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    Clinical Trial Results:
    A Two-Part Seamless, Multi-Center, Randomized, Placebo-Controlled, Double Blind Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Efficacy of Risdiplam (RO7034067) in Type 2 and 3 Spinal Muscular Atrophy Patients

    Summary
    EudraCT number
    2016-000750-35
    Trial protocol
    ES   GB   IT   BE   DE   FR   PL   HR   BG  
    Global end of trial date

    Results information
    Results version number
    v1(current)
    This version publication date
    13 Sep 2020
    First version publication date
    13 Sep 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    BP39055
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02908685
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    F. Hoffmann-La Roche AG
    Sponsor organisation address
    Grenzacherstrasse 124., Basel, Switzerland, CH-4070
    Public contact
    F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, 41 616878333, global.trial_information@roche.com
    Scientific contact
    F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, 41 616878333, global.trial_information@roche.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    EMEA-002070-PIP01-16
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    Yes
    Results analysis stage
    Analysis stage
    Interim
    Date of interim/final analysis
    06 Sep 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    06 Sep 2019
    Global end of trial reached?
    No
    General information about the trial
    Main objective of the trial
    Part 1: To evaluate the safety, tolerability, Pharmacokinetics (PK) and Pharmacodynamics (PD) of risdiplam in subjects with Type 2 and Type 3 (ambulant or non-ambulant) SMA, and to select the dose for Part 2 of the study; Part 2: To evaluate efficacy of risdiplam compared to placebo in terms of motor function in Type 2 and non-ambulant Type 3 SMA subjects, as assessed by the change from baseline in the total score of the Motor Function Measure (MFM) at 12 months
    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
    19 Oct 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
    Spain: 21
    Country: Number of subjects enrolled
    Turkey: 1
    Country: Number of subjects enrolled
    United States: 4
    Country: Number of subjects enrolled
    Belgium: 19
    Country: Number of subjects enrolled
    Brazil: 2
    Country: Number of subjects enrolled
    Canada: 18
    Country: Number of subjects enrolled
    China: 16
    Country: Number of subjects enrolled
    Croatia: 11
    Country: Number of subjects enrolled
    France: 25
    Country: Number of subjects enrolled
    Germany: 4
    Country: Number of subjects enrolled
    Italy: 51
    Country: Number of subjects enrolled
    Japan: 15
    Country: Number of subjects enrolled
    Poland: 32
    Country: Number of subjects enrolled
    Russian Federation: 4
    Country: Number of subjects enrolled
    Serbia: 8
    Worldwide total number of subjects
    231
    EEA total number of subjects
    163
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    143
    Adolescents (12-17 years)
    62
    Adults (18-64 years)
    26
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Study Part 1 was conducted at 5 investigational sites across 4 countries, and Part 2 was conducted at 42 investigational sites across 14 countries.

    Pre-assignment
    Screening details
    The 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
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Monitor, Carer, Data analyst, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Part 1 Group A: Adolescents and Adults (Risdiplam)
    Arm description
    Adolescent and adult subjects aged 12-25 years received risdiplam for at least 12 weeks. Once the placebo-controlled period was completed and Part 2 dose was selected, subjects switched to Part 2 dose and were treated in an open-label phase.
    Arm type
    Experimental

    Investigational medicinal product name
    risdiplam
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    Part 1 was a does-finding exploratory part. Risdiplam was administered once daily with meal orally or through gastric tube. Subjects receiving risdiplam orally followed this by rinsing their mouth with water and swallowing. Subjects unable to swallow were to receive risdiplam by bolus via their naso-gastric or gastrostomy tube. This was followed by a bolus flush of water through the tube.

    Arm title
    Part 1 Group A: Adolescents and Adults (Placebo)
    Arm description
    Adolescent and adult subjects aged 12-25 years received placebo matching to risdiplam for at least 12 weeks. Once the placebo-controlled period was completed, subjects first switched to their cohort risdiplam dose. After the Part 2 dose was selected, subjects switched to Part 2 dose and were treated in an open-label phase.
    Arm type
    Placebo

    Investigational medicinal product name
    risdiplam matching placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    Part 1 was a dose-finding exploratory part. Risdiplam matching placebo was administered once daily with meal orally or through gastric tube. Subjects receiving risdiplam matching placebo orally followed this by rinsing their mouth with water and swallowing. Subjects unable to swallow were to receive risdiplam matching placebo by bolus via their naso-gastric or gastrostomy tube. This was followed by a bolus flush of water through the tube.

    Arm title
    Part 1 Group B: Children (Risdiplam)
    Arm description
    Children aged 2-11 years received risdiplam for at least 12 weeks. Once the placebo-controlled period was completed and Part 2 dose was selected, subjects switched to Part 2 dose and were treated in an open-label phase.
    Arm type
    Experimental

    Investigational medicinal product name
    risdiplam
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    Part 1 was a dose-finding exploratory part. Risdiplam was administered once daily with meal orally or through gastric tube. Subjects receiving risdiplam orally followed this by rinsing their mouth with water and swallowing. Subjects unable to swallow were to receive risdiplam by bolus via their naso-gastric or gastrostomy tube. This was followed by a bolus flush of water through the tube.

    Arm title
    Part 1 Group B: Children (Placebo)
    Arm description
    Children aged 2-11 years received placebo matching to risdiplam for at least 12 weeks. Once the placebo-controlled period was completed, subjects first switched to their cohort risdiplam dose. After the Part 2 dose was selected, subjects switched to Part 2 dose and were treated in an open-label phase.
    Arm type
    Placebo

    Investigational medicinal product name
    risdiplam matching placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    Part 1 was a dose-finding exploratory part. Risdiplam matching placebo was administered once daily with meal orally or through gastric tube. Subjects receiving risdiplam matching placebo orally followed this by rinsing their mouth with water and swallowing. Subjects unable to swallow were to receive risdiplam matching placebo by bolus via their naso-gastric or gastrostomy tube. This was followed by a bolus flush of water through the tube.

    Arm title
    Part 2: Risdiplam
    Arm description
    Subjects aged 2-25 years received risdiplam at the dose of 5 mg once daily for subjects with a body weight (BW) >/=20kg or 0.25 mg/kg for subjects with a BW <20 kg for 12 months.
    Arm type
    Experimental

    Investigational medicinal product name
    risdiplam
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    Risdiplam was administered once daily with meal orally or through gastric tube at 5 mg for subjects with body weight (BW) >/=20 kg and 0.25 mg/kg for subjects with BW <20 kg. Subjects receiving risdiplam orally followed this by rinsing their mouth with water and swallowing. Subjects unable to swallow were to receive risdiplam by bolus via their naso-gastric or gastrostomy tube. This was followed by a bolus flush of water through the tube.

    Arm title
    Part 2: Placebo
    Arm description
    Subjects aged 2-25 years received placebo matching to risdiplam for 12 months. After 12 months of treatment with placebo, subjects switched to risdiplam (5 mg once daily for subjects with a body weight (BW) >/=20kg or 0.25 mg/kg for subjects with a BW <20) in a blinded manner and subjects will continue with treatment and observations.
    Arm type
    Placebo

    Investigational medicinal product name
    risdiplam matching placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    Risdiplam matching placebo was administered once daily with meal orally or through gastric tube. Subjects receiving risdiplam matching placebo orally followed this by rinsing their mouth with water and swallowing. Subjects unable to swallow were to receive risdiplam matching placebo by bolus via their naso-gastric or gastrostomy tube. This was followed by a bolus flush of water through the tube.

    Number of subjects in period 1
    Part 1 Group A: Adolescents and Adults (Risdiplam) Part 1 Group A: Adolescents and Adults (Placebo) Part 1 Group B: Children (Risdiplam) Part 1 Group B: Children (Placebo) Part 2: Risdiplam Part 2: Placebo
    Started
    14
    6
    21
    10
    120
    60
    Completed
    13
    6
    21
    10
    117
    59
    Not completed
    1
    0
    0
    0
    3
    1
         Changed to Spinraza
    -
    -
    -
    -
    2
    1
         Changed to other treatment
    -
    -
    -
    -
    1
    -
         Consent withdrawn by subject
    1
    -
    -
    -
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Part 1 Group A: Adolescents and Adults (Risdiplam)
    Reporting group description
    Adolescent and adult subjects aged 12-25 years received risdiplam for at least 12 weeks. Once the placebo-controlled period was completed and Part 2 dose was selected, subjects switched to Part 2 dose and were treated in an open-label phase.

    Reporting group title
    Part 1 Group A: Adolescents and Adults (Placebo)
    Reporting group description
    Adolescent and adult subjects aged 12-25 years received placebo matching to risdiplam for at least 12 weeks. Once the placebo-controlled period was completed, subjects first switched to their cohort risdiplam dose. After the Part 2 dose was selected, subjects switched to Part 2 dose and were treated in an open-label phase.

    Reporting group title
    Part 1 Group B: Children (Risdiplam)
    Reporting group description
    Children aged 2-11 years received risdiplam for at least 12 weeks. Once the placebo-controlled period was completed and Part 2 dose was selected, subjects switched to Part 2 dose and were treated in an open-label phase.

    Reporting group title
    Part 1 Group B: Children (Placebo)
    Reporting group description
    Children aged 2-11 years received placebo matching to risdiplam for at least 12 weeks. Once the placebo-controlled period was completed, subjects first switched to their cohort risdiplam dose. After the Part 2 dose was selected, subjects switched to Part 2 dose and were treated in an open-label phase.

    Reporting group title
    Part 2: Risdiplam
    Reporting group description
    Subjects aged 2-25 years received risdiplam at the dose of 5 mg once daily for subjects with a body weight (BW) >/=20kg or 0.25 mg/kg for subjects with a BW <20 kg for 12 months.

    Reporting group title
    Part 2: Placebo
    Reporting group description
    Subjects aged 2-25 years received placebo matching to risdiplam for 12 months. After 12 months of treatment with placebo, subjects switched to risdiplam (5 mg once daily for subjects with a body weight (BW) >/=20kg or 0.25 mg/kg for subjects with a BW <20) in a blinded manner and subjects will continue with treatment and observations.

    Reporting group values
    Part 1 Group A: Adolescents and Adults (Risdiplam) Part 1 Group A: Adolescents and Adults (Placebo) Part 1 Group B: Children (Risdiplam) Part 1 Group B: Children (Placebo) Part 2: Risdiplam Part 2: Placebo Total
    Number of subjects
    14 6 21 10 120 60 231
    Age categorical
    Units: Subjects
        In utero
    0 0 0 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0 0 0 0 0 0
        Newborns (0-27 days)
    0 0 0 0 0 0 0
        Infants and toddlers (28 days-23 months)
    0 0 0 0 0 0 0
        Children (2-11 years)
    0 0 21 10 76 36 143
        Adolescents (12-17 years)
    11 5 0 0 30 16 62
        Adults (18-64 years)
    3 1 0 0 14 8 26
        From 65-84 years
    0 0 0 0 0 0 0
        85 years and over
    0 0 0 0 0 0 0
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    15.7 ± 4.1 16.0 ± 3.7 5.5 ± 2.5 4.6 ± 2.0 9.9 ± 5.8 10.3 ± 6.1 -
    Sex: Female, Male
    Units: Participants
        Female
    10 3 12 2 61 30 118
        Male
    4 3 9 8 59 30 113
    Race/Ethnicity, Customized
    Units: Subjects
        Asian
    0 0 1 0 23 12 36
        White
    14 6 19 9 80 41 169
        Multiple
    0 0 1 1 1 0 3
        Black or African American
    0 0 0 0 2 0 2
        Not stated
    0 0 0 0 14 7 21
    Race/Ethnicity, Customized
    Units: Subjects
        Hispanic or Latino
    0 0 0 0 5 2 7
        Not Hispanic or Latino
    14 6 20 10 114 57 221
        Unknown
    0 0 1 0 1 1 3

    End points

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    End points reporting groups
    Reporting group title
    Part 1 Group A: Adolescents and Adults (Risdiplam)
    Reporting group description
    Adolescent and adult subjects aged 12-25 years received risdiplam for at least 12 weeks. Once the placebo-controlled period was completed and Part 2 dose was selected, subjects switched to Part 2 dose and were treated in an open-label phase.

    Reporting group title
    Part 1 Group A: Adolescents and Adults (Placebo)
    Reporting group description
    Adolescent and adult subjects aged 12-25 years received placebo matching to risdiplam for at least 12 weeks. Once the placebo-controlled period was completed, subjects first switched to their cohort risdiplam dose. After the Part 2 dose was selected, subjects switched to Part 2 dose and were treated in an open-label phase.

    Reporting group title
    Part 1 Group B: Children (Risdiplam)
    Reporting group description
    Children aged 2-11 years received risdiplam for at least 12 weeks. Once the placebo-controlled period was completed and Part 2 dose was selected, subjects switched to Part 2 dose and were treated in an open-label phase.

    Reporting group title
    Part 1 Group B: Children (Placebo)
    Reporting group description
    Children aged 2-11 years received placebo matching to risdiplam for at least 12 weeks. Once the placebo-controlled period was completed, subjects first switched to their cohort risdiplam dose. After the Part 2 dose was selected, subjects switched to Part 2 dose and were treated in an open-label phase.

    Reporting group title
    Part 2: Risdiplam
    Reporting group description
    Subjects aged 2-25 years received risdiplam at the dose of 5 mg once daily for subjects with a body weight (BW) >/=20kg or 0.25 mg/kg for subjects with a BW <20 kg for 12 months.

    Reporting group title
    Part 2: Placebo
    Reporting group description
    Subjects aged 2-25 years received placebo matching to risdiplam for 12 months. After 12 months of treatment with placebo, subjects switched to risdiplam (5 mg once daily for subjects with a body weight (BW) >/=20kg or 0.25 mg/kg for subjects with a BW <20) in a blinded manner and subjects will continue with treatment and observations.

    Subject analysis set title
    Part 1: All Risdiplam
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Children aged 2-11 years and adolescent and adult subjects aged 12-25 years received risdiplam or risdiplam matching placebo.

    Subject analysis set title
    Part 1 Intent-to Treat (ITT)
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    The ITT population in Part 1 is defined as all randomized subjects. Subjects were grouped by treatment and by age group of 2-11 or 12-25 years old.

    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 or placebo) whether prematurely withdrawn or not 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 ITT population defined as all randomized subjects in Part 2 are the primary analysis population for all efficacy analyses. Subjects under the ITT population are reported according to the treatment they were randomized to.

    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 or placebo) were included in the safety population. Subjects were grouped according to the treatment received.

    Primary: Part 1: Selected Part 2 Dose of Risdiplam for Subjects with a Body Weight (BW) of >/=20kg

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    End point title
    Part 1: Selected Part 2 Dose of Risdiplam for Subjects with a Body Weight (BW) of >/=20kg [1]
    End point description
    The Internal Monitoring Committee (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.
    End point type
    Primary
    End point timeframe
    Day 1 up to at least 4 weeks on study (Up to CCOD of 25 July 2017)
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive statistics was planned to be reported in the endpoint.
    End point values
    Part 1: All Risdiplam
    Number of subjects analysed
    51
    Units: milligram (mg)
    5
    No statistical analyses for this end point

    Primary: Part 1: Selected Part 2 Dose of Risdiplam for Subjects with BW of <20kg

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    End point title
    Part 1: Selected Part 2 Dose of Risdiplam for Subjects with BW of <20kg [2]
    End point description
    The Internal Monitoring Committee (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.
    End point type
    Primary
    End point timeframe
    Day 1 up to at least 4 weeks on study (Up to CCOD of 25 July 2017)
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive statistics was planned to be reported in the endpoint.
    End point values
    Part 1: All Risdiplam
    Number of subjects analysed
    51
    Units: milligram/kilogramm (mg/kg)
        number (not applicable)
    0.25
    No statistical analyses for this end point

    Primary: Part 2: Change from Baseline in the Total Motor Function Measure 32 (MFM-32) Total Score at Month 12

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    End point title
    Part 2: Change from Baseline in the Total Motor Function Measure 32 (MFM-32) Total Score at Month 12 [3]
    End point description
    The Motor Function Measure 32 (MFM32) is a scale constructed for use in neuromuscular disorders. It comprises 32 items that evaluate physical function in three dimensions: D1 function related to standing and transfer; D2 axial and proximal function; D3 distal motor function. Tasks are scored with a 4-point Likert scale: 0 - cannot initiate the task or maintain the starting position; 1 - performs the task partially; 2 - performs the task incompletely or imperfectly; 3 - performs the task fully and “normally”. The 32 scores are summed and expressed on a 0-100 scale for the MFM32 total score. Higher scores indicate increased motor function. A positive change from Baseline indicates improvement. MMRM analysis was performed based on primary efficacy hypothetical estimand, which included subjects data assuming no prohibited medication intended for treatment of SMA was received and subjects continued on their randomized treatment until the analysis time point at Month 12.
    End point type
    Primary
    End point timeframe
    Baseline (Day -1) and Month 12
    Notes
    [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: Data for this endpoint was provided only for those arms which were planned to be reported.
    End point values
    Part 2: Risdiplam Part 2: Placebo
    Number of subjects analysed
    115 [4]
    59 [5]
    Units: Scores on a Scale
        least squares mean (confidence interval 95%)
    1.36 (0.61 to 2.11)
    -0.19 (-1.22 to 0.84)
    Notes
    [4] - Subjects with missing MFM32 total score at Baseline were not included in the analysis.
    [5] - Subjects with missing MFM32 total score at Baseline were not included in the analysis.
    Statistical analysis title
    Risdiplam vs Placebo
    Statistical analysis description
    This is the first end point and first family tested in the hierarchical testing. The variables included in the MMRM model are: baseline total score, treatment, age group, visit, treatment-by-visit and baseline score-by-visit interaction.
    Comparison groups
    Part 2: Risdiplam v Part 2: Placebo
    Number of subjects included in analysis
    174
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0156
    Method
    Mixed Model Repeated Measure Analysis
    Parameter type
    Least Square Mean Difference
    Point estimate
    1.55
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.3
         upper limit
    2.81

    Secondary: Part 2: Percentage of Subjects with Marked Improvement (Defined as >= 3) in the Total Motor Function Measure (MFM32) Score at Month 12

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    End point title
    Part 2: Percentage of Subjects with Marked Improvement (Defined as >= 3) in the Total Motor Function Measure (MFM32) Score at Month 12 [6]
    End point description
    The MFM32 comprises 32 items that evaluate physical function. The scoring of each task uses a 4-point Likert scale: 0 - cannot initiate the task or maintain the starting position; 1 - performs the task partially; 2 - performs the task incompletely or imperfectly; 3 - performs the task fully and “normally”. The 32 scores are summed and expressed on a 0-100 scale for the MFM32 total score. A change in MFM32 total score of threshold >/=3 represents marked improvement in this measure. Logistic regression analysis was performed based on efficacy hypothetical estimand, which included subjects data assuming no prohibited medication intended for treatment of SMA was received and subjects continued on their randomized treatment until the analysis time point at Month 12. Missing results at Month 12 are considered as non-responders.
    End point type
    Secondary
    End point timeframe
    At Month 12
    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: Data for this endpoint was provided only for those arms which were planned to be reported.
    End point values
    Part 2: Risdiplam Part 2: Placebo
    Number of subjects analysed
    115 [7]
    59 [8]
    Units: Percentage of Subjects
        least squares mean (confidence interval 95%)
    38.3 (28.94 to 47.58)
    23.7 (12.03 to 35.43)
    Notes
    [7] - Subjects with missing MFM32 total score at Baseline were not included in the analysis.
    [8] - Subjects with missing MFM32 total score at Baseline were not included in the analysis.
    Statistical analysis title
    Risdiplam vs Placebo
    Statistical analysis description
    This is the second end point and second family tested in the hierarchical testing. Logistic Regression Model.The variables included in the logistic regression are: baseline total score, treatment and age group.
    Comparison groups
    Part 2: Risdiplam v Part 2: Placebo
    Number of subjects included in analysis
    174
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0469 [9]
    Method
    Wald test
    Parameter type
    Odds ratio (OR)
    Point estimate
    2.35
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.01
         upper limit
    5.44
    Notes
    [9] - Adjusted p-Value The adjusted p-values were derived based on all the p-values from end points in order of the hierarchical testing up to the current endpoint.

    Secondary: Part 2: Change from Baseline in the Total Score of the Revised Upper Limb Module (RULM) at Month 12

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    End point title
    Part 2: Change from Baseline in the Total Score of the Revised Upper Limb Module (RULM) at Month 12 [10]
    End point description
    The RULM is a 20 items scale that assesses the proximal and distal motor functions of the arm. There is an entry item and the remaining 18 items are scored on the 3 point scale of : 0: cannot complete task independently; 1: modified method but can complete task independently; 2: completes task without any assistance, and with 1 item scored on a 2 point scale of as a can/cannot score with 1 as the highest score. The RULM total score is the sum of 19 items scores with range of 0-37, and the entry item does not contribute to the total score. Higher scores indicate greater upper limb function. A positive change from Baseline indicates improvement. MMRM analysis was performed based on the efficacy hypothetical estimand, which included subjects data assuming no prohibited medication intended for treatment of SMA was received and subjects continued on their randomized treatment until the analysis time point at Month 12.
    End point type
    Secondary
    End point timeframe
    Baseline (Day-1) and 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: Data for this endpoint was provided only for those arms which were planned to be reported.
    End point values
    Part 2: Risdiplam Part 2: Placebo
    Number of subjects analysed
    119 [11]
    58 [12]
    Units: Scores on a Scale
        least squares mean (confidence interval 95%)
    1.61 (1.00 to 2.22)
    0.02 (-0.83 to 0.87)
    Notes
    [11] - Subjects with missing RULM total score at Baseline were not included in the analysis.
    [12] - Subjects with missing RULM total score at Baseline were not included in the analysis.
    Statistical analysis title
    Risdiplam vs Placebo
    Statistical analysis description
    This is the third end point and third family tested in the hierarchical testing. The variables included in the MMRM model are: baseline total score, treatment, age group, visit, treatment-by-visit and baseline score-by-visit interaction.
    Comparison groups
    Part 2: Risdiplam v Part 2: Placebo
    Number of subjects included in analysis
    177
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0469 [13]
    Method
    Mixed Model Repeated Measure Analysis
    Parameter type
    Least Square Mean Difference
    Point estimate
    1.59
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.55
         upper limit
    2.62
    Notes
    [13] - Adjusted p-Value The adjusted p-values were derived based on all the p-values from end points in order of the hierarchical testing up to the current endpoint.

    Secondary: Part 2: Change from Baseline in Total Score of Hammersmith Functional Motor Scale Expanded (HFMSE) at Month 12

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    End point title
    Part 2: Change from Baseline in Total Score of Hammersmith Functional Motor Scale Expanded (HFMSE) at Month 12 [14]
    End point description
    The HFMSE scale contains 33 items, which are scored on a 3-point Likert-type scale (0-2) and summed to derive the total score, with lower scores indicating greater impairment. The HFMSE contains a series of assessments designed to assess important functional abilities, including standing, transfers, ambulation, and proximal and axial function. The overall score is the sum of the scores for all activities with a maximum achievable score of 66. Higher scores indicate greater motor function. A positive change from Baseline indicates improvement. MMRM analysis was performed based on the efficacy hypothetical estimand, which included subjects data assuming no prohibited medication intended for treatment of SMA was received and subjects continued on their randomized treatment until the analysis time point at Month 12.
    End point type
    Secondary
    End point timeframe
    Baseline (Day-1) and Month 12
    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: Data for this endpoint was provided only for those arms which were planned to be reported.
    End point values
    Part 2: Risdiplam Part 2: Placebo
    Number of subjects analysed
    120
    60
    Units: Scores on a Scale
        least squares mean (confidence interval 95%)
    0.95 (0.29 to 1.61)
    0.37 (-0.54 to 1.28)
    Statistical analysis title
    Risdiplam vs Placebo
    Statistical analysis description
    This is one of the two end points in family four in the hierarchical testing. The variables included in the MMRM model are: baseline total score, treatment, age group, visit, treatment-by-visit and baseline score-by-visit interaction.
    Comparison groups
    Part 2: Risdiplam v Part 2: Placebo
    Number of subjects included in analysis
    180
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.3902 [15]
    Method
    Mixed Model Repeated Measure Analysis
    Parameter type
    Least Square Mean Difference
    Point estimate
    0.58
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.53
         upper limit
    1.69
    Notes
    [15] - Adjusted p-Value The adjusted p-values were derived based on all the p-values from end points in order of the hierarchical testing up to the current endpoint.

    Secondary: Part 2: Change from Baseline in Forced Vital Capacity (FVC) at Month 12 in Subjects Aged 6-25 Years

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    End point title
    Part 2: Change from Baseline in Forced Vital Capacity (FVC) at Month 12 in Subjects Aged 6-25 Years [16]
    End point description
    Spirometry is a pulmonary function test that assesses how the lungs work by measuring how much air moves through the airways. Spirometry was performed by all subjects aged 6 or older. Forced vital capacity (FVC) is the total volume that can be exhaled after inhaling maximally. The best % predicted value out of all attempts were used for the analysis. MMRM analysis was performed based on the efficacy hypothetical estimand, which included subjects data assuming no prohibited medication intended for treatment of SMA was received and subjects continued on their randomized treatment until the analysis time point at Month 12.
    End point type
    Secondary
    End point timeframe
    Baseline (Day-1) and Month 12
    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: Data for this endpoint was provided only for those arms which were planned to be reported.
    End point values
    Part 2: Risdiplam Part 2: Placebo
    Number of subjects analysed
    83 [17]
    40 [18]
    Units: Percentage Predicted
        least squares mean (confidence interval 95%)
    -5.16 (-7.93 to -2.39)
    -3.11 (-6.59 to 0.74)
    Notes
    [17] - Subjects with missing FVC data at Baseline were not included in the analysis.
    [18] - Subjects with missing FVC data at Baseline were not included in the analysis.
    Statistical analysis title
    Risdiplam vs Placebo
    Statistical analysis description
    This is one of the two end points in family four in the hierarchical testing. The variables included in the MMRM model are: baseline total score, treatment, age group, visit, treatment-by-visit and baseline score-by-visit interaction.
    Comparison groups
    Part 2: Risdiplam v Part 2: Placebo
    Number of subjects included in analysis
    123
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.3902 [19]
    Method
    Mixed Model Repeated Measure Analysis
    Parameter type
    Least Square Mean Difference
    Point estimate
    -2.05
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -6.67
         upper limit
    2.56
    Notes
    [19] - Adjusted p-Value The adjusted p-values were derived based on all the p-values from end points in order of the hierarchical testing up to the current endpoint.

    Secondary: Part 2: Change from Baseline in the Caregiver-Reported SMA Independence Scale (SMAIS) Total Score at Month 12

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    End point title
    Part 2: Change from Baseline in the Caregiver-Reported SMA Independence Scale (SMAIS) Total Score at Month 12 [20]
    End point description
    The SMA Independence Scale (SMAIS) was developed specifically for SMA subjects in order to assess function-related independence. The SMAIS contains 29 items, assessing the amount of assistance required from another individual to perform daily activities such as eating, or bathing. Each item is scored on a 0-4 scale (with an additional option to indicate that an item is non-applicable). The SMAIS total score ranging from 0-44 is obtained based on 22 items with each item on the 0-2 scale. Lower scores indicate greater dependence on another individual. The SMAIS was completed by subjects aged 12 years or older and caregivers of subjects aged 2-25 years. MMRM analysis was performed based on efficacy hypothetical estimand, which included subjects data assuming no prohibited medication intended for treatment of SMA was received and subjects continued on their randomized treatment until the analysis time point at Month 12.
    End point type
    Secondary
    End point timeframe
    Baseline (Day-1) and Month 12
    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: Data for this endpoint was provided only for those arms which were planned to be reported.
    End point values
    Part 2: Risdiplam Part 2: Placebo
    Number of subjects analysed
    116 [21]
    60
    Units: Scores on a Scale
        least squares mean (confidence interval 95%)
    1.65 (0.66 to 2.63)
    -0.91 (-2.23 to 0.42)
    Notes
    [21] - Subjects with missing SMAIS total score at Baseline were not included in the analysis.
    Statistical analysis title
    Risdiplam vs Placebo
    Statistical analysis description
    This is the sixth endpoint and the fifth family tested in the hierarchical testing. The variables included in the MMRM model are: baseline total score, treatment, age group, visit, treatment-by-visit and baseline score-by-visit interaction.
    Comparison groups
    Part 2: Risdiplam v Part 2: Placebo
    Number of subjects included in analysis
    176
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.3902 [22]
    Method
    Mixed Model Repeated Measure Analysis
    Parameter type
    Least Square Mean Difference
    Point estimate
    2.55
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.93
         upper limit
    4.17
    Notes
    [22] - Adjusted p-Value The adjusted p-values were derived based on all the p-values from end points in order of the hierarchical testing up to the current endpoint.

    Secondary: Part 2: Percentage of Subjects Rated by Clinicians as Improved in the Clinical Global Impression of Change (CGI-C) Scale Ratings at Month 12

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    End point title
    Part 2: Percentage of Subjects Rated by Clinicians as Improved in the Clinical Global Impression of Change (CGI-C) Scale Ratings at Month 12 [23]
    End point description
    The Clinical Global Impression of Change (CGI-C) is used to score a clinician’s impression of a subject’s change in global health. The CGI-C is a single item measure of change in global health, using seven response options: “very much improved”, “much improved”, “minimally improved”, “no change”, “minimally worse”, “much worse”, and “very much worse”. Subjects considered as "improved" included responses of "very much improved, "much improved" and "minimally improved". Logistic regression analysis was performed based on efficacy hypothetical estimand, which included subjects data assuming no prohibited medication intended for treatment of SMA was received and subjects continued on their randomized treatment until the analysis time point at Month 12.
    End point type
    Secondary
    End point timeframe
    At Month 12
    Notes
    [23] - 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: Data for this endpoint was provided only for those arms which were planned to be reported.
    End point values
    Part 2: Risdiplam Part 2: Placebo
    Number of subjects analysed
    120 [24]
    60 [25]
    Units: Percentage of Subjects
        number (confidence interval 95%)
    47.5 (38.15 to 56.86)
    40.0 (26.77 to 53.23)
    Notes
    [24] - Missing results at Month 12 are considered as non-responders.
    [25] - Missing results at Month 12 are considered as non-responders.
    Statistical analysis title
    CGI Improved
    Statistical analysis description
    This is the seventh endpoint and the sixth family tested in the hierarchical testing. Logistic Regression Model. The variables included in the logistic regression are: baseline total score, treatment and age group.
    Comparison groups
    Part 2: Risdiplam v Part 2: Placebo
    Number of subjects included in analysis
    180
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.3902 [26]
    Method
    Wald-test
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.38
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.7
         upper limit
    2.74
    Notes
    [26] - Adjusted p-Value The adjusted p-values were derived based on all the p-values from end points in order of the hierarchical testing up to the current endpoint.

    Secondary: Part 2: Percentage of Subjects who Achieve Stabilization or Improvement (Defined as >= 0) in the Total Motor Function Measure (MFM) Score at Month 12

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    End point title
    Part 2: Percentage of Subjects who Achieve Stabilization or Improvement (Defined as >= 0) in the Total Motor Function Measure (MFM) Score at Month 12 [27]
    End point description
    The MFM32 comprises 32 items that evaluate physical function in three dimensions: D1 function related to standing and transfer; D2 axial and proximal function; D3 distal motor function. Tasks are scored with a 4-point Likert scale: 0 - cannot initiate the task or maintain the starting position; 1 - performs the task partially; 2 - performs the task incompletely or imperfectly; 3 - performs the task fully and “normally”. The 32 scores are summed and expressed on a 0-100 scale for the MFM32 total score. Higher scores indicate increased motor function. Logistic regression analysis was performed based on efficacy hypothetical estimand, which included subjects data assuming no prohibited medication intended for treatment of SMA was received and subjects continued on their randomized treatment until the analysis time point at Month 12. Missing results at Month 12 are considered as non-responders.
    End point type
    Secondary
    End point timeframe
    At 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: Data for this endpoint was provided only for those arms which were planned to be reported.
    End point values
    Part 2: Risdiplam Part 2: Placebo
    Number of subjects analysed
    115 [28]
    59 [29]
    Units: Percentage of Subjects
        number (confidence interval 95%)
    69.6 (60.72 to 78.41)
    54.2 (40.68 to 67.80)
    Notes
    [28] - Subjects with missing MFM32 total score at Baseline were not included in the analysis.
    [29] - Subjects with missing MFM32 total score at Baseline were not included in the analysis.
    Statistical analysis title
    Risdiplam vs Placebo
    Statistical analysis description
    Logistic Regression Model. The variables included in the logistic regression are: baseline total score, treatment and age group.
    Comparison groups
    Part 2: Risdiplam v Part 2: Placebo
    Number of subjects included in analysis
    174
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.043
    Method
    Wald test
    Parameter type
    Odds ratio (OR)
    Point estimate
    2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.02
         upper limit
    3.93

    Secondary: Part 2: Percentage of Subjects who Achieve an Improvement of at Least One Standard Error of Measurement (SEM) on the Total MFM Score at Month 12

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    End point title
    Part 2: Percentage of Subjects who Achieve an Improvement of at Least One Standard Error of Measurement (SEM) on the Total MFM Score at Month 12 [30]
    End point description
    The MFM32 comprises 32 items that evaluate physical function in three dimensions: D1 standing and transfer; D2 axial and proximal function; D3 distal motor function. Tasks are scored with a 4-point Likert scale: 0-cannot initiate the task or maintain the starting position; 1-performs the task partially; 2-performs the task incompletely or imperfectly; 3-performs the task fully and “normally”. The 32 scores are summed and expressed on a 0-100 scale for the total score. Higher scores indicate increased motor function. Standard error of measurement (SEM) is derived using 32 items scores and total scores at baseline. Change from baseline >= one SEM is equivalent to a change >= 4. Logistic regression analysis was performed based on efficacy hypothetical estimand included subjects data assuming no prohibited medication intended for treatment of SMA was received and subjects continued on their randomized treatment until the analysis time point at Month 12.
    End point type
    Secondary
    End point timeframe
    At Month 12
    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: Data for this endpoint was provided only for those arms which were planned to be reported.
    End point values
    Part 2: Risdiplam Part 2: Placebo
    Number of subjects analysed
    115 [31]
    59 [32]
    Units: Percentage of Subjects
    number (confidence interval 95%)
        Week 52
    28.7 (20.65 to 37.88)
    16.9 (8.44 to 28.97)
    Notes
    [31] - Subjects with missing MFM32 total score at Baseline were not included in the analysis.
    [32] - Subjects with missing MFM32 total score at Baseline were not included in the analysis.
    No statistical analyses for this end point

    Secondary: Part 2: Change from Baseline in the MFM Domain 1 (D1) Score at Month 12

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    End point title
    Part 2: Change from Baseline in the MFM Domain 1 (D1) Score at Month 12 [33]
    End point description
    The MFM32 comprises 32 items that evaluate physical function in three dimensions: D1 function related to standing and transfer; D2 axial and proximal function; D3 distal motor function. Tasks are scored with a 4-point Likert scale: 0 - cannot initiate the task or maintain the starting position; 1 - performs the task partially; 2 - performs the task incompletely or imperfectly; 3 - performs the task fully and “normally”. The D1 items score are summed and expressed on 0-100 scale for the MFM D1 total score. Higher scores indicate increased motor function. A positive change from Baseline indicates improvement. MMRM analysis was performed based on efficacy hypothetical estimand, which included subjects data assuming no prohibited medication intended for treatment of SMA was received and subjects continued on their randomized treatment until the analysis time point at Month 12.
    End point type
    Secondary
    End point timeframe
    Baseline (Day-1) and Month 12
    Notes
    [33] - 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: Data for this endpoint was provided only for those arms which were planned to be reported.
    End point values
    Part 2: Risdiplam Part 2: Placebo
    Number of subjects analysed
    118 [34]
    60
    Units: Scores on a Scale
        least squares mean (confidence interval 95%)
    0.37 (-0.12 to 0.87)
    -0.26 (-0.94 to 0.42)
    Notes
    [34] - Subjects with missing MFM32 D1 score at Baseline were not included in the analysis.
    Statistical analysis title
    Risdiplam vs Placebo
    Statistical analysis description
    The variables included in the MMRM model are: baseline total score, treatment, age group, visit, treatment-by-visit and baseline score-by-visit interaction.
    Comparison groups
    Part 2: Risdiplam v Part 2: Placebo
    Number of subjects included in analysis
    178
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1328
    Method
    Mixed Model Repeated Measure Analysis
    Parameter type
    Least Square Mean Difference
    Point estimate
    0.64
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.2
         upper limit
    1.47

    Secondary: Part 2: Change from Baseline in the MFM Domain 2 (D2) Score at Month 12

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    End point title
    Part 2: Change from Baseline in the MFM Domain 2 (D2) Score at Month 12 [35]
    End point description
    The MFM32 comprises 32 items that evaluate physical function in three dimensions: D1 function related to standing and transfer; D2 axial and proximal function; D3 distal motor function. Tasks are scored with a 4-point Likert scale: 0 - cannot initiate the task or maintain the starting position; 1 - performs the task partially; 2 - performs the task incompletely or imperfectly; 3 - performs the task fully and “normally”. The D2 items score are summed and expressed on 0-100 scale for the MFM D2 total score. Higher scores indicate increased motor function. A positive change from Baseline indicates improvement. MMRM analysis was performed based on efficacy hypothetical estimand, which included subjects data assuming no prohibited medication intended for treatment of SMA was received and subjects continued on their randomized treatment until the analysis time point at Month 12.
    End point type
    Secondary
    End point timeframe
    Baseline (Day-1) and Month 12
    Notes
    [35] - 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: Data for this endpoint was provided only for those arms which were planned to be reported.
    End point values
    Part 2: Risdiplam Part 2: Placebo
    Number of subjects analysed
    118 [36]
    60
    Units: Scores on a Scale
        least squares mean (confidence interval 95%)
    1.04 (-0.38 to 2.46)
    -0.93 (-2.87 to 1.02)
    Notes
    [36] - Subjects with missing MFM32 D2 total score at Baseline were not included in the analysis.
    Statistical analysis title
    Risdiplam vs Placebo
    Statistical analysis description
    The variables included in the MMRM model are: baseline total score, treatment, age group, visit, treatment-by-visit and baseline score-by-visit interaction.
    Comparison groups
    Part 2: Risdiplam v Part 2: Placebo
    Number of subjects included in analysis
    178
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.103
    Method
    Mixed Model Repeated Measure Analysis
    Parameter type
    Least Square Mean Difference
    Point estimate
    1.97
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.4
         upper limit
    4.34

    Secondary: Part 2: Change from Baseline in the MFM Domain 3 (D3) Score at Month 12

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    End point title
    Part 2: Change from Baseline in the MFM Domain 3 (D3) Score at Month 12 [37]
    End point description
    The MFM32 comprises 32 items that evaluate physical function in three dimensions: D1 function related to standing and transfer; D2 axial and proximal function; D3 distal motor function. Tasks are scored with a 4-point Likert scale: 0 - cannot initiate the task or maintain the starting position; 1 - performs the task partially; 2 - performs the task incompletely or imperfectly; 3 - performs the task fully and “normally”. The D3 items score are summed and expressed on 0-100 scale for the MFM D3 total score. Higher scores indicate increased motor function. A positive change from Baseline indicates improvement. MMRM analysis was performed based on efficacy hypothetical estimand, which included subjects data assuming no prohibited medication intended for treatment of SMA was received and subjects continued on their randomized treatment until the analysis time point at Month 12.
    End point type
    Secondary
    End point timeframe
    Baseline (Day-1) and Month 12
    Notes
    [37] - 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: Data for this endpoint was provided only for those arms which were planned to be reported.
    End point values
    Part 2: Risdiplam Part 2: Placebo
    Number of subjects analysed
    115 [38]
    59 [39]
    Units: Scores on a Scale
        least squares mean (confidence interval 95%)
    3.68 (2.31 to 5.04)
    1.34 (-0.54 to 3.22)
    Notes
    [38] - Subjects with missing MFM32 D3 total score at Baseline were not included in the analysis.
    [39] - Subjects with missing MFM32 D3 total score at Baseline were not included in the analysis.
    Statistical analysis title
    Risdiplam vs Placebo
    Statistical analysis description
    The variables included in the MMRM model are: baseline total score, treatment, age group, visit, treatment-by-visit and baseline score-by-visit interaction.
    Comparison groups
    Part 2: Risdiplam v Part 2: Placebo
    Number of subjects included in analysis
    174
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0451
    Method
    Mixed Model Repeated Measure Analysis
    Parameter type
    Least Square Mean Difference
    Point estimate
    2.34
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.05
         upper limit
    4.62

    Secondary: Part 2: Change from Baseline in the Total Combined Scores of MFM Domains 1 and 2 at Month 12

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    End point title
    Part 2: Change from Baseline in the Total Combined Scores of MFM Domains 1 and 2 at Month 12 [40]
    End point description
    The MFM32 comprises 32 items that evaluate physical function in three dimensions: D1 function related to standing and transfer; D2 axial and proximal function; D3 distal motor function. Tasks are scored with a 4-point Likert scale: 0 - cannot initiate the task or maintain the starting position; 1 - performs the task partially; 2 - performs the task incompletely or imperfectly; 3 - performs the task fully and “normally”. The D1+D2 items score are summed and expressed on 0-100 scale for the MFM D1+D2 total score. Higher scores indicate increased motor function. A positive change from Baseline indicates improvement. MMRM analysis was performed based on efficacy hypothetical estimand, which included subjects data assuming no prohibited medication intended for treatment of SMA was received and subjects continued on their randomized treatment until the analysis time point at Month 12.
    End point type
    Secondary
    End point timeframe
    Baseline (Day-1) and Month 12
    Notes
    [40] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Data for this endpoint was provided only for those arms which were planned to be reported.
    End point values
    Part 2: Risdiplam Part 2: Placebo
    Number of subjects analysed
    118 [41]
    60
    Units: Scores on a Scale
        least squares mean (confidence interval 95%)
    0.69 (-0.07 to 1.45)
    -0.59 (-1.64 to 0.45)
    Notes
    [41] - Subjects with missing MFM32 D1+D2 total score at Baseline were not included in the analysis.
    Statistical analysis title
    Risdiplam vs Placebo
    Statistical analysis description
    The variables included in the MMRM model are: baseline total score, treatment, age group, visit, treatment-by-visit and baseline score-by-visit interaction.
    Comparison groups
    Part 2: Risdiplam v Part 2: Placebo
    Number of subjects included in analysis
    178
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0489
    Method
    Mixed Model Repeated Measure Analysis
    Parameter type
    Least Square Mean Difference
    Point estimate
    1.28
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.01
         upper limit
    2.56

    Secondary: Part 2: Change from Baseline in Forced Expiratory Volume in 1 Second (FEV1) at Month 12 in Subjects Aged 6-25 Years

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    End point title
    Part 2: Change from Baseline in Forced Expiratory Volume in 1 Second (FEV1) at Month 12 in Subjects Aged 6-25 Years [42]
    End point description
    Spirometry is a pulmonary function test that assesses how the lungs work by measuring how much air moves through the airways. Spirometry was performed by all subjects aged 6 or older. Forced expiratory volume (FEV1) is the volume forcefully exhaled in the first second of the forced vital capacity test. The best % predicted value out of all attempts were used for the analysis. MMRM analysis was performed based on efficacy hypothetical estimand, which included subjects data assuming no prohibited medication intended for treatment of SMA was received and subjects continued on their randomized treatment until the analysis time point at Month 12.
    End point type
    Secondary
    End point timeframe
    Baseline (Day-1) and Month 12
    Notes
    [42] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Data for this endpoint was provided only for those arms which were planned to be reported.
    End point values
    Part 2: Risdiplam Part 2: Placebo
    Number of subjects analysed
    83 [43]
    40 [44]
    Units: Percentage Predicted
        least squares mean (confidence interval 95%)
    -4.22 (-7.49 to -0.96)
    -1.35 (-5.91 to 3.20)
    Notes
    [43] - Subjects with missing FEV1 data at Baseline were not included in the analysis.
    [44] - Subjects with missing FEV1 data at Baseline were not included in the analysis.
    Statistical analysis title
    Risdiplam vs Placebo
    Statistical analysis description
    The variables included in the MMRM model are: baseline total score, treatment, age group, visit, treatment-by-visit and baseline score-by-visit interaction.
    Comparison groups
    Part 2: Risdiplam v Part 2: Placebo
    Number of subjects included in analysis
    123
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.3029
    Method
    Mixed Model Repeated Measure Analysis
    Parameter type
    Least Square Mean Difference
    Point estimate
    -2.87
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -8.36
         upper limit
    2.62

    Secondary: Part 2: Change from Baseline in the Peak Cough Flow (PCF) at Month 12 in Subjects Aged 6-25 Years

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    End point title
    Part 2: Change from Baseline in the Peak Cough Flow (PCF) at Month 12 in Subjects Aged 6-25 Years [45]
    End point description
    Spirometry is a pulmonary function test that assesses how the lungs work by measuring how much air moves through the airways. Spirometry was performed by all subjects aged 6 or older. Peak cough flow (PCF) is an assessment of cough strength. The best % predicted value out of all attempts were used for the analysis MMRM analysis was performed based on efficacy hypothetical estimand, which included subjects data assuming no prohibited medication intended for treatment of SMA was received and subjects continued on their randomized treatment until the analysis time point at Month 12.
    End point type
    Secondary
    End point timeframe
    Baseline (Day-1) and Month 12
    Notes
    [45] - 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: Data for this endpoint was provided only for those arms which were planned to be reported.
    End point values
    Part 2: Risdiplam Part 2: Placebo
    Number of subjects analysed
    83 [46]
    42 [47]
    Units: Percent Predicted
        least squares mean (confidence interval 95%)
    1.06 (-1.18 to 3.31)
    -0.22 (-3.27 to 2.83)
    Notes
    [46] - Subjects with missing PCF data at Baseline were not included in the analysis.
    [47] - Subjects with missing PCF data at Baseline were not included in the analysis.
    Statistical analysis title
    Risdiplam vs Placebo
    Statistical analysis description
    The variables included in the MMRM model are: baseline total score, treatment, age group, visit, treatment-by-visit and baseline score-by-visit interaction.
    Comparison groups
    Part 2: Risdiplam v Part 2: Placebo
    Number of subjects included in analysis
    125
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.4937
    Method
    Mixed Model Repeated Measure Analysis
    Parameter type
    Least Square Mean Difference
    Point estimate
    1.28
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.42
         upper limit
    4.99

    Secondary: Part 2: Change from Baseline in the Best Sniff Nasal Inspiratory Pressure (SNIP) at Month 12

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    End point title
    Part 2: Change from Baseline in the Best Sniff Nasal Inspiratory Pressure (SNIP) at Month 12 [48]
    End point description
    The Sniff Nasal Inspiratory Pressure (SNIP) is a volitional, non-invasive test of inspiratory muscle strength that has been successfully applied to children > 2 years of age. Advantages include the simplicity of the maneuver and the absence of a mouthpiece, which is particularly helpful for subjects with SMA, who may have bulbar weakness. SNIP also has the advantage of measuring inspiratory pressure during a natural maneuver that is easily performed even by young children with neuromuscular disorders. The best % predicted value out of all attempts were used for the analysis. MMRM analysis was performed based on efficacy hypothetical estimand, which included subjects data assuming no prohibited medication intended for treatment of SMA was received and subjects continued on their randomized treatment until the analysis time point at Month 12.
    End point type
    Secondary
    End point timeframe
    Baseline (Day-1) and Month 12
    Notes
    [48] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Data for this endpoint was provided only for those arms which were planned to be reported.
    End point values
    Part 2: Risdiplam Part 2: Placebo
    Number of subjects analysed
    118 [49]
    59 [50]
    Units: Percentage Predicted
        least squares mean (confidence interval 95%)
    3.42 (0.22 to 6.62)
    1.07 (-3.42 to 5.57)
    Notes
    [49] - Subjects with missing SNIP data at Baseline were not included in the analysis.
    [50] - Subjects with missing SNIP data at Baseline were not included in the analysis.
    Statistical analysis title
    Risdiplam vs Placebo
    Statistical analysis description
    The variables included in the MMRM model are: baseline total score, treatment, age group, visit, treatment-by-visit and baseline score-by-visit interaction.
    Comparison groups
    Part 2: Risdiplam v Part 2: Placebo
    Number of subjects included in analysis
    177
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.3967
    Method
    Mixed Model Repeated Measure Analysis
    Parameter type
    Least Square Mean Difference
    Point estimate
    2.35
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.11
         upper limit
    7.8

    Secondary: Part 2: Change from Baseline in Maximal Inspiratory Pressure (MIP) at Month 12 in Subjects Aged 6-25 Years

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    End point title
    Part 2: Change from Baseline in Maximal Inspiratory Pressure (MIP) at Month 12 in Subjects Aged 6-25 Years [51]
    End point description
    The maximal inspiratory pressure (MIP) is a non-invasive test of muscle strength, which measures the maximum strength of the diaphragm and other inspiratory muscles. MIP was measured in subjects aged 6 or older. Subjects were asked to perform a forceful inspiration against an occluded mouth piece. The best % predicted value out of all attempts were used for the analysis. MMRM analysis was performed based on efficacy hypothetical estimand, which included subjects data assuming no prohibited medication intended for treatment of SMA was received and subjects continued on their randomized treatment until the analysis time point at Month 12.
    End point type
    Secondary
    End point timeframe
    Baseline (Day-1) and Month 12
    Notes
    [51] - 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: Data for this endpoint was provided only for those arms which were planned to be reported.
    End point values
    Part 2: Risdiplam Part 2: Placebo
    Number of subjects analysed
    81 [52]
    40 [53]
    Units: Percentage Predicted
        least squares mean (confidence interval 95%)
    1.99 (-6.13 to 10.11)
    -0.97 (-12.33 to 10.38)
    Notes
    [52] - Subjects with missing MIP data at Baseline were not included in the analysis.
    [53] - Subjects with missing MIP data at Baseline were not included in the analysis.
    Statistical analysis title
    Risdiplam vs Placebo
    Statistical analysis description
    The variables included in the MMRM model are: baseline total score, treatment, age group, visit, treatment-by-visit and baseline score-by-visit interaction.
    Comparison groups
    Part 2: Risdiplam v Part 2: Placebo
    Number of subjects included in analysis
    121
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.6704
    Method
    Mixed Model Repeated Measure Analysis
    Parameter type
    Least Square Mean Difference
    Point estimate
    2.96
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -10.78
         upper limit
    16.7

    Secondary: Part 2: Change from Baseline in Maximal Expiratory Pressure (MEP) at Month 12 in Subjects Aged 6-25 Years

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    End point title
    Part 2: Change from Baseline in Maximal Expiratory Pressure (MEP) at Month 12 in Subjects Aged 6-25 Years [54]
    End point description
    The maximal expiratory pressure (MEP) is a non-invasive test of muscle strength, which measures the maximum strength of the abdominal muscles and other expiratory muscles. MEP was measured in subjects aged 6 or older. Subjects were asked to perform a forceful inspiration against an occluded mouth piece. The best % predicted value out of all attempts were used for the analysis. MMRM analysis was performed based on efficacy hypothetical estimand, which included subjects data assuming no prohibited medication intended for treatment of SMA was received and subjects continued on their randomized treatment until the analysis time point at Month 12.
    End point type
    Secondary
    End point timeframe
    Baseline (Day-1) and Month 12
    Notes
    [54] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Data for this endpoint was provided only for those arms which were planned to be reported.
    End point values
    Part 2: Risdiplam Part 2: Placebo
    Number of subjects analysed
    83 [55]
    41 [56]
    Units: Percentage Predicted
        least squares mean (confidence interval 95%)
    -2.75 (-6.22 to 0.72)
    -2.33 (-7.21 to 2.56)
    Notes
    [55] - Subjects with missing MEP data at Baseline were not included in the analysis.
    [56] - Subjects with missing MEP data at Baseline were not included in the analysis.
    Statistical analysis title
    Risdiplam vs Placebo
    Statistical analysis description
    The variables included in the MMRM model are: baseline total score, treatment, age group, visit, treatment-by-visit and baseline score-by-visit interaction.
    Comparison groups
    Part 2: Risdiplam v Part 2: Placebo
    Number of subjects included in analysis
    124
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.8856
    Method
    Mixed Model Repeated Measure Analysis
    Parameter type
    Least Square Mean Difference
    Point estimate
    -0.43
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -6.3
         upper limit
    5.45

    Secondary: Part 2: Change from Baseline in the Subject-Reported SMA Independence Scale (SMAIS) Total Score at Month 12

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    End point title
    Part 2: Change from Baseline in the Subject-Reported SMA Independence Scale (SMAIS) Total Score at Month 12 [57]
    End point description
    The SMAIS was developed specifically for SMA subjects in order to assess function-related independence. It contains 29 items, assessing the amount of assistance required from another individual to perform daily activities such as eating, or bathing. Each item is scored on a 0-4 scale (with an additional option to indicate that an item is non-applicable). The SMAIS total score ranging from 0-44 is obtained based on 22 items with each item on the 0-2 scale. Lower scores indicate greater dependence on another individual. The SMAIS was completed by subjects aged 12 years or older and caregivers of subjects aged 2-25 years. MMRM analysis was performed based on efficacy hypothetical estimand, which included subjects data assuming no prohibited medication intended for treatment of SMA was received and subjects continued on their randomized treatment until the analysis time point at Month 12.
    End point type
    Secondary
    End point timeframe
    Baseline (Day-1) and Month 12
    Notes
    [57] - 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: Data for this endpoint was provided only for those arms which were planned to be reported.
    End point values
    Part 2: Risdiplam Part 2: Placebo
    Number of subjects analysed
    43 [58]
    23 [59]
    Units: Scores on a Scale
        least squares mean (confidence interval 95%)
    1.04 (-0.26 to 2.35)
    -0.40 (-2.13 to 1.32)
    Notes
    [58] - Subjects with missing SMAIS total score at Baseline were not included in the analysis.
    [59] - Subjects with missing SMAIS total score at Baseline were not included in the analysis.
    Statistical analysis title
    Risdiplam vs Placebo
    Statistical analysis description
    The variables included in the MMRM model are: baseline total score, treatment, age group, visit, treatment-by-visit and baseline score-by-visit interaction.
    Comparison groups
    Part 2: Risdiplam v Part 2: Placebo
    Number of subjects included in analysis
    66
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1778
    Method
    Mixed Model Repeated Measure Analysis
    Parameter type
    Least Square Mean Difference
    Point estimate
    1.45
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.68
         upper limit
    3.57

    Secondary: Part 2: Percentage of Subjects Rated by Clinicians as No Change or Improved in the Clinical Global Impression of Change (CGI-C) Scale Ratings at Month 12

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    End point title
    Part 2: Percentage of Subjects Rated by Clinicians as No Change or Improved in the Clinical Global Impression of Change (CGI-C) Scale Ratings at Month 12 [60]
    End point description
    The CGI-C is used to score a clinician’s impression of a participant’s change in global health. It is a single item measure of change in global health, using seven response options: “very much improved”, “much improved”, “minimally improved”, “no change”, “minimally worse”, “much worse”, and “very much worse”. Participants considered as "no change or improved" included responses of "no change", "very much improved", "much improved" and "minimally improved". Logistic regression analysis was performed based on efficacy hypothetical estimand, which included participants data assuming no prohibited medication intended for treatment of SMA was received and participants continued on their randomized treatment until the analysis time point at Month 12.
    End point type
    Secondary
    End point timeframe
    At Month 12
    Notes
    [60] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Data for this endpoint was provided only for those arms which were planned to be reported.
    End point values
    Part 2: Risdiplam Part 2: Placebo
    Number of subjects analysed
    120 [61]
    60 [62]
    Units: Percentage of Subjects
        number (confidence interval 95%)
    85.8 (79.18 to 92.49)
    83.3 (73.07 to 93.60)
    Notes
    [61] - Missing results at Month 12 are considered as non-responders.
    [62] - Missing results at Month 12 are considered as non-responders.
    Statistical analysis title
    CGI No Change or Improved
    Statistical analysis description
    Logistic Regression Model. The variables included in the logistic regression are: baseline total score, treatment and age group.
    Comparison groups
    Part 2: Risdiplam v Part 2: Placebo
    Number of subjects included in analysis
    180
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.6636
    Method
    Wald-test
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.21
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.52
         upper limit
    2.83

    Secondary: Part 2: Percentage of Subjects who Experience at Least One Disease-Related Adverse Event at Month 12

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    End point title
    Part 2: Percentage of Subjects who Experience at Least One Disease-Related Adverse Event at Month 12 [63]
    End point description
    Disease-related adverse events (AEs) were identified by applying two different types of baskets to the AE dataset: Narrow prospectively defined baskets of MedDRA lowest level terms. This basket was defined based on a group of CDC terms selected from an age and gender matched case control study comparing CDC code rates observed in subjects with and without SMA using commercially available insurance claim data (CLAIMS and Market scan data). The lowest level terms included in each basket, coded using the latest version of MedDRA; Broad prospectively defined basket with events selected at preferred term level from all AEs reported in ongoing clinical trials up to January 2019, i.e., prior to unblinding of Part 2 of Study BP39055.
    End point type
    Secondary
    End point timeframe
    Baseline up to Month 12 (Week 52; up to CCOD of 06 September 2019)
    Notes
    [63] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Data for this endpoint was provided only for those arms which were planned to be reported.
    End point values
    Part 2: Risdiplam Part 2: Placebo
    Number of subjects analysed
    120
    60
    Units: Percentage of Subjects
    number (confidence interval 95%)
        Narrow Basket AEs
    46.7 (37.51 to 55.99)
    53.3 (40.00 to 66.33)
        Broad Basket AEs
    65.0 (55.76 to 73.48)
    60.0 (46.54 to 72.44)
    No statistical analyses for this end point

    Secondary: Part 2: Number of Disease-Related Adverse Events Per Patient-Years at Month 12

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    End point title
    Part 2: Number of Disease-Related Adverse Events Per Patient-Years at Month 12 [64]
    End point description
    Disease-related AEs were collected through the AE reporting of the study, and the disease-related AE rate was adjusted for patient years (AE rate per 100 patient-years). They were identified by applying two different types of baskets to the AE dataset: Narrow prospectively defined baskets of MedDRA lowest level terms and Broad prospectively defined basket with events selected at preferred term level from all AEs reported in ongoing clinical trials up to January 2019, i.e., prior to unblinding of Part 2 of Study BP39055.
    End point type
    Secondary
    End point timeframe
    Baseline up to Month 12 (Week 52; up to CCOD of 06 September 2019)
    Notes
    [64] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Data for this endpoint was provided only for those arms which were planned to be reported.
    End point values
    Part 2: Risdiplam Part 2: Placebo
    Number of subjects analysed
    120
    60
    Units: Number of Events per 100 Patient-Years
    number (confidence interval 95%)
        Narrow Basket AEs
    101.51 (84.23 to 121.29)
    119.77 (93.71 to 150.82)
        Broad Basket AEs
    217.29 (191.63 to 245.42)
    199.61 (165.50 to 238.68)
    No statistical analyses for this end point

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

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    End point title
    Part 1: 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. All subjects in Part 1 who received at least one dose of study medication (risdiplam or placebo) whether prematurely withdrawn or not were included in the safety population.
    End point type
    Secondary
    End point timeframe
    Day 1 on risdiplam up to at least 12 months (up to CCOD of 09 January 2019)
    End point values
    Part 1: All Risdiplam
    Number of subjects analysed
    51
    Units: Percentage of Subjects
    number (not applicable)
        With at Least One AE
    94.1
        With at Least One SAE
    17.6
    No statistical analyses for this end point

    Secondary: Part 2: Percentage of Subjects with Adverse Events (AEs) and Serious Adverse Events (SAEs) in the Placebo-Controlled Period

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    End point title
    Part 2: Percentage of Subjects with Adverse Events (AEs) and Serious Adverse Events (SAEs) in the Placebo-Controlled Period [65]
    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 subjects in Part 2 who receive at least one dose of study medication (risdiplam or placebo) were included in the safety population.
    End point type
    Secondary
    End point timeframe
    Day 1 up to 12 months of the placebo-controlled period
    Notes
    [65] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Data for this endpoint was provided only for those arms which were planned to be reported.
    End point values
    Part 2: Risdiplam Part 2: Placebo
    Number of subjects analysed
    120
    60
    Units: Percentage of Subjects
    number (not applicable)
        With at Least One AE
    92.5
    91.7
        With at Least One SAE
    20.0
    18.3
    No statistical analyses for this end point

    Secondary: Part 2: Percentage of Subjects with Treatment Discontinuation due to Adverse Events (AEs) and Serious Adverse Events (SAEs) in the Placebo-Controlled Period

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    End point title
    Part 2: Percentage of Subjects with Treatment Discontinuation due to Adverse Events (AEs) and Serious Adverse Events (SAEs) in the Placebo-Controlled Period [66]
    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 subjects in Part 2 who receive at least one dose of study medication (risdiplam or placebo) were included in the safety population.
    End point type
    Secondary
    End point timeframe
    Day 1 up to 12 months of the placebo-controlled period
    Notes
    [66] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Data for this endpoint was provided only for those arms which were planned to be reported.
    End point values
    Part 2: Risdiplam Part 2: Placebo
    Number of subjects analysed
    120
    60
    Units: Percentage of Subjects
    number (not applicable)
        Due to AE
    0.0
    0.0
        Due to SAE
    0.0
    0.0
    No statistical analyses for this end point

    Secondary: Part 2: Number of Subjects Aged 6-25 Years with Suicidal Ideation Based on Columbia-Suicide Severity Rating Scale (C-SSRS) in the Placebo-Controlled Period

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    End point title
    Part 2: Number of Subjects Aged 6-25 Years with Suicidal Ideation Based on Columbia-Suicide Severity Rating Scale (C-SSRS) in the Placebo-Controlled Period [67]
    End point description
    The Columbia Suicide Severity Rating Scale (C-SSRS) is used to assess the lifetime suicidality of a subject (C-SSRS baseline) as well as any new instances of suicidality (C-SSRS since last visit). The structured interview prompts recollection of suicidal ideation, including the intensity of the ideation, behavior, and attempts with actual/potential lethality. The C-SSRS assessments results were collected for subjects aged 6 years and older.
    End point type
    Secondary
    End point timeframe
    Day 1 up to 12 months of the placebo-controlled period
    Notes
    [67] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Data for this endpoint was provided only for those arms which were planned to be reported.
    End point values
    Part 2: Risdiplam Part 2: Placebo
    Number of subjects analysed
    83 [68]
    42 [69]
    Units: Number of Subjects
    number (not applicable)
        Wish to be Dead
    1
    1
        Non-specific Active Suicidal Thoughts
    1
    1
        Ideation with Any Methods, No Intent to Act
    1
    1
        Ideation with Some Intent to Act, No Plan
    0
    1
        Ideation with Specific Plan and Intent
    0
    1
    Notes
    [68] - Data were collected for subjects aged 6-25 years.
    [69] - Data were collected for subjects aged 6-25 years.
    No statistical analyses for this end point

    Secondary: Part 2: Number of Subjects Aged 6-25 Years with Suicidal Behavior Based on Columbia-Suicide Severity Rating Scale (C-SSRS) in the Placebo-Controlled Period

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    End point title
    Part 2: Number of Subjects Aged 6-25 Years with Suicidal Behavior Based on Columbia-Suicide Severity Rating Scale (C-SSRS) in the Placebo-Controlled Period [70]
    End point description
    The Columbia Suicide Severity Rating Scale (C-SSRS) is used to assess the lifetime suicidality of a subject (C-SSRS baseline) as well as any new instances of suicidality (C-SSRS since last visit). The structured interview prompts recollection of suicidal ideation, including the intensity of the ideation, behavior, and attempts with actual/potential lethality. The C-SSRS assessments results were collected for subjects aged 6 years and older.
    End point type
    Secondary
    End point timeframe
    Day 1 up to 12 months of the placebo-controlled period
    Notes
    [70] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Data for this endpoint was provided only for those arms which were planned to be reported.
    End point values
    Part 2: Risdiplam Part 2: Placebo
    Number of subjects analysed
    83 [71]
    42 [72]
    Units: Number of Subjects
    number (not applicable)
        Preparatory Acts or Behavior
    0
    0
        Aborted Attempt
    0
    0
        Interrupted Attempt
    0
    0
        Actual Attempt (non-fatal)
    0
    0
        Completed Suicide
    0
    0
    Notes
    [71] - Data were collected for subjects aged 6-25 years.
    [72] - Data were collected for subjects aged 6-25 years.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Part 1: Day 1 up to at least 12 months (up to CCOD of 09 January 2019); Part 2: At least 12 months (up to CCOD of 06 September 2019)
    Adverse event reporting additional description
    All subjects in Part 1 who received at least one dose of study medication (risdiplam or placebo) whether prematurely withdrawn or not were included in the safety population. All subjects in Part 2 who receive at least one dose of study medication (risdiplam or placebo) were included in the safety population.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    22.0
    Reporting groups
    Reporting group title
    Part 1 Group A: Adolescents and Adults (Risdiplam)
    Reporting group description
    Adolescent and adult participants aged 12-25 years received Risdiplam for 12 weeks. Once 12-week treatment was completed and Part 2 dose was selected, participants switched to Part 2 dose and were followed up in open-label extension (OLE) phase.

    Reporting group title
    Part 1 Group A: Adolescents and Adults (Placebo)
    Reporting group description
    Adolescent and adult participants aged 12-25 years received placebo matching to Risdiplam for 12 weeks. Once 12-week treatment was completed and Part 2 dose was selected, participants switched to Part 2 dose and were followed up in OLE phase.

    Reporting group title
    Part 1 Group B: Children (Risdiplam)
    Reporting group description
    Children aged 2-11 years received Risdiplam for 12 weeks. Once 12-week treatment was completed and Part 2 dose was selected, participants switched to Part 2 dose and were followed up in OLE phase.

    Reporting group title
    Part 2: Risdiplam
    Reporting group description
    Participants aged 2-25 years received Risdiplam at the dose of 5 mg once daily for participants with a body weight (BW) >/=20kg or 0.25 mg/kg for participants with a BW <20 kg, for 24 months. After 24-month treatment, participants were offered the opportunity to enter the OLE phase.

    Reporting group title
    Part 1 Group B: Children (Placebo)
    Reporting group description
    Children aged 2-11 years received placebo matching to Risdiplam for 12 weeks. Once 12-week treatment was completed and Part 2 dose was selected, participants switched to Part 2 dose and were followed up in OLE phase.

    Reporting group title
    Part 2: Placebo
    Reporting group description
    Participants aged 2-25 years received placebo matching to Risdiplam. After 12 months of treatment with placebo, participants switched to Risdiplam in a blinded manner and treatment then continued until Month 24. After 24-month treatment, participants were offered the opportunity to enter the OLE phase.

    Serious adverse events
    Part 1 Group A: Adolescents and Adults (Risdiplam) Part 1 Group A: Adolescents and Adults (Placebo) Part 1 Group B: Children (Risdiplam) Part 2: Risdiplam Part 1 Group B: Children (Placebo) Part 2: Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 14 (14.29%)
    2 / 6 (33.33%)
    3 / 21 (14.29%)
    26 / 120 (21.67%)
    2 / 10 (20.00%)
    11 / 60 (18.33%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 21 (0.00%)
    1 / 120 (0.83%)
    0 / 10 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 21 (0.00%)
    1 / 120 (0.83%)
    1 / 10 (10.00%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Surgical and medical procedures
    Lung operation
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 21 (0.00%)
    1 / 120 (0.83%)
    0 / 10 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal stone removal
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 21 (0.00%)
    0 / 120 (0.00%)
    0 / 10 (0.00%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Oxygen saturation decreased
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 21 (0.00%)
    0 / 120 (0.00%)
    0 / 10 (0.00%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 6 (16.67%)
    0 / 21 (0.00%)
    0 / 120 (0.00%)
    0 / 10 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Aspiration
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 21 (0.00%)
    1 / 120 (0.83%)
    0 / 10 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Asthma
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 21 (0.00%)
    1 / 120 (0.83%)
    0 / 10 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atelectasis
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 21 (0.00%)
    1 / 120 (0.83%)
    0 / 10 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 21 (0.00%)
    1 / 120 (0.83%)
    0 / 10 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 21 (0.00%)
    0 / 120 (0.00%)
    0 / 10 (0.00%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sleep apnoea syndrome
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 21 (0.00%)
    0 / 120 (0.00%)
    0 / 10 (0.00%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chronic respiratory failure
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    1 / 21 (4.76%)
    0 / 120 (0.00%)
    0 / 10 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Febrile convulsion
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 21 (0.00%)
    1 / 120 (0.83%)
    0 / 10 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Partial seizures
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 21 (0.00%)
    1 / 120 (0.83%)
    0 / 10 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Medical device pain
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 21 (0.00%)
    1 / 120 (0.83%)
    0 / 10 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 21 (0.00%)
    2 / 120 (1.67%)
    0 / 10 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 21 (0.00%)
    1 / 120 (0.83%)
    0 / 10 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 6 (0.00%)
    0 / 21 (0.00%)
    0 / 120 (0.00%)
    0 / 10 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 6 (0.00%)
    0 / 21 (0.00%)
    0 / 120 (0.00%)
    1 / 10 (10.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Hydronephrosis
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 21 (0.00%)
    1 / 120 (0.83%)
    0 / 10 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 21 (0.00%)
    1 / 120 (0.83%)
    0 / 10 (0.00%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 21 (0.00%)
    1 / 120 (0.83%)
    0 / 10 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    1 / 21 (4.76%)
    0 / 120 (0.00%)
    0 / 10 (0.00%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Decreased appetite
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 21 (0.00%)
    0 / 120 (0.00%)
    1 / 10 (10.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 21 (0.00%)
    0 / 120 (0.00%)
    0 / 10 (0.00%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 21 (0.00%)
    2 / 120 (1.67%)
    0 / 10 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 21 (0.00%)
    1 / 120 (0.83%)
    0 / 10 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    1 / 21 (4.76%)
    2 / 120 (1.67%)
    0 / 10 (0.00%)
    2 / 60 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 3
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal infection
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 21 (0.00%)
    0 / 120 (0.00%)
    0 / 10 (0.00%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 21 (0.00%)
    2 / 120 (1.67%)
    0 / 10 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Laryngitis
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 21 (0.00%)
    1 / 120 (0.83%)
    0 / 10 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lower respiratory tract infection viral
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 21 (0.00%)
    1 / 120 (0.83%)
    0 / 10 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 21 (0.00%)
    1 / 120 (0.83%)
    0 / 10 (0.00%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lymph gland infection
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 21 (0.00%)
    0 / 120 (0.00%)
    0 / 10 (0.00%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 14 (7.14%)
    1 / 6 (16.67%)
    0 / 21 (0.00%)
    9 / 120 (7.50%)
    0 / 10 (0.00%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 12
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia bacterial
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 21 (0.00%)
    1 / 120 (0.83%)
    0 / 10 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia mycoplasmal
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 21 (0.00%)
    1 / 120 (0.83%)
    0 / 10 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 6 (16.67%)
    0 / 21 (0.00%)
    1 / 120 (0.83%)
    0 / 10 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory tract infection viral
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 21 (0.00%)
    0 / 120 (0.00%)
    0 / 10 (0.00%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    1 / 21 (4.76%)
    1 / 120 (0.83%)
    0 / 10 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Viral upper respiratory tract infection
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 21 (0.00%)
    1 / 120 (0.83%)
    0 / 10 (0.00%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Part 1 Group A: Adolescents and Adults (Risdiplam) Part 1 Group A: Adolescents and Adults (Placebo) Part 1 Group B: Children (Risdiplam) Part 2: Risdiplam Part 1 Group B: Children (Placebo) Part 2: Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    13 / 14 (92.86%)
    5 / 6 (83.33%)
    20 / 21 (95.24%)
    102 / 120 (85.00%)
    9 / 10 (90.00%)
    50 / 60 (83.33%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 6 (0.00%)
    0 / 21 (0.00%)
    0 / 120 (0.00%)
    0 / 10 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    General disorders and administration site conditions
    Malaise
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 6 (16.67%)
    1 / 21 (4.76%)
    1 / 120 (0.83%)
    0 / 10 (0.00%)
    3 / 60 (5.00%)
         occurrences all number
    0
    1
    1
    1
    0
    3
    Pyrexia
         subjects affected / exposed
    3 / 14 (21.43%)
    2 / 6 (33.33%)
    13 / 21 (61.90%)
    27 / 120 (22.50%)
    6 / 10 (60.00%)
    11 / 60 (18.33%)
         occurrences all number
    13
    2
    16
    45
    16
    21
    Asthenia
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 6 (0.00%)
    0 / 21 (0.00%)
    0 / 120 (0.00%)
    0 / 10 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    0
    Fatigue
         subjects affected / exposed
    2 / 14 (14.29%)
    0 / 6 (0.00%)
    1 / 21 (4.76%)
    0 / 120 (0.00%)
    1 / 10 (10.00%)
    0 / 60 (0.00%)
         occurrences all number
    2
    0
    3
    0
    2
    0
    Hyperpyrexia
         subjects affected / exposed
    2 / 14 (14.29%)
    0 / 6 (0.00%)
    0 / 21 (0.00%)
    0 / 120 (0.00%)
    1 / 10 (10.00%)
    0 / 60 (0.00%)
         occurrences all number
    2
    0
    0
    0
    2
    0
    Hyperthermia
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 21 (0.00%)
    0 / 120 (0.00%)
    1 / 10 (10.00%)
    0 / 60 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Pain
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 6 (0.00%)
    0 / 21 (0.00%)
    0 / 120 (0.00%)
    0 / 10 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Psychiatric disorders
    Initial insomnia
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 6 (0.00%)
    0 / 21 (0.00%)
    0 / 120 (0.00%)
    0 / 10 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Reproductive system and breast disorders
    Amenorrhoea
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 6 (0.00%)
    0 / 21 (0.00%)
    0 / 120 (0.00%)
    0 / 10 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Dysmenorrhoea
         subjects affected / exposed
    2 / 14 (14.29%)
    1 / 6 (16.67%)
    0 / 21 (0.00%)
    0 / 120 (0.00%)
    0 / 10 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    12
    9
    0
    0
    0
    0
    Injury, poisoning and procedural complications
    Arthropod bite
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    2 / 21 (9.52%)
    0 / 120 (0.00%)
    0 / 10 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    0
    0
    4
    0
    0
    0
    Contusion
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    2 / 21 (9.52%)
    0 / 120 (0.00%)
    1 / 10 (10.00%)
    0 / 60 (0.00%)
         occurrences all number
    0
    0
    2
    0
    1
    0
    Fall
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    1 / 21 (4.76%)
    0 / 120 (0.00%)
    1 / 10 (10.00%)
    0 / 60 (0.00%)
         occurrences all number
    0
    0
    1
    0
    1
    0
    Foot fracture
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 6 (0.00%)
    0 / 21 (0.00%)
    0 / 120 (0.00%)
    0 / 10 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Ligament sprain
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    2 / 21 (9.52%)
    0 / 120 (0.00%)
    0 / 10 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    0
    Muscle rupture
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 21 (0.00%)
    0 / 120 (0.00%)
    1 / 10 (10.00%)
    0 / 60 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Investigations
    Hepatic enzyme increased
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 6 (0.00%)
    0 / 21 (0.00%)
    0 / 120 (0.00%)
    0 / 10 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Cardiac disorders
    Tachycardia
         subjects affected / exposed
    2 / 14 (14.29%)
    1 / 6 (16.67%)
    0 / 21 (0.00%)
    0 / 120 (0.00%)
    1 / 10 (10.00%)
    0 / 60 (0.00%)
         occurrences all number
    2
    1
    0
    0
    2
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    3 / 14 (21.43%)
    1 / 6 (16.67%)
    7 / 21 (33.33%)
    17 / 120 (14.17%)
    7 / 10 (70.00%)
    13 / 60 (21.67%)
         occurrences all number
    3
    1
    9
    29
    21
    21
    Epistaxis
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 21 (0.00%)
    3 / 120 (2.50%)
    0 / 10 (0.00%)
    3 / 60 (5.00%)
         occurrences all number
    0
    0
    0
    4
    0
    5
    Oropharyngeal pain
         subjects affected / exposed
    5 / 14 (35.71%)
    1 / 6 (16.67%)
    3 / 21 (14.29%)
    6 / 120 (5.00%)
    3 / 10 (30.00%)
    8 / 60 (13.33%)
         occurrences all number
    8
    1
    4
    6
    5
    9
    Productive cough
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 21 (0.00%)
    0 / 120 (0.00%)
    0 / 10 (0.00%)
    3 / 60 (5.00%)
         occurrences all number
    0
    0
    0
    0
    0
    3
    Rhinorrhoea
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    3 / 21 (14.29%)
    5 / 120 (4.17%)
    0 / 10 (0.00%)
    3 / 60 (5.00%)
         occurrences all number
    0
    0
    8
    6
    0
    3
    Catarrh
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 21 (0.00%)
    0 / 120 (0.00%)
    1 / 10 (10.00%)
    0 / 60 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Dyspnoea
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 6 (16.67%)
    0 / 21 (0.00%)
    0 / 120 (0.00%)
    0 / 10 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Respiratory tract inflammation
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    3 / 21 (14.29%)
    0 / 120 (0.00%)
    0 / 10 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    0
    0
    4
    0
    0
    0
    Rhinitis allergic
         subjects affected / exposed
    1 / 14 (7.14%)
    1 / 6 (16.67%)
    0 / 21 (0.00%)
    0 / 120 (0.00%)
    0 / 10 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    5
    1
    0
    0
    0
    0
    Upper respiratory tract inflammation
         subjects affected / exposed
    2 / 14 (14.29%)
    1 / 6 (16.67%)
    3 / 21 (14.29%)
    0 / 120 (0.00%)
    3 / 10 (30.00%)
    0 / 60 (0.00%)
         occurrences all number
    4
    2
    5
    0
    5
    0
    Blood and lymphatic system disorders
    Iron deficiency anaemia
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 6 (16.67%)
    0 / 21 (0.00%)
    0 / 120 (0.00%)
    0 / 10 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Neutropenia
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 6 (0.00%)
    0 / 21 (0.00%)
    0 / 120 (0.00%)
    0 / 10 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    3 / 14 (21.43%)
    1 / 6 (16.67%)
    3 / 21 (14.29%)
    25 / 120 (20.83%)
    2 / 10 (20.00%)
    11 / 60 (18.33%)
         occurrences all number
    13
    8
    38
    139
    3
    46
    Dizziness
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    1 / 21 (4.76%)
    0 / 120 (0.00%)
    1 / 10 (10.00%)
    0 / 60 (0.00%)
         occurrences all number
    0
    0
    1
    0
    1
    0
    Eye disorders
    Conjunctival hyperaemia
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 21 (0.00%)
    0 / 120 (0.00%)
    1 / 10 (10.00%)
    0 / 60 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Ear and labyrinth disorders
    Ear pain
         subjects affected / exposed
    1 / 14 (7.14%)
    1 / 6 (16.67%)
    2 / 21 (9.52%)
    0 / 120 (0.00%)
    1 / 10 (10.00%)
    0 / 60 (0.00%)
         occurrences all number
    1
    1
    2
    0
    1
    0
    Motion sickness
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 21 (0.00%)
    0 / 120 (0.00%)
    1 / 10 (10.00%)
    0 / 60 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    Vertigo
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 6 (16.67%)
    0 / 21 (0.00%)
    0 / 120 (0.00%)
    0 / 10 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    3 / 14 (21.43%)
    0 / 6 (0.00%)
    2 / 21 (9.52%)
    9 / 120 (7.50%)
    2 / 10 (20.00%)
    5 / 60 (8.33%)
         occurrences all number
    3
    0
    3
    12
    2
    8
    Abdominal pain upper
         subjects affected / exposed
    2 / 14 (14.29%)
    1 / 6 (16.67%)
    2 / 21 (9.52%)
    7 / 120 (5.83%)
    1 / 10 (10.00%)
    2 / 60 (3.33%)
         occurrences all number
    4
    1
    3
    7
    1
    3
    Constipation
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    2 / 21 (9.52%)
    9 / 120 (7.50%)
    1 / 10 (10.00%)
    5 / 60 (8.33%)
         occurrences all number
    0
    0
    3
    11
    1
    7
    Diarrhoea
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 6 (0.00%)
    2 / 21 (9.52%)
    22 / 120 (18.33%)
    1 / 10 (10.00%)
    8 / 60 (13.33%)
         occurrences all number
    1
    0
    3
    29
    4
    8
    Nausea
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 6 (0.00%)
    3 / 21 (14.29%)
    11 / 120 (9.17%)
    1 / 10 (10.00%)
    4 / 60 (6.67%)
         occurrences all number
    3
    0
    4
    13
    1
    6
    Vomiting
         subjects affected / exposed
    2 / 14 (14.29%)
    2 / 6 (33.33%)
    8 / 21 (38.10%)
    18 / 120 (15.00%)
    3 / 10 (30.00%)
    15 / 60 (25.00%)
         occurrences all number
    2
    3
    14
    38
    6
    29
    Aphthous ulcer
         subjects affected / exposed
    2 / 14 (14.29%)
    0 / 6 (0.00%)
    0 / 21 (0.00%)
    0 / 120 (0.00%)
    0 / 10 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    0
    Faecaloma
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 6 (0.00%)
    0 / 21 (0.00%)
    0 / 120 (0.00%)
    0 / 10 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Hyperchlorhydria
         subjects affected / exposed
    1 / 14 (7.14%)
    1 / 6 (16.67%)
    0 / 21 (0.00%)
    0 / 120 (0.00%)
    0 / 10 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    2
    1
    0
    0
    0
    0
    Oral mucosal erythema
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    1 / 21 (4.76%)
    0 / 120 (0.00%)
    1 / 10 (10.00%)
    0 / 60 (0.00%)
         occurrences all number
    0
    0
    1
    0
    1
    0
    Tongue oedema
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 6 (16.67%)
    0 / 21 (0.00%)
    0 / 120 (0.00%)
    0 / 10 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Renal and urinary disorders
    Urinary tract pain
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 21 (0.00%)
    0 / 120 (0.00%)
    1 / 10 (10.00%)
    0 / 60 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Skin and subcutaneous tissue disorders
    Eczema
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    2 / 21 (9.52%)
    6 / 120 (5.00%)
    0 / 10 (0.00%)
    1 / 60 (1.67%)
         occurrences all number
    0
    0
    2
    6
    0
    1
    Rash
         subjects affected / exposed
    2 / 14 (14.29%)
    0 / 6 (0.00%)
    5 / 21 (23.81%)
    9 / 120 (7.50%)
    0 / 10 (0.00%)
    1 / 60 (1.67%)
         occurrences all number
    2
    0
    6
    11
    0
    1
    Acne
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 6 (0.00%)
    0 / 21 (0.00%)
    0 / 120 (0.00%)
    0 / 10 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Alopecia
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 6 (0.00%)
    0 / 21 (0.00%)
    0 / 120 (0.00%)
    0 / 10 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Dermatitis
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 6 (16.67%)
    0 / 21 (0.00%)
    0 / 120 (0.00%)
    0 / 10 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Dermatitis diaper
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 21 (0.00%)
    0 / 120 (0.00%)
    1 / 10 (10.00%)
    0 / 60 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Dry skin
         subjects affected / exposed
    1 / 14 (7.14%)
    1 / 6 (16.67%)
    1 / 21 (4.76%)
    0 / 120 (0.00%)
    0 / 10 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    1
    1
    1
    0
    0
    0
    Erythema
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    2 / 21 (9.52%)
    0 / 120 (0.00%)
    2 / 10 (20.00%)
    0 / 60 (0.00%)
         occurrences all number
    0
    0
    2
    0
    4
    0
    Hyperhidrosis
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 21 (0.00%)
    0 / 120 (0.00%)
    1 / 10 (10.00%)
    0 / 60 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Hyperkeratosis
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 6 (0.00%)
    0 / 21 (0.00%)
    0 / 120 (0.00%)
    0 / 10 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Palmar erythema
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 6 (0.00%)
    1 / 21 (4.76%)
    0 / 120 (0.00%)
    0 / 10 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    0
    Pruritus
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 6 (16.67%)
    0 / 21 (0.00%)
    0 / 120 (0.00%)
    0 / 10 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    0
    3
    0
    0
    0
    0
    Rash papular
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    1 / 21 (4.76%)
    0 / 120 (0.00%)
    1 / 10 (10.00%)
    0 / 60 (0.00%)
         occurrences all number
    0
    0
    1
    0
    1
    0
    Seborrhoeic dermatitis
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 6 (0.00%)
    0 / 21 (0.00%)
    0 / 120 (0.00%)
    0 / 10 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Skin induration
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 6 (0.00%)
    0 / 21 (0.00%)
    0 / 120 (0.00%)
    0 / 10 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    2 / 21 (9.52%)
    7 / 120 (5.83%)
    1 / 10 (10.00%)
    0 / 60 (0.00%)
         occurrences all number
    0
    0
    3
    10
    2
    0
    Pain in extremity
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    3 / 21 (14.29%)
    4 / 120 (3.33%)
    3 / 10 (30.00%)
    3 / 60 (5.00%)
         occurrences all number
    0
    0
    5
    4
    3
    5
    Back pain
         subjects affected / exposed
    3 / 14 (21.43%)
    0 / 6 (0.00%)
    1 / 21 (4.76%)
    0 / 120 (0.00%)
    0 / 10 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    16
    0
    1
    0
    0
    0
    Fracture pain
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 21 (0.00%)
    0 / 120 (0.00%)
    1 / 10 (10.00%)
    0 / 60 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Groin pain
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 21 (0.00%)
    0 / 120 (0.00%)
    1 / 10 (10.00%)
    0 / 60 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Myalgia
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 6 (0.00%)
    1 / 21 (4.76%)
    0 / 120 (0.00%)
    0 / 10 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    0
    Neck pain
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 6 (16.67%)
    0 / 21 (0.00%)
    0 / 120 (0.00%)
    1 / 10 (10.00%)
    0 / 60 (0.00%)
         occurrences all number
    0
    1
    0
    0
    1
    0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 6 (0.00%)
    0 / 21 (0.00%)
    0 / 120 (0.00%)
    1 / 10 (10.00%)
    0 / 60 (0.00%)
         occurrences all number
    2
    0
    0
    0
    1
    0
    Iron deficiency
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 6 (16.67%)
    0 / 21 (0.00%)
    0 / 120 (0.00%)
    0 / 10 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    4 / 21 (19.05%)
    7 / 120 (5.83%)
    2 / 10 (20.00%)
    10 / 60 (16.67%)
         occurrences all number
    0
    0
    7
    9
    4
    12
    Conjunctivitis
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 21 (0.00%)
    4 / 120 (3.33%)
    2 / 10 (20.00%)
    4 / 60 (6.67%)
         occurrences all number
    0
    0
    0
    6
    2
    5
    Gastroenteritis
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 6 (0.00%)
    3 / 21 (14.29%)
    8 / 120 (6.67%)
    2 / 10 (20.00%)
    5 / 60 (8.33%)
         occurrences all number
    1
    0
    4
    11
    2
    7
    Influenza
         subjects affected / exposed
    2 / 14 (14.29%)
    2 / 6 (33.33%)
    1 / 21 (4.76%)
    3 / 120 (2.50%)
    1 / 10 (10.00%)
    3 / 60 (5.00%)
         occurrences all number
    2
    4
    1
    3
    1
    4
    Nasopharyngitis
         subjects affected / exposed
    1 / 14 (7.14%)
    1 / 6 (16.67%)
    5 / 21 (23.81%)
    32 / 120 (26.67%)
    3 / 10 (30.00%)
    16 / 60 (26.67%)
         occurrences all number
    1
    1
    8
    57
    8
    22
    Pharyngitis
         subjects affected / exposed
    2 / 14 (14.29%)
    1 / 6 (16.67%)
    2 / 21 (9.52%)
    7 / 120 (5.83%)
    2 / 10 (20.00%)
    3 / 60 (5.00%)
         occurrences all number
    2
    1
    2
    9
    2
    3
    Pneumonia
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 6 (0.00%)
    0 / 21 (0.00%)
    4 / 120 (3.33%)
    1 / 10 (10.00%)
    3 / 60 (5.00%)
         occurrences all number
    1
    0
    0
    5
    1
    3
    Respiratory tract infection
         subjects affected / exposed
    2 / 14 (14.29%)
    1 / 6 (16.67%)
    3 / 21 (14.29%)
    9 / 120 (7.50%)
    0 / 10 (0.00%)
    7 / 60 (11.67%)
         occurrences all number
    2
    1
    5
    12
    0
    10
    Rhinitis
         subjects affected / exposed
    1 / 14 (7.14%)
    1 / 6 (16.67%)
    1 / 21 (4.76%)
    5 / 120 (4.17%)
    1 / 10 (10.00%)
    3 / 60 (5.00%)
         occurrences all number
    1
    1
    1
    9
    2
    4
    Tonsillitis
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    1 / 21 (4.76%)
    3 / 120 (2.50%)
    1 / 10 (10.00%)
    3 / 60 (5.00%)
         occurrences all number
    0
    0
    1
    4
    1
    5
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 14 (7.14%)
    1 / 6 (16.67%)
    7 / 21 (33.33%)
    39 / 120 (32.50%)
    3 / 10 (30.00%)
    20 / 60 (33.33%)
         occurrences all number
    1
    2
    15
    58
    7
    31
    Urinary tract infection
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 21 (0.00%)
    6 / 120 (5.00%)
    0 / 10 (0.00%)
    1 / 60 (1.67%)
         occurrences all number
    0
    0
    0
    7
    0
    1
    Varicella
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 21 (0.00%)
    3 / 120 (2.50%)
    0 / 10 (0.00%)
    3 / 60 (5.00%)
         occurrences all number
    0
    0
    0
    3
    0
    3
    Cystitis
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 6 (0.00%)
    0 / 21 (0.00%)
    0 / 120 (0.00%)
    0 / 10 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Ear infection
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 6 (0.00%)
    1 / 21 (4.76%)
    0 / 120 (0.00%)
    2 / 10 (20.00%)
    0 / 60 (0.00%)
         occurrences all number
    1
    0
    1
    0
    3
    0
    Fungal skin infection
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 21 (0.00%)
    0 / 120 (0.00%)
    1 / 10 (10.00%)
    0 / 60 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Gastroenteritis viral
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 6 (0.00%)
    0 / 21 (0.00%)
    0 / 120 (0.00%)
    0 / 10 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Gastrointestinal viral infection
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 21 (0.00%)
    0 / 120 (0.00%)
    1 / 10 (10.00%)
    0 / 60 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Infection
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 6 (0.00%)
    0 / 21 (0.00%)
    0 / 120 (0.00%)
    0 / 10 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Laryngitis
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 6 (0.00%)
    1 / 21 (4.76%)
    0 / 120 (0.00%)
    0 / 10 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    0
    Laryngitis viral
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 21 (0.00%)
    0 / 120 (0.00%)
    1 / 10 (10.00%)
    0 / 60 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Paronychia
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 6 (0.00%)
    0 / 21 (0.00%)
    0 / 120 (0.00%)
    0 / 10 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Scarlet fever
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    2 / 21 (9.52%)
    0 / 120 (0.00%)
    0 / 10 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    0
    Skin infection
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 6 (16.67%)
    0 / 21 (0.00%)
    0 / 120 (0.00%)
    0 / 10 (0.00%)
    0 / 60 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Tracheitis
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 21 (0.00%)
    0 / 120 (0.00%)
    1 / 10 (10.00%)
    0 / 60 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Viral infection
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 6 (0.00%)
    0 / 21 (0.00%)
    0 / 120 (0.00%)
    1 / 10 (10.00%)
    0 / 60 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    05 Oct 2016
    Details were added regarding neurological examinations specified in the protocol; Urine and blood pregnancy tests were added to the schedule of assessments for both Part 1 and Part 2 of the study; Stopping rules for cohorts in the dose-escalation part of the study were changed to allow the decision to terminate a cohort to be made by the iDMC
    07 Mar 2017
    The randomization ratio was changed from 1:1 to 2 (active):1 (placebo), and the sample size increased to maintain the same statistical power; Subjects initially randomized to placebo were switched to active treatment after 12 months; Age group stratification was subdivided: in place of one group of subjects aged 6 to 17 years, two groups were specified, aged 6 to 11 and 12 to 17 years; A new market formulation was introduced; Clarification that following the dose selection for Part 2, data from the exploratory Part 1 of this study (and the Part 1 extension phase) could be locked at intervals in order to analyze and report the safety, PK/PD and exploratory efficacy of those subjects enrolled into Part 1 only, which does not impact the integrity of Part 2 of the study; Two new scales were added, the SMAIS and CGI-C; The respiratory measures MEP and MIP were added; Based on Study BP29840, no interaction with CYP3A inducers or inhibitors was expected; therefore, some prohibited drugs were removed from the exclusion criteria and prohibited therapy; A summary of Part 1 data was provided. The pivotal dose was incorporated into the protocol; PedsQL subject-reported outcome measurements were included in Part 1 for up to 12 months of risdiplam treatment; Home nursing visits were removed (for U.S. only) as these were not utilized by the sites except to deliver study drug. These visits were replaced with a study drug service; The age limit at time of randomization was clarified for the completion of pulmonary function testing required for the study
    01 Mar 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; Studies in animals have shown that risdiplam is teratogenic and fetotoxic. The “Background on RO7034067” and “Safety Precautions” sections were updated accordingly; Responder analyses for the Hammersmith Functional Motor Scale Expanded (HFMSE) and Revised Upper Limb Module (RULM) were added as secondary objectives; The end of the study was revised. A subject’s treatment in the open-label extension phase of the study may continue for 3 years. Thereafter, treatment will continue until the drug is available commercially in the subject’s country. The end of the study is when the last patient completes 5 years into the study; An exclusion criterion was added for the use of inhibitors or inducers of FMO1 or FMO3. FMO1 and FMO3 inhibitors and inducers was added to the prohibited therapy section; Chronic treatment was defined as a minimum of 8 weeks to ensure that all sites in the study are applying the same definition;
    01 Mar 2019
    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; Adverse events of skin or subcutaneous reaction, pharyngeal/laryngeal or mucosal reaction, and clinically relevant retinal abnormalities on optical coherence tomography/fundus photography were removed from the list of non-serious adverse events of special interest (AESI) as the independent data monitoring committee (iDMC) provided independent safety surveillance; Blood samples for SMN protein every 26 weeks following the Week 104 visit were added in order to assess whether any increase in SMN protein observed in the first 104 weeks is sustained over the long term

    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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