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    Clinical Trial Results:
    A Two Part Seamless, Open-Label, Multi-center Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Efficacy of Risdiplam (RO7034067) in Infants with Type 1 Spinal Muscular Atrophy

    Summary
    EudraCT number
    		 2016-000778-40
    Trial protocol
    		 DE   ES   IT   BE   FR   PL   HR  
    Global end of trial date

    Results information
    Results version number
    		 v3(current)
    This version publication date
    21 Nov 2021
    First version publication date
    26 Nov 2020
    Other versions
    		 v1 , v2
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    BP39056
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02913482
    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?
    No
    Results analysis stage
    Analysis stage
    Interim
    Date of interim/final analysis
    12 Nov 2020
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    No
    General information about the trial
    Main objective of the trial
    Part 1: To evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of risdiplam in infants with Type 1 spinal muscular atrophy (SMA) and to select the dose for Part 2. Part 2: To assess the efficacy of risdiplam measured as the percentage of infants with SMA who are sitting without support after 12 months of treatment, as assessed in the gross motor scale of the Bayley Scales of Infant and Toddler Development -Third Edition (BSID-III) (defined as sitting without support for 5 seconds).
    Protection of trial subjects
    All study subjects, parent or legal guardian were required to read and sign an Informed Consent Form.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    23 Dec 2016
    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
    Belgium: 2
    Country: Number of subjects enrolled
    Switzerland: 1
    Country: Number of subjects enrolled
    France: 8
    Country: Number of subjects enrolled
    Italy: 21
    Country: Number of subjects enrolled
    United States: 4
    Country: Number of subjects enrolled
    Brazil: 3
    Country: Number of subjects enrolled
    China: 11
    Country: Number of subjects enrolled
    Croatia: 1
    Country: Number of subjects enrolled
    Japan: 1
    Country: Number of subjects enrolled
    Poland: 4
    Country: Number of subjects enrolled
    Russian Federation: 5
    Country: Number of subjects enrolled
    Turkey: 1
    Worldwide total number of subjects
    62
    EEA total number of subjects
    36
    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)
    62
    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
    		 Part 1 was conducted at 7 investigational sites across 5 countries; Part 2 was conducted at 14 investigational sites across 10 countries.

    Pre-assignment
    Screening details
    		 Infants with type 1 spinal muscular atrophy (SMA) were screened for this study. Screening in both Part 1 and 2 was up to 30 days prior to first dose.

    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
    		 Exploratory Part 1 - Cohort 1
    Arm description
    		 Subjects received risdiplam in a staggered, dose-escalation manner once daily at Dose Level 1 for a minimum of 4 weeks to select the dose for Part 2. Dose Level 1 was targeting an exposure of mean AUC0-24h,ss 700 ng*h/mL.
    Arm type
    		 Experimental

    Investigational medicinal product name
    risdiplam
    Investigational medicinal product code
    Other name
    Evrysdi
    Pharmaceutical forms
    Powder and solvent for oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    Throughout the study, risdiplam should be taken orally once daily. In the case of breastfeeding, the subject should be fed prior to dosing, winded, and risdiplam administered. In subjects able to swallow, risdiplam is administered with a syringe inserted between baby's gum and cheek. Thereafter, water (approx. 10–20 mL) should be administered with a baby’s bottle to prevent prolonged contact of study drug with buccal mucosa. Similarly, the peribuccal- area of the SMA infant is washed with water in case of drug drooling or spitting. Subjects unable to swallow the study medication and who have a naso-gastric or gastrostomy tube in situ should receive the study medication by bolus via the tube. This should be followed by a bolus flush of water through the tube.

    Arm title
    		 Exploratory Part 1 - Cohort 2
    Arm description
    		 Subjects received risdiplam in a staggered, dose-escalation manner once daily at Dose Level 2 for a minimum of 4 weeks to select the dose for Part 2. Dose Level 2 was targeting an exposure of mean AUC0-24h,ss </= 2000 ng*h/mL. Cohort 2 included one infant who started at Dose Level 1 and was escalated to Dose Level 2 on Day 83.
    Arm type
    		 Experimental

    Investigational medicinal product name
    risdiplam
    Investigational medicinal product code
    Other name
    Evrysdi
    Pharmaceutical forms
    Powder and solvent for oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    Throughout the study, risdiplam should be taken orally once daily. In the case of breastfeeding, the subject should be fed prior to dosing, winded, and risdiplam administered. In subjects able to swallow, risdiplam is administered with a syringe inserted between baby's gum and cheek. Thereafter, water (approx. 10–20 mL) should be administered with a baby’s bottle to prevent prolonged contact of study drug with buccal mucosa. Similarly, the peribuccal- area of the SMA infant is washed with water in case of drug drooling or spitting. Subjects unable to swallow the study medication and who have a naso-gastric or gastrostomy tube in situ should receive the study medication by bolus via the tube. This should be followed by a bolus flush of water through the tube.

    Arm title
    		 Confirmatory Part 2 - Risdiplam
    Arm description
    		 Subjects received risdiplam orally once daily at a dose of target exposure cap of a mean AUC0-24h,ss of 2000 ng*h/mL, for a duration of 24 months with a primary analysis after 12 months. Starting doses were either 0.04mg/kg, 0.08mg/kg or 0.2mg/kg depending on the subject’s age. All subjects had their dose adjusted to 0.2mg/kg within a few months of starting treatment. The dose was adjusted to 0.25mg/kg when subject reached 2 years of age.
    Arm type
    		 Experimental

    Investigational medicinal product name
    risdiplam
    Investigational medicinal product code
    Other name
    Evrysdi
    Pharmaceutical forms
    Powder and solvent for oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    Throughout the study, risdiplam should be taken orally once daily. In the case of breastfeeding, the subject should be fed prior to dosing, winded, and risdiplam administered. In subjects able to swallow, risdiplam is administered with a syringe inserted between baby's gum and cheek. Thereafter, water (approx. 10–20 mL) should be administered with a baby’s bottle to prevent prolonged contact of study drug with buccal mucosa. Similarly, the peribuccal- area of the SMA infant is washed with water in case of drug drooling or spitting. Subjects unable to swallow the study medication and who have a naso-gastric or gastrostomy tube in situ should receive the study medication by bolus via the tube. This should be followed by a bolus flush of water through the tube.

    Number of subjects in period 1
    		Exploratory Part 1 - Cohort 1 Exploratory Part 1 - Cohort 2 Confirmatory Part 2 - Risdiplam
    Started
    4
    17
    41
    Completed
    3
    14
    38
    Not completed
    1
    3
    3
         Adverse event, serious fatal
    -
    2
    2
         Progressive Disease
    1
    1
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Exploratory Part 1 - Cohort 1
    Reporting group description
    		 Subjects received risdiplam in a staggered, dose-escalation manner once daily at Dose Level 1 for a minimum of 4 weeks to select the dose for Part 2. Dose Level 1 was targeting an exposure of mean AUC0-24h,ss 700 ng*h/mL.

    Reporting group title
    Exploratory Part 1 - Cohort 2
    Reporting group description
    		 Subjects received risdiplam in a staggered, dose-escalation manner once daily at Dose Level 2 for a minimum of 4 weeks to select the dose for Part 2. Dose Level 2 was targeting an exposure of mean AUC0-24h,ss </= 2000 ng*h/mL. Cohort 2 included one infant who started at Dose Level 1 and was escalated to Dose Level 2 on Day 83.

    Reporting group title
    Confirmatory Part 2 - Risdiplam
    Reporting group description
    		 Subjects received risdiplam orally once daily at a dose of target exposure cap of a mean AUC0-24h,ss of 2000 ng*h/mL, for a duration of 24 months with a primary analysis after 12 months. Starting doses were either 0.04mg/kg, 0.08mg/kg or 0.2mg/kg depending on the subject’s age. All subjects had their dose adjusted to 0.2mg/kg within a few months of starting treatment. The dose was adjusted to 0.25mg/kg when subject reached 2 years of age.

    Reporting group values
    		 Exploratory Part 1 - Cohort 1 Exploratory Part 1 - Cohort 2 Confirmatory Part 2 - Risdiplam Total
    Number of subjects
    		 4 17 41 62
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 4 17 41 62
        Children (2-11 years)
    		 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0
        Adults (18-64 years)
    		 0 0 0 0
        From 65-84 years
    		 0 0 0 0
        85 years and over
    		 0 0 0 0
    Age Continuous
    Units: months
        arithmetic mean (standard deviation)
    		 6.84 ± 0.10 5.56 ± 1.43 5.20 ± 1.47 -
    Sex: Female, Male
    Units:
        Male
    		 0 6 19 25
        Female
    		 4 11 22 37
    Race/Ethnicity, Customized
    Units: Subjects
        Not Hispanic or Latino
    		 4 17 36 57
        Hispanic or Latino
    		 0 0 5 5
    Race/Ethnicity, Customized
    Units: Subjects
        Asian
    		 0 4 14 18
        White
    		 4 9 22 35
        Unknown
    		 0 4 5 9

    End points

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    End points reporting groups
    Reporting group title
    Exploratory Part 1 - Cohort 1
    Reporting group description
    		 Subjects received risdiplam in a staggered, dose-escalation manner once daily at Dose Level 1 for a minimum of 4 weeks to select the dose for Part 2. Dose Level 1 was targeting an exposure of mean AUC0-24h,ss 700 ng*h/mL.

    Reporting group title
    Exploratory Part 1 - Cohort 2
    Reporting group description
    		 Subjects received risdiplam in a staggered, dose-escalation manner once daily at Dose Level 2 for a minimum of 4 weeks to select the dose for Part 2. Dose Level 2 was targeting an exposure of mean AUC0-24h,ss </= 2000 ng*h/mL. Cohort 2 included one infant who started at Dose Level 1 and was escalated to Dose Level 2 on Day 83.

    Reporting group title
    Confirmatory Part 2 - Risdiplam
    Reporting group description
    		 Subjects received risdiplam orally once daily at a dose of target exposure cap of a mean AUC0-24h,ss of 2000 ng*h/mL, for a duration of 24 months with a primary analysis after 12 months. Starting doses were either 0.04mg/kg, 0.08mg/kg or 0.2mg/kg depending on the subject’s age. All subjects had their dose adjusted to 0.2mg/kg within a few months of starting treatment. The dose was adjusted to 0.25mg/kg when subject reached 2 years of age.

    Subject analysis set title
    Part 1: Intent-to-Treat (ITT)
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The intent-to-treat (ITT) population was defined as all subjects enrolled in Part 1 of the study, regardless of whether they received treatment or not.

    Subject analysis set title
    Part 1: Safety Population
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All subjects in Part 1 who received at least one dose of study medication (risdiplam) were included in the safety population.

    Subject analysis set title
    Part 2: ITT
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The intent-to-treat (ITT) population for Part 2 was defined as all subjects enrolled in Part 2 of the study, regardless of whether they received treatment or not. The ITT population was the primary analysis population for all efficacy analyses.

    Subject analysis set title
    Part 2: Safety Population
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All subjects in Part 2 who received at least one dose of study medication (risdiplam) were included in the safety population.

    Subject analysis set title
    Exploratory Part 1 - Risdiplam
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Infants aged between 28 days (1 month) of life and 210 days (7 months) received at least one dose of risdiplam orally or by bolus via naso-gastric or gastrostomy tube, and had available data at the time of the data snapshot for selecting the Part 2 dose.

    Primary: Part 1: Selected Part 2 Dose of Risdiplam

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    End point title
    		 Part 1: Selected Part 2 Dose of Risdiplam [1]
    End point description
    All safety, tolerability, PK and PD data available up to the database snapshot on 6 February 2018 were included in the Internal Monitoring Committee (IMC) review. The IMC was responsible for selecting the dose for Part 2 of the study (pivotal dose). An external Independent Data Monitoring Committee (iDMC) reviewed data from Part 1 and confirmed the dose-selection decision of the IMC. The dose for Part 2 selected by the IMC was a dose that: 1.Was judged to be safe and well-tolerated, based on all available safety data from Part 1 and as confirmed by the iDMC; 2. Resulted in an exposure at steady-state below the exposure cap (mean value) of AUC0-24h,ss 2000 ng*h/mL (adjusted for free-fraction, if required); 3. Resulted in an SMN protein increase that was expected to be clinically relevant. The analysis population included all participants in Part 1 who received at least one dose of risdiplam and had available data at the time of the data snapshot for selecting the Part 2 dose.
    End point type
    Primary
    End point timeframe
    Minimum of 2 weeks at steady state exposure
    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: No statistical analyses can be performed for this endpoint.
    End point values
    		 Exploratory Part 1 - Risdiplam
    Number of subjects analysed
    18
    Units: mg/kg
        number (not applicable)
    0.2
    No statistical analyses for this end point

    Primary: Part 2: Percentage of Infants who are Sitting Without Support for at least 5 Seconds as Assessed by Item 22 of the Gross Motor Scale of the Bayley Scales of Infant and Toddler development Third Edition (BSID-III) at Month 12

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    End point title
    		 Part 2: Percentage of Infants who are Sitting Without Support for at least 5 Seconds as Assessed by Item 22 of the Gross Motor Scale of the Bayley Scales of Infant and Toddler development Third Edition (BSID-III) at Month 12 [2] [3]
    End point description
    The BSID-III is a standardized assessment commonly used to evaluate development across five domains in infants and young children aged between 1 and 42 months. The gross motor subscale of the BSID-III is evaluated based on the linear and hierarchical obtainment of motor skills, as seen in typically developing children and consists of 72 items scored at 0 (unable to perform the activity) or 1 (criteria for item achieved). Item 22 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. The assessment was video recorded at study sites and reviewed/scored by two independent raters. 90% CI for one sample binomial was computed using Clopper-Pearson (exact) method. The result was compared to a performance criterion of 5% derived from natural history data (p<0.0001). The intent-to-treat (ITT) population is defined as all infants enrolled in Part 2 of the study.
    End point type
    Primary
    End point timeframe
    Month 12
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: The result for the only arm in Part 2 was compared to a performance criterion of 5% derived from natural history data (p<0.0001).
    [3] - 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: The endpoint was only assessed in Part 2 of the study.
    End point values
    		 Confirmatory Part 2 - Risdiplam
    Number of subjects analysed
    41
    Units: Percentage of Subjects
        number (confidence interval 90%)
    29.3 (17.84 to 43.07)
    No statistical analyses for this end point

    Secondary: Part 2: Percentage of Infants who Achieve a Score of 40 or Higher in the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND) at Month 12

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    End point title
    		 Part 2: Percentage of Infants who Achieve a Score of 40 or Higher in the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND) at Month 12 [4]
    End point description
    The CHOP-INTEND instrument was developed to evaluate motor function in infants with SMA from the ages of 1.4 to 37.9 months. It consists of 16 items, where each item assesses a specific motor task graded on a scale of 0 to 4, where zero is no response and 4 is a complete response. The total score ranges from 0 to 64, with higher scores consistent with better motor function. 90% CI for one sample binomial was computed using Clopper-Pearson (exact) method. The result was compared to a performance criterion of 17% derived from natural history data (p<0.0001). The intent-to-treat (ITT) population is defined as all infants enrolled in Part 2 of the study, regardless of whether they received treatment or not.
    End point type
    Secondary
    End point timeframe
    Month 12
    Notes
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The endpoint was only assessed in Part 2 of the study.
    End point values
    		 Confirmatory Part 2 - Risdiplam
    Number of subjects analysed
    41
    Units: Percentage of Subjects
        number (confidence interval 90%)
    56.1 (42.13 to 69.38)
    No statistical analyses for this end point

    Secondary: Part 2: Percentage of Infants Achieving an Increase of >/= 4 Points in their CHOP-INTEND Score from Baseline at Month 8 and 12

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    End point title
    		 Part 2: Percentage of Infants Achieving an Increase of >/= 4 Points in their CHOP-INTEND Score from Baseline at Month 8 and 12 [5]
    End point description
    The CHOP-INTEND instrument was developed to evaluate motor function in infants with SMA from the ages of 1.4 to 37.9 months. It consists of 16 items, where each item assesses a specific motor task graded on a scale of 0 to 4, where zero is no response and 4 is a complete response. The total score ranges from 0 to 64, with higher scores consistent with better motor function. 90% CI for one sample binomial was computed using Clopper-Pearson (exact) method. The result was compared to a performance criterion of 17% derived from natural history data (p<0.0001). Statistical analysis was only performed for Month 12 data. The intent-to-treat (ITT) population is defined as all infants enrolled in Part 2 of the study, regardless of whether they received treatment or not.
    End point type
    Secondary
    End point timeframe
    At Month 8 and Month 12 (Up to the CCOD of 14 November 2019)
    Notes
    [5] - 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: The endpoint was only assessed in Part 2 of the study.
    End point values
    		 Confirmatory Part 2 - Risdiplam
    Number of subjects analysed
    41
    Units: Percentage of Subjects
    number (confidence interval 90%)
        Month 8
    87.8 (76.05 to 95.07)
        Month 12
    90.2 (79.05 to 96.60)
    No statistical analyses for this end point

    Secondary: Part 2: Percentage of Infants Achieving Head Control (Defined as a Score of >/= 3 for CHOP-INTEND Item 12) at Months 8, 12 and 24

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    End point title
    		 Part 2: Percentage of Infants Achieving Head Control (Defined as a Score of >/= 3 for CHOP-INTEND Item 12) at Months 8, 12 and 24 [6]
    End point description
    The CHOP-INTEND instrument was developed to evaluate motor function in infants with SMA from the ages of 1.4 to 37.9 months. It consists of 16 items, where each item assesses a specific motor task graded on a scale of 0 to 4, where zero is no response and 4 is a complete response. The total score ranges from 0 to 64, with higher scores consistent with better motor function. 90% CI for one sample binomial was computed using Clopper-Pearson (exact) method. The intent-to-treat (ITT) population is defined as all infants enrolled in Part 2 of the study, regardless of whether they received treatment or not.
    End point type
    Secondary
    End point timeframe
    Month 8, Month 12, Month 24
    Notes
    [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The endpoint was only assessed in Part 2 of the study.
    End point values
    		 Confirmatory Part 2 - Risdiplam
    Number of subjects analysed
    41
    Units: Percentage of Subjects
    number (confidence interval 90%)
        Month 8
    46.3 (32.87 to 60.23)
        Month 12
    53.7 (39.77 to 67.13)
        Month 24
    70.7 (56.93 to 82.16)
    No statistical analyses for this end point

    Secondary: Part 2: Change From Baseline in the Total Raw Score of the BSID-III Gross Motor Scale at Months 12 and 24

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    End point title
    		 Part 2: Change From Baseline in the Total Raw Score of the BSID-III Gross Motor Scale at Months 12 and 24 [7]
    End point description
    The BSID-III is a standardized assessment commonly used to evaluate development across five domains in infants and young children aged between 1 and 42 months. The gross motor subscale of the BSID-III is evaluated based on the linear and hierarchical obtainment of motor skills, as seen in typically developing children. The gross motor scale consists of 72 items scored at 0 (unable to perform the activity) or 1 (criteria for item achieved). In this study the gross motor scale was assessed in a modified way compared with the standard administration. A total raw score was calculated by summing the item scores to give a maximum possible score of 72. The intent-to-treat (ITT) population is defined as all infants enrolled in Part 2 of the study, regardless of whether they received treatment or not.
    End point type
    Secondary
    End point timeframe
    Baseline, Month 12, Month 24
    Notes
    [7] - 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: The endpoint was only assessed in Part 2 of the study.
    End point values
    		 Confirmatory Part 2 - Risdiplam
    Number of subjects analysed
    41 [8]
    Units: Scores on a Scale
    arithmetic mean (standard deviation)
        Baseline (n=41)
    1.85 ± 1.61
        Change from Baseline at Month 12 (n=38)
    7.21 ± 5.71
        Change from Baseline at Month 24 (n=38)
    12.89 ± 6.89
    Notes
    [8] - Only subjects for whom data were collected are included in the analysis at each time point.
    No statistical analyses for this end point

    Secondary: Part 2: Percentage of Infants who Achieve the Attainment Levels of a Subset of Motor Milestones Assessed in the Hammersmith Infant Neurological Examination Module 2 (HINE-2) at Month 8

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    End point title
    		 Part 2: Percentage of Infants who Achieve the Attainment Levels of a Subset of Motor Milestones Assessed in the Hammersmith Infant Neurological Examination Module 2 (HINE-2) at Month 8 [9]
    End point description
    The HINE was designed to evaluate infants between 2 months and 24 months of age. It is a simple and standardized instrument that includes 26 items assessing different aspects of neurological examinations, such as cranial nerves, posture, movements, tone, and reflexes. In this study, Module 2 of the HINE (HINE-2) was assessed. The HINE-2 evaluates 8 developmental milestones (head control, sitting, voluntary grasp, ability to kick, rolling, crawling, standing, and walking) scored on a 3, 4, or 5-point scale, with 0 indicating inability to perform a task and a score of 2, 3, or 4 (depending on the task) indicating full milestone development. The total score is calculated by summing the item scores to give a maximum possible score of 26. This measure represents subset numbers at Month 8 for head control, ability to kick and rolling milestones only. The ITT population is defined as all infants enrolled in Part 2 of the study, regardless of whether they received treatment or not.
    End point type
    Secondary
    End point timeframe
    Month 8
    Notes
    [9] - 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: The endpoint was only assessed in Part 2 of the study.
    End point values
    		 Confirmatory Part 2 - Risdiplam
    Number of subjects analysed
    41
    Units: Percentage of Subjects
    number (not applicable)
        Unable to maintain head upright (Head Control)
    36.6
        Wobbles (Head Control)
    14.6
        All the time maintained upright (Head Control)
    39.0
        No kicking (Ability to Kick [supine])
    24.4
        Kicks horizontally;legs don’t lift (Kick [supine])
    58.5
        Upward (vertically) (Ability to Kick [supine])
    7.3
        Touches leg (Ability to Kick [supine])
    0
        Touches toes (Ability to Kick [supine])
    0
        No rolling (Rolling)
    56.1
        Rolling to side (Rolling)
    29.3
        Prone to supine (Rolling)
    2.4
        Supine to prone (Rolling)
    2.4
    No statistical analyses for this end point

    Secondary: Part 2: Percentage of Infants who Achieve the Attainment Levels of the Motor Milestones Assessed in the Hammersmith Infant Neurological Examination Module 2 (HINE-2) at Month 12

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    End point title
    		 Part 2: Percentage of Infants who Achieve the Attainment Levels of the Motor Milestones Assessed in the Hammersmith Infant Neurological Examination Module 2 (HINE-2) at Month 12 [10]
    End point description
    The HINE was designed to evaluate infants between 2 months and 24 months of age. It is a simple and standardized instrument that includes 26 items assessing different aspects of neurological examinations, such as cranial nerves, posture, movements, tone, and reflexes. In this study, Module 2 of the HINE (HINE-2) was assessed. The HINE-2 evaluates 8 developmental milestones (head control, sitting, voluntary grasp, ability to kick, rolling, crawling, standing, and walking) scored on a 3, 4, or 5-point scale, with 0 indicating inability to perform a task and a score of 2, 3, or 4 (depending on the task) indicating full milestone development. The total score is calculated by summing the item scores to give a maximum possible score of 26. The ITT population is defined as all infants enrolled in Part 2 of the study, regardless of whether they received treatment or not.
    End point type
    Secondary
    End point timeframe
    Month 12
    Notes
    [10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The endpoint was only assessed in Part 2 of the study.
    End point values
    		 Confirmatory Part 2 - Risdiplam
    Number of subjects analysed
    41
    Units: Percentage of Subjects
    number (not applicable)
        Unable to maintain head upright (Head Control)
    17.1
        Wobbles (Head Control)
    31.7
        All the time maintained upright (Head Control)
    43.9
        Cannot sit (Sitting)
    31.7
        Sits with support at hips (Sitting)
    17.1
        Props (Sitting)
    19.5
        Stable sit (Sitting)
    14.6
        Pivots (rotates) (Sitting)
    9.8
        No grasp (Voluntary Grasp)
    2.4
        Uses whole hand (Voluntary Grasp)
    29.3
        Index finger/thumb immature grasp(Voluntary Grasp)
    48.8
        Pincer grasp (Voluntary Grasp)
    12.2
        No kicking (Ability to Kick [supine])
    12.2
        Kicks horizontally;legs don’t lift (Kick [supine])
    58.5
        Upward (vertically) (Ability to Kick [supine])
    7.3
        Touches leg (Ability to Kick [supine])
    4.9
        Touches toes (Ability to Kick [supine])
    9.8
        No rolling (Rolling)
    36.6
        Rolling to side (Rolling)
    31.7
        Prone to supine (Rolling)
    14.6
        Supine to prone (Rolling)
    9.8
        Does not lift head (Crawling)
    85.4
        On elbow (Crawling)
    2.4
        On outstretched hand (Crawling)
    2.4
        Crawling flat on abdomen (Crawling)
    0
        Crawling on hands and knees (Crawling)
    0
        Cannot test (Crawling)
    2.4
        Does not support weight (Standing)
    61.0
        Supports weight (Standing)
    17.1
        Stands with support (Standing)
    4.9
        Stands unaided (Standing)
    0
        Cannot test (Standing)
    4.9
        Not done (Standing)
    4.9
        Bouncing (Walking)
    2.4
        Cruising (walks holding on) (Walking)
    0
        Walking independently (Walking)
    0
        Cannot test (Walking)
    82.9
        Not Done (Walking)
    7.3
    No statistical analyses for this end point

    Secondary: Part 2: Percentage of Infants Who Achieve the Attainment Levels of the Motor Milestones Assessed in the Hammersmith Infant Neurological Examination Module 2 (HINE-2) at Month 24

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    End point title
    		 Part 2: Percentage of Infants Who Achieve the Attainment Levels of the Motor Milestones Assessed in the Hammersmith Infant Neurological Examination Module 2 (HINE-2) at Month 24 [11]
    End point description
    The HINE was designed to evaluate infants between 2 months and 24 months of age. It is a simple and standardized instrument that includes 26 items assessing different aspects of neurological examinations, such as cranial nerves, posture, movements, tone, and reflexes. In this study, Module 2 of the HINE (HINE-2) was assessed. The HINE-2 evaluates 8 developmental milestones (head control, sitting, voluntary grasp, ability to kick, rolling, crawling, standing, and walking) scored on a 3, 4, or 5-point scale, with 0 indicating inability to perform a task and a score of 2, 3, or 4 (depending on the task) indicating full milestone development. The total score is calculated by summing the item scores to give a maximum possible score of 26. The ITT population is defined as all infants enrolled in Part 2 of the study, regardless of whether they received treatment or not.
    End point type
    Secondary
    End point timeframe
    Month 24
    Notes
    [11] - 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: The endpoint was only assessed in Part 2 of the study.
    End point values
    		 Confirmatory Part 2 - Risdiplam
    Number of subjects analysed
    41
    Units: Percentage of Subjects
    number (not applicable)
        Unable to maintain head upright (Head Control)
    7.3
        Wobbles (Head Control)
    19.5
        All the time maintained upright (Head Control)
    63.4
        Not done (Head Control)
    2.4
        Cannot sit (Sitting)
    19.5
        Sits with support at hips (Sitting)
    7.3
        Props (Sitting)
    9.8
        Stable sit (Sitting)
    24.4
        Pivots (rotates) (Sitting)
    29.3
        Not done (Sitting)
    2.4
        No grasp (Voluntary Grasp)
    2.4
        Uses whole hand (Voluntary Grasp)
    4.9
        Index finger/thumb immature grasp(Voluntary Grasp)
    39.0
        Pincer grasp (Voluntary Grasp)
    41.5
        Not done (Voluntary Grasp)
    4.9
        No kicking (Ability to Kick [supine])
    7.3
        Kicks horizontally;legs don't lift (Kick [supine])
    31.7
        Upward (vertically) (Ability to Kick [supine])
    9.8
        Touches leg (Ability to Kick [supine])
    9.8
        Touches toes (Ability to Kick [supine])
    31.7
        Not Done (Ability to Kick [supine])
    2.4
        No rolling (Rolling)
    9.8
        Rolling to side (Rolling)
    29.3
        Prone to supine (Rolling)
    7.3
        Supine to prone (Rolling)
    43.9
        Not Done (Rolling)
    2.4
        Does not lift head (Crawling)
    75.6
        On elbow (Crawling)
    7.3
        On outstretched hand (Crawling)
    2.4
        Crawling flat on abdomen (Crawling)
    0
        Crawling on hands and knees (Crawling)
    4.9
        Not done (Crawling)
    2.4
        Does not support weight (Standing)
    63.4
        Supports weight (Standing)
    12.2
        Stands with support (Standing)
    14.6
        Stands unaided (Standing)
    0
        Not done (Standing)
    2.4
        Bouncing (Walking)
    2.4
        Cruising (walks holding on) (Walking)
    2.4
        Walking independently (Walking)
    0
        Cannot test (Walking)
    75.6
        Not Done (Walking)
    12.2
    No statistical analyses for this end point

    Secondary: Part 2: Percentage of Motor Milestone Responders as Assessed by HINE-2 at Months 12 and 24

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    End point title
    		 Part 2: Percentage of Motor Milestone Responders as Assessed by HINE-2 at Months 12 and 24 [12]
    End point description
    The HINE-2 evaluates 8 developmental milestones scored on a 3, 4, or 5-point scale, with 0 indicating inability to perform a task and a score of 2, 3, or 4 (depending on the task) indicating full milestone development. For the responder definition, an improvement in a motor milestone is defined as at least a 2-point increase in ability to kick (or maximal score) or a 1-point increase in head control, rolling, sitting, crawling, standing, or walking. Worsening is defined as a 2-point decrease in ability to kick (or lowest score) or a 1-point decrease in head control, rolling, sitting, crawling, standing, or walking. Voluntary grasp is excluded. An infant is a responder if more motor milestones show improvement than show worsening. 90% CI for one sample binomial was computed using Clopper-Pearson (exact) method. Result at Month 12 was compared to a performance criterion of 12% derived from natural history data (p<0.0001). ITT population: all infants enrolled in Part 2 of the study.
    End point type
    Secondary
    End point timeframe
    Month 12, Month 24
    Notes
    [12] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The endpoint was only assessed in Part 2 of the study.
    End point values
    		 Confirmatory Part 2 - Risdiplam
    Number of subjects analysed
    41
    Units: Percentage of Subjects
    number (confidence interval 90%)
        Month 12
    78.0 (64.82 to 88.04)
        Month 24
    85.4 (73.15 to 93.43)
    No statistical analyses for this end point

    Secondary: Part 2: Highest Motor Milestone Achieved of Six Specified Milestones Assessed in the BSID-III Gross Motor Scale by Months 12 and 24

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    End point title
    		 Part 2: Highest Motor Milestone Achieved of Six Specified Milestones Assessed in the BSID-III Gross Motor Scale by Months 12 and 24 [13]
    End point description
    The BSID-III is a standardized assessment commonly used to evaluate development across five domains in infants and young children aged between 1 and 42 months. The gross motor subscale of the BSID-III is evaluated based on the linear and hierarchical obtainment of motor skills, as seen in typically developing children. The gross motor scale consists of 72 items scored at 0 (unable to perform the activity) or 1 (criteria for item achieved). This measure included 6 milestones: Item 9 ‘Controls head while upright for 15 seconds’, Item 14 ‘Rolls from side to back’, Item 22 ‘Sits without support for 5 seconds’, Item 30 ‘Crawls on stomach’, Item 40 ‘Stands alone’ and Item 42 ‘Walks alone’. M12 indicates Month 12 and M24 indicates Month 24. Reported here is the percentage of participants for whom the reported item was the highest item achieved out of these six items by Months 12 and 24. ITT population is defined as all infants enrolled in Part 2 of the study.
    End point type
    Secondary
    End point timeframe
    Month 12, Month 24
    Notes
    [13] - 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: The endpoint was only assessed in Part 2 of the study.
    End point values
    		 Confirmatory Part 2 - Risdiplam
    Number of subjects analysed
    41
    Units: Percentage of Subjects
    number (not applicable)
        Item 9: Controls Head While Upright for 15 sec M12
    0
        Item 14: Rolls from Side to Back at Month 12
    56.1
        Item 22: Sits Without Support for 5 sec Month 12
    29.3
        Item 30: Crawls on Stomach at Month 12
    0
        Item 40: Stands Alone at Month 12
    0
        Item 42: Walks Alone at Month 12
    0
        Item 9: Controls Head While Upright for 15 sec M24
    0
        Item 14: Rolls from Side to Back at Month 24
    29.3
        Item 22: Sits Without Support for 5 sec Month 24
    61.0
        Item 30: Crawls on Stomach at Month 24
    0
        Item 40: Stands Alone at Month 24
    0
        Item 42: Walks Alone at Month 24
    0
    No statistical analyses for this end point

    Secondary: Part 2: Percentage of Infants Who Are Sitting Without Support for at Least 5 Seconds as Assessed by Item 22 of the BSID-III Gross Motor Scale at Month 24

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    End point title
    		 Part 2: Percentage of Infants Who Are Sitting Without Support for at Least 5 Seconds as Assessed by Item 22 of the BSID-III Gross Motor Scale at Month 24 [14]
    End point description
    The BSID-III is a standardized assessment commonly used to evaluate development across five domains in infants and young children aged between 1 and 42 months. The gross motor subscale of the BSID-III is evaluated based on the linear and hierarchical obtainment of motor skills, as seen in typically developing children. The gross motor scale consists of 72 items scored at 0 (unable to perform the activity) or 1 (criteria for item achieved). Item 22 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. The assessment was video recorded at study sites and reviewed/scored by two independent raters. 90% CI for one sample binomial was computed using Clopper-Pearson (exact) method. The result was compared to a performance criterion of 5% derived from natural history data (p<0.0001). ITT population is defined as all infants enrolled in Part 2 of the study.
    End point type
    Secondary
    End point timeframe
    Month 24
    Notes
    [14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The endpoint was only assessed in Part 2 of the study.
    End point values
    		 Confirmatory Part 2 - Risdiplam
    Number of subjects analysed
    41
    Units: Percentage of Subjects
        number (confidence interval 90%)
    61.0 (46.94 to 73.77)
    No statistical analyses for this end point

    Secondary: Part 2: Percentage of Infants Who Are Sitting Without Support for at Least 30 Seconds as Assessed by Item 26 of the BSID-III Gross Motor Scale at Month 24

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    End point title
    		 Part 2: Percentage of Infants Who Are Sitting Without Support for at Least 30 Seconds as Assessed by Item 26 of the BSID-III Gross Motor Scale at Month 24 [15]
    End point description
    The BSID-III is a standardized assessment commonly used to evaluate development across five domains in infants and young children aged between 1 and 42 months. The gross motor subscale of the BSID-III is evaluated based on the linear and hierarchical obtainment of motor skills, as seen in typically developing children. The gross motor scale consists of 72 items scored at 0 (unable to perform the activity) or 1 (criteria for item achieved). Item 26 is not considered achieved if the infant sits alone for less than 30 seconds before losing balance and falling over, or if the infant uses his or her arms to prop him- or herself up. The assessment was video recorded at study sites and reviewed/scored by two independent raters. 90% CI for one sample binomial was computed using Clopper-Pearson (exact) method. The result was compared to a performance criterion of 5% derived from natural history data (p<0.0001). ITT population is defined as all infants enrolled in Part 2 of the study.
    End point type
    Secondary
    End point timeframe
    Month 24
    Notes
    [15] - 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: The endpoint was only assessed in Part 2 of the study.
    End point values
    		 Confirmatory Part 2 - Risdiplam
    Number of subjects analysed
    41
    Units: Percentage of Subjects
        number (confidence interval 90%)
    43.9 (30.62 to 57.87)
    No statistical analyses for this end point

    Secondary: Part 2: Percentage of Infants Who Are Standing Alone as Assessed by Item 40 of the BSID-III Gross Motor Scale at Month 24

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    End point title
    		 Part 2: Percentage of Infants Who Are Standing Alone as Assessed by Item 40 of the BSID-III Gross Motor Scale at Month 24 [16]
    End point description
    The BSID-III is a standardized assessment commonly used to evaluate development across five domains in infants and young children aged between 1 and 42 months. The gross motor subscale of the BSID-III is evaluated based on the linear and hierarchical obtainment of motor skills, as seen in typically developing children. The gross motor scale consists of 72 items scored at 0 (unable to perform the activity) or 1 (criteria for item achieved). Reported here is the percentage of participants who achieved item 40 ‘Stands alone’ at Month 24. The assessment was video recorded at study sites and reviewed/scored by two independent raters. 90% CI for one sample binomial was computed using Clopper-Pearson (exact) method. The result was compared to a performance criterion of 5% derived from natural history data (p=1.0000). ITT population is defined as all infants enrolled in Part 2 of the study.
    End point type
    Secondary
    End point timeframe
    Month 24
    Notes
    [16] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The endpoint was only assessed in Part 2 of the study.
    End point values
    		 Confirmatory Part 2 - Risdiplam
    Number of subjects analysed
    41
    Units: Percentage of Subjects
        number (confidence interval 90%)
    0 (0.00 to 7.05)
    No statistical analyses for this end point

    Secondary: Part 2: Percentage of Infants Who Are Walking Alone as Assessed by Item 42 of the BSID-III Gross Motor Scale at Month 24

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    End point title
    		 Part 2: Percentage of Infants Who Are Walking Alone as Assessed by Item 42 of the BSID-III Gross Motor Scale at Month 24 [17]
    End point description
    The BSID-III is a standardized assessment commonly used to evaluate development across five domains in infants and young children aged between 1 and 42 months. The gross motor subscale of the BSID-III is evaluated based on the linear and hierarchical obtainment of motor skills, as seen in typically developing children. The gross motor scale consists of 72 items scored at 0 (unable to perform the activity) or 1 (criteria for item achieved). Reported here is the percentage of participants who achieved item 42 ‘Walks alone’ at Month 24. The assessment was video recorded at study sites and reviewed/scored by two independent raters. 90% CI for one sample binomial was computed using Clopper-Pearson (exact) method. The result was compared to a performance criterion of 5% derived from natural history data (p=1.0000). ITT population is defined as all infants enrolled in Part 2 of the study.
    End point type
    Secondary
    End point timeframe
    Month 24
    Notes
    [17] - 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: The endpoint was only assessed in Part 2 of the study.
    End point values
    		 Confirmatory Part 2 - Risdiplam
    Number of subjects analysed
    41
    Units: Percentage of Subjects
        number (confidence interval 90%)
    0 (0.00 to 7.05)
    No statistical analyses for this end point

    Secondary: Part 2: Time to Death

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    End point title
    		 Part 2: Time to Death [18]
    End point description
    The median time to event was estimated using Kaplan-Meier methodology. 90% CI was estimated using the method of Brookmeyer and Crowley. ITT population is defined as all infants enrolled in Part 2 of the study, regardless of whether they received treatment or not. The median time to death was not estimable as few subjects had an event. 9999=not estimable
    End point type
    Secondary
    End point timeframe
    Up to 24 months (up to the Clinical Cut-off Date [CCOD] of 12 November 2020)
    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: The endpoint was only assessed in Part 2 of the study.
    End point values
    		 Confirmatory Part 2 - Risdiplam
    Number of subjects analysed
    41 [19]
    Units: Months
        median (confidence interval 90%)
    9999 (9999 to 9999)
    Notes
    [19] - The median time to death was not estimable as few subjects had an event.
    No statistical analyses for this end point

    Secondary: Part 2: Time to Death or Permanent Ventilation

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    End point title
    		 Part 2: Time to Death or Permanent Ventilation [20]
    End point description
    Permanent ventilation is defined as >/=16 hours of non-invasive ventilation per day or intubation for >21 consecutive days in the absence of, or following the resolution of, an acute reversible event; or tracheostomy. Permanent ventilation events were reviewed and confirmed by an independent adjudication committee. The median time to event was estimated using Kaplan-Meier methodology. 90% CI was estimated using the method of Brookmeyer and Crowley. ITT population is defined as all infants enrolled in Part 2 of the study, regardless of whether they received treatment or not. The median time to death or permanent ventilation was not estimable as few subjects had an event. 9999=not estimable
    End point type
    Secondary
    End point timeframe
    Up to 24 months (up to the CCOD of 12 November 2020)
    Notes
    [20] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The endpoint was only assessed in Part 2 of the study.
    End point values
    		 Confirmatory Part 2 - Risdiplam
    Number of subjects analysed
    41 [21]
    Units: Months
        median (confidence interval 90%)
    9999 (9999 to 9999)
    Notes
    [21] - The median time to death or permanent ventilation was not estimable as few subjects had an event.
    No statistical analyses for this end point

    Secondary: Part 2: Time to Permanent Ventilation

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    End point title
    		 Part 2: Time to Permanent Ventilation [22]
    End point description
    Permanent ventilation is defined as >/=16 hours of non-invasive ventilation per day or intubation for >21 consecutive days in the absence of, or following the resolution of, an acute reversible event; or tracheostomy. Permanent ventilation events were reviewed and confirmed by an independent adjudication committee. The median time to event was estimated using Kaplan-Meier methodology. 90% CI was estimated using the method of Brookmeyer and Crowley. ITT population is defined as all infants enrolled in Part 2 of the study, regardless of whether they received treatment or not. The median time to permanent ventilation was not estimable as few subjects had an event. 9999=not estimable
    End point type
    Secondary
    End point timeframe
    Up to 24 months (up to the CCOD of 12 November 2020)
    Notes
    [22] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The endpoint was only assessed in Part 2 of the study.
    End point values
    		 Confirmatory Part 2 - Risdiplam
    Number of subjects analysed
    41 [23]
    Units: Months
        median (confidence interval 90%)
    9999 (9999 to 9999)
    Notes
    [23] - The median time to permanent ventilation was not estimable as few subjects had an event.
    No statistical analyses for this end point

    Secondary: Part 2: Percentage of Infants Who Are Alive Without Permanent Ventilation at Months 12 and 24

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    End point title
    		 Part 2: Percentage of Infants Who Are Alive Without Permanent Ventilation at Months 12 and 24 [24]
    End point description
    Permanent ventilation is defined as >/=16 hours of non-invasive ventilation per day or intubation for >21 consecutive days in the absence of, or following the resolution of, an acute reversible event; or tracheostomy. Permanent ventilation events were reviewed and confirmed by an independent adjudication committee. Kaplan-Meier methodology was used to estimate the percentages. 90% CI was computed using the complementary log-log transformation. The result was compared to a performance criterion of 42% derived from natural history data (p<0.0001). Statistical analysis was only performed for Month 12 data. ITT population is defined as all infants enrolled in Part 2 of the study, regardless of whether they received treatment or not.
    End point type
    Secondary
    End point timeframe
    Month 12, Month 24
    Notes
    [24] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The endpoint was only assessed in Part 2 of the study.
    End point values
    		 Confirmatory Part 2 - Risdiplam
    Number of subjects analysed
    41
    Units: Percentage of Subjects
    number (confidence interval 90%)
        Month 12
    85.37 (73.35 to 92.24)
        Month 24
    82.93 (70.54 to 90.44)
    No statistical analyses for this end point

    Secondary: Part 2: Percentage of Infants Who Are Alive at Months 12 and 24

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    End point title
    		 Part 2: Percentage of Infants Who Are Alive at Months 12 and 24 [25]
    End point description
    Kaplan-Meier methodology was used to estimate the percentages. 90% CI was computed using the complementary log-log transformation. The result was compared to a performance criterion of 60% derived from natural history data (p=0.0005). Statistical analysis was only performed for Month 12 data. ITT population is defined as all infants enrolled in Part 2 of the study, regardless of whether they received treatment or not.
    End point type
    Secondary
    End point timeframe
    Month 12, Month 24
    Notes
    [25] - 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: The endpoint was only assessed in Part 2 of the study.
    End point values
    		 Confirmatory Part 2 - Risdiplam
    Number of subjects analysed
    41
    Units: Percentage of Subjects
    number (confidence interval 90%)
        Month 12
    92.68 (82.16 to 97.10)
        Month 24
    92.68 (82.16 to 97.10)
    No statistical analyses for this end point

    Secondary: Part 2: Percentage of Infants Who Are Without Permanent Ventilation at Months 12 and 24

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    End point title
    		 Part 2: Percentage of Infants Who Are Without Permanent Ventilation at Months 12 and 24 [26]
    End point description
    Permanent ventilation is defined as >/=16 hours of non-invasive ventilation per day or intubation for >21 consecutive days in the absence of, or following the resolution of, an acute reversible event; or tracheostomy. Permanent ventilation events were reviewed and confirmed by an independent adjudication committee. Kaplan-Meier methodology was used to estimate the percentages. 90% CI was computed using the complementary log-log transformation. The result was compared to a performance criterion of 89% derived from natural history data (p=0.2595). Statistical analysis was only performed for Month 12 data. ITT population is defined as all infants enrolled in Part 2 of the study, regardless of whether they received treatment or not.
    End point type
    Secondary
    End point timeframe
    Month 12, Month 24
    Notes
    [26] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The endpoint was only assessed in Part 2 of the study.
    End point values
    		 Confirmatory Part 2 - Risdiplam
    Number of subjects analysed
    41
    Units: Percentage of Subjects
    number (confidence interval 90%)
        Month 12
    92.29 (81.24 to 96.95)
        Month 24
    89.65 (77.96 to 95.32)
    No statistical analyses for this end point

    Secondary: Part 2: Percentage of Infants who Achieve a Reduction of At Least 30 Degrees in Phase Angle From Baseline, as Measured by Respiratory Plethysmography (RP) at Month 12

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    End point title
    		 Part 2: Percentage of Infants who Achieve a Reduction of At Least 30 Degrees in Phase Angle From Baseline, as Measured by Respiratory Plethysmography (RP) at Month 12 [27]
    End point description
    RP measures the degree of synchrony between abdominal and thoracic cage-driven breathing. The weakness of intercostal muscles leads to asynchrony of the thorax with the diaphragm, resulting in inefficient and paradoxical breathing patterns. The degree of synchrony between the movement of the chest wall and abdomen during the respiratory cycle can be expressed as the phase angle between the two compartments and measured by placing two RP bands around the thorax and abdomen. In paradoxical breathing, the phase angle is reversed compared with the normal ventilation cycle. A phase angle of 0° indicates perfect in-phase movement, while a value of 180° indicates completely out-of-phase movement between the two compartments. In this measure, 8 or more valid breaths were required to determine the phase angle at each visit. 90% CI for one sample binomial was computed using Clopper-Pearson (exact) method. ITT population is defined as all infants enrolled in Part 2 of the study.
    End point type
    Secondary
    End point timeframe
    Month 12
    Notes
    [27] - 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: The endpoint was only assessed in Part 2 of the study.
    End point values
    		 Confirmatory Part 2 - Risdiplam
    Number of subjects analysed
    41
    Units: Percentage of Subjects
        number (confidence interval 90%)
    34.1 (21.96 to 48.13)
    No statistical analyses for this end point

    Secondary: Part 2: Percentage of Infants not Requiring Respiratory Support (Invasive or Non-Invasive) at Months 12 and 24

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    End point title
    		 Part 2: Percentage of Infants not Requiring Respiratory Support (Invasive or Non-Invasive) at Months 12 and 24 [28]
    End point description
    90% CI for one sample binomial was computed using Clopper-Pearson (exact) method. ITT population is defined as all infants enrolled in Part 2 of the study, regardless of whether they received treatment or not.
    End point type
    Secondary
    End point timeframe
    Month 12, Month 24
    Notes
    [28] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The endpoint was only assessed in Part 2 of the study.
    End point values
    		 Confirmatory Part 2 - Risdiplam
    Number of subjects analysed
    41
    Units: Percentage of Subjects
    number (confidence interval 90%)
        Month 12
    24.4 (13.87 to 37.85)
        Month 24
    19.5 (10.10 to 32.46)
    No statistical analyses for this end point

    Secondary: Part 2: Percentage of Infants Able to Feed Orally at Months 12 and 24

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    End point title
    		 Part 2: Percentage of Infants Able to Feed Orally at Months 12 and 24 [29]
    End point description
    Able to feed orally includes subjects fed orally and subjects fed via a combination of oral and tube feeding. 90% CI for one sample binomial was computed using Clopper-Pearson (exact) method. ITT population is defined as all infants enrolled in Part 2 of the study, regardless of whether they received treatment or not.
    End point type
    Secondary
    End point timeframe
    Month 12, Month 24
    Notes
    [29] - 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: The endpoint was only assessed in Part 2 of the study.
    End point values
    		 Confirmatory Part 2 - Risdiplam
    Number of subjects analysed
    41
    Units: Percentage of Subjects
    number (confidence interval 90%)
        Month 12
    82.9 (70.31 to 91.70)
        Month 24
    85.4 (73.15 to 93.43)
    No statistical analyses for this end point

    Secondary: Part 1 and Part 2: Percentage of Subjects With Adverse Events (AEs) and Serious Adverse Events (SAEs)

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    End point title
    		 Part 1 and Part 2: Percentage of Subjects With Adverse Events (AEs) and Serious Adverse Events (SAEs)
    End point description
    An adverse event (AE) is any untoward medical occurrence in a subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as adverse events. Adverse events reported during the safety follow-up period are excluded from this interim analysis. All infants who received at least one dose of study medication (risdiplam) were included in the safety population.
    End point type
    Secondary
    End point timeframe
    From first dose of risdiplam up to a minimum of 24 months (CCOD of 12 November 2020)
    End point values
    		 Exploratory Part 1 - Cohort 1 Exploratory Part 1 - Cohort 2 Confirmatory Part 2 - Risdiplam
    Number of subjects analysed
    4
    17
    41
    Units: Percentage of Subjects
    number (not applicable)
        With at least one AE
    100.0
    100.0
    100.0
        With at least one SAE
    100.0
    70.6
    68.3
    No statistical analyses for this end point

    Secondary: Part 2: Percentage of Subjects With AEs and SAEs Leading to Treatment Discontinuation

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    End point title
    		 Part 2: Percentage of Subjects With AEs and SAEs Leading to Treatment Discontinuation [30]
    End point description
    An adverse event (AE) is any untoward medical occurrence in a subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as adverse events. All infants who received at least one dose of study medication (risdiplam) were included in the safety population.
    End point type
    Secondary
    End point timeframe
    From first dose of risdiplam up to a minimum of 24 months (CCOD of 12 November 2020)
    Notes
    [30] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The endpoint was only assessed in Part 2 of the study.
    End point values
    		 Confirmatory Part 2 - Risdiplam
    Number of subjects analysed
    41
    Units: Percentage of Subjects
    number (not applicable)
        Due to AE
    0
        Due to SAE
    0
    No statistical analyses for this end point

    Secondary: Part 2: Percentage of Subjects With AEs and SAEs Leading to Treatment Modification/Interruption

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    End point title
    		 Part 2: Percentage of Subjects With AEs and SAEs Leading to Treatment Modification/Interruption [31]
    End point description
    An adverse event (AE) is any untoward medical occurrence in a subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as adverse events. All infants who received at least one dose of study medication (risdiplam) were included in the safety population.
    End point type
    Secondary
    End point timeframe
    From first dose of risdiplam up to a minimum of 24 months (CCOD of 12 November 2020)
    Notes
    [31] - 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: The endpoint was only assessed in Part 2 of the study.
    End point values
    		 Confirmatory Part 2 - Risdiplam
    Number of subjects analysed
    41
    Units: Percentage of Subjects
    number (not applicable)
        Due to AE
    4.9
        Due to SAE
    2.4
    No statistical analyses for this end point

    Secondary: Part 2: Anthropometric Examination of Weight Measured in Kilograms

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    End point title
    		 Part 2: Anthropometric Examination of Weight Measured in Kilograms [32]
    End point description
    Anthropometric examination included weight, height, head circumference and chest circumference. All infants who received at least one dose of study medication (risdiplam) were included in the safety population. Only participants for whom data were collected are included in the analysis.
    End point type
    Secondary
    End point timeframe
    Month 12, Month 24
    Notes
    [32] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The endpoint was only assessed in Part 2 of the study.
    End point values
    		 Confirmatory Part 2 - Risdiplam
    Number of subjects analysed
    38 [33]
    Units: kilogram (kg)
    arithmetic mean (standard deviation)
        Month 12 (n=38)
    9.59 ± 1.40
        Month 24 (n=36)
    11.28 ± 1.91
    Notes
    [33] - Only subjects for whom data were collected are included in the analysis at each time point.
    No statistical analyses for this end point

    Secondary: Part 2: Anthropometric Examination of Height, Head Circumference and Chest Circumference Measured in Centimeter

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    End point title
    		 Part 2: Anthropometric Examination of Height, Head Circumference and Chest Circumference Measured in Centimeter [34]
    End point description
    Anthropometric examination included weight, height, head circumference and chest circumference. All infants who received at least one dose of study medication (risdiplam) were included in the safety population. Only participants for whom data were collected are included in the analysis.
    End point type
    Secondary
    End point timeframe
    Month 12, Month 24
    Notes
    [34] - 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: The endpoint was only assessed in Part 2 of the study.
    End point values
    		 Confirmatory Part 2 - Risdiplam
    Number of subjects analysed
    38 [35]
    Units: centimeter (cm)
    arithmetic mean (standard deviation)
        Height at Month 12 (n=38)
    80.47 ± 4.00
        Height at Month 24 (n=36)
    89.13 ± 5.12
        Head Circumference at Month 12 (n=38)
    47.09 ± 1.72
        Head Circumference at Month 24 (n=35)
    49.28 ± 2.13
        Chest Circumference at Month 12 (n=38)
    45.77 ± 2.31
        Chest Circumference at Month 24 (n=34)
    48.35 ± 3.10
    Notes
    [35] - Only subjects for whom data were collected are included in the analysis at each time point.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first dose of risdiplam up to a minimum of 24 months (CCOD of 12 November 2020)
    Adverse event reporting additional description
    All infants who received at least one dose of risdiplam were included in the safety population. Adverse events reported during the safety follow-up period are excluded from this interim analysis. All deaths are included in the report.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23.1
    Reporting groups
    Reporting group title
    Exploratory Part 1 - Cohort 1
    Reporting group description
    		 Subjects received risdiplam in a staggered, dose-escalation manner once daily at Dose Level 1 for a minimum of 4 weeks to select the dose for Part 2. Dose Level 1 was targeting an exposure of mean AUC0-24h,ss 700 ng*h/mL.

    Reporting group title
    Confirmatory Part 2 - Risdiplam
    Reporting group description
    		 Subjects received risdiplam orally once daily at a dose of target exposure cap of a mean AUC0-24h,ss of 2000 ng*h/mL, for a duration of 24 months with a primary analysis after 12 months. Starting doses were either 0.04mg/kg, 0.08mg/kg or 0.2mg/kg depending on the subject’s age. All subjects had their dose adjusted to 0.2mg/kg within a few months of starting treatment. The dose was adjusted to 0.25mg/kg when subject reached 2 years of age.

    Reporting group title
    Exploratory Part 1 - Cohort 2
    Reporting group description
    		 Subjects received risdiplam in a staggered, dose-escalation manner once daily at Dose Level 2 for a minimum of 4 weeks to select the dose for Part 2. Dose Level 2 was targeting an exposure of mean AUC0-24h,ss </= 2000 ng*h/mL. Cohort 2 included one infant who started at Dose Level 1 and was escalated to Dose Level 2 on Day 83.

    Serious adverse events
    		 Exploratory Part 1 - Cohort 1 Confirmatory Part 2 - Risdiplam Exploratory Part 1 - Cohort 2
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 4 (100.00%)
    28 / 41 (68.29%)
    12 / 17 (70.59%)
         number of deaths (all causes)
    1
    3
    3
         number of deaths resulting from adverse events
    Investigations
    Weight decreased
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 41 (0.00%)
    1 / 17 (5.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oxygen saturation abnormal
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 41 (2.44%)
    0 / 17 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Near drowning
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 41 (2.44%)
    0 / 17 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Cryptorchism
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 41 (2.44%)
    0 / 17 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intestinal malrotation
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 41 (2.44%)
    0 / 17 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac arrest
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 41 (2.44%)
    1 / 17 (5.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Sinus tachycardia
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 41 (2.44%)
    0 / 17 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Hypotonia
         subjects affected / exposed
    0 / 4 (0.00%)
    2 / 41 (4.88%)
    0 / 17 (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
    Hydrocephalus
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 41 (2.44%)
    0 / 17 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 41 (0.00%)
    0 / 17 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 41 (2.44%)
    0 / 17 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 41 (2.44%)
    0 / 17 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 41 (2.44%)
    0 / 17 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 41 (2.44%)
    0 / 17 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pneumonia aspiration
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 41 (0.00%)
    1 / 17 (5.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atelectasis
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 41 (2.44%)
    1 / 17 (5.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    1 / 4 (25.00%)
    2 / 41 (4.88%)
    1 / 17 (5.88%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Hypoxia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 41 (0.00%)
    1 / 17 (5.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 41 (0.00%)
    1 / 17 (5.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory distress
         subjects affected / exposed
    0 / 4 (0.00%)
    3 / 41 (7.32%)
    2 / 17 (11.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 4 (0.00%)
    2 / 41 (4.88%)
    1 / 17 (5.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Aspiration
         subjects affected / exposed
    0 / 4 (0.00%)
    2 / 41 (4.88%)
    0 / 17 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory tract inflammation
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 41 (2.44%)
    0 / 17 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sleep apnoea syndrome
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 41 (2.44%)
    0 / 17 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchial secretion retention
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 41 (0.00%)
    1 / 17 (5.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cough
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 41 (2.44%)
    0 / 17 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    2 / 4 (50.00%)
    16 / 41 (39.02%)
    4 / 17 (23.53%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 20
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 41 (2.44%)
    1 / 17 (5.88%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Influenza
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 41 (2.44%)
    0 / 17 (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
    Respiratory tract infection viral
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 41 (0.00%)
    0 / 17 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 41 (0.00%)
    1 / 17 (5.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchiolitis
         subjects affected / exposed
    0 / 4 (0.00%)
    2 / 41 (4.88%)
    0 / 17 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Escherichia urinary tract infection
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 41 (2.44%)
    0 / 17 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 41 (2.44%)
    0 / 17 (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
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 41 (2.44%)
    1 / 17 (5.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 41 (2.44%)
    0 / 17 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pharyngitis
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 41 (2.44%)
    0 / 17 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia bacterial
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 41 (2.44%)
    0 / 17 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tracheobronchitis
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 41 (2.44%)
    0 / 17 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia viral
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 41 (2.44%)
    1 / 17 (5.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tracheitis
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 41 (2.44%)
    0 / 17 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 41 (2.44%)
    0 / 17 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis rotavirus
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 41 (2.44%)
    0 / 17 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory syncytial virus bronchiolitis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 41 (0.00%)
    1 / 17 (5.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Viral upper respiratory tract infection
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 41 (2.44%)
    1 / 17 (5.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Failure to thrive
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 41 (0.00%)
    1 / 17 (5.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    1 / 4 (25.00%)
    2 / 41 (4.88%)
    0 / 17 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Decreased appetite
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 41 (0.00%)
    1 / 17 (5.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 41 (0.00%)
    1 / 17 (5.88%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Exploratory Part 1 - Cohort 1 Confirmatory Part 2 - Risdiplam Exploratory Part 1 - Cohort 2
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    3 / 4 (75.00%)
    38 / 41 (92.68%)
    16 / 17 (94.12%)
    Vascular disorders
    Haematoma
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 41 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    0
    1
    General disorders and administration site conditions
    Discomfort
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 41 (2.44%)
    1 / 17 (5.88%)
         occurrences all number
    0
    1
    1
    Pyrexia
         subjects affected / exposed
    3 / 4 (75.00%)
    18 / 41 (43.90%)
    13 / 17 (76.47%)
         occurrences all number
    23
    47
    36
    Ill-defined disorder
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 41 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    0
    1
    No coding available
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 41 (2.44%)
    1 / 17 (5.88%)
         occurrences all number
    0
    1
    1
    Respiratory, thoracic and mediastinal disorders
    Atelectasis
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 41 (2.44%)
    1 / 17 (5.88%)
         occurrences all number
    0
    1
    4
    Cough
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 41 (0.00%)
    7 / 17 (41.18%)
         occurrences all number
    0
    0
    10
    Epistaxis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 41 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    0
    1
    Hypoxia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 41 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    0
    1
    Nasal congestion
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 41 (0.00%)
    3 / 17 (17.65%)
         occurrences all number
    0
    0
    3
    Upper respiratory tract inflammation
         subjects affected / exposed
    2 / 4 (50.00%)
    0 / 41 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    2
    0
    2
    Upper respiratory tract congestion
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 41 (2.44%)
    1 / 17 (5.88%)
         occurrences all number
    0
    1
    1
    Sleep apnoea syndrome
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 41 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    0
    1
    Rhinorrhoea
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 41 (2.44%)
    2 / 17 (11.76%)
         occurrences all number
    0
    2
    3
    Respiratory tract congestion
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 41 (2.44%)
    2 / 17 (11.76%)
         occurrences all number
    0
    1
    2
    Investigations
    Weight decreased
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 41 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    0
    1
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 41 (0.00%)
    2 / 17 (11.76%)
         occurrences all number
    0
    0
    2
    Head injury
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 41 (2.44%)
    1 / 17 (5.88%)
         occurrences all number
    0
    1
    1
    Incorrect dose administered
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 41 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    0
    1
    Joint dislocation
         subjects affected / exposed
    0 / 4 (0.00%)
    3 / 41 (7.32%)
    2 / 17 (11.76%)
         occurrences all number
    0
    3
    2
    Stoma site hypergranulation
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 41 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    0
    1
    Thermal burn
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 41 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    0
    1
    Humerus fracture
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 41 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    0
    1
    Congenital, familial and genetic disorders
    Phimosis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 41 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    0
    1
    Cryptorchism
         subjects affected / exposed
    0 / 4 (0.00%)
    2 / 41 (4.88%)
    2 / 17 (11.76%)
         occurrences all number
    0
    2
    2
    Nervous system disorders
    Loss of consciousness
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 41 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    0
    1
    Blood and lymphatic system disorders
    Lymphadenopathy
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 41 (2.44%)
    1 / 17 (5.88%)
         occurrences all number
    0
    1
    1
    Leukocytosis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 41 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    0
    1
    Eye disorders
    Conjunctival hyperaemia
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 41 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    1
    0
    1
    Macular cyst
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 41 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    0
    1
    Retinal exudates
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 41 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    0
    1
    Strabismus
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 41 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    0
    1
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 41 (0.00%)
    0 / 17 (0.00%)
         occurrences all number
    1
    0
    0
    Abnormal faeces
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 41 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    0
    1
    Aphthous ulcer
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 41 (0.00%)
    0 / 17 (0.00%)
         occurrences all number
    1
    0
    0
    Diarrhoea
         subjects affected / exposed
    0 / 4 (0.00%)
    5 / 41 (12.20%)
    6 / 17 (35.29%)
         occurrences all number
    0
    5
    8
    Constipation
         subjects affected / exposed
    1 / 4 (25.00%)
    12 / 41 (29.27%)
    3 / 17 (17.65%)
         occurrences all number
    1
    19
    4
    Dysphagia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 41 (0.00%)
    2 / 17 (11.76%)
         occurrences all number
    0
    0
    2
    Haematochezia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 41 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    0
    1
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 41 (2.44%)
    3 / 17 (17.65%)
         occurrences all number
    0
    2
    5
    Flatulence
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 41 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    1
    0
    1
    Faeces discoloured
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 41 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    0
    1
    Toothache
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 41 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    0
    1
    Teething
         subjects affected / exposed
    0 / 4 (0.00%)
    3 / 41 (7.32%)
    5 / 17 (29.41%)
         occurrences all number
    0
    5
    7
    Salivary hypersecretion
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 41 (2.44%)
    1 / 17 (5.88%)
         occurrences all number
    0
    1
    1
    Vomiting
         subjects affected / exposed
    1 / 4 (25.00%)
    4 / 41 (9.76%)
    6 / 17 (35.29%)
         occurrences all number
    1
    10
    12
    Infrequent bowel movements
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 41 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    0
    1
    Intestinal dilatation
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 41 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    0
    1
    Dental caries
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 41 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    0
    1
    Skin and subcutaneous tissue disorders
    Dermatitis atopic
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 41 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    0
    2
    Dermatitis allergic
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 41 (2.44%)
    1 / 17 (5.88%)
         occurrences all number
    0
    1
    1
    Dermatitis
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 41 (2.44%)
    0 / 17 (0.00%)
         occurrences all number
    1
    1
    0
    Eczema
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 41 (2.44%)
    3 / 17 (17.65%)
         occurrences all number
    0
    1
    3
    Erythema
         subjects affected / exposed
    2 / 4 (50.00%)
    0 / 41 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    3
    0
    2
    Macule
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 41 (0.00%)
    0 / 17 (0.00%)
         occurrences all number
    1
    0
    0
    Rash maculo-papular
         subjects affected / exposed
    0 / 4 (0.00%)
    4 / 41 (9.76%)
    0 / 17 (0.00%)
         occurrences all number
    0
    4
    0
    Miliaria
         subjects affected / exposed
    0 / 4 (0.00%)
    3 / 41 (7.32%)
    0 / 17 (0.00%)
         occurrences all number
    0
    3
    0
    Rash
         subjects affected / exposed
    0 / 4 (0.00%)
    3 / 41 (7.32%)
    2 / 17 (11.76%)
         occurrences all number
    0
    3
    3
    Petechiae
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 41 (2.44%)
    1 / 17 (5.88%)
         occurrences all number
    0
    1
    2
    Musculoskeletal and connective tissue disorders
    Kyphosis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 41 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    0
    1
    Scoliosis
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 41 (2.44%)
    1 / 17 (5.88%)
         occurrences all number
    0
    1
    1
    Osteoporosis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 41 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    0
    1
    Joint instability
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 41 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    0
    1
    Kyphoscoliosis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 41 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    0
    1
    Infections and infestations
    Ear infection
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 41 (0.00%)
    3 / 17 (17.65%)
         occurrences all number
    1
    0
    4
    Conjunctivitis
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 41 (2.44%)
    1 / 17 (5.88%)
         occurrences all number
    0
    1
    1
    Folliculitis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 41 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    0
    1
    Exanthema subitum
         subjects affected / exposed
    1 / 4 (25.00%)
    2 / 41 (4.88%)
    0 / 17 (0.00%)
         occurrences all number
    1
    2
    0
    Gastroenteritis
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 41 (2.44%)
    3 / 17 (17.65%)
         occurrences all number
    0
    1
    4
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 41 (0.00%)
    2 / 17 (11.76%)
         occurrences all number
    0
    0
    5
    Nasopharyngitis
         subjects affected / exposed
    0 / 4 (0.00%)
    7 / 41 (17.07%)
    5 / 17 (29.41%)
         occurrences all number
    0
    13
    12
    Otitis media
         subjects affected / exposed
    0 / 4 (0.00%)
    2 / 41 (4.88%)
    1 / 17 (5.88%)
         occurrences all number
    0
    2
    1
    Oral candidiasis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 41 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    0
    1
    Pharyngitis
         subjects affected / exposed
    1 / 4 (25.00%)
    2 / 41 (4.88%)
    0 / 17 (0.00%)
         occurrences all number
    1
    2
    0
    Pneumonia staphylococcal
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 41 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    0
    1
    Rhinitis
         subjects affected / exposed
    1 / 4 (25.00%)
    5 / 41 (12.20%)
    5 / 17 (29.41%)
         occurrences all number
    1
    7
    8
    Pneumonia
         subjects affected / exposed
    0 / 4 (0.00%)
    6 / 41 (14.63%)
    0 / 17 (0.00%)
         occurrences all number
    0
    6
    0
    Viral infection
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 41 (2.44%)
    2 / 17 (11.76%)
         occurrences all number
    0
    1
    2
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 4 (25.00%)
    22 / 41 (53.66%)
    10 / 17 (58.82%)
         occurrences all number
    4
    47
    21
    Urinary tract infection
         subjects affected / exposed
    1 / 4 (25.00%)
    3 / 41 (7.32%)
    0 / 17 (0.00%)
         occurrences all number
    2
    4
    0
    Varicella post vaccine
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 41 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    0
    1
    Viral upper respiratory tract infection
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 41 (2.44%)
    1 / 17 (5.88%)
         occurrences all number
    0
    1
    1
    Bronchitis
         subjects affected / exposed
    0 / 4 (0.00%)
    5 / 41 (12.20%)
    0 / 17 (0.00%)
         occurrences all number
    0
    6
    0
    Gastroenteritis adenovirus
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 41 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    0
    1
    Stoma site cellulitis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 41 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    0
    1
    Influenza
         subjects affected / exposed
    1 / 4 (25.00%)
    2 / 41 (4.88%)
    1 / 17 (5.88%)
         occurrences all number
    1
    2
    1
    Upper respiratory tract infection bacterial
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 41 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    0
    1
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 41 (2.44%)
    2 / 17 (11.76%)
         occurrences all number
    0
    1
    3
    Iron deficiency
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 41 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    0
    1

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    10 Feb 2017
    The protocol was updated to clarify the nature of the decisions to be taken by the IMC and the meeting schedule of the IMC; Exclusion criterion #3 was updated to reflect the fact that some subjects may have taken the recently approved drug, Spinraza™, as part of medical care, rather than only in a study; Exclusion criterion #22 was updated to clarify the term ‘use’ (in relation to prohibited medication use within 90 days prior to enrollment) as administration for at least 8 weeks within 90 days of beginning the study; Details on dilution factors for drug preparation were removed from the protocol as they are provided in the pharmacy manual (referenced in the protocol); The protocol was updated to clarify that subjects could be breastfed and winded if needed, followed by study drug administration.
    22 May 2017
    A new, optimized formulation was introduced. Subjects participating in the Part 1 extension of the study continued to use the Part 1 clinical formulation until they switched to the Part 2 clinical formulation upon availability of the new formulation. Subjects in Part 2 of the study receive the Part 2 formulation throughout their participation in the study; In Part 2, compound muscle action potential (CMAP) acquired from below the elbow stimulation was included following suggestions from different therapeutic area experts. This technical change was expected to give better wave forms in smaller infants, as the size of the hand may be too small for consistent placement of electrodes on the hand and wrist, and ultimately more consistent results.
    06 Apr 2018
    The Part 2 dose was incorporated into the protocol based on the Part 1 data, as reviewed by the internal monitoring committee (IMC) and the independent data monitoring committee (iDMC) in February 2018. In addition, the protocol was updated to allow all subjects in Part 1 to receive the dose selected for Part 2, including the first enrolled subject who per protocol thus far remained at the low target exposure of AUC 700 ng*h/mL; Following experience gained in Part 1, some ophthalmology assessments were modified to decrease unnecessary burden to subjects while optimizing quality of the main assessment (OCT); An option to enroll subjects in a specifically extended China enrollment phase after the global enrollment phase at China Food and Drug Administration (CFDA)-recognized sites, was added to ensure approximately 10 subjects are included in the China subpopulation; The definition of permanent ventilation was changed to >/= 16 hours of non-invasive ventilation per day or intubation for > 21 consecutive days in the absence of, or following the resolution of, an acute reversible event or tracheostomy. This definition better reflects the clinical situation in which an acute but reversible event could necessitate the use of non-invasive ventilation for several hours a day after which the subjects could be weaned, thus not truly meeting the original definition; An independent Permanent Ventilation Adjudication Committee was added to review all pertinent data for subjects who may have met the definition of permanent ventilation. This committee has been added to address the change in the definition of permanent ventilation described above and to provide greater transparency if a patient met this endpoint;
    06 Apr 2018
    Pharmacokinetic (PK) monitoring and dose adjustments as required were added to ensure subjects are within the targeted exposure and are in compliance with the exposure cap; The secondary objective to investigate muscle electrophysiology, as assessed by CMAP was changed to an exploratory objective as it is less well defined with regards to clinical meaningfulness than the multiple motor assessments already being performed; An efficacy outcome measure of ability to swallow and feed orally was added because these data are an important clinical outcome for subjects with SMA Type 1, who in the natural history of the disease lose the ability to swallow; In the context of the independent safety surveillance provided by the iDMC once Part 2 was initiated, AEs of skin or subcutaneous reaction, pharyngeal/laryngeal or mucosal reaction; and clinically relevant retinal abnormalities on OCT/fundus photography were removed from the list of non-serious AEs of special interest (AESI).
    27 Jan 2019
    Results from in vitro studies characterizing the inhibition of CYP3A4 by risdiplam were added. This inhibition has the potential to increase the concentration of concomitant medications predominantly metabolized by the CYP3A4 enzyme; The permitted therapy section was updated to state that concomitant medications that are CYP3A4 substrates are permitted if required; however, as per usual clinical practice, potential toxicities should be monitored carefully, in particular for medications with a narrow therapeutic window. If possible, a different concomitant medication should be chosen; The Clinical Domain Level Global Impression assessment was added to collect information on the respiratory function and swallowing ability of subjects which will be compared with their abilities at baseline, with untreated patients with Type 1 SMA, and with typically developing infants. Exploring the effect of treatment with risdiplam on respiratory function and the ability to swallow, as assessed by the clinical domain level items, was added as an exploratory efficacy objective; Evaluation of the change from baseline in weight and height at 12 and 24 months was added as an exploratory efficacy objective; Text was added to clarify that the dose of risdiplam administered may be higher than the dose levels explicitly listed in the protocol in order to maintain the exposure level over time in an individual growing subject.
    18 May 2020
    Protocol was released but is not effective.
    17 Jun 2020
    Given the absence of any risdiplam-induced ophthalmological findings to date in 471 subjects exposed to risdiplam for up to 3 years, the frequency of ophthalmology assessments has been reduced to every 6 months and colour fundus photography will no longer be performed; The length of the open-label extension phase has been defined as 3 years for each subject to allow for a longer safety follow-up period. Continued access to risdiplam will be provided until the end of study, provided that risdiplam is not commercially available in the subject's country. The length of the study has been modified and will not exceed 5 years after the last subject is enrolled in the study; Cautionary language on the concomitant use of CYP3A4 substrates has been removed, based on the recent results of the clinical drug-drug interaction Study BP41361 and subsequent physiologically-based pharmacokinetic modelling for extrapolation to children and infants. The study showed that coadministration with risdiplam led to only a small increase in exposure of the sensitive CYP3A substrate midazolam, which is not considered to be clinically relevant;
    17 Jun 2020
    The safety monitoring period has been modified to extend from screening through the open-label extension, the study completion/early withdrawal visit, and follow-up (phone call). Language related to the study completion/early withdrawal visit and follow-up has been clarified to ensure that all assessments are performed at the last visit for each subject, and that the follow-up should occur 30 days after that visit; Safety monitoring and stopping rules for adverse events affecting the skin, mouth, pharynx, and larynx have been removed to align with current data on potential risks updated in the Risdiplam Investigator's Brochure, Version 7; The adverse event reporting period has been reduced to 30 days after the study completion/early withdrawal visit (i.e., at least 30 days after the last dose of study drug), to reflect that adverse events are not expected beyond this reporting period; the elimination half-life of risdiplam will not exceed 30 days.

    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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