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    Clinical Trial Results:
    A Phase 2, randomized, double-blind, sham-procedure-controlled study to assess the safety and tolerability and explore the efficacy of ISIS 396443 (BIIB058) administered intrathecally in subjects with spinal muscular atrophy who are not eligible to participate in the clinical studies ISIS 396443-CS3B or ISIS 396443-CS4

    Summary
    EudraCT number
    		 2014-003657-33
    Trial protocol
    		 DE   GB  
    Global end of trial date
    24 Sep 2018

    Results information
    Results version number
    		 v2
    This version publication date
    03 May 2019
    First version publication date
    12 Apr 2019
    Other versions
    		 v1 , v3
    Version creation reason
    • Correction of full data set
    There was an update in MedDRA version and due to update in MedDRA version, a couple of preferred terms were changed.

    Trial information

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    Trial identification
    Sponsor protocol code
    232SM202
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02462759
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Biogen
    Sponsor organisation address
    250 Binney Street, Cambridge, 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)
    No
    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?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    24 Sep 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    24 Sep 2018
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The primary objective of Part 1 of this study was to assess the safety and tolerability of ISIS 396443 in subjects with spinal muscular atrophy (SMA) who were not eligible to participate in the clinical studies ISIS 396443-CS3B or ISIS 396443-CS4. The primary objective of Part 2 of this study was to assess the long-term safety and tolerability of ISIS 396443 in subjects with SMA who participated in Part 1 and completed their End of Part 1 Evaluation assessments.
    Protection of trial subjects
    Written informed consent was obtained from each subject or subject’s legally authorized representative (e.g., parent or legal guardian), as applicable, prior to evaluations performed for eligibility. Subjects or the subject’s legally authorized representative were given adequate time to review the information in the informed consent/assent and were allowed to ask, and have answered, questions concerning all portions of the conduct of the study.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    19 Aug 2015
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety
    Long term follow-up duration
    		 4 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United States: 16
    Country: Number of subjects enrolled
    Germany: 5
    Worldwide total number of subjects
    21
    EEA total number of subjects
    5
    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)
    16
    Children (2-11 years)
    5
    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
    		 Subjects were recruited from sites in the US and Germany. Part 1 was terminated early as positive efficacy results were observed in interim analysis of study 201300442229 and it was considered unethical to continue this part of study. Part 2 was also terminated early to rollover and continue to follow subjects in study 201500187016.

    Pre-assignment
    Screening details
    		 A total of 21 subjects with SMA were randomised in Part 1 of the study (7 subjects in sham procedure group, 14 subjects in ISIS 396443 group). One subject died in sham procedure group of Part 1. A total of 20 subjects were enrolled to receive ISIS 396443 in open-label phase of Part 2. Integrated analysis was performed for Part 1 and 2 of the study.

    Period 1
    Period 1 title
    Part 1: Double Blind
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Carer

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Sham Procedure (Part 1)
    Arm description
    		 Sham procedure on Day 1, 15, 29, 64, 183 and 302.
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 ISIS 396443 (Part 1)
    Arm description
    		 Single dose of 9.6 milligrams (mg) to 12.0 mg ISIS 396443, based on subject’s age, intrathecal bolus injection loading doses on Day 1, 15, 29, 64 and maintenance doses, every 4 months, on Day 183 and 302.
    Arm type
    		 Experimental

    Investigational medicinal product name
    ISIS 396443
    Investigational medicinal product code
    Other name
    BIIB058, Nusinersen
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intrathecal use
    Dosage and administration details
    Single dose of 9.6 mg to 12.0 mg ISIS 396443, based on subject's age, intrathecal bolus injection loading doses on Day 1, 15, 29, 64 and maintenance doses, every 4 months, on Day 183 and 302.

    Number of subjects in period 1
    		Sham Procedure (Part 1) ISIS 396443 (Part 1)
    Started
    7
    14
    Completed
    6
    14
    Not completed
    1
    0
         Death
    1
    -
    Period 2
    Period 2 title
    Part 2: Open-Label Phase
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 ISIS 396443 (Part 2)
    Arm description
    		 Subjects who were in Sham procedure group in Part 1, received single dose of 12.0 mg ISIS 396443 intrathecal bolus injection loading doses on Day 1, 15, 29, 64 and maintenance doses, every 4 months, on Day 183, 302, 421, 540, 659 and 778 in Part 2; subjects who were in ISIS 396443 group in Part 1 continued to receive a single dose of 9.6 mg to 12.0 mg ISIS 396443 intrathecal bolus injection maintenance doses on Day 1, 120, 239, 358, 477, 596 and 715 in Part 2.
    Arm type
    		 Experimental

    Investigational medicinal product name
    ISIS 396443
    Investigational medicinal product code
    Other name
    BIIB058, Nusinersen
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intrathecal use
    Dosage and administration details
    Subjects who were in Sham procedure group in Part 1, received single dose of 12.0 mg ISIS 396443 intrathecal bolus injection loading doses on Day 1, 15, 29, 64 and maintenance doses, every 4 months, on Day 183, 302, 421, 540, 659 and 778 in Part 2; subjects who were in ISIS 396443 group in Part 1 continued to receive a single dose of 9.6 mg to 12.0 mg ISIS 396443 intrathecal bolus injection maintenance doses on Day 1, 120, 239, 358, 477, 596 and 715 in Part 2.

    Number of subjects in period 2
    		ISIS 396443 (Part 2)
    Started
    20
    Completed
    20

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Sham Procedure (Part 1)
    Reporting group description
    		 Sham procedure on Day 1, 15, 29, 64, 183 and 302.

    Reporting group title
    ISIS 396443 (Part 1)
    Reporting group description
    		 Single dose of 9.6 milligrams (mg) to 12.0 mg ISIS 396443, based on subject’s age, intrathecal bolus injection loading doses on Day 1, 15, 29, 64 and maintenance doses, every 4 months, on Day 183 and 302.

    Reporting group values
    		 Sham Procedure (Part 1) ISIS 396443 (Part 1) Total
    Number of subjects
    		 7 14 21
    Age Categorical
    Units: Subjects
    Age Continuous
    Units: months
        arithmetic mean (standard deviation)
    		 24.42 ( 13.839 ) 19.40 ( 10.115 ) -
    Gender Categorical
    Units: Subjects
        Female
    		 5 5 10
        Male
    		 2 9 11
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 2 1 3
        Not Hispanic or Latino
    		 4 9 13
        Not reported due to confidentiality
    		 1 4 5
    Race
    Units: Subjects
        Asian
    		 3 2 5
        White
    		 2 7 9
        Other
    		 1 1 2
        Not reported due to confidentiality
    		 1 4 5

    End points

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    End points reporting groups
    Reporting group title
    Sham Procedure (Part 1)
    Reporting group description
    		 Sham procedure on Day 1, 15, 29, 64, 183 and 302.

    Reporting group title
    ISIS 396443 (Part 1)
    Reporting group description
    		 Single dose of 9.6 milligrams (mg) to 12.0 mg ISIS 396443, based on subject’s age, intrathecal bolus injection loading doses on Day 1, 15, 29, 64 and maintenance doses, every 4 months, on Day 183 and 302.
    Reporting group title
    ISIS 396443 (Part 2)
    Reporting group description
    		 Subjects who were in Sham procedure group in Part 1, received single dose of 12.0 mg ISIS 396443 intrathecal bolus injection loading doses on Day 1, 15, 29, 64 and maintenance doses, every 4 months, on Day 183, 302, 421, 540, 659 and 778 in Part 2; subjects who were in ISIS 396443 group in Part 1 continued to receive a single dose of 9.6 mg to 12.0 mg ISIS 396443 intrathecal bolus injection maintenance doses on Day 1, 120, 239, 358, 477, 596 and 715 in Part 2.

    Subject analysis set title
    Sham Procedure in Part 1
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Subjects who received single dose of sham procedure on Day 1, 15, 29, 64, 183 and 302 in Part 1 of the study.

    Subject analysis set title
    ISIS 396443 in Part 2 (subjects on sham in Part 1)
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Subjects who received single dose of ISIS 396443 on Day 1, 15, 29, 64, 183, 302, 421, 540, 659 and 778 in Part 2.

    Subject analysis set title
    ISIS 396443 in Part 1 & 2 (subjects on ISIS 396443 in Part 1)
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Subjects who received single dose of ISIS 396443 on Day 1, 15, 29, 64, 183 and 302 in Part 1 of the study and then received single dose of ISIS 396443 on Day 1, 120, 239, 358, 477, 596 and 715 in Part 2 of the study.

    Primary: Number of Subjects with Adverse Events (AEs) and Serious Adverse Events (SAEs)

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    End point title
    		 Number of Subjects with Adverse Events (AEs) and Serious Adverse Events (SAEs) [1]
    End point description
    An AE is any untoward medical occurrence in a subject or clinical investigation subject administered a pharmaceutical product and that does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product. A SAE is any untoward medical occurrence that at any dose results in death, life-threatening event, requires inpatient hospitalization, significant disability/incapacity or congenital anomaly. The safety population included all subjects who were randomised and received at least 1 dose of study treatment or sham procedure.
    End point type
    Primary
    End point timeframe
    Part 1 and 2: From first dose/sham procedure to end of study (up to 1080 days)
    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 data was planned to be reported for this endpoint.
    End point values
    		 Sham Procedure in Part 1 ISIS 396443 in Part 2 (subjects on sham in Part 1) ISIS 396443 in Part 1 & 2 (subjects on ISIS 396443 in Part 1)
    Number of subjects analysed
    7
    6
    14
    Units: subjects
        AEs
    6
    6
    14
        SAEs
    3
    4
    9
    No statistical analyses for this end point

    Primary: Number of Subjects with Change from Baseline in Clinical Laboratory Parameters

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    End point title
    		 Number of Subjects with Change from Baseline in Clinical Laboratory Parameters [2]
    End point description
    Clinically significant changes in blood chemistry, hematology and urinalysis assessments were evaluated. The safety population included all subjects who were randomised and received at least 1 dose of study treatment or sham procedure.
    End point type
    Primary
    End point timeframe
    Part 1 and 2: From first dose/sham procedure to end of study (up to 1080 days)
    Notes
    [2] - 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 data was planned to be reported for this endpoint.
    End point values
    		 Sham Procedure in Part 1 ISIS 396443 in Part 2 (subjects on sham in Part 1) ISIS 396443 in Part 1 & 2 (subjects on ISIS 396443 in Part 1)
    Number of subjects analysed
    7
    6
    14
    Units: subjects
    0
    0
    0
    No statistical analyses for this end point

    Primary: Number of Subjects with Change from Baseline in Electrocardiograms (ECGs)

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    End point title
    		 Number of Subjects with Change from Baseline in Electrocardiograms (ECGs) [3]
    End point description
    Clinically significant changes in ECG measurements were evaluated for assessing the safety of ISIS 396443. The safety population included all subjects who were randomised and received at least 1 dose of study treatment or sham procedure.
    End point type
    Primary
    End point timeframe
    Part 1: Day 2, 29 and 422; Part 2: Day 1 to 596
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be reported for this endpoint.
    End point values
    		 Sham Procedure in Part 1 ISIS 396443 in Part 2 (subjects on sham in Part 1) ISIS 396443 in Part 1 & 2 (subjects on ISIS 396443 in Part 1)
    Number of subjects analysed
    7
    6
    14
    Units: subjects
    0
    0
    0
    No statistical analyses for this end point

    Primary: Number of Subjects with Change from Baseline in Vital Signs

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    End point title
    		 Number of Subjects with Change from Baseline in Vital Signs [4]
    End point description
    Clinically significant changes in vital signs were evaluated for assessing the safety of ISIS 396443. Vital signs that were assessed included resting systolic and diastolic blood pressure, pulse rate, respiratory rate, temperature, pulse oximetry, and transcutaneous carbon dioxide. The safety population included all subjects who were randomised and received at least 1 dose of study treatment or sham procedure.
    End point type
    Primary
    End point timeframe
    Part 1: Baseline to Day 422; Part 2: Baseline to Day 596
    Notes
    [4] - 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 data was planned to be reported for this endpoint.
    End point values
    		 Sham Procedure in Part 1 ISIS 396443 in Part 2 (subjects on sham in Part 1) ISIS 396443 in Part 1 & 2 (subjects on ISIS 396443 in Part 1)
    Number of subjects analysed
    7
    6
    14
    Units: subjects
    0
    0
    0
    No statistical analyses for this end point

    Primary: Change from Baseline in Head Circumference

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    End point title
    		 Change from Baseline in Head Circumference [5]
    End point description
    Subjects were analysed for change in growth parameter of head circumference to evaluate clinical efficacy. WHO Child Growth Standards were used to determine the head circumference percentile. Study days were windowed for integrated analysis and labelled as follows: Days <=1 as Baseline;Days >1 to <= 22 as Day 15;Days >22 to <=47 as Day 29;Days >47 to <= 123 as Day 64;Days >123 to <=242 as Day 183;Days >242 to <=362 as Day 302;Days >362 to <=482 as Day 422;Days >482 to <= 600 as Day 540;Days >600 to <= 719 as Day 659;Days >719 to <= 838 as Day 778;Days >838 to <= 958 as Day 898;Days >958 to <= 1078 as Day 1018;Days >1078 to <= 1198 as Day 1138. The safety population included all subjects who were randomised and received at least 1 dose of study treatment or sham procedure. Here “99999” denotes that data was not evaluable at the given time point for the analysis set ISIS 396443 in Part 2 (subjects on sham in Part 1). “n” is the number of subjects evaluated at specified time point.
    End point type
    Primary
    End point timeframe
    Part 2: Baseline, Day 15, 29, 64, 183, 302, 422, 540, 659, 778, 898, 1018 and 1138
    Notes
    [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be reported for this endpoint.
    End point values
    		 ISIS 396443 in Part 2 (subjects on sham in Part 1) ISIS 396443 in Part 1 & 2 (subjects on ISIS 396443 in Part 1)
    Number of subjects analysed
    6
    14
    Units: centimetre (cm)
    arithmetic mean (standard deviation)
        Baseline (n=6,14)
    50.8 ( 3.83 )
    47.3 ( 1.51 )
        Change at Day 15 (n=5,14)
    -0.7 ( 3.34 )
    0.1 ( 0.36 )
        Change at Day 29 (n=6,13)
    0.0 ( 2.76 )
    0.3 ( 0.65 )
        Change at Day 64 (n=6,14)
    0.1 ( 2.64 )
    0.5 ( 0.73 )
        Change at Day 183 (n=6,14)
    0.3 ( 3.10 )
    1.0 ( 1.12 )
        Change at Day 302 (n=6,14)
    1.0 ( 3.28 )
    1.6 ( 1.05 )
        Change at Day 422 (n=6,13)
    0.9 ( 2.47 )
    2.0 ( 1.24 )
        Change at Day 540 (n=6,14)
    1.3 ( 1.97 )
    2.5 ( 1.24 )
        Change at Day 659 (n=6,14)
    1.5 ( 2.53 )
    2.6 ( 1.37 )
        Change at Day 778 (n=0,14)
    99999 ( 99999 )
    2.8 ( 0.92 )
        Change at Day 898 (n=0,12)
    99999 ( 99999 )
    3.5 ( 1.05 )
        Change at Day 1018 (n=0,5)
    99999 ( 99999 )
    3.5 ( 2.06 )
        Change at Day 1138 (n=0,1)
    99999 ( 99999 )
    4.0 ( 0 )
    No statistical analyses for this end point

    Primary: Change from Baseline in Chest Circumference

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    End point title
    		 Change from Baseline in Chest Circumference [6]
    End point description
    Subjects were analysed for change in growth parameter of chest circumference to evaluate clinical efficacy. WHO Child Growth Standards were used to determine the chest circumference percentile. Study days were windowed for integrated analysis and labelled as follows: Days <=1 as Baseline;Days >1 to <= 22 as Day 15;Days >22 to <=47 as Day 29;Days >47 to <= 123 as Day 64;Days >123 to <=242 as Day 183;Days >242 to <=362 as Day 302;Days >362 to <=482 as Day 422;Days >482 to <= 600 as Day 540;Days >600 to <= 719 as Day 659;Days >719 to <= 838 as Day 778;Days >838 to <= 958 as Day 898;Days >958 to <= 1078 as Day 1018;Days >1078 to <= 1198 as Day 1138. The safety population included all subjects who were randomised and received at least 1 dose of study treatment or sham procedure. Here “99999” denotes that data was not evaluable at the given time point for the analysis set ISIS 396443 in Part 2 (subjects on sham in Part 1). “n” is the number of subjects evaluated at specified time point.
    End point type
    Primary
    End point timeframe
    Part 2: Baseline, Day 15, 29, 64, 183, 302, 422, 540, 659, 778, 898, 1018 and 1138
    Notes
    [6] - 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 data was planned to be reported for this endpoint.
    End point values
    		 ISIS 396443 in Part 2 (subjects on sham in Part 1) ISIS 396443 in Part 1 & 2 (subjects on ISIS 396443 in Part 1)
    Number of subjects analysed
    6
    14
    Units: cm
    arithmetic mean (standard deviation)
        Baseline (n=6,14)
    51.3 ( 5.45 )
    46.9 ( 3.91 )
        Change at Day 15 (n=5,14)
    -0.2 ( 3.86 )
    -0.4 ( 1.53 )
        Change at Day 29 (n=6,13)
    -1.1 ( 2.70 )
    0.2 ( 1.39 )
        Change at Day 64 (n=6,14)
    -0.9 ( 3.50 )
    0.2 ( 1.92 )
        Change at Day 183 (n=6,14)
    0.2 ( 3.04 )
    1.4 ( 2.02 )
        Change at Day 302 (n=6,14)
    1.2 ( 3.07 )
    1.6 ( 2.86 )
        Change at Day 422 (n=6,14)
    0.5 ( 3.72 )
    2.8 ( 2.73 )
        Change at Day 540 (n=6,14)
    1.8 ( 2.42 )
    3.8 ( 3.23 )
        Change at Day 659 (n=6,14)
    2.9 ( 3.85 )
    5.1 ( 3.29 )
        Change at Day 778 (n=0,14)
    99999 ( 99999 )
    5.5 ( 3.52 )
        Change at Day 898 (n=0,12)
    99999 ( 99999 )
    7.1 ( 3.04 )
        Change at Day 1018 (n=0,5)
    99999 ( 99999 )
    9.7 ( 4.92 )
        Change at Day 1138 (n=0,1)
    99999 ( 99999 )
    9.1 ( 0 )
    No statistical analyses for this end point

    Primary: Change from Baseline in Arm Circumference

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    End point title
    		 Change from Baseline in Arm Circumference [7]
    End point description
    Subjects were analysed for change in growth parameter of arm circumference to evaluate clinical efficacy. WHO Child Growth Standards were used to determine the arm circumference percentile. Study days were windowed for integrated analysis and labelled as follows: Days <=1 as Baseline;Days >1 to <= 22 as Day 15;Days >22 to <=47 as Day 29;Days >47 to <= 123 as Day 64;Days >123 to <=242 as Day 183;Days >242 to <=362 as Day 302;Days >362 to <=482 as Day 422;Days >482 to <= 600 as Day 540;Days >600 to <= 719 as Day 659;Days >719 to <= 838 as Day 778;Days >838 to <= 958 as Day 898;Days >958 to <= 1078 as Day 1018;Days >1078 to <= 1198 as Day 1138. The safety population included all subjects who were randomised and received at least 1 dose of study treatment or sham procedure. Here “99999” denotes that data was not evaluable at the given time point for the analysis set ISIS 396443 in Part 2 (subjects on sham in Part 1). “n” is the number of subjects evaluated at specified time point.
    End point type
    Primary
    End point timeframe
    Part 2: Baseline, Day 15, 29, 64, 183, 302, 422, 540, 659, 778, 898, 1018 and 1138
    Notes
    [7] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be reported for this endpoint.
    End point values
    		 ISIS 396443 in Part 2 (subjects on sham in Part 1) ISIS 396443 in Part 1 & 2 (subjects on ISIS 396443 in Part 1)
    Number of subjects analysed
    6
    14
    Units: cm
    arithmetic mean (standard deviation)
        Baseline (n=6,14)
    16.2 ( 1.19 )
    14.5 ( 1.85 )
        Change at Day 15 (n=5,14)
    -0.4 ( 1.04 )
    0.3 ( 0.61 )
        Change at Day 29 (n=6,13)
    -0.5 ( 1.08 )
    -0.1 ( 0.54 )
        Change at Day 64 (n=6,14)
    -0.3 ( 0.49 )
    -0.4 ( 0.89 )
        Change at Day 183 (n=6,14)
    0.0 ( 0.89 )
    0.0 ( 0.85 )
        Change at Day 302 (n=6,14)
    -0.6 ( 0.89 )
    0.2 ( 1.17 )
        Change at Day 422 (n=6,14)
    -0.6 ( 1.82 )
    0.5 ( 1.71 )
        Change at Day 540 (n=6,14)
    -0.2 ( 2.24 )
    0.5 ( 1.89 )
        Change at Day 659 (n=6,14)
    0.6 ( 0.93 )
    0.6 ( 1.93 )
        Change at Day 778 (n=0,14)
    99999 ( 99999 )
    0.0 ( 2.18 )
        Change at Day 898 (n=0,12)
    99999 ( 99999 )
    0.8 ( 2.70 )
        Change at Day 1018 (n=0,5)
    99999 ( 99999 )
    1.0 ( 2.02 )
        Change at Day 1138 (n=0,1)
    99999 ( 99999 )
    1.5 ( 0 )
    No statistical analyses for this end point

    Primary: Change from Baseline in Weight for Age

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    End point title
    		 Change from Baseline in Weight for Age [8]
    End point description
    Subjects were analysed for change in growth parameter of weight for age to evaluate clinical efficacy. WHO Child Growth Standards were used to determine the head circumference percentile. Study days were windowed for integrated analysis and labelled as follows: Days <=1 as Baseline;Days >1 to <= 22 as Day 15;Days >22 to <=47 as Day 29;Days >47 to <= 123 as Day 64;Days >123 to <=242 as Day 183;Days >242 to <=362 as Day 302;Days >362 to <=482 as Day 422;Days >482 to <= 600 as Day 540;Days >600 to <= 719 as Day 659;Days >719 to <= 838 as Day 778;Days >838 to <= 958 as Day 898;Days >958 to <= 1078 as Day 1018;Days >1078 to <= 1198 as Day 1138. The safety population included all subjects who were randomised and received at least 1 dose of study treatment or sham procedure. Here “99999” denotes that data was not evaluable at the given time point for the analysis set ISIS 396443 in Part 2 (subjects on sham in Part 1). “n” is the number of subjects evaluated at specified time point.
    End point type
    Primary
    End point timeframe
    Part 2: Baseline, Day 15, 29, 64, 183, 302, 422, 540, 659, 778, 898, 1018 and 1138
    Notes
    [8] - 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 data was planned to be reported for this endpoint.
    End point values
    		 ISIS 396443 in Part 2 (subjects on sham in Part 1) ISIS 396443 in Part 1 & 2 (subjects on ISIS 396443 in Part 1)
    Number of subjects analysed
    6
    14
    Units: kilogram (kg)
    arithmetic mean (standard deviation)
        Baseline (n=6,14)
    42.5 ( 40.87 )
    25.3 ( 28.41 )
        Change at Day 15 (n=6,14)
    -1.3 ( 1.41 )
    3.6 ( 12.12 )
        Change at Day 29 (n=6,14)
    -2.4 ( 1.61 )
    -1.4 ( 4.82 )
        Change at Day 64 (n=6,14)
    -2.9 ( 2.58 )
    0.5 ( 8.17 )
        Change at Day 183 (n=6,14)
    -3.8 ( 6.93 )
    -5.9 ( 8.73 )
        Change at Day 302 (n=6,14)
    -10.1 ( 13.04 )
    -8.0 ( 15.42 )
        Change at Day 422 (n=6,14)
    -6.3 ( 9.45 )
    -7.5 ( 17.52 )
        Change at Day 540 (n=6,14)
    -7.0 ( 6.56 )
    -8.1 ( 17.26 )
        Change at Day 659 (n=6,14)
    -8.5 ( 17.64 )
    -10.5 ( 22.23 )
        Change at Day 778 (n=0,14)
    99999 ( 99999 )
    -13.2 ( 16.95 )
        Change at Day 898 (n=0,12)
    99999 ( 99999 )
    -10.5 ( 24.10 )
        Change at Day 1018 (n=0,5)
    99999 ( 99999 )
    -7.0 ( 34.14 )
        Change at Day 1138 (n=0,1)
    99999 ( 99999 )
    0.3 ( 0 )
    No statistical analyses for this end point

    Primary: Change from Baseline in Weight for Length

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    End point title
    		 Change from Baseline in Weight for Length [9]
    End point description
    Subjects were analysed for change in growth parameter of weight for length to evaluate clinical efficacy. WHO Child Growth Standards were used to determine the weight for length percentile. Study days were windowed for integrated analysis and labelled as follows: Days <=1 as Baseline;Days >1 to <= 22 as Day 15;Days >22 to <=47 as Day 29;Days >47 to <= 123 as Day 64;Days >123 to <=242 as Day 183;Days >242 to <=362 as Day 302;Days >362 to <=482 as Day 422;Days >482 to <= 600 as Day 540;Days >600 to <= 719 as Day 659;Days >719 to <= 838 as Day 778;Days >838 to <= 958 as Day 898;Days >958 to <= 1078 as Day 1018;Days >1078 to <= 1198 as Day 1138. The safety population included all subjects who were randomised and received at least 1 dose of study treatment or sham procedure. Here “99999” denotes that data was not evaluable at the given time point for the analysis set ISIS 396443 in Part 2 (subjects on sham in Part 1). “n” is the number of subjects evaluated at specified time point.
    End point type
    Primary
    End point timeframe
    Part 2: Baseline, Day 15, 29, 64, 183, 302, 422, 540, 659, 778, 898, 1018 and 1138
    Notes
    [9] - 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 data was planned to be reported for this endpoint.
    End point values
    		 ISIS 396443 in Part 2 (subjects on sham in Part 1) ISIS 396443 in Part 1 & 2 (subjects on ISIS 396443 in Part 1)
    Number of subjects analysed
    6
    14
    Units: kg
    arithmetic mean (standard deviation)
        Baseline (n=6,14)
    13.0 ( 2.00 )
    9.5 ( 1.37 )
        Change at Day 15 (n=6,14)
    -0.1 ( 0.23 )
    0.2 ( 0.44 )
        Change at Day 29 (n=6,14)
    -0.1 ( 0.26 )
    0.1 ( 0.23 )
        Change at Day 64 (n=6,14)
    0.0 ( 0.39 )
    0.4 ( 0.42 )
        Change at Day 183 (n=6,14)
    0.8 ( 0.61 )
    0.7 ( 0.48 )
        Change at Day 302 (n=6,14)
    0.7 ( 1.04 )
    1.3 ( 0.87 )
        Change at Day 422 (n=6,14)
    1.8 ( 1.03 )
    1.9 ( 1.02 )
        Change at Day 540 (n=6,14)
    2.3 ( 1.33 )
    2.2 ( 1.17 )
        Change at Day 659 (n=6,14)
    3.1 ( 1.39 )
    2.8 ( 1.41 )
        Change at Day 778 (n=0,14)
    99999 ( 99999 )
    3.2 ( 1.87 )
        Change at Day 898 (n=0,12)
    99999 ( 99999 )
    3.9 ( 2.86 )
        Change at Day 1018 (n=0,5)
    99999 ( 99999 )
    4.3 ( 1.96 )
        Change at Day 1138 (n=0,1)
    99999 ( 99999 )
    5.0 ( 0 )
    No statistical analyses for this end point

    Primary: Change from Baseline in Head to Chest Circumference (HCC) Ratio

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    End point title
    		 Change from Baseline in Head to Chest Circumference (HCC) Ratio [10]
    End point description
    Subjects were analysed for change in growth parameter of HCC to evaluate clinical efficacy. WHO Child Growth Standards were used to determine the HCC circumference percentile. Study days were windowed for integrated analysis and labelled as follows: Days <=1 as Baseline;Days >1 to <= 22 as Day 15;Days >22 to <=47 as Day 29;Days >47 to <= 123 as Day 64;Days >123 to <=242 as Day 183;Days >242 to <=362 as Day 302;Days >362 to <=482 as Day 422;Days >482 to <= 600 as Day 540;Days >600 to <= 719 as Day 659;Days >719 to <= 838 as Day 778;Days >838 to <= 958 as Day 898;Days >958 to <= 1078 as Day 1018;Days >1078 to <= 1198 as Day 1138. The safety population included all subjects who were randomised and received at least 1 dose of study treatment or sham procedure. Here “99999” denotes that data was not evaluable at the given time point for the analysis set ISIS 396443 in Part 2 (subjects on sham in Part 1). “n” is the number of subjects evaluated at specified time point.
    End point type
    Primary
    End point timeframe
    Part 2: Baseline, Day 15, 29, 64, 183, 302, 422, 540, 659, 778, 898, 1018 and 1138
    Notes
    [10] - 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 data was planned to be reported for this endpoint.
    End point values
    		 ISIS 396443 in Part 2 (subjects on sham in Part 1) ISIS 396443 in Part 1 & 2 (subjects on ISIS 396443 in Part 1)
    Number of subjects analysed
    6
    14
    Units: ratio
    arithmetic mean (standard deviation)
        Baseline (n=6,14)
    1.0 ( 0.05 )
    1.0 ( 0.08 )
        Change at Day 15 (n=5,14)
    0.0 ( 0.03 )
    0.0 ( 0.03 )
        Change at Day 29 (n=6,13)
    0.0 ( 0.04 )
    0.0 ( 0.04 )
        Change at Day 64 (n=6,14)
    0.0 ( 0.04 )
    0.0 ( 0.05 )
        Change at Day 183 (n=6,14)
    0.0 ( 0.05 )
    0.0 ( 0.05 )
        Change at Day 302 (n=6,14)
    0.0 ( 0.03 )
    0.0 ( 0.06 )
        Change at Day 422 (n=6,13)
    0.0 ( 0.04 )
    0.0 ( 0.06 )
        Change at Day 540 (n=6,14)
    0.0 ( 0.03 )
    0.0 ( 0.06 )
        Change at Day 659 (n=6,14)
    0.0 ( 0.03 )
    -0.1 ( 0.06 )
        Change at Day 778 (n=0,14)
    99999 ( 99999 )
    -0.1 ( 0.07 )
        Change at Day 898 (n=0,12)
    99999 ( 99999 )
    -0.1 ( 0.06 )
        Change at Day 1018 (n=0,5)
    99999 ( 99999 )
    -0.1 ( 0.10 )
        Change at Day 1138 (n=0,1)
    99999 ( 99999 )
    -0.1 ( 0 )
    No statistical analyses for this end point

    Primary: Change from Baseline in Body Length

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    End point title
    		 Change from Baseline in Body Length [11]
    End point description
    Subjects were analysed for change in growth parameter of body length to evaluate clinical efficacy. WHO Child Growth Standards were used to determine the body length percentile. Study days were windowed for integrated analysis and labelled as follows: Days <=1 as Baseline;Days >1 to <= 22 as Day 15;Days >22 to <=47 as Day 29;Days >47 to <= 123 as Day 64;Days >123 to <=242 as Day 183;Days >242 to <=362 as Day 302;Days >362 to <=482 as Day 422;Days >482 to <= 600 as Day 540;Days >600 to <= 719 as Day 659;Days >719 to <= 838 as Day 778;Days >838 to <= 958 as Day 898;Days >958 to <= 1078 as Day 1018;Days >1078 to <= 1198 as Day 1138. The safety population included all subjects who were randomised and received at least 1 dose of study treatment or sham procedure. Here “99999” denotes that data was not evaluable at the given time point for the analysis set ISIS 396443 in Part 2 (subjects on sham in Part 1). “n” is the number of subjects evaluated at specified time point.
    End point type
    Primary
    End point timeframe
    Part 2: Baseline, Day 15, 29, 64, 183, 302, 422, 540, 659, 778, 898, 1018 and 1138
    Notes
    [11] - 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 data was planned to be reported for this endpoint.
    End point values
    		 ISIS 396443 in Part 2 (subjects on sham in Part 1) ISIS 396443 in Part 1 & 2 (subjects on ISIS 396443 in Part 1)
    Number of subjects analysed
    6
    14
    Units: cm
    arithmetic mean (standard deviation)
        Baseline (n=6,14)
    95.0 ( 9.48 )
    79.9 ( 5.25 )
        Change at Day 15 (n=5,14)
    -1.6 ( 3.19 )
    -0.1 ( 1.81 )
        Change at Day 29 (n=6,13)
    -0.9 ( 3.49 )
    0.9 ( 1.66 )
        Change at Day 64 (n=6,14)
    0.5 ( 4.77 )
    1.8 ( 2.40 )
        Change at Day 183 (n=6,14)
    3.0 ( 4.16 )
    5.6 ( 2.36 )
        Change at Day 302 (n=6,14)
    2.9 ( 5.76 )
    7.1 ( 2.70 )
        Change at Day 422 (n=6,14)
    4.2 ( 5.42 )
    9.3 ( 3.09 )
        Change at Day 540 (n=6,14)
    4.6 ( 7.18 )
    11.6 ( 3.93 )
        Change at Day 659 (6,14)
    10.8 ( 4.12 )
    13.1 ( 3.79 )
        Change at Day 778 (n=0,14)
    99999 ( 99999 )
    14.8 ( 3.94 )
        Change at Day 898 (n=0,12)
    99999 ( 99999 )
    17.2 ( 5.62 )
        Change at Day 1018 (n=0,5)
    99999 ( 99999 )
    19.0 ( 6.67 )
        Change at Day 1138 (n=0,1)
    99999 ( 99999 )
    15.8 ( 0 )
    No statistical analyses for this end point

    Primary: Number of Subjects with Change from Baseline in Neurological Examination Outcomes

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    End point title
    		 Number of Subjects with Change from Baseline in Neurological Examination Outcomes [12]
    End point description
    Neurological examinations included assessment of mental status, level of consciousness, sensory function, motor function, cranial nerve function, reflexes, mood, speech/language and hearing. The safety population included all subjects who were randomised and received at least 1 dose of study treatment or sham procedure.
    End point type
    Primary
    End point timeframe
    Part 1: Baseline to Day 422; Part 2: Baseline to Day 596
    Notes
    [12] - 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 data was planned to be reported for this endpoint.
    End point values
    		 Sham Procedure in Part 1 ISIS 396443 in Part 2 (subjects on sham in Part 1) ISIS 396443 in Part 1 & 2 (subjects on ISIS 396443 in Part 1)
    Number of subjects analysed
    7
    6
    14
    Units: subjects
        Mental Status
    0
    1
    3
        Level of consciousness
    0
    1
    2
        Sensory function
    0
    0
    0
        Motor function
    0
    0
    0
        Cranial nerve function: Eye Movement
    0
    0
    1
        Cranial nerve function: Vision
    0
    0
    1
        Reflexes
    0
    0
    0
        Mood
    5
    5
    12
        Speech/Language
    0
    1
    1
        Hearing
    0
    0
    0
    No statistical analyses for this end point

    Primary: Number of Subjects with Change From Baseline in Activated Partial Thromboplastin Time [aPTT]

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    End point title
    		 Number of Subjects with Change From Baseline in Activated Partial Thromboplastin Time [aPTT] [13]
    End point description
    Activated partial thromboplastin time was evaluated to assess safety. "Shift to low" measured change in normal, high and unknown values of aPTT at baseline to low values postbaseline. “Shift to high” measured change in normal, high and unknown values of aPTT at baseline to high values postbaseline. The safety population included all subjects who were randomised and received at least 1 dose of study treatment or sham procedure. Here 'n' is the number of subjects whose baseline value was not low (or high) and who had at least one post-baseline.
    End point type
    Primary
    End point timeframe
    Part 2: Up to 1080 days
    Notes
    [13] - 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 data was planned to be reported for this endpoint.
    End point values
    		 ISIS 396443 in Part 2 (subjects on sham in Part 1) ISIS 396443 in Part 1 & 2 (subjects on ISIS 396443 in Part 1)
    Number of subjects analysed
    6
    14
    Units: subjects
        Shift to Low (n=6,9)
    0
    0
        Shift to High (n=6,10)
    0
    0
    No statistical analyses for this end point

    Primary: Number of Subjects with Change From Baseline in Partial Thromboplastin Time [PTT]

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    End point title
    		 Number of Subjects with Change From Baseline in Partial Thromboplastin Time [PTT] [14]
    End point description
    PTT was evaluated to assess safety. "Shift to low" measured change in normal, high and unknown values of PTT at baseline to low values postbaseline. “Shift to high” measured change in normal, high and unknown values of PTT at baseline to high values postbaseline. The safety population included all subjects who were randomised and received at least 1 dose of study treatment or sham procedure. Here 'n' is the number of subjects whose baseline value was not low (or high) and who had at least one post-baseline value.
    End point type
    Primary
    End point timeframe
    Part 2: Up to 1080 days
    Notes
    [14] - 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 data was planned to be reported for this endpoint.
    End point values
    		 ISIS 396443 in Part 2 (subjects on sham in Part 1) ISIS 396443 in Part 1 & 2 (subjects on ISIS 396443 in Part 1)
    Number of subjects analysed
    6
    14
    Units: subjects
        Shift to Low (n=5,6)
    0
    0
        Shift to High (n=5,6)
    0
    0
    No statistical analyses for this end point

    Primary: Number of Subjects With Change From Baseline in International Normalized Ratio [INR])

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    End point title
    		 Number of Subjects With Change From Baseline in International Normalized Ratio [INR]) [15]
    End point description
    INR was evaluated to assess safety. "Shift to low" measured change in normal, high and unknown values of INR at baseline to low values postbaseline. “Shift to high” measured change in normal, high and unknown values of INR at baseline to high values postbaseline. The safety population included all subjects who were randomised and received at least 1 dose of study treatment or sham procedure. Here 'n' is the number of subjects whose baseline value was not low (or high) and who had at least one post-baseline value.
    End point type
    Primary
    End point timeframe
    Part 2: Up to 1080 days
    Notes
    [15] - 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 data was planned to be reported for this endpoint.
    End point values
    		 ISIS 396443 in Part 2 (subjects on sham in Part 1) ISIS 396443 in Part 1 & 2 (subjects on ISIS 396443 in Part 1)
    Number of subjects analysed
    6
    14
    Units: subjects
        Shift to Low (n=4,7)
    0
    0
        Shift to High (n=4,7)
    0
    0
    No statistical analyses for this end point

    Primary: Number of Subjects With Presence of Urine Total Protein Post-baseline

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    End point title
    		 Number of Subjects With Presence of Urine Total Protein Post-baseline [16]
    End point description
    Urine total protein was evaluated to assess safety. The safety population included all subjects who were randomised and received at least 1 dose of study treatment or sham procedure.
    End point type
    Primary
    End point timeframe
    Part 2: Up to 1080 days
    Notes
    [16] - 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 data was planned to be reported for this endpoint.
    End point values
    		 ISIS 396443 in Part 2 (subjects on sham in Part 1) ISIS 396443 in Part 1 & 2 (subjects on ISIS 396443 in Part 1)
    Number of subjects analysed
    6
    14
    Units: subjects
        Baseline
    0
    1
        High/Postive
    2
    8
    No statistical analyses for this end point

    Secondary: Plasma Concentration of ISIS 396443 in Part 2 of Study in Subjects who Received Sham Procedure in Part 1 of the Study

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    End point title
    		 Plasma Concentration of ISIS 396443 in Part 2 of Study in Subjects who Received Sham Procedure in Part 1 of the Study
    End point description
    Study days were windowed for integrated analysis and labelled as follows: Days >47 to <= 123 as Day 64;Days >123 to <=242 as Day 183;Days >482 to <= 600 as Day 540;Days >600 to <= 719 as Day 659. The pharmacokinetic (PK) population included all subjects who were randomised and have at least 1 evaluable post dose or post sham-procedure PK sample.
    End point type
    Secondary
    End point timeframe
    Pre-dose on Days 64, 183, 540 and 659
    End point values
    		 ISIS 396443 in Part 2 (subjects on sham in Part 1)
    Number of subjects analysed
    6
    Units: nanogram per millilitre (ng/mL)
    arithmetic mean (standard deviation)
        Day 64
    1.983 ( 0.7320 )
        Day 183
    0.776 ( 0.3994 )
        Day 540
    0.425 ( 0.2200 )
        Day 659
    0.365 ( 0.1146 )
    No statistical analyses for this end point

    Secondary: Plasma Concentration of ISIS 396443 in Part 1 and 2 of Study in Subjects who Received ISIS 396443 in Part 1 of the Study

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    End point title
    		 Plasma Concentration of ISIS 396443 in Part 1 and 2 of Study in Subjects who Received ISIS 396443 in Part 1 of the Study
    End point description
    Study days were windowed for integrated analysis and labelled as follows: Days >47 to <= 123 as Day 64;Days >123 to <=242 as Day 183;Days >242 to <=362 as Day 302;Days >362 to <=482 as Day 422;Days >482 to <= 600 as Day 540;Days >600 to <= 719 as Day 659;Days >719 to <= 838 as Day 778;Days >838 to <= 958 as Day 898;Days >958 to <= 1078 as Day 1018;Days >1078 to <= 1198 as Day 1138. The PK population included all subjects who were randomised and have at least 1 evaluable post dose or post sham-procedure PK sample. Here "n" is the number of subjects evaluated at the specified time point.
    End point type
    Secondary
    End point timeframe
    Pre-dose on Days 64, 183, 302, 422, 540, 659, 778, 898, 1018 and 1138
    End point values
    		 ISIS 396443 in Part 1 & 2 (subjects on ISIS 396443 in Part 1)
    Number of subjects analysed
    14
    Units: ng/mL
    arithmetic mean (standard deviation)
        Day 64 (n=14)
    2.139 ( 0.8811 )
        Day 183 (n=13)
    1.059 ( 0.5569 )
        Day 302 (n=5)
    0.667 ( 0.1852 )
        Day 422 (n=9)
    0.858 ( 0.4636 )
        Day 540 (n=5)
    0.608 ( 0.2736 )
        Day 659 (n=9)
    0.739 ( 0.2812 )
        Day 778 (n=5)
    0.590 ( 0.3414 )
        Day 898 (n=10)
    0.661 ( 0.2558 )
        Day 1018 (n=4)
    0.329 ( 0.1020 )
        Day 1138 (n=1)
    0.423 ( 0 )
    No statistical analyses for this end point

    Secondary: Cerebrospinal Fluid (CSF) Concentration of ISIS 396443 in Part 2 of Study in Subjects who Received Sham Procedure in Part 1 of the Study

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    End point title
    		 Cerebrospinal Fluid (CSF) Concentration of ISIS 396443 in Part 2 of Study in Subjects who Received Sham Procedure in Part 1 of the Study
    End point description
    CSF samples were analysed for ISIS 396443 concentrations in subjects. Study days were windowed for integrated analysis and labelled as follows: Days >1 to <= 22 as Day 15;Days >22 to <=47 as Day 29;Days >47 to <= 123 as Day 64;Days >123 to <=242 as Day 183;Days >242 to <=362 as Day 302;Days >362 to <=482 as Day 422;Days >482 to <= 600 as Day 540. The PK population included all subjects who were randomised and have at least 1 evaluable post dose or post sham-procedure PK sample. Here "99999" denotes that mean was below the lower limit of quantification (LLOQ) hence standard deviation was not evaluated. LLOQ is 50 picogram per millilitre. "n" is the number of subjects evaluated at the specified time point.
    End point type
    Secondary
    End point timeframe
    Pre-dose on Days 15, 29, 64, 183, 302, 422 and 540
    End point values
    		 ISIS 396443 in Part 2 (subjects on sham in Part 1)
    Number of subjects analysed
    6
    Units: ng/mL
    arithmetic mean (standard deviation)
        Day 1 (n=5)
    99999 ( 99999 )
        Day 15 (n=5)
    3.094 ( 1.2172 )
        Day 29 (n=6)
    4.805 ( 2.6706 )
        Day 64 (n=6)
    4.357 ( 2.3229 )
        Day 183 (n=6)
    4.110 ( 2.4535 )
        Day 302 (n=6)
    5.397 ( 2.7503 )
        Day 422 (n=6)
    6.460 ( 2.9428 )
        Day 540 (n=6)
    8.405 ( 6.2423 )
    No statistical analyses for this end point

    Secondary: CSF Concentration of ISIS 396443 in Part 1 and 2 of Study in Subjects who Received ISIS 396443 in Part 1 of the Study

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    End point title
    		 CSF Concentration of ISIS 396443 in Part 1 and 2 of Study in Subjects who Received ISIS 396443 in Part 1 of the Study
    End point description
    CSF samples were analysed for ISIS 396443 concentrations in subjects. Study days were windowed for integrated analysis and labelled as follows: Days >1 to <= 22 as Day 15;Days >22 to <=47 as Day 29;Days >47 to <= 123 as Day 64;Days >123 to <=242 as Day 183;Days >242 to <=362 as Day 302;Days >362 to <=482 as Day 422;Days >482 to <= 600 as Day 540;Days >600 to <= 719 as Day 659;Days >719 to <= 838 as Day 778;Days >838 to <= 958 as Day 898;Days >958 to <= 1078 as Day 1018. The PK population included all subjects who were randomised and have at least 1 evaluable post dose or post sham-procedure PK sample.Here "99999" denotes that mean was below the lower limit of quantification (LLOQ) hence standard deviation was not evaluated. LLOQ is 50 picogram per millilitre. "n" is the number of subjects evaluated at the specified time point.
    End point type
    Secondary
    End point timeframe
    Pre-dose on Days 15, 29, 64, 183, 302, 422, 540, 659, 778, 898 and 1018
    End point values
    		 ISIS 396443 in Part 1 & 2 (subjects on ISIS 396443 in Part 1)
    Number of subjects analysed
    14
    Units: ng/mL
    arithmetic mean (standard deviation)
        Day 1 (n=8)
    99999 ( 99999 )
        Day 15 (n=13)
    3.925 ( 2.0525 )
        Day 29 (n=14)
    7.273 ( 4.4786 )
        Day 64 (n=14)
    7.176 ( 2.8487 )
        Day 183 (n=14)
    8.226 ( 3.6450 )
        Day 302 (n=13)
    8.968 ( 3.1188 )
        Day 422 (n=13)
    9.251 ( 4.0631 )
        Day 540 (n=14)
    9.026 ( 2.6864 )
        Day 659 (n=14)
    9.785 ( 3.3725 )
        Day 778 (n=13)
    8.632 ( 2.4131 )
        Day 898 (n=8)
    11.321 ( 8.9351 )
        Day 1018 (n=1)
    7.010 ( 0 )
    No statistical analyses for this end point

    Secondary: Number of Subjects with Plasma Antibodies to ISIS 396443

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    End point title
    		 Number of Subjects with Plasma Antibodies to ISIS 396443
    End point description
    The safety population included all subjects who were randomised and received at least 1 dose of study treatment or sham procedure.
    End point type
    Secondary
    End point timeframe
    Part 2: Baseline to Day 596
    End point values
    		 ISIS 396443 in Part 2 (subjects on sham in Part 1) ISIS 396443 in Part 1 & 2 (subjects on ISIS 396443 in Part 1)
    Number of subjects analysed
    6
    14
    Units: subjects
    0
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From start to end of study (up to 1133 days)
    Adverse event reporting additional description
    The safety population included all subjects who were randomised and received at least 1 dose of study treatment or sham procedure.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.0
    Reporting groups
    Reporting group title
    Sham Procedure in Part 1
    Reporting group description
    		 Subjects who received single dose of sham procedure on Day 1, 15, 29, 64, 183 and 302 in Part 1 of the study.

    Reporting group title
    ISIS 396443 in Part 1 & 2 (subjects on ISIS 396443 in Part 1)
    Reporting group description
    		 Subjects who received single dose of ISIS 396443 on Day 1, 15, 29, 64, 183 and 302 in Part 1 of the study and then received single dose of ISIS 396443 on Day 1, 120, 239, 358, 477, 596 and 715 in Part 2 of the study.

    Reporting group title
    ISIS 396443 in Part 2 (subjects on sham in Part 1)
    Reporting group description
    		 Subjects who received single dose of ISIS 396443 on Day 1, 15, 29, 64, 183, 302, 421, 540, 659 and 778 in Part 2.

    Serious adverse events
    		 Sham Procedure in Part 1 ISIS 396443 in Part 1 & 2 (subjects on ISIS 396443 in Part 1) ISIS 396443 in Part 2 (subjects on sham in Part 1)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 7 (42.86%)
    9 / 14 (64.29%)
    4 / 6 (66.67%)
         number of deaths (all causes)
    1
    0
    0
         number of deaths resulting from adverse events
    Injury, poisoning and procedural complications
    Femur fracture
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 14 (0.00%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Cardio-respiratory arrest
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sinus bradycardia
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Hypoxic-ischaemic encephalopathy
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Loss of consciousness
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Brain death
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Dental caries
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 14 (7.14%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 5
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchial secretion retention
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cough
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypoventilation
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 14 (0.00%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    0 / 7 (0.00%)
    3 / 14 (21.43%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory distress
         subjects affected / exposed
    1 / 7 (14.29%)
    2 / 14 (14.29%)
    2 / 6 (33.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 6
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 7 (0.00%)
    2 / 14 (14.29%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Bronchiolitis
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchitis moraxella
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 14 (0.00%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Enterovirus infection
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 14 (0.00%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 14 (7.14%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis norovirus
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis viral
         subjects affected / exposed
    0 / 7 (0.00%)
    2 / 14 (14.29%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Parainfluenzae virus infection
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 14 (7.14%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 7 (0.00%)
    7 / 14 (50.00%)
    3 / 6 (50.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 12
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia haemophilus
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 14 (0.00%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia moraxella
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 14 (0.00%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia pneumococcal
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 14 (0.00%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia respiratory syncytial viral
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 14 (0.00%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory syncytial virus bronchiolitis
         subjects affected / exposed
    0 / 7 (0.00%)
    2 / 14 (14.29%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory syncytial virus infection
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 14 (7.14%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 14 (7.14%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rhinovirus infection
         subjects affected / exposed
    1 / 7 (14.29%)
    2 / 14 (14.29%)
    2 / 6 (33.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Staphylococcal infection
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 14 (0.00%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nasopharyngitis
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 14 (7.14%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Failure to thrive
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolic acidosis
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Sham Procedure in Part 1 ISIS 396443 in Part 1 & 2 (subjects on ISIS 396443 in Part 1) ISIS 396443 in Part 2 (subjects on sham in Part 1)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    6 / 7 (85.71%)
    14 / 14 (100.00%)
    6 / 6 (100.00%)
    Vascular disorders
    Flushing
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    Haematoma
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 14 (7.14%)
    1 / 6 (16.67%)
         occurrences all number
    0
    2
    1
    Hypertension
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    Hypotension
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 14 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    1
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 7 (0.00%)
    2 / 14 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    0
    2
    0
    Complication associated with device
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Influenza like illness
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 14 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    1
    Fatigue
         subjects affected / exposed
    0 / 7 (0.00%)
    2 / 14 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    0
    2
    0
    Oedema peripheral
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    0
    2
    0
    Pyrexia
         subjects affected / exposed
    1 / 7 (14.29%)
    12 / 14 (85.71%)
    4 / 6 (66.67%)
         occurrences all number
    2
    60
    16
    Swelling
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    1
    1
    0
    Seasonal allergy
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Reproductive system and breast disorders
    Penile adhesion
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Aspiration
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    Atelectasis
         subjects affected / exposed
    0 / 7 (0.00%)
    2 / 14 (14.29%)
    1 / 6 (16.67%)
         occurrences all number
    0
    2
    3
    Bronchial secretion retention
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 14 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    1
    Chronic respiratory failure
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Cough
         subjects affected / exposed
    1 / 7 (14.29%)
    11 / 14 (78.57%)
    3 / 6 (50.00%)
         occurrences all number
    2
    31
    13
    Dysphonia
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Dyspnoea
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Epistaxis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 14 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    1
    Hypoventilation
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Hypoxia
         subjects affected / exposed
    2 / 7 (28.57%)
    3 / 14 (21.43%)
    0 / 6 (0.00%)
         occurrences all number
    3
    3
    0
    Increased bronchial secretion
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    Larynx irritation
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    Lower respiratory tract congestion
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 14 (7.14%)
    2 / 6 (33.33%)
         occurrences all number
    0
    3
    4
    Nasal congestion
         subjects affected / exposed
    0 / 7 (0.00%)
    6 / 14 (42.86%)
    2 / 6 (33.33%)
         occurrences all number
    0
    12
    7
    Oropharyngeal pain
         subjects affected / exposed
    0 / 7 (0.00%)
    2 / 14 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    0
    2
    0
    Pneumonia aspiration
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Productive cough
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Pulmonary congestion
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Restrictive pulmonary disease
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Rhinitis allergic
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Rhinorrhoea
         subjects affected / exposed
    0 / 7 (0.00%)
    6 / 14 (42.86%)
    1 / 6 (16.67%)
         occurrences all number
    0
    16
    4
    Sinus congestion
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 14 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    1
    Sleep apnoea syndrome
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    1
    1
    0
    Tachypnoea
         subjects affected / exposed
    0 / 7 (0.00%)
    2 / 14 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    0
    5
    0
    Tonsillar hypertrophy
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 14 (7.14%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    1
    Upper respiratory tract congestion
         subjects affected / exposed
    0 / 7 (0.00%)
    2 / 14 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    0
    2
    0
    Upper-airway cough syndrome
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 14 (7.14%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    1
    Use of accessory respiratory muscles
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Psychiatric disorders
    Dysphemia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 14 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    1
    Intermittent explosive disorder
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    Irritability
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    1
    1
    0
    Product issues
    Device extrusion
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Investigations
    Aspiration bronchial
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 14 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    1
    Blood urea increased
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Bone density decreased
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 14 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    1
    Carnitine decreased
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Enterobacter test positive
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Full blood count increased
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Heart rate increased
         subjects affected / exposed
    0 / 7 (0.00%)
    2 / 14 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    0
    3
    0
    Oxygen saturation decreased
         subjects affected / exposed
    0 / 7 (0.00%)
    2 / 14 (14.29%)
    1 / 6 (16.67%)
         occurrences all number
    0
    4
    2
    Pco2 increased
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Urine output decreased
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Urine output increased
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    Weight decreased
         subjects affected / exposed
    0 / 7 (0.00%)
    2 / 14 (14.29%)
    1 / 6 (16.67%)
         occurrences all number
    0
    2
    1
    Weight increased
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    White blood cell count increased
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Injury, poisoning and procedural complications
    Ankle fracture
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Arthropod bite
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Contusion
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    1
    1
    0
    Fall
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 14 (7.14%)
    2 / 6 (33.33%)
         occurrences all number
    0
    1
    2
    Femur fracture
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 14 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    1
    Incision site erythema
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Incision site pain
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Joint dislocation
         subjects affected / exposed
    0 / 7 (0.00%)
    3 / 14 (21.43%)
    0 / 6 (0.00%)
         occurrences all number
    0
    3
    0
    Laceration
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Muscle strain
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    Procedural pain
         subjects affected / exposed
    0 / 7 (0.00%)
    3 / 14 (21.43%)
    0 / 6 (0.00%)
         occurrences all number
    0
    3
    0
    Procedural vomiting
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    Skin abrasion
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 14 (7.14%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    1
    Stoma site haemorrhage
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Stoma site hypergranulation
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Thermal burn
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Traumatic haematoma
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Upper limb fracture
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Vaccination complication
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Congenital, familial and genetic disorders
    Congenital nystagmus
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Plagiocephaly
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Cardiac disorders
    Bradycardia
         subjects affected / exposed
    0 / 7 (0.00%)
    2 / 14 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    0
    2
    0
    Sinus tachycardia
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Tachycardia
         subjects affected / exposed
    2 / 7 (28.57%)
    3 / 14 (21.43%)
    0 / 6 (0.00%)
         occurrences all number
    2
    4
    0
    Nervous system disorders
    Cranial nerve disorder
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Dysarthria
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 14 (7.14%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    1
    Headache
         subjects affected / exposed
    0 / 7 (0.00%)
    2 / 14 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    0
    2
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 7 (0.00%)
    2 / 14 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    0
    2
    0
    Leukocytosis
         subjects affected / exposed
    0 / 7 (0.00%)
    2 / 14 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    0
    2
    0
    Thrombocytosis
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Ear and labyrinth disorders
    Ear pain
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Eye disorders
    Myopia
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Ocular hyperaemia
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Abdominal pain upper
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Aphthous ulcer
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 14 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    Constipation
         subjects affected / exposed
    1 / 7 (14.29%)
    4 / 14 (28.57%)
    0 / 6 (0.00%)
         occurrences all number
    1
    4
    0
    Dental caries
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Diarrhoea
         subjects affected / exposed
    0 / 7 (0.00%)
    5 / 14 (35.71%)
    1 / 6 (16.67%)
         occurrences all number
    0
    8
    1
    Dyspepsia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 14 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    1
    Dysphagia
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Flatulence
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Gingival pain
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Lip swelling
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Oral contusion
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Salivary hypersecretion
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 14 (7.14%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    1
    Teething
         subjects affected / exposed
    2 / 7 (28.57%)
    2 / 14 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    2
    2
    0
    Vomiting
         subjects affected / exposed
    1 / 7 (14.29%)
    7 / 14 (50.00%)
    2 / 6 (33.33%)
         occurrences all number
    2
    20
    2
    Skin and subcutaneous tissue disorders
    Decubitus ulcer
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Dermatitis contact
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Dermatitis diaper
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Erythema
         subjects affected / exposed
    2 / 7 (28.57%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    2
    3
    0
    Dry skin
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Miliaria
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Petechiae
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Rash
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    0
    3
    0
    Rash erythematous
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Rash generalised
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Rash macular
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    0
    3
    0
    Rash papular
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Skin irritation
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    2
    1
    0
    Urticaria
         subjects affected / exposed
    0 / 7 (0.00%)
    2 / 14 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    0
    5
    0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Urinary retention
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 14 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 14 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    1
    Back pain
         subjects affected / exposed
    0 / 7 (0.00%)
    2 / 14 (14.29%)
    1 / 6 (16.67%)
         occurrences all number
    0
    2
    3
    Hip deformity
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 14 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    1
    Joint contracture
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 14 (7.14%)
    1 / 6 (16.67%)
         occurrences all number
    0
    2
    2
    Joint hyperextension
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    0
    2
    0
    Muscle spasms
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Muscle tightness
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Musculoskeletal pain
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Musculoskeletal stiffness
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Myalgia
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Osteopenia
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 14 (7.14%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    1
    Pain in extremity
         subjects affected / exposed
    0 / 7 (0.00%)
    6 / 14 (42.86%)
    2 / 6 (33.33%)
         occurrences all number
    0
    6
    2
    Scoliosis
         subjects affected / exposed
    0 / 7 (0.00%)
    4 / 14 (28.57%)
    0 / 6 (0.00%)
         occurrences all number
    0
    5
    0
    Spinal pain
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Tendinous contracture
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Torticollis
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Infections and infestations
    Bronchiolitis
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Bronchitis
         subjects affected / exposed
    1 / 7 (14.29%)
    2 / 14 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    1
    2
    0
    Cellulitis
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Conjunctivitis
         subjects affected / exposed
    0 / 7 (0.00%)
    4 / 14 (28.57%)
    0 / 6 (0.00%)
         occurrences all number
    0
    4
    0
    Conjunctivitis bacterial
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Ear infection
         subjects affected / exposed
    0 / 7 (0.00%)
    2 / 14 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    0
    6
    0
    Gastroenteritis
         subjects affected / exposed
    0 / 7 (0.00%)
    5 / 14 (35.71%)
    0 / 6 (0.00%)
         occurrences all number
    0
    5
    0
    Gastroenteritis adenovirus
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Gastroenteritis norovirus
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 14 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    1
    Gastroenteritis viral
         subjects affected / exposed
    0 / 7 (0.00%)
    2 / 14 (14.29%)
    1 / 6 (16.67%)
         occurrences all number
    0
    2
    1
    Hand-foot-and-mouth disease
         subjects affected / exposed
    0 / 7 (0.00%)
    2 / 14 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    0
    2
    0
    Influenza
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 14 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    1
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 7 (0.00%)
    5 / 14 (35.71%)
    1 / 6 (16.67%)
         occurrences all number
    0
    7
    2
    Otitis externa
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Otitis media
         subjects affected / exposed
    0 / 7 (0.00%)
    2 / 14 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    0
    2
    0
    Otitis media acute
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Parainfluenzae virus infection
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 14 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    1
    Pharyngitis streptococcal
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Pneumonia
         subjects affected / exposed
    0 / 7 (0.00%)
    7 / 14 (50.00%)
    2 / 6 (33.33%)
         occurrences all number
    0
    12
    2
    Pneumonia haemophilus
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 14 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    1
    Pneumonia moraxella
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 14 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    1
    Respiratory syncytial virus infection
         subjects affected / exposed
    0 / 7 (0.00%)
    3 / 14 (21.43%)
    1 / 6 (16.67%)
         occurrences all number
    0
    3
    1
    Respiratory tract infection
         subjects affected / exposed
    1 / 7 (14.29%)
    5 / 14 (35.71%)
    1 / 6 (16.67%)
         occurrences all number
    2
    13
    1
    Rhinovirus infection
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    0
    2
    0
    Stoma site infection
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 14 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    1
    Sinusitis
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    0
    2
    0
    Upper respiratory tract infection
         subjects affected / exposed
    2 / 7 (28.57%)
    9 / 14 (64.29%)
    3 / 6 (50.00%)
         occurrences all number
    2
    22
    10
    Urinary tract infection
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    0
    2
    0
    Vaginal infection
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Viral rash
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Viral upper respiratory tract infection
         subjects affected / exposed
    1 / 7 (14.29%)
    5 / 14 (35.71%)
    1 / 6 (16.67%)
         occurrences all number
    1
    14
    2
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    0 / 7 (0.00%)
    2 / 14 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    0
    2
    0
    Dehydration
         subjects affected / exposed
    0 / 7 (0.00%)
    3 / 14 (21.43%)
    0 / 6 (0.00%)
         occurrences all number
    0
    5
    0
    Failure to thrive
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Feeding disorder
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Hyperchloraemia
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Hyperglycaemia
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Hypernatraemia
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Hypochloraemia
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Hypoglycaemia
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Hypokalaemia
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    1
    1
    0
    Hyponatraemia
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Hypophagia
         subjects affected / exposed
    0 / 7 (0.00%)
    2 / 14 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    0
    3
    0
    Metabolic acidosis
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    0
    2
    0
    Weight gain poor
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 14 (7.14%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    05 May 2016
    The protocol was amended to add an open-label extension (OLE) Part 2 phase to provide subjects with SMA the opportunity to receive open-label ISIS 396443 for up to 24 months (or until availability of commercial product) in the event that Part 1 of the study was terminated early (based on emergent data from the ISIS 396443 clinical development program).
    01 Jun 2016
    The Schedule of Assessments for Parts 1 and 2 of the study was updated.
    16 Jun 2017
    The protocol was amended to add safety laboratory assessments for coagulation parameters and renal toxicity as well as efficacy growth parameters. The language regarding the approval of nusinersen in the US and Europe was updated. The Schedule of Events tables were updated to include a window for telephone calls for safety follow up and to make consistent with the rest of the protocol.

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

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