 396443. Here 'n' signifies the number of participants available for analysis at a specified time point.
    End point type
    Secondary
    End point timeframe
    Predose on Days 64, 183, 302, 421, 540, 659, 778, 897, 1016, 1135, 1254, 1373, 1492, 1611, 1730, 1849, 1968, 2087, 2206, 2325, 2444, 2563, 2682, 2801 and 4-hour post-dose on Day 1
    End point values
    		 ISIS 396443 2 SMN2 Copies ISIS 396443 3 SMN2 Copies
    Number of subjects analysed
    15
    10
    Units: ng/ml
    geometric mean (geometric coefficient of variation)
        Day 1, 4 hours post-dose (n= 12, 9)
    391.66 ( 113.16 )
    406.69 ( 82.92 )
        Day 64, Pre-dose (n= 15, 10)
    1.60 ( 34.52 )
    1.56 ( 46.54 )
        Day 183, Pre-dose (n= 13, 10)
    0.73 ( 27.03 )
    0.81 ( 19.82 )
        Day 302, Pre-dose (n= 14, 9)
    0.82 ( 54.28 )
    0.81 ( 21.12 )
        Day 421, Pre-dose (n= 15, 10)
    0.78 ( 39.94 )
    0.82 ( 29.31 )
        Day 540, Pre-dose (n= 15, 9)
    0.72 ( 29.72 )
    0.72 ( 19.16 )
        Day 659, Pre-dose (n= 15, 10)
    0.74 ( 26.78 )
    0.78 ( 32.51 )
        Day 778, Pre-dose (n= 15, 10)
    0.68 ( 48.37 )
    0.81 ( 23.52 )
        Day 897, Pre-dose (n= 15, 10)
    0.71 ( 34.77 )
    0.63 ( 40.31 )
        Day 1016, Pre-dose (n= 15, 10)
    0.69 ( 38.47 )
    0.74 ( 21.97 )
        Day 1135, Pre-dose (n= 13, 10)
    0.67 ( 33.70 )
    0.58 ( 33.78 )
        Day 1254, Pre-dose (n= 15, 8)
    0.63 ( 27.16 )
    0.60 ( 24.10 )
        Day 1373, Pre-dose (n= 15, 10)
    0.60 ( 39.79 )
    0.59 ( 17.98 )
        Day 1492, Pre-dose (n= 14, 7)
    0.69 ( 40.55 )
    0.68 ( 43.50 )
        Day 1611, Pre-dose (n= 13, 7)
    0.62 ( 38.14 )
    0.53 ( 43.12 )
        Day 1730, Pre-dose (n= 8, 9)
    0.54 ( 16.13 )
    0.53 ( 30.84 )
        Day 1849, Pre-dose (n= 9, 9)
    0.47 ( 52.05 )
    0.49 ( 36.37 )
        Day 1968, Pre-dose (n= 10, 8)
    0.53 ( 25.66 )
    0.43 ( 22.96 )
        Day 2087, Pre-dose (n= 14, 9)
    0.55 ( 40.43 )
    0.47 ( 31.50 )
        Day 2206, Pre-dose (n= 14, 9)
    0.43 ( 43.01 )
    0.40 ( 32.58 )
        Day 2325, Pre-dose (n= 12, 9)
    0.46 ( 56.98 )
    0.45 ( 35.19 )
        Day 2444, Pre-dose (n= 13, 9)
    0.43 ( 35.15 )
    0.51 ( 17.26 )
        Day 2563, Pre-dose (n= 13, 9)
    0.38 ( 61.73 )
    0.42 ( 31.10 )
        Day 2682, Pre-dose (n= 12, 9)
    0.36 ( 55.66 )
    0.40 ( 24.48 )
        Day 2801, Pre-dose (n= 13, 9)
    0.39 ( 36.16 )
    0.35 ( 65.12 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the signing of the informed consent form (ICF) up to the end of the study (up to Day 2891)
    Adverse event reporting additional description
    The ITT set included all participants who received at least 1 dose of ISIS 396443.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    27.1
    Reporting groups
    Reporting group title
    ISIS 396443 3 SMN2 copies
    Reporting group description
    		 Participants with 3 SMN2 copies received 12 mg nusinersen, IT on Days 1, 15, 29, 64, 183, 302, 421, 540, 659, 778, 897, 1016, 1135, 1254, 1373, 1492, 1611, 1730, 1849, 1968, 2087, 2206, 2325, 2444, 2563, 2682, and 2801.

    Reporting group title
    ISIS 396443 2 SMN2 copies
    Reporting group description
    		 Participants with 2 SMN2 copies received 12 mg nusinersen, IT on Days 1, 15, 29, 64, 183, 302, 421, 540, 659, 778, 897, 1016, 1135, 1254, 1373, 1492, 1611, 1730, 1849, 1968, 2087, 2206, 2325, 2444, 2563, 2682, and 2801.

    Serious adverse events
    		 ISIS 396443 3 SMN2 copies ISIS 396443 2 SMN2 copies
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 10 (40.00%)
    10 / 15 (66.67%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Investigations
    Respirovirus test positive
         subjects affected / exposed
    0 / 10 (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
    Influenza a virus test positive
         subjects affected / exposed
    0 / 10 (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
    Cardiac disorders
    Tachycardia
         subjects affected / exposed
    0 / 10 (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
    Surgical and medical procedures
    Tonsillectomy
         subjects affected / exposed
    0 / 10 (0.00%)
    2 / 15 (13.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Medical device change
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Hyperreflexia
         subjects affected / exposed
    0 / 10 (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
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    0 / 10 (0.00%)
    2 / 15 (13.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Anaphylactic reaction
         subjects affected / exposed
    0 / 10 (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
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Faecaloma
         subjects affected / exposed
    0 / 10 (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
    Abdominal distension
         subjects affected / exposed
    0 / 10 (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
    Vomiting
         subjects affected / exposed
    0 / 10 (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
    Hepatobiliary disorders
    Hypertransaminasaemia
         subjects affected / exposed
    0 / 10 (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
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Choking
         subjects affected / exposed
    0 / 10 (0.00%)
    3 / 15 (20.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory distress
         subjects affected / exposed
    0 / 10 (0.00%)
    2 / 15 (13.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Obstructive sleep apnoea syndrome
         subjects affected / exposed
    0 / 10 (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
    Respiratory failure
         subjects affected / exposed
    0 / 10 (0.00%)
    2 / 15 (13.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Tendon disorder
         subjects affected / exposed
    0 / 10 (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
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    0 / 10 (0.00%)
    5 / 15 (33.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 11
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis viral
         subjects affected / exposed
    0 / 10 (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
    Enterovirus infection
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronavirus infection
         subjects affected / exposed
    0 / 10 (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
    Bronchitis
         subjects affected / exposed
    0 / 10 (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
    Pneumonia bacterial
         subjects affected / exposed
    0 / 10 (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
    Pneumonia respiratory syncytial viral
         subjects affected / exposed
    0 / 10 (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
    Pneumonia pseudomonal
         subjects affected / exposed
    0 / 10 (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
    Pneumonia pneumococcal
         subjects affected / exposed
    0 / 10 (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
    Pneumonia mycoplasmal
         subjects affected / exposed
    0 / 10 (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
    Respiratory syncytial virus bronchiolitis
         subjects affected / exposed
    0 / 10 (0.00%)
    2 / 15 (13.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral upper respiratory tract infection
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 10 (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
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tonsillitis
         subjects affected / exposed
    1 / 10 (10.00%)
    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 syncytial virus infection
         subjects affected / exposed
    1 / 10 (10.00%)
    2 / 15 (13.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Feeding disorder
         subjects affected / exposed
    0 / 10 (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
    Failure to thrive
         subjects affected / exposed
    0 / 10 (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
    Dehydration
         subjects affected / exposed
    0 / 10 (0.00%)
    2 / 15 (13.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 ISIS 396443 3 SMN2 copies ISIS 396443 2 SMN2 copies
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    10 / 10 (100.00%)
    15 / 15 (100.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Seborrhoeic keratosis
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Aortic dilatation
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    Pallor
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Pregnancy, puerperium and perinatal conditions
    Umbilical granuloma
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    General disorders and administration site conditions
    Influenza like illness
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    Infusion site bruising
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Gait disturbance
         subjects affected / exposed
    2 / 10 (20.00%)
    4 / 15 (26.67%)
         occurrences all number
    3
    4
    Fatigue
         subjects affected / exposed
    2 / 10 (20.00%)
    0 / 15 (0.00%)
         occurrences all number
    2
    0
    Chills
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Catheter site pain
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Application site erythema
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Infusion site extravasation
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Medical device site rash
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Pain
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Pyrexia
         subjects affected / exposed
    8 / 10 (80.00%)
    14 / 15 (93.33%)
         occurrences all number
    40
    78
    Malaise
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 15 (6.67%)
         occurrences all number
    1
    2
    Immune system disorders
    Allergy to arthropod bite
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Anaphylactic reaction
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Drug hypersensitivity
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Dust allergy
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 15 (0.00%)
         occurrences all number
    2
    0
    Food allergy
         subjects affected / exposed
    0 / 10 (0.00%)
    2 / 15 (13.33%)
         occurrences all number
    0
    3
    Hypersensitivity
         subjects affected / exposed
    1 / 10 (10.00%)
    2 / 15 (13.33%)
         occurrences all number
    1
    2
    Immunodeficiency
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Multiple allergies
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Seasonal allergy
         subjects affected / exposed
    4 / 10 (40.00%)
    3 / 15 (20.00%)
         occurrences all number
    4
    3
    Reproductive system and breast disorders
    Vulvovaginal rash
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 15 (6.67%)
         occurrences all number
    1
    1
    Respiratory, thoracic and mediastinal disorders
    Aspiration
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Asthma
         subjects affected / exposed
    1 / 10 (10.00%)
    3 / 15 (20.00%)
         occurrences all number
    1
    4
    Adenoidal hypertrophy
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Atelectasis
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    Bronchial hyperreactivity
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Bronchitis chronic
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    2
    Bronchospasm
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Catarrh
         subjects affected / exposed
    0 / 10 (0.00%)
    2 / 15 (13.33%)
         occurrences all number
    0
    2
    Choking
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Cough
         subjects affected / exposed
    7 / 10 (70.00%)
    11 / 15 (73.33%)
         occurrences all number
    30
    31
    Cyanosis central
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Dysphonia
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    Dyspnoea
         subjects affected / exposed
    0 / 10 (0.00%)
    3 / 15 (20.00%)
         occurrences all number
    0
    4
    Epistaxis
         subjects affected / exposed
    4 / 10 (40.00%)
    0 / 15 (0.00%)
         occurrences all number
    4
    0
    Hypoxia
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Increased bronchial secretion
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    2
    Acute respiratory failure
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    2
    Lower respiratory tract congestion
         subjects affected / exposed
    0 / 10 (0.00%)
    2 / 15 (13.33%)
         occurrences all number
    0
    2
    Increased upper airway secretion
         subjects affected / exposed
    0 / 10 (0.00%)
    2 / 15 (13.33%)
         occurrences all number
    0
    2
    Rhinitis allergic
         subjects affected / exposed
    2 / 10 (20.00%)
    1 / 15 (6.67%)
         occurrences all number
    3
    1
    Respiratory muscle weakness
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Respiratory distress
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Respiratory disorder
         subjects affected / exposed
    2 / 10 (20.00%)
    2 / 15 (13.33%)
         occurrences all number
    6
    4
    Respiratory acidosis
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Pulmonary artery dilatation
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    Productive cough
         subjects affected / exposed
    0 / 10 (0.00%)
    2 / 15 (13.33%)
         occurrences all number
    0
    3
    Pneumonitis
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Pharyngeal erythema
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    Oropharyngeal pain
         subjects affected / exposed
    3 / 10 (30.00%)
    4 / 15 (26.67%)
         occurrences all number
    4
    5
    Obstructive sleep apnoea syndrome
         subjects affected / exposed
    1 / 10 (10.00%)
    3 / 15 (20.00%)
         occurrences all number
    1
    4
    Lower respiratory tract inflammation
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Nasal congestion
         subjects affected / exposed
    4 / 10 (40.00%)
    5 / 15 (33.33%)
         occurrences all number
    7
    12
    Nasal septum deviation
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Stridor
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Sputum retention
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Rhinorrhoea
         subjects affected / exposed
    5 / 10 (50.00%)
    7 / 15 (46.67%)
         occurrences all number
    21
    16
    Tonsillar hypertrophy
         subjects affected / exposed
    0 / 10 (0.00%)
    2 / 15 (13.33%)
         occurrences all number
    0
    2
    Upper respiratory tract congestion
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 15 (6.67%)
         occurrences all number
    1
    1
    Upper respiratory tract inflammation
         subjects affected / exposed
    1 / 10 (10.00%)
    2 / 15 (13.33%)
         occurrences all number
    1
    2
    Wheezing
         subjects affected / exposed
    0 / 10 (0.00%)
    2 / 15 (13.33%)
         occurrences all number
    0
    2
    Upper-airway cough syndrome
         subjects affected / exposed
    2 / 10 (20.00%)
    0 / 15 (0.00%)
         occurrences all number
    2
    0
    Psychiatric disorders
    Procedural anxiety
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    Disturbance in social behaviour
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Automatism
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Autism spectrum disorder
         subjects affected / exposed
    0 / 10 (0.00%)
    2 / 15 (13.33%)
         occurrences all number
    0
    3
    Investigations
    Adenovirus test positive
         subjects affected / exposed
    2 / 10 (20.00%)
    1 / 15 (6.67%)
         occurrences all number
    2
    1
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 10 (0.00%)
    2 / 15 (13.33%)
         occurrences all number
    0
    2
    Audiogram abnormal
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    Blood alkaline phosphatase increased
         subjects affected / exposed
    0 / 10 (0.00%)
    2 / 15 (13.33%)
         occurrences all number
    0
    2
    Blood calcium increased
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Blood glucose decreased
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    Blood iron decreased
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 15 (0.00%)
         occurrences all number
    2
    0
    Body temperature increased
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Bone density decreased
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    2
    Enterovirus test positive
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 15 (6.67%)
         occurrences all number
    1
    1
    C-reactive protein increased
         subjects affected / exposed
    0 / 10 (0.00%)
    2 / 15 (13.33%)
         occurrences all number
    0
    3
    Candida test positive
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Carnitine decreased
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Crystal urine present
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 15 (6.67%)
         occurrences all number
    1
    1
    Cystatin c increased
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Breath sounds abnormal
         subjects affected / exposed
    0 / 10 (0.00%)
    2 / 15 (13.33%)
         occurrences all number
    0
    2
    Eosinophil count increased
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Haemoglobin decreased
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Heart rate increased
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Human rhinovirus test positive
         subjects affected / exposed
    3 / 10 (30.00%)
    1 / 15 (6.67%)
         occurrences all number
    3
    1
    Lymphocyte count increased
         subjects affected / exposed
    0 / 10 (0.00%)
    2 / 15 (13.33%)
         occurrences all number
    0
    2
    Nerve conduction studies abnormal
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 15 (6.67%)
         occurrences all number
    1
    1
    Streptococcus test positive
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Oxygen saturation decreased
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Platelet count increased
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 15 (6.67%)
         occurrences all number
    1
    2
    Protein urine present
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 15 (6.67%)
         occurrences all number
    1
    1
    Respirovirus test positive
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Sars-cov-2 test positive
         subjects affected / exposed
    1 / 10 (10.00%)
    2 / 15 (13.33%)
         occurrences all number
    1
    2
    Serratia test positive
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Neutrophil count increased
         subjects affected / exposed
    0 / 10 (0.00%)
    2 / 15 (13.33%)
         occurrences all number
    0
    2
    White blood cell count increased
         subjects affected / exposed
    0 / 10 (0.00%)
    2 / 15 (13.33%)
         occurrences all number
    0
    2
    Weight decreased
         subjects affected / exposed
    1 / 10 (10.00%)
    2 / 15 (13.33%)
         occurrences all number
    1
    2
    Weight increased
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Walking distance test abnormal
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Injury, poisoning and procedural complications
    Accident
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal procedural complication
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Nail injury
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Lip injury
         subjects affected / exposed
    2 / 10 (20.00%)
    1 / 15 (6.67%)
         occurrences all number
    2
    1
    Ligament sprain
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Nasal injury
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    Foreign body in respiratory tract
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 15 (6.67%)
         occurrences all number
    1
    1
    Fall
         subjects affected / exposed
    6 / 10 (60.00%)
    8 / 15 (53.33%)
         occurrences all number
    12
    12
    Contusion
         subjects affected / exposed
    2 / 10 (20.00%)
    4 / 15 (26.67%)
         occurrences all number
    2
    4
    Arthropod sting
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Arthropod bite
         subjects affected / exposed
    1 / 10 (10.00%)
    3 / 15 (20.00%)
         occurrences all number
    1
    5
    Humerus fracture
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Subcutaneous haematoma
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Post lumbar puncture syndrome
         subjects affected / exposed
    4 / 10 (40.00%)
    2 / 15 (13.33%)
         occurrences all number
    9
    3
    Post procedural complication
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 15 (6.67%)
         occurrences all number
    1
    1
    Post procedural discomfort
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Post procedural swelling
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    2
    Procedural pain
         subjects affected / exposed
    5 / 10 (50.00%)
    3 / 15 (20.00%)
         occurrences all number
    6
    4
    Procedural vomiting
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Radial head dislocation
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 15 (0.00%)
         occurrences all number
    2
    0
    Skin abrasion
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 15 (6.67%)
         occurrences all number
    2
    1
    Skin laceration
         subjects affected / exposed
    2 / 10 (20.00%)
    2 / 15 (13.33%)
         occurrences all number
    2
    2
    Stoma site hypergranulation
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Stoma site pain
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Subdural haematoma
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Thermal burn
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Tooth fracture
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Upper limb fracture
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Urethral injury
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    Venomous sting
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    Wound
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    Congenital, familial and genetic disorders
    Developmental hip dysplasia
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Cryptorchism
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Epilepsy congenital
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    Hypermobility syndrome
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    Micrognathia
         subjects affected / exposed
    0 / 10 (0.00%)
    2 / 15 (13.33%)
         occurrences all number
    0
    2
    Cardiac disorders
    Tachycardia
         subjects affected / exposed
    1 / 10 (10.00%)
    5 / 15 (33.33%)
         occurrences all number
    1
    6
    Angina pectoris
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Nervous system disorders
    Areflexia
         subjects affected / exposed
    1 / 10 (10.00%)
    2 / 15 (13.33%)
         occurrences all number
    1
    2
    Generalised tonic-clonic seizure
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    Dysarthria
         subjects affected / exposed
    1 / 10 (10.00%)
    7 / 15 (46.67%)
         occurrences all number
    1
    8
    Extensor plantar response
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Facial paresis
         subjects affected / exposed
    0 / 10 (0.00%)
    2 / 15 (13.33%)
         occurrences all number
    0
    2
    Febrile convulsion
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 15 (0.00%)
         occurrences all number
    5
    0
    Clonus
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Gross motor delay
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Headache
         subjects affected / exposed
    3 / 10 (30.00%)
    3 / 15 (20.00%)
         occurrences all number
    5
    7
    Hyperreflexia
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 15 (6.67%)
         occurrences all number
    1
    1
    Hypotonia
         subjects affected / exposed
    0 / 10 (0.00%)
    4 / 15 (26.67%)
         occurrences all number
    0
    4
    Loss of consciousness
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Migraine
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    Motor developmental delay
         subjects affected / exposed
    0 / 10 (0.00%)
    2 / 15 (13.33%)
         occurrences all number
    0
    2
    Muscle contractions involuntary
         subjects affected / exposed
    1 / 10 (10.00%)
    8 / 15 (53.33%)
         occurrences all number
    1
    8
    Myoclonus
         subjects affected / exposed
    0 / 10 (0.00%)
    2 / 15 (13.33%)
         occurrences all number
    0
    2
    Peripheral sensory neuropathy
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Pleocytosis
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Presyncope
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    Speech disorder developmental
         subjects affected / exposed
    0 / 10 (0.00%)
    5 / 15 (33.33%)
         occurrences all number
    0
    5
    Speech disorder
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    Unresponsive to stimuli
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    2
    Tremor
         subjects affected / exposed
    0 / 10 (0.00%)
    8 / 15 (53.33%)
         occurrences all number
    0
    8
    Blood and lymphatic system disorders
    Eosinophilia
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    2
    Hypochromic anaemia
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Iron deficiency anaemia
         subjects affected / exposed
    0 / 10 (0.00%)
    2 / 15 (13.33%)
         occurrences all number
    0
    2
    Anaemia
         subjects affected / exposed
    3 / 10 (30.00%)
    4 / 15 (26.67%)
         occurrences all number
    4
    6
    Lymphadenopathy
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Lymphocytosis
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Neutropenia
         subjects affected / exposed
    0 / 10 (0.00%)
    2 / 15 (13.33%)
         occurrences all number
    0
    2
    Neutrophilia
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Ear and labyrinth disorders
    Deafness bilateral
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Tympanic membrane perforation
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    Excessive cerumen production
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 15 (6.67%)
         occurrences all number
    1
    1
    Motion sickness
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Hyperacusis
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Ear pain
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    Eye disorders
    Strabismus
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    Ocular hyperaemia
         subjects affected / exposed
    1 / 10 (10.00%)
    3 / 15 (20.00%)
         occurrences all number
    1
    3
    Myopia
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    Hypermetropia
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    Heterophoria
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Eye discharge
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Eczema eyelids
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Dacryostenosis acquired
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Astigmatism
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 15 (6.67%)
         occurrences all number
    1
    1
    Anisocoria
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    Vision blurred
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 15 (6.67%)
         occurrences all number
    1
    1
    Abdominal discomfort
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Lip swelling
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Lip pain
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    Infantile colic
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Gastrooesophageal reflux disease
         subjects affected / exposed
    2 / 10 (20.00%)
    2 / 15 (13.33%)
         occurrences all number
    3
    3
    Frequent bowel movements
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    Flatulence
         subjects affected / exposed
    0 / 10 (0.00%)
    2 / 15 (13.33%)
         occurrences all number
    0
    2
    Abdominal pain
         subjects affected / exposed
    3 / 10 (30.00%)
    0 / 15 (0.00%)
         occurrences all number
    4
    0
    Dyspepsia
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Diarrhoea
         subjects affected / exposed
    6 / 10 (60.00%)
    4 / 15 (26.67%)
         occurrences all number
    11
    4
    Dental caries
         subjects affected / exposed
    2 / 10 (20.00%)
    3 / 15 (20.00%)
         occurrences all number
    4
    3
    Constipation
         subjects affected / exposed
    1 / 10 (10.00%)
    7 / 15 (46.67%)
         occurrences all number
    2
    9
    Breath odour
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Abdominal pain upper
         subjects affected / exposed
    2 / 10 (20.00%)
    0 / 15 (0.00%)
         occurrences all number
    2
    0
    Dysphagia
         subjects affected / exposed
    0 / 10 (0.00%)
    5 / 15 (33.33%)
         occurrences all number
    0
    5
    Vomiting
         subjects affected / exposed
    5 / 10 (50.00%)
    10 / 15 (66.67%)
         occurrences all number
    15
    30
    Toothache
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    Tooth loss
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Teething
         subjects affected / exposed
    2 / 10 (20.00%)
    1 / 15 (6.67%)
         occurrences all number
    2
    1
    Salivary hypersecretion
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Nausea
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 15 (6.67%)
         occurrences all number
    1
    3
    Malocclusion
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Hepatobiliary disorders
    Hypertransaminasaemia
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Skin and subcutaneous tissue disorders
    Dry skin
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    Dermatitis
         subjects affected / exposed
    0 / 10 (0.00%)
    2 / 15 (13.33%)
         occurrences all number
    0
    2
    Dermatitis allergic
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 15 (6.67%)
         occurrences all number
    1
    1
    Dermatitis atopic
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 15 (6.67%)
         occurrences all number
    2
    1
    Dermatitis contact
         subjects affected / exposed
    3 / 10 (30.00%)
    1 / 15 (6.67%)
         occurrences all number
    4
    1
    Dermatitis diaper
         subjects affected / exposed
    2 / 10 (20.00%)
    3 / 15 (20.00%)
         occurrences all number
    2
    3
    Erythema
         subjects affected / exposed
    0 / 10 (0.00%)
    2 / 15 (13.33%)
         occurrences all number
    0
    2
    Eczema nummular
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 15 (0.00%)
         occurrences all number
    2
    0
    Eczema
         subjects affected / exposed
    0 / 10 (0.00%)
    3 / 15 (20.00%)
         occurrences all number
    0
    10
    Hidradenitis
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Seborrhoeic dermatitis
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    Rash pruritic
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Rash papular
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Rash maculo-papular
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    Rash erythematous
         subjects affected / exposed
    2 / 10 (20.00%)
    0 / 15 (0.00%)
         occurrences all number
    2
    0
    Rash
         subjects affected / exposed
    2 / 10 (20.00%)
    2 / 15 (13.33%)
         occurrences all number
    4
    2
    Ichthyosis acquired
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    Miliaria
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Petechiae
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Photosensitivity reaction
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    Skin irritation
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    Skin hypopigmentation
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    Urticaria
         subjects affected / exposed
    2 / 10 (20.00%)
    1 / 15 (6.67%)
         occurrences all number
    3
    2
    Superficial inflammatory dermatosis
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Renal and urinary disorders
    Proteinuria
         subjects affected / exposed
    0 / 10 (0.00%)
    2 / 15 (13.33%)
         occurrences all number
    0
    2
    Micturition urgency
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Leukocyturia
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Dysuria
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Bladder hypertrophy
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal and connective tissue disorders
    Ligament laxity
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    Acquired plagiocephaly
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Arthralgia
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 15 (0.00%)
         occurrences all number
    2
    0
    Back pain
         subjects affected / exposed
    2 / 10 (20.00%)
    0 / 15 (0.00%)
         occurrences all number
    2
    0
    Barrel chest
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Clubbing
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Coccydynia
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    Foot deformity
         subjects affected / exposed
    0 / 10 (0.00%)
    2 / 15 (13.33%)
         occurrences all number
    0
    4
    Growth failure
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Joint contracture
         subjects affected / exposed
    0 / 10 (0.00%)
    2 / 15 (13.33%)
         occurrences all number
    0
    2
    Joint range of motion decreased
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Kyphosis
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Osteopenia
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Pain in extremity
         subjects affected / exposed
    2 / 10 (20.00%)
    2 / 15 (13.33%)
         occurrences all number
    2
    3
    Scoliosis
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 15 (6.67%)
         occurrences all number
    1
    1
    Synovitis
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Tendon disorder
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Toe walking
         subjects affected / exposed
    0 / 10 (0.00%)
    2 / 15 (13.33%)
         occurrences all number
    0
    2
    Neck pain
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Muscle atrophy
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Muscle contracture
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Muscle spasms
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    Muscle twitching
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    Muscular weakness
         subjects affected / exposed
    1 / 10 (10.00%)
    9 / 15 (60.00%)
         occurrences all number
    1
    10
    Lordosis
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Torticollis
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 15 (6.67%)
         occurrences all number
    1
    1
    Trismus
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Winged scapula
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Infections and infestations
    Atypical pneumonia
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Bacterial labyrinthitis
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Ear infection bacterial
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    4
    Ear infection
         subjects affected / exposed
    2 / 10 (20.00%)
    4 / 15 (26.67%)
         occurrences all number
    4
    7
    Dysentery
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    Cystitis
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Croup infectious
         subjects affected / exposed
    0 / 10 (0.00%)
    3 / 15 (20.00%)
         occurrences all number
    0
    3
    Covid-19
         subjects affected / exposed
    2 / 10 (20.00%)
    5 / 15 (33.33%)
         occurrences all number
    2
    7
    Conjunctivitis
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 15 (6.67%)
         occurrences all number
    1
    1
    Cellulitis
         subjects affected / exposed
    0 / 10 (0.00%)
    2 / 15 (13.33%)
         occurrences all number
    0
    2
    Bronchitis viral
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Bronchitis
         subjects affected / exposed
    1 / 10 (10.00%)
    5 / 15 (33.33%)
         occurrences all number
    4
    11
    Bronchiolitis
         subjects affected / exposed
    0 / 10 (0.00%)
    4 / 15 (26.67%)
         occurrences all number
    0
    4
    Influenza
         subjects affected / exposed
    4 / 10 (40.00%)
    6 / 15 (40.00%)
         occurrences all number
    9
    7
    Impetigo
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Hand-foot-and-mouth disease
         subjects affected / exposed
    0 / 10 (0.00%)
    3 / 15 (20.00%)
         occurrences all number
    0
    3
    Gingivitis
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Gastrointestinal viral infection
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Labyrinthitis
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Gastroenteritis
         subjects affected / exposed
    2 / 10 (20.00%)
    2 / 15 (13.33%)
         occurrences all number
    3
    2
    Fungal skin infection
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    Eye infection
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 15 (0.00%)
         occurrences all number
    2
    0
    Enterovirus infection
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 15 (6.67%)
         occurrences all number
    2
    1
    Ear infection staphylococcal
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Gastroenteritis viral
         subjects affected / exposed
    4 / 10 (40.00%)
    4 / 15 (26.67%)
         occurrences all number
    5
    5
    Otitis media acute
         subjects affected / exposed
    1 / 10 (10.00%)
    3 / 15 (20.00%)
         occurrences all number
    1
    3
    Respiratory tract infection
         subjects affected / exposed
    2 / 10 (20.00%)
    3 / 15 (20.00%)
         occurrences all number
    4
    7
    Otitis externa
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Oral herpes
         subjects affected / exposed
    2 / 10 (20.00%)
    0 / 15 (0.00%)
         occurrences all number
    3
    0
    Oral candidiasis
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Nasopharyngitis
         subjects affected / exposed
    7 / 10 (70.00%)
    11 / 15 (73.33%)
         occurrences all number
    34
    34
    Metapneumovirus infection
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Lice infestation
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Laryngitis
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    Otitis media bacterial
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    Pharyngitis
         subjects affected / exposed
    1 / 10 (10.00%)
    2 / 15 (13.33%)
         occurrences all number
    1
    2
    Pharyngitis streptococcal
         subjects affected / exposed
    1 / 10 (10.00%)
    5 / 15 (33.33%)
         occurrences all number
    2
    5
    Pneumonia
         subjects affected / exposed
    1 / 10 (10.00%)
    7 / 15 (46.67%)
         occurrences all number
    1
    13
    Pneumonia aspiration
         subjects affected / exposed
    0 / 10 (0.00%)
    3 / 15 (20.00%)
         occurrences all number
    0
    3
    Pneumonia moraxella
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Respiratory syncytial virus infection
         subjects affected / exposed
    1 / 10 (10.00%)
    3 / 15 (20.00%)
         occurrences all number
    1
    4
    Otitis media
         subjects affected / exposed
    5 / 10 (50.00%)
    6 / 15 (40.00%)
         occurrences all number
    7
    10
    Stoma site infection
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Skin infection
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Sinusitis bacterial
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    4
    Sinusitis
         subjects affected / exposed
    3 / 10 (30.00%)
    4 / 15 (26.67%)
         occurrences all number
    3
    5
    Rotavirus infection
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Rhinovirus infection
         subjects affected / exposed
    0 / 10 (0.00%)
    2 / 15 (13.33%)
         occurrences all number
    0
    3
    Rhinitis
         subjects affected / exposed
    2 / 10 (20.00%)
    3 / 15 (20.00%)
         occurrences all number
    4
    10
    Respiratory tract infection viral
         subjects affected / exposed
    2 / 10 (20.00%)
    0 / 15 (0.00%)
         occurrences all number
    2
    0
    Respiratory tract infection bacterial
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Streptococcal infection
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Tinea pedis
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 15 (0.00%)
         occurrences all number
    2
    0
    Tinea infection
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    Tonsillitis
         subjects affected / exposed
    2 / 10 (20.00%)
    2 / 15 (13.33%)
         occurrences all number
    4
    3
    Upper respiratory tract infection
         subjects affected / exposed
    7 / 10 (70.00%)
    11 / 15 (73.33%)
         occurrences all number
    20
    49
    Vulvovaginal mycotic infection
         subjects affected / exposed
    2 / 10 (20.00%)
    0 / 15 (0.00%)
         occurrences all number
    2
    0
    Vulvovaginal candidiasis
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    Viral upper respiratory tract infection
         subjects affected / exposed
    3 / 10 (30.00%)
    6 / 15 (40.00%)
         occurrences all number
    7
    11
    Viral rhinitis
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Viral rash
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Viral pharyngitis
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Viral infection
         subjects affected / exposed
    0 / 10 (0.00%)
    3 / 15 (20.00%)
         occurrences all number
    0
    3
    Varicella
         subjects affected / exposed
    0 / 10 (0.00%)
    2 / 15 (13.33%)
         occurrences all number
    0
    2
    Urinary tract infection bacterial
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 15 (6.67%)
         occurrences all number
    4
    1
    Urinary tract infection
         subjects affected / exposed
    3 / 10 (30.00%)
    4 / 15 (26.67%)
         occurrences all number
    4
    5
    Metabolism and nutrition disorders
    Iron deficiency
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Acidosis
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Decreased appetite
         subjects affected / exposed
    3 / 10 (30.00%)
    0 / 15 (0.00%)
         occurrences all number
    4
    0
    Dehydration
         subjects affected / exposed
    1 / 10 (10.00%)
    3 / 15 (20.00%)
         occurrences all number
    1
    3
    Failure to thrive
         subjects affected / exposed
    0 / 10 (0.00%)
    2 / 15 (13.33%)
         occurrences all number
    0
    2
    Feeding disorder
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Feeding intolerance
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Food intolerance
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Hypocalcaemia
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    Hypoglycaemia
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Hypophagia
         subjects affected / exposed
    0 / 10 (0.00%)
    2 / 15 (13.33%)
         occurrences all number
    0
    3
    Lipid metabolism disorder
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Vitamin d deficiency
         subjects affected / exposed
    2 / 10 (20.00%)
    1 / 15 (6.67%)
         occurrences all number
    2
    1
    Weight gain poor
         subjects affected / exposed
    0 / 10 (0.00%)
    2 / 15 (13.33%)
         occurrences all number
    0
    3
    Metabolic acidosis
         subjects affected / exposed
    0 / 10 (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
    23 Oct 2014
    - The primary reason was to update the Sponsor Information.
    18 Dec 2014
    - The primary reason for this amendment to Protocol 232SM201 is to accommodate the inclusion of twins with spinal muscular atrophy (SMA).
    30 Sep 2015
    - The Schedule of Activities (SoA) was updated to include sibling SMA data collection at Screening and Day 868/Early Termination. - A footnote was added to the SoA to indicate that optional videotaping during the CHOP INTEND test will be conducted. - Inclusion criterion 5 was updated to provide additional clarification regarding the location of the CMAP assessment.
    15 Dec 2015
    - The interim analysis section was updated to include formal data reviews.
    20 Mar 2017
    - The primary reason for this amendment to Protocol 232SM201 is to provide subjects with presymptomatic spinal muscular atrophy (SMA) with the opportunity to receive open-label nusinersen until subjects are 5 years of age (60 months).
    02 Oct 2019
    - The scheduled visit period was extended up to 8 years after the first injection of nusinersen. Table 3 was revised to present the schedule of activities from Day 897 through Day 1730. Table 4 was added to present the schedule of activities from Day 1849 through Day 2891 (end of study). - Allowed concomitant therapy was edited, and disallowed concomitant therapy was removed. - The clarification on the use of cognitive scales was provided. - New assessments quality of voice, echocardiograms, and speech and sensory nerve action potential were added. - Clarification on the adverse events was provided.
    12 Nov 2019
    - The collection of CSF samples taken predose for pharmacokinetic (PK) and SMN protein analysis and plasma samples for PK analysis was added at Days 1849, 1968, 2206, 2325, 2563, and 2682. In addition, the footnote for plasma samples for PK analysis was updated to specify that plasma will be used to assess phosphorylated neurofilament heavy subunit.
    17 Oct 2021
    - The primary reason for this amendment to Protocol 232SM201 is to limit the number of participants who are receiving nusinersen concomitantly with other SMA therapies to 20% (n= 5) of the total population.

    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
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