Flag of the European Union EU Clinical Trials Register Help

Clinical trials

The European Union Clinical Trials Register   allows you to search for protocol and results information on:
  • interventional clinical trials that were approved in the European Union (EU)/European Economic Area (EEA) under the Clinical Trials Directive 2001/20/EC
  • clinical trials conducted outside the EU/EEA that are linked to European paediatric-medicine development

  • EU/EEA interventional clinical trials approved under or transitioned to the Clinical Trial Regulation 536/2014 are publicly accessible through the
    Clinical Trials Information System (CTIS).


    The EU Clinical Trials Register currently displays   44334   clinical trials with a EudraCT protocol, of which   7366   are clinical trials conducted with subjects less than 18 years old.   The register also displays information on   18700   older paediatric trials (in scope of Article 45 of the Paediatric Regulation (EC) No 1901/2006).

    Phase 1 trials conducted solely on adults and that are not part of an agreed paediatric investigation plan (PIP) are not publicly available (see Frequently Asked Questions ).  
     
    Examples: Cancer AND drug name. Pneumonia AND sponsor name.
    How to search [pdf]
    Search Tips: Under advanced search you can use filters for Country, Age Group, Gender, Trial Phase, Trial Status, Date Range, Rare Diseases and Orphan Designation. For these items you should use the filters and not add them to your search terms in the text field.
    Advanced Search: Search tools
     

    < Back to search results

    Download PDF

    Clinical Trial Results:
    Escalating Dose and Randomized, Controlled Study of Nusinersen (BIIB058) in Participants With Spinal Muscular Atrophy

    Summary
    EudraCT number
    2019-002663-10
    Trial protocol
    LV   IE   HU   PL   ES   GB   DE   FR   GR   IT   NL  
    Global end of trial date
    30 May 2024

    Results information
    Results version number
    v1(current)
    This version publication date
    13 Dec 2024
    First version publication date
    13 Dec 2024
    Other versions

    Trial information

    Close Top of page
    Trial identification
    Sponsor protocol code
    232SM203
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT04089566
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Biogen
    Sponsor organisation address
    225 Binney Street, Cambridge, Massachusetts, United States, 02142
    Public contact
    Study Medical Director, Biogen, clinicaltrials@biogen.com
    Scientific contact
    Study Medical Director, Biogen, clinicaltrials@biogen.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    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?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    30 May 2024
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    30 May 2024
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objectives of this study are to examine the clinical efficacy of nusinersen administered intrathecally at higher doses to participants with spinal muscular atrophy (SMA), as measured by change in Children's Hospital of Philadelphia-Infant Test of Neuromuscular Disorders (CHOP-INTEND) total score (Part B); to examine the safety and tolerability of nusinersen administered intrathecally at higher doses to participants with SMA (Parts A and C).
    Protection of trial subjects
    Written informed consent was obtained from each subject’s parent or legal guardian prior to evaluations being performed for eligibility. Adequate time to review the information in the informed consent and ask questions concerning all portions of the conduct of the study was provided. Through the informed consent process, awareness of the purpose of the study, the procedures, the benefits and risks of the study, the discomforts and the precautions taken was made. Any side effects or other health issues occurring during the study were followed up by the study doctor. Subjects were able to stop taking part in the study at any time without giving any reason.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    26 Mar 2020
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United States: 23
    Country: Number of subjects enrolled
    Japan: 6
    Country: Number of subjects enrolled
    Germany: 4
    Country: Number of subjects enrolled
    Italy: 4
    Country: Number of subjects enrolled
    Spain: 19
    Country: Number of subjects enrolled
    Canada: 2
    Country: Number of subjects enrolled
    Taiwan: 9
    Country: Number of subjects enrolled
    Estonia: 1
    Country: Number of subjects enrolled
    Mexico: 15
    Country: Number of subjects enrolled
    Saudi Arabia: 15
    Country: Number of subjects enrolled
    China: 11
    Country: Number of subjects enrolled
    Chile: 7
    Country: Number of subjects enrolled
    Brazil: 10
    Country: Number of subjects enrolled
    Poland: 4
    Country: Number of subjects enrolled
    Russian Federation: 8
    Country: Number of subjects enrolled
    Lebanon: 3
    Country: Number of subjects enrolled
    Colombia: 2
    Country: Number of subjects enrolled
    Hungary: 2
    Worldwide total number of subjects
    145
    EEA total number of subjects
    34
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    4
    Infants and toddlers (28 days-23 months)
    71
    Children (2-11 years)
    39
    Adolescents (12-17 years)
    7
    Adults (18-64 years)
    23
    From 65 to 84 years
    1
    85 years and over
    0

    Subject disposition

    Close Top of page
    Recruitment
    Recruitment details
    Participants took part at the investigative sites in the United States, Brazil, Canada, Chile, China, Colombia, Estonia, Germany, Hungary, Italy, Japan, Lebanon, Mexico, Poland, Russia, Saudi Arabia, Spain, and Taiwan from 26 March 2020 to 30 May 2024.

    Pre-assignment
    Screening details
    A total of 145 participants diagnosed with spinal muscular atrophy (SMA)  were enrolled in the 3-parts (Parts A, B, and C). Of which, 117 of participants completed the study.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Part A: 28/28 Milligrams (mg) Nusinersen
    Arm description
    Participants with later-onset SMA received 3 loading doses of 28 mg of nusinersen, intrathecally (IT), on Days 1, 15 and 29 followed by 2 maintenance doses of 28 mg on Days 149 and 269.
    Arm type
    Experimental

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

    Arm title
    Part B: Infantile-Onset SMA: 12/12 mg Nusinersen
    Arm description
    Participants with infantile-onset SMA in the control group received 4 loading doses of 12 mg of nusinersen, IT, on Days 1, 15, 29, and 64 followed by 2 maintenance doses of 12 mg on Days 183 and 279. Sham procedure was administered on Day 135.
    Arm type
    Experimental

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

    Arm title
    Part B: Infantile-Onset SMA: 50/28 mg Nusinersen
    Arm description
    Participants with infantile-onset SMA received 2 loading doses of 50 mg of nusinersen, IT, on Days 1 and 15 followed by 2 maintenance doses of 28 mg on Days 135 and 279. Sham procedure was administered on Days 29, 64 and 183.
    Arm type
    Experimental

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

    Arm title
    Part B: Later-Onset SMA: 12/12 mg Nusinersen
    Arm description
    Participants with later-onset SMA in the control group received 4 loading doses of 12 mg of nusinersen, IT, on Days 1, 15, 29, and 64 followed by 2 maintenance doses of 12 mg on Days 183 and 279. Sham procedure was administered on Day 135.
    Arm type
    Experimental

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

    Arm title
    Part B: Later-Onset SMA: 50/28 mg Nusinersen
    Arm description
    Participants with later-onset SMA received 2 loading doses of 50 mg of nusinersen, IT, on Days 1 and 15 followed by 2 maintenance doses of 28 mg on Days 135 and 279. Sham procedure was administered on Days 29, 64 and 183.
    Arm type
    Experimental

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

    Arm title
    Part C: 50/28 mg Nusinersen
    Arm description
    Participants with infantile and later-onset SMA who had been receiving the approved dose of 12 mg for at least 1 year prior to entry, received a single bolus dose of 50 mg of nusinersen, IT, on Day 1 (4 months after their most recent maintenance dose of 12 mg) followed by 2 maintenance doses of 28 mg on Days 121 and 241.
    Arm type
    Experimental

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

    Number of subjects in period 1
    Part A: 28/28 Milligrams (mg) Nusinersen Part B: Infantile-Onset SMA: 12/12 mg Nusinersen Part B: Infantile-Onset SMA: 50/28 mg Nusinersen Part B: Later-Onset SMA: 12/12 mg Nusinersen Part B: Later-Onset SMA: 50/28 mg Nusinersen Part C: 50/28 mg Nusinersen
    Started
    6
    25
    50
    8
    16
    40
    Completed
    6
    13
    35
    7
    16
    40
    Not completed
    0
    12
    15
    1
    0
    0
         Adverse event, serious fatal
    -
    6
    10
    -
    -
    -
         Withdrawal by Parent or Guardian
    -
    2
    1
    -
    -
    -
         Reason not Specified
    -
    4
    4
    1
    -
    -

    Baseline characteristics

    Close Top of page
    Baseline characteristics reporting groups
    Reporting group title
    Part A: 28/28 Milligrams (mg) Nusinersen
    Reporting group description
    Participants with later-onset SMA received 3 loading doses of 28 mg of nusinersen, intrathecally (IT), on Days 1, 15 and 29 followed by 2 maintenance doses of 28 mg on Days 149 and 269.

    Reporting group title
    Part B: Infantile-Onset SMA: 12/12 mg Nusinersen
    Reporting group description
    Participants with infantile-onset SMA in the control group received 4 loading doses of 12 mg of nusinersen, IT, on Days 1, 15, 29, and 64 followed by 2 maintenance doses of 12 mg on Days 183 and 279. Sham procedure was administered on Day 135.

    Reporting group title
    Part B: Infantile-Onset SMA: 50/28 mg Nusinersen
    Reporting group description
    Participants with infantile-onset SMA received 2 loading doses of 50 mg of nusinersen, IT, on Days 1 and 15 followed by 2 maintenance doses of 28 mg on Days 135 and 279. Sham procedure was administered on Days 29, 64 and 183.

    Reporting group title
    Part B: Later-Onset SMA: 12/12 mg Nusinersen
    Reporting group description
    Participants with later-onset SMA in the control group received 4 loading doses of 12 mg of nusinersen, IT, on Days 1, 15, 29, and 64 followed by 2 maintenance doses of 12 mg on Days 183 and 279. Sham procedure was administered on Day 135.

    Reporting group title
    Part B: Later-Onset SMA: 50/28 mg Nusinersen
    Reporting group description
    Participants with later-onset SMA received 2 loading doses of 50 mg of nusinersen, IT, on Days 1 and 15 followed by 2 maintenance doses of 28 mg on Days 135 and 279. Sham procedure was administered on Days 29, 64 and 183.

    Reporting group title
    Part C: 50/28 mg Nusinersen
    Reporting group description
    Participants with infantile and later-onset SMA who had been receiving the approved dose of 12 mg for at least 1 year prior to entry, received a single bolus dose of 50 mg of nusinersen, IT, on Day 1 (4 months after their most recent maintenance dose of 12 mg) followed by 2 maintenance doses of 28 mg on Days 121 and 241.

    Reporting group values
    Part A: 28/28 Milligrams (mg) Nusinersen Part B: Infantile-Onset SMA: 12/12 mg Nusinersen Part B: Infantile-Onset SMA: 50/28 mg Nusinersen Part B: Later-Onset SMA: 12/12 mg Nusinersen Part B: Later-Onset SMA: 50/28 mg Nusinersen Part C: 50/28 mg Nusinersen Total
    Number of subjects
    6 25 50 8 16 40 145
    Age categorical
    Units: participants
        In Utero
    0 0 0 0 0 0 0
        Preterm newborn infants(gestational age<37 wks)
    0 0 0 0 0 0 0
        Newborns (0-27 days)
    0 1 3 0 0 0 4
        Infants and toddlers (28 days - 23 months)
    0 24 47 0 0 0 71
        Children (2 - 11 years)
    5 0 0 8 16 10 39
        Adolescents (12 - 17 years)
    1 0 0 0 0 6 7
        Adults (18 - 64 years)
    0 0 0 0 0 23 23
        From 65 - 84 years
    0 0 0 0 0 1 1
        85 years and over
    0 0 0 0 0 0 0
    Gender categorical
    Units: participants
        Male
    5 14 26 2 2 25 74
        Female
    1 11 24 6 14 15 71
    Race
    Units: Subjects
        American Indian or Alaska Native
    0 0 2 0 0 0 2
        Asian
    2 4 10 2 5 7 30
        Black or African American
    0 0 0 0 1 0 1
        Native Hawaiian or other Pacific Islander
    0 0 0 0 0 0 0
        White
    4 17 29 3 8 32 93
        Not Reported Due to Confidentiality Regulations
    0 0 2 0 0 0 2
        Other
    0 4 7 3 2 1 17
        Multiple
    0 0 0 0 0 0 0
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    1 10 18 2 6 5 42
        Not Hispanic or Latino
    5 13 30 6 10 35 99
        Not reported
    0 2 2 0 0 0 4
    Subject analysis sets

    Subject analysis set title
    CS3B Matched Sham Control Group
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Historical data of participants who received sham treatment, IT, on Days 1, 15, 29, 64, 183, and 302 in the double-blind, phase 3 study CS3B (2013-004422-29), was used as control in the current study.

    Subject analysis sets values
    CS3B Matched Sham Control Group
    Number of subjects
    20
    Age categorical
    Units: participants
        In Utero
    0
        Preterm newborn infants(gestational age<37 wks)
    0
        Newborns (0-27 days)
    0
        Infants and toddlers (28 days - 23 months)
    0
        Children (2 - 11 years)
    0
        Adolescents (12 - 17 years)
    0
        Adults (18 - 64 years)
    0
        From 65 - 84 years
    0
        85 years and over
    0
    Age continuous
    Units:
        
    ( )
    Gender categorical
    Units: participants
        Male
    0
        Female
    0
    Race
    Units: Subjects
        American Indian or Alaska Native
    0
        Asian
    0
        Black or African American
    0
        Native Hawaiian or other Pacific Islander
    0
        White
    0
        Not Reported Due to Confidentiality Regulations
    0
        Other
    0
        Multiple
    0
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    0
        Not Hispanic or Latino
    0
        Not reported
    0

    End points

    Close Top of page
    End points reporting groups
    Reporting group title
    Part A: 28/28 Milligrams (mg) Nusinersen
    Reporting group description
    Participants with later-onset SMA received 3 loading doses of 28 mg of nusinersen, intrathecally (IT), on Days 1, 15 and 29 followed by 2 maintenance doses of 28 mg on Days 149 and 269.

    Reporting group title
    Part B: Infantile-Onset SMA: 12/12 mg Nusinersen
    Reporting group description
    Participants with infantile-onset SMA in the control group received 4 loading doses of 12 mg of nusinersen, IT, on Days 1, 15, 29, and 64 followed by 2 maintenance doses of 12 mg on Days 183 and 279. Sham procedure was administered on Day 135.

    Reporting group title
    Part B: Infantile-Onset SMA: 50/28 mg Nusinersen
    Reporting group description
    Participants with infantile-onset SMA received 2 loading doses of 50 mg of nusinersen, IT, on Days 1 and 15 followed by 2 maintenance doses of 28 mg on Days 135 and 279. Sham procedure was administered on Days 29, 64 and 183.

    Reporting group title
    Part B: Later-Onset SMA: 12/12 mg Nusinersen
    Reporting group description
    Participants with later-onset SMA in the control group received 4 loading doses of 12 mg of nusinersen, IT, on Days 1, 15, 29, and 64 followed by 2 maintenance doses of 12 mg on Days 183 and 279. Sham procedure was administered on Day 135.

    Reporting group title
    Part B: Later-Onset SMA: 50/28 mg Nusinersen
    Reporting group description
    Participants with later-onset SMA received 2 loading doses of 50 mg of nusinersen, IT, on Days 1 and 15 followed by 2 maintenance doses of 28 mg on Days 135 and 279. Sham procedure was administered on Days 29, 64 and 183.

    Reporting group title
    Part C: 50/28 mg Nusinersen
    Reporting group description
    Participants with infantile and later-onset SMA who had been receiving the approved dose of 12 mg for at least 1 year prior to entry, received a single bolus dose of 50 mg of nusinersen, IT, on Day 1 (4 months after their most recent maintenance dose of 12 mg) followed by 2 maintenance doses of 28 mg on Days 121 and 241.

    Subject analysis set title
    CS3B Matched Sham Control Group
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Historical data of participants who received sham treatment, IT, on Days 1, 15, 29, 64, 183, and 302 in the double-blind, phase 3 study CS3B (2013-004422-29), was used as control in the current study.

    Primary: Part B Infantile-onset SMA: Change From Baseline in CHOP-INTEND Total Score for 50/28mg Nusinersen Versus CS3B Matched Sham Control Group

    Close Top of page
    End point title
    Part B Infantile-onset SMA: Change From Baseline in CHOP-INTEND Total Score for 50/28mg Nusinersen Versus CS3B Matched Sham Control Group [1]
    End point description
    The CHOP-INTEND test was designed to evaluate the motor skills of infants with significant motor weakness. It included 16 items (capturing neck, trunk, and proximal and distal limb strength), nine of which were scored 0, 1, 2, 3, or 4, five were scored as 0, 2, or 4, one was scored as 0, 1, 2, or 4, and one as 0, 2, 3, or 4 with greater scores indicating greater muscle strength. Total score ranged from 0 (worst possible score) and 64 (best possible score). The change from baseline to Day 183 in the CHOP-INTEND total score was compared to CS3B study (2013-004422-29) sham control group using the joint-rank methodology to account for mortality. As stated in protocol a matched sham set was defined for the analysis of this outcome measure. Matched sham set comprised of sham control participants of the CS3B study (2013-004422-29) identified by a matching algorithm and all of 50/28 mg participants in the ITT set.
    End point type
    Primary
    End point timeframe
    Baseline, Day 183
    Notes
    [1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Part B Infantile-onset SMA arms were planned to be analysed for this end point.
    End point values
    Part B: Infantile-Onset SMA: 50/28 mg Nusinersen CS3B Matched Sham Control Group
    Number of subjects analysed
    50
    20
    Units: score on scale
        least squares mean (confidence interval 95%)
    42.9 (38.7 to 47.2)
    16.9 (10.1 to 23.7)
    Statistical analysis title
    Change From Baseline in CHOP-INTEND Total Score
    Comparison groups
    Part B: Infantile-Onset SMA: 50/28 mg Nusinersen v CS3B Matched Sham Control Group
    Number of subjects included in analysis
    70
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [2]
    Method
    ANCOVA
    Parameter type
    Least square (LS) mean difference
    Point estimate
    26.06
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    17.941
         upper limit
    34.172
    Variability estimate
    Standard error of the mean
    Dispersion value
    4.141
    Notes
    [2] - The Analysis of Covariance (ANCOVA) model used rank score as response, treatment as fixed effect and disease duration at screening, baseline HINE 2, baseline CHOP INTEND total score as covariates. Rank score of baseline covariates was used in model.

    Primary: Parts A and C: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (TESAEs)

    Close Top of page
    End point title
    Parts A and C: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (TESAEs) [3] [4]
    End point description
    An adverse event (AE):any unfavorable & unintended sign (including an abnormal assessment such as an abnormal laboratory value), symptom, or disease temporally associated with use of an investigational product, whether or not related to investigational product. SAE:any untoward medical occurrence that at any dose resulted in death, in view of Investigator, placed participant at immediate risk of death, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, resulted in a birth defect. AE and SAEs were regarded as treatment-emergent if it was present prior to receiving first dose of nusinersen in current study and subsequently worsened in severity or was not present prior to receiving first dose of nusinersen and subsequently appeared Part A: safety analysis set. Part C: ITT set. Safety set and ITT set included all participants who received at least one dose of nusinersen in the current study.
    End point type
    Primary
    End point timeframe
    Part A: From the first dose of the study drug up to Day 389, Part C: From the first dose of the study drug up to Day 361
    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 statistics were planned for this endpoint.
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Parts A and C arms were planned to be analysed for this end point.
    End point values
    Part A: 28/28 Milligrams (mg) Nusinersen Part C: 50/28 mg Nusinersen
    Number of subjects analysed
    6
    40
    Units: participants
        TEAEs
    4
    37
        TESAEs
    1
    6
    No statistical analyses for this end point

    Primary: Parts A and C: Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Blood Chemistry Parameters)

    Close Top of page
    End point title
    Parts A and C: Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Blood Chemistry Parameters) [5] [6]
    End point description
    Blood chemistry parameters included protein, albumin, creatinine, blood urea nitrogen, bilirubin (total and direct), alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transferase, glucose, calcium, phosphorus, bicarbonate, chloride, sodium, potassium, cystatin C, and creatine kinase. Parameters were flagged as low, normal/ high relative to normal range/ as unknown if no result was available, by Investigator. Here, shift to low indicates values that were normal, high/ unknown at baseline and shifted to low values postbaseline. Shift to high indicates values that were normal, low or unknown at baseline and shifted to high postbaseline. Categories with at least one participant with shift from baseline are reported. Part A: safety analysis set. Part C: ITT set. Safety and ITT set included all participants who received at least one dose of nusinersen. Number analyzed ‘n’ is number of participants evaluable for analysis of the specified parameter.
    End point type
    Primary
    End point timeframe
    Parts A and C: Baseline up to Day 302
    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 statistics were planned for this endpoint.
    [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Parts A and C arms were planned to be analysed for this end point.
    End point values
    Part A: 28/28 Milligrams (mg) Nusinersen Part C: 50/28 mg Nusinersen
    Number of subjects analysed
    6
    40
    Units: participants
        Alkaline Phosphatase Shift to High (n=6,39)
    1
    2
        Alanine Aminotransferase Shift to High(n=6,34)
    0
    6
        Aspartate Aminotransferase Shift to High (n=6,37)
    0
    8
        Bicarbonate Shift to Low (n=2,31)
    1
    6
        Bicarbonate Shift to High (n=2,40)
    0
    2
        Bilirubin Shift to High (n=6,40)
    0
    1
        Indirect Bilirubin Shift to Low (n=4,26)
    4
    12
        Indirect Bilirubin Shift to High (n=6,40)
    0
    1
        Calcium Shift to High (n=6,39)
    0
    1
        Creatine Kinase Shift to Low (n=6,39)
    0
    0
        Creatine Kinase Shift to High (n=3,22)
    0
    1
        Chloride Shift to Low (n=6,40)
    0
    1
        Creatinine Shift to Low (n=1,2)
    0
    1
        Glucose Shift to Low (n=6,37)
    0
    3
        Glucose Shift to High (n=5,33)
    3
    9
        Potassium Shift to High (n=6,39)
    1
    1
        Phosphate Shift to High (n=5,36)
    2
    10
        Sodium Shift to High (n=6,40)
    0
    1
        Urea Nitrogen Shift to Low (n=6,39)
    0
    1
        Urea Nitrogen Shift to High (n=6,39)
    1
    3
    No statistical analyses for this end point

    Primary: Parts A and C: Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Hematology Parameters)

    Close Top of page
    End point title
    Parts A and C: Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Hematology Parameters) [7] [8]
    End point description
    Hematology parameters included complete blood cell count, with differential and platelet count, and absolute neutrophil count. These parameters were flagged as low, normal, or high relative to parameter’s normal range or as unknown if no result was available, by the Investigator. Here, shift to low indicates values that were normal, high or unknown at baseline and shifted to low values postbaseline. Shift to high indicates values that were normal, low or unknown at baseline and shifted to high postbaseline. The categories with at least one participant with shift from baseline in these parameters are reported. Part A: safety analysis set. Part C: ITT set. Safety set and ITT set included all participants who received at least one dose of nusinersen in the current study. ‘Number analysed (n)’ indicates the number of participants evaluable for the specified hematology parameter.
    End point type
    Primary
    End point timeframe
    Parts A and C: Baseline up to Day 302
    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 statistics were planned for this endpoint.
    [8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Parts A and C arms were planned to be analysed for this end point.
    End point values
    Part A: 28/28 Milligrams (mg) Nusinersen Part C: 50/28 mg Nusinersen
    Number of subjects analysed
    6
    40
    Units: participants
        Basophils Shift to High (n=3,37)
    2
    6
        Basophils/Leukocytes Shift to High(n=2,35)
    2
    6
        Eosinophils Shift to High(n=5,39)
    1
    3
        Eosinophils/Leukocytes Shift to High(n=4,36)
    3
    9
        Hematocrit Shift to Low(n=5,40)
    0
    2
        Hematocrit Shift to High(n=6,40)
    1
    0
        Hemoglobin Shift to Low(n=6,40)
    0
    3
        Lymphocytes Shift to High(n=5,39)
    0
    1
        Lymphocytes/Leukocytes Shift to Low(n=6,39)
    0
    2
        Lymphocytes/Leukocytes Shift to High(n=6,36)
    0
    3
        Monocytes Shift to Low(n=4,39)
    1
    4
        Monocytes/Leukocytes Shift to Low(n=4,35)
    3
    2
        Monocytes/Leukocytes Shift to High(n=6,40)
    0
    2
        Neutrophils Shift to Low(n=6,35)
    0
    5
        Neutrophils Shift to High(n=6,40)
    0
    2
        Neutrophils/Leukocytes Shift to Low (n=5,38)
    1
    4
        Neutrophils/Leukocytes Shift to High(n=6,39)
    0
    2
        Platelets Shift to Low(n=6,39)
    0
    1
        Platelets Shift to High(n=6,40)
    0
    1
        Leukocytes Shift to Low(n=6,36)
    0
    3
        Leukocytes Shift to High(n=6,40)
    0
    3
    No statistical analyses for this end point

    Primary: Parts A and C: Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Urinalysis Parameters)

    Close Top of page
    End point title
    Parts A and C: Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Urinalysis Parameters) [9] [10]
    End point description
    Urinalysis included assessments of urine total protein, specific gravity, pH, protein, glucose, ketones, bilirubin, blood, red blood cells, white blood cells, epithelial cells, bacteria, casts and crystals. These parameters were flagged as low, normal, or high relative to parameter’s normal range or as unknown if no result was available, by the Investigator. Here, shift to low indicates values that were normal, high or unknown at baseline and shifted to low values postbaseline. Shift to high indicates values that were normal, low or unknown at baseline and shifted to high postbaseline. The categories with at least one participant with shift from baseline in these parameters are reported. Part A: safety analysis set. Part C: ITT set. Safety set and ITT set included all participants who received at least one dose of nusinersen in the current study. ‘Number analysed (n)’ indicates the number of participants evaluable for the specified urinalysis parameter.
    End point type
    Primary
    End point timeframe
    Parts A and C: Baseline up to Day 302
    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 statistics were planned for this endpoint.
    [10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Parts A and C arms were planned to be analysed for this end point.
    End point values
    Part A: 28/28 Milligrams (mg) Nusinersen Part C: 50/28 mg Nusinersen
    Number of subjects analysed
    6
    40
    Units: participants
        Specific Gravity Shift to High (n=5,40)
    2
    1
        pH Shift to High (n=6,40)
    0
    2
        Protein High/positive (n=5,38)
    4
    9
        Glucose High/positive (n=6,40)
    0
    2
        Ketones High/positive (n=5,36)
    1
    8
        Occult Blood High/positive (n=6,38)
    2
    4
        RBC High/positive (n=4,12)
    1
    1
        WBC High/positive (n=2,23)
    0
    2
        Epithelial Cells High/positive (n=1,4)
    0
    4
        Bacteria High/positive (n=1,2)
    1
    2
    No statistical analyses for this end point

    Primary: Parts A and C: Number of Participants With Shifts From Baseline in Cerebrospinal Fluid (CSF) Parameters

    Close Top of page
    End point title
    Parts A and C: Number of Participants With Shifts From Baseline in Cerebrospinal Fluid (CSF) Parameters [11] [12]
    End point description
    CSF parameters included cell count, total protein, and glucose. These parameters were flagged as low, normal, or high relative to parameter’s normal range or as unknown if no result was available, by the Investigator. Here, shift to low indicates values that were normal, high or unknown at baseline and shifted to low values postbaseline. Shift to high indicates values that were normal, low or unknown at baseline and shifted to high postbaseline. The categories with at least one participant with shift from baseline in these parameters are reported. Part A: safety analysis set. Part C: ITT set. Safety set and ITT set included all participants who received at least one dose of nusinersen in the current study. ‘Number analysed (n)’ indicates the number of participants evaluable for the specified urinalysis parameter.
    End point type
    Primary
    End point timeframe
    Parts A: Baseline up to Day 269 Parts C: Baseline up to Day 241
    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 statistics were planned for this endpoint.
    [12] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Parts A and C arms were planned to be analysed for this end point.
    End point values
    Part A: 28/28 Milligrams (mg) Nusinersen Part C: 50/28 mg Nusinersen
    Number of subjects analysed
    6
    40
    Units: participants
        Glucose Shift to Low (n=5,38)
    1
    2
        Glucose Shift to High (n=6,38)
    0
    2
        Protein Shift to Low (n=6,39)
    0
    3
        Protein Shift to High (n=6,37)
    0
    8
        Erythrocytes Shift to High (n=5,34)
    2
    8
        Leukocytes Shift to High (n=5,36)
    1
    6
    No statistical analyses for this end point

    Primary: Parts A and C: Number of Participants With Shifts From Baseline in Electrocardiograms (ECGs)

    Close Top of page
    End point title
    Parts A and C: Number of Participants With Shifts From Baseline in Electrocardiograms (ECGs) [13] [14]
    End point description
    The ECGs were assessed by the investigator to be normal, abnormal and abnormal AE. The number of participants with ECG shifts from normal to each of the categorical values denoting an abnormal scan (abnormal not AE, abnormal AE) was assessed. Shift from baseline to worst post-baseline values were reported. The categories with at least one participant with shift from baseline in ECG are reported. Part A: safety analysis set. Part C: ITT set. Safety set and ITT set included all participants who received at least one dose of nusinersen in the current study.
    End point type
    Primary
    End point timeframe
    Parts A and C: Baseline up to Day 302
    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 statistics were planned for this endpoint.
    [14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Parts A and C arms were planned to be analysed for this end point.
    End point values
    Part A: 28/28 Milligrams (mg) Nusinersen Part C: 50/28 mg Nusinersen
    Number of subjects analysed
    6
    40
    Units: participants
        Normal to Normal
    0
    10
        Normal to Abnormal, not AE
    3
    12
        Abnormal, not AE to Abnormal, not AE
    3
    17
        Unknown to Abnormal, not AE
    0
    1
    No statistical analyses for this end point

    Primary: Parts A and C: Number of Participants With Abnormalities in Vital Sign Parameters

    Close Top of page
    End point title
    Parts A and C: Number of Participants With Abnormalities in Vital Sign Parameters [15] [16]
    End point description
    Vital sign assessment included temperature, pulse rate systolic blood pressure, diastolic blood pressure, and respiratory rate. As pre-specified in protocol, the criteria for determining potentially clinically relevant abnormalities in vital signs included: temperature < 36 and > 38 degrees Celsius (C), pulse rate < 60 and > 100 beats per minute (bpm), systolic blood pressure [< 90, > 140 and > 160 millimeters of mercury (mmHg)], diastolic blood pressure < 50, > 90 and > 100 mmHg and respiratory rate < 12 and > 20 breaths per minute. The categories with at least one participant with clinically relevant vital sign abnormalities are reported. Part A: safety analysis set. Part C: ITT set. Safety set and ITT set included all participants who received at least one dose of nusinersen.
    End point type
    Primary
    End point timeframe
    Parts A and C: Baseline up to Day 302
    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 statistics were planned for this endpoint.
    [16] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Parts A and C arms were planned to be analysed for this end point.
    End point values
    Part A: 28/28 Milligrams (mg) Nusinersen Part C: 50/28 mg Nusinersen
    Number of subjects analysed
    6
    40
    Units: participants
        Temperature <36.0 C
    4
    13
        Pulse rate <60 bpm
    1
    14
        Pulse rate >100 bpm
    6
    19
        Systolic blood pressure <90 mmHg
    4
    13
        Systolic blood pressure >140 mmHg
    0
    3
        Diastolic blood pressure <50 mmHg
    3
    10
        Diastolic blood pressure >90 mmHg
    1
    7
        Respiratory rate <12 breaths/min
    0
    1
        Respiratory rate >20 breaths/min
    6
    27
    No statistical analyses for this end point

    Primary: Parts A and C: Change From Baseline in Growth Parameters (Ulnar Length)

    Close Top of page
    End point title
    Parts A and C: Change From Baseline in Growth Parameters (Ulnar Length) [17] [18]
    End point description
    As pre-specified in the protocol, ulnar length was measured for participants with later-onset SMA. Part A: Safety set included all participants who received at least one dose of nusinersen. Part C:ITT set included all participants who received at least one a dose of nusinersen in the current study. ‘Subjects analysed' signifies number of participants evaluable in this endpoint.
    End point type
    Primary
    End point timeframe
    Parts A and C: Baseline, Day 302
    Notes
    [17] - 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 statistics were planned for this endpoint.
    [18] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Parts A and C arms were planned to be analysed for this end point.
    End point values
    Part A: 28/28 Milligrams (mg) Nusinersen Part C: 50/28 mg Nusinersen
    Number of subjects analysed
    6
    27
    Units: cm
        arithmetic mean (standard deviation)
    1.8 ( 1.43 )
    0.0 ( 1.27 )
    No statistical analyses for this end point

    Primary: Part C: Change From Baseline in Growth Parameters (Arm Circumference)

    Close Top of page
    End point title
    Part C: Change From Baseline in Growth Parameters (Arm Circumference) [19] [20]
    End point description
    As pre-specified in the protocol, arm circumference was measured for participants with infantile-onset SMA. ‘99999’ signifies that since only one participant was evaluable, standard deviation (SD) was not estimated. ITT set included all participants who received at least one dose of nusinersen in the current study. ‘Subjects analysed' signifies number of participants evaluable in this endpoint.
    End point type
    Primary
    End point timeframe
    Baseline, Day 302
    Notes
    [19] - 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 statistics were planned for this endpoint.
    [20] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Part C arm was planned to be analysed for this end point.
    End point values
    Part C: 50/28 mg Nusinersen
    Number of subjects analysed
    1
    Units: cm
        arithmetic mean (standard deviation)
    -1.0 ( 99999 )
    No statistical analyses for this end point

    Primary: Part C: Change From Baseline in Growth Parameters (Chest Circumference)

    Close Top of page
    End point title
    Part C: Change From Baseline in Growth Parameters (Chest Circumference) [21] [22]
    End point description
    As pre-specified in protocol, chest circumference was measured for participants with infantile-onset SMA only. ‘99999’ signifies that since only one participant was evaluable, standard deviation (SD) was not estimated. ITT set included all participants who received at least one dose of nusinersen in the current study. ‘Subjects analysed' signifies number of participants evaluable in this endpoint.
    End point type
    Primary
    End point timeframe
    Baseline, Day 302
    Notes
    [21] - 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 statistics were planned for this endpoint.
    [22] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Part C arm was planned to be analysed for this end point.
    End point values
    Part C: 50/28 mg Nusinersen
    Number of subjects analysed
    1
    Units: cm
        arithmetic mean (standard deviation)
    2.5 ( 99999 )
    No statistical analyses for this end point

    Primary: Part C: Change From Baseline in Growth Parameters (Head Circumference)

    Close Top of page
    End point title
    Part C: Change From Baseline in Growth Parameters (Head Circumference) [23] [24]
    End point description
    As pre-specified in the protocol, head circumference was measured for participants with infantile-onset SMA only. ITT set included all participants who received at least one a dose of nusinersen in the current study. ‘99999’ signifies that since only one participant was evaluable, standard deviation (SD) was not estimated. ‘Subjects analysed' signifies number of participants evaluable in this endpoint.
    End point type
    Primary
    End point timeframe
    Baseline, Day 302
    Notes
    [23] - 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 statistics were planned for this endpoint.
    [24] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Part C arm was planned to be analysed for this end point.
    End point values
    Part C: 50/28 mg Nusinersen
    Number of subjects analysed
    1
    Units: cm
        arithmetic mean (standard deviation)
    2.0 ( 99999 )
    No statistical analyses for this end point

    Primary: Parts A and C: Change From Baseline in Growth Parameters (Body Height)

    Close Top of page
    End point title
    Parts A and C: Change From Baseline in Growth Parameters (Body Height) [25] [26]
    End point description
    Part A: safety analysis set. Part C: ITT set. Safety set and ITT set included all participants who received at least one dose of nusinersen in the current study. ‘Subjects analysed' signifies number of participants evaluable in this endpoint.
    End point type
    Primary
    End point timeframe
    Parts A and C: Baseline, Day 302
    Notes
    [25] - 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 statistics were planned for this endpoint.
    [26] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Parts A and C arms were planned to be analysed for this end point.
    End point values
    Part A: 28/28 Milligrams (mg) Nusinersen Part C: 50/28 mg Nusinersen
    Number of subjects analysed
    2
    32
    Units: centimeters (cm)
        arithmetic mean (standard deviation)
    7.2 ( 1.70 )
    0.8 ( 3.12 )
    No statistical analyses for this end point

    Primary: Parts A and C: Number of Participants With Shifts from Baseline in Coagulation Parameters (Activated Partial Thromboplastin Time (aPTT))

    Close Top of page
    End point title
    Parts A and C: Number of Participants With Shifts from Baseline in Coagulation Parameters (Activated Partial Thromboplastin Time (aPTT)) [27] [28]
    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. Part A: Safety set included all participants who received at least one dose of nusinersen. Part C:ITT set included all participants who received at least one a dose of nusinersen in the current study. ‘Number analysed (n)' signifies number of participants evaluable for this outcome measure
    End point type
    Primary
    End point timeframe
    Parts A and C: Baseline up to Day 269
    Notes
    [27] - 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 statistics were planned for this endpoint.
    [28] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Parts A and C arms were planned to be analysed for this end point.
    End point values
    Part A: 28/28 Milligrams (mg) Nusinersen Part C: 50/28 mg Nusinersen
    Number of subjects analysed
    6
    40
    Units: participants
        Shift to Low (n=6,40)
    0
    5
        Shift to High (n=5,36)
    0
    1
    No statistical analyses for this end point

    Primary: Parts A and C: Number of Participants With Shifts From Baseline in Coagulation Parameters (Prothrombin Time (PT))

    Close Top of page
    End point title
    Parts A and C: Number of Participants With Shifts From Baseline in Coagulation Parameters (Prothrombin Time (PT)) [29] [30]
    End point description
     Prothrombin time was evaluated to assess safety. "Shift to low" measured change in normal, high and unknown values of  PT at baseline to low values postbaseline. "Shift to high" measured change in normal, high and unknown values of PT at baseline to high values postbaseline. Part A: Safety set included all participants who received at least one dose of nusinersen. Part C:ITT set included all participants who received at least one a dose of nusinersen in the current study. ‘Number analysed (n)' signifies number of participants evaluable for this outcome measure.
    End point type
    Primary
    End point timeframe
    Parts A and C: Baseline up to Day 269
    Notes
    [29] - 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 statistics were planned for this endpoint.
    [30] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Parts A and C arms were planned to be analysed for this end point.
    End point values
    Part A: 28/28 Milligrams (mg) Nusinersen Part C: 50/28 mg Nusinersen
    Number of subjects analysed
    6
    40
    Units: participants
        Shift to Low (n=6,34)
    0
    0
        Shift to High (n=6,32)
    0
    1
    No statistical analyses for this end point

    Primary: Parts A and C: Change From Baseline in Growth Parameters (Weight for Length Ratio)

    Close Top of page
    End point title
    Parts A and C: Change From Baseline in Growth Parameters (Weight for Length Ratio) [31] [32]
    End point description
    Part A: Safety set included all participants who received at least one dose of nusinersen. Part C:ITT set included all participants who received at least one dose of nusinersen in the current study.
    End point type
    Primary
    End point timeframe
    Parts A and C: Baseline, Day 302
    Notes
    [31] - 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 statistics were planned for this endpoint.
    [32] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Parts A and C arms were planned to be analysed for this end point.
    End point values
    Part A: 28/28 Milligrams (mg) Nusinersen Part C: 50/28 mg Nusinersen
    Number of subjects analysed
    0 [33]
    0 [34]
    Units: ratio
        arithmetic mean (standard deviation)
    ( )
    ( )
    Notes
    [33] - As the number of subjects analyzed was zero, mean and SD was not calculated.
    [34] - As the number of subjects analyzed was zero, mean and SD was not calculated.
    No statistical analyses for this end point

    Primary: Parts A and C: Change From Baseline in Growth Parameters (Weight for Age Percentile)

    Close Top of page
    End point title
    Parts A and C: Change From Baseline in Growth Parameters (Weight for Age Percentile) [35] [36]
    End point description
    WHO child growth standards (WHO Child Growth Standards, 2006) was used to calculate the weight for age percentile in the infantile-onset participants. The 2000 CDC Growth Charts was used to calculate the weight for age percentile for later-onset participants. Part A: Safety set included all participants who received at least one dose of nusinersen. Part C:ITT set included all participants who received at least one dose of nusinersen in the current study. ‘Subjects analysed' signifies number of participants evaluable in this endpoint.
    End point type
    Primary
    End point timeframe
    Parts A and C: Baseline, Day 302
    Notes
    [35] - 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 statistics were planned for this endpoint.
    [36] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Parts A and C arms were planned to be analysed for this end point.
    End point values
    Part A: 28/28 Milligrams (mg) Nusinersen Part C: 50/28 mg Nusinersen
    Number of subjects analysed
    6
    17
    Units: percentile
        arithmetic mean (standard deviation)
    12.2 ( 12.84 )
    -2.7 ( 9.47 )
    No statistical analyses for this end point

    Primary: Part C: Change From Baseline in Growth Parameters (Head-to-Chest Circumference Ratio)

    Close Top of page
    End point title
    Part C: Change From Baseline in Growth Parameters (Head-to-Chest Circumference Ratio) [37] [38]
    End point description
    As pre-specified in the protocol, head to chest circumference ratio was assessed only for the participants with infantile-onset SMA. ‘99999’ signifies that since one or no participant was evaluable, standard deviation (SD) was not estimated. ITT set included all participants who received at least one dose of nusinersen in the current study. ‘Subjects analysed' signifies number of participants evaluable in this endpoint.
    End point type
    Primary
    End point timeframe
    Baseline, Day 302
    Notes
    [37] - 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 statistics were planned for this endpoint.
    [38] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Part C arm was planned to be analysed for this end point.
    End point values
    Part C: 50/28 mg Nusinersen
    Number of subjects analysed
    1
    Units: ratio
        arithmetic mean (standard deviation)
    0.0 ( 99999 )
    No statistical analyses for this end point

    Primary: Parts A and C: Number of Participants With Shifts From Baseline in Coagulation Parameters (International Normalized Ratio (INR))

    Close Top of page
    End point title
    Parts A and C: Number of Participants With Shifts From Baseline in Coagulation Parameters (International Normalized Ratio (INR)) [39] [40]
    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 category with at least one participant with shift from baseline in INR ratio is reported. Part A: Safety set included all participants who received at least one dose of nusinersen. Part C:ITT set included all participants who received at least one a dose of nusinersen in the current study. ‘Number analysed (n)' signifies number of participants evaluable for this outcome measure.
    End point type
    Primary
    End point timeframe
    Parts A and C: Baseline up to Day 269
    Notes
    [39] - 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 statistics were planned for this endpoint.
    [40] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Parts A and C arms were planned to be analysed for this end point.
    End point values
    Part A: 28/28 Milligrams (mg) Nusinersen Part C: 50/28 mg Nusinersen
    Number of subjects analysed
    6
    40
    Units: participants
        Shift to Low (n=6,40)
    0
    3
        Shift to High (n=6,39)
    0
    0
    No statistical analyses for this end point

    Primary: Parts A and C: Change From Baseline in Urine Total Protein

    Close Top of page
    End point title
    Parts A and C: Change From Baseline in Urine Total Protein [41] [42]
    End point description
    Part A: Safety set included all participants who received at least one dose of nusinersen. Part C:ITT set included all participants who received at least one dose of nusinersen in the current study. 'Subjects analysed' signifies number of participants evaluable in this endpoint.
    End point type
    Primary
    End point timeframe
    Parts A and C: Baseline, Day 302
    Notes
    [41] - 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 statistics were planned for this endpoint.
    [42] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Parts A and C arms were planned to be analysed for this end point.
    End point values
    Part A: 28/28 Milligrams (mg) Nusinersen Part C: 50/28 mg Nusinersen
    Number of subjects analysed
    3
    29
    Units: grams per liter (g/L)
        arithmetic mean (standard deviation)
    0.010 ( 0.1235 )
    -0.692 ( 3.7040 )
    No statistical analyses for this end point

    Primary: Parts A and C: Number of Participants With Neurological Examination Abnormalities Reported as AEs

    Close Top of page
    End point title
    Parts A and C: Number of Participants With Neurological Examination Abnormalities Reported as AEs [43] [44]
    End point description
    Participants with abnormalities in neurological examinations recorded as AEs were reported.
    End point type
    Primary
    End point timeframe
    Parts A and C: Baseline up to Day 302
    Notes
    [43] - 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 statistics were planned for this endpoint.
    [44] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Parts A and C arms were planned to be analysed for this end point.
    End point values
    Part A: 28/28 Milligrams (mg) Nusinersen Part C: 50/28 mg Nusinersen
    Number of subjects analysed
    6
    40
    Units: participants
    number (not applicable)
        Vestibular Disorder
    0
    1
        Asthenia
    0
    1
        Gait Disturbance
    0
    1
        Balance Disorder
    0
    1
        Disturbance in Attention
    0
    1
        Paraesthesia
    1
    0
    No statistical analyses for this end point

    Primary: Parts A and C: Percentage of Participants With a Postbaseline Corrected QT Interval Using Fridericia's Formula (QTcF) of > 500 milliseconds (msec) and an Increase From Baseline to any Postbaseline Timepoint in QTcF of > 60 msec

    Close Top of page
    End point title
    Parts A and C: Percentage of Participants With a Postbaseline Corrected QT Interval Using Fridericia's Formula (QTcF) of > 500 milliseconds (msec) and an Increase From Baseline to any Postbaseline Timepoint in QTcF of > 60 msec [45] [46]
    End point description
    As a part of safety assessment, QTcF was evaluated for determining the incidence of clinically relevant abnormalities. Post baseline QTcF of > 500 msec and maximum increase from baseline to post baseline QTcF > 60 msec was considered as a criteria for clinically relevant abnormality in ECG. Part A: Safety set included all participants who received at least one dose of nusinersen. Part C:ITT set included all participants who received at least one dose of nusinersen in the current study. 'Subjects analysed' signifies number of participants evaluable in this endpoint.
    End point type
    Primary
    End point timeframe
    Parts A and C: Baseline up to Day 302
    Notes
    [45] - 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 statistics were planned for this endpoint.
    [46] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Parts A and C arms were planned to be analysed for this end point.
    End point values
    Part A: 28/28 Milligrams (mg) Nusinersen Part C: 50/28 mg Nusinersen
    Number of subjects analysed
    6
    39
    Units: percentage of participants
    number (not applicable)
        Maximum Increase from Baseline QTcF>60msec
    0
    0
        Maximum Post Baseline QTcF > 500 msec
    0
    0
    No statistical analyses for this end point

    Primary: Parts A and C: Percentage of Participants With a Postbaseline Platelet Count Below the Lower Limit of Normal on at Least 2 Consecutive Measurements

    Close Top of page
    End point title
    Parts A and C: Percentage of Participants With a Postbaseline Platelet Count Below the Lower Limit of Normal on at Least 2 Consecutive Measurements [47] [48]
    End point description
    Part A: Safety set included all participants who received at least one dose of nusinersen. Part C:ITT set included all participants who received at least one a dose of nusinersen in the current study.
    End point type
    Primary
    End point timeframe
    Parts A and C: Baseline up to Day 302
    Notes
    [47] - 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 statistics were planned for this endpoint.
    [48] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Parts A and C arms were planned to be analysed for this end point.
    End point values
    Part A: 28/28 Milligrams (mg) Nusinersen Part C: 50/28 mg Nusinersen
    Number of subjects analysed
    6
    40
    Units: percentage of participants
        number (not applicable)
    0
    2.5
    No statistical analyses for this end point

    Secondary: Part B Infantile-onset SMA: Percentage of Hammersmith Infant Neurological Examination (HINE) Section 2 Motor Milestone Responders for 50/28mg Nusinersen Versus CS3B Matched Sham Control Group

    Close Top of page
    End point title
    Part B Infantile-onset SMA: Percentage of Hammersmith Infant Neurological Examination (HINE) Section 2 Motor Milestone Responders for 50/28mg Nusinersen Versus CS3B Matched Sham Control Group [49]
    End point description
    Section 2 of HINE was used to assess motor milestones of participants. It’s composed of 8 motor milestone categories: voluntary grasp, ability to kick in supine position, head control, rolling, sitting, crawling, standing, & walking. Motor milestone responder: a participant that demonstrated atleast a 2-point increase in ability to kick category or increase to maximal score on that category or a 1-point increase in motor milestones category of head control, rolling, sitting, crawling, standing, or walking & demonstrated improvement in more categories than worsening. Participants who died or withdrew from study were considered as non-responders. A matched sham set was defined per protocol for analysis of this outcome measure. Matched sham set comprised of sham control participants of CS3B study (2013-004422-29) identified by a matching algorithm& all of 50/28 mg participants in the ITT set.
    End point type
    Secondary
    End point timeframe
    Baseline up to Day 183
    Notes
    [49] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Part B Infantile-onset SMA arms were planned to be analysed for this end point.
    End point values
    Part B: Infantile-Onset SMA: 50/28 mg Nusinersen CS3B Matched Sham Control Group
    Number of subjects analysed
    41
    9
    Units: percentage of responders
    number (not applicable)
        Ability to kick: At least a 2-point increase
    18
    0
        Ability to kick: Achievement of touching toes
    8
    0
        Head control: at least a 1-point increase
    46
    0
        Rolling: at least a 1-point increase
    28
    0
        Sitting: at least a 1-point increase
    30
    0
        Crawling: at least a 1-point increase
    6
    0
        Standing: at least a 1-point increase
    14
    0
        Walking: at least a 1-point increase
    0
    0
        Improvement in more categories than worsening
    58
    0
    No statistical analyses for this end point

    Secondary: Part B Infantile-onset SMA: Change From (Ratio to) Baseline in Plasma Concentration of Neurofilament Light Chain (NF-L) for 50/28mg Nusinersen Versus CS3B Matched Sham Control Group

    Close Top of page
    End point title
    Part B Infantile-onset SMA: Change From (Ratio to) Baseline in Plasma Concentration of Neurofilament Light Chain (NF-L) for 50/28mg Nusinersen Versus CS3B Matched Sham Control Group [50]
    End point description
    The change from baseline in the plasma concentration of NF-L was compared to the study CS3B (2013-004422-29) matched sham control group. Joint rank methodology was used for the analysis to account for mortality. The change from baseline data was reported in terms of least square geometric mean ratio to baseline. Lower ratios to baseline represent greater reductions in concentrations of NF-L from baseline. As stated in protocol a matched sham set was defined for the analysis of this outcome measure. Matched sham set comprised of sham control participants of the CS3B study (2013-004422-29) identified by a matching algorithm and all of 50/28 mg participants in the ITT set.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 183
    Notes
    [50] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Part B Infantile-onset SMA arms were planned to be analysed for this end point.
    End point values
    Part B: Infantile-Onset SMA: 50/28 mg Nusinersen CS3B Matched Sham Control Group
    Number of subjects analysed
    50
    20
    Units: ratio
        least squares mean (confidence interval 95%)
    0.06 (0.05 to 0.06)
    0.70 (0.43 to 1.12)
    Statistical analysis title
    Change From Baseline in NF-L Plasma Concentration
    Comparison groups
    Part B: Infantile-Onset SMA: 50/28 mg Nusinersen v CS3B Matched Sham Control Group
    Number of subjects included in analysis
    70
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [51]
    Method
    ANCOVA
    Parameter type
    LS geometric mean ratio
    Point estimate
    0.08
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.05
         upper limit
    0.14
    Notes
    [51] - ANCOVA model was used with treatment as a fixed effect and adjustment for each participant disease duration at screening, baseline log plasma NF-L and baseline CHOP INTEND total score.

    Secondary: Part B Infantile-onset SMA: Change From Baseline in HINE Section 2 Motor Milestones Total Score for 50/28mg Nusinersen Versus CS3B Matched Sham Control Group

    Close Top of page
    End point title
    Part B Infantile-onset SMA: Change From Baseline in HINE Section 2 Motor Milestones Total Score for 50/28mg Nusinersen Versus CS3B Matched Sham Control Group [52]
    End point description
    Section 2 of the HINE was used to assess motor milestones of the participants. It’s composed of 8 motor milestone categories: voluntary grasp, ability to kick in supine position, head control, rolling, sitting, crawling, standing, and walking. Within each category, 3 to 5 levels can be achieved. The total HINE section 2 motor milestones score was calculated as sum of each level & ranged from 0 to 26, higher score indicating improvement in motor milestones. A negative change from baseline indicates decline in motor milestones.Change from baseline in HINE section 2 motor milestones total score was compared to study CS3B (2013-004422-29) matched sham control group, was analysed using joint rank methodology. As stated in protocol a matched sham set was defined for analysis of this outcome measure. Matched sham set comprised of sham control participants of CS3B study (2013-004422-29) identified by a matching algorithm and all of 50/28 mg participants in ITT set.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 183
    Notes
    [52] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Part B Infantile-onset SMA arms were planned to be analysed for this end point.
    End point values
    Part B: Infantile-Onset SMA: 50/28 mg Nusinersen CS3B Matched Sham Control Group
    Number of subjects analysed
    50
    20
    Units: score on scale
        least squares mean (confidence interval 95%)
    43.1 (39.0 to 47.2)
    16.5 (9.9 to 23.0)
    Statistical analysis title
    Change From Baseline in HINE Section Total Score
    Comparison groups
    Part B: Infantile-Onset SMA: 50/28 mg Nusinersen v CS3B Matched Sham Control Group
    Number of subjects included in analysis
    70
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [53]
    Method
    ANCOVA
    Parameter type
    Least squares mean difference
    Point estimate
    26.67
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    18.812
         upper limit
    34.526
    Variability estimate
    Standard error of the mean
    Dispersion value
    4.009
    Notes
    [53] - ANCOVA model was used, rank score as response, treatment as fixed effect and disease duration at screening, baseline HINE 2, baseline CHOP INTEND total score as covariates. Rank score of baseline covariates was used in model.

    Secondary: Part B Infantile-onset SMA: Change From Baseline in CHOP-INTEND Total Score for 50/28mg Nusinersen Versus 12/12mg Nusinersen

    Close Top of page
    End point title
    Part B Infantile-onset SMA: Change From Baseline in CHOP-INTEND Total Score for 50/28mg Nusinersen Versus 12/12mg Nusinersen [54]
    End point description
    The CHOP-INTEND test was designed to evaluate the motor skills of infants with significant motor weakness. It included 16 items (capturing neck, trunk, and proximal and distal limb strength), nine of which were scored 0, 1, 2, 3, or 4, five were scored as 0, 2, or 4, one was scored as 0, 1, 2, or 4, and one as 0, 2, 3, or 4 with greater scores indicating greater muscle strength. Total scores ranged from 0 (worst possible score) and 64 (best possible score). The change from baseline to Day 302 in the CHOP-INTEND total score was analyzed using the joint-rank methodology to account for mortality. ITT set included all participants who were randomized and received at least one dose of nusinersen.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 302
    Notes
    [54] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Part B Infantile-onset SMA arms were planned to be analysed for this end point.
    End point values
    Part B: Infantile-Onset SMA: 12/12 mg Nusinersen Part B: Infantile-Onset SMA: 50/28 mg Nusinersen
    Number of subjects analysed
    25
    50
    Units: score on scale
        least squares mean (confidence interval 95%)
    37.3 (29.1 to 45.5)
    38.3 (32.7 to 44.0)
    Statistical analysis title
    Change From Baseline in CHOP INTEND Total Score
    Comparison groups
    Part B: Infantile-Onset SMA: 12/12 mg Nusinersen v Part B: Infantile-Onset SMA: 50/28 mg Nusinersen
    Number of subjects included in analysis
    75
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.8484 [55]
    Method
    ANCOVA
    Parameter type
    Least squares mean difference
    Point estimate
    1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -9.29
         upper limit
    11.299
    Variability estimate
    Standard error of the mean
    Dispersion value
    5.251
    Notes
    [55] - ANCOVA model used rank score as response, treatment as fixed effect and disease duration at screening, baseline HINE 2, baseline CHOP INTEND total score as covariates. Rank score of baseline covariates was used in model.

    Secondary: Part B Infantile-onset SMA: Change From Baseline in HINE Section 2 Motor Milestones Total Score for 50/28mg Nusinersen Versus 12/12mg Nusinersen

    Close Top of page
    End point title
    Part B Infantile-onset SMA: Change From Baseline in HINE Section 2 Motor Milestones Total Score for 50/28mg Nusinersen Versus 12/12mg Nusinersen [56]
    End point description
    Section 2 of the HINE was used to assess motor milestones of the participants. It’s composed of 8 motor milestone categories: voluntary grasp, ability to kick in supine position, head control, rolling, sitting, crawling, standing, and walking. Within each of these categories, participants can progress from complete absence of a motor ability (the lowest level in each category) through multiple milestones (2 to 4 levels in each category) to the highest level within the category. The total motor milestones score for HINE section was calculated as the sum of each level and ranged from 0 to a maximum score of 26, higher score indicating improvement in motor milestones. ITT set included all participants who were randomized and received at least one dose of nusinersen.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 302
    Notes
    [56] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Part B Infantile-onset SMA arms were planned to be analysed for this end point.
    End point values
    Part B: Infantile-Onset SMA: 12/12 mg Nusinersen Part B: Infantile-Onset SMA: 50/28 mg Nusinersen
    Number of subjects analysed
    25
    50
    Units: score on scale
        least squares mean (confidence interval 95%)
    33.9 (26.9 to 41.0)
    40.0 (35.1 to 44.9)
    Statistical analysis title
    Change From Baseline in HINE Section Total Score
    Comparison groups
    Part B: Infantile-Onset SMA: 12/12 mg Nusinersen v Part B: Infantile-Onset SMA: 50/28 mg Nusinersen
    Number of subjects included in analysis
    75
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1734 [57]
    Method
    ANCOVA
    Parameter type
    Least squares mean difference
    Point estimate
    6.12
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.693
         upper limit
    14.939
    Variability estimate
    Standard error of the mean
    Dispersion value
    4.497
    Notes
    [57] - ANCOVA model used rank score as response, treatment as fixed effect and disease duration at screening, baseline HINE 2, baseline CHOP INTEND total score as covariates. Rank score of baseline covariates was used in model.

    Secondary: Part B Infantile-onset SMA: Change From (Ratio to) Baseline in Plasma Concentration of NF-L for 50/28mg Nusinersen Versus 12/12mg Nusinersen

    Close Top of page
    End point title
    Part B Infantile-onset SMA: Change From (Ratio to) Baseline in Plasma Concentration of NF-L for 50/28mg Nusinersen Versus 12/12mg Nusinersen [58]
    End point description
    The change from baseline in plasma concentration of NF-L was analysed using the joint rank methodology to account for mortality. The change from baseline data was reported in terms of LS geometric mean ratio to baseline. Lower ratios to baseline represent greater reductions in concentrations of NF-L from baseline. ITT set included all participants who were randomized and received at least one dose of nusinersen.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 64
    Notes
    [58] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Part B Infantile-onset SMA arms were planned to be analysed for this end point.
    End point values
    Part B: Infantile-Onset SMA: 12/12 mg Nusinersen Part B: Infantile-Onset SMA: 50/28 mg Nusinersen
    Number of subjects analysed
    25
    50
    Units: ratio
        least squares mean (confidence interval 95%)
    0.23 (0.16 to 0.32)
    0.12 (0.09 to 0.15)
    Statistical analysis title
    Change From Baseline in NF-L Plasma Concentration
    Comparison groups
    Part B: Infantile-Onset SMA: 12/12 mg Nusinersen v Part B: Infantile-Onset SMA: 50/28 mg Nusinersen
    Number of subjects included in analysis
    75
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.002 [59]
    Method
    ANCOVA
    Parameter type
    LS geometric mean ratio
    Point estimate
    0.51
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.33
         upper limit
    0.78
    Notes
    [59] - ANCOVA model was used with treatment as a fixed effect and adjustment for each participant disease duration at screening, baseline log plasma NF-L and baseline CHOP INTEND total score.

    Secondary: Part B Infantile-onset SMA: Time to Death or Permanent Ventilation for 50/28mg Nusinersen Versus CS3B Matched Sham Control Group

    Close Top of page
    End point title
    Part B Infantile-onset SMA: Time to Death or Permanent Ventilation for 50/28mg Nusinersen Versus CS3B Matched Sham Control Group [60]
    End point description
    Permanent ventilation was defined as tracheostomy or ≥ 16 hours of ventilation/day continuously for > 21 days in absence of an acute reversible event. An independent endpoint adjudication committee (EAC) determined date at which a participant was considered to have met protocol-specified criteria of an acute reversible event. Only events that were adjudicated by the EAC as meeting the criteria for permanent ventilation or death were included in analysis. As stated in protocol a matched sham set was defined for analysis of this outcome measure. Matched sham set comprised of sham control participants of the CS3B study (2013-004422-29) identified by a matching algorithm and all of 50/28 mg participants in the ITT set. ‘99999’ signifies that median and upper range of 95% confidence interval (CI) were not estimable due to low number events of permanent ventilation or death.
    End point type
    Secondary
    End point timeframe
    Screening up to Day 399
    Notes
    [60] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Part B Infantile-onset SMA arms were planned to be analysed for this end point.
    End point values
    Part B: Infantile-Onset SMA: 50/28 mg Nusinersen CS3B Matched Sham Control Group
    Number of subjects analysed
    50
    20
    Units: weeks
        median (confidence interval 95%)
    99999 (39.86 to 99999)
    19.1 (10.00 to 31.29)
    No statistical analyses for this end point

    Secondary: Part B Infantile-onset SMA: Time to Death (Overall Survival) for 50/28mg Nusinersen Versus CS3B Matched Sham Control Group

    Close Top of page
    End point title
    Part B Infantile-onset SMA: Time to Death (Overall Survival) for 50/28mg Nusinersen Versus CS3B Matched Sham Control Group [61]
    End point description
    Time to death was determined by an independent EAC. Time to death (overall survival) was compared to the study CS3B (2013-004422-29) matched sham control group. As stated in protocol a matched sham set was defined for the analysis of this outcome measure. Matched sham set comprised of sham control participants of the CS3B study (2013-004422-29) identified by a matching algorithm and all of 50/28 mg participants in the ITT set. ‘99999’ signifies that median and 95% CI were not estimable due to low number of events of death.
    End point type
    Secondary
    End point timeframe
    Screening up to Day 399
    Notes
    [61] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Part B Infantile-onset SMA arms were planned to be analysed for this end point.
    End point values
    Part B: Infantile-Onset SMA: 50/28 mg Nusinersen CS3B Matched Sham Control Group
    Number of subjects analysed
    50
    20
    Units: weeks
        median (confidence interval 95%)
    99999 (99999 to 99999)
    33.6 (11.29 to 99999)
    No statistical analyses for this end point

    Secondary: Part B Later-onset SMA: Change From Baseline in Revised Upper Limb Module (RULM) Score for 50/28mg Nusinersen Versus 12/12mg Nusinersen

    Close Top of page
    End point title
    Part B Later-onset SMA: Change From Baseline in Revised Upper Limb Module (RULM) Score for 50/28mg Nusinersen Versus 12/12mg Nusinersen [62]
    End point description
    The RULM test was used in participants with later-onset SMA to assess upper limb functional ability items that are reflective of activities of daily living (i.e., raise a can to mouth as if drinking, take a coin and place it in a box, remove the lid of a container). The RULM test had a total of 20 items with an entry item that served as functional class identification and did not contribute to the total score. The remaining 19 scorable items reflected different functional domains and were graded on a 3-point system with a score of 0 (unable), 1 (able, with modification), and a maximum of 2 (able, no difficulty). Scorable items were summed for a total score range of 0-37, with higher scores indicating increased upper limb function. ITT set included all participants who were randomized and received at least one dose of nusinersen. ‘Subjects analysed' signifies number of participants evaluable at the specified timepoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 302
    Notes
    [62] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Part B Later-onset SMA arms were planned to be analysed for this end point.
    End point values
    Part B: Later-Onset SMA: 12/12 mg Nusinersen Part B: Later-Onset SMA: 50/28 mg Nusinersen
    Number of subjects analysed
    7
    16
    Units: score on scale
        least squares mean (confidence interval 95%)
    1.8 (-0.8 to 4.4)
    2.5 (0.7 to 4.2)
    No statistical analyses for this end point

    Secondary: Part B Infantile-onset SMA: Time to Death or Permanent Ventilation for 50/28mg Nusinersen Versus 12/12mg Nusinersen

    Close Top of page
    End point title
    Part B Infantile-onset SMA: Time to Death or Permanent Ventilation for 50/28mg Nusinersen Versus 12/12mg Nusinersen [63]
    End point description
    Permanent ventilation was defined as tracheostomy or ≥ 16 hours of ventilation/day continuously for > 21 days in the absence of an acute reversible event. An independent EAC determined the date at which a participant was considered to have met the protocol-specified criteria of an acute reversible event. Only events that were adjudicated by the EAC as meeting the protocol defined criteria for permanent ventilation or death was included in the analysis. ITT set included all participants who were randomized and received at least one dose of nusinersen. ‘ 99999’ signifies that median or upper range of 95% confidence interval (CI) were not estimable due to low number events of permanent ventilation or death.
    End point type
    Secondary
    End point timeframe
    Screening up to Day 399
    Notes
    [63] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Part B Infantile-onset SMA arms were planned to be analysed for this end point.
    End point values
    Part B: Infantile-Onset SMA: 12/12 mg Nusinersen Part B: Infantile-Onset SMA: 50/28 mg Nusinersen
    Number of subjects analysed
    25
    50
    Units: weeks
        median (confidence interval 95%)
    24.7 (14.43 to 99999)
    99999 (39.86 to 99999)
    No statistical analyses for this end point

    Secondary: Part B Infantile-onset SMA: Time to Death (Overall Survival) for 50/28mg Nusinersen Versus 12/12mg Nusinersen

    Close Top of page
    End point title
    Part B Infantile-onset SMA: Time to Death (Overall Survival) for 50/28mg Nusinersen Versus 12/12mg Nusinersen [64]
    End point description
    Time to death was determined by an independent EAC. ITT set included all participants who were randomized and received at least one dose of nusinersen. ‘99999’ signifies that median and 95% CI was not estimable due to low number events of death.
    End point type
    Secondary
    End point timeframe
    Screening up to Day 399
    Notes
    [64] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Part B Infantile-onset SMA arms were planned to be analysed for this end point.
    End point values
    Part B: Infantile-Onset SMA: 12/12 mg Nusinersen Part B: Infantile-Onset SMA: 50/28 mg Nusinersen
    Number of subjects analysed
    25
    50
    Units: weeks
        median (confidence interval 95%)
    99999 (24.71 to 99999)
    99999 (99999 to 99999)
    No statistical analyses for this end point

    Secondary: Part B Later-onset SMA: Change From Baseline in Hammersmith Functional Motor Scale Expanded (HFMSE) Score for 50/28mg Nusinersen Versus 12/12mg Nusinersen

    Close Top of page
    End point title
    Part B Later-onset SMA: Change From Baseline in Hammersmith Functional Motor Scale Expanded (HFMSE) Score for 50/28mg Nusinersen Versus 12/12mg Nusinersen [65]
    End point description
    HFMSE scale was a tool used to assess motor function in children with later-onset SMA. The original 20 item Hammersmith Functional Motor Scale was expanded to include 13 additional adapted items from the Gross Motor Function Measure to improve sensitivity for the higher functioning ambulant population. Each item is scored 0 (unable), 1 (performs with modification or adaptation) or 2 (able) and the total score was calculated by summing the 33 items and ranged from 0 to 66 with higher scores indicating greater motor function. ITT set included all participants who were randomized and received at least one dose of nusinersen. ‘Subjects analysed' signifies number of participants evaluable in this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 302
    Notes
    [65] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Part B Later-onset SMA arms were planned to be analysed for this end point.
    End point values
    Part B: Later-Onset SMA: 12/12 mg Nusinersen Part B: Later-Onset SMA: 50/28 mg Nusinersen
    Number of subjects analysed
    7
    15
    Units: score on scale
        least squares mean (confidence interval 95%)
    2.6 (0.2 to 5.1)
    3.3 (1.5 to 5.0)
    No statistical analyses for this end point

    Secondary: Part B Later-onset SMA: Number of New World Health Organization (WHO) Motor Milestones for 50/28mg Nusinersen Versus 12/12mg Nusinersen

    Close Top of page
    End point title
    Part B Later-onset SMA: Number of New World Health Organization (WHO) Motor Milestones for 50/28mg Nusinersen Versus 12/12mg Nusinersen [66]
    End point description
    The WHO motor milestones were a set of six milestones in motor development: sitting without support, standing with assistance, hands and knees crawling, walking with assistance, standing alone and walking alone. The examiner recorded an overall rating of the participant’s emotional state and then for each milestone one of the following four classifications: no (inability) - child tried but failed to perform the milestone, no (refusal) - child refused to perform despite being calm and alert, yes - child was able to perform the milestone, unable to test - could not be tested because of irritability, drowsiness or sickness. Mean of number of new milestones achieved was calculated and reported in this outcome measure. ITT set included all participants who were randomized and received at least one dose of nusinersen. ‘Subjects analysed' signifies number of participants evaluable for this outcome measure.
    End point type
    Secondary
    End point timeframe
    Baseline up to Day 302
    Notes
    [66] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Part B Later-onset SMA arms were planned to be analysed for this end point.
    End point values
    Part B: Later-Onset SMA: 12/12 mg Nusinersen Part B: Later-Onset SMA: 50/28 mg Nusinersen
    Number of subjects analysed
    7
    16
    Units: motor milestones
        arithmetic mean (standard deviation)
    0.0 ( 0.00 )
    0.3 ( 1.00 )
    No statistical analyses for this end point

    Secondary: Part B Later-onset SMA: Change From Baseline in Assessment of Caregiver Experience with Neuromuscular Disease (ACEND) for 50/28mg Nusinersen Versus 12/12mg Nusinersen

    Close Top of page
    End point title
    Part B Later-onset SMA: Change From Baseline in Assessment of Caregiver Experience with Neuromuscular Disease (ACEND) for 50/28mg Nusinersen Versus 12/12mg Nusinersen [67]
    End point description
    This assessment instrument was designed to quantify the caregiver impact experienced by parents/caregivers of children affected with severe neuromuscular diseases, including children with SMA. ACEND included domains assessing physical impact (including feeding/grooming/dressing, sitting/play, transfers, and mobility) and general caregiver impact (including time, emotion, and finance) and each domain comprises several items. The total score ranges from 0 to 100 with a higher score indicating decreased caregiver burden A negative change from baseline indicates an increase in impact on caregiver. ITT set included all participants who were randomized and received at least one dose of nusinersen. ‘Subjects analysed' signifies number of participants evaluable for the specified parameter.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 302
    Notes
    [67] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Part B Later-onset SMA arms were planned to be analysed for this end point.
    End point values
    Part B: Later-Onset SMA: 12/12 mg Nusinersen Part B: Later-Onset SMA: 50/28 mg Nusinersen
    Number of subjects analysed
    7
    16
    Units: score on scale
    least squares mean (confidence interval 95%)
        Feeding/Grooming/Dressing Total Score
    7.9 (-4.8 to 20.6)
    8.3 (-0.2 to 16.7)
        Sitting/Play Total Score
    10.3 (0.6 to 20.0)
    10.1 (3.6 to 16.6)
        Transfers Total Score
    -0.0 (-10.9 to 10.9)
    9.9 (2.6 to 17.2)
        Mobility Total Score
    6.9 (-7.2 to 20.9)
    8.1 (-0.9 to 17.0)
        Time Total Score
    -4.4 (-17.9 to 9.2)
    11.9 (2.9 to 20.9)
        Emotion Total Score
    2.6 (-8.7 to 13.9)
    2.5 (-5.0 to 10.0)
        Finance Total Score
    -7.7 (-20.9 to 5.6)
    7.8 (-0.7 to 31.7)
    No statistical analyses for this end point

    Secondary: Part B Later-onset SMA: Change From Baseline in Pediatric Quality of Life Inventory™ (PedsQL) for 50/28mg Nusinersen Versus 12/12mg Nusinersen

    Close Top of page
    End point title
    Part B Later-onset SMA: Change From Baseline in Pediatric Quality of Life Inventory™ (PedsQL) for 50/28mg Nusinersen Versus 12/12mg Nusinersen [68]
    End point description
    PedsQL was used to measure health related quality of life (HRQOL) in children & adolescents. PedsQL generic core scale included assessment of physical functioning, emotional functioning, social functioning, and school functioning [PedsQL Inventory total score (PQLI)] and PedsQL Neuromuscular Module [Neuromuscular total score (PQLN)] measured HRQOL dimensions specific to with neuromuscular disorders, including SMA. Four dimensions were collected,each item scored on a 5-point ordinal scale (0=Never to 4=Almost Always). Items were reversed scored and were linearly transformed to a 0-100 scale. Total scale score was calculated as sum of all items over number of items answered on all scales. If more than 50% of items or more were missing, scale score was not computed. Higher scores indicated better health related quality of life. ITT set. Subjects analysed: number of participants evaluable for this endpoint. ‘Number analysed (n)':number of participants evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 302
    Notes
    [68] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Part B Later-onset SMA arms were planned to be analysed for this end point.
    End point values
    Part B: Later-Onset SMA: 12/12 mg Nusinersen Part B: Later-Onset SMA: 50/28 mg Nusinersen
    Number of subjects analysed
    7
    16
    Units: score on scale
    least squares mean (standard error)
        PQLI-Total Score-Subject (n=4,12)
    -5.1 ( 4.73 )
    3.8 ( 2.61 )
        PQLI-Total Score-Parent (n=7,14)
    -9.6 ( 4.32 )
    -6.9 ( 2.96 )
        PQLN-Total Score-Subject (n=4,12)
    -4.8 ( 3.41 )
    10.4 ( 1.91 )
        PQLN-Total Score-Parent (n=7,16)
    -6.4 ( 4.25 )
    -0.7 ( 2.81 )
    No statistical analyses for this end point

    Secondary: Part B Later-onset SMA: Change From (Ratio to) Baseline in CSF Concentration of NF-L for 50/28mg Nusinersen Versus 12/12mg Nusinersen

    Close Top of page
    End point title
    Part B Later-onset SMA: Change From (Ratio to) Baseline in CSF Concentration of NF-L for 50/28mg Nusinersen Versus 12/12mg Nusinersen [69]
    End point description
    The change from baseline data was reported in terms of geometric mean ratio to baseline. Lower ratios to baseline represent greater reductions in concentrations of NF-L from baseline. ITT set included all participants who were randomized and received at least one dose of nusinersen. ‘Subjects analysed' signifies number of participants evaluable in this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 279
    Notes
    [69] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Part B Later-onset SMA arms were planned to be analysed for this end point.
    End point values
    Part B: Later-Onset SMA: 12/12 mg Nusinersen Part B: Later-Onset SMA: 50/28 mg Nusinersen
    Number of subjects analysed
    7
    16
    Units: pg/mL
        geometric mean (confidence interval 95%)
    0.34 (0.23 to 0.50)
    0.34 (0.25 to 0.45)
    No statistical analyses for this end point

    Secondary: Part B Later-onset SMA: Change From (Ratio to) Baseline in Plasma Concentration of NF-L for 50/28mg Nusinersen Versus 12/12mg Nusinersen

    Close Top of page
    End point title
    Part B Later-onset SMA: Change From (Ratio to) Baseline in Plasma Concentration of NF-L for 50/28mg Nusinersen Versus 12/12mg Nusinersen [70]
    End point description
    The change from baseline data was reported in terms of geometric mean ratio to baseline. Lower ratios to baseline represent greater reductions in concentrations of NF-L from baseline. ITT set included all participants who were randomized and received at least one dose of nusinersen. ‘Subjects analysed' signifies number of participants evaluable in this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 302
    Notes
    [70] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Part B Later-onset SMA arms were planned to be analysed for this end point.
    End point values
    Part B: Later-Onset SMA: 12/12 mg Nusinersen Part B: Later-Onset SMA: 50/28 mg Nusinersen
    Number of subjects analysed
    5
    16
    Units: pg/mL
        geometric mean (confidence interval 95%)
    0.28 (0.14 to 0.56)
    0.35 (0.24 to 0.51)
    No statistical analyses for this end point

    Secondary: Part B: Number of Participants with TEAEs and TESAEs

    Close Top of page
    End point title
    Part B: Number of Participants with TEAEs and TESAEs [71]
    End point description
    AE was any unfavorable and unintended sign (including an abnormal assessment such as an abnormal laboratory value), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product. An SAE was any untoward medical occurrence that at any dose resulted in death, in the view of the Investigator, placed the participant at immediate risk of death, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, resulted in a birth defect. AE was regarded as treatment-emergent if it was present prior to receiving the first dose of nusinersen in the current study and subsequently worsened in severity or was not present prior to receiving the first dose of nusinersen and subsequently appeared. Safety set included all participants who received at least one dose of nusinersen.
    End point type
    Secondary
    End point timeframe
    From the first dose of the study drug up to Day 399
    Notes
    [71] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Part B Infantile-onset SMA and Part B Later-onset SMA arms were planned to be analysed for this end point.
    End point values
    Part B: Infantile-Onset SMA: 12/12 mg Nusinersen Part B: Infantile-Onset SMA: 50/28 mg Nusinersen Part B: Later-Onset SMA: 12/12 mg Nusinersen Part B: Later-Onset SMA: 50/28 mg Nusinersen
    Number of subjects analysed
    25
    50
    8
    16
    Units: participants
        TEAEs
    22
    45
    7
    14
        TESAEs
    18
    30
    4
    2
    No statistical analyses for this end point

    Secondary: Part B: Number of Participants with Shifts from Baseline in Clinical Laboratory Parameters (Hematology Parameters)

    Close Top of page
    End point title
    Part B: Number of Participants with Shifts from Baseline in Clinical Laboratory Parameters (Hematology Parameters) [72]
    End point description
    Hematology parameters included complete blood cell count, with differential and platelet count, and absolute neutrophil count. These parameters were flagged as low, normal, or high relative to parameter’s normal range or as unknown if no result was available, by the Investigator. Here, shift to low indicates values that were normal, high or unknown at baseline and shifted to low values postbaseline. Shift to high indicates values that were normal, low or unknown at baseline and shifted to high postbaseline. The categories with at least one participant with shift from baseline in these parameters are reported. ‘Number analysed (n)' signifies number of participants evaluable for analysis of the specified hematology parameter.
    End point type
    Secondary
    End point timeframe
    Baseline up to Day 302
    Notes
    [72] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Part B Infantile-onset SMA and Part B Later-onset SMA arms were planned to be analysed for this end point.
    End point values
    Part B: Infantile-Onset SMA: 12/12 mg Nusinersen Part B: Infantile-Onset SMA: 50/28 mg Nusinersen Part B: Later-Onset SMA: 12/12 mg Nusinersen Part B: Later-Onset SMA: 50/28 mg Nusinersen
    Number of subjects analysed
    25
    50
    8
    16
    Units: participants
        Basophils Shift to Low (n=22,46,8,16)
    0
    2
    0
    0
        Basophils Shift to High (n=12,24,5,13)
    7
    17
    4
    8
        Basophils/Leukocytes Shift to High (n=11,21,4,9)
    7
    14
    3
    9
        Eosinophils Shift to Low (n=20,47,7,16)
    0
    7
    1
    0
        Eosinophils Shift to High (n=19,43,5,14)
    6
    15
    0
    1
        Eosinophil/Leukocyte Shift toLow(n=21,47,8,16)
    0
    4
    0
    0
        Eosinophil/Leukocyte Shift to High(n=15,28,5,12)
    8
    12
    1
    5
        Hematocrit Shift to Low (n=20,43,8,16)
    6
    12
    0
    2
        Hematocrit Shift to High (n=22,47,8,15)
    4
    10
    2
    1
        Hemoglobin Shift to Low (n=22,45,7,14)
    11
    18
    0
    2
        Hemoglobin Shift to High (n=23,46,8,16)
    3
    2
    0
    0
        Lymphocytes Shift to Low (n=22,47,8,16)
    3
    6
    1
    1
        Lymphocytes Shift to High (n=19,41,7,14)
    4
    14
    2
    2
        Lymphocyte Atypical Shift to High(n=1,7,8,16)
    0
    5
    0
    0
        LymphocyteAtypical/LeukocyteShifttoHighn=1,7,8,16
    0
    4
    0
    0
        Lymphocyte/Leukocyte Shift to Low(n=22,45,8,16)
    4
    5
    1
    2
        Lymphocyte/Leukocyte Shift to High(n=20,43,7,16)
    4
    7
    3
    1
        Ery Mean Corpuscular Vol Shift to Lown=5,10,8,16
    2
    2
    0
    0
        Ery Mean Corpuscular Vol Shift to Highn=4,8,8,16
    1
    2
    0
    0
        Monocytes Shift to Low (n=22,46,7,15)
    5
    12
    1
    6
        Monocytes Shift to High (n=20,42,8,16)
    5
    13
    2
    2
        Monocytes/Leukocytes Shift to Low (n=21,44,6,14)
    7
    20
    1
    9
        Monocytes/Leukocytes Shift to High n=20,45,8,16
    3
    9
    1
    1
        Neutrophils Shift to Low (n=19,42,5,16)
    5
    9
    1
    2
        Neutrophils Shift to High (n=21,46,8,16)
    11
    13
    1
    1
        Neutrophils/Leukocytes Shift to Low n=19,39,7,16
    4
    13
    4
    0
        Neutrophils/Leukocytes ShifttoHigh n=21,45,7,16
    6
    6
    1
    1
        Platelets Shift to Low (n=23,47, 8,16)
    1
    2
    0
    1
        Platelets Shift to High (n=10,28,6,15)
    4
    14
    1
    4
        Erythrocytes Shift to Low (n=23,46,6,15
    4
    10
    0
    0
        Erythrocytes Shift to High (n=22,47,8,13)
    3
    6
    1
    0
        Leukocytes Shift to Low (n=21,44,8,16)
    4
    13
    2
    0
        Leukocytes Shift to High (n=21,41,7,15)
    10
    15
    1
    2
    No statistical analyses for this end point

    Secondary: Part B: Number of Participants with Shifts from Baseline in Clinical Laboratory Parameters (Blood Chemistry Parameters)

    Close Top of page
    End point title
    Part B: Number of Participants with Shifts from Baseline in Clinical Laboratory Parameters (Blood Chemistry Parameters) [73]
    End point description
    Blood chemistry parameters included protein, albumin, creatinine, blood urea nitrogen, bilirubin (total and direct), alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transferase, glucose, calcium, phosphorus, bicarbonate, chloride, sodium, potassium, cystatin C, and creatine kinase. Parameters were flagged as low, normal, or high relative to parameter’s normal range or as unknown if no result was available, by the Investigator. Here, shift to low indicates values that were normal, high or unknown at baseline and shifted to low values postbaseline. Shift to high indicates values that were normal, low or unknown at baseline and shifted to high postbaseline. Categories with at least one participant with shift from baseline in these parameters are reported. Safety set included all participants who received at least a dose of nusinersen. ‘Number analysed (n)' signifies number of participants evaluable for analysis of the specified parameter.
    End point type
    Secondary
    End point timeframe
    Baseline up to Day 302
    Notes
    [73] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Part B Infantile-onset SMA and Part B Later-onset SMA arms were planned to be analysed for this end point.
    End point values
    Part B: Infantile-Onset SMA: 12/12 mg Nusinersen Part B: Infantile-Onset SMA: 50/28 mg Nusinersen Part B: Later-Onset SMA: 12/12 mg Nusinersen Part B: Later-Onset SMA: 50/28 mg Nusinersen
    Number of subjects analysed
    25
    50
    8
    16
    Units: participants
        Albumin Shift to Low (n=20,46,8,15)
    6
    13
    1
    1
        Albumin Shift to High (n=23,50,8,16)
    1
    2
    0
    0
        Alkaline Phosphatase Shift to Low (n=23,50,8,16)
    0
    3
    0
    0
        Alkaline Phosphatase Shift to High (n=23,50,8,16)
    3
    3
    0
    0
        Alanine AminotransferaseShift to Low n=23,50,8,16
    0
    0
    0
    1
        Alanine AminotransferaseShift to Highn=14,39,6,15
    4
    14
    0
    3
        AspartateAminotransferaseShifttoHigh n=21,45,7,16
    5
    9
    0
    1
        Bicarbonate Shift to Low (n=5,14,3,4)
    4
    12
    3
    4
        Bicarbonate Shift to High (n=22,49,8,16)
    1
    1
    0
    0
        Direct Bilirubin Shift to Low (n=22,45,8,16)
    1
    0
    0
    0
        Bilirubin Shift to Low (n=21,49,8,16)
    2
    2
    0
    1
        Bilirubin Shift to High (n=20,45,8,16)
    1
    1
    0
    0
        Indirect Bilirubin Shift to Low (n=22,46,2,4)
    11
    21
    2
    3
        Calcium Shift to Low (n=23,50,8,15)
    1
    4
    2
    1
        Calcium Shift to High (n=19,45,8,15)
    8
    17
    0
    0
        Creatine Kinase Shift to High (n=14,27,6,10)
    6
    12
    3
    3
        Chloride Shift to Low (n=23,50,8,16)
    3
    3
    0
    1
        Chloride Shift to High (n=23,48,7,16)
    3
    6
    1
    1
        Creatinine Shift to Low (n=2,5,0,1)
    2
    5
    0
    1
        Creatinine Shift to High (n=23,50,8,16)
    0
    1
    0
    0
        Cystatin C Shift to Low(n=23,48,8,16)
    2
    0
    1
    1
        Cystatin C Shift to High(n=23,48,8,16)
    2
    1
    0
    0
        Gamma GlutamylTransferase ShifttoLown=18,45,8,16
    7
    11
    0
    1
        GammaGlutamylTransferase ShifttoHighn=23,49,8,16
    2
    5
    0
    3
        Glucose Shift to Low(n=23,49,8,16)
    0
    2
    0
    1
        Glucose Shift to High(n=20,44,7,15)
    6
    17
    2
    6
        Potassium Shift to Low(n=23,50,8,16)
    1
    2
    0
    1
        Potassium Shift to High(n=21,44,8,16)
    5
    15
    3
    4
        Lactate Dehydrogenase Shift to High(n=0,1,8,16)
    0
    1
    0
    0
        Magnesium Shift to High(n=3,5,8,16)
    0
    2
    0
    0
        Phosphate Shift to Low(n=23,50,8,16)
    3
    2
    0
    0
        Phosphate Shift to High(n=18,42,4,13)
    5
    16
    2
    10
        Protein Shift to Low(n=21,48,7,15)
    7
    9
    1
    2
        Protein Shift to High(n=23,47,8,16)
    2
    6
    0
    2
        Sodium Shift to Low(n=20,47,7,15)
    3
    15
    2
    3
        Sodium Shift to High(n=23,50,8,16)
    0
    0
    0
    1
        Urea Nitrogen Shift to Low(n=23,44,8,16)
    1
    3
    2
    1
        Urea Nitrogen Shift to High(n=23,50,8,15)
    0
    0
    2
    1
    No statistical analyses for this end point

    Secondary: Part B: Number of Participants with Shifts from Baseline in Urinalysis

    Close Top of page
    End point title
    Part B: Number of Participants with Shifts from Baseline in Urinalysis [74]
    End point description
    Urinalysis included assessments of urine total protein, specific gravity, pH, protein, glucose, ketones, bilirubin, blood, RBC , WBC, epithelial cells, bacteria, casts and crystals. These parameters were flagged as low, normal, or high relative to parameter’s normal range or as unknown if no result was available, by the Investigator. Here, shift to low indicates values that were normal, high, positive, abnormal or unknown at baseline and shifted to low values postbaseline. Shift to high indicates values that were normal, negative, absent, low or unknown at baseline and shifted to high postbaseline. The categories with at least one participant with shift from baseline in these parameters are reported. Part A: safety analysis set. Safety set included all participants who received at least one dose of nusinersen. ‘Number analysed (n)' signifies number of participants evaluable for analysis of the specified parameter.
    End point type
    Secondary
    End point timeframe
    Baseline up to Day 302
    Notes
    [74] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Part B Infantile-onset SMA and Part B Later-onset SMA arms were planned to be analysed for this end point.
    End point values
    Part B: Infantile-Onset SMA: 12/12 mg Nusinersen Part B: Infantile-Onset SMA: 50/28 mg Nusinersen Part B: Later-Onset SMA: 12/12 mg Nusinersen Part B: Later-Onset SMA: 50/28 mg Nusinersen
    Number of subjects analysed
    25
    50
    8
    16
    Units: participants
        Specific Gravity Shift to Low (n=20,47,8,16)
    2
    2
    1
    1
        Specific Gravity Shift to High (n=22,50,7,15)
    3
    3
    1
    1
        pH Shift to Low (n=21,48,8,16)
    2
    1
    0
    1
        pH Shift to High (n=21,47,8,16)
    5
    8
    1
    1
        Protein High/positive (n=18,45,5,13)
    12
    27
    3
    9
        Glucose High/positive (n=21,46,8,16)
    2
    2
    0
    0
        Ketones High/positive (n=20,44,8,14)
    5
    16
    4
    4
        Occult Blood High/positive (n=16,43,7,14)
    4
    12
    2
    1
        RBC High/positive (n=13,26,7,12)
    0
    3
    0
    0
        WBC High/positive (n=15,25,6,10)
    3
    12
    3
    4
        Epithelial Cells High/positive (n=2,7,5,3)
    0
    6
    5
    2
        Bacteria High/positive (n=10,18,2,8)
    10
    18
    2
    8
        Casts High/positive (n=3,3,8,16)
    0
    1
    0
    0
        Crystals High/positive (n=5,4,8,16)
    2
    1
    0
    0
    No statistical analyses for this end point

    Secondary: Part B: Number of Participants With Shifts From Baseline in CSF Parameters

    Close Top of page
    End point title
    Part B: Number of Participants With Shifts From Baseline in CSF Parameters [75]
    End point description
    CSF parameters included cell count, total protein, and glucose. These parameters were flagged as low, normal, or high relative to parameter’s normal range or as unknown if no result was available, by the Investigator. Here, shift to low indicates values that were normal, high or unknown at baseline and shifted to low values postbaseline. Shift to high indicates values that were normal, low or unknown at baseline and shifted to high postbaseline. The categories with at least one participant with shift from baseline in these parameters are reported. Safety set included all participants who received at least one dose of nusinersen. ‘Number analysed (n)' signifies number of participants evaluable for analysis of the specified parameter.
    End point type
    Secondary
    End point timeframe
    Baseline up to Day 302
    Notes
    [75] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Part B Infantile-onset SMA and Part B Later-onset SMA arms were planned to be analysed for this end point.
    End point values
    Part B: Infantile-Onset SMA: 12/12 mg Nusinersen Part B: Infantile-Onset SMA: 50/28 mg Nusinersen Part B: Later-Onset SMA: 12/12 mg Nusinersen Part B: Later-Onset SMA: 50/28 mg Nusinersen
    Number of subjects analysed
    25
    50
    8
    16
    Units: participants
        Glucose Shift to Low (n=16,36,7,12)
    4
    3
    1
    0
        Glucose Shift to High (n=19,46,8,16)
    0
    1
    0
    0
        Protein Shift to Low (n=18,45,5,11)
    2
    6
    0
    4
        Protein Shift to High (n=12,25,8,15)
    4
    7
    2
    2
        Erythrocytes Shift to Low (n=18,47,8,15)
    1
    0
    0
    0
        Erythrocytes Shift to High (n=14,37,5,11)
    3
    9
    2
    7
        Leukocytes Shift to Low (n=17,47,8,11)
    1
    2
    0
    1
        Leukocytes Shift to High (n=16,38,8,11)
    1
    5
    0
    4
    No statistical analyses for this end point

    Secondary: Part B: Number of Participants With Shift From Baseline in ECGs

    Close Top of page
    End point title
    Part B: Number of Participants With Shift From Baseline in ECGs [76]
    End point description
    The ECGs were assessed by the investigator to be normal, abnormal and abnormal AE. The number of participants with ECG shifts from normal to each of the categorical values denoting an abnormal scan (abnormal not AE, abnormal AE) was assessed. Shift from baseline to worst post-baseline values were reported. The categories with at least one participant with shift from baseline in ECG are reported. Safety set included all participants who received at least one dose of nusinersen.
    End point type
    Secondary
    End point timeframe
    Baseline up to Day 302
    Notes
    [76] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Part B Infantile-onset SMA and Part B Later-onset SMA arms were planned to be analysed for this end point.
    End point values
    Part B: Infantile-Onset SMA: 12/12 mg Nusinersen Part B: Infantile-Onset SMA: 50/28 mg Nusinersen Part B: Later-Onset SMA: 12/12 mg Nusinersen Part B: Later-Onset SMA: 50/28 mg Nusinersen
    Number of subjects analysed
    25
    50
    8
    16
    Units: participants
        Normal to Normal
    2
    7
    0
    0
        Normal to Abnormal, not AE
    9
    10
    2
    4
        Normal to Abnormal, AE
    1
    0
    0
    0
        Abnormal, not AE to Abnormal, not AE
    12
    30
    6
    12
        Abnormal, not AE to Abnormal, AE
    1
    2
    0
    0
        Unknown to Abnormal, not AE
    0
    1
    0
    0
    No statistical analyses for this end point

    Secondary: Part B: Number of Participants With Abnormalities in Vital Sign Parameters

    Close Top of page
    End point title
    Part B: Number of Participants With Abnormalities in Vital Sign Parameters [77]
    End point description
    Vital sign assessment included temperature, pulse rate systolic blood pressure, diastolic blood pressure, and respiratory rate. As pre-specified in protocol, the criteria for determining potentially clinically relevant abnormalities in vital signs included: temperature < 36 and > 38 degrees C, pulse rate < 60 and > 100 bpm, systolic blood pressure < 90, > 140 and > 160 mmHg, diastolic blood pressure < 50, > 90 and > 100 mmHg and respiratory rate < 12 and > 20 breaths per minute. The categories with at least one participant with clinically relevant vital sign abnormalities are reported. Safety set included all participants who received at least one dose of nusinersen. ‘Number analysed (n)' signifies number of participants evaluable for analysis of the specified parameter.
    End point type
    Secondary
    End point timeframe
    Baseline up to Day 302
    Notes
    [77] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Part B Infantile-onset SMA and Part B Later-onset SMA arms were planned to be analysed for this end point.
    End point values
    Part B: Infantile-Onset SMA: 12/12 mg Nusinersen Part B: Infantile-Onset SMA: 50/28 mg Nusinersen Part B: Later-Onset SMA: 12/12 mg Nusinersen Part B: Later-Onset SMA: 50/28 mg Nusinersen
    Number of subjects analysed
    25
    50
    8
    16
    Units: participants
        Temperature <36.0 C (n=25,50,8,16)
    6
    23
    3
    7
        Temperature >38.0 C (n=25,50,8,16)
    0
    6
    0
    1
        Pulse Rate <60 bpm (n=25,50,8,16)
    1
    2
    0
    0
        Pulse Rate >100 bpm (n=25,50,8,16)
    25
    50
    8
    16
        Systolic Blood Pressure <90 mmHg (n=25,49,8,16)
    24
    47
    7
    10
        Systolic Blood Pressure >140 mmHg (n=25,49,8,16)
    3
    0
    0
    0
        Diastolic Blood Pressure <50 mmHg (n=25,49,8,16)
    22
    44
    4
    10
        Diastolic Blood Pressure >90 mmHg(n=25,49,8,16)
    5
    8
    1
    2
        Diastolic Blood Pressure >100 mmHg(n=25,49,8,16)
    2
    0
    0
    1
        Respiratory Rate >20 breaths/min (n=25,50,8,16)
    25
    50
    8
    16
    No statistical analyses for this end point

    Secondary: Part B: Change From Baseline in Growth Parameters (Body Height)

    Close Top of page
    End point title
    Part B: Change From Baseline in Growth Parameters (Body Height) [78]
    End point description
    Body height was measured for all participants (infantile-onset and later-onset SMA). Safety set included all participants who received at least one dose of nusinersen. ‘Subjects analysed' signifies number of participants evaluable in this endpoint.. ‘99999’ signifies that since only one participant was evaluable, standard deviation (SD) was not estimated.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 302
    Notes
    [78] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Part B Infantile-onset SMA and Part B Later-onset SMA arms were planned to be analysed for this end point.
    End point values
    Part B: Infantile-Onset SMA: 12/12 mg Nusinersen Part B: Infantile-Onset SMA: 50/28 mg Nusinersen Part B: Later-Onset SMA: 12/12 mg Nusinersen Part B: Later-Onset SMA: 50/28 mg Nusinersen
    Number of subjects analysed
    1
    4
    1
    8
    Units: cm
        arithmetic mean (standard deviation)
    8.00 ( 99999 )
    10.25 ( 2.217 )
    11.2 ( 99999 )
    6.9 ( 3.65 )
    No statistical analyses for this end point

    Secondary: Part B Infantile-onset SMA: Change From Baseline in Growth Parameters (Head Circumference)

    Close Top of page
    End point title
    Part B Infantile-onset SMA: Change From Baseline in Growth Parameters (Head Circumference) [79]
    End point description
    Head circumference was measured in participants with infantile-onset SMA. Safety set included all participants who received at least one dose of nusinersen. ‘Subjects analysed’ signifies number of participants evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 302
    Notes
    [79] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Part B Infantile-onset SMA arms were planned to be analysed for this end point.
    End point values
    Part B: Infantile-Onset SMA: 12/12 mg Nusinersen Part B: Infantile-Onset SMA: 50/28 mg Nusinersen
    Number of subjects analysed
    13
    35
    Units: cm
        arithmetic mean (standard deviation)
    4.52 ( 1.703 )
    5.50 ( 2.766 )
    No statistical analyses for this end point

    Secondary: Part B Infantile-onset SMA: Change From Baseline in Growth Parameters (Chest Circumference)

    Close Top of page
    End point title
    Part B Infantile-onset SMA: Change From Baseline in Growth Parameters (Chest Circumference) [80]
    End point description
    Chest circumference was measured in participants with infantile-onset SMA. Safety set included all participants who received at least one dose of nusinersen. ‘Subjects analysed’ signifies number of participants evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 302
    Notes
    [80] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Part B Infantile-onset SMA arms were planned to be analysed for this end point.
    End point values
    Part B: Infantile-Onset SMA: 12/12 mg Nusinersen Part B: Infantile-Onset SMA: 50/28 mg Nusinersen
    Number of subjects analysed
    13
    35
    Units: cm
        arithmetic mean (standard deviation)
    5.67 ( 4.868 )
    6.64 ( 6.362 )
    No statistical analyses for this end point

    Secondary: Part B Infantile-onset SMA: Change From Baseline in Growth Parameters (Arm Circumference)

    Close Top of page
    End point title
    Part B Infantile-onset SMA: Change From Baseline in Growth Parameters (Arm Circumference) [81]
    End point description
    Arm circumference was measured in participants with infantile-onset SMA. Safety set included all participants who received at least one dose of nusinersen. ‘Subjects analysed’ signifies number of participants evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 302
    Notes
    [81] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Part B Infantile-onset SMA arms were planned to be analysed for this end point.
    End point values
    Part B: Infantile-Onset SMA: 12/12 mg Nusinersen Part B: Infantile-Onset SMA: 50/28 mg Nusinersen
    Number of subjects analysed
    13
    35
    Units: cm
        arithmetic mean (standard deviation)
    0.45 ( 2.141 )
    1.16 ( 2.144 )
    No statistical analyses for this end point

    Secondary: Part B Later-onset SMA: Change From Baseline in Growth Parameters (Ulnar Length)

    Close Top of page
    End point title
    Part B Later-onset SMA: Change From Baseline in Growth Parameters (Ulnar Length) [82]
    End point description
    Ulnar length was measured in participants with later-onset SMA. Safety set included all participants who received at least one dose of nusinersen. ‘Subjects analysed’ signifies number of participants evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 302
    Notes
    [82] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Part B Later-onset SMA arms were planned to be analysed for this end point.
    End point values
    Part B: Later-Onset SMA: 12/12 mg Nusinersen Part B: Later-Onset SMA: 50/28 mg Nusinersen
    Number of subjects analysed
    5
    16
    Units: cm
        arithmetic mean (standard deviation)
    2.8 ( 4.16 )
    1.2 ( 1.39 )
    No statistical analyses for this end point

    Secondary: Part B: Change From Baseline in Growth Parameters (Weight for Age Percentile)

    Close Top of page
    End point title
    Part B: Change From Baseline in Growth Parameters (Weight for Age Percentile) [83]
    End point description
    WHO child growth standards (WHO Child Growth Standards, 2006) was used to calculate the weight for age percentile in the infantile-onset participants. The 2000 CDC Growth Charts was used to calculate the weight for age percentile for later-onset participants. Safety set included all participants who received at least one dose of nusinersen. ‘Subjects analysed’ signifies number of participants evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 302
    Notes
    [83] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Part B Infantile-onset SMA and Part B Later-onset SMA arms were planned to be analysed for this end point.
    End point values
    Part B: Infantile-Onset SMA: 12/12 mg Nusinersen Part B: Infantile-Onset SMA: 50/28 mg Nusinersen Part B: Later-Onset SMA: 12/12 mg Nusinersen Part B: Later-Onset SMA: 50/28 mg Nusinersen
    Number of subjects analysed
    13
    35
    7
    16
    Units: percentile
        arithmetic mean (standard deviation)
    -6.70 ( 23.133 )
    -3.60 ( 35.202 )
    9.1 ( 20.23 )
    -0.3 ( 6.96 )
    No statistical analyses for this end point

    Secondary: Part B: Change From Baseline in Growth Parameters (Weight for Length Percentile)

    Close Top of page
    End point title
    Part B: Change From Baseline in Growth Parameters (Weight for Length Percentile) [84]
    End point description
    As pre-specified in the protocol, weight for length percentile was assessed only for the participants with infantile-onset SMA. Safety set included all participants who received at least one dose of nusinersen. 'Subjects analysed' signifies number of participants evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 302
    Notes
    [84] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Part B Infantile-onset SMA and Part B Later-onset SMA arms were planned to be analysed for this end point.
    End point values
    Part B: Infantile-Onset SMA: 12/12 mg Nusinersen Part B: Infantile-Onset SMA: 50/28 mg Nusinersen Part B: Later-Onset SMA: 12/12 mg Nusinersen Part B: Later-Onset SMA: 50/28 mg Nusinersen
    Number of subjects analysed
    12
    30
    0 [85]
    0 [86]
    Units: percentile
        arithmetic mean (standard deviation)
    -4.23 ( 35.817 )
    6.05 ( 40.119 )
    ( )
    ( )
    Notes
    [85] - As the number of subjects analyzed was zero, mean and SD was not calculated.
    [86] - As the number of subjects analyzed was zero, mean and SD was not calculated.
    No statistical analyses for this end point

    Secondary: Part B: Change From Baseline in Growth Parameters (Head-to-Chest Circumference Ratio)

    Close Top of page
    End point title
    Part B: Change From Baseline in Growth Parameters (Head-to-Chest Circumference Ratio) [87]
    End point description
    As pre-specified in the protocol, head to chest circumference ratio was assessed only for the participants with infantile-onset SMA. Safety set included all participants who received at least one dose of nusinersen. Subjects analysed signifies number of participants evaluable for this endpoint. ‘99999’ signifies that since one or no participant was evaluable, SD was not estimated.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 302
    Notes
    [87] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Part B Infantile-onset SMA and Part B Later-onset SMA arms were planned to be analysed for this end point.
    End point values
    Part B: Infantile-Onset SMA: 12/12 mg Nusinersen Part B: Infantile-Onset SMA: 50/28 mg Nusinersen
    Number of subjects analysed
    13
    35
    Units: ratio
        arithmetic mean (standard deviation)
    -0.03 ( 0.085 )
    -0.05 ( 0.269 )
    No statistical analyses for this end point

    Secondary: Part B: Number of Participants With Shifts From Baseline in Coagulation Parameters (aPTT)

    Close Top of page
    End point title
    Part B: Number of Participants With Shifts From Baseline in Coagulation Parameters (aPTT) [88]
    End point description
    aPTT 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. Safety set included all participants who received at least one dose of nusinersen. ‘Number analysed (n)' signifies number of participants evaluable for analysis of the specified parameter.
    End point type
    Secondary
    End point timeframe
    Baseline up to Day 279
    Notes
    [88] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Part B Infantile-onset SMA and Part B Later-onset SMA arms were planned to be analysed for this end point.
    End point values
    Part B: Infantile-Onset SMA: 12/12 mg Nusinersen Part B: Infantile-Onset SMA: 50/28 mg Nusinersen Part B: Later-Onset SMA: 12/12 mg Nusinersen Part B: Later-Onset SMA: 50/28 mg Nusinersen
    Number of subjects analysed
    25
    50
    8
    16
    Units: participants
        Shift to Low (n=22,48,7,16)
    4
    14
    2
    2
        Shift to High (n=17,40,8,15)
    6
    7
    1
    1
    No statistical analyses for this end point

    Secondary: Part B: Number of Participants With Shifts From Baseline in Coagulation Parameters (PT)

    Close Top of page
    End point title
    Part B: Number of Participants With Shifts From Baseline in Coagulation Parameters (PT) [89]
    End point description
    Prothrombin time was evaluated to assess safety. "Shift to low" measured change in normal, high and unknown values of PT at baseline to low values postbaseline. "Shift to high" measured change in normal, high and unknown values of PT at baseline to high values postbaseline. Safety set included all participants who received at least one dose of nusinersen. ‘Number analysed (n)' signifies number of participants evaluable for analysis of the specified parameter.
    End point type
    Secondary
    End point timeframe
    Baseline up to Day 279
    Notes
    [89] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Part B Infantile-onset SMA and Part B Later-onset SMA arms were planned to be analysed for this end point.
    End point values
    Part B: Infantile-Onset SMA: 12/12 mg Nusinersen Part B: Infantile-Onset SMA: 50/28 mg Nusinersen Part B: Later-Onset SMA: 12/12 mg Nusinersen Part B: Later-Onset SMA: 50/28 mg Nusinersen
    Number of subjects analysed
    25
    50
    8
    16
    Units: participants
        Shift to Low (n=22,48,8,15)
    3
    6
    1
    1
        Shift to High (n=20,45,8,14)
    2
    6
    0
    1
    No statistical analyses for this end point

    Secondary: Part B: Number of Participants With Shifts From Baseline in Coagulation Parameters (INR)

    Close Top of page
    End point title
    Part B: Number of Participants With Shifts From Baseline in Coagulation Parameters (INR) [90]
    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 category with at least one participant with shift from baseline in INR ratio is reported. Safety set included all participants who received at least one dose of nusinersen. ‘Number analysed (n)' signifies number of participants evaluable for analysis of specified parameter.
    End point type
    Secondary
    End point timeframe
    Baseline up to Day 279
    Notes
    [90] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Part B Infantile-onset SMA and Part B Later-onset SMA arms were planned to be analysed for this end point.
    End point values
    Part B: Infantile-Onset SMA: 12/12 mg Nusinersen Part B: Infantile-Onset SMA: 50/28 mg Nusinersen Part B: Later-Onset SMA: 12/12 mg Nusinersen Part B: Later-Onset SMA: 50/28 mg Nusinersen
    Number of subjects analysed
    25
    50
    8
    16
    Units: participants
        Shift to Low (n=22,49,8,16)
    1
    5
    0
    0
        Shift to High (n=21,44,8,16)
    2
    6
    1
    0
    No statistical analyses for this end point

    Secondary: Part B: Change From Baseline in Urine Total Protein

    Close Top of page
    End point title
    Part B: Change From Baseline in Urine Total Protein [91]
    End point description
    Safety set included all participants who received at least one dose of nusinersen. Subjects analysed signifies number of participants evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 302
    Notes
    [91] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Part B Infantile-onset SMA and Part B Later-onset SMA arms were planned to be analysed for this end point.
    End point values
    Part B: Infantile-Onset SMA: 12/12 mg Nusinersen Part B: Infantile-Onset SMA: 50/28 mg Nusinersen Part B: Later-Onset SMA: 12/12 mg Nusinersen Part B: Later-Onset SMA: 50/28 mg Nusinersen
    Number of subjects analysed
    7
    18
    3
    11
    Units: g/L
        arithmetic mean (standard deviation)
    -0.130 ( 0.4126 )
    -3.274 ( 14.1387 )
    -0.213 ( 0.2873 )
    0.004 ( 0.0608 )
    No statistical analyses for this end point

    Secondary: Part B: Percentage of Participants With a Postbaseline Platelet Count Below the Lower Limit of Normal on at Least 2 Consecutive Measurements

    Close Top of page
    End point title
    Part B: Percentage of Participants With a Postbaseline Platelet Count Below the Lower Limit of Normal on at Least 2 Consecutive Measurements [92]
    End point description
    Safety set included all participants who received at least one dose of nusinersen.
    End point type
    Secondary
    End point timeframe
    Baseline up to Day 302
    Notes
    [92] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Part B Infantile-onset SMA and Part B Later-onset SMA arms were planned to be analysed for this end point.
    End point values
    Part B: Infantile-Onset SMA: 12/12 mg Nusinersen Part B: Infantile-Onset SMA: 50/28 mg Nusinersen Part B: Later-Onset SMA: 12/12 mg Nusinersen Part B: Later-Onset SMA: 50/28 mg Nusinersen
    Number of subjects analysed
    25
    50
    8
    16
    Units: percentage of participants
        number (not applicable)
    4
    0
    0
    0
    No statistical analyses for this end point

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

    Close Top of page
    End point title
    Part B: Number of Participants With Neurological Examination Abnormalities Reported as AEs [93]
    End point description
    Participants with abnormalities in neurological examinations recorded as AEs were reported.
    End point type
    Secondary
    End point timeframe
    Baseline up to Day 302
    Notes
    [93] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Part B Infantile-onset SMA and Part B Later-onset SMA arms were planned to be analysed for this end point.
    End point values
    Part B: Infantile-Onset SMA: 12/12 mg Nusinersen Part B: Infantile-Onset SMA: 50/28 mg Nusinersen Part B: Later-Onset SMA: 12/12 mg Nusinersen Part B: Later-Onset SMA: 50/28 mg Nusinersen
    Number of subjects analysed
    25
    50
    8
    16
    Units: participants
    number (not applicable)
        Muscular Weakness
    0
    1
    0
    0
        Bulbar Palsy
    1
    0
    0
    0
        Tremor
    0
    0
    0
    1
    No statistical analyses for this end point

    Secondary: Part B: Percentage of Participants With a Postbaseline QTcF of > 500 msec and an Increase from Baseline to any Postbaseline Timepoint in QTcF of > 60 msec

    Close Top of page
    End point title
    Part B: Percentage of Participants With a Postbaseline QTcF of > 500 msec and an Increase from Baseline to any Postbaseline Timepoint in QTcF of > 60 msec [94]
    End point description
    As a part of safety assessment, QTcF was evaluated for determining the incidence of clinically relevant abnormalities. Post baseline QTcF of > 500 msec and maximum increase from baseline to post baseline QTcF > 60 msec was considered as a criteria for clinically relevant abnormality in ECG. Safety set included all participants who received at least one dose of nusinersen. 'Subjects analysed' signifies number of participants evaluable in this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline up to Day 302
    Notes
    [94] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Part B Infantile-onset SMA and Part B Later-onset SMA arms were planned to be analysed for this end point.
    End point values
    Part B: Infantile-Onset SMA: 12/12 mg Nusinersen Part B: Infantile-Onset SMA: 50/28 mg Nusinersen Part B: Later-Onset SMA: 12/12 mg Nusinersen Part B: Later-Onset SMA: 50/28 mg Nusinersen
    Number of subjects analysed
    25
    49
    8
    15
    Units: percentage of participants
        number (not applicable)
    8
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Parts A, B and C: Number of Participants With Hospitalizations

    Close Top of page
    End point title
    Parts A, B and C: Number of Participants With Hospitalizations
    End point description
    Parts A, B and C: ITT set included all participants who received at least one dose of nusinersen in the current study.
    End point type
    Secondary
    End point timeframe
    Parts A, B, and C: Baseline up to Day 302
    End point values
    Part A: 28/28 Milligrams (mg) Nusinersen Part B: Infantile-Onset SMA: 12/12 mg Nusinersen Part B: Infantile-Onset SMA: 50/28 mg Nusinersen Part B: Later-Onset SMA: 12/12 mg Nusinersen Part B: Later-Onset SMA: 50/28 mg Nusinersen Part C: 50/28 mg Nusinersen
    Number of subjects analysed
    6
    25
    50
    8
    16
    40
    Units: number of participants
    1
    19
    26
    3
    6
    12
    No statistical analyses for this end point

    Secondary: Parts A, B and C: Duration of Hospitalizations

    Close Top of page
    End point title
    Parts A, B and C: Duration of Hospitalizations
    End point description
    Parts A, B and C: ITT set included all participants who received at least one dose of nusinersen in the current study. ‘Subjects analysed' signifies number of participants evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Parts A, B, and C: Baseline up to Day 302
    End point values
    Part A: 28/28 Milligrams (mg) Nusinersen Part B: Infantile-Onset SMA: 12/12 mg Nusinersen Part B: Infantile-Onset SMA: 50/28 mg Nusinersen Part B: Later-Onset SMA: 12/12 mg Nusinersen Part B: Later-Onset SMA: 50/28 mg Nusinersen Part C: 50/28 mg Nusinersen
    Number of subjects analysed
    6
    25
    50
    8
    16
    12
    Units: percentage of days
        median (full range (min-max))
    0 (0 to 2)
    6.4 (0 to 100)
    1.9 (0 to 100)
    0.0 (0 to 8)
    0.0 (0 to 10)
    1.34 (0.3 to 10.4)
    No statistical analyses for this end point

    Secondary: Parts A, B and C: Number of Participants With Clinical Global Impression of Change (CGIC)

    Close Top of page
    End point title
    Parts A, B and C: Number of Participants With Clinical Global Impression of Change (CGIC)
    End point description
    The CGIC scale was a 7 point scale that required the clinician to assess how much the participant's illness had changed relative to a baseline state at the beginning of the intervention, where 1=very much improved, 2=much improved, 3=minimally improved, 4=no change, 5=minimally worse, 6=much worse, 7=very much worse. Higher rating indicates worsening of the condition. A separate CGIC assessment was performed by the Investigator (I) and caregiver (C). The categories with at least one participant having a CGIC score was reported. ITT set included all participants who received at least one dose of nusinersen in the current study. 'Subjects analysed' signifies number of participants evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Parts A, B, and C: Day 302
    End point values
    Part A: 28/28 Milligrams (mg) Nusinersen Part B: Infantile-Onset SMA: 12/12 mg Nusinersen Part B: Infantile-Onset SMA: 50/28 mg Nusinersen Part B: Later-Onset SMA: 12/12 mg Nusinersen Part B: Later-Onset SMA: 50/28 mg Nusinersen Part C: 50/28 mg Nusinersen
    Number of subjects analysed
    6
    13
    25
    7
    16
    24
    Units: participants
        CGIC-I-Very Much Improved
    0
    0
    8
    0
    1
    0
        CGIC-I-Much Improved
    1
    10
    20
    3
    5
    5
        CGIC-I-Minimally Improved
    5
    3
    7
    4
    9
    19
        CGIC-I-No Change
    0
    0
    0
    0
    1
    14
        CGIC-I-Minimally Worse
    0
    0
    0
    0
    0
    2
        CGIC-C-Very Much Improved
    1
    3
    18
    1
    0
    2
        CGIC-C-Much Improved
    2
    7
    13
    2
    8
    6
        CGIC-C-Minimally Improved
    2
    3
    3
    4
    7
    9
        CGIC-C-No Change
    0
    0
    1
    0
    1
    5
        CGIC-C-Minimally Worse
    1
    0
    0
    0
    0
    2
    No statistical analyses for this end point

    Secondary: Parts A, B and C: Number of Serious Respiratory Events

    Close Top of page
    End point title
    Parts A, B and C: Number of Serious Respiratory Events
    End point description
    ITT set included all participants who received at least one dose of nusinersen in the current study.
    End point type
    Secondary
    End point timeframe
    Parts A, B, and C: Baseline up to Day 399
    End point values
    Part A: 28/28 Milligrams (mg) Nusinersen Part B: Infantile-Onset SMA: 12/12 mg Nusinersen Part B: Infantile-Onset SMA: 50/28 mg Nusinersen Part B: Later-Onset SMA: 12/12 mg Nusinersen Part B: Later-Onset SMA: 50/28 mg Nusinersen Part C: 50/28 mg Nusinersen
    Number of subjects analysed
    6
    25
    50
    8
    16
    40
    Units: number of events
        number (not applicable)
    0
    34
    60
    6
    2
    0
    No statistical analyses for this end point

    Secondary: Parts A, B and C: Number of Participants With Ventilator Use

    Close Top of page
    End point title
    Parts A, B and C: Number of Participants With Ventilator Use
    End point description
    ITT set included all participants who received at least a dose of nusinersen.
    End point type
    Secondary
    End point timeframe
    Parts A, B, and C: Screening up to Day 302
    End point values
    Part A: 28/28 Milligrams (mg) Nusinersen Part B: Infantile-Onset SMA: 12/12 mg Nusinersen Part B: Infantile-Onset SMA: 50/28 mg Nusinersen Part B: Later-Onset SMA: 12/12 mg Nusinersen Part B: Later-Onset SMA: 50/28 mg Nusinersen Part C: 50/28 mg Nusinersen
    Number of subjects analysed
    6
    25
    50
    8
    16
    40
    Units: participants
    0
    9
    22
    4
    5
    8
    No statistical analyses for this end point

    Secondary: Part B Infantile-onset SMA: Percentage of Time on Ventilation

    Close Top of page
    End point title
    Part B Infantile-onset SMA: Percentage of Time on Ventilation [95]
    End point description
    ITT set included all participants who received at least one dose of nusinersen.
    End point type
    Secondary
    End point timeframe
    Baseline up to Day 302
    Notes
    [95] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Part B Infantile-onset SMA arms were planned to be analysed for this end point.
    End point values
    Part B: Infantile-Onset SMA: 12/12 mg Nusinersen Part B: Infantile-Onset SMA: 50/28 mg Nusinersen
    Number of subjects analysed
    25
    50
    Units: percentage of hours
        median (full range (min-max))
    5.6 (0 to 100)
    7.5 (0 to 100)
    No statistical analyses for this end point

    Secondary: Part A: Change From Baseline in the Parent Assessment of Swallowing Ability (PASA) Scale

    Close Top of page
    End point title
    Part A: Change From Baseline in the Parent Assessment of Swallowing Ability (PASA) Scale [96]
    End point description
    PASA questionnaire was developed to assess the signs and symptoms of dysphagia. It included 33 items across 4 domains. General feeding, drinking liquids and eating solid foods were assessed with 5 levels of response (Never, Rarely, Sometimes, Often, and Always), and 2 items were assessed with 'Yes'/'No'. The assessment of swallowing concerns has 4 levels of response: Strongly Agree, Agree, Disagree, and Strongly Disagree. ⁠Higher score indicates improvement. ITT set included all participants who received at least one dose of nusinersen.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 302
    Notes
    [96] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Part A arm was planned to be analysed for this endpoint.
    End point values
    Part A: 28/28 Milligrams (mg) Nusinersen
    Number of subjects analysed
    6
    Units: score on scale
    arithmetic mean (standard deviation)
        Had Difficulty Feeding Themselves
    0.2 ( 0.41 )
        Had to Suction Excess Saliva/Drool
    0.0 ( 0.00 )
        Not Able Eat as Much as Would Like
    0.2 ( 0.41 )
        Not Able Eat Food Variety Would Like
    -0.2 ( 0.41 )
        Been Tube-Fed
    0.0 ( 0.00 )
        Attempted to Drink Liquid Foods
    0.0 ( 0.00 )
        Refused Liquid Foods
    0.0 ( 0.00 )
        Difficulty Drinking Thin Liquids
    0.0 ( 0.00 )
        Difficulty Drinking Thick Liquids
    0.0 ( 0.00 )
        Cough/Clear Throat Swallow Liquid Food
    0.0 ( 0.00 )
        Gagged or Choked on Liquid Food
    0.0 ( 0.00 )
        Retching/Vomiting Drinking Liquids
    0.0 ( 0.00 )
        Taken > 30 Minutes Drink Liquids
    0.0 ( 0.00 )
        Attempted to Eat Solid Foods
    0.0 ( 0.00 )
        Refused Solid Foods
    0.2 ( 0.41 )
        Difficulty Swallowing Soft Foods
    0.0 ( 0.00 )
        Difficulty Swallowing Solid Foods
    -0.2 ( 0.41 )
        Had Difficulty Swallowing Pills
    0.2 ( 0.98 )
        Cough/Clear Throat Eat/Swallow Solid Food
    0.2 ( 0.41 )
        Had Food Stuck in Throat/Chest
    0.0 ( 0.00 )
        Gagged/Choked on Their Solid Food
    0.2 ( 0.41 )
        Retching/Vomiting Eating Solids
    0.2 ( 0.41 )
        Required Food to Be Cut Up
    0.7 ( 1.21 )
        Experienced/Shown Pain When Eating
    0.0 ( 0.00 )
        Has Taken > 30 Minutes Eat Solids
    0.3 ( 0.52 )
        Concern Child's Swallowing Ability
    0.8 ( 1.72 )
        Concerned About Child's Weight
    1.2 ( 1.60 )
        Concern Variety Foods Child Eats
    0.7 ( 1.51 )
        Concern Child Not Able Eat as Much
    1.3 ( 1.51 )
        Concern Child Unable Eat Variety
    1.3 ( 1.37 )
        Concern Not Get Goodness From Diet
    1.8 ( 1.17 )
        Concerned Child Aspirating Food
    1.0 ( 1.55 )
        Concern Child Choking When Eating
    1.2 ( 1.60 )
    No statistical analyses for this end point

    Secondary: Part B: Change From Baseline in the PASA Scale

    Close Top of page
    End point title
    Part B: Change From Baseline in the PASA Scale [97]
    End point description
    PASA questionnaire was developed to assess the signs and symptoms of dysphagia. It included 33 items across 4 domains. General feeding, drinking liquids and eating solid foods were assessed with 5 levels of response (Never, Rarely, Sometimes, Often, and Always), and 2 items were assessed with 'Yes'/'No'. The assessment of swallowing concerns has 4 levels of response: Strongly Agree, Agree, Disagree, and Strongly Disagree. As pre-specified in statistical analysis plan (SAP), PASA scale was assessed for the domain General feeding only. ⁠Higher score indicates improvement. ITT set included all participants who received at least one a dose of nusinersen. 'Subjects analysed' signifies number of participants evaluable in this endpoint. 'Number analysed (n)', signifies the number of participants evaluable for the specified parameter.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 302
    Notes
    [97] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Part B Infantile-onset SMA and Part B Later-onset SMA arms were planned to be analysed for this end point.
    End point values
    Part B: Infantile-Onset SMA: 12/12 mg Nusinersen Part B: Infantile-Onset SMA: 50/28 mg Nusinersen Part B: Later-Onset SMA: 12/12 mg Nusinersen Part B: Later-Onset SMA: 50/28 mg Nusinersen
    Number of subjects analysed
    7
    32
    7
    14
    Units: score on scale
    arithmetic mean (standard deviation)
        Had Difficulty Feeding Themselves (n=7,29)
    -1.6 ( 1.81 )
    -0.6 ( 1.55 )
    -0.4 ( 0.53 )
    0.3 ( 0.73 )
        Had To Suction Excess Saliva or Drool(n=7,31)
    -1.7 ( 1.38 )
    -0.2 ( 1.58 )
    0.1 ( 0.38 )
    0.1 ( 0.36 )
        Not Able To Eat As Much As Would Like(n=7,31)
    -1.6 ( 1.72 )
    -0.2 ( 1.45 )
    0.3 ( 0.95 )
    0.0 ( 0.39 )
        Not Able To Eat Food Variety They Like(n=7,29)
    -1.6 ( 1.72 )
    -1.0 ( 1.18 )
    0.1 ( 0.69 )
    -0.4 ( 0.93 )
        Been Tube-Fed
    -1.8 ( 2.11 )
    -0.9 ( 1.76 )
    0.0 ( 0.00 )
    0.0 ( 0.00 )
    No statistical analyses for this end point

    Secondary: Part B: Infantile SMA-onset: Change From (Ratio to) Baseline in CSF Concentration of NF-L

    Close Top of page
    End point title
    Part B: Infantile SMA-onset: Change From (Ratio to) Baseline in CSF Concentration of NF-L [98]
    End point description
    The change from baseline data was reported in terms of geometric mean ratio to baseline. Lower ratios to baseline represent greater reductions in concentrations of NF-L from baseline. ITT set included all participants who received at least one dose of nusinersen.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 279
    Notes
    [98] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Part B Infantile-onset SMA arms were planned to be analysed for this end point.
    End point values
    Part B: Infantile-Onset SMA: 12/12 mg Nusinersen Part B: Infantile-Onset SMA: 50/28 mg Nusinersen
    Number of subjects analysed
    25
    50
    Units: pg/mL
        geometric mean (confidence interval 95%)
    0.06 (0.05 to 0.08)
    0.05 (0.04 to 0.06)
    Statistical analysis title
    Change From Baseline in NF-L CSF Concentration
    Comparison groups
    Part B: Infantile-Onset SMA: 12/12 mg Nusinersen v Part B: Infantile-Onset SMA: 50/28 mg Nusinersen
    Number of subjects included in analysis
    75
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.3785 [99]
    Method
    ANCOVA
    Parameter type
    LS geometric mean ratio
    Point estimate
    0.86
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.62
         upper limit
    1.2
    Notes
    [99] - ANCOVA model was used with treatment as a fixed effect and adjustment for each participant disease duration at screening, baseline log CSF NF-L and baseline CHOP INTEND total score.

    Secondary: Parts A and C: Change From Baseline in HFMSE Total Score

    Close Top of page
    End point title
    Parts A and C: Change From Baseline in HFMSE Total Score [100]
    End point description
    HFMSE scale was a tool used to assess motor function in children with SMA. The original 20 item Hammersmith Functional Motor Scale was expanded to include 13 additional adapted items from the Gross Motor Function Measure to improve sensitivity for the higher functioning ambulant population. Each item is scored 0 (unable), 1 (performs with modification or adaptation) or 2 (able) and the total score was calculated by summing the 33 items and ranged from 0 to 66 with higher scores indicating greater motor function. ITT set included all participants who received at least one dose of nusinersen. ‘Subjects analysed' signifies number of participants evaluable in this endpoint.
    End point type
    Secondary
    End point timeframe
    Parts A and C: Baseline, Day 302
    Notes
    [100] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Parts A and C arms were planned to be analysed for this end point.
    End point values
    Part A: 28/28 Milligrams (mg) Nusinersen Part C: 50/28 mg Nusinersen
    Number of subjects analysed
    6
    38
    Units: score on scale
        arithmetic mean (standard deviation)
    -0.8 ( 3.76 )
    1.8 ( 3.99 )
    No statistical analyses for this end point

    Secondary: Parts A and C: Change From Baseline in RULM Total Score

    Close Top of page
    End point title
    Parts A and C: Change From Baseline in RULM Total Score [101]
    End point description
    The RULM Test was used in participants with SMA to assess upper limb functional ability items that are reflective of activities of daily living (i.e., raise a can to mouth as if drinking, take a coin and place it in a box, remove the lid of a container). The RULM test had a total of 20 items with an entry item that served as functional class identification and did not contribute to the total score. The remaining 19 scorable items reflected different functional domains and were graded on a 3-point system with a score of 0 (unable), 1 (able, with modification), and a maximum of 2 (able, no difficulty). Scorable items were summed for a total score range of 0-37, with higher scores indicating increased great upper limb function. ITT set included all participants who received at least one dose of nusinersen. ‘Subjects analysed' signifies number of participants evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Parts A and C: Baseline, Day 302
    Notes
    [101] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Parts A and C arms were planned to be analysed for this end point.
    End point values
    Part A: 28/28 Milligrams (mg) Nusinersen Part C: 50/28 mg Nusinersen
    Number of subjects analysed
    6
    37
    Units: score on scale
        arithmetic mean (standard deviation)
    1.5 ( 1.52 )
    1.2 ( 2.14 )
    No statistical analyses for this end point

    Secondary: Parts A and C: Total Number of New WHO Motor Milestones

    Close Top of page
    End point title
    Parts A and C: Total Number of New WHO Motor Milestones [102]
    End point description
    The WHO motor milestones were a set of six milestones in motor development: sitting without support, standing with assistance, hands and knees crawling, walking with assistance, standing alone and walking alone. The examiner recorded an overall rating of the participant’s emotional state and then for each milestone one of the following four classifications: no (inability) - child tried but failed to perform the milestone, no (refusal) - child refused to perform despite being calm and alert, yes - child was able to perform the milestone, unable to test - could not be tested because of irritability, drowsiness or sickness. ITT set included all participants who received at least one dose of nusinersen. ‘Number analysed (n)' signifies number of participants evaluable for this outcome measure.
    End point type
    Secondary
    End point timeframe
    Parts A and C: Baseline up to Day 302
    Notes
    [102] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Parts A and C arms were planned to be analysed for this end point.
    End point values
    Part A: 28/28 Milligrams (mg) Nusinersen Part C: 50/28 mg Nusinersen
    Number of subjects analysed
    6
    40
    Units: motor milestones
        Gain of one or More Motor Milestones (n=6,37)
    0
    3
        No Change (n=6,37)
    0
    32
        Loss of one or More Motor Milestones (n=6,37)
    0
    2
    No statistical analyses for this end point

    Secondary: Parts A and C: Change From Baseline in ACEND Total Score

    Close Top of page
    End point title
    Parts A and C: Change From Baseline in ACEND Total Score [103]
    End point description
    This assessment instrument was designed to quantify the caregiver impact experienced by parents/caregivers of children affected with severe neuromuscular diseases, including children with SMA. ACEND included domains assessing physical impact (including feeding/grooming/dressing, sitting/play, transfers, and mobility) and general caregiver impact (including time, emotion, and finance) and each domain comprises several items. The total score ranges from 0 to 100 with a higher score indicating a greater impact on the caregiver. A negative change from baseline indicates an increase in impact on caregiver. ITT set included all participants who received at least one dose of nusinersen. Subjects analysed signifies number of participants evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Parts A and C: Baseline, Day 302
    Notes
    [103] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Parts A and C arms were planned to be analysed for this end point.
    End point values
    Part A: 28/28 Milligrams (mg) Nusinersen Part C: 50/28 mg Nusinersen
    Number of subjects analysed
    6
    17
    Units: score on scale
    arithmetic mean (standard deviation)
        Feeding/Grooming/Dressing Total Score
    0.6 ( 2.51 )
    0.8 ( 7.50 )
        Sitting/Play Total Score
    0.0 ( 11.03 )
    -2.8 ( 14.48 )
        Transfers Total Score
    -8.0 ( 12.39 )
    -2.0 ( 15.34 )
        Mobility Total Score
    7.1 ( 13.85 )
    -0.8 ( 15.01 )
        Time Total Score
    6.3 ( 14.25 )
    0.4 ( 10.47 )
        Emotion Total Score
    11.1 ( 7.66 )
    -2.4 ( 9.44 )
        Finance Total Score
    15.8 ( 14.29 )
    -2.4 ( 12.00 )
    No statistical analyses for this end point

    Secondary: Parts A and C: Change From Baseline in PedsQL™ Total Score

    Close Top of page
    End point title
    Parts A and C: Change From Baseline in PedsQL™ Total Score [104]
    End point description
    PedsQL was used to measure health related quality of life (HRQOL) in children & adolescents. PedsQL generic core scale included assessment of physical functioning, emotional functioning, social functioning, and school functioning [PedsQL Inventory total score (PQLI)] and PedsQL Neuromuscular Module [Neuromuscular total score (PQLN)] measured HRQOL dimensions specific to with neuromuscular disorders, including SMA. Four dimensions were collected,each item scored on a 5-point ordinal scale (0=Never to 4=Almost Always). Items were reversed scored and were linearly transformed to a 0-100 scale. Total scale score was calculated as sum of all items over number of items answered on all scales. If more than 50% of items or more were missing, scale score was not computed. Higher scores indicated better health related quality of life. ITT set. Subjects analysed: number of participants evaluable for this endpoint. ‘Number analysed (n)':number of participants evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Parts A and C: Baseline, Day 302
    Notes
    [104] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Parts A and C arms were planned to be analysed for this end point.
    End point values
    Part A: 28/28 Milligrams (mg) Nusinersen Part C: 50/28 mg Nusinersen
    Number of subjects analysed
    5
    14
    Units: score on scale
    arithmetic mean (standard deviation)
        PQLI-Total Score-Subject (n=5,12)
    6.1 ( 18.28 )
    1.1 ( 9.74 )
        PQLI-Total Score-Parent (n=5,14)
    3.3 ( 12.51 )
    0.7 ( 8.15 )
        PQLN-Total Score-Subject (n=5,12)
    9.9 ( 6.94 )
    6.7 ( 13.11 )
        PQLN-Total Score-Parent (n=6,13)
    4.7 ( 5.72 )
    0.1 ( 9.65 )
    No statistical analyses for this end point

    Secondary: Part C: Change From Baseline in CHOP-INTEND Total Score

    Close Top of page
    End point title
    Part C: Change From Baseline in CHOP-INTEND Total Score [105]
    End point description
    The CHOP-INTEND test was designed to evaluate the motor skills of infants with significant motor weakness. It included 16 items (capturing neck, trunk, and proximal and distal limb strength), nine of which were scored 0, 1, 2, 3, or 4, five were scored as 0, 2, or 4, one was scored as 0, 1, 2, or 4, and one as 0, 2, 3, or 4 with greater scores indicating greater muscle strength. Total score ranged from 0 (worst possible score) and 64 (best possible score). ITT set included all participants who received at least one dose of nusinersen in the current study. ‘99999’ signifies that since only one participant was evaluable, standard deviation (SD) was not estimated. Subjects analysed signifies number of participants evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 302
    Notes
    [105] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Part C arm was planned to be analysed for this endpoint.
    End point values
    Part C: 50/28 mg Nusinersen
    Number of subjects analysed
    1
    Units: score on scale
        arithmetic mean (standard deviation)
    0.0 ( 99999 )
    No statistical analyses for this end point

    Secondary: Part C: Change From Baseline in HINE Section 2 Motor Milestones Total Score

    Close Top of page
    End point title
    Part C: Change From Baseline in HINE Section 2 Motor Milestones Total Score [106]
    End point description
    Section 2 of the HINE was used to assess motor milestones of the participants. Its composed of 8 motor milestone categories: voluntary grasp, ability to kick in supine position, head control, rolling, sitting, crawling, standing, and walking. Within each of these categories, participants can progress from complete absence of a motor ability (the lowest level in each category) through multiple milestones (2 to 4 levels in each category) to the highest level within the category. The 8 categories of HINE Section 2 can be summed to give a total score that ranges from 0 to 26. Safety set included all participants who received at least one dose of nusinersen. Subjects analysed signifies number of participants evaluable for this endpoint. ‘99999’ signifies that since only one participant was evaluable, standard deviation (SD) was not estimated.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 302
    Notes
    [106] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Part C arm was planned to be analysed for this endpoint.
    End point values
    Part C: 50/28 mg Nusinersen
    Number of subjects analysed
    1
    Units: score on scale
        arithmetic mean (standard deviation)
    2.0 ( 99999 )
    No statistical analyses for this end point

    Adverse events

    Close Top of page
    Adverse events information
    Timeframe for reporting adverse events
    From first dose of study drug up to end of study (up to 1527 days)
    Adverse event reporting additional description
    Safety set included all participants who received at least a dose of nusinersen. MedDRA version 24.0 was applied for Part A, MedDRA version 26.1 was applied for Part B, and MedDRA version 26.0 was applied for Part C.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    24,26,26.1
    Reporting groups
    Reporting group title
    Part A: Nusinersen 28/28 Milligrams (mg)
    Reporting group description
    Participants with later-onset SMA received 3 loading doses of 28 mg of nusinersen, intrathecally (IT), on Days 1, 15 and 29 followed by 2 maintenance doses of 28 mg on Days 149 and 269.

    Reporting group title
    Part C: Nusinersen 50/28 mg
    Reporting group description
    Participants with infantile and later-onset SMA who had been receiving the approved dose of 12 mg for at least 1 year prior to entry, received a single bolus dose of 50 mg of nusinersen intrathecally on Day 1 (4 months after their most recent maintenance dose of 12 mg) followed by 2 maintenance doses of 28 mg on Days 121 and 241.

    Reporting group title
    Part B: Later-Onset SMA: 12/12 mg Nusinersen
    Reporting group description
    Participants with later-onset SMA received 4 loading doses of 12 mg of nusinersen intrathecally on Days 1, 15, 29, and 64 followed by 2 maintenance doses of 12 mg on Days 183 and 279. Sham procedure was administered on Day 135.

    Reporting group title
    Part B: Later-Onset SMA: 50/28 mg Nusinersen
    Reporting group description
    Participants with later-onset SMA received 2 loading doses of 50 mg of nusinersen intrathecally on Days 1 and 15 followed by 2 maintenance doses of 28 mg on Days 135 and 279. Sham procedure was administered on Days 29, 64 and 183.

    Reporting group title
    Part B: Infantile-Onset SMA: 12/12 mg Nusinersen
    Reporting group description
    Participants with infantile-onset SMA received 4 loading doses of 12 mg of nusinersen intrathecally on Days 1, 15, 29, and 64 followed by 2 maintenance doses of 12 mg on Days 183 and 279. Sham procedure was administered on Day 135.

    Reporting group title
    Part B: Infantile-Onset SMA: 50/28 mg Nusinersen
    Reporting group description
    Participants with infantile-onset SMA received 2 loading doses of 50 mg of nusinersen intrathecally on Days 1 and 15 followed by 2 maintenance doses of 28 mg on Days 135 and 279. Sham procedure was administered on Days 29, 64 and 183.

    Serious adverse events
    Part A: Nusinersen 28/28 Milligrams (mg) Part C: Nusinersen 50/28 mg Part B: Later-Onset SMA: 12/12 mg Nusinersen Part B: Later-Onset SMA: 50/28 mg Nusinersen Part B: Infantile-Onset SMA: 12/12 mg Nusinersen Part B: Infantile-Onset SMA: 50/28 mg Nusinersen
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 6 (16.67%)
    6 / 40 (15.00%)
    4 / 8 (50.00%)
    2 / 16 (12.50%)
    18 / 25 (72.00%)
    30 / 50 (60.00%)
         number of deaths (all causes)
    0
    0
    0
    0
    6
    10
         number of deaths resulting from adverse events
    0
    0
    0
    0
    6
    10
    Vascular disorders
    Shock haemorrhagic
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    0 / 25 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Abortion spontaneous
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 40 (2.50%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    0 / 25 (0.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 40 (2.50%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    0 / 25 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gait disturbance
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 40 (2.50%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    0 / 25 (0.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sudden infant death syndrome
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    1 / 25 (4.00%)
    2 / 50 (4.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 2
    Organ failure
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    0 / 25 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Respiratory, thoracic and mediastinal disorders
    Atelectasis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    1 / 8 (12.50%)
    0 / 16 (0.00%)
    2 / 25 (8.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Aspiration
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    0 / 25 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Acute respiratory failure
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    3 / 25 (12.00%)
    2 / 50 (4.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 4
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Chronic respiratory failure
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    0 / 25 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cough
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    1 / 25 (4.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    0 / 25 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Obstructive airways disorder
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    0 / 25 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory acidosis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    1 / 25 (4.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Respiratory arrest
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    1 / 25 (4.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory disorder
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    0 / 25 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory distress
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    1 / 25 (4.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    4 / 25 (16.00%)
    8 / 50 (16.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    2 / 5
    0 / 11
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Asthma
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    1 / 8 (12.50%)
    0 / 16 (0.00%)
    0 / 25 (0.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Oxygen saturation decreased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    0 / 25 (0.00%)
    2 / 50 (4.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Electrocardiogram qt prolonged
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    1 / 25 (4.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    1 / 6 (16.67%)
    2 / 40 (5.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    0 / 25 (0.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    1 / 6 (16.67%)
    2 / 40 (5.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    0 / 25 (0.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Traumatic haemothorax
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    0 / 25 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tracheostomy malfunction
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    0 / 25 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac arrest
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    2 / 25 (8.00%)
    3 / 50 (6.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 1
    Cardiomyopathy
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    1 / 25 (4.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Cardio-respiratory arrest
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    2 / 25 (8.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Hypoglycaemic seizure
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    1 / 25 (4.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebral infarction
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    1 / 25 (4.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Brain stem infarction
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    1 / 25 (4.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Hypoxic-ischaemic encephalopathy
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    1 / 25 (4.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Blood and lymphatic system disorders
    Leukocytosis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    1 / 25 (4.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Dysphagia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    1 / 25 (4.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Acquired macrocephaly
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    0 / 25 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Muscular weakness
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    0 / 25 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Adenoviral upper respiratory infection
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    0 / 25 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchiolitis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    1 / 25 (4.00%)
    3 / 50 (6.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Covid-19
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    1 / 16 (6.25%)
    0 / 25 (0.00%)
    3 / 50 (6.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Enterovirus infection
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    0 / 25 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Escherichia urinary tract infection
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    1 / 25 (4.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis adenovirus
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    1 / 25 (4.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis bacterial
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    0 / 25 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis escherichia coli
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    1 / 25 (4.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Human coronavirus OC43 infection
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    0 / 25 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lower respiratory tract infection viral
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    1 / 25 (4.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Measles
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    1 / 25 (4.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Norovirus infection
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    0 / 25 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    5 / 25 (20.00%)
    7 / 50 (14.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 7
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 1
    Pneumonia acinetobacter
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    1 / 25 (4.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    1 / 8 (12.50%)
    0 / 16 (0.00%)
    1 / 25 (4.00%)
    7 / 50 (14.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia bacterial
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    1 / 25 (4.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia influenzal
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    1 / 25 (4.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia mycoplasmal
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    1 / 8 (12.50%)
    0 / 16 (0.00%)
    0 / 25 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia pseudomonal
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    1 / 25 (4.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia respiratory syncytial viral
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    1 / 8 (12.50%)
    1 / 16 (6.25%)
    0 / 25 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia viral
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    1 / 25 (4.00%)
    2 / 50 (4.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Respiratory tract infection
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    2 / 25 (8.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rhinovirus infection
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    0 / 25 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    1 / 25 (4.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    1 / 25 (4.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Stoma site infection
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    0 / 25 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    0 / 25 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Staphylococcal bacteraemia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    1 / 25 (4.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Staphylococcal sepsis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    0 / 25 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Pneumonia pneumococcal
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    1 / 8 (12.50%)
    0 / 16 (0.00%)
    0 / 25 (0.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis rotavirus
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    1 / 8 (12.50%)
    0 / 16 (0.00%)
    0 / 25 (0.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis 
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 40 (2.50%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    0 / 25 (0.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hypoglycaemia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    1 / 25 (4.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    Part A: Nusinersen 28/28 Milligrams (mg) Part C: Nusinersen 50/28 mg Part B: Later-Onset SMA: 12/12 mg Nusinersen Part B: Later-Onset SMA: 50/28 mg Nusinersen Part B: Infantile-Onset SMA: 12/12 mg Nusinersen Part B: Infantile-Onset SMA: 50/28 mg Nusinersen
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    4 / 6 (66.67%)
    36 / 40 (90.00%)
    7 / 8 (87.50%)
    14 / 16 (87.50%)
    19 / 25 (76.00%)
    37 / 50 (74.00%)
    Vascular disorders
    Lymphoedema
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 40 (2.50%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    0 / 25 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Peripheral coldness
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 40 (2.50%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    0 / 25 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Hypotension
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    0 / 25 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Hypertension
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    1 / 25 (4.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    Cyanosis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    0 / 25 (0.00%)
    2 / 50 (4.00%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    General disorders and administration site conditions
    Chills
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    0 / 25 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    0
    Pyrexia
         subjects affected / exposed
    0 / 6 (0.00%)
    3 / 40 (7.50%)
    0 / 8 (0.00%)
    1 / 16 (6.25%)
    4 / 25 (16.00%)
    9 / 50 (18.00%)
         occurrences all number
    0
    3
    0
    2
    6
    12
    Vaccination site haemorrhage
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 40 (2.50%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    0 / 25 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Feeling hot
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 40 (2.50%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    0 / 25 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Infusion site rash
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 40 (2.50%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    0 / 25 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Medical device pain
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 40 (2.50%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    0 / 25 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Medical device site discomfort
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 40 (2.50%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    0 / 25 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Vaccination site erythema
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 40 (2.50%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    0 / 25 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Asthenia
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 40 (2.50%)
    0 / 8 (0.00%)
    10 / 16 (62.50%)
    0 / 25 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Vessel puncture site haemorrhage
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 40 (2.50%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    0 / 25 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Oedema
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    0 / 25 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    Medical device site rash
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    0 / 25 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Medical device site hypersensitivity
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    0 / 25 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Oedema peripheral
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    0 / 25 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Respiratory complication associated with device
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    1 / 25 (4.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Immune system disorders
    Mite allergy
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 40 (2.50%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    0 / 25 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Milk allergy
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    0 / 25 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 40 (2.50%)
    0 / 8 (0.00%)
    2 / 16 (12.50%)
    2 / 25 (8.00%)
    5 / 50 (10.00%)
         occurrences all number
    0
    1
    0
    2
    2
    5
    Rhinorrhoea
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    2 / 16 (12.50%)
    0 / 25 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    0
    Epistaxis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    1 / 16 (6.25%)
    0 / 25 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Rhinitis allergic
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    1 / 16 (6.25%)
    0 / 25 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Bronchial obstruction
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    1 / 8 (12.50%)
    0 / 16 (0.00%)
    0 / 25 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    1
    0
    0
    2
    Respiratory failure
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    0 / 25 (0.00%)
    3 / 50 (6.00%)
         occurrences all number
    0
    0
    0
    0
    0
    3
    Respiratory muscle weakness
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    0 / 25 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Productive cough
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    0 / 25 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Pleural effusion
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    0 / 25 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Interstitial lung disease
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    0 / 25 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Sneezing
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    0 / 25 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Acute respiratory failure
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    0 / 25 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Acute respiratory distress syndrome
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    0 / 25 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Respiratory distress
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    0 / 25 (0.00%)
    2 / 50 (4.00%)
         occurrences all number
    0
    0
    0
    0
    0
    3
    Increased bronchial secretion
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    1 / 25 (4.00%)
    2 / 50 (4.00%)
         occurrences all number
    0
    0
    0
    0
    1
    2
    Atelectasis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    1 / 25 (4.00%)
    2 / 50 (4.00%)
         occurrences all number
    0
    0
    0
    0
    1
    4
    Bronchospasm
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    0 / 25 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Pneumothorax
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    2 / 25 (8.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    Hypoxia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    1 / 25 (4.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Decreased bronchial secretion
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    1 / 25 (4.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Psychiatric disorders
    Dysphoria
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    0 / 25 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    Investigations
    CSF pressure increased
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 40 (5.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    0 / 25 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    0
    Crystal urine present
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 40 (5.00%)
    0 / 8 (0.00%)
    1 / 16 (6.25%)
    0 / 25 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    2
    0
    1
    0
    0
    CSF protein increased
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 40 (2.50%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    0 / 25 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Body height below normal
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    1 / 16 (6.25%)
    0 / 25 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    0
    1
    0
    1
    Weight decreased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    1 / 16 (6.25%)
    1 / 25 (4.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    Staphylococcus test positive
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    1 / 8 (12.50%)
    0 / 16 (0.00%)
    0 / 25 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Bacterial test positive
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    0 / 25 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Body temperature increased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    0 / 25 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Electrocardiogram QT prolonged
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    0 / 25 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Oxygen saturation decreased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    1 / 25 (4.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    1 / 25 (4.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Blood albumin decreased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    1 / 25 (4.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Myocardial necrosis marker increased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    0 / 25 (0.00%)
    3 / 50 (6.00%)
         occurrences all number
    0
    0
    0
    0
    0
    3
    Blood phosphorus increased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    1 / 25 (4.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Blood creatinine decreased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    1 / 25 (4.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Blood creatine phosphokinase increased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    1 / 25 (4.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Blood bicarbonate decreased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    1 / 25 (4.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Coronavirus test positive
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    1 / 25 (4.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    1 / 25 (4.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Injury, poisoning and procedural complications
    Procedural pain
         subjects affected / exposed
    2 / 6 (33.33%)
    8 / 40 (20.00%)
    3 / 8 (37.50%)
    3 / 16 (18.75%)
    0 / 25 (0.00%)
    3 / 50 (6.00%)
         occurrences all number
    3
    12
    5
    8
    0
    3
    Procedural headache
         subjects affected / exposed
    1 / 6 (16.67%)
    13 / 40 (32.50%)
    0 / 8 (0.00%)
    4 / 16 (25.00%)
    0 / 25 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    1
    20
    0
    7
    0
    0
    Anaesthetic complication neurological
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 40 (2.50%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    0 / 25 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Fall
         subjects affected / exposed
    0 / 6 (0.00%)
    4 / 40 (10.00%)
    0 / 8 (0.00%)
    1 / 16 (6.25%)
    0 / 25 (0.00%)
    2 / 50 (4.00%)
         occurrences all number
    0
    5
    0
    1
    0
    2
    Procedural vomiting
         subjects affected / exposed
    0 / 6 (0.00%)
    3 / 40 (7.50%)
    0 / 8 (0.00%)
    1 / 16 (6.25%)
    0 / 25 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    4
    0
    1
    0
    0
    Post procedural discomfort
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 40 (2.50%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    0 / 25 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    2
    0
    0
    0
    3
    Road traffic accident
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 40 (5.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    0 / 25 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    0
    Anaesthetic complication
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 40 (2.50%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    0 / 25 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Craniocerebral injury
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 40 (2.50%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    0 / 25 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Procedural nausea
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 40 (2.50%)
    0 / 8 (0.00%)
    1 / 16 (6.25%)
    0 / 25 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    0
    Skin abrasion
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 40 (2.50%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    0 / 25 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Foreign body ingestion
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    1 / 16 (6.25%)
    0 / 25 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Post procedural fever
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    1 / 16 (6.25%)
    0 / 25 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Traumatic haematoma
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    1 / 16 (6.25%)
    0 / 25 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Head injury
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    0 / 25 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Femur fracture
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    0 / 25 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Periorbital haemorrhage
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    0 / 25 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Post procedural swelling
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    0 / 25 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Neurological procedural complication
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 40 (2.50%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    1 / 25 (4.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    0
    1
    0
    Post procedural haemorrhage
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    1 / 16 (6.25%)
    1 / 25 (4.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    Congenital, familial and genetic disorders
    Cryptorchism
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    0 / 25 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Developmental hip dysplasia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    0 / 25 (0.00%)
    2 / 50 (4.00%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    Cardiac disorders
    Sinus tachycardia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    1 / 16 (6.25%)
    0 / 25 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Tachycardia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    0 / 25 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    2 / 6 (33.33%)
    5 / 40 (12.50%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    0 / 25 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    3
    7
    0
    0
    0
    0
    Paraesthesia
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    0 / 25 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    0
    Balance disorder
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 40 (2.50%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    0 / 25 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    0
    Dizziness
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 40 (5.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    0 / 25 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    0
    Disturbance in attention
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 40 (2.50%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    0 / 25 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Dizziness postural
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 40 (2.50%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    0 / 25 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Intracranial pressure increased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    1 / 16 (6.25%)
    0 / 25 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Tremor
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    1 / 16 (6.25%)
    0 / 25 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Febrile convulsion
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    1 / 25 (4.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Bulbar palsy
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    1 / 25 (4.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Blood and lymphatic system disorders
    Eosinophilia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    1 / 16 (6.25%)
    0 / 25 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    0
    1
    0
    1
    Anaemia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    1 / 25 (4.00%)
    3 / 50 (6.00%)
         occurrences all number
    0
    0
    0
    0
    1
    3
    Leukocytosis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    2 / 25 (8.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    Iron deficiency anaemia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    1 / 25 (4.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Deficiency anaemia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    1 / 25 (4.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    Hypofibrinogenaemia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    0 / 25 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Normochromic normocytic anaemia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    1 / 25 (4.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Thrombocytosis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    1 / 25 (4.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Secondary thrombocytosis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    1 / 25 (4.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Ear and labyrinth disorders
    Vestibular disorder
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 40 (2.50%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    0 / 25 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Eye disorders
    Myopia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    1 / 16 (6.25%)
    0 / 25 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Eye discharge
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    0 / 25 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    2 / 6 (33.33%)
    1 / 40 (2.50%)
    1 / 8 (12.50%)
    2 / 16 (12.50%)
    2 / 25 (8.00%)
    4 / 50 (8.00%)
         occurrences all number
    2
    2
    1
    2
    3
    6
    Diarrhoea
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 40 (2.50%)
    0 / 8 (0.00%)
    2 / 16 (12.50%)
    0 / 25 (0.00%)
    2 / 50 (4.00%)
         occurrences all number
    0
    2
    0
    2
    0
    2
    Nausea
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 40 (5.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    1 / 25 (4.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    2
    0
    0
    1
    0
    Constipation
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 40 (5.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    1 / 25 (4.00%)
    7 / 50 (14.00%)
         occurrences all number
    0
    2
    0
    0
    2
    8
    Abdominal pain
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    1 / 16 (6.25%)
    0 / 25 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    1 / 25 (4.00%)
    2 / 50 (4.00%)
         occurrences all number
    0
    0
    0
    0
    1
    2
    Dysphagia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    2 / 25 (8.00%)
    5 / 50 (10.00%)
         occurrences all number
    0
    0
    0
    0
    2
    6
    Dysbiosis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    0 / 25 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Salivary hypersecretion
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    0 / 25 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Infantile diarrhoea
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    0 / 25 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Functional gastrointestinal disorder
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    0 / 25 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Hepatobiliary disorders
    Hyperbilirubinaemia
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 40 (2.50%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    0 / 25 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Hepatic function abnormal
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    0 / 25 (0.00%)
    2 / 50 (4.00%)
         occurrences all number
    0
    0
    0
    0
    0
    3
    Skin and subcutaneous tissue disorders
    Urticaria
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    0 / 25 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Dermatitis allergic
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    1 / 16 (6.25%)
    0 / 25 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Rash
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    1 / 8 (12.50%)
    0 / 16 (0.00%)
    0 / 25 (0.00%)
    3 / 50 (6.00%)
         occurrences all number
    0
    0
    1
    0
    0
    3
    Dermatitis contact
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    2 / 25 (8.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    Acne infantile
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    1 / 25 (4.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Rash erythematous
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    0 / 25 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Eczema infantile
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    0 / 25 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Dermatitis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    0 / 25 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Eczema
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    0 / 25 (0.00%)
    2 / 50 (4.00%)
         occurrences all number
    0
    0
    0
    0
    0
    3
    Dermatitis diaper
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    0 / 25 (0.00%)
    3 / 50 (6.00%)
         occurrences all number
    0
    0
    0
    0
    0
    3
    Renal and urinary disorders
    Nephrolithiasis
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 40 (2.50%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    0 / 25 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Proteinuria
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 40 (2.50%)
    0 / 8 (0.00%)
    1 / 16 (6.25%)
    0 / 25 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    0
    Leukocyturia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    1 / 25 (4.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Musculoskeletal and connective tissue disorders
    Foot deformity
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    0 / 25 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    0
    Myalgia
         subjects affected / exposed
    0 / 6 (0.00%)
    3 / 40 (7.50%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    0 / 25 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    5
    0
    0
    0
    0
    Muscle contracture
         subjects affected / exposed
    0 / 6 (0.00%)
    3 / 40 (7.50%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    0 / 25 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    3
    0
    0
    0
    1
    Pain in extremity
         subjects affected / exposed
    0 / 6 (0.00%)
    3 / 40 (7.50%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    0 / 25 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    3
    0
    0
    0
    0
    Osteopenia
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 40 (2.50%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    0 / 25 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Joint contracture
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 40 (2.50%)
    0 / 8 (0.00%)
    1 / 16 (6.25%)
    0 / 25 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    2
    0
    1
    0
    0
    Neck pain
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 40 (5.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    0 / 25 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    0
    Limb discomfort
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 40 (2.50%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    0 / 25 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Musculoskeletal stiffness
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 40 (2.50%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    0 / 25 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Myalgia intercostal
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 40 (2.50%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    0 / 25 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Arthralgia
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 40 (5.00%)
    1 / 8 (12.50%)
    0 / 16 (0.00%)
    0 / 25 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    2
    1
    0
    0
    0
    Osteoporosis
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 40 (2.50%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    0 / 25 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Scoliosis
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 40 (2.50%)
    0 / 8 (0.00%)
    1 / 16 (6.25%)
    0 / 25 (0.00%)
    2 / 50 (4.00%)
         occurrences all number
    0
    1
    0
    1
    0
    2
    Short stature
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 40 (2.50%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    0 / 25 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Tendinous contracture
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 40 (2.50%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    0 / 25 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Acquired plagiocephaly
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    0 / 25 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Joint range of motion decreased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    0 / 25 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Muscular weakness
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    0 / 25 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Extremity contracture
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    1 / 25 (4.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 6 (16.67%)
    2 / 40 (5.00%)
    2 / 8 (25.00%)
    2 / 16 (12.50%)
    3 / 25 (12.00%)
    8 / 50 (16.00%)
         occurrences all number
    2
    3
    3
    2
    3
    9
    Gingivitis
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    1 / 16 (6.25%)
    0 / 25 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    0
    Tonsillitis
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 40 (0.00%)
    1 / 8 (12.50%)
    2 / 16 (12.50%)
    0 / 25 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    1
    2
    0
    0
    COVID-19
         subjects affected / exposed
    0 / 6 (0.00%)
    11 / 40 (27.50%)
    1 / 8 (12.50%)
    0 / 16 (0.00%)
    2 / 25 (8.00%)
    5 / 50 (10.00%)
         occurrences all number
    0
    12
    1
    0
    2
    6
    Cystitis
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 40 (2.50%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    0 / 25 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Bronchitis
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 40 (2.50%)
    0 / 8 (0.00%)
    1 / 16 (6.25%)
    3 / 25 (12.00%)
    2 / 50 (4.00%)
         occurrences all number
    0
    2
    0
    1
    3
    2
    Gastroenteritis
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 40 (5.00%)
    0 / 8 (0.00%)
    1 / 16 (6.25%)
    0 / 25 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    2
    0
    1
    0
    2
    Urinary tract infection
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 40 (5.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    0 / 25 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    0
    Nasopharyngitis
         subjects affected / exposed
    0 / 6 (0.00%)
    4 / 40 (10.00%)
    0 / 8 (0.00%)
    2 / 16 (12.50%)
    1 / 25 (4.00%)
    2 / 50 (4.00%)
         occurrences all number
    0
    6
    0
    2
    1
    2
    Influenza
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 40 (2.50%)
    1 / 8 (12.50%)
    1 / 16 (6.25%)
    1 / 25 (4.00%)
    2 / 50 (4.00%)
         occurrences all number
    0
    1
    1
    1
    1
    3
    Sinusitis
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 40 (2.50%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    0 / 25 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Respiratory tract infection
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    1 / 16 (6.25%)
    1 / 25 (4.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    0
    1
    1
    1
    Asymptomatic bacteriuria
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    1 / 16 (6.25%)
    0 / 25 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Hand-foot-and-mouth disease
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    1 / 16 (6.25%)
    0 / 25 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    0
    1
    0
    1
    Lice infestation
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    1 / 16 (6.25%)
    0 / 25 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Otitis media acute
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    1 / 16 (6.25%)
    0 / 25 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Suspected COVID-19
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    1 / 16 (6.25%)
    0 / 25 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Vulvovaginal candidiasis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    1 / 16 (6.25%)
    0 / 25 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Vulvovaginitis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    1 / 16 (6.25%)
    0 / 25 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Gastroenteritis rotavirus
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    1 / 8 (12.50%)
    0 / 16 (0.00%)
    0 / 25 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Otitis media
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    1 / 8 (12.50%)
    0 / 16 (0.00%)
    0 / 25 (0.00%)
    2 / 50 (4.00%)
         occurrences all number
    0
    0
    1
    0
    0
    2
    Pneumonia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    1 / 8 (12.50%)
    0 / 16 (0.00%)
    0 / 25 (0.00%)
    3 / 50 (6.00%)
         occurrences all number
    0
    0
    1
    0
    0
    3
    Bronchiolitis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    0 / 25 (0.00%)
    2 / 50 (4.00%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    Pneumonia klebsiella
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    0 / 25 (0.00%)
    2 / 50 (4.00%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    Stoma site infection
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    0 / 25 (0.00%)
    2 / 50 (4.00%)
         occurrences all number
    0
    0
    0
    0
    0
    4
    Herpangina
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    1 / 25 (4.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    Bronchitis viral
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    0 / 25 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Cystitis bacterial
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    0 / 25 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Enterovirus infection
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    0 / 25 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Eye infection
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    0 / 25 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Helminthic infection
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    0 / 25 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Viral infection
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    0 / 25 (0.00%)
    2 / 50 (4.00%)
         occurrences all number
    0
    0
    0
    0
    0
    3
    Otitis externa
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    0 / 25 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Pharyngitis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    0 / 25 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Pneumonia moraxella
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    0 / 25 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Pneumonia pseudomonal
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    1 / 25 (4.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    Respiratory syncytial virus bronchiolitis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    0 / 25 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Respiratory tract infection viral
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    0 / 25 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Rhinovirus infection
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    1 / 25 (4.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    Sepsis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    1 / 25 (4.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    Septic shock
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    0 / 25 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Varicella
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    1 / 25 (4.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    Vascular device infection
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    0 / 25 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Viral upper respiratory tract infection
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    2 / 25 (8.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    0
    0
    2
    1
    Gastroenteritis adenovirus
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    1 / 25 (4.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Gastroenteritis Escherichia coli
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    1 / 25 (4.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Urinary tract infection enterococcal
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    1 / 25 (4.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Staphylococcal infection
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    1 / 25 (4.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    Pneumonia respiratory syncytial viral
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    1 / 25 (4.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Klebsiella urinary tract infection
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    1 / 25 (4.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Klebsiella infection
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    2 / 25 (8.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    Gastroenteritis viral
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    1 / 25 (4.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Gastroenteritis norovirus
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    1 / 25 (4.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Acinetobacter infection
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    1 / 25 (4.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Conjunctivitis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    1 / 25 (4.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Enterobacter infection
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    1 / 25 (4.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    0 / 25 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Hyponatraemia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    0 / 25 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Dairy intolerance
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    0 / 25 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Malnutrition
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    2 / 25 (8.00%)
    5 / 50 (10.00%)
         occurrences all number
    0
    0
    0
    0
    3
    5
    Hypoalbuminaemia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    1 / 25 (4.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Hypoglycaemia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    1 / 25 (4.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Hypokalaemia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    1 / 25 (4.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Lactose intolerance
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    1 / 25 (4.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Protein deficiency
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    1 / 25 (4.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Hyperglycaemia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    1 / 25 (4.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Electrolyte imbalance
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    1 / 25 (4.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Underweight
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    0 / 25 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Iron deficiency
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 40 (0.00%)
    0 / 8 (0.00%)
    0 / 16 (0.00%)
    0 / 25 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1

    More information

    Close Top of page

    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    03 Dec 2019
    - Clarified that the primary objective for Part B was to examine efficacy, as measured by the change from baseline in CHOP INTEND total score. - Clarified that the remaining assessments that were used to evaluate the clinical efficacy of nusinersen for participants in Part B were secondary endpoints related to a secondary objective. - A separate table for Parts A and C objectives and endpoints was added to emphasize the differences between Part B and Parts A and C, and to clarify that safety was the primary objective for Parts A and C.
    05 Jun 2020
    - Made revision to the study stopping rules to clarify that they only apply to the primary safety portions of the study. - The footnotes regarding ECG monitoring in schedule of activities (SoA) tables were revised to adjust the postdose ECG timing and address abnormal ECG results. - The loading dose visit windows for Parts A and B of Study 232SM203 were clarified and revised. - A footnote was added to SoA tables to ensure that efficacy assessments (CHOP INTEND, HFMSE, and RULM) were conducted twice prior to the first dose of study treatment. - Guidance was added on the number of participants with scoliosis and/or severe contractures to be included in Part C of the study. - The study duration was extended, in order to align the requirements of contraception use and reporting, the follow-up period of the study was extended for those participants who require contraception use and an assessment was added on Day 410, Day 420, and Day 382 for Part A, Part B, and Part C, respectively. - Inclusion and exclusion criteria was updated. - A new section was added to the protocol to provide additional details on ventilation use.
    05 Aug 2020
    - Made revision to the study stopping rules so that they apply to all participants in Parts A and B of the study. - Language was added to the protocol regarding remote monitoring of study sites during the global coronavirus disease (COVID-19) pandemic.
    01 Oct 2021
    - Increased the sample size by including an additional cohort of up to approximately 20 adult participants in Part C to allow collection of clinical data in adults transitioning from the currently approved nusinersen dosing regimen to a higher dose. - The timepoints for collection of vital signs, neurological examinations, and ECGs and the collection windows for plasma PK samples were updated for Parts B and C. - A schedule of activities table specifically for Part C Cohort 2 was added. - A new table was added for participants in Part B who discontinued study treatment but agreed to remain in the study for follow-up. - Inclusion and exclusion criteria was updated for Parts A,B and C. - Added details on contracture assessment, to update the information on PedsQL for the adult participants who enrolled in Cohort 2 of Part C. - Updated growth parameters to allow for measurement of length for participants with later-onset SMA who were not able to have height measured.
    05 May 2022
    - Reduced the sample size for Part B infantile onset participants to 75. As a result, the total sample size for the study was adjusted to 145 participants. - Part B exclusion criteria was updated. - The PedsQL Measurement 4.0 Generic Core Scales and 3.0 Neuromuscular Module for participants ≥ 26 years of age were added. - Language was updated in laboratory safety assessments to further specify that total protein would be measured for the CSF local laboratory sample. - All references to an interim analysis being performed to assess the feasibility of borrowing participant data from Study CS3B were removed

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
    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.

    European Medicines Agency © 1995-Fri May 02 21:29:54 CEST 2025 | Domenico Scarlattilaan 6, 1083 HS Amsterdam, The Netherlands
    EMA HMA