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

    Summary
    EudraCT number
    		 2014-001947-18
    Trial protocol
    		 DE   GB   SE   ES   IT   FR  
    Global end of trial date
    20 Feb 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    06 Sep 2017
    First version publication date
    06 Sep 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    ISIS 396443-CS4
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02865109
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Biogen
    Sponsor organisation address
    225 Binney Street, Cambridge, United States, 02142
    Public contact
    Biogen Study Medical Director, Biogen, clinicaltrials@biogen.com
    Scientific contact
    Biogen Study Medical Director, Biogen, +1 866-633-4636, clinicaltrials@biogen.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-001448-PIP13-02
    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
    20 Feb 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    20 Feb 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    20 Feb 2017
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The primary objective of this study is to examine the clinical efficacy of nusinersen (ISIS 396443) administered intrathecally to participants with later-onset Spinal Muscular Atrophy (SMA). The secondary objective is to examine the safety and tolerability of nusinersen administered intrathecally to participants with later-onset SMA.
    Protection of trial subjects
    Written informed consent was obtained from the parent or legal guardian of the subject and, in cases where institutional guidelines and the subject’s age dictate, informed assent from the subject after adequate explanation of the aims, methods, anticipated benefits, and potential hazards of the study and before any protocol-specific screening procedures or any study treatment was administered. Sufficient time was given to consider whether to participate in the study.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    24 Nov 2014
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United States: 65
    Country: Number of subjects enrolled
    Italy: 19
    Country: Number of subjects enrolled
    Germany: 12
    Country: Number of subjects enrolled
    Japan: 8
    Country: Number of subjects enrolled
    Spain: 6
    Country: Number of subjects enrolled
    Canada: 5
    Country: Number of subjects enrolled
    France: 3
    Country: Number of subjects enrolled
    Hong Kong: 3
    Country: Number of subjects enrolled
    Korea, Republic of: 3
    Country: Number of subjects enrolled
    Sweden: 2
    Worldwide total number of subjects
    126
    EEA total number of subjects
    42
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    126
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 After parental informed consent was obtained and prior to any treatment, participants entered a Screening Period of up to 21 days to determine their eligibility for the study. Of the 179 participants screened, 53 were screening failures.

    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, Monitor, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Sham procedure
    Arm description
    		 Sham comparator on Days 1, 29, 85 and 274.
    Arm type
    		 Sham procedure

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 Nusinersen
    Arm description
    		 Nusinersen 12 mg solution via intrathecal (IT) injection on Days 1, 29, 85 and 274.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Nusinersen
    Investigational medicinal product code
    ISIS 396443
    Other name
    BIIB058, Spinraza, IONIS-SMN Rx, ISIS SMNRx
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intrathecal use
    Dosage and administration details
    Nusinersen 12 mg solution via intrathecal (IT) injection on Days 1, 29, 85 and 274.

    Number of subjects in period 1
    		Sham procedure Nusinersen
    Started
    42
    84
    Completed Treatment
    42
    83 [1]
    Completed
    42
    84
    Notes
    [1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: 1 participant completed the study but did not complete treatments due to early study closure

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Sham procedure
    Reporting group description
    		 Sham comparator on Days 1, 29, 85 and 274.

    Reporting group title
    Nusinersen
    Reporting group description
    		 Nusinersen 12 mg solution via intrathecal (IT) injection on Days 1, 29, 85 and 274.

    Reporting group values
    		 Sham procedure Nusinersen Total
    Number of subjects
    		 42 84 126
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 42 84 126
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 0 0 0
        From 65-84 years
    		 0 0 0
        85 years and over
    		 0 0 0
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 3.4 ± 1.61 3.8 ± 1.63 -
    Gender, Male/Female
    Units: Subjects
        Female
    		 21 46 67
        Male
    		 21 38 59
    Study Specific Characteristic | Hammersmith Functional Motor Scale - Expanded (HFMSE) Score
    The HFMSE consists of 33 scored activities used to assess motor function in children with SMA. Participants were asked to do a specific activity (such as rolling) and they were then graded on the quality and execution of that movement on a scale of 0=being unable, 1=performed with some compensation, and 2=unaided. The overall score is the sum of the scores for all activities with a maximum achievable score of 66. Higher scores indicate increased motor function.
    Units: scores on a scale
        arithmetic mean (standard deviation)
    		 19.9 ± 7.23 22.4 ± 8.33 -

    End points

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    End points reporting groups
    Reporting group title
    Sham procedure
    Reporting group description
    		 Sham comparator on Days 1, 29, 85 and 274.

    Reporting group title
    Nusinersen
    Reporting group description
    		 Nusinersen 12 mg solution via intrathecal (IT) injection on Days 1, 29, 85 and 274.

    Primary: Change from Baseline in Hammersmith Functional Motor Scale - Expanded (HFMSE) Score at Month 15

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    End point title
    		 Change from Baseline in Hammersmith Functional Motor Scale - Expanded (HFMSE) Score at Month 15
    End point description
    The HFMSE consists of 33 scored activities used to assess motor function in children with SMA. The scale was originally developed with 20 scored activities and was devised for use in children with SMA Type 2 and Type 3 with limited ambulation to give objective information on motor ability and clinical progression. The expanded scale includes an additional module of 13 items developed to allow for evaluation of ambulatory SMA patients. Participants were asked to do a specific activity (such as rolling) and they were then graded on the quality and execution of that movement on a scale of 0=being unable, 1=performed with some compensation, and 2=unaided. The overall score is the sum of the scores for all activities with a maximum achievable score of 66. Higher scores indicate increased motor function. A positive change from Baseline indicates improvement.
    End point type
    Primary
    End point timeframe
    Baseline and Month 15
    End point values
    		 Sham procedure Nusinersen
    Number of subjects analysed
    42
    84
    Units: scores on a scale
        least squares mean (confidence interval 95%)
    -1 (-2.5 to 0.5)
    3.9 (3 to 4.9)
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Nusinersen v Sham procedure
    Number of subjects included in analysis
    126
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 = 1E-7 [2]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean Difference
    Point estimate
    4.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 3.1
         upper limit
    		 6.7
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.91
    Notes
    [1] - ITT Set: All participants who were randomized and received at least 1 dose of study drug/sham procedure. Missing postbaseline HFMSE data were imputed using multiple imputation.
    [2] - ANCOVA model with treatment group as a factor and age at Screening and baseline HFMSE score as covariates. Missing postbaseline HFMSE data were imputed using multiple imputation.

    Secondary: Percentage of Participants Who Achieved a 3-Point Increase from Baseline in HFMSE Score at Month 15

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    End point title
    		 Percentage of Participants Who Achieved a 3-Point Increase from Baseline in HFMSE Score at Month 15
    End point description
    The HFMSE consists of 33 scored activities used to assess motor function in children with SMA. The scale was originally developed with 20 scored activities and was devised for use in children with SMA Type 2 and Type 3 with limited ambulation to give objective information on motor ability and clinical progression. The expanded scale includes an additional module of 13 items developed to allow for evaluation of ambulatory SMA patients. Participants were asked to do a specific activity (such as rolling) and they were then graded on the quality and execution of that movement on a scale of 0=being unable, 1=performed with some compensation, and 2=unaided. The overall score is the sum of the scores for all activities with a maximum achievable score of 66. Higher scores indicate increased motor function. A positive change from Baseline indicates improvement.
    End point type
    Secondary
    End point timeframe
    Baseline and Month 15
    End point values
    		 Sham procedure Nusinersen
    Number of subjects analysed
    42
    84
    Units: percentage of participants
        number (confidence interval 95%)
    26.3 (12.4 to 40.22)
    56.8 (45.62 to 68.05)
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Sham procedure v Nusinersen
    Number of subjects included in analysis
    126
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [3]
    P-value
    		 = 0.0006 [4]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    5.59
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.09
         upper limit
    		 14.91
    Notes
    [3] - ITT Set: All participants who were randomized and received at least 1 dose of study drug/sham procedure. Missing postbaseline HFMSE data were imputed using multiple imputation.
    [4] - Based on logistic regression with treatment effect and adjustment for each participant's age at screening and HFMSE score at baseline. Missing postbaseline HFMSE data were imputed using multiple imputation.
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Difference in proportions of Nusinersen minus Sham Procedure are from the MI procedure and are based on binomial proportions.
    Comparison groups
    Sham procedure v Nusinersen
    Number of subjects included in analysis
    126
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [5]
    Method
    Parameter type
    		 Difference in Proportions
    Point estimate
    30.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 12.74
         upper limit
    		 48.31
    Notes
    [5] - ITT Set: All participants who were randomized and received at least 1 dose of study drug/sham procedure. Missing postbaseline HFMSE data were imputed using the MI.

    Secondary: Percentage of Participants that Achieved any New Motor Milestone at Month 15

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    End point title
    		 Percentage of Participants that Achieved any New Motor Milestone at Month 15
    End point description
    New motor milestones are defined as sitting without support, hands-and-knees crawling, standing with assistance, walking with assistance, standing alone and walking alone.
    End point type
    Secondary
    End point timeframe
    Month 15
    End point values
    		 Sham procedure Nusinersen
    Number of subjects analysed
    34
    66
    Units: percentage of participants
        number (confidence interval 95%)
    5.9 (0.72 to 19.68)
    19.7 (10.93 to 31.32)
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Difference in proportions of Nusinersen minus Sham Procedure is based on exact unconditional confidence interval.
    Comparison groups
    Sham procedure v Nusinersen
    Number of subjects included in analysis
    100
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [6]
    Method
    Parameter type
    		 Difference in Proportions
    Point estimate
    13.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.64
         upper limit
    		 34.17
    Notes
    [6] - Efficacy Set: All participants with a Day 456 Visit and all participants with a time difference of at least 463 days (456 days plus a 7-day window) between the date of first dose and the date for the final analysis. Based on imputed data where there was missing data.

    Secondary: Number of New Motor Milestones Achieved per Participant

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    End point title
    		 Number of New Motor Milestones Achieved per Participant
    End point description
    New motor milestones are defined as sitting without support, hands-and-knees crawling, standing with assistance, walking with assistance, standing alone and walking alone.
    End point type
    Secondary
    End point timeframe
    Month 15
    End point values
    		 Sham procedure Nusinersen
    Number of subjects analysed
    34
    66
    Units: milestones achieved
        arithmetic mean (standard deviation)
    -0.2 ± 0.54
    0.2 ± 0.51
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Based on ANCOVA with treatment as a fixed effect and adjustment for each participant's age at screening and number of milestones at baseline.
    Comparison groups
    Sham procedure v Nusinersen
    Number of subjects included in analysis
    100
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [7]
    Method
    Parameter type
    		 LS Mean Difference
    Point estimate
    0.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.2
         upper limit
    		 0.7
    Notes
    [7] - Efficacy Set: All participants with a Day 456 Visit and all participants with a time difference of at least 463 days (456 days plus a 7-day window) between the date of first dose and the date for the final analysis. Based on imputed data where there was missing data.

    Secondary: Change from Baseline in Revised Upper Limb Module (RULM) Test

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    End point title
    		 Change from Baseline in Revised Upper Limb Module (RULM) Test
    End point description
    The RULM Test is used in patients 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 has a total of 20 items with an entry item that serves as functional class identification and does not contribute to the total score. The remaining 19 scorable items reflect different functional domains and are graded on a 3-point system with a score of 0 (unable), 1 (able, with modification), and a maximum of 2 (able, no difficulty). There is only 1 item (item I) that is scored as a can/cannot score, with 1 as the highest score. Scorable items are summed for a total score range of 0-37, with higher scores increased great upper limb function. A positive change from Baseline indicates improvement.
    End point type
    Secondary
    End point timeframe
    Baseline and Month 15
    End point values
    		 Sham procedure Nusinersen
    Number of subjects analysed
    42
    84
    Units: scores on a scale
        least squares mean (confidence interval 95%)
    0.5 (-0.6 to 1.6)
    4.2 (3.4 to 5)
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    From multiple imputation procedure, based on ANCOVA with treatment as a fixed effect and adjustment for each participant's age at screening and derived total score at baseline.
    Comparison groups
    Sham procedure v Nusinersen
    Number of subjects included in analysis
    126
    Analysis specification
    Pre-specified
    Analysis type
    		 [8]
    Method
    Parameter type
    		 LS Mean Difference
    Point estimate
    3.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.3
         upper limit
    		 5
    Notes
    [8] - ITT Set: All participants who were randomized and received at least 1 dose of study drug/sham procedure. Missing postbaseline data were imputed using the multiple imputation.

    Secondary: Percentage of Participants that Achieved Standing Alone

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    End point title
    		 Percentage of Participants that Achieved Standing Alone
    End point description
    If the participant was unable to achieve standing alone at Baseline but could achieve this at Month 15 then they were considered a responder. If they could not achieve this or if a participant terminated the study prior to the 15-month assessment due to treatment failure or death, then any imputed value was ignored and the participant was considered as a non-responder.
    End point type
    Secondary
    End point timeframe
    Month 15
    End point values
    		 Sham procedure Nusinersen
    Number of subjects analysed
    34
    66
    Units: percentage of participants
        number (confidence interval 95%)
    2.9 (0.07 to 15.33)
    1.5 (0.04 to 8.16)
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Difference in proportions of Nusinersen minus Sham Procedure is based on exact unconditional confidence interval.
    Comparison groups
    Sham procedure v Nusinersen
    Number of subjects included in analysis
    100
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [9]
    Method
    Parameter type
    		 Difference in Proportions
    Point estimate
    -1.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -21.84
         upper limit
    		 19.34
    Notes
    [9] - Efficacy Set: All participants with a Day 456 Visit and all participants with a time difference of at least 463 days (456 days plus a 7-day window) between the date of first dose and the date for the final analysis. Based on imputed data where there was missing data.

    Secondary: Percentage of Participants that Achieved Walking with Assistance

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    End point title
    		 Percentage of Participants that Achieved Walking with Assistance
    End point description
    If the participant was unable to achieve walking with assistance at baseline but could achieve this at Month 15 then they were considered a responder. If they could not achieve this or if a participant terminated the study prior to the 15-month assessment due to treatment failure or death, then any imputed value was ignored and the participant was considered as a non-responder.
    End point type
    Secondary
    End point timeframe
    Month 15
    End point values
    		 Sham procedure Nusinersen
    Number of subjects analysed
    34
    66
    Units: percentage pf participants
        number (confidence interval 95%)
    0 (0 to 10.28)
    1.5 (0.04 to 8.16)
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Difference in proportions of Nusinersen minus Sham Procedure is based on exact unconditional confidence interval.
    Comparison groups
    Sham procedure v Nusinersen
    Number of subjects included in analysis
    100
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [10]
    Method
    Parameter type
    		 Difference in Proportions
    Point estimate
    1.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -19.1
         upper limit
    		 22.1
    Notes
    [10] - Efficacy Set: All participants with a Day 456 Visit and all participants with a time difference of at least 463 days (456 days plus a 7-day window) between the date of first dose and the date for the final analysis. Based on imputed data where there was missing data.

    Secondary: Number of Participants that Experienced Adverse Events (AEs) and Serious Adverse Events (SAEs)

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    End point title
    		 Number of Participants that Experienced Adverse Events (AEs) and Serious Adverse Events (SAEs)
    End point description
    AEs: any sign, symptom, or diagnosis/disease that is unfavorable or unintended, that is new, or if pre-existing, worsens in participants administered a pharmaceutical product and that does not necessarily have a causal relationship with this treatment. SAEs: an event that results in death; an event that, in the view of the investigator, places the participant at immediate risk of death (a life-threatening event); an outcome that results in a congenital anomaly/birth defect diagnosed in a child of a participant; an event that requires or prolongs inpatient hospitalization; an event that results in persistent or significant disability/incapacity. Any other medically important event that, in the opinion of the investigator, may jeopardize the participant or may require intervention to prevent one of the other outcomes listed in the definition above.
    End point type
    Secondary
    End point timeframe
    Baseline through Month 15
    End point values
    		 Sham procedure Nusinersen
    Number of subjects analysed
    42
    84
    Units: participants
        AEs
    42
    78
        SAEs
    12
    14
    No statistical analyses for this end point

    Secondary: Number of Participants with Clinically Significant Vital Sign Abnormalities

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    End point title
    		 Number of Participants with Clinically Significant Vital Sign Abnormalities
    End point description
    Vital signs assessed for clinical significance include resting blood pressure, pulse, respiratory rate, and temperature.
    End point type
    Secondary
    End point timeframe
    Baseline through Month 15
    End point values
    		 Sham procedure Nusinersen
    Number of subjects analysed
    0 [11]
    0 [12]
    Units: participants
    Notes
    [11] - New or worsening vital sign findings were reported as AEs and are presented in the AE/SAE section.
    [12] - New or worsening vital sign findings were reported as AEs and are presented in the AE/SAE section.
    No statistical analyses for this end point

    Secondary: Number of Participants with Clinically Significant Weight Abnormalities

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    End point title
    		 Number of Participants with Clinically Significant Weight Abnormalities
    End point description
    Weight changes assessed for clinical significance include body weight (including weight for age), ulnar length, and height (including height for age).
    End point type
    Secondary
    End point timeframe
    Baseline through Month 15
    End point values
    		 Sham procedure Nusinersen
    Number of subjects analysed
    0 [13]
    0 [14]
    Units: participants
    Notes
    [13] - New or worsening weight abnormalities were reported as AEs and are presented in the AE/SAE section.
    [14] - New or worsening weight abnormalities were reported as AEs and are presented in the AE/SAE section.
    No statistical analyses for this end point

    Secondary: Number of Participants with Clinically Significant Neurological Examination Abnormalities

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    End point title
    		 Number of Participants with Clinically Significant Neurological Examination Abnormalities
    End point description
    Neurological changes assessed for clinical significance include assessment of mental status, level of consciousness, sensory function, motor function, cranial nerve function, and reflexes.
    End point type
    Secondary
    End point timeframe
    Baseline through Month 15
    End point values
    		 Sham procedure Nusinersen
    Number of subjects analysed
    0 [15]
    0 [16]
    Units: participants
    Notes
    [15] - New or worsening neurological findings were reported as AEs and are presented in the AE/SAE section.
    [16] - New or worsening neurological findings were reported as AEs and are presented in the AE/SAE section.
    No statistical analyses for this end point

    Secondary: Number of Participants with Clinically Significant Physical Examination Abnormalities

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    End point title
    		 Number of Participants with Clinically Significant Physical Examination Abnormalities
    End point description
    Physical examination changes were assessed for clinical significance.
    End point type
    Secondary
    End point timeframe
    Baseline through Month 15
    End point values
    		 Sham procedure Nusinersen
    Number of subjects analysed
    0 [17]
    0 [18]
    Units: participants
    Notes
    [17] - New or worsening physical exam findings were reported as AEs and are in the AE/SAE section.
    [18] - New or worsening physical exam findings were reported as AEs and are in the AE/SAE section.
    No statistical analyses for this end point

    Secondary: Number of Participants with Clinically Significant Laboratory Parameters

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    End point title
    		 Number of Participants with Clinically Significant Laboratory Parameters
    End point description
    Laboratory parameter changes assessed for clinical significance include serum chemistry, hematology, coagulation and urinalysis.
    End point type
    Secondary
    End point timeframe
    Baseline through Month 15
    End point values
    		 Sham procedure Nusinersen
    Number of subjects analysed
    0 [19]
    0 [20]
    Units: participants
    Notes
    [19] - New or worsening laboratory parameter findings were reported as AEs and are in the AE/SAE section.
    [20] - New or worsening laboratory parameter findings were reported as AEs and are in the AE/SAE section.
    No statistical analyses for this end point

    Secondary: Number of Participants with Abnormal, Clinically Relevant Post-Baseline Worsening in Electrocardiogram (ECG) in Results

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    End point title
    		 Number of Participants with Abnormal, Clinically Relevant Post-Baseline Worsening in Electrocardiogram (ECG) in Results
    End point description
    The number of participants with abnormal, clinically relevant worsening, defined as participants with an ECG interpreted as abnormal and clinically relevant, with a comparison with Baseline value is reported.
    End point type
    Secondary
    End point timeframe
    Baseline through Month 15
    End point values
    		 Sham procedure Nusinersen
    Number of subjects analysed
    42
    84
    Units: participants
    2
    0
    No statistical analyses for this end point

    Secondary: Number of Participants Taking Any Concomitant Medication Related to Dosing Procedure or Sham Procedure

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    End point title
    		 Number of Participants Taking Any Concomitant Medication Related to Dosing Procedure or Sham Procedure
    End point description
    Concomitant medications include prescription and over-the-counter medications administered to participants on or after the first day of study treatment.
    End point type
    Secondary
    End point timeframe
    Baseline through Month 15
    End point values
    		 Sham procedure Nusinersen
    Number of subjects analysed
    42
    84
    Units: participants
    42
    84
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From signing of Informed Consent to the end of the Follow-up period (Month 15)
    Adverse event reporting additional description
    Treatment emergent AEs are presented regardless of seriousness or relationship to investigational product.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.1
    Reporting groups
    Reporting group title
    Nusinersen
    Reporting group description
    		 Nusinersen 12 mg solution via intrathecal (IT) injection on Days 1, 29, 85 and 274.

    Reporting group title
    Sham procedure
    Reporting group description
    		 Sham comparator on Days 1, 29, 85 and 274.

    Serious adverse events
    		 Nusinersen Sham procedure
    Total subjects affected by serious adverse events
         subjects affected / exposed
    14 / 84 (16.67%)
    12 / 42 (28.57%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    Injury, poisoning and procedural complications
    Post lumbar puncture syndrome
         subjects affected / exposed
    1 / 84 (1.19%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pain
         subjects affected / exposed
    1 / 84 (1.19%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    1 / 84 (1.19%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Faecaloma
         subjects affected / exposed
    0 / 84 (0.00%)
    2 / 42 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pneumonia aspiration
         subjects affected / exposed
    1 / 84 (1.19%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory distress
         subjects affected / exposed
    2 / 84 (2.38%)
    2 / 42 (4.76%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Bacteraemia
         subjects affected / exposed
    1 / 84 (1.19%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    1 / 84 (1.19%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    2 / 84 (2.38%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    0 / 84 (0.00%)
    2 / 42 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Parainfluenzae virus infection
         subjects affected / exposed
    1 / 84 (1.19%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    2 / 84 (2.38%)
    6 / 42 (14.29%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia adenoviral
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia parainfluenzae viral
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia viral
         subjects affected / exposed
    3 / 84 (3.57%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory syncytial virus bronchitis
         subjects affected / exposed
    1 / 84 (1.19%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory syncytial virus infection
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 84 (0.00%)
    2 / 42 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Nusinersen Sham procedure
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    75 / 84 (89.29%)
    42 / 42 (100.00%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    24 / 84 (28.57%)
    3 / 42 (7.14%)
         occurrences all number
    30
    4
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    36 / 84 (42.86%)
    15 / 42 (35.71%)
         occurrences all number
    52
    30
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    5 / 84 (5.95%)
    4 / 42 (9.52%)
         occurrences all number
    5
    6
    Diarrhoea
         subjects affected / exposed
    8 / 84 (9.52%)
    3 / 42 (7.14%)
         occurrences all number
    9
    3
    Vomiting
         subjects affected / exposed
    24 / 84 (28.57%)
    5 / 42 (11.90%)
         occurrences all number
    29
    5
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    21 / 84 (25.00%)
    9 / 42 (21.43%)
         occurrences all number
    37
    16
    Epistaxis
         subjects affected / exposed
    6 / 84 (7.14%)
    0 / 42 (0.00%)
         occurrences all number
    6
    0
    Rhinorrhoea
         subjects affected / exposed
    6 / 84 (7.14%)
    7 / 42 (16.67%)
         occurrences all number
    10
    15
    Upper respiratory tract congestion
         subjects affected / exposed
    5 / 84 (5.95%)
    2 / 42 (4.76%)
         occurrences all number
    6
    2
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    4 / 84 (4.76%)
    4 / 42 (9.52%)
         occurrences all number
    4
    5
    Back pain
         subjects affected / exposed
    21 / 84 (25.00%)
    0 / 42 (0.00%)
         occurrences all number
    24
    0
    Joint contracture
         subjects affected / exposed
    4 / 84 (4.76%)
    7 / 42 (16.67%)
         occurrences all number
    4
    8
    Pain in extremity
         subjects affected / exposed
    4 / 84 (4.76%)
    3 / 42 (7.14%)
         occurrences all number
    4
    3
    Scoliosis
         subjects affected / exposed
    3 / 84 (3.57%)
    3 / 42 (7.14%)
         occurrences all number
    3
    3
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    7 / 84 (8.33%)
    4 / 42 (9.52%)
         occurrences all number
    8
    6
    Conjunctivitis
         subjects affected / exposed
    6 / 84 (7.14%)
    2 / 42 (4.76%)
         occurrences all number
    6
    2
    Ear infection
         subjects affected / exposed
    7 / 84 (8.33%)
    5 / 42 (11.90%)
         occurrences all number
    10
    6
    Gastroenteritis
         subjects affected / exposed
    9 / 84 (10.71%)
    8 / 42 (19.05%)
         occurrences all number
    11
    10
    Gastroenteritis viral
         subjects affected / exposed
    8 / 84 (9.52%)
    4 / 42 (9.52%)
         occurrences all number
    10
    7
    Influenza
         subjects affected / exposed
    8 / 84 (9.52%)
    2 / 42 (4.76%)
         occurrences all number
    8
    4
    Nasopharyngitis
         subjects affected / exposed
    20 / 84 (23.81%)
    15 / 42 (35.71%)
         occurrences all number
    40
    25
    Otitis media
         subjects affected / exposed
    5 / 84 (5.95%)
    4 / 42 (9.52%)
         occurrences all number
    5
    4
    Pharyngitis streptococcal
         subjects affected / exposed
    4 / 84 (4.76%)
    3 / 42 (7.14%)
         occurrences all number
    4
    3
    Pneumonia
         subjects affected / exposed
    4 / 84 (4.76%)
    6 / 42 (14.29%)
         occurrences all number
    6
    9
    Upper respiratory tract infection
         subjects affected / exposed
    25 / 84 (29.76%)
    19 / 42 (45.24%)
         occurrences all number
    39
    32

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    26 Sep 2014
    Revised the statistical methods used to perform the interim analysis, revised the statistical methods used to perform the interim analysis, clarified the intention to continue safety follow-up via scheduled study visits for subjects who discontinue treatment without withdrawal of consent, added the main findings from nonclinical studies with ISIS 396443, clarified that general and local anesthesia and sedation were allowed to be used for LP procedure, added the neurological examination and HFMSE as appendices.
    30 Jun 2016
    Clarified the interim analysis plan, including its timing, subset of the total study population to be included, endpoints, and analytical methods used, clarified disposition of study subjects under the scenario of a premature study termination based on the results of a positive interim analysis, added language to describe the potential changes to study conduct that may occur on the basis of a positive benefit-risk assessment of the results of the interim analysis, added a statement regarding unblinding of certain representatives of the Sponsor during the interim analysis, updated clinical experience information to match Investigator’s Brochure, Version 6.0, January 2016, clarified adjustment of visit schedule for subjects who experience treatment delays as a result of illness, specific descriptions of the methodology for the efficacy endpoints was added, made minor changes to correct errors and improve clarity.

    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.
    After the positive interim analysis of the study, the decision was made in October 2016 to terminate the study early and participants were invited for end-of-study visits.
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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