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Trial record 1 of 1 for:    NCT02908685 BP39055
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A Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Efficacy of Risdiplam (RO7034067) in Type 2 and 3 Spinal Muscular Atrophy (SMA) Participants (SUNFISH)

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ClinicalTrials.gov Identifier: NCT02908685
Recruitment Status : Active, not recruiting
First Posted : September 21, 2016
Results First Posted : June 15, 2021
Last Update Posted : September 29, 2021
Sponsor:
Information provided by (Responsible Party):
Hoffmann-La Roche

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Sequential Assignment;   Masking: Double (Participant, Investigator);   Primary Purpose: Treatment
Condition Muscular Atrophy, Spinal
Interventions Drug: Placebo
Drug: Risdiplam
Enrollment 231
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. The Screening in both Part 1 and 2 was up to 30 days prior to first dose.
Pre-assignment Details  
Arm/Group Title Part 1 Group A Cohort 1: Adolescents and Adults (3 mg Risdiplam) Part 1 Group A Cohort 2: Adolescents and Adults (5 mg Risdiplam) Part 1 Group A Cohort 1: Adolescents and Adults (Placebo) Part 1 Group A Cohort 2: Adolescents and Adults (Placebo) Part 1 Group B Cohort 1: Children (0.02 mg/kg Risdiplam) Part 1 Group B Cohort 2: Children (0.05 mg/kg Risdiplam) Part 1 Group B Cohort 3: Children (0.25 mg/kg Risdiplam) Part 1 Group B Cohort 1: Children (Placebo) Part 1 Group B Cohort 2: Children (Placebo) Part 1 Group B Cohort 3: Children (Placebo) Part 2: Risdiplam Part 2: Placebo
Hide Arm/Group Description Adolescent and adult participants aged 12-25 years received risdiplam for at least 12 weeks. Once the placebo-controlled period was completed and Part 2 dose was selected, participants switched to Part 2 dose and were treated in an open-label phase. Adolescent and adult participants aged 12-25 years received risdiplam for at least 12 weeks. Once the placebo-controlled period was completed and Part 2 dose was selected, participants switched to Part 2 dose and were treated in an open-label phase. Adolescent and adult participants aged 12-25 years received placebo matching to risdiplam for at least 12 weeks. Once the placebo-controlled period was completed, participants first switched to their cohort risdiplam dose (i.e. 3 mg). After the Part 2 dose was selected, participants switched to Part 2 dose and were treated in an open-label phase. Adolescent and adult participants aged 12-25 years received placebo matching to risdiplam for at least 12 weeks. Once the placebo-controlled period was completed, participants first switched to their cohort risdiplam dose (i.e. 5 mg). After the Part 2 dose was selected, participants switched to Part 2 dose and were treated in an open-label phase. Children aged 2-11 years received risdiplam for at least 12 weeks. During the placebo-controlled period, participants escalated to 0.05 mg/kg and then to 0.15 mg/kg in two steps. Once the placebo-controlled period was completed, and after Part 2 dose was selected, participants switched to Part 2 dose and were treated in an open-label phase. Children aged 2-11 years received risdiplam for at least 12 weeks. During the placebo-controlled period, participants escalated to 0.15 mg/kg in one step. Once the placebo-controlled period was completed, and after Part 2 dose was selected, participants switched to Part 2 dose and were treated in an open-label phase. Children aged 2-11 years received risdiplam for at least 12 weeks. Once the placebo-controlled period was completed, and after Part 2 dose was selected, participants switched to Part 2 dose and were treated in an open-label phase. Children aged 2-11 years received placebo matching to risdiplam for at least 12 weeks. Once the placebo-controlled period was completed, participants first switched to the final 0.15 mg/kg cohort risdiplam dose. After the Part 2 dose was selected, participants switched to Part 2 dose and were treated in an open-label phase. Children aged 2-11 years received placebo matching to risdiplam for at least 12 weeks. Once the placebo-controlled period was completed, participants first switched to the final 0.15 mg/kg cohort risdiplam dose. After the Part 2 dose was selected, participants switched to Part 2 dose and were treated in an open-label phase. Children aged 2-11 years received placebo matching to risdiplam for at least 12 weeks. Once the placebo-controlled period was completed, and after Part 2 dose was selected, participants switched to Part 2 dose and were treated in an open-label phase. 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 12 months. Participants aged 2-25 years received placebo matching to risdiplam for 12 months. After 12 months of treatment with placebo, participants switched to risdiplam (5 mg once daily for participants with a body weight (BW) >/=20kg or 0.25 mg/kg for participants with a BW <20) in a blinded manner and participants will continue with treatment and observations.
Period Title: Part 1 Exploratory
Started 7 7 3 3 7 7 7 3 4 3 0 0
Completed 7 6 3 3 7 7 7 3 4 3 0 0
Not Completed 0 1 0 0 0 0 0 0 0 0 0 0
Reason Not Completed
Withdrawal by Subject             0             1             0             0             0             0             0             0             0             0             0             0
Period Title: Part 2 Confirmatory
Started 0 0 0 0 0 0 0 0 0 0 120 60
Completed 0 0 0 0 0 0 0 0 0 0 117 59
Not Completed 0 0 0 0 0 0 0 0 0 0 3 1
Reason Not Completed
Changed to Spinraza             0             0             0             0             0             0             0             0             0             0             2             1
Changed to other treatment             0             0             0             0             0             0             0             0             0             0             1             0
Arm/Group Title Part 1 Group A Cohort 1: Adolescents and Adults (3 mg Risdiplam) Part 1 Group A Cohort 2: Adolescents and Adults (5 mg Risdiplam) Part 1 Group A Cohort 1: Adolescents and Adults (Placebo) Part 1 Group A Cohort 2: Adolescents and Adults (Placebo) Part 1 Group B Cohort 1: Children (0.02 mg/kg Risdiplam) Part 1 Group B Cohort 2: Children (0.05 mg/kg Risdiplam) Part 1 Group B Cohort 3: Children (0.25 mg/kg Risdiplam) Part 1 Group B Cohort 1: Children (Placebo) Part 1 Group B Cohort 2: Children (Placebo) Part 1 Group B Cohort 3: Children (Placebo) Part 2: Risdiplam Part 2: Placebo Total
Hide Arm/Group Description Adolescent and adult participants aged 12-25 years received risdiplam for at least 12 weeks. Once the placebo-controlled period was completed and Part 2 dose was selected, participants switched to Part 2 dose and were treated in an open-label phase. Adolescent and adult participants aged 12-25 years received risdiplam for at least 12 weeks. Once the placebo-controlled period was completed and Part 2 dose was selected, participants switched to Part 2 dose and were treated in an open-label phase. Adolescent and adult participants aged 12-25 years received placebo matching to risdiplam for at least 12 weeks. Once the placebo-controlled period was completed, participants first switched to their cohort risdiplam dose (i.e. 3 mg). After the Part 2 dose was selected, participants switched to Part 2 dose and were treated in an open-label phase. Adolescent and adult participants aged 12-25 years received placebo matching to risdiplam for at least 12 weeks. Once the placebo-controlled period was completed, participants first switched to their cohort risdiplam dose (i.e. 5 mg). After the Part 2 dose was selected, participants switched to Part 2 dose and were treated in an open-label phase. Children aged 2-11 years received risdiplam for at least 12 weeks. During the placebo-controlled period, participants escalated to 0.05 mg/kg and then to 0.15 mg/kg in two steps. Once the placebo-controlled period was completed, and after Part 2 dose was selected, participants switched to Part 2 dose and were treated in an open-label phase. Children aged 2-11 years received risdiplam for at least 12 weeks. During the placebo-controlled period, participants escalated to 0.15 mg/kg in one step. Once the placebo-controlled period was completed, and after Part 2 dose was selected, participants switched to Part 2 dose and were treated in an open-label phase. Children aged 2-11 years received risdiplam for at least 12 weeks. Once the placebo-controlled period was completed, and after Part 2 dose was selected, participants switched to Part 2 dose and were treated in an open-label phase. Children aged 2-11 years received placebo matching to risdiplam for at least 12 weeks. Once the placebo-controlled period was completed, participants first switched to the final 0.15 mg/kg cohort risdiplam dose. After the Part 2 dose was selected, participants switched to Part 2 dose and were treated in an open-label phase. Children aged 2-11 years received placebo matching to risdiplam for at least 12 weeks. Once the placebo-controlled period was completed, participants first switched to the final 0.15 mg/kg cohort risdiplam dose. After the Part 2 dose was selected, participants switched to Part 2 dose and were treated in an open-label phase. Children aged 2-11 years received placebo matching to risdiplam for at least 12 weeks. Once the placebo-controlled period was completed, and after Part 2 dose was selected, participants switched to Part 2 dose and were treated in an open-label phase. 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 12 months. Participants aged 2-25 years received placebo matching to risdiplam for 12 months. After 12 months of treatment with placebo, participants switched to risdiplam (5 mg once daily for participants with a body weight (BW) >/=20kg or 0.25 mg/kg for participants with a BW <20) in a blinded manner and participants will continue with treatment and observations. Total of all reporting groups
Overall Number of Baseline Participants 7 7 3 3 7 7 7 3 4 3 120 60 231
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous   [1] 
Mean (Standard Deviation)
Unit of measure:  Years
Part 1 Number Analyzed 7 participants 7 participants 3 participants 3 participants 7 participants 7 participants 7 participants 3 participants 4 participants 3 participants 0 participants 0 participants 51 participants
13.3  (1.1) 18.1  (4.6) 14.7  (1.5) 17.3  (5.1) 6.1  (2.9) 4.3  (1.7) 6.0  (2.7) 5.3  (2.1) 3.5  (0.6) 5.3  (2.9) 9.4  (6.0)
Part 2 Number Analyzed 0 participants 0 participants 0 participants 0 participants 0 participants 0 participants 0 participants 0 participants 0 participants 0 participants 120 participants 60 participants 180 participants
9.9  (5.8) 10.3  (6.0) 10.0  (5.8)
[1]
Measure Analysis Population Description: Intent-to-Treat (ITT) population: Part 1 and Part 2 were analyzed separately and population results are provided for each part in the study.
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 7 participants 7 participants 3 participants 3 participants 7 participants 7 participants 7 participants 3 participants 4 participants 3 participants 120 participants 60 participants 231 participants
Female
5
  71.4%
5
  71.4%
1
  33.3%
2
  66.7%
5
  71.4%
3
  42.9%
4
  57.1%
0
   0.0%
2
  50.0%
0
   0.0%
61
  50.8%
30
  50.0%
118
  51.1%
Male
2
  28.6%
2
  28.6%
2
  66.7%
1
  33.3%
2
  28.6%
4
  57.1%
3
  42.9%
3
 100.0%
2
  50.0%
3
 100.0%
59
  49.2%
30
  50.0%
113
  48.9%
Race/Ethnicity, Customized  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 7 participants 7 participants 3 participants 3 participants 7 participants 7 participants 7 participants 3 participants 4 participants 3 participants 120 participants 60 participants 231 participants
Asian
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
1
  14.3%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
23
  19.2%
12
  20.0%
36
  15.6%
White
7
 100.0%
7
 100.0%
3
 100.0%
3
 100.0%
6
  85.7%
6
  85.7%
7
 100.0%
3
 100.0%
3
  75.0%
3
 100.0%
80
  66.7%
41
  68.3%
169
  73.2%
Multiple
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
1
  14.3%
0
   0.0%
0
   0.0%
1
  25.0%
0
   0.0%
1
   0.8%
0
   0.0%
3
   1.3%
Black or African American
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
2
   1.7%
0
   0.0%
2
   0.9%
Unknown
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
14
  11.7%
7
  11.7%
21
   9.1%
Race/Ethnicity, Customized  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 7 participants 7 participants 3 participants 3 participants 7 participants 7 participants 7 participants 3 participants 4 participants 3 participants 120 participants 60 participants 231 participants
Hispanic or Latino
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
5
   4.2%
2
   3.3%
7
   3.0%
Not Hispanic or Latino
7
 100.0%
7
 100.0%
3
 100.0%
3
 100.0%
6
  85.7%
7
 100.0%
7
 100.0%
3
 100.0%
4
 100.0%
3
 100.0%
114
  95.0%
57
  95.0%
221
  95.7%
Not Stated
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
1
  14.3%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
1
   1.7%
2
   0.9%
Unknown
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
1
   0.8%
0
   0.0%
1
   0.4%
1.Primary Outcome
Title Part 1: Selected Part 2 Dose of Risdiplam for Participants With a Body Weight (BW) of >/=20kg
Hide 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.
Time Frame Day 1 up to at least 4 weeks on study (Up to CCOD of 25 July 2017)
Hide Outcome Measure Data
Hide Analysis Population Description
All participants in Part 1.
Arm/Group Title Part 1: All Risdiplam
Hide Arm/Group Description:
Children aged 2-11 years and adolescent and adult participants aged 12-25 years received risdiplam or risdiplam matching placebo.
Overall Number of Participants Analyzed 51
Measure Type: Number
Unit of Measure: milligram (mg)
5
2.Primary Outcome
Title Part 1: Selected Part 2 Dose of Risdiplam for Participants With BW of <20kg
Hide 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.
Time Frame Day 1 up to at least 4 weeks on study (Up to CCOD of 25 July 2017)
Hide Outcome Measure Data
Hide Analysis Population Description
All participants in Part 1.
Arm/Group Title Part 1: All Risdiplam
Hide Arm/Group Description:
Children aged 2-11 years and adolescent and adult participants aged 12-25 years received risdiplam or risdiplam matching placebo.
Overall Number of Participants Analyzed 51
Measure Type: Number
Unit of Measure: milligram/kilogram (mg/kg)
0.25
3.Primary Outcome
Title Part 2: Change From Baseline in the Total Motor Function Measure 32 (MFM-32) Total Score at Month 12
Hide 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 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.
Time Frame Baseline (Day-1) and Month 12
Hide Outcome Measure Data
Hide Analysis Population Description
The intent-to-treat (ITT) population defined as all randomized participants in Part 2. Participants with missing MFM32 total score at Baseline were not included in the analysis.
Arm/Group Title Part 2: Risdiplam Part 2: Placebo
Hide Arm/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 12 months.
Participants aged 2-25 years received placebo matching to risdiplam for 12 months. After 12 months of treatment with placebo, participants switched to risdiplam (5 mg once daily for participants with a body weight (BW) >/=20kg or 0.25 mg/kg for participants with a BW <20) in a blinded manner and participants will continue with treatment and observations.
Overall Number of Participants Analyzed 115 59
Least Squares Mean (95% Confidence Interval)
Unit of Measure: Scores on a Scale
1.36
(0.61 to 2.11)
-0.19
(-1.22 to 0.84)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Part 2: Risdiplam, Part 2: Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments 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.
Statistical Test of Hypothesis P-Value 0.0156
Comments [Not Specified]
Method Mixed Model Repeated Measure Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Least Square Mean Difference
Estimated Value 1.55
Confidence Interval (2-Sided) 95%
0.30 to 2.81
Estimation Comments [Not Specified]
4.Secondary Outcome
Title Part 2: Percentage of Participants With Marked Improvement (Defined as >= 3) in the Total Motor Function Measure (MFM32) Score at Month 12
Hide 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 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.
Time Frame At Month 12
Hide Outcome Measure Data
Hide Analysis Population Description
The intent-to-treat (ITT) population defined as all randomized participants in Part 2. Participants with missing MFM32 total score at Baseline were not included in the analysis. Missing results at Month 12 are considered as non-responders.
Arm/Group Title Part 2: Risdiplam Part 2: Placebo
Hide Arm/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 12 months.
Participants aged 2-25 years received placebo matching to risdiplam for 12 months. After 12 months of treatment with placebo, participants switched to risdiplam (5 mg once daily for participants with a body weight (BW) >/=20kg or 0.25 mg/kg for participants with a BW <20) in a blinded manner and participants will continue with treatment and observations.
Overall Number of Participants Analyzed 115 59
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Percentage of Participants
38.3
(28.94 to 47.58)
23.7
(12.03 to 35.43)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Part 2: Risdiplam, Part 2: Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments 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.
Statistical Test of Hypothesis P-Value 0.0469
Comments 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.
Method Wald test
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 2.35
Confidence Interval (2-Sided) 95%
1.01 to 5.44
Estimation Comments [Not Specified]
5.Secondary Outcome
Title Part 2: Change From Baseline in the Total Score of the Revised Upper Limb Module (RULM) at Month 12
Hide 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 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.
Time Frame Baseline (Day-1) and Month 12
Hide Outcome Measure Data
Hide Analysis Population Description
The intent-to-treat (ITT) population defined as all randomized participants in Part 2. Participants with missing RULM total score at Baseline were not included in the analysis.
Arm/Group Title Part 2: Risdiplam Part 2: Placebo
Hide Arm/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 12 months.
Participants aged 2-25 years received placebo matching to risdiplam for 12 months. After 12 months of treatment with placebo, participants switched to risdiplam (5 mg once daily for participants with a body weight (BW) >/=20kg or 0.25 mg/kg for participants with a BW <20) in a blinded manner and participants will continue with treatment and observations.
Overall Number of Participants Analyzed 119 58
Least Squares Mean (95% Confidence Interval)
Unit of Measure: Scores on a Scale
1.61
(1.00 to 2.22)
0.02
(-0.83 to 0.87)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Part 2: Risdiplam, Part 2: Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments 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.
Statistical Test of Hypothesis P-Value 0.0469
Comments 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.
Method Mixed Model Repeated Measure Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Least Square Mean Difference
Estimated Value 1.59
Confidence Interval (2-Sided) 95%
0.55 to 2.62
Estimation Comments [Not Specified]
6.Secondary Outcome
Title Part 2: Change From Baseline in Total Score of Hammersmith Functional Motor Scale Expanded (HFMSE) at Month 12
Hide 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 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.
Time Frame Baseline (Day-1) and Month 12
Hide Outcome Measure Data
Hide Analysis Population Description
The intent-to-treat (ITT) population defined as all randomized participants in Part 2.
Arm/Group Title Part 2: Risdiplam Part 2: Placebo
Hide Arm/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 12 months.
Participants aged 2-25 years received placebo matching to risdiplam for 12 months. After 12 months of treatment with placebo, participants switched to risdiplam (5 mg once daily for participants with a body weight (BW) >/=20kg or 0.25 mg/kg for participants with a BW <20) in a blinded manner and participants will continue with treatment and observations.
Overall Number of Participants Analyzed 120 60
Least Squares Mean (95% Confidence Interval)
Unit of Measure: Scores on a Scale
0.95
(0.29 to 1.61)
0.37
(-0.54 to 1.28)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Part 2: Risdiplam, Part 2: Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments 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.
Statistical Test of Hypothesis P-Value 0.3902
Comments 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.
Method Mixed Model Repeated Measure Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Least Square Mean Difference
Estimated Value 0.58
Confidence Interval (2-Sided) 95%
-0.53 to 1.69
Estimation Comments [Not Specified]
7.Secondary Outcome
Title Part 2: Change From Baseline in Forced Vital Capacity (FVC) at Month 12 in Participants Aged 6-25 Years
Hide 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 participants 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 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.
Time Frame Baseline (Day-1) and Month 12
Hide Outcome Measure Data
Hide Analysis Population Description
The intent-to-treat (ITT) population defined as all randomized participants in Part 2. Participants with missing FVC data at Baseline were not included in the analysis.
Arm/Group Title Part 2: Risdiplam Part 2: Placebo
Hide Arm/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 12 months.
Participants aged 2-25 years received placebo matching to risdiplam for 12 months. After 12 months of treatment with placebo, participants switched to risdiplam (5 mg once daily for participants with a body weight (BW) >/=20kg or 0.25 mg/kg for participants with a BW <20) in a blinded manner and participants will continue with treatment and observations.
Overall Number of Participants Analyzed 83 40
Least Squares Mean (95% Confidence Interval)
Unit of Measure: Percentage Predicted
-5.16
(-7.93 to -2.39)
-3.11
(-6.59 to 0.74)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Part 2: Risdiplam, Part 2: Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments 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.
Statistical Test of Hypothesis P-Value 0.3902
Comments 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.
Method Mixed Model Repeated Measure Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Least Square Mean Difference
Estimated Value -2.05
Confidence Interval (2-Sided) 95%
-6.67 to 2.56
Estimation Comments [Not Specified]
8.Secondary Outcome
Title Part 2: Change From Baseline in the Caregiver-Reported SMA Independence Scale (SMAIS) Total Score at Month 12
Hide Description The SMA Independence Scale (SMAIS) was developed specifically for SMA participants 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 participants aged 12 years or older and caregivers of participants aged 2-25 years. MMRM 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.
Time Frame Baseline (Day-1) and Month 12
Hide Outcome Measure Data
Hide Analysis Population Description
The intent-to-treat (ITT) population defined as all randomized participants in Part 2. Participants with missing SMAIS total score at Baseline were not included in the analysis.
Arm/Group Title Part 2: Risdiplam Part 2: Placebo
Hide Arm/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 12 months.
Participants aged 2-25 years received placebo matching to risdiplam for 12 months. After 12 months of treatment with placebo, participants switched to risdiplam (5 mg once daily for participants with a body weight (BW) >/=20kg or 0.25 mg/kg for participants with a BW <20) in a blinded manner and participants will continue with treatment and observations.
Overall Number of Participants Analyzed 116 60
Least Squares Mean (95% Confidence Interval)
Unit of Measure: Scores on a Scale
1.65
(0.66 to 2.63)
-0.91
(-2.23 to 0.42)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Part 2: Risdiplam, Part 2: Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments 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.
Statistical Test of Hypothesis P-Value 0.3902
Comments 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.
Method Mixed Model Repeated Measure Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Least Square Mean Difference
Estimated Value 2.55
Confidence Interval (2-Sided) 95%
0.93 to 4.17
Estimation Comments [Not Specified]
9.Secondary Outcome
Title Part 2: Percentage of Participants Rated by Clinicians as Improved in the Clinical Global Impression of Change (CGI-C) Scale Ratings at Month 12
Hide Description The Clinical Global Impression of Change (CGI-C) is used to score a clinician's impression of a participant'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". Participants 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 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.
Time Frame At Month 12
Hide Outcome Measure Data
Hide Analysis Population Description
The intent-to-treat (ITT) population defined as all randomized participants in Part 2. Missing results at Month 12 are considered as non-responders.
Arm/Group Title Part 2: Risdiplam Part 2: Placebo
Hide Arm/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 12 months.
Participants aged 2-25 years received placebo matching to risdiplam for 12 months. After 12 months of treatment with placebo, participants switched to risdiplam (5 mg once daily for participants with a body weight (BW) >/=20kg or 0.25 mg/kg for participants with a BW <20) in a blinded manner and participants will continue with treatment and observations.
Overall Number of Participants Analyzed 120 60
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Percentage of Participants
47.5
(38.15 to 56.86)
40.0
(26.77 to 53.23)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Part 2: Risdiplam, Part 2: Placebo
Comments CGI Improved
Type of Statistical Test Superiority
Comments 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.
Statistical Test of Hypothesis P-Value 0.3902
Comments 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.
Method Wald-test
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 1.38
Confidence Interval (2-Sided) 95%
0.70 to 2.74
Estimation Comments [Not Specified]
10.Secondary Outcome
Title Part 2: Percentage of Participants Who Achieve Stabilization or Improvement (Defined as >= 0) in the Total Motor Function Measure (MFM-32) Score at Month 12
Hide 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 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.
Time Frame At Month 12
Hide Outcome Measure Data
Hide Analysis Population Description
The intent-to-treat (ITT) population defined as all randomized participants in Part 2. Participants with missing MFM32 total score at Baseline were not included in the analysis. Missing results at Month 12 are considered as non-responders.
Arm/Group Title Part 2: Risdiplam Part 2: Placebo
Hide Arm/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 12 months.
Participants aged 2-25 years received placebo matching to risdiplam for 12 months. After 12 months of treatment with placebo, participants switched to risdiplam (5 mg once daily for participants with a body weight (BW) >/=20kg or 0.25 mg/kg for participants with a BW <20) in a blinded manner and participants will continue with treatment and observations.
Overall Number of Participants Analyzed 115 59
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Percentage of Participants
69.6
(60.72 to 78.41)
54.2
(40.68 to 67.80)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Part 2: Risdiplam, Part 2: Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments Logistic Regression Model. The variables included in the logistic regression are: baseline total score, treatment and age group.
Statistical Test of Hypothesis P-Value 0.0430
Comments [Not Specified]
Method Wald test
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 2.00
Confidence Interval (2-Sided) 95%
1.02 to 3.93
Estimation Comments [Not Specified]
11.Secondary Outcome
Title Part 2: Percentage of Participants Who Achieve an Improvement of at Least One Standard Error of Measurement on the Total MFM-32 Score at Month 12
Hide 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 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.
Time Frame At Month 12
Hide Outcome Measure Data
Hide Analysis Population Description
The intent-to-treat (ITT) population defined as all randomized participants in Part 2. Participants with missing MFM32 total score at Baseline were not included in the analysis.
Arm/Group Title Part 2: Risdiplam Part 2: Placebo
Hide Arm/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 12 months.
Participants aged 2-25 years received placebo matching to risdiplam for 12 months. After 12 months of treatment with placebo, participants switched to risdiplam (5 mg once daily for participants with a body weight (BW) >/=20kg or 0.25 mg/kg for participants with a BW <20) in a blinded manner and participants will continue with treatment and observations.
Overall Number of Participants Analyzed 115 59
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Percentage of Participants
28.7
(20.65 to 37.88)
16.9
(8.44 to 28.97)
12.Secondary Outcome
Title Part 2: Change From Baseline in the MFM-32 Domain 1 (D1) Score at Month 12
Hide 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 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.
Time Frame Baseline (Day-1) and Month 12
Hide Outcome Measure Data
Hide Analysis Population Description
The intent-to-treat (ITT) population defined as all randomized participants in Part 2. Participants with missing MFM32 D1 score at Baseline were not included in the analysis.
Arm/Group Title Part 2: Risdiplam Part 2: Placebo
Hide Arm/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 12 months.
Participants aged 2-25 years received placebo matching to risdiplam for 12 months. After 12 months of treatment with placebo, participants switched to risdiplam (5 mg once daily for participants with a body weight (BW) >/=20kg or 0.25 mg/kg for participants with a BW <20) in a blinded manner and participants will continue with treatment and observations.
Overall Number of Participants Analyzed 118 60
Least Squares Mean (95% Confidence Interval)
Unit of Measure: Scores on a Scale
0.37
(-0.12 to 0.87)
-0.26
(-0.94 to 0.42)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Part 2: Risdiplam, Part 2: Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments The variables included in the MMRM model are: baseline total score, treatment, age group, visit, treatment-by-visit and baseline score-by-visit interaction.
Statistical Test of Hypothesis P-Value 0.1328
Comments [Not Specified]
Method Mixed Model Repeated Measure Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Least Square Mean Difference
Estimated Value 0.64
Confidence Interval (2-Sided) 95%
-0.20 to 1.47
Estimation Comments [Not Specified]
13.Secondary Outcome
Title Part 2: Change From Baseline in the MFM-32 Domain 2 (D2) Score at Month 12
Hide 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 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.
Time Frame Baseline (Day-1) and Month 12
Hide Outcome Measure Data
Hide Analysis Population Description
The intent-to-treat (ITT) population defined as all randomized participants in Part 2. Participants with missing MFM32 D2 score at Baseline were not included in the analysis.
Arm/Group Title Part 2: Risdiplam Part 2: Placebo
Hide Arm/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 12 months.
Participants aged 2-25 years received placebo matching to risdiplam for 12 months. After 12 months of treatment with placebo, participants switched to risdiplam (5 mg once daily for participants with a body weight (BW) >/=20kg or 0.25 mg/kg for participants with a BW <20) in a blinded manner and participants will continue with treatment and observations.
Overall Number of Participants Analyzed 118 60
Least Squares Mean (95% Confidence Interval)
Unit of Measure: Scores on a Scale
1.04
(-0.38 to 2.46)
-0.93
(-2.87 to 1.02)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Part 2: Risdiplam, Part 2: Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments The variables included in the MMRM model are: baseline total score, treatment, age group, visit, treatment-by-visit and baseline score-by-visit interaction.
Statistical Test of Hypothesis P-Value 0.1030
Comments [Not Specified]
Method Mixed Model Repeated Measure Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Least Square Mean Difference
Estimated Value 1.97
Confidence Interval (2-Sided) 95%
-0.40 to 4.34
Estimation Comments [Not Specified]
14.Secondary Outcome
Title Part 2: Change From Baseline in the MFM-32 Domain 3 (D3) Score at Month 12
Hide 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 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.
Time Frame Baseline (Day-1) and Month 12
Hide Outcome Measure Data
Hide Analysis Population Description
The intent-to-treat (ITT) population defined as all randomized participants in Part 2. Participants with missing MFM32 D3 score at Baseline were not included in the analysis.
Arm/Group Title Part 2: Risdiplam Part 2: Placebo
Hide Arm/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 12 months.
Participants aged 2-25 years received placebo matching to risdiplam for 12 months. After 12 months of treatment with placebo, participants switched to risdiplam (5 mg once daily for participants with a body weight (BW) >/=20kg or 0.25 mg/kg for participants with a BW <20) in a blinded manner and participants will continue with treatment and observations.
Overall Number of Participants Analyzed 115 59
Least Squares Mean (95% Confidence Interval)
Unit of Measure: Scores on a Scale
3.68
(2.31 to 5.04)
1.34
(-0.54 to 3.22)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Part 2: Risdiplam, Part 2: Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments The variables included in the MMRM model are: baseline total score, treatment, age group, visit, treatment-by-visit and baseline score-by-visit interaction.
Statistical Test of Hypothesis P-Value 0.0451
Comments [Not Specified]
Method Mixed Model Repeated Measure Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Least Square Mean Difference
Estimated Value 2.34
Confidence Interval (2-Sided) 95%
0.05 to 4.62
Estimation Comments [Not Specified]
15.Secondary Outcome
Title Part 2: Change From Baseline in the Total Combined Scores of MFM-32 Domains 1 and 2 at Month 12
Hide 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 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.
Time Frame Baseline (Day-1) and Month 12
Hide Outcome Measure Data
Hide Analysis Population Description
The intent-to-treat (ITT) population defined as all randomized participants in Part 2. Participants with missing MFM32 D1+D2 scores at Baseline were not included in the analysis.
Arm/Group Title Part 2: Risdiplam Part 2: Placebo
Hide Arm/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 12 months.
Participants aged 2-25 years received placebo matching to risdiplam for 12 months. After 12 months of treatment with placebo, participants switched to risdiplam (5 mg once daily for participants with a body weight (BW) >/=20kg or 0.25 mg/kg for participants with a BW <20) in a blinded manner and participants will continue with treatment and observations.
Overall Number of Participants Analyzed 118 60
Least Squares Mean (95% Confidence Interval)
Unit of Measure: Scores on a Scale
0.69
(-0.07 to 1.45)
-0.59
(-1.64 to 0.45)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Part 2: Risdiplam, Part 2: Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments The variables included in the MMRM model are: baseline total score, treatment, age group, visit, treatment-by-visit and baseline score-by-visit interaction.
Statistical Test of Hypothesis P-Value 0.0489
Comments [Not Specified]
Method Mixed Model Repeated Measure Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Least Square Mean Difference
Estimated Value 1.28
Confidence Interval (2-Sided) 95%
0.01 to 2.56
Estimation Comments [Not Specified]
16.Secondary Outcome
Title Part 2: Change From Baseline in the Total Combined Scores of MFM-32 Domains 2 and 3 at Month 12
Hide 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+D3 items score are summed and expressed on 0-100 scale for the MFM D2+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 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.
Time Frame Baseline (Day-1) and Month 12
Hide Outcome Measure Data
Hide Analysis Population Description
The intent-to-treat (ITT) population defined as all randomized participants in Part 2. Participants with missing MFM32 D2+D3 scores at Baseline were not included in the analysis.
Arm/Group Title Part 2: Risdiplam Part 2: Placebo
Hide Arm/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 12 months.
Participants aged 2-25 years received placebo matching to risdiplam for 12 months. After 12 months of treatment with placebo, participants switched to risdiplam (5 mg once daily for participants with a body weight (BW) >/=20kg or 0.25 mg/kg for participants with a BW <20) in a blinded manner and participants will continue with treatment and observations.
Overall Number of Participants Analyzed 115 59
Least Squares Mean (95% Confidence Interval)
Unit of Measure: Scores on a Scale
2.02
(0.84 to 3.20)
-0.14
(-1.76 to 1.48)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Part 2: Risdiplam, Part 2: Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments The variables included in the MMRM model are: baseline total score, treatment, age group, visit, treatment-by-visit and baseline score-by-visit interaction.
Statistical Test of Hypothesis P-Value 0.0326
Comments [Not Specified]
Method Mixed Model Repeated Measure Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Least Square Mean Difference
Estimated Value 2.16
Confidence Interval (2-Sided) 95%
0.18 to 4.14
Estimation Comments [Not Specified]
17.Secondary Outcome
Title Part 2: Change From Baseline in Forced Expiratory Volume in 1 Second (FEV1) at Month 12 in Participants Aged 6-25 Years
Hide 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 participants 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 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.
Time Frame Baseline (Day-1) and Month 12
Hide Outcome Measure Data
Hide Analysis Population Description
The intent-to-treat (ITT) population defined as all randomized participants in Part 2. Participants with missing FEV1 data at Baseline were not included in the analysis.
Arm/Group Title Part 2: Risdiplam Part 2: Placebo
Hide Arm/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 12 months.
Participants aged 2-25 years received placebo matching to risdiplam for 12 months. After 12 months of treatment with placebo, participants switched to risdiplam (5 mg once daily for participants with a body weight (BW) >/=20kg or 0.25 mg/kg for participants with a BW <20) in a blinded manner and participants will continue with treatment and observations.
Overall Number of Participants Analyzed 83 40
Least Squares Mean (95% Confidence Interval)
Unit of Measure: Percentage Predicted
-4.22
(-7.49 to -0.96)
-1.35
(-5.91 to 3.20)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Part 2: Risdiplam, Part 2: Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments The variables included in the MMRM model are: baseline total score, treatment, age group, visit, treatment-by-visit and baseline score-by-visit interaction.
Statistical Test of Hypothesis P-Value 0.3029
Comments [Not Specified]
Method Mixed Model Repeated Measure Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Least Square Mean Difference
Estimated Value -2.87
Confidence Interval (2-Sided) 95%
-8.36 to 2.62
Estimation Comments [Not Specified]
18.Secondary Outcome
Title Part 2: Change From Baseline in the Peak Cough Flow (PCF) at Month 12 in Participants Aged 6-25 Years
Hide 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 participants 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 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.
Time Frame Baseline (Day-1) and Month 12
Hide Outcome Measure Data
Hide Analysis Population Description
The intent-to-treat (ITT) population defined as all randomized participants in Part 2. Participants with missing PCF data at Baseline were not included in the analysis.
Arm/Group Title Part 2: Risdiplam Part 2: Placebo
Hide Arm/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 12 months.
Participants aged 2-25 years received placebo matching to risdiplam for 12 months. After 12 months of treatment with placebo, participants switched to risdiplam (5 mg once daily for participants with a body weight (BW) >/=20kg or 0.25 mg/kg for participants with a BW <20) in a blinded manner and participants will continue with treatment and observations.
Overall Number of Participants Analyzed 83 42
Least Squares Mean (95% Confidence Interval)
Unit of Measure: Percent Predicted
1.06
(-1.18 to 3.31)
-0.22
(-3.27 to 2.83)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Part 2: Risdiplam, Part 2: Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments The variables included in the MMRM model are: baseline total score, treatment, age group, visit, treatment-by-visit and baseline score-by-visit interaction.
Statistical Test of Hypothesis P-Value 0.4937
Comments [Not Specified]
Method Mixed Model Repeated Measure Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Least Square Mean Difference
Estimated Value 1.28
Confidence Interval (2-Sided) 95%
-2.42 to 4.99
Estimation Comments [Not Specified]
19.Secondary Outcome
Title Part 2: Change From Baseline in the Best Sniff Nasal Inspiratory Pressure (SNIP) at Month 12
Hide 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 participants 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 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.
Time Frame Baseline (Day-1) and Month 12
Hide Outcome Measure Data
Hide Analysis Population Description
The intent-to-treat (ITT) population defined as all randomized participants in Part 2. Participants with missing SNIP data at Baseline were not included in the analysis.
Arm/Group Title Part 2: Risdiplam Part 2: Placebo
Hide Arm/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 12 months.
Participants aged 2-25 years received placebo matching to risdiplam for 12 months. After 12 months of treatment with placebo, participants switched to risdiplam (5 mg once daily for participants with a body weight (BW) >/=20kg or 0.25 mg/kg for participants with a BW <20) in a blinded manner and participants will continue with treatment and observations.
Overall Number of Participants Analyzed 118 59
Least Squares Mean (95% Confidence Interval)
Unit of Measure: Percentage Predicted
3.42
(0.22 to 6.62)
1.07
(-3.42 to 5.57)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Part 2: Risdiplam, Part 2: Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments The variables included in the MMRM model are: baseline total score, treatment, age group, visit, treatment-by-visit and baseline score-by-visit interaction.
Statistical Test of Hypothesis P-Value 0.3967
Comments [Not Specified]
Method Mixed Model Repeated Measure Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Least Square Mean Difference
Estimated Value 2.35
Confidence Interval (2-Sided) 95%
-3.11 to 7.80
Estimation Comments [Not Specified]
20.Secondary Outcome
Title Part 2: Change From Baseline in Maximal Inspiratory Pressure (MIP) at Month 12 in Participants Aged 6-25 Years
Hide 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 participants aged 6 or older. Participants 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 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.
Time Frame Baseline (Day-1) and Month 12
Hide Outcome Measure Data
Hide Analysis Population Description
The intent-to-treat (ITT) population defined as all randomized participants in Part 2. Participants with missing MIP data at Baseline were not included in the analysis.
Arm/Group Title Part 2: Risdiplam Part 2: Placebo
Hide Arm/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 12 months.
Participants aged 2-25 years received placebo matching to risdiplam for 12 months. After 12 months of treatment with placebo, participants switched to risdiplam (5 mg once daily for participants with a body weight (BW) >/=20kg or 0.25 mg/kg for participants with a BW <20) in a blinded manner and participants will continue with treatment and observations.
Overall Number of Participants Analyzed 81 40
Least Squares Mean (95% Confidence Interval)
Unit of Measure: Percentage Predicted
1.99
(-6.13 to 10.11)
-0.97
(-12.33 to 10.38)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Part 2: Risdiplam, Part 2: Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments The variables included in the MMRM model are: baseline total score, treatment, age group, visit, treatment-by-visit and baseline score-by-visit interaction.
Statistical Test of Hypothesis P-Value 0.6704
Comments [Not Specified]
Method Mixed Model Repeated Measure Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Least Square Mean Difference
Estimated Value 2.96
Confidence Interval (2-Sided) 95%
-10.78 to 16.70
Estimation Comments [Not Specified]
21.Secondary Outcome
Title Part 2: Change From Baseline in Maximal Expiratory Pressure (MEP) at Month 12 in Participants Aged 6-25 Years
Hide 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 participants aged 6 or older. Participants 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 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.
Time Frame Baseline (Day-1) and Month 12
Hide Outcome Measure Data
Hide Analysis Population Description
The intent-to-treat (ITT) population defined as all randomized participants in Part 2. Participants with missing MEP data at Baseline were not included in the analysis.
Arm/Group Title Part 2: Risdiplam Part 2: Placebo
Hide Arm/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 12 months.
Participants aged 2-25 years received placebo matching to risdiplam for 12 months. After 12 months of treatment with placebo, participants switched to risdiplam (5 mg once daily for participants with a body weight (BW) >/=20kg or 0.25 mg/kg for participants with a BW <20) in a blinded manner and participants will continue with treatment and observations.
Overall Number of Participants Analyzed 83 41
Least Squares Mean (95% Confidence Interval)
Unit of Measure: Percentage Predicted
-2.75
(-6.22 to 0.72)
-2.33
(-7.21 to 2.56)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Part 2: Risdiplam, Part 2: Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments The variables included in the MMRM model are: baseline total score, treatment, age group, visit, treatment-by-visit and baseline score-by-visit interaction.
Statistical Test of Hypothesis P-Value 0.8856
Comments [Not Specified]
Method Mixed Model Repeated Measure Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Least Square Mean Difference
Estimated Value -0.43
Confidence Interval (2-Sided) 95%
-6.30 to 5.45
Estimation Comments [Not Specified]
22.Secondary Outcome
Title Part 2: Change From Baseline in the Participant-Reported SMA Independence Scale (SMAIS) Total Score at Month 12
Hide Description The SMAIS was developed specifically for SMA participants 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 participants aged 12 years or older and caregivers of participants aged 2-25 years. MMRM 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.
Time Frame Baseline (Day-1) and Month 12
Hide Outcome Measure Data
Hide Analysis Population Description
The intent-to-treat (ITT) population defined as all randomized participants in Part 2. Participants with missing SMAIS total score at Baseline were not included in the analysis.
Arm/Group Title Part 2: Risdiplam Part 2: Placebo
Hide Arm/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 12 months.
Participants aged 2-25 years received placebo matching to risdiplam for 12 months. After 12 months of treatment with placebo, participants switched to risdiplam (5 mg once daily for participants with a body weight (BW) >/=20kg or 0.25 mg/kg for participants with a BW <20) in a blinded manner and participants will continue with treatment and observations.
Overall Number of Participants Analyzed 43 23
Least Squares Mean (95% Confidence Interval)
Unit of Measure: Scores on a Scale
1.04
(-0.26 to 2.35)
-0.40
(-2.13 to 1.32)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Part 2: Risdiplam, Part 2: Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments The variables included in the MMRM model are: baseline total score, treatment, age group, visit, treatment-by-visit and baseline score-by-visit interaction.
Statistical Test of Hypothesis P-Value 0.1778
Comments [Not Specified]
Method Mixed Model Repeated Measure Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Least Square Mean Difference
Estimated Value 1.45
Confidence Interval (2-Sided) 95%
-0.68 to 3.57
Estimation Comments [Not Specified]
23.Secondary Outcome
Title Part 2: Percentage of Participants Rated by Clinicians as No Change or Improved in the Clinical Global Impression of Change (CGI-C) Scale Ratings at Month 12
Hide 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.
Time Frame At Month 12
Hide Outcome Measure Data
Hide Analysis Population Description
The intent-to-treat (ITT) population defined as all randomized participants in Part 2. Missing results at Month 12 are considered as non-responders.
Arm/Group Title Part 2: Risdiplam Part 2: Placebo
Hide Arm/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 12 months.
Participants aged 2-25 years received placebo matching to risdiplam for 12 months. After 12 months of treatment with placebo, participants switched to risdiplam (5 mg once daily for participants with a body weight (BW) >/=20kg or 0.25 mg/kg for participants with a BW <20) in a blinded manner and participants will continue with treatment and observations.
Overall Number of Participants Analyzed 120 60
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Percentage of Participants
85.8
(79.18 to 92.49)
83.3
(73.07 to 93.60)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Part 2: Risdiplam, Part 2: Placebo
Comments CGI No Change or Improved
Type of Statistical Test Superiority
Comments Logistic Regression Model. The variables included in the logistic regression are: baseline total score, treatment and age group.
Statistical Test of Hypothesis P-Value 0.6636
Comments [Not Specified]
Method Wald-test
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 1.21
Confidence Interval (2-Sided) 95%
0.52 to 2.83
Estimation Comments [Not Specified]
24.Secondary Outcome
Title Part 2: Percentage of Participants Who Experience at Least One Disease-Related Adverse Event at Month 12
Hide 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 participants 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.
Time Frame Baseline up to Month 12 (Week 52; up to CCOD of 06 September 2019)
Hide Outcome Measure Data
Hide Analysis Population Description
The intent-to-treat (ITT) population defined as all randomized participants in Part 2.
Arm/Group Title Part 2: Risdiplam Part 2: Placebo
Hide Arm/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 12 months.
Participants aged 2-25 years received placebo matching to risdiplam for 12 months. After 12 months of treatment with placebo, participants switched to risdiplam (5 mg once daily for participants with a body weight (BW) >/=20kg or 0.25 mg/kg for participants with a BW <20) in a blinded manner and participants will continue with treatment and observations.
Overall Number of Participants Analyzed 120 60
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Percentage of Participants
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)
25.Secondary Outcome
Title Part 2: Number of Disease-related Adverse Events Per Patient-years at Month 12
Hide 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.
Time Frame Baseline up to Month 12 (Week 52; up to CCOD of 06 September 2019)
Hide Outcome Measure Data
Hide Analysis Population Description
The intent-to-treat (ITT) population defined as all randomized participants in Part 2.
Arm/Group Title Part 2: Risdiplam Part 2: Placebo
Hide Arm/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 12 months.
Participants aged 2-25 years received placebo matching to risdiplam for 12 months. After 12 months of treatment with placebo, participants switched to risdiplam (5 mg once daily for participants with a body weight (BW) >/=20kg or 0.25 mg/kg for participants with a BW <20) in a blinded manner and participants will continue with treatment and observations.
Overall Number of Participants Analyzed 120 60
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Number of Events per 100 Patient-Years
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)
26.Secondary Outcome
Title Part 1: Percentage of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
Hide 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.
Time Frame Day 1 on risdiplam up to end of study (up to approximately 7 years)
Outcome Measure Data Not Reported
27.Secondary Outcome
Title Part 2: Percentage of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) in the Placebo-Controlled Period
Hide 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.
Time Frame Day 1 up to 12 months of the placebo-controlled period
Hide Outcome Measure Data
Hide Analysis Population Description
All participants in Part 2 who receive at least one dose of study medication (risdiplam or placebo) were included in the safety population.
Arm/Group Title Part 2: Risdiplam Part 2: Placebo
Hide Arm/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 12 months.
Participants aged 2-25 years received placebo matching to risdiplam for 12 months. After 12 months of treatment with placebo, participants switched to risdiplam (5 mg once daily for participants with a body weight (BW) >/=20kg or 0.25 mg/kg for participants with a BW <20) in a blinded manner and participants will continue with treatment and observations.
Overall Number of Participants Analyzed 120 60
Measure Type: Number
Unit of Measure: Percentage of Participants
With at Least One AE 92.5 91.7
With at Least One SAE 20.0 18.3
28.Secondary Outcome
Title Part 2: Percentage of Participants With Treatment Discontinuation Due to Adverse Events (AEs) and Serious Adverse Events (SAEs) in the Placebo-Controlled Period
Hide 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.
Time Frame Day 1 up to 12 months of the placebo-controlled period
Hide Outcome Measure Data
Hide Analysis Population Description
All participants in Part 2 who received at least one dose of study medication (risdiplam or placebo) were included in the safety population.
Arm/Group Title Part 2: Risdiplam Part 2: Placebo
Hide Arm/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 12 months.
Participants aged 2-25 years received placebo matching to risdiplam for 12 months. After 12 months of treatment with placebo, participants switched to risdiplam (5 mg once daily for participants with a body weight (BW) >/=20kg or 0.25 mg/kg for participants with a BW <20) in a blinded manner and participants will continue with treatment and observations.
Overall Number of Participants Analyzed 120 60
Measure Type: Number
Unit of Measure: Percentage of Participants
Due to AE 0.0 0.0
Due to SAE 0.0 0.0
29.Secondary Outcome
Title Part 2: Number of Participants Aged 6-25 Years With Suicidal Ideation Based on Columbia-Suicide Severity Rating Scale (C-SSRS) in the Placebo-Controlled Period
Hide Description The Columbia Suicide Severity Rating Scale (C-SSRS) is used to assess the lifetime suicidality of a participant (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 participants aged 6 years and older.
Time Frame Day 1 up to 12 months of the placebo-controlled period
Hide Outcome Measure Data
Hide Analysis Population Description
The intent-to-treat (ITT) population defined as all randomized participants in Part 2. Data was collected for participants aged 6-25 years.
Arm/Group Title Part 2: Risdiplam Part 2: Placebo
Hide Arm/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 12 months.
Participants aged 2-25 years received placebo matching to risdiplam for 12 months. After 12 months of treatment with placebo, participants switched to risdiplam (5 mg once daily for participants with a body weight (BW) >/=20kg or 0.25 mg/kg for participants with a BW <20) in a blinded manner and participants will continue with treatment and observations.
Overall Number of Participants Analyzed 83 42
Measure Type: Number
Unit of Measure: Number of Participants
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
30.Secondary Outcome
Title Part 2: Number of Participants Aged 6-25 Years With Suicidal Behavior Based on Columbia-Suicide Severity Rating Scale (C-SSRS) in the Placebo-Controlled Period
Hide Description The Columbia Suicide Severity Rating Scale (C-SSRS) is used to assess the lifetime suicidality of a participant (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 participants aged 6 years and older.
Time Frame Day 1 up to 12 months of the placebo-controlled period
Hide Outcome Measure Data
Hide Analysis Population Description
The intent-to-treat (ITT) population defined as all randomized participants in Part 2. Data was collected for participants aged 6-25 years.
Arm/Group Title Part 2: Risdiplam Part 2: Placebo
Hide Arm/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 12 months.
Participants aged 2-25 years received placebo matching to risdiplam for 12 months. After 12 months of treatment with placebo, participants switched to risdiplam (5 mg once daily for participants with a body weight (BW) >/=20kg or 0.25 mg/kg for participants with a BW <20) in a blinded manner and participants will continue with treatment and observations.
Overall Number of Participants Analyzed 83 42
Measure Type: Number
Unit of Measure: Number of Participants
Preparatory Acts or Behavior 0 0
Aborted Attempt 0 0
Interrupted Attempt 0 0
Actual Attempt (non-fatal) 0 0
Completed Suicide 0 0
31.Secondary Outcome
Title Survival of Motor Neuron 2 (SMN2) Messenger Ribonucleic Acid (mRNA) Levels in Blood
Hide Description [Not Specified]
Time Frame Part 2: Days -1, 1, 7, 28, 120, 246, 365, 729
Outcome Measure Data Not Reported
32.Secondary Outcome
Title Survival of Motor Neuron (SMN) Protein Levels in Blood
Hide Description [Not Specified]
Time Frame Part 2: Days -1, 7, 28, 120, 246, 365, 729
Outcome Measure Data Not Reported
33.Secondary Outcome
Title Part 1 and 2: Maximum Plasma Concentration (Cmax) of Risdiplam
Hide Description [Not Specified]
Time Frame Part 1 and 2: 1, 2, 4, 6 hours post dose on Day 1; Pre-dose (Hour 0) on Days 7, 14, 56 (Part 2), 120, 246, 490, 729; pre-dose (Hour 0) and 1, 2, 4, 6 hours post dose on Days 28, 56 (Part 1), 365, 609
Outcome Measure Data Not Reported
34.Secondary Outcome
Title Part 1 and 2: Area Under the Curve (AUC) of Risdiplam
Hide Description [Not Specified]
Time Frame Part 1 and 2: 1, 2, 4, 6 hours post dose on Day 1; Pre-dose (Hour 0) on Days 7, 14, 56 (Part 2), 120, 246, 490, 729; pre-dose (Hour 0) and 1, 2, 4, 6 hours post dose on Days 28, 56 (Part 1), 365, 609
Outcome Measure Data Not Reported
35.Secondary Outcome
Title Part 1 and 2: Concentration at the End of a Dosing Interval (Ctrough) of Risdiplam
Hide Description [Not Specified]
Time Frame Part 1 and 2: Pre-dose (Hour 0) on Days 7, 14, 28, 56, 120, 246, 365, 490, 609, 729
Outcome Measure Data Not Reported
Time Frame 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 Description All participants in Part 1 or who received at least one dose of study medication (risdiplam or placebo) whether prematurely withdrawn or not were included in the safety population. All participants in Part 2 who receive at least one dose of study medication (risdiplam or placebo) were included in the safety population.
 
Arm/Group Title Part 1 Group A: Adolescents and Adults (3 mg Risdiplam) Part 1 Group A: Adolescents and Adults (5 mg Risdiplam) Part 1 Group A: Adolescents and Adults (Placebo-Control Period Pooled) Part 1 Group B: Children (0.02 mg/kg Risdiplam) Part 1 Group B: Children (0.05 mg/kg Risdiplam) Part 1 Group B: Children (0.15 mg/kg Risdiplam) Part 1 Group B: Children (0.25 mg/kg Risdiplam) Part 1 Group B: Children (Placebo-Control Period Pooled) Part 1 Group A: OLE Part 1 Group B: OLE Part 2: Risdiplam Part 2: Placebo
Hide Arm/Group Description Adolescent and adult participants aged 12-25 years received risdiplam for at least 12 weeks during the placebo-controlled period. Adolescent and adult participants aged 12-25 years received risdiplam for at least 12 weeks during the placebo-controlled period. Adolescent and adult participants aged 12-25 years received placebo matching to risdiplam for at least 12 weeks during the placebo-controlled period. Children aged 2-11 years received risdiplam for at least 12 weeks during the placebo-controlled period. Children aged 2-11 years received risdiplam for at least 12 weeks during the placebo-controlled period. Children aged 2-11 years received risdiplam for at least 12 weeks during the placebo-controlled period. Children aged 2-11 years received risdiplam for at least 12 weeks during the placebo-controlled period. Children aged 2-11 years received placebo matching to risdiplam for at least 12 weeks during the placebo-controlled period. Once the placebo-controlled period was completed and Part 2 dose was selected, adolescents and adults switched to Part 2 dose and were treated in an open-label extension (OLE) phase. Once the placebo-controlled period was completed and Part 2 dose was selected, children switched to Part 2 dose and were treated in an open-label extension (OLE) phase. 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 12 months. Participants aged 2-25 years received placebo matching to risdiplam for 12 months. After 12 months of treatment with placebo, participants switched to risdiplam (5 mg once daily for participants with a body weight (BW) >/=20kg or 0.25 mg/kg for participants with a BW <20) in a blinded manner and participants will continue with treatment and observations.
All-Cause Mortality
Part 1 Group A: Adolescents and Adults (3 mg Risdiplam) Part 1 Group A: Adolescents and Adults (5 mg Risdiplam) Part 1 Group A: Adolescents and Adults (Placebo-Control Period Pooled) Part 1 Group B: Children (0.02 mg/kg Risdiplam) Part 1 Group B: Children (0.05 mg/kg Risdiplam) Part 1 Group B: Children (0.15 mg/kg Risdiplam) Part 1 Group B: Children (0.25 mg/kg Risdiplam) Part 1 Group B: Children (Placebo-Control Period Pooled) Part 1 Group A: OLE Part 1 Group B: OLE Part 2: Risdiplam Part 2: Placebo
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   0/10 (0.00%)      0/10 (0.00%)      0/6 (0.00%)      0/7 (0.00%)      0/14 (0.00%)      0/21 (0.00%)      0/7 (0.00%)      0/10 (0.00%)      0/31 (0.00%)      0/20 (0.00%)      0/120 (0.00%)      0/60 (0.00%)    
Hide Serious Adverse Events
Part 1 Group A: Adolescents and Adults (3 mg Risdiplam) Part 1 Group A: Adolescents and Adults (5 mg Risdiplam) Part 1 Group A: Adolescents and Adults (Placebo-Control Period Pooled) Part 1 Group B: Children (0.02 mg/kg Risdiplam) Part 1 Group B: Children (0.05 mg/kg Risdiplam) Part 1 Group B: Children (0.15 mg/kg Risdiplam) Part 1 Group B: Children (0.25 mg/kg Risdiplam) Part 1 Group B: Children (Placebo-Control Period Pooled) Part 1 Group A: OLE Part 1 Group B: OLE Part 2: Risdiplam Part 2: Placebo
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   2/10 (20.00%)      2/10 (20.00%)      0/6 (0.00%)      0/7 (0.00%)      0/14 (0.00%)      1/21 (4.76%)      4/7 (57.14%)      1/10 (10.00%)      5/31 (16.13%)      2/20 (10.00%)      26/120 (21.67%)      11/60 (18.33%)    
Cardiac disorders                         
Atrial fibrillation  1  1/10 (10.00%)  1 0/10 (0.00%)  0 0/6 (0.00%)  0 0/7 (0.00%)  0 0/14 (0.00%)  0 0/21 (0.00%)  0 0/7 (0.00%)  0 0/10 (0.00%)  0 0/31 (0.00%)  0 0/20 (0.00%)  0 0/120 (0.00%)  0 0/60 (0.00%)  0
Gastrointestinal disorders                         
Constipation  1  0/10 (0.00%)  0 0/10 (0.00%)  0 0/6 (0.00%)  0 0/7 (0.00%)  0 0/14 (0.00%)  0 0/21 (0.00%)  0 0/7 (0.00%)  0 0/10 (0.00%)  0 0/31 (0.00%)  0 0/20 (0.00%)  0 1/120 (0.83%)  1 0/60 (0.00%)  0
Nausea  1  0/10 (0.00%)  0 1/10 (10.00%)  1 0/6 (0.00%)  0 0/7 (0.00%)  0 0/14 (0.00%)  0 0/21 (0.00%)  0 0/7 (0.00%)  0 0/10 (0.00%)  0 0/31 (0.00%)  0 0/20 (0.00%)  0 0/120 (0.00%)  0 0/60 (0.00%)  0
Vomiting  1  0/10 (0.00%)  0 1/10 (10.00%)  2 0/6 (0.00%)  0 0/7 (0.00%)  0 0/14 (0.00%)  0 0/21 (0.00%)  0 0/7 (0.00%)  0 1/10 (10.00%)  1 0/31 (0.00%)  0 0/20 (0.00%)  0 0/120 (0.00%)  0 0/60 (0.00%)  0
General disorders                         
Medical device pain  1  0/10 (0.00%)  0 0/10 (0.00%)  0 0/6 (0.00%)  0 0/7 (0.00%)  0 0/14 (0.00%)  0 0/21 (0.00%)  0 0/7 (0.00%)  0 0/10 (0.00%)  0 0/31 (0.00%)  0 0/20 (0.00%)  0 1/120 (0.83%)  1 0/60 (0.00%)  0
Pyrexia  1  0/10 (0.00%)  0 0/10 (0.00%)  0 0/6 (0.00%)  0 0/7 (0.00%)  0 0/14 (0.00%)  0 0/21 (0.00%)  0 0/7 (0.00%)  0 0/10 (0.00%)  0 0/31 (0.00%)  0 0/20 (0.00%)  0 2/120 (1.67%)  2 0/60 (0.00%)  0
Infections and infestations                         
Appendicitis  1  0/10 (0.00%)  0 0/10 (0.00%)  0 0/6 (0.00%)  0 0/7 (0.00%)  0 0/14 (0.00%)  0 0/21 (0.00%)  0 0/7 (0.00%)  0 0/10 (0.00%)  0 0/31 (0.00%)  0 0/20 (0.00%)  0 0/120 (0.00%)  0 1/60 (1.67%)  1
Bacteraemia  1  0/10 (0.00%)  0 0/10 (0.00%)  0 0/6 (0.00%)  0 0/7 (0.00%)  0 0/14 (0.00%)  0 0/21 (0.00%)  0 0/7 (0.00%)  0 0/10 (0.00%)  0 0/31 (0.00%)  0 0/20 (0.00%)  0 2/120 (1.67%)  2 0/60 (0.00%)  0
Bronchitis  1  0/10 (0.00%)  0 0/10 (0.00%)  0 0/6 (0.00%)  0 0/7 (0.00%)  0 0/14 (0.00%)  0 0/21 (0.00%)  0 0/7 (0.00%)  0 0/10 (0.00%)  0 0/31 (0.00%)  0 0/20 (0.00%)  0 1/120 (0.83%)  1 0/60 (0.00%)  0
Gastroenteritis  1  0/10 (0.00%)  0 0/10 (0.00%)  0 0/6 (0.00%)  0 0/7 (0.00%)  0 0/14 (0.00%)  0 0/21 (0.00%)  0 1/7 (14.29%)  1 0/10 (0.00%)  0 1/31 (3.23%)  1 0/20 (0.00%)  0 2/120 (1.67%)  3 2/60 (3.33%)  2
Gastrointestinal infection  1  0/10 (0.00%)  0 0/10 (0.00%)  0 0/6 (0.00%)  0 0/7 (0.00%)  0 0/14 (0.00%)  0 0/21 (0.00%)  0 0/7 (0.00%)  0 0/10 (0.00%)  0 0/31 (0.00%)  0 0/20 (0.00%)  0 0/120 (0.00%)  0 1/60 (1.67%)  1
Influenza  1  0/10 (0.00%)  0 0/10 (0.00%)  0 0/6 (0.00%)  0 0/7 (0.00%)  0 0/14 (0.00%)  0 0/21 (0.00%)  0 0/7 (0.00%)  0 0/10 (0.00%)  0 0/31 (0.00%)  0 0/20 (0.00%)  0 2/120 (1.67%)  2 0/60 (0.00%)  0
Laryngitis  1  0/10 (0.00%)  0 0/10 (0.00%)  0 0/6 (0.00%)  0 0/7 (0.00%)  0 0/14 (0.00%)  0 0/21 (0.00%)  0 0/7 (0.00%)  0 0/10 (0.00%)  0 0/31 (0.00%)  0 0/20 (0.00%)  0 1/120 (0.83%)  1 0/60 (0.00%)  0
Lower respiratory tract infection viral  1  0/10 (0.00%)  0 0/10 (0.00%)  0 0/6 (0.00%)  0 0/7 (0.00%)  0 0/14 (0.00%)  0 0/21 (0.00%)  0 0/7 (0.00%)  0 0/10 (0.00%)  0 0/31 (0.00%)  0 0/20 (0.00%)  0 1/120 (0.83%)  1 0/60 (0.00%)  0
Lung infection  1  0/10 (0.00%)  0 0/10 (0.00%)  0 0/6 (0.00%)  0 0/7 (0.00%)  0 0/14 (0.00%)  0 0/21 (0.00%)  0 0/7 (0.00%)  0 0/10 (0.00%)  0 0/31 (0.00%)  0 0/20 (0.00%)  0 1/120 (0.83%)  1 1/60 (1.67%)  1
Lymph gland infection  1  0/10 (0.00%)  0 0/10 (0.00%)  0 0/6 (0.00%)  0 0/7 (0.00%)  0 0/14 (0.00%)  0 0/21 (0.00%)  0 0/7 (0.00%)  0 0/10 (0.00%)  0 0/31 (0.00%)  0 0/20 (0.00%)  0 0/120 (0.00%)  0 1/60 (1.67%)  1
Pneumonia  1  1/10 (10.00%)  1 1/10 (10.00%)  1 0/6 (0.00%)  0 0/7 (0.00%)  0 0/14 (0.00%)  0 0/21 (0.00%)  0 0/7 (0.00%)  0 0/10 (0.00%)  0 0/31 (0.00%)  0 1/20 (5.00%)  1 9/120 (7.50%)  12 1/60 (1.67%)  1
Pneumonia bacterial  1  0/10 (0.00%)  0 0/10 (0.00%)  0 0/6 (0.00%)  0 0/7 (0.00%)  0 0/14 (0.00%)  0 0/21 (0.00%)  0 0/7 (0.00%)  0 0/10 (0.00%)  0 0/31 (0.00%)  0 0/20 (0.00%)  0 1/120 (0.83%)  1 0/60 (0.00%)  0
Pneumonia mycoplasmal  1  0/10 (0.00%)  0 0/10 (0.00%)  0 0/6 (0.00%)  0 0/7 (0.00%)  0 0/14 (0.00%)  0 0/21 (0.00%)  0 0/7 (0.00%)  0 0/10 (0.00%)  0 0/31 (0.00%)  0 0/20 (0.00%)  0 1/120 (0.83%)  1 0/60 (0.00%)  0
Respiratory tract infection  1  0/10 (0.00%)  0 0/10 (0.00%)  0 0/6 (0.00%)  0 0/7 (0.00%)  0 0/14 (0.00%)  0 0/21 (0.00%)  0 0/7 (0.00%)  0 0/10 (0.00%)  0 0/31 (0.00%)  0 1/20 (5.00%)  1 1/120 (0.83%)  1 0/60 (0.00%)  0
Respiratory tract infection viral  1  0/10 (0.00%)  0 0/10 (0.00%)  0 0/6 (0.00%)  0 0/7 (0.00%)  0 0/14 (0.00%)  0 0/21 (0.00%)  0 0/7 (0.00%)  0 0/10 (0.00%)  0 0/31 (0.00%)  0 0/20 (0.00%)  0 0/120 (0.00%)  0 1/60 (1.67%)  1
Upper respiratory tract infection  1  0/10 (0.00%)  0 0/10 (0.00%)  0 0/6 (0.00%)  0 0/7 (0.00%)  0 0/14 (0.00%)  0 1/21 (4.76%)  1 1/7 (14.29%)  1 0/10 (0.00%)  0 1/31 (3.23%)  1 0/20 (0.00%)  0 1/120 (0.83%)  1 0/60 (0.00%)  0
Viral upper respiratory tract infection  1  0/10 (0.00%)  0 0/10 (0.00%)  0 0/6 (0.00%)  0 0/7 (0.00%)  0 0/14 (0.00%)  0 0/21 (0.00%)  0 0/7 (0.00%)  0 0/10 (0.00%)  0 0/31 (0.00%)  0 0/20 (0.00%)  0 1/120 (0.83%)  1 0/60 (0.00%)  0
Injury, poisoning and procedural complications                         
Fall  1  0/10 (0.00%)  0 0/10 (0.00%)  0 0/6 (0.00%)  0 0/7 (0.00%)  0 0/14 (0.00%)  0 0/21 (0.00%)  0 0/7 (0.00%)  0 0/10 (0.00%)  0 0/31 (0.00%)  0 0/20 (0.00%)  0 1/120 (0.83%)  1 0/60 (0.00%)  0
Femur fracture  1  0/10 (0.00%)  0 0/10 (0.00%)  0 0/6 (0.00%)  0 0/7 (0.00%)  0 0/14 (0.00%)  0 0/21 (0.00%)  0 0/7 (0.00%)  0 0/10 (0.00%)  0 1/31 (3.23%)  1 0/20 (0.00%)  0 1/120 (0.83%)  1 1/60 (1.67%)  1
Investigations                         
Oxygen saturation decreased  1  0/10 (0.00%)  0 0/10 (0.00%)  0 0/6 (0.00%)  0 0/7 (0.00%)  0 0/14 (0.00%)  0 0/21 (0.00%)  0 0/7 (0.00%)  0 0/10 (0.00%)  0 0/31 (0.00%)  0 0/20 (0.00%)  0 0/120 (0.00%)  0 1/60 (1.67%)  1
Metabolism and nutrition disorders                         
Dehydration  1  0/10 (0.00%)  0 0/10 (0.00%)  0 0/6 (0.00%)  0 0/7 (0.00%)  0 0/14 (0.00%)  0 0/21 (0.00%)  0 1/7 (14.29%)  1 0/10 (0.00%)  0 1/31 (3.23%)  1 0/20 (0.00%)  0 0/120 (0.00%)  0 1/60 (1.67%)  1
Decreased appetite  1  0/10 (0.00%)  0 0/10 (0.00%)  0 0/6 (0.00%)  0 0/7 (0.00%)  0 0/14 (0.00%)  0 0/21 (0.00%)  0 1/7 (14.29%)  1 0/10 (0.00%)  0 1/31 (3.23%)  1 0/20 (0.00%)  0 0/120 (0.00%)  0 0/60 (0.00%)  0
Musculoskeletal and connective tissue disorders                         
Back pain  1  0/10 (0.00%)  0 0/10 (0.00%)  0 0/6 (0.00%)  0 0/7 (0.00%)  0 0/14 (0.00%)  0 0/21 (0.00%)  0 0/7 (0.00%)  0 0/10 (0.00%)  0 0/31 (0.00%)  0 0/20 (0.00%)  0 1/120 (0.83%)  1 0/60 (0.00%)  0
Nervous system disorders                         
Febrile convulsion  1  0/10 (0.00%)  0 0/10 (0.00%)  0 0/6 (0.00%)  0 0/7 (0.00%)  0 0/14 (0.00%)  0 0/21 (0.00%)  0 0/7 (0.00%)  0 0/10 (0.00%)  0 0/31 (0.00%)  0 0/20 (0.00%)  0 1/120 (0.83%)  1 0/60 (0.00%)  0
Partial seizures  1  0/10 (0.00%)  0 0/10 (0.00%)  0 0/6 (0.00%)  0 0/7 (0.00%)  0 0/14 (0.00%)  0 0/21 (0.00%)  0 0/7 (0.00%)  0 0/10 (0.00%)  0 0/31 (0.00%)  0 0/20 (0.00%)  0 1/120 (0.83%)  1 0/60 (0.00%)  0
Renal and urinary disorders                         
Hydronephrosis  1  0/10 (0.00%)  0 0/10 (0.00%)  0 0/6 (0.00%)  0 0/7 (0.00%)  0 0/14 (0.00%)  0 0/21 (0.00%)  0 0/7 (0.00%)  0 0/10 (0.00%)  0 0/31 (0.00%)  0 0/20 (0.00%)  0 1/120 (0.83%)  1 0/60 (0.00%)  0
Nephrolithiasis  1  0/10 (0.00%)  0 0/10 (0.00%)  0 0/6 (0.00%)  0 0/7 (0.00%)  0 0/14 (0.00%)  0 0/21 (0.00%)  0 0/7 (0.00%)  0 0/10 (0.00%)  0 0/31 (0.00%)  0 0/20 (0.00%)  0 1/120 (0.83%)  1 1/60 (1.67%)  1
Respiratory, thoracic and mediastinal disorders                         
Aspiration  1  0/10 (0.00%)  0 0/10 (0.00%)  0 0/6 (0.00%)  0 0/7 (0.00%)  0 0/14 (0.00%)  0 0/21 (0.00%)  0 0/7 (0.00%)  0 0/10 (0.00%)  0 0/31 (0.00%)  0 0/20 (0.00%)  0 1/120 (0.83%)  1 0/60 (0.00%)  0
Asthma  1  0/10 (0.00%)  0 0/10 (0.00%)  0 0/6 (0.00%)  0 0/7 (0.00%)  0 0/14 (0.00%)  0 0/21 (0.00%)  0 0/7 (0.00%)  0 0/10 (0.00%)  0 0/31 (0.00%)  0 0/20 (0.00%)  0 1/120 (0.83%)  1 0/60 (0.00%)  0
Atelectasis  1  0/10 (0.00%)  0 0/10 (0.00%)  0 0/6 (0.00%)  0 0/7 (0.00%)  0 0/14 (0.00%)  0 0/21 (0.00%)  0 0/7 (0.00%)  0 0/10 (0.00%)  0 0/31 (0.00%)  0 0/20 (0.00%)  0 1/120 (0.83%)  1 0/60 (0.00%)  0
Pneumonia aspiration  1  0/10 (0.00%)  0 0/10 (0.00%)  0 0/6 (0.00%)  0 0/7 (0.00%)  0 0/14 (0.00%)  0 0/21 (0.00%)  0 0/7 (0.00%)  0 0/10 (0.00%)  0 0/31 (0.00%)  0 0/20 (0.00%)  0 1/120 (0.83%)  1 0/60 (0.00%)  0
Respiratory failure  1  0/10 (0.00%)  0 0/10 (0.00%)  0 0/6 (0.00%)  0 0/7 (0.00%)  0 0/14 (0.00%)  0 0/21 (0.00%)  0 0/7 (0.00%)  0 0/10 (0.00%)  0 0/31 (0.00%)  0 0/20 (0.00%)  0 0/120 (0.00%)  0 1/60 (1.67%)  1
Sleep apnoea syndrome  1  0/10 (0.00%)  0 0/10 (0.00%)  0 0/6 (0.00%)  0 0/7 (0.00%)  0 0/14 (0.00%)  0 0/21 (0.00%)  0 0/7 (0.00%)  0 0/10 (0.00%)  0 0/31 (0.00%)  0 0/20 (0.00%)  0 0/120 (0.00%)  0 1/60 (1.67%)  1
Chronic respiratory failure  1  0/10 (0.00%)  0 0/10 (0.00%)  0 0/6 (0.00%)  0 0/7 (0.00%)  0 0/14 (0.00%)  0 0/21 (0.00%)  0 1/7 (14.29%)  1 0/10 (0.00%)  0 1/31 (3.23%)  1 0/20 (0.00%)  0 0/120 (0.00%)  0 0/60 (0.00%)  0
Surgical and medical procedures                         
Lung operation  1  0/10 (0.00%)  0 0/10 (0.00%)  0 0/6 (0.00%)  0 0/7 (0.00%)  0 0/14 (0.00%)  0 0/21 (0.00%)  0 0/7 (0.00%)  0 0/10 (0.00%)  0 0/31 (0.00%)  0 0/20 (0.00%)  0 1/120 (0.83%)  1 0/60 (0.00%)  0
Renal stone removal  1  0/10 (0.00%)  0 0/10 (0.00%)  0 0/6 (0.00%)  0 0/7 (0.00%)  0 0/14 (0.00%)  0 0/21 (0.00%)  0 0/7 (0.00%)  0 0/10 (0.00%)  0 0/31 (0.00%)  0 0/20 (0.00%)  0 0/120 (0.00%)  0 1/60 (1.67%)  1
1
Term from vocabulary, MedDRA 22.0
Indicates events were collected by systematic assessment
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Part 1 Group A: Adolescents and Adults (3 mg Risdiplam) Part 1 Group A: Adolescents and Adults (5 mg Risdiplam) Part 1 Group A: Adolescents and Adults (Placebo-Control Period Pooled) Part 1 Group B: Children (0.02 mg/kg Risdiplam) Part 1 Group B: Children (0.05 mg/kg Risdiplam) Part 1 Group B: Children (0.15 mg/kg Risdiplam) Part 1 Group B: Children (0.25 mg/kg Risdiplam) Part 1 Group B: Children (Placebo-Control Period Pooled) Part 1 Group A: OLE Part 1 Group B: OLE Part 2: Risdiplam Part 2: Placebo
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   7/10 (70.00%)      9/10 (90.00%)      4/6 (66.67%)      4/7 (57.14%)      10/14 (71.43%)      12/21 (57.14%)      7/7 (100.00%)      9/10 (90.00%)      23/31 (74.19%)      9/20 (45.00%)      102/120 (85.00%)      50/60 (83.33%)    
Blood and lymphatic system disorders                         
Iron deficiency anaemia  1  0/10 (0.00%)  0 0/10 (0.00%)  0 0/6 (0.00%)  0 0/7 (0.00%)  0 0/14 (0.00%)  0 0/21 (0.00%)  0 0/7 (0.00%)  0 0/10 (0.00%)  0 0/31 (0.00%)  0 1/20 (5.00%)  1 1/120 (0.83%)  1 0/60 (0.00%)  0
Neutropenia  1  1/10 (10.00%)  1 0/10 (0.00%)  0 0/6 (0.00%)  0 0/7 (0.00%)  0 0/14 (0.00%)  0 0/21 (0.00%)  0 0/7 (0.00%)  0 0/10 (0.00%)  0 0/31 (0.00%)  0 0/20 (0.00%)  0 1/120 (0.83%)  1 1/60 (1.67%)  1
Cardiac disorders                         
Tachycardia  1  2/10 (20.00%)  2 0/10 (0.00%)  0 1/6 (16.67%)  1 0/7 (0.00%)  0 0/14 (0.00%)  0 0/21 (0.00%)  0 0/7 (0.00%)  0 0/10 (0.00%)  0 1/31 (3.23%)  2 0/20 (0.00%)  0 0/120 (0.00%)  0 0/60 (0.00%)  0
Ear and labyrinth disorders                         
Ear pain  1  1/10 (10.00%)  1 0/10 (0.00%)  0 0/6 (0.00%)  0 0/7 (0.00%)  0 0/14 (0.00%)  0 0/21 (0.00%)  0 2/7 (28.57%)  2 0/10 (0.00%)  0 3/31 (9.68%)  3 1/20 (5.00%)  1 4/120 (3.33%)  5 2/60 (3.33%)  2
Motion sickness  1  0/10 (0.00%)  0 0/10 (0.00%)  0 0/6 (0.00%)  0 0/7 (0.00%)  0 0/14 (0.00%)  0 0/21 (0.00%)  0 0/7 (0.00%)  0 1/10 (10.00%)  2 0/31 (0.00%)  0 0/20 (0.00%)  0 2/120 (1.67%)  2 1/60 (1.67%)  1
Vertigo  1  0/10 (0.00%)  0 1/10 (10.00%)  1 0/6 (0.00%)  0 0/7 (0.00%)  0 0/14 (0.00%)  0 0/21 (0.00%)  0 0/7 (0.00%)  0 0/10 (0.00%)  0 0/31 (0.00%)  0 1/20 (5.00%)  1 0/120 (0.00%)  0 0/60 (0.00%)  0
Eye disorders                         
Conjunctival hyperaemia  1  0/10 (0.00%)  0 0/10 (0.00%)  0 0/6 (0.00%)  0 0/7 (0.00%)  0 0/14 (0.00%)  0 0/21 (0.00%)  0 0/7 (0.00%)  0 1/10 (10.00%)  1 0/31 (0.00%)  0 0/20 (0.00%)  0 0/120 (0.00%)  0 0/60 (0.00%)  0
Blepharitis  1  0/10 (0.00%)  0 0/10 (0.00%)  0 0/6 (0.00%)  0 1/7 (14.29%)  1 0/14 (0.00%)  0 0/21 (0.00%)  0 0/7 (0.00%)  0 0/10 (0.00%)  0 0/31 (0.00%)  0 0/20 (0.00%)  0 0/120 (0.00%)  0 0/60 (0.00%)  0
Eczema eyelids  1  0/10 (0.00%)  0 0/10 (0.00%)  0 0/6 (0.00%)  0 0/7 (0.00%)  0 0/14 (0.00%)  0 0/21 (0.00%)  0 1/7 (14.29%)  1 0/10 (0.00%)  0 1/31 (3.23%)  1 0/20 (0.00%)  0 0/120 (0.00%)  0 0/60 (0.00%)  0
Vision blurred  1  0/10 (0.00%)  0 0/10 (0.00%)  0 0/6 (0.00%)  0 1/7 (14.29%)  1 0/14 (0.00%)  0 0/21 (0.00%)  0 0/7 (0.00%)  0 0/10 (0.00%)  0 0/31 (0.00%)  0 0/20 (0.00%)  0 1/120 (0.83%)  1 0/60 (0.00%)  0
Gastrointestinal disorders                         
Abdominal pain  1  2/10 (20.00%)  2 1/10 (10.00%)  1 0/6 (0.00%)  0 0/7 (0.00%)  0 0/14 (0.00%)  0 0/21 (0.00%)  0 1/7 (14.29%)  2 1/10 (10.00%)  1 2/31 (6.45%)  2 0/20 (0.00%)  0 9/120 (7.50%)  12 5/60 (8.33%)  8
Abdominal pain upper  1  0/10 (0.00%)  0 1/10 (10.00%)  2 0/6 (0.00%)  0 0/7 (0.00%)  0 0/14 (0.00%)  0 0/21 (0.00%)  0 1/7 (14.29%)  2 1/10 (10.00%)  1 2/31 (6.45%)  3 3/20 (15.00%)  4 7/120 (5.83%)  7 2/60 (3.33%)  3
Constipation  1  0/10 (0.00%)  0 0/10 (0.00%)  0 0/6 (0.00%)  0 0/7 (0.00%)  0 0/14 (0.00%)  0 0/21 (0.00%)  0 1/7 (14.29%)  2 1/10 (10.00%)  1 2/31 (6.45%)  3 0/20 (0.00%)  0 9/120 (7.50%)  11 5/60 (8.33%)  7
Diarrhoea  1  0/10 (0.00%)  0 1/10 (10.00%)  1 0/6 (0.00%)  0 0/7 (0.00%)  0 0/14 (0.00%)  0 1/21 (4.76%)  3 3/7 (42.86%)  4 0/10 (0.00%)  0 2/31 (6.45%)  3 0/20 (0.00%)  0 22/120 (18.33%)  29 8/60 (13.33%)  8
Nausea  1  0/10 (0.00%)  0 1/10 (10.00%)  3 0/6 (0.00%)  0 0/7 (0.00%)  0 1/14 (7.14%)  1 0/21 (0.00%)  0 1/7 (14.29%)  2 1/10 (10.00%)  1 2/31 (6.45%)  2 1/20 (5.00%)  2 11/120 (9.17%)  13 4/60 (6.67%)  6
Vomiting  1  1/10 (10.00%)  1 3/10 (30.00%)  4 0/6 (0.00%)  0 2/7 (28.57%)  2 1/14 (7.14%)  1 5/21 (23.81%)  5 2/7 (28.57%)  4 1/10 (10.00%)  1 7/31 (22.58%)  10 2/20 (10.00%)  3 18/120 (15.00%)  38 15/60 (25.00%)  29
Aphthous ulcer  1  1/10 (10.00%)  1 1/10 (10.00%)  1 0/6 (0.00%)  0 0/7 (0.00%)  0 0/14 (0.00%)  0 0/21 (0.00%)  0 0/7 (0.00%)  0 0/10 (0.00%)  0 0/31 (0.00%)  0 0/20 (0.00%)  0 3/120 (2.50%)  4 0/60 (0.00%)  0
Faecaloma  1  1/10 (10.00%)  1 0/10 (0.00%)  0 0/6 (0.00%)  0 0/7 (0.00%)  0 0/14 (0.00%)  0 0/21 (0.00%)  0 0/7 (0.00%)  0 0/10 (0.00%)  0 0/31 (0.00%)  0 0/20 (0.00%)  0 1/120 (0.83%)  1 0/60 (0.00%)  0
Hyperchlorhydria  1  0/10 (0.00%)  0 1/10 (10.00%)  2 0/6 (0.00%)  0 0/7 (0.00%)  0 0/14 (0.00%)  0 0/21 (0.00%)  0 0/7 (0.00%)  0 0/10 (0.00%)  0 0/31 (0.00%)  0 2/20 (10.00%)  3 0/120 (0.00%)  0 0/60 (0.00%)  0
Oral mucosal erythema  1  0/10 (0.00%)  0 0/10 (0.00%)  0 0/6 (0.00%)  0 0/7 (0.00%)  0 1/14 (7.14%)  1 0/21 (0.00%)  0 0/7 (0.00%)  0 0/10 (0.00%)  0 1/31 (3.23%)  1 0/20 (0.00%)  0 0/120 (0.00%)  0 1/60 (1.67%)  1
Tongue oedema  1  0/10 (0.00%)  0 1/10 (10.00%)  1 0/6 (0.00%)  0 0/7 (0.00%)  0 0/14 (0.00%)  0 0/21 (0.00%)  0 0/7 (0.00%)  0 0/10 (0.00%)  0 0/31 (0.00%)  0 1/20 (5.00%)  1 0/120 (0.00%)  0 0/60 (0.00%)  0
Lip pruritus  1  0/10 (0.00%)  0 0/10 (0.00%)  0 0/6 (0.00%)  0 0/7 (0.00%)  0 1/14 (7.14%)  1 0/21 (0.00%)  0 0/7 (0.00%)  0 0/10 (0.00%)  0 0/31 (0.00%)  0 0/20 (0.00%)  0 0/120 (0.00%)  0 0/60 (0.00%)  0
General disorders                         
Malaise  1  0/10 (0.00%)  0 1/10 (10.00%)  1 0/6 (0.00%)  0 0/7 (0.00%)  0 0/14 (0.00%)  0 0/21 (0.00%)  0 1/7 (14.29%)  1 0/10 (0.00%)  0 1/31 (3.23%)  1 0/20 (0.00%)  0 1/120 (0.83%)  1 3/60 (5.00%)  3
Pyrexia  1  3/10 (30.00%)  7 2/10 (20.00%)  3 0/6 (0.00%)  0 0/7 (0.00%)  0 3/14 (21.43%)  4 2/21 (9.52%)  2 7/7 (100.00%)  12 3/10 (30.00%)  5 11/31 (35.48%)  20 3/20 (15.00%)  6 27/120 (22.50%)  45 11/60 (18.33%)  21
Asthenia  1  1/10 (10.00%)  1 0/10 (0.00%)  0 0/6 (0.00%)  0 0/7 (0.00%)  0 0/14 (0.00%)  0 0/21 (0.00%)  0 0/7 (0.00%)  0 0/10 (0.00%)  0 0/31 (0.00%)  0 1/20 (5.00%)  1 0/120 (0.00%)  0 0/60 (0.00%)  0
Fatigue  1  2/10 (20.00%)  2 0/10 (0.00%)  0 0/6 (0.00%)  0 0/7 (0.00%)  0 0/14 (0.00%)  0 0/21 (0.00%)  0 1/7 (14.29%)  3 0/10 (0.00%)  0 2/31 (6.45%)  4 0/20 (0.00%)  0 2/120 (1.67%)  2 1/60 (1.67%)  1
Hyperpyrexia  1  2/10 (20.00%)  2 0/10 (0.00%)  0 0/6 (0.00%)  0 0/7 (0.00%)  0 0/14 (0.00%)  0 0/21 (0.00%)  0 0/7 (0.00%)  0 1/10 (10.00%)  2 0/31 (0.00%)  0 0/20 (0.00%)  0 1/120 (0.83%)  1 0/60 (0.00%)  0
Hyperthermia  1  0/10 (0.00%)  0 0/10 (0.00%)  0 0/6 (0.00%)  0 0/7 (0.00%)  0 0/14 (0.00%)  0 0/21 (0.00%)  0 0/7 (0.00%)  0 1/10 (10.00%)  1 0/31 (0.00%)  0 0/20 (0.00%)  0 0/120 (0.00%)  0 0/60 (0.00%)  0
Pain  1  0/10 (0.00%)  0 1/10 (10.00%)  1 0/6 (0.00%)  0 0/7 (0.00%)  0 0/14 (0.00%)  0 0/21 (0.00%)  0 0/7 (0.00%)  0 0/10 (0.00%)  0 0/31 (0.00%)  0 1/20 (5.00%)  1 0/120 (0.00%)  0 0/60 (0.00%)  0
Catheter site extravasation  1  0/10 (0.00%)  0 0/10 (0.00%)  0 0/6 (0.00%)  0 0/7 (0.00%)  0 1/14 (7.14%)  1 0/21 (0.00%)  0 0/7 (0.00%)  0 0/10 (0.00%)  0 0/31 (0.00%)  0 0/20 (0.00%)  0 0/120 (0.00%)  0 0/60 (0.00%)  0
Immune system disorders                         
Allergy to arthropod bite  1  0/10 (0.00%)  0 0/10 (0.00%)  0 0/6 (0.00%)  0 0/7 (0.00%)  0 0/14 (0.00%)  0 0/21 (0.00%)  0 1/7 (14.29%)  1 0/10 (0.00%)  0 1/31 (3.23%)  1 0/20 (0.00%)  0 0/120 (0.00%)  0 0/60 (0.00%)  0
Infections and infestations                         
Bronchitis  1  0/10 (0.00%)  0 0/10 (0.00%)  0 0/6 (0.00%)  0 0/7 (0.00%)  0 0/14 (0.00%)  0 1/21 (4.76%)  1 3/7 (42.86%)  5 1/10 (10.00%)  1 6/31 (19.35%)  9 0/20 (0.00%)  0 7/120 (5.83%)  9 10/60 (16.67%)  12
Conjunctivitis  1  0/10 (0.00%)  0 0/10 (0.00%)  0 0/6 (0.00%)  0 0/7 (0.00%)  0 0/14 (0.00%)  0 0/21 (0.00%)  0 0/7 (0.00%)  0 0/10 (0.00%)  0 2/31 (6.45%)  2 0/20 (0.00%)  0 4/120 (3.33%)  6 4/60 (6.67%)  5
Gastroenteritis  1  0/10 (0.00%)  0 0/10 (0.00%)  0 0/6 (0.00%)  0 0/7 (0.00%)  0 0/14 (0.00%)  0 0/21 (0.00%)  0 3/7 (42.86%)  4 1/10 (10.00%)  1 3/31 (9.68%)  3 1/20 (5.00%)  1 8/120 (6.67%)  11 5/60 (8.33%)  7
Influenza  1  0/10 (0.00%)  0 3/10 (30.00%)  5 1/6 (16.67%)  1 0/7 (0.00%)  0 0/14 (0.00%)  0 0/21 (0.00%)  0 1/7 (14.29%)  1 0/10 (0.00%)  0 2/31 (6.45%)  2 2/20 (10.00%)  3 3/120 (2.50%)  3 3/60 (5.00%)  4
Nasopharyngitis  1  0/10 (0.00%)  0 1/10 (10.00%)  1 0/6 (0.00%)  0 0/7 (0.00%)  0 0/14 (0.00%)  0 2/21 (9.52%)  4 3/7 (42.86%)  6 1/10 (10.00%)  1 7/31 (22.58%)  10 2/20 (10.00%)  2 32/120 (26.67%)  57 16/60 (26.67%)  22
Pharyngitis  1  2/10 (20.00%)  2 1/10 (10.00%)  1 0/6 (0.00%)  0 1/7 (14.29%)  1