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    Clinical Trial Results:
    A Phase 3, Randomized, Double-blind, Sham-Procedure Controlled Study to Assess the Clinical Efficacy and Safety of ISIS 396443 Administered Intrathecally in Patients with Infantile-onset Spinal Muscular Atrophy

    Summary
    EudraCT number
    		 2013-004422-29
    Trial protocol
    		 IT   GB   ES   SE   DE   BE  
    Global end of trial date
    21 Nov 2016

    Results information
    Results version number
    		 v2(current)
    This version publication date
    15 Jul 2017
    First version publication date
    01 Jun 2017
    Other versions
    		 v1
    Version creation reason
    • Correction of full data set
    Updated study start date

    Trial information

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    Trial identification
    Sponsor protocol code
    ISIS 396443-CS3B
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02193074
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Biogen
    Sponsor organisation address
    225 Binney Street, Cambridge, United States, United States, 02142
    Public contact
    Biogen Study Medical Director, Biogen, clinicaltrials@biogen.com
    Scientific contact
    Biogen 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
    21 Nov 2016
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    21 Nov 2016
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The primary objective of the study is to examine the clinical efficacy of nusinersen (ISIS 396443) administered intrathecally (IT) to subjects with infantile-onset spinal muscular atrophy (SMA). The secondary objective of the study is to examine the safety and tolerability of nusinersen administered IT to subjects with infantile-onset SMA.
    Protection of trial subjects
    Written informed consent was obtained from each subject prior to evaluations being performed for eligibility. Subjects were given adequate time to review the information in the informed consent and were allowed to ask, and have answered, questions concerning all portions of the conduct of the study. Through the informed consent process each subject was made aware of the purpose of the study, the procedures, the benefits and risks of the study, the discomforts and the precautions taken. 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
    19 Aug 2014
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Spain: 11
    Country: Number of subjects enrolled
    Sweden: 3
    Country: Number of subjects enrolled
    Turkey: 5
    Country: Number of subjects enrolled
    United Kingdom: 5
    Country: Number of subjects enrolled
    United States: 55
    Country: Number of subjects enrolled
    Australia: 5
    Country: Number of subjects enrolled
    Belgium: 1
    Country: Number of subjects enrolled
    Canada: 6
    Country: Number of subjects enrolled
    France: 8
    Country: Number of subjects enrolled
    Germany: 10
    Country: Number of subjects enrolled
    Italy: 9
    Country: Number of subjects enrolled
    Japan: 3
    Country: Number of subjects enrolled
    Korea, Republic of: 1
    Worldwide total number of subjects
    122
    EEA total number of subjects
    47
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    122
    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
    		 -

    Pre-assignment
    Screening details
    		 After parental informed consent was obtained and prior to any treatment, subjects entered a Screening Period of up to 21 days to determine their eligibility for the study. Of the 149 subjects screened, 27 were screening failures.

    Pre-assignment period milestones
    Number of subjects started
    		 122
    Number of subjects completed
    		 121

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 Withdrew prior to receiving treatment: 1
    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Carer

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Control
    Arm description
    		 Sham procedure administered on Study Days 1, 15, 29, 64, 183, and 302.
    Arm type
    		 Sham Comparator

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 Nusinersen
    Arm description
    		 Nusinersen (2.4 mg/mL) administered as an intrathecal (IT) lumbar puncture injection on Study Days 1, 15, 29, 64, 183, and 302.
    Arm type
    		 Experimental

    Investigational medicinal product name
    nusinersen
    Investigational medicinal product code
    ISIS 396443
    Other name
    BIIB058, Spinraza, IONIS-SMN Rx, ISIS SMNRx
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intrathecal use
    Dosage and administration details
    Subjects randomized to the ISIS 396443 treatment group received a single IT LP injection of study treatment as a slow bolus (1 to 3 minutes) using a spinal anesthesia needle and 5-mL syringe on Study Days 1, 15, 29, 64, 183, and 302.

    Number of subjects in period 1 [1]
    		Control Nusinersen
    Started
    41
    80
    Completed During Follow-Up Period
    11 [2]
    26 [3]
    Completed Due to Early Study Termination
    13 [4]
    39 [5]
    Completed
    24
    65
    Not completed
    17
    15
         Consent withdrawn by subject
    1
    2
         Adverse event, non-fatal
    16
    13
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: One subject withdrew prior to receiving treatment and is accounted for in the Pre-Assignment Details.
    [2] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Milestones describe the subjects' completion status.
    [3] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Milestones describe the subjects' completion status.
    [4] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Milestones describe the subjects' completion status.
    [5] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Milestones describe the subjects' completion status.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Control
    Reporting group description
    		 Sham procedure administered on Study Days 1, 15, 29, 64, 183, and 302.

    Reporting group title
    Nusinersen
    Reporting group description
    		 Nusinersen (2.4 mg/mL) administered as an intrathecal (IT) lumbar puncture injection on Study Days 1, 15, 29, 64, 183, and 302.

    Reporting group values
    		 Control Nusinersen Total
    Number of subjects
    		 41 80 121
    Age categorical
    Units: Subjects
    Age Continuous
    Units: days
        arithmetic mean (standard deviation)
    		 164.7 ± 48.54 147.2 ± 46.85 -
    Gender, Male/Female
    Units: Subjects
        Female
    		 24 43 67
        Male
    		 17 37 54
    Age Continuous | Age at First Dose
    Units: days
        arithmetic mean (standard deviation)
    		 180.5 ± 50.92 163.4 ± 49.57 -

    End points

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    End points reporting groups
    Reporting group title
    Control
    Reporting group description
    		 Sham procedure administered on Study Days 1, 15, 29, 64, 183, and 302.

    Reporting group title
    Nusinersen
    Reporting group description
    		 Nusinersen (2.4 mg/mL) administered as an intrathecal (IT) lumbar puncture injection on Study Days 1, 15, 29, 64, 183, and 302.

    Primary: Percentage of Motor Milestones Responders

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    End point title
    		 Percentage of Motor Milestones Responders
    End point description
    The definition of a motor milestones responder was based on improvement in the motor milestones categories in Section 2 of the Hammersmith Infant Neurological Examination (HINE), with the exclusion of voluntary grasp, as follows: (i) subject demonstrates ≥ 2-point increase in the motor milestones category of ability to kick or achievement of maximal score on that category (touching toes), or a 1-point increase in the motor milestones category of head control, rolling, sitting, crawling, standing, or walking, and (ii) among the motor milestone categories, with the exclusion of voluntary grasp, there are more categories where there is improvement as defined in (i) than worsening. (For the category of ability to kick, worsening is defined as ≥ 2-point decrease or decrease to the lowest possible score of no kicking. For the other categories, worsening is defined as ≥ 1-point decrease.) The lowest possible score for the HINE is 0 (zero), and the highest possible score for the HINE is 28.
    End point type
    Primary
    End point timeframe
    assessed at the later of the Day 183, Day 302, or Day 394 study visits
    End point values
    		 Control Nusinersen
    Number of subjects analysed
    37
    73
    Units: percentage of participants
    0
    51
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Control v Nusinersen
    Number of subjects included in analysis
    110
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Fisher exact
    Parameter type
    		 Difference in percentages
    Point estimate
    50.68
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 31.81
         upper limit
    		 66.48

    Primary: Time to Death or Permanent Ventilation

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    End point title
    		 Time to Death or Permanent Ventilation
    End point description
    Estimated proportion of participants who died or required permanent ventilation by a given study day, based on the Kaplan-Meier product-limit method. Time to death or permanent ventilation was defined as either tracheostomy or ≥ 16 hours ventilation/day continuously for > 21 days in the absence of an acute reversible event. This endpoint was adjudicated by a blinded, independent group of experienced clinicians, the Event Adjudication Committee (EAC), based on review of clinical study data and supporting information. Results are based on all available data.
    End point type
    Primary
    End point timeframe
    Day 91, Day 182, Day 273, Day 364, Day 394
    End point values
    		 Control Nusinersen
    Number of subjects analysed
    28
    31
    Units: proportion of participants
    number (not applicable)
        By Day 91 (13 weeks/3 months)
    0.268
    0.24
        By Day 182 (26 weeks/6 months)
    0.605
    0.294
        By Day 273 (39 weeks/9 months)
    0.702
    0.404
        By Day 364 (52 weeks/12 months)
    0.735
    0.447
        By Day 394 (13 months)
    0.735
    0.447
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Control v Nusinersen
    Number of subjects included in analysis
    59
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0046
    Method
    		 Logrank
    Confidence interval
    Statistical analysis title
    		 Statistical Analysis 2
    Comparison groups
    Control v Nusinersen
    Number of subjects included in analysis
    59
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0164
    Method
    		 Cox proportional hazards model
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.53
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.3156
         upper limit
    		 0.8902

    Secondary: Percentage of Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND) Responders

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    End point title
    		 Percentage of Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND) Responders
    End point description
    A participant was considered a CHOP-INTEND responder if the change from baseline in CHOP-INTEND total score is ≥ 4 points based on assessment at the later of the Day 183, Day 302, or Day 394 study visits. CHOP-INTEND tests includes 16 items structured to move from easiest to hardest with the grading including gravity eliminated (lower scores) to antigravity movements (higher scores). Total scores range from 0 to 64, with higher scores indicating better movement functioning. Results are based on all available data.
    End point type
    Secondary
    End point timeframe
    assessed at Baseline and the later of the Day 183, Day 302, or Day 394 study visits
    End point values
    		 Control Nusinersen
    Number of subjects analysed
    37
    73
    Units: percentage of participants
    3
    71
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Control v Nusinersen
    Number of subjects included in analysis
    110
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Fisher exact
    Parameter type
    		 DIfference in percentages
    Point estimate
    68.53
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 51.27
         upper limit
    		 81.99

    Secondary: Summary of Time to Death

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    End point title
    		 Summary of Time to Death
    End point description
    Estimated proportion of participants who died by given duration thresholds, based on the Kaplan-Meier product-limit method.
    End point type
    Secondary
    End point timeframe
    Day 91, Day 182, Day 273, Day 364, Day 394
    End point values
    		 Control Nusinersen
    Number of subjects analysed
    16
    13
    Units: proportion of particiants
    number (not applicable)
        by Day 91
    0.195
    0.101
        by Day 182
    0.348
    0.141
        by Day 273
    0.382
    0.173
        by Day 364
    0.419
    0.173
        by Day 394
    0.419
    0.173
    Statistical analysis title
    		 Statistical Analysis 2
    Comparison groups
    Control v Nusinersen
    Number of subjects included in analysis
    29
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0082
    Method
    		 Cox proportional hazards
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.372
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.1787
         upper limit
    		 0.7745
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Control v Nusinersen
    Number of subjects included in analysis
    29
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0041
    Method
    		 Logrank
    Confidence interval

    Secondary: Percentage of Participants Not Requiring Permanent Ventilation

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    End point title
    		 Percentage of Participants Not Requiring Permanent Ventilation
    End point description
    End point type
    Secondary
    End point timeframe
    Up to Day 394
    End point values
    		 Control Nusinersen
    Number of subjects analysed
    41
    80
    Units: percentage of participants
    68
    77
    No statistical analyses for this end point

    Secondary: Percentage of Compound Muscular Action Potential (CMAP) Responders

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    End point title
    		 Percentage of Compound Muscular Action Potential (CMAP) Responders
    End point description
    CMAP is an electrophysiological technique that can be used to determine the approximate number of motor neurons in a muscle or group of muscles. A participant was defined as a CMAP responder if the CMAP amplitude at the peroneal nerve was increasing to or maintained at ≥ 1 mV (comparing to the baseline) based on assessment at the later of the Day 183, Day 302, or Day 394 study visits. Results are based on all available data.
    End point type
    Secondary
    End point timeframe
    assessed at the later of the Day 183, Day 302, or Day 394 study visits
    End point values
    		 Control Nusinersen
    Number of subjects analysed
    37
    73
    Units: percentage of participants
    5
    36
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Control v Nusinersen
    Number of subjects included in analysis
    110
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0004
    Method
    		 Fisher exact
    Parameter type
    		 Difference in percentages
    Point estimate
    30.21
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 10.35
         upper limit
    		 48.09

    Secondary: Time to Death or Respiratory Intervention in the Subgroup of Participants Below the Study Median Disease Duration

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    End point title
    		 Time to Death or Respiratory Intervention in the Subgroup of Participants Below the Study Median Disease Duration
    End point description
    Estimated proportion of participants who died or required permanent ventilation (EAC-adjudicated events) among participants below the study median disease duration (13.1 weeks), by given duration thresholds, based on the Kaplan-Meier product-limit method.
    End point type
    Secondary
    End point timeframe
    Day 91, Day 182, Day 273, Day 364, Day 394
    End point values
    		 Control Nusinersen
    Number of subjects analysed
    21
    39
    Units: proportion of participants
    number (not applicable)
        by Day 91
    0.238
    0.128
        by Day 182
    0.546
    0.128
        by Day 273
    0.697
    0.228
        by Day 364
    0.773
    0.271
        by Day 394
    0.773
    0.271
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Control v Nusinersen
    Number of subjects included in analysis
    60
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0003
    Method
    		 Logrank
    Confidence interval
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Control v Nusinersen
    Number of subjects included in analysis
    60
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0014
    Method
    		 Cox proportional hazards
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.24
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.1002
         upper limit
    		 0.5753

    Secondary: Time to Death or Respiratory Intervention in the Subgroup of Participants Above the Study Median Disease Duration

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    End point title
    		 Time to Death or Respiratory Intervention in the Subgroup of Participants Above the Study Median Disease Duration
    End point description
    Estimated proportion of participants who died or required permanent ventilation (EAC-adjudicated events) among participants above the study median disease duration (13.1 weeks), by given duration thresholds, based on the Kaplan-Meier product-limit method.
    End point type
    Secondary
    End point timeframe
    Day 91, Day 182, Day 273, Day 364, Day 394
    End point values
    		 Control Nusinersen
    Number of subjects analysed
    20
    41
    Units: proportion of participants
    number (not applicable)
        by Day 91
    0.3
    0.35
        by Day 182
    0.67
    0.462
        by Day 273
    0.725
    0.584
        by Day 364
    0.725
    0.625
        by Day 394
    0.725
    0.625
    Statistical analysis title
    		 Statistical Analysis 2
    Comparison groups
    Control v Nusinersen
    Number of subjects included in analysis
    61
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6268
    Method
    		 Cox proportional hazards
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.844
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.427
         upper limit
    		 1.6698
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Control v Nusinersen
    Number of subjects included in analysis
    61
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3953
    Method
    		 Logrank
    Confidence interval

    Secondary: Number of Participants Experiencing Adverse Events (AEs), Serious AEs (SAEs) and Discontinuations Due to AEs

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    End point title
    		 Number of Participants Experiencing Adverse Events (AEs), Serious AEs (SAEs) and Discontinuations Due to AEs
    End point description
    AE: any unfavorable and unintended sign, symptom, or disease temporally associated with the study or use of investigational drug product, whether or not the AE is considered related to the investigational drug product. SAE: any AE that in the view of either the Investigator or Sponsor, meets any of the following criteria: results in death; is life threatening: that is, poses an immediate risk of death at the time of the event; requires in-patient hospitalization or prolongation of existing hospitalization; results in a persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions; results in congenital anomaly or birth defect in the offspring of the participant (whether male or female); is an important medical event in the opinion of the Investigator or Sponsor.
    End point type
    Secondary
    End point timeframe
    Screening through Day 394 (± 7 days) or early termination
    End point values
    		 Control Nusinersen
    Number of subjects analysed
    41
    80
    Units: partiicipants
        Any event
    40
    77
        Moderate or severe event
    39
    70
        Severe event
    33
    45
        Possibly related or related event
    6
    9
        Related event
    0
    0
        Serious event
    39
    61
        Related serious event
    0
    0
        Treatment discontinuation due to an event
    16
    13
    No statistical analyses for this end point

    Secondary: Number of Participants With AEs Corresponding to Changes in Hematology Values

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    End point title
    		 Number of Participants With AEs Corresponding to Changes in Hematology Values
    End point description
    End point type
    Secondary
    End point timeframe
    up to Day 394 (± 7 days) or early termination
    End point values
    		 Control Nusinersen
    Number of subjects analysed
    41
    80
    Units: participants
        Anemia
    1
    1
        Neutrophil count increased
    0
    1
        Leukocytosis
    1
    0
    No statistical analyses for this end point

    Secondary: Number of Participants With AEs Corresponding to Changes in Blood Chemistry Values

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    End point title
    		 Number of Participants With AEs Corresponding to Changes in Blood Chemistry Values
    End point description
    End point type
    Secondary
    End point timeframe
    up to Day 394 (± 7 days) or early termination
    End point values
    		 Control Nusinersen
    Number of subjects analysed
    41
    80
    Units: participants
        Blood potassium decreased
    0
    2
        Liver function test abnormal
    0
    1
        Alanine aminotransferase increased
    0
    1
        Aspartate aminotransferase increased
    0
    1
        Blood chloride decreased
    0
    1
        Blood iron decreased
    0
    1
        Blood sodium decreased
    0
    1
        C-reactive protein increased
    1
    2
        Hypokalemia
    3
    2
        Hypoglycemia
    2
    0
        Hyperglycemia
    1
    0
        Transaminases increased
    1
    0
    No statistical analyses for this end point

    Secondary: Number of Participants Meeting Selected Vital Sign Criteria Post-Baseline

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    End point title
    		 Number of Participants Meeting Selected Vital Sign Criteria Post-Baseline
    End point description
    End point type
    Secondary
    End point timeframe
    up to Day 394 (± 7 days) or early termination
    End point values
    		 Control Nusinersen
    Number of subjects analysed
    41 [1]
    80
    Units: participants
        Systolic blood pressure <90 mmHg
    36
    74
        Systolic blood pressure >140 mmHg
    4
    4
        Systolic blood pressure >160 mmHg
    0
    0
        Diastolic blood pressure <50 mmHg
    26
    71
        Diastolic blood pressure >90 mmHg
    13
    12
        Diastolic blood pressure >100 mmHg
    3
    0
        Pulse rate <60 bpm
    0
    0
        Pulse rate >100 bpm
    41
    80
        Temperature >38.0 C
    7
    6
        Temperature <36.0 C
    21
    45
        Respiratory rate <12 breaths/min
    0
    0
        Respiratory rate >20 breaths/min
    41
    80
        Body weight ≥7% decrease from BL
    1
    4
        Body weight ≥7% increase from BL
    33
    67
    Notes
    [1] - subjects with an assessment
    No statistical analyses for this end point

    Secondary: Summary of Shifts in 12-lead Electrocardiogram (ECG) Results

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    End point title
    		 Summary of Shifts in 12-lead Electrocardiogram (ECG) Results
    End point description
    Shift to ‘abnormal, not clinically significant’ includes ‘unknown’ or ‘normal’ to ‘abnormal, not clinically significant’. Shift to ‘abnormal, clinically significant’ includes ‘unknown’ or ‘normal’ to ‘abnormal, clinically significant’.
    End point type
    Secondary
    End point timeframe
    up to Day 394 (± 7 days) or early termination
    End point values
    		 Control Nusinersen
    Number of subjects analysed
    34 [2]
    65 [3]
    Units: participants
        Shift to abnormal, not clinically significant
    5
    17
        Shift to abnormal, clinically significant
    0
    8
        From unknown to abnormal, clinically significant
    0
    0
    Notes
    [2] - subjects whose baseline value was not abnormal and who had at least one post-baseline value.
    [3] - subjects whose baseline value was not abnormal and who had at least one post-baseline value.
    No statistical analyses for this end point

    Secondary: Number of Participants With Clinically Significant Changes From Baseline in Urinalysis Values

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    End point title
    		 Number of Participants With Clinically Significant Changes From Baseline in Urinalysis Values
    End point description
    End point type
    Secondary
    End point timeframe
    up to Day 394 (± 7 days) or early termination
    End point values
    		 Control Nusinersen
    Number of subjects analysed
    41
    80
    Units: participants
    0
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Screening through Day 394 (± 7 days) or early termination
    Adverse event reporting additional description
    Treatment-emergent events are presented.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.1
    Reporting groups
    Reporting group title
    Control
    Reporting group description
    		 Sham procedure administered on Study Days 1, 15, 29, 64, 183, and 302.

    Reporting group title
    Nusinersen
    Reporting group description
    		 Nusinersen (2.4 mg/mL) administered as an IT lumbar puncture injection on Study Days 1, 15, 29, 64, 183, and 302.

    Serious adverse events
    		 Control Nusinersen
    Total subjects affected by serious adverse events
         subjects affected / exposed
    39 / 41 (95.12%)
    61 / 80 (76.25%)
         number of deaths (all causes)
    16
    13
         number of deaths resulting from adverse events
    Investigations
    Body temperature increased
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Heart rate decreased
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Medical observation
         subjects affected / exposed
    0 / 41 (0.00%)
    2 / 80 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oxygen saturation decreased
         subjects affected / exposed
    2 / 41 (4.88%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respirovirus test positive
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Delayed recovery from anaesthesia
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Feeding tube complication
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Head injury
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tracheal haemorrhage
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tracheal obstruction
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vaccination complication
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Shock
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombosis
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac arrest
         subjects affected / exposed
    2 / 41 (4.88%)
    2 / 80 (2.50%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardio-respiratory arrest
         subjects affected / exposed
    5 / 41 (12.20%)
    5 / 80 (6.25%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 5
         deaths causally related to treatment / all
    0 / 3
    0 / 2
    Cyanosis
         subjects affected / exposed
    1 / 41 (2.44%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinus tachycardia
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Brain injury
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Hypoxic-ischaemic encephalopathy
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    General disorders and administration site conditions
    Death
         subjects affected / exposed
    1 / 41 (2.44%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    General physical health deterioration
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pyrexia
         subjects affected / exposed
    0 / 41 (0.00%)
    4 / 80 (5.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical failure
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Dysphagia
         subjects affected / exposed
    1 / 41 (2.44%)
    2 / 80 (2.50%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric haemorrhage
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Retching
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Salivary hypersecretion
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 41 (2.44%)
    3 / 80 (3.75%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    9 / 41 (21.95%)
    11 / 80 (13.75%)
         occurrences causally related to treatment / all
    0 / 11
    0 / 29
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Acute respiratory distress syndrome
         subjects affected / exposed
    1 / 41 (2.44%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Apnoea
         subjects affected / exposed
    2 / 41 (4.88%)
    2 / 80 (2.50%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Apparent life threatening event
         subjects affected / exposed
    2 / 41 (4.88%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspiration
         subjects affected / exposed
    1 / 41 (2.44%)
    3 / 80 (3.75%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Atelectasis
         subjects affected / exposed
    4 / 41 (9.76%)
    14 / 80 (17.50%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 26
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchial secretion retention
         subjects affected / exposed
    5 / 41 (12.20%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic respiratory failure
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypercapnia
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    2 / 41 (4.88%)
    4 / 80 (5.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoventilation
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    1 / 41 (2.44%)
    4 / 80 (5.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Increased bronchial secretion
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung disorder
         subjects affected / exposed
    1 / 41 (2.44%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Obstructive airways disorder
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    5 / 41 (12.20%)
    8 / 80 (10.00%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory arrest
         subjects affected / exposed
    4 / 41 (9.76%)
    5 / 80 (6.25%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Respiratory disorder
         subjects affected / exposed
    0 / 41 (0.00%)
    2 / 80 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory distress
         subjects affected / exposed
    8 / 41 (19.51%)
    21 / 80 (26.25%)
         occurrences causally related to treatment / all
    0 / 13
    0 / 28
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    Respiratory failure
         subjects affected / exposed
    16 / 41 (39.02%)
    20 / 80 (25.00%)
         occurrences causally related to treatment / all
    0 / 21
    0 / 22
         deaths causally related to treatment / all
    0 / 8
    0 / 4
    Respiratory tract congestion
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Dermatitis
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Agitation
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Bronchiolitis
         subjects affected / exposed
    1 / 41 (2.44%)
    4 / 80 (5.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    0 / 41 (0.00%)
    4 / 80 (5.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis viral
         subjects affected / exposed
    0 / 41 (0.00%)
    3 / 80 (3.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Candida sepsis
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Corona virus infection
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear infection
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis rotavirus
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 41 (0.00%)
    4 / 80 (5.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection viral
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Moraxella infection
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nasopharyngitis
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    5 / 41 (12.20%)
    19 / 80 (23.75%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 25
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia influenzal
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 80 (1.25%)
         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
    2 / 41 (4.88%)
    3 / 80 (3.75%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia moraxella
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia parainfluenzae viral
         subjects affected / exposed
    1 / 41 (2.44%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia pneumococcal
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 80 (1.25%)
         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
    1 / 41 (2.44%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia respiratory syncytial viral
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia viral
         subjects affected / exposed
    2 / 41 (4.88%)
    6 / 80 (7.50%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 80 (1.25%)
         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
    3 / 41 (7.32%)
    4 / 80 (5.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    1 / 41 (2.44%)
    6 / 80 (7.50%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection viral
         subjects affected / exposed
    1 / 41 (2.44%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rhinovirus infection
         subjects affected / exposed
    2 / 41 (4.88%)
    7 / 80 (8.75%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal sepsis
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stoma site abscess
         subjects affected / exposed
    0 / 41 (0.00%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Systemic infection
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 41 (0.00%)
    4 / 80 (5.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 41 (0.00%)
    3 / 80 (3.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    1 / 41 (2.44%)
    5 / 80 (6.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral upper respiratory tract infection
         subjects affected / exposed
    6 / 41 (14.63%)
    3 / 80 (3.75%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    1 / 41 (2.44%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Failure to thrive
         subjects affected / exposed
    1 / 41 (2.44%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Feeding disorder of infancy or early childhood
         subjects affected / exposed
    2 / 41 (4.88%)
    2 / 80 (2.50%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Feeding intolerance
         subjects affected / exposed
    0 / 41 (0.00%)
    2 / 80 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Weight gain poor
         subjects affected / exposed
    2 / 41 (4.88%)
    3 / 80 (3.75%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Control Nusinersen
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    35 / 41 (85.37%)
    70 / 80 (87.50%)
    Investigations
    Weight decreased
         subjects affected / exposed
    1 / 41 (2.44%)
    4 / 80 (5.00%)
         occurrences all number
    1
    4
    Oxygen saturation decreased
         subjects affected / exposed
    9 / 41 (21.95%)
    9 / 80 (11.25%)
         occurrences all number
    14
    15
    Injury, poisoning and procedural complications
    Feeding tube complication
         subjects affected / exposed
    3 / 41 (7.32%)
    1 / 80 (1.25%)
         occurrences all number
    4
    1
    Cardiac disorders
    Bradycardia
         subjects affected / exposed
    3 / 41 (7.32%)
    4 / 80 (5.00%)
         occurrences all number
    4
    4
    Tachycardia
         subjects affected / exposed
    5 / 41 (12.20%)
    7 / 80 (8.75%)
         occurrences all number
    11
    9
    General disorders and administration site conditions
    Oedema
         subjects affected / exposed
    3 / 41 (7.32%)
    0 / 80 (0.00%)
         occurrences all number
    3
    0
    Pyrexia
         subjects affected / exposed
    24 / 41 (58.54%)
    43 / 80 (53.75%)
         occurrences all number
    43
    110
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    9 / 41 (21.95%)
    28 / 80 (35.00%)
         occurrences all number
    9
    31
    Diarrhoea
         subjects affected / exposed
    7 / 41 (17.07%)
    11 / 80 (13.75%)
         occurrences all number
    13
    14
    Flatulence
         subjects affected / exposed
    1 / 41 (2.44%)
    4 / 80 (5.00%)
         occurrences all number
    1
    4
    Dysphagia
         subjects affected / exposed
    9 / 41 (21.95%)
    7 / 80 (8.75%)
         occurrences all number
    11
    10
    Gastrooesophageal reflux disease
         subjects affected / exposed
    8 / 41 (19.51%)
    10 / 80 (12.50%)
         occurrences all number
    8
    11
    Salivary hypersecretion
         subjects affected / exposed
    1 / 41 (2.44%)
    6 / 80 (7.50%)
         occurrences all number
    1
    6
    Teething
         subjects affected / exposed
    3 / 41 (7.32%)
    14 / 80 (17.50%)
         occurrences all number
    3
    14
    Vomiting
         subjects affected / exposed
    7 / 41 (17.07%)
    11 / 80 (13.75%)
         occurrences all number
    7
    20
    Respiratory, thoracic and mediastinal disorders
    Atelectasis
         subjects affected / exposed
    9 / 41 (21.95%)
    9 / 80 (11.25%)
         occurrences all number
    14
    19
    Bronchial secretion retention
         subjects affected / exposed
    2 / 41 (4.88%)
    4 / 80 (5.00%)
         occurrences all number
    2
    5
    Cough
         subjects affected / exposed
    8 / 41 (19.51%)
    9 / 80 (11.25%)
         occurrences all number
    11
    11
    Dyspnoea
         subjects affected / exposed
    4 / 41 (9.76%)
    3 / 80 (3.75%)
         occurrences all number
    5
    3
    Nasal congestion
         subjects affected / exposed
    5 / 41 (12.20%)
    8 / 80 (10.00%)
         occurrences all number
    6
    12
    Hypoxia
         subjects affected / exposed
    2 / 41 (4.88%)
    4 / 80 (5.00%)
         occurrences all number
    3
    5
    Pneumonia aspiration
         subjects affected / exposed
    3 / 41 (7.32%)
    3 / 80 (3.75%)
         occurrences all number
    3
    4
    Respiratory distress
         subjects affected / exposed
    6 / 41 (14.63%)
    4 / 80 (5.00%)
         occurrences all number
    7
    4
    Respiratory failure
         subjects affected / exposed
    6 / 41 (14.63%)
    0 / 80 (0.00%)
         occurrences all number
    7
    0
    Sleep apnoea syndrome
         subjects affected / exposed
    4 / 41 (9.76%)
    0 / 80 (0.00%)
         occurrences all number
    4
    0
    Rhinorrhoea
         subjects affected / exposed
    3 / 41 (7.32%)
    6 / 80 (7.50%)
         occurrences all number
    3
    7
    Upper respiratory tract congestion
         subjects affected / exposed
    1 / 41 (2.44%)
    6 / 80 (7.50%)
         occurrences all number
    1
    6
    Skin and subcutaneous tissue disorders
    Decubitus ulcer
         subjects affected / exposed
    3 / 41 (7.32%)
    0 / 80 (0.00%)
         occurrences all number
    3
    0
    Dermatitis contact
         subjects affected / exposed
    3 / 41 (7.32%)
    2 / 80 (2.50%)
         occurrences all number
    3
    3
    Erythema
         subjects affected / exposed
    3 / 41 (7.32%)
    1 / 80 (1.25%)
         occurrences all number
    3
    1
    Dermatitis diaper
         subjects affected / exposed
    4 / 41 (9.76%)
    6 / 80 (7.50%)
         occurrences all number
    4
    6
    Rash
         subjects affected / exposed
    4 / 41 (9.76%)
    9 / 80 (11.25%)
         occurrences all number
    5
    11
    Musculoskeletal and connective tissue disorders
    Scoliosis
         subjects affected / exposed
    2 / 41 (4.88%)
    4 / 80 (5.00%)
         occurrences all number
    2
    5
    Infections and infestations
    Bronchiolitis
         subjects affected / exposed
    2 / 41 (4.88%)
    4 / 80 (5.00%)
         occurrences all number
    2
    4
    Bacterial tracheitis
         subjects affected / exposed
    4 / 41 (9.76%)
    1 / 80 (1.25%)
         occurrences all number
    9
    2
    Candida infection
         subjects affected / exposed
    3 / 41 (7.32%)
    0 / 80 (0.00%)
         occurrences all number
    6
    0
    Conjunctivitis
         subjects affected / exposed
    3 / 41 (7.32%)
    5 / 80 (6.25%)
         occurrences all number
    3
    5
    Influenza
         subjects affected / exposed
    0 / 41 (0.00%)
    5 / 80 (6.25%)
         occurrences all number
    0
    5
    Ear infection
         subjects affected / exposed
    1 / 41 (2.44%)
    5 / 80 (6.25%)
         occurrences all number
    1
    7
    Nasopharyngitis
         subjects affected / exposed
    4 / 41 (9.76%)
    14 / 80 (17.50%)
         occurrences all number
    4
    20
    Oral candidiasis
         subjects affected / exposed
    3 / 41 (7.32%)
    7 / 80 (8.75%)
         occurrences all number
    4
    9
    Pneumonia
         subjects affected / exposed
    3 / 41 (7.32%)
    7 / 80 (8.75%)
         occurrences all number
    3
    8
    Respiratory tract infection
         subjects affected / exposed
    2 / 41 (4.88%)
    4 / 80 (5.00%)
         occurrences all number
    2
    10
    Rhinovirus infection
         subjects affected / exposed
    4 / 41 (9.76%)
    4 / 80 (5.00%)
         occurrences all number
    5
    5
    Rhinitis
         subjects affected / exposed
    3 / 41 (7.32%)
    2 / 80 (2.50%)
         occurrences all number
    4
    6
    Stoma site infection
         subjects affected / exposed
    3 / 41 (7.32%)
    1 / 80 (1.25%)
         occurrences all number
    4
    1
    Upper respiratory tract infection
         subjects affected / exposed
    9 / 41 (21.95%)
    22 / 80 (27.50%)
         occurrences all number
    12
    36
    Urinary tract infection
         subjects affected / exposed
    0 / 41 (0.00%)
    6 / 80 (7.50%)
         occurrences all number
    0
    7
    Viral infection
         subjects affected / exposed
    3 / 41 (7.32%)
    4 / 80 (5.00%)
         occurrences all number
    3
    5
    Viral upper respiratory tract infection
         subjects affected / exposed
    1 / 41 (2.44%)
    6 / 80 (7.50%)
         occurrences all number
    1
    9
    Metabolism and nutrition disorders
    Hypokalaemia
         subjects affected / exposed
    3 / 41 (7.32%)
    0 / 80 (0.00%)
         occurrences all number
    3
    0

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    25 Apr 2014
    - Finalized aspects of the study design.
    20 Jun 2014
    - Added language explaining that all primary endpoint events were to be reviewed in a blinded fashion by a central, independent adjudication committee. - Added language to specify the segregation of responsibilities and blinding for personnel making decisions regarding subjects’ ventilation and performing efficacy evaluations.
    22 Apr 2016
    - Clarification was made to allow subjects who complete all study assessments to rollover into a long-term extension study in the scenario of the study being terminated early based on the assessment of risk-benefit of ISIS 396443 as a result of the interim analysis. - A statement was added related to unblinding of certain representatives from the study Sponsor during the conduct of the interim analysis. - Clarification was made on the adjustment of visit schedule for subjects who experience treatment delays as a result of an illness. - Changes were made to the primary and secondary efficacy endpoints based on new information from Phase 2 and natural history data and to improve ability to interpret some of the endpoints in the event that the study is terminated early. - A sample size justification was added based on the power analysis using the new primary endpoint of motor milestone responders. - Timing of the interim and final analyses was clarified. - Clinical experience was updated to reflect the most recent version of the Investigator’s Brochure. - A definition for Interim Efficacy Set was added. - A description of the endpoints and timing of the interim analysis was added. - Details on the definitions of primary, secondary, and tertiary endpoints were added. - References related to analytical methods were added.

    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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