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    Clinical Trial Results:
    An Open-Label Study of Risdiplam in Infants With Genetically Diagnosed and Presymptomatic Spinal Muscular Atrophy

    Summary
    EudraCT number
    		 2018-002087-12
    Trial protocol
    		 BE   PL   IT  
    Global end of trial date

    Results information
    Results version number
    		 v1(current)
    This version publication date
    06 Mar 2024
    First version publication date
    06 Mar 2024
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    BN40703
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03779334
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    F. Hoffmann-La Roche AG
    Sponsor organisation address
    Grenzacherstrasse 124, Basel, Switzerland, CH-4070
    Public contact
    F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, 41 616878333, global.trial_information@roche.com
    Scientific contact
    F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, 41 616878333, global.trial_information@roche.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-002070-PIP01-16
    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
    Interim
    Date of interim/final analysis
    20 Feb 2023
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    20 Feb 2023
    Global end of trial reached?
    No
    General information about the trial
    Main objective of the trial
    The main objective of the clinical study is to investigate the efficacy of risdiplam in infants aged from birth to 6 weeks who have been genetically diagnosed with spinal muscular atrophy (SMA) but are not yet presenting with symptoms.
    Protection of trial subjects
    A legally authorized representative for the participant was required to read and sign an informed Consent Form.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    07 Aug 2019
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety
    Long term follow-up duration
    		 1 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Australia: 8
    Country: Number of subjects enrolled
    Belgium: 3
    Country: Number of subjects enrolled
    Brazil: 3
    Country: Number of subjects enrolled
    Poland: 3
    Country: Number of subjects enrolled
    Russian Federation: 5
    Country: Number of subjects enrolled
    Taiwan: 2
    Country: Number of subjects enrolled
    United States: 2
    Worldwide total number of subjects
    26
    EEA total number of subjects
    6
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    15
    Infants and toddlers (28 days-23 months)
    11
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Overall, 26 infants with spinal muscular atrophy (SMA) were enrolled in the study across 7 different sites in 7 countries.

    Pre-assignment
    Screening details
    		 The study enrolled infants aged from birth to 6 weeks who were genetically diagnosed with SMA but were not yet presenting with symptoms. Study arms were based on the number of copies of the SMN2 gene.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 2 SMN2 Copies, Risdiplam
    Arm description
    		 Infants with 2 copies of SMN2 were enrolled to receive risdiplam orally once daily at a dose selected to achieve the targeted exposure range.
    Arm type
    		 Experimental

    Investigational medicinal product name
    risdiplam
    Investigational medicinal product code
    Other name
    Evrysdi
    Pharmaceutical forms
    Powder for oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    Risdiplam was administered orally at a dose selected to achieve the targeted exposure range of close to 2000 ng*hr/mL.

    Arm title
    		 3 SMN2 Copies, Risdiplam
    Arm description
    		 Infants with 3 copies of SMN2 were enrolled to receive risdiplam orally once daily at a dose selected to achieve the targeted exposure range.
    Arm type
    		 Experimental

    Investigational medicinal product name
    risdiplam
    Investigational medicinal product code
    Other name
    Evrysdi
    Pharmaceutical forms
    Powder for oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    Risdiplam was administered orally at a dose selected to achieve the targeted exposure range of close to 2000 ng*hr/mL.

    Arm title
    		 >/=4 SMN2 Copies, Risdiplam
    Arm description
    		 Infants with 4 or more copies of SMN2 were enrolled to receive risdiplam orally once daily at a dose selected to achieve the targeted exposure range.
    Arm type
    		 Experimental

    Investigational medicinal product name
    risdiplam
    Investigational medicinal product code
    Other name
    Evrysdi
    Pharmaceutical forms
    Powder for oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    Risdiplam was administered orally at a dose selected to achieve the targeted exposure range of close to 2000 ng*hr/mL.

    Number of subjects in period 1
    		2 SMN2 Copies, Risdiplam 3 SMN2 Copies, Risdiplam >/=4 SMN2 Copies, Risdiplam
    Started
    8
    13
    5
    Primary Efficacy Population
    5
    0
    0
    Completed
    0
    0
    0
    Not completed
    8
    13
    5
         Consent withdrawn by subject
    3
    -
    -
         Ongoing in Study
    5
    13
    5

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    2 SMN2 Copies, Risdiplam
    Reporting group description
    		 Infants with 2 copies of SMN2 were enrolled to receive risdiplam orally once daily at a dose selected to achieve the targeted exposure range.

    Reporting group title
    3 SMN2 Copies, Risdiplam
    Reporting group description
    		 Infants with 3 copies of SMN2 were enrolled to receive risdiplam orally once daily at a dose selected to achieve the targeted exposure range.

    Reporting group title
    >/=4 SMN2 Copies, Risdiplam
    Reporting group description
    		 Infants with 4 or more copies of SMN2 were enrolled to receive risdiplam orally once daily at a dose selected to achieve the targeted exposure range.

    Reporting group values
    		 2 SMN2 Copies, Risdiplam 3 SMN2 Copies, Risdiplam >/=4 SMN2 Copies, Risdiplam Total
    Number of subjects
    		 8 13 5 26
    Age categorical
    Units: Subjects
    Age Continuous
    Units: days
        arithmetic mean (standard deviation)
    		 22.8 ( 5.0 ) 28.9 ( 7.5 ) 31.2 ( 6.1 ) -
    Sex: Female, Male
    Units: participants
        Female
    		 4 9 3 16
        Male
    		 4 4 2 10

    End points

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    End points reporting groups
    Reporting group title
    2 SMN2 Copies, Risdiplam
    Reporting group description
    		 Infants with 2 copies of SMN2 were enrolled to receive risdiplam orally once daily at a dose selected to achieve the targeted exposure range.

    Reporting group title
    3 SMN2 Copies, Risdiplam
    Reporting group description
    		 Infants with 3 copies of SMN2 were enrolled to receive risdiplam orally once daily at a dose selected to achieve the targeted exposure range.

    Reporting group title
    >/=4 SMN2 Copies, Risdiplam
    Reporting group description
    		 Infants with 4 or more copies of SMN2 were enrolled to receive risdiplam orally once daily at a dose selected to achieve the targeted exposure range.

    Primary: Percentage of participants with two copies of the survival motor neuron (SMN) 2 gene (excluding the known SMN2 gene modifier mutation c.859G>C) and baseline compound muscle action potential (CMAP) >=1.5 millivolt (mV) who are sitting without support

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    End point title
    		 Percentage of participants with two copies of the survival motor neuron (SMN) 2 gene (excluding the known SMN2 gene modifier mutation c.859G>C) and baseline compound muscle action potential (CMAP) >=1.5 millivolt (mV) who are sitting without support [1] [2]
    End point description
    The Bayley Scales of Infant and Toddler Development, Third Edition (BSID-III) Gross Motor Scale is a commonly used measure of infant and toddler development (0 to 42 months). The gross motor scale consists of 72 items scored at 0 (unable to perform the activity) or 1 (item achieved). Item 22, “sits without support for 5 seconds”, is not considered achieved if the infant sits alone for less than 5 seconds before losing balance and falling over, or if the infant uses his or her arms to prop him- or herself up. Primary efficacy population included all infants in the ITT population with two SMN2 copies (excluding the known SMN2 gene modifier mutation c.859G>C) and a baseline compound muscle action potential (CMAP) amplitude >/= 1.5 mV. 90% CI for one sample binomial was computed using Clopper-Pearson (exact) method. An exact binomial test was performed. If the lower limit of the two-sided 90% CI was above the 5% threshold, the primary objective of the study was considered achieved.
    End point type
    Primary
    End point timeframe
    At Month 12
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Data were reported for only one arm and no statistical analysis could be conducted.
    [2] - 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: Only one arm in the study met the requirements for the primary efficacy analysis population of this endpoint.
    End point values
    		 2 SMN2 Copies, Risdiplam
    Number of subjects analysed
    5
    Units: percentage of participants
        number (confidence interval 90%)
    80.0 (34.26 to 98.98)
    No statistical analyses for this end point

    Secondary: Percentage of participants developing clinically manifested SMA

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    End point title
    		 Percentage of participants developing clinically manifested SMA
    End point description
    End point type
    Secondary
    End point timeframe
    At Month 12 and 24
    End point values
    		 2 SMN2 Copies, Risdiplam 3 SMN2 Copies, Risdiplam >/=4 SMN2 Copies, Risdiplam
    Number of subjects analysed
    0 [3]
    0 [4]
    0 [5]
    Units: percentage of participants
        number (confidence interval 90%)
    ( to )
    ( to )
    ( to )
    Notes
    [3] - Data collection is still ongoing. Results to be reported at two-year interim analysis.
    [4] - Data collection is still ongoing. Results to be reported at two-year interim analysis.
    [5] - Data collection is still ongoing. Results to be reported at two-year interim analysis.
    No statistical analyses for this end point

    Secondary: Percentage of participants who are alive without permanent ventilation

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    End point title
    		 Percentage of participants who are alive without permanent ventilation
    End point description
    End point type
    Secondary
    End point timeframe
    At Month 12 and 24
    End point values
    		 2 SMN2 Copies, Risdiplam 3 SMN2 Copies, Risdiplam >/=4 SMN2 Copies, Risdiplam
    Number of subjects analysed
    0 [6]
    0 [7]
    0 [8]
    Units: percentage of participants
        number (confidence interval 90%)
    ( to )
    ( to )
    ( to )
    Notes
    [6] - Data collection is still ongoing. Results to be reported at two-year interim analysis.
    [7] - Data collection is still ongoing. Results to be reported at two-year interim analysis.
    [8] - Data collection is still ongoing. Results to be reported at two-year interim analysis.
    No statistical analyses for this end point

    Secondary: Time to permanent ventilation and/or death

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    End point title
    		 Time to permanent ventilation and/or death
    End point description
    End point type
    Secondary
    End point timeframe
    Up to 7 years
    End point values
    		 2 SMN2 Copies, Risdiplam 3 SMN2 Copies, Risdiplam >/=4 SMN2 Copies, Risdiplam
    Number of subjects analysed
    0 [9]
    0 [10]
    0 [11]
    Units: months
        median (full range (min-max))
    ( to )
    ( to )
    ( to )
    Notes
    [9] - Data collection is still ongoing. Results to be reported at final analysis.
    [10] - Data collection is still ongoing. Results to be reported at final analysis.
    [11] - Data collection is still ongoing. Results to be reported at final analysis.
    No statistical analyses for this end point

    Secondary: Percentage of participants alive

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    End point title
    		 Percentage of participants alive
    End point description
    End point type
    Secondary
    End point timeframe
    At Month 12 and 24
    End point values
    		 2 SMN2 Copies, Risdiplam 3 SMN2 Copies, Risdiplam >/=4 SMN2 Copies, Risdiplam
    Number of subjects analysed
    0 [12]
    0 [13]
    0 [14]
    Units: percentage of participants
        number (not applicable)
    Notes
    [12] - Data collection is still ongoing. Results to be reported at two-year interim analysis.
    [13] - Data collection is still ongoing. Results to be reported at two-year interim analysis.
    [14] - Data collection is still ongoing. Results to be reported at two-year interim analysis.
    No statistical analyses for this end point

    Secondary: Percentage of participants who achieve the attainment level of the motor milestones as assessed in the Hammersmith Infant Neurological Examination-2 (HINE-2)

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    End point title
    		 Percentage of participants who achieve the attainment level of the motor milestones as assessed in the Hammersmith Infant Neurological Examination-2 (HINE-2)
    End point description
    HINE-2 assessment includes head control, sitting, voluntary grasp, ability to kick, rolling, crawling, standing, and walking
    End point type
    Secondary
    End point timeframe
    At Month 12 and 24
    End point values
    		 2 SMN2 Copies, Risdiplam 3 SMN2 Copies, Risdiplam >/=4 SMN2 Copies, Risdiplam
    Number of subjects analysed
    0 [15]
    0 [16]
    0 [17]
    Units: percentage of participants
        number (confidence interval 90%)
    ( to )
    ( to )
    ( to )
    Notes
    [15] - Data collection is still ongoing. Results to be reported at two-year interim analysis.
    [16] - Data collection is still ongoing. Results to be reported at two-year interim analysis.
    [17] - Data collection is still ongoing. Results to be reported at two-year interim analysis.
    No statistical analyses for this end point

    Secondary: Percentage of participants with two copies of the SMN2 gene sitting without support for 5 seconds (independent of the CMAP value at baseline).

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    End point title
    		 Percentage of participants with two copies of the SMN2 gene sitting without support for 5 seconds (independent of the CMAP value at baseline). [18]
    End point description
    Assessed in Item 22 of the BSID-III Gross Motor Scale. The BSID-III is a commonly used measure of infant and toddler development (0 to 42 months). The normed-scores derived from the BSID-III are used in clinical practice to detect infants with developmental delays, as well as to evaluate developmental progress and the impact of therapeutic interventions. The gross motor scale consists of 72 items scored at 0 (unable to perform the activity) or 1 (criteria for item achieved). Item 22, “sits without support for 5 seconds”, is not considered achieved if the infant sits alone for less than 5 seconds before losing balance and falling over, or if the infant uses his or her arms to prop him- or herself up. Intent-to-treat (ITT) population included all enrolled participants, regardless of whether they received risdiplam or not. Only participants with two copies of the SMN2 gene were included in this endpoint. 90% CI for one sample binomial was computed used Clopper-Pearson (exact) method.
    End point type
    Secondary
    End point timeframe
    At Month 12
    Notes
    [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: Only one arm in the study met the requirements for the efficacy analysis population of this endpoint.
    End point values
    		 2 SMN2 Copies, Risdiplam
    Number of subjects analysed
    8
    Units: percentage of participants
        number (confidence interval 90%)
    87.5 (52.93 to 99.36)
    No statistical analyses for this end point

    Secondary: Percentage of participants sitting without support for 30 seconds

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    End point title
    		 Percentage of participants sitting without support for 30 seconds
    End point description
    Assessed with BSID-III Gross Motor Scale
    End point type
    Secondary
    End point timeframe
    At Month 12 and 24
    End point values
    		 2 SMN2 Copies, Risdiplam 3 SMN2 Copies, Risdiplam >/=4 SMN2 Copies, Risdiplam
    Number of subjects analysed
    0 [19]
    0 [20]
    0 [21]
    Units: percentage of participants
        number (confidence interval 90%)
    ( to )
    ( to )
    ( to )
    Notes
    [19] - Data collection is still ongoing. Results to be reported at two-year interim analysis.
    [20] - Data collection is still ongoing. Results to be reported at two-year interim analysis.
    [21] - Data collection is still ongoing. Results to be reported at two-year interim analysis.
    No statistical analyses for this end point

    Secondary: Percentage of participants standing for at least 3 seconds

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    End point title
    		 Percentage of participants standing for at least 3 seconds
    End point description
    Assessed with BSID-III Gross Motor Scale
    End point type
    Secondary
    End point timeframe
    At Month 24
    End point values
    		 2 SMN2 Copies, Risdiplam 3 SMN2 Copies, Risdiplam >/=4 SMN2 Copies, Risdiplam
    Number of subjects analysed
    0 [22]
    0 [23]
    0 [24]
    Units: percentage of participants
        number (confidence interval 90%)
    ( to )
    ( to )
    ( to )
    Notes
    [22] - Data collection is still ongoing. Results to be reported at two-year interim analysis.
    [23] - Data collection is still ongoing. Results to be reported at two-year interim analysis.
    [24] - Data collection is still ongoing. Results to be reported at two-year interim analysis.
    No statistical analyses for this end point

    Secondary: Percentage of participants sitting without support for 5 seconds

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    End point title
    		 Percentage of participants sitting without support for 5 seconds
    End point description
    Assessed with BSID-III Gross Motor Scale
    End point type
    Secondary
    End point timeframe
    At Month 24
    End point values
    		 2 SMN2 Copies, Risdiplam 3 SMN2 Copies, Risdiplam >/=4 SMN2 Copies, Risdiplam
    Number of subjects analysed
    0 [25]
    0 [26]
    0 [27]
    Units: percentage of participants
        number (confidence interval 90%)
    ( to )
    ( to )
    ( to )
    Notes
    [25] - Data collection is still ongoing. Results to be reported at two-year interim analysis.
    [26] - Data collection is still ongoing. Results to be reported at two-year interim analysis.
    [27] - Data collection is still ongoing. Results to be reported at two-year interim analysis.
    No statistical analyses for this end point

    Secondary: Change from baseline score in the Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) motor function scale at Month 12

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    End point title
    		 Change from baseline score in the Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) motor function scale at Month 12
    End point description
    The CHOP-INTEND is a measure of motor function that was developed from the Test of Infant Motor Performance specifically for weak infants with neuromuscular disease. It consists of 16 items, where each item assesses a specific motor task (such as spontaneous movement of upper and lower extremity, hand grasping, rolling, head control, and others) graded on a scale of 0 to 4, where zero is no response and 4 is a complete response. A total score is calculated by summing the item scores (range 0 to 64) with lower scores indicating greater severity. A positive change from baseline indicates an improvement. ITT population included all enrolled participants, regardless of whether they received risdiplam or not. n indicates the number of participants analyzed for each time point.
    End point type
    Secondary
    End point timeframe
    Baseline, Month 12
    End point values
    		 2 SMN2 Copies, Risdiplam 3 SMN2 Copies, Risdiplam >/=4 SMN2 Copies, Risdiplam
    Number of subjects analysed
    8
    13
    5
    Units: score on a scale
    median (full range (min-max))
        Baseline (n=8, 13, 5)
    46.50 (35.0 to 52.0)
    55.00 (44.0 to 62.0)
    50.00 (44.0 to 52.0)
        Change from Baseline at Month 12 (n=8, 13, 4)
    9.50 (-6.0 to 20.0)
    8.00 (2.0 to 20.0)
    16.00 (8.0 to 19.0)
    No statistical analyses for this end point

    Secondary: Percentage of participants demonstrating the ability to achieve a scaled score on BSID-III Gross Motor Subtests within 1.5 standard deviations of chronological reference standard

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    End point title
    		 Percentage of participants demonstrating the ability to achieve a scaled score on BSID-III Gross Motor Subtests within 1.5 standard deviations of chronological reference standard
    End point description
    Assessed through BSID-III Gross Motor Scale
    End point type
    Secondary
    End point timeframe
    At Month 24 and 42
    End point values
    		 2 SMN2 Copies, Risdiplam 3 SMN2 Copies, Risdiplam >/=4 SMN2 Copies, Risdiplam
    Number of subjects analysed
    0 [28]
    0 [29]
    0 [30]
    Units: percentage of participants
        number (confidence interval 90%)
    ( to )
    ( to )
    ( to )
    Notes
    [28] - Data collection is still ongoing. Results to be reported at final analysis.
    [29] - Data collection is still ongoing. Results to be reported at final analysis.
    [30] - Data collection is still ongoing. Results to be reported at final analysis.
    No statistical analyses for this end point

    Secondary: Percentage of participants walking (takes at least 3 steps)

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    End point title
    		 Percentage of participants walking (takes at least 3 steps)
    End point description
    Assessed with BSID-III Gross Motor Scale
    End point type
    Secondary
    End point timeframe
    At Month 24
    End point values
    		 2 SMN2 Copies, Risdiplam 3 SMN2 Copies, Risdiplam >/=4 SMN2 Copies, Risdiplam
    Number of subjects analysed
    0 [31]
    0 [32]
    0 [33]
    Units: percentage of participants
        number (confidence interval 90%)
    ( to )
    ( to )
    ( to )
    Notes
    [31] - Data collection is still ongoing. Results to be reported at two-year interim analysis.
    [32] - Data collection is still ongoing. Results to be reported at two-year interim analysis.
    [33] - Data collection is still ongoing. Results to be reported at two-year interim analysis.
    No statistical analyses for this end point

    Secondary: Percentage of participants who meet CHOP INTEND stopping criteria at any point

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    End point title
    		 Percentage of participants who meet CHOP INTEND stopping criteria at any point
    End point description
    End point type
    Secondary
    End point timeframe
    Up to Month 24
    End point values
    		 2 SMN2 Copies, Risdiplam 3 SMN2 Copies, Risdiplam >/=4 SMN2 Copies, Risdiplam
    Number of subjects analysed
    0 [34]
    0 [35]
    0 [36]
    Units: percentage of participants
        number (confidence interval 90%)
    ( to )
    ( to )
    ( to )
    Notes
    [34] - Data collection is still ongoing. Results to be reported at two-year interim analysis.
    [35] - Data collection is still ongoing. Results to be reported at two-year interim analysis.
    [36] - Data collection is still ongoing. Results to be reported at two-year interim analysis.
    No statistical analyses for this end point

    Secondary: Percentage of participants who achieve a score of 40 or higher, 50 or higher, and 60 or higher in the CHOP INTEND motor function scale at Month 12

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    End point title
    		 Percentage of participants who achieve a score of 40 or higher, 50 or higher, and 60 or higher in the CHOP INTEND motor function scale at Month 12
    End point description
    The CHOP-INTEND is a measure of motor function that was developed from the Test of Infant Motor Performance specifically for weak infants with neuromuscular disease. It consists of 16 items, where each item assesses a specific motor task (such as spontaneous movement of upper and lower extremity, hand grasping, rolling, head control, and others) graded on a scale of 0 to 4, where zero is no response and 4 is a complete response. A total score is calculated by summing the item scores (range 0 to 64) with lower scores indicating greater severity. ITT population included all enrolled participants, regardless of whether they received risdiplam or not. Data are presented with a two-sided 90% Clopper-Pearson (exact) CI for the proportion.
    End point type
    Secondary
    End point timeframe
    At Month 12
    End point values
    		 2 SMN2 Copies, Risdiplam 3 SMN2 Copies, Risdiplam >/=4 SMN2 Copies, Risdiplam
    Number of subjects analysed
    8
    13
    4
    Units: percentage of participants
    number (confidence interval 90%)
        Score >=40
    75.0 (40.03 to 95.36)
    100 (79.42 to 100.00)
    100 (47.29 to 100.00)
        Score >=50
    75.0 (40.03 to 95.36)
    100 (79.42 to 100.00)
    100 (47.29 to 100.00)
        Score >=60
    37.5 (11.11 to 71.08)
    100 (79.42 to 100.00)
    100 (47.29 to 100.00)
    No statistical analyses for this end point

    Secondary: Change from baseline in the Hammersmith Functional Motor Scale Expanded (HFMSE) score

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    End point title
    		 Change from baseline in the Hammersmith Functional Motor Scale Expanded (HFMSE) score
    End point description
    End point type
    Secondary
    End point timeframe
    At Month 60
    End point values
    		 2 SMN2 Copies, Risdiplam 3 SMN2 Copies, Risdiplam >/=4 SMN2 Copies, Risdiplam
    Number of subjects analysed
    0 [37]
    0 [38]
    0 [39]
    Units: score on a scale
        arithmetic mean (standard deviation)
    ( )
    ( )
    ( )
    Notes
    [37] - Data collection is still ongoing. Results to be reported at final analysis.
    [38] - Data collection is still ongoing. Results to be reported at final analysis.
    [39] - Data collection is still ongoing. Results to be reported at final analysis.
    No statistical analyses for this end point

    Secondary: Percentage of participants within 3rd percentile of normal range for head circumference-for-age

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    End point title
    		 Percentage of participants within 3rd percentile of normal range for head circumference-for-age
    End point description
    Based on the WHO Child Growth Standards (WHO 2019)
    End point type
    Secondary
    End point timeframe
    At Month 12 and 24
    End point values
    		 2 SMN2 Copies, Risdiplam 3 SMN2 Copies, Risdiplam >/=4 SMN2 Copies, Risdiplam
    Number of subjects analysed
    0 [40]
    0 [41]
    0 [42]
    Units: percentage of participants
        number (confidence interval 90%)
    ( to )
    ( to )
    ( to )
    Notes
    [40] - Data collection is still ongoing. Results to be reported at two-year interim analysis.
    [41] - Data collection is still ongoing. Results to be reported at two-year interim analysis.
    [42] - Data collection is still ongoing. Results to be reported at two-year interim analysis.
    No statistical analyses for this end point

    Secondary: Percentage of participants within 3rd percentile of normal range for weight‑for‑age, length/height‑for‑age and weight‑for‑length/height

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    End point title
    		 Percentage of participants within 3rd percentile of normal range for weight‑for‑age, length/height‑for‑age and weight‑for‑length/height
    End point description
    Based on the WHO Child Growth Standards (WHO 2019)
    End point type
    Secondary
    End point timeframe
    At Month 12, 24, 36, 48 and 60
    End point values
    		 2 SMN2 Copies, Risdiplam 3 SMN2 Copies, Risdiplam >/=4 SMN2 Copies, Risdiplam
    Number of subjects analysed
    0 [43]
    0 [44]
    0 [45]
    Units: percentage of participants
        number (confidence interval 90%)
    ( to )
    ( to )
    ( to )
    Notes
    [43] - Data collection is still ongoing. Results to be reported at final analysis.
    [44] - Data collection is still ongoing. Results to be reported at final analysis.
    [45] - Data collection is still ongoing. Results to be reported at final analysis.
    No statistical analyses for this end point

    Secondary: Change from baseline percentiles for head circumference- for-age

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    End point title
    		 Change from baseline percentiles for head circumference- for-age
    End point description
    End point type
    Secondary
    End point timeframe
    At Month 12 and 24
    End point values
    		 2 SMN2 Copies, Risdiplam 3 SMN2 Copies, Risdiplam >/=4 SMN2 Copies, Risdiplam
    Number of subjects analysed
    0 [46]
    0 [47]
    0 [48]
    Units: percentile
        number (not applicable)
    Notes
    [46] - Data collection is still ongoing. Results to be reported at two-year interim analysis.
    [47] - Data collection is still ongoing. Results to be reported at two-year interim analysis.
    [48] - Data collection is still ongoing. Results to be reported at two-year interim analysis.
    No statistical analyses for this end point

    Secondary: Change from baseline in chest circumference

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    End point title
    		 Change from baseline in chest circumference
    End point description
    End point type
    Secondary
    End point timeframe
    At Month 12 and 24
    End point values
    		 2 SMN2 Copies, Risdiplam 3 SMN2 Copies, Risdiplam >/=4 SMN2 Copies, Risdiplam
    Number of subjects analysed
    0 [49]
    0 [50]
    0 [51]
    Units: percentile
        number (not applicable)
    Notes
    [49] - Data collection is still ongoing. Results to be reported at two-year interim analysis.
    [50] - Data collection is still ongoing. Results to be reported at two-year interim analysis.
    [51] - Data collection is still ongoing. Results to be reported at two-year interim analysis.
    No statistical analyses for this end point

    Secondary: Change from baseline percentiles for weight-for-age, length/height-for-age, and weight-for- length/height

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    End point title
    		 Change from baseline percentiles for weight-for-age, length/height-for-age, and weight-for- length/height
    End point description
    End point type
    Secondary
    End point timeframe
    At Month 12, 24, 36, 48 and 60
    End point values
    		 2 SMN2 Copies, Risdiplam 3 SMN2 Copies, Risdiplam >/=4 SMN2 Copies, Risdiplam
    Number of subjects analysed
    0 [52]
    0 [53]
    0 [54]
    Units: percentile
        number (not applicable)
    Notes
    [52] - Data collection is still ongoing. Results to be reported at final analysis.
    [53] - Data collection is still ongoing. Results to be reported at final analysis.
    [54] - Data collection is still ongoing. Results to be reported at final analysis.
    No statistical analyses for this end point

    Secondary: Ratio between chest and head circumferences

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    End point title
    		 Ratio between chest and head circumferences
    End point description
    End point type
    Secondary
    End point timeframe
    At Month 12 and 24
    End point values
    		 2 SMN2 Copies, Risdiplam 3 SMN2 Copies, Risdiplam >/=4 SMN2 Copies, Risdiplam
    Number of subjects analysed
    0 [55]
    0 [56]
    0 [57]
    Units: chest/head ratio
        number (not applicable)
    Notes
    [55] - Data collection is still ongoing. Results to be reported at two-year interim analysis.
    [56] - Data collection is still ongoing. Results to be reported at two-year interim analysis.
    [57] - Data collection is still ongoing. Results to be reported at two-year interim analysis.
    No statistical analyses for this end point

    Secondary: Percentage of participants with the ability to swallow and to feed orally

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    End point title
    		 Percentage of participants with the ability to swallow and to feed orally
    End point description
    End point type
    Secondary
    End point timeframe
    At Month 12, 24, 36, 48 and 60
    End point values
    		 2 SMN2 Copies, Risdiplam 3 SMN2 Copies, Risdiplam >/=4 SMN2 Copies, Risdiplam
    Number of subjects analysed
    0 [58]
    0 [59]
    0 [60]
    Units: percentage of participants
        number (confidence interval 90%)
    ( to )
    ( to )
    ( to )
    Notes
    [58] - Data collection is still ongoing. Results to be reported at final analysis.
    [59] - Data collection is still ongoing. Results to be reported at final analysis.
    [60] - Data collection is still ongoing. Results to be reported at final analysis.
    No statistical analyses for this end point

    Secondary: Change from baseline in compound muscle action potential (CMAP) amplitude

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    End point title
    		 Change from baseline in compound muscle action potential (CMAP) amplitude
    End point description
    Measured by CMAP
    End point type
    Secondary
    End point timeframe
    At Month 12 and 24
    End point values
    		 2 SMN2 Copies, Risdiplam 3 SMN2 Copies, Risdiplam >/=4 SMN2 Copies, Risdiplam
    Number of subjects analysed
    0 [61]
    0 [62]
    0 [63]
    Units: mV
        arithmetic mean (standard deviation)
    ( )
    ( )
    ( )
    Notes
    [61] - Data collection is still ongoing. Results to be reported at two-year interim analysis.
    [62] - Data collection is still ongoing. Results to be reported at two-year interim analysis.
    [63] - Data collection is still ongoing. Results to be reported at two-year interim analysis.
    No statistical analyses for this end point

    Secondary: Percentage of participants with adverse events

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    End point title
    		 Percentage of participants with adverse events
    End point description
    Adverse event severity is determined according to the National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5 (NCI CTCAE) v5
    End point type
    Secondary
    End point timeframe
    Up to 7 years
    End point values
    		 2 SMN2 Copies, Risdiplam 3 SMN2 Copies, Risdiplam >/=4 SMN2 Copies, Risdiplam
    Number of subjects analysed
    0 [64]
    0 [65]
    0 [66]
    Units: percentage of participants
        number (not applicable)
    Notes
    [64] - Data collection is still ongoing. Results to be reported at final analysis.
    [65] - Data collection is still ongoing. Results to be reported at final analysis.
    [66] - Data collection is still ongoing. Results to be reported at final analysis.
    No statistical analyses for this end point

    Secondary: Percentage of participants with clinically meaningful changes in ophthalmological measures as appropriate for age

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    End point title
    		 Percentage of participants with clinically meaningful changes in ophthalmological measures as appropriate for age
    End point description
    End point type
    Secondary
    End point timeframe
    Up to 7 years
    End point values
    		 2 SMN2 Copies, Risdiplam 3 SMN2 Copies, Risdiplam >/=4 SMN2 Copies, Risdiplam
    Number of subjects analysed
    0 [67]
    0 [68]
    0 [69]
    Units: percentage of participants
        number (not applicable)
    Notes
    [67] - Data collection is still ongoing. Results to be reported at final analysis.
    [68] - Data collection is still ongoing. Results to be reported at final analysis.
    [69] - Data collection is still ongoing. Results to be reported at final analysis.
    No statistical analyses for this end point

    Secondary: Plasma concentration of risdiplam and its metabolites to characterize the PK profile

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    End point title
    		 Plasma concentration of risdiplam and its metabolites to characterize the PK profile
    End point description
    End point type
    Secondary
    End point timeframe
    Up to 7 years
    End point values
    		 2 SMN2 Copies, Risdiplam 3 SMN2 Copies, Risdiplam >/=4 SMN2 Copies, Risdiplam
    Number of subjects analysed
    0 [70]
    0 [71]
    0 [72]
    Units: ng/mL
        arithmetic mean (standard deviation)
    ( )
    ( )
    ( )
    Notes
    [70] - Data collection is still ongoing. Results to be reported at final analysis.
    [71] - Data collection is still ongoing. Results to be reported at final analysis.
    [72] - Data collection is still ongoing. Results to be reported at final analysis.
    No statistical analyses for this end point

    Secondary: Measurement of pharmacodynamic marker levels in blood

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    End point title
    		 Measurement of pharmacodynamic marker levels in blood
    End point description
    End point type
    Secondary
    End point timeframe
    Day 1, 56, 196, 364, 728 and at early withdrawal
    End point values
    		 2 SMN2 Copies, Risdiplam 3 SMN2 Copies, Risdiplam >/=4 SMN2 Copies, Risdiplam
    Number of subjects analysed
    0 [73]
    0 [74]
    0 [75]
    Units: nanograms/milliliter (ng/mL)
        arithmetic mean (standard deviation)
    ( )
    ( )
    ( )
    Notes
    [73] - Data collection is still ongoing. Results to be reported at final analysis.
    [74] - Data collection is still ongoing. Results to be reported at final analysis.
    [75] - Data collection is still ongoing. Results to be reported at final analysis.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From baseline up to the clinical cut off date (a minimum of 12 months and a maximum of 3.5 years)
    Adverse event reporting additional description
    The safety population included all participants who received at least one dose of risdiplam, whether prematurely withdrawn from the study or not.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    25.1
    Reporting groups
    Reporting group title
    2 SMN2 Copies, Risdiplam
    Reporting group description
    		 Infants with 2 copies of SMN2 were enrolled to receive risdiplam orally once daily at a dose selected to achieve the targeted exposure range.

    Reporting group title
    >/=4 SMN2 Copies, Risdiplam
    Reporting group description
    		 Infants with 4 or more copies of SMN2 were enrolled to receive risdiplam orally once daily at a dose selected to achieve the targeted.

    Reporting group title
    3 SMN2 Copies, Risdiplam
    Reporting group description
    		 Infants with 3 copies of SMN2 were enrolled to receive risdiplam orally once daily at a dose selected to achieve the targeted exposure range.

    Serious adverse events
    		 2 SMN2 Copies, Risdiplam >/=4 SMN2 Copies, Risdiplam 3 SMN2 Copies, Risdiplam
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 8 (37.50%)
    1 / 5 (20.00%)
    0 / 13 (0.00%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Injury, poisoning and procedural complications
    Femur fracture
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 5 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Soft tissue injury
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 5 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Jaundice neonatal
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 5 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 5 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Gastroenteritis
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 5 (20.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 5 (20.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 2 SMN2 Copies, Risdiplam >/=4 SMN2 Copies, Risdiplam 3 SMN2 Copies, Risdiplam
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    8 / 8 (100.00%)
    4 / 5 (80.00%)
    12 / 13 (92.31%)
    Pregnancy, puerperium and perinatal conditions
    Umbilical granuloma
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    1
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    1 / 8 (12.50%)
    2 / 5 (40.00%)
    4 / 13 (30.77%)
         occurrences all number
    1
    5
    7
    Malaise
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 5 (20.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 5 (20.00%)
    2 / 13 (15.38%)
         occurrences all number
    0
    1
    2
    Epistaxis
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 5 (20.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    3
    1
    Nasal congestion
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 5 (20.00%)
    3 / 13 (23.08%)
         occurrences all number
    1
    1
    3
    Rhinitis allergic
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    1
    Rhinorrhoea
         subjects affected / exposed
    2 / 8 (25.00%)
    0 / 5 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    2
    0
    0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    1
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    1
    Cardiac murmur
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    1
    Injury, poisoning and procedural complications
    Accidental overdose
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    3 / 13 (23.08%)
         occurrences all number
    0
    0
    3
    Arthropod bite
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    1
    Contusion
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    1
    Expired product administered
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 5 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    1
    0
    1
    Fall
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    1
    Incorrect dose administered
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 5 (20.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    1
    Intercepted medication error
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 5 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    0
    Limb injury
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    1
    Overdose
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 5 (20.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    Underdose
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 5 (20.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    Congenital, familial and genetic disorders
    Cryptorchism
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 5 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 5 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    1
    0
    1
    Eye disorders
    Retinal vascular disorder
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 5 (20.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    Retinal pigmentation
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 5 (20.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    Cystoid macular oedema
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 5 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    0
    Gastrointestinal disorders
    Gastrointestinal pain
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    1
    Dyspepsia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    1
    Diarrhoea
         subjects affected / exposed
    0 / 8 (0.00%)
    2 / 5 (40.00%)
    4 / 13 (30.77%)
         occurrences all number
    0
    2
    4
    Constipation
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 5 (20.00%)
    3 / 13 (23.08%)
         occurrences all number
    2
    1
    3
    Abdominal pain
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 5 (20.00%)
    0 / 13 (0.00%)
         occurrences all number
    2
    1
    0
    Vomiting
         subjects affected / exposed
    1 / 8 (12.50%)
    2 / 5 (40.00%)
    2 / 13 (15.38%)
         occurrences all number
    2
    2
    7
    Teething
         subjects affected / exposed
    2 / 8 (25.00%)
    2 / 5 (40.00%)
    6 / 13 (46.15%)
         occurrences all number
    2
    2
    6
    Regurgitation
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    2
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 5 (20.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    Skin and subcutaneous tissue disorders
    Skin discolouration
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 5 (20.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    Dermatitis
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 5 (20.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    Dermatitis atopic
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 5 (20.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    1
    0
    Dermatitis contact
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 5 (20.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    Dermatitis diaper
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    1
    Eczema
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 5 (20.00%)
    4 / 13 (30.77%)
         occurrences all number
    1
    1
    5
    Erythema
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    1
    Papule
         subjects affected / exposed
    2 / 8 (25.00%)
    0 / 5 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    3
    0
    0
    Rash
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 5 (0.00%)
    2 / 13 (15.38%)
         occurrences all number
    1
    0
    2
    Rash maculo-papular
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    1
    Musculoskeletal and connective tissue disorders
    Pain in extremity
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    1
    Infections and infestations
    Conjunctivitis
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 5 (20.00%)
    2 / 13 (15.38%)
         occurrences all number
    0
    1
    2
    COVID-19
         subjects affected / exposed
    2 / 8 (25.00%)
    0 / 5 (0.00%)
    7 / 13 (53.85%)
         occurrences all number
    2
    0
    7
    Bronchitis
         subjects affected / exposed
    0 / 8 (0.00%)
    2 / 5 (40.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    3
    0
    Bronchiolitis
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 5 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    0
    Croup infectious
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 5 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    0
    Cytomegalovirus infection
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 5 (20.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    Suspected COVID-19
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 5 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    0
    Exanthema subitum
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 5 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    0
    Gastroenteritis
         subjects affected / exposed
    1 / 8 (12.50%)
    2 / 5 (40.00%)
    2 / 13 (15.38%)
         occurrences all number
    1
    3
    2
    Gastroenteritis norovirus
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    1
    Gastrointestinal viral infection
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    2 / 13 (15.38%)
         occurrences all number
    0
    0
    3
    Hand-foot-and-mouth disease
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 5 (20.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    Impetigo
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    1
    Influenza
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 5 (20.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    2
    0
    Nasopharyngitis
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 5 (20.00%)
    3 / 13 (23.08%)
         occurrences all number
    1
    2
    3
    Oral candidiasis
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 5 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    1
    0
    2
    Otitis media acute
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 5 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    0
    Respiratory syncytial virus bronchitis
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 5 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    0
    Respiratory syncytial virus infection
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 5 (20.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    Respiratory tract infection
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 5 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    0
    Respiratory tract infection bacterial
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    1
    Respiratory tract infection viral
         subjects affected / exposed
    2 / 8 (25.00%)
    0 / 5 (0.00%)
    2 / 13 (15.38%)
         occurrences all number
    4
    0
    2
    Rhinitis
         subjects affected / exposed
    1 / 8 (12.50%)
    2 / 5 (40.00%)
    2 / 13 (15.38%)
         occurrences all number
    1
    5
    2
    Skin infection
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 5 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    0
    Ear infection
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    1
    Tonsillitis
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 5 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 5 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    1
    0
    1
    Varicella
         subjects affected / exposed
    0 / 8 (0.00%)
    2 / 5 (40.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    2
    0
    Viral infection
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 5 (20.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    1
    Viral rash
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    1
    Vulvovaginitis
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    1
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 5 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    0
    Hyperphosphatasaemia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    1
    Hypoglycaemia
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 5 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    0
    Vitamin D deficiency
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    2 / 13 (15.38%)
         occurrences all number
    0
    0
    2
    Iron deficiency
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 5 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    26 Feb 2019
    The protocol was amended primarily based on in vitro data indicating that risdiplam may be a cytochrome P450 3A4 (CYP3A4) inhibitor in humans. This inhibition has the potential to increase the concentration of concomitant medications predominantly metabolized by the CYP3A4 enzyme. For the secondary efficacy objective of achieving motor milestones defined in the BSID-III, an additional endpoint was added at the request of the European Medicines Agency's Paediatric Committee (PDCO). Specifically, the endpoint was to evaluate the percentage of participants demonstrating the ability to achieve a scaled score within 1.5 standard deviations of the chronological reference standard. The option to use a cognition scale other than the BSID-III Cognitive Scale was removed. A new series for the sitting, standing, and walking items was added to the assessments. An additional trial of the BSID-III Gross Motor test was allowed in case the child was uncooperative during the first administration. Additional pharmacokinetic samples were allowed, if required for safety reasons. Dosing could be stopped if safety, tolerability, or efficacy data would suggest risdiplam was not beneficial for the participant, in the investigator's judgment.
    18 Sep 2020
    The protocol was amended primarily to include age-appropriate motor function and development milestones beyond Month 24 and to remove some ophthalmological assessments. Major changes were as follows: The pharmacokinetics of risdiplam was updated with data on Type 1 SMA patients, and the very low dose of 0.004 mg/kg will not be required during the study. Given the absence of any risdiplam-induced ophthalmological findings in 470 patients exposed to risdiplam for up to 3 years, intraocular pressure measurement was no longer included and fundus photography did no longer need to be performed after 1 year. Motor function and development milestones were updated throughout: the HFMSE was added as a motor function measure, commencing at Month 24; WHO motor milestones was added as a developmental measure, commencing at Week 208 (Month 48); the six-minute walk test (6MWT) was added as a motor function measure, commencing at Week 182 (Month 42); the stopping criteria for the CHOP-INTEND were amended; the final visit date for BSID-III assessments was clarified as Week 182; it was clarified that after Week 104 in the study, HINE assessment should be stopped for each infant once the maximum score was reached at two consecutive visits; percentage of participants sitting without support at Month 12 of treatment (as assessed in Item 26 of the BSID-III Gross Motor Scale) for 30 seconds was added as a secondary efficacy endpoint; the respiratory plethysmography assessment and associated endpoints were removed; anthropometric and nutritional endpoints were extended to Month 60; the study visit schedule was amended to include a study completion/early withdrawal visit for all participants, and a follow-up call to take place 30 days after the study completion/early withdrawal visit. The 30-day follow-up call replaced the previous 52 weeks of follow-up visits.
    30 Mar 2021
    The protocol was amended primarily to reduce the overall number of ophthalmological assessments, including revision of the ophthalmological assessment requirements at baseline, and to modify the conditions for closure of recruitment. Given that ophthalmological monitoring conducted in 461 patients across the risdiplam clinical development program had not revealed any ophthalmological safety concerns, the frequency of ophthalmological assessments was reduced to the following visits: screening, Weeks 8, 28, and 52, and yearly thereafter. In order not to delay the start of treatment in presymptomatic SMA infants, the time window for obtaining high quality screening ophthalmologic assessments was expanded from Day 42 to Day 14. The conditions for the closure of recruitment were updated. The timing of the primary analysis was updated to account for the possibility that recruitment could be completed prior to 10 PE population participants being enrolled. The primary analysis was updated to occur when the last participant enrolled overall reached Month 12 of treatment. The description of the sample size was updated to include the requirements for a statistically significant result in the event that recruitment stopped prior to enrolling 10 participants with two SMN2 copies and a baseline CMAP amplitude >=1.5 mV.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

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