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Investigate Safety, Tolerability, PK, PD and Efficacy of Risdiplam (RO7034067) in Infants With Type1 Spinal Muscular Atrophy (FIREFISH)

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ClinicalTrials.gov Identifier: NCT02913482
Recruitment Status : Active, not recruiting
First Posted : September 23, 2016
Results First Posted : January 8, 2021
Last Update Posted : March 16, 2021
Sponsor:
Information provided by (Responsible Party):
Hoffmann-La Roche

Study Type Interventional
Study Design Allocation: Non-Randomized;   Intervention Model: Sequential Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition Muscular Atrophy, Spinal
Intervention Drug: Risdiplam
Enrollment 62
Recruitment Details Part 1 was conducted at 7 investigational sites across 5 countries; Part 2 was conducted at 14 investigational sites across 10 countries.
Pre-assignment Details  
Arm/Group Title Exploratory Part 1 - Cohort 1 Exploratory Part 1 - Cohort 2 Confirmatory Part 2 - Risdiplam
Hide Arm/Group Description Participants received risdiplam in a staggered, dose-escalation manner once daily at Dose Level 1 for a minimum of 4 weeks to select the dose for Part 2. Dose Level 1 was targeting an exposure of mean AUC0-24h,ss 700 ng*h/mL. Participants received risdiplam in a staggered, dose-escalation manner once daily at Dose Level 2 for a minimum of 4 weeks to select the dose for Part 2. Dose Level 2 was targeting an exposure of mean AUC0-24h,ss </= 2000 ng*h/mL. Cohort 2 included one infant who started at Dose Level 1 and was escalated to Dose Level 2 on Day 83. Participants received risdiplam orally once daily at a dose of target exposure cap of a mean AUC0-24h,ss of 2000 ng*h/mL, for a duration of 24 months with a primary analysis after 12 months. Starting doses were either 0.04mg/kg, 0.08mg/kg or 0.2mg/kg depending on the participant's age. All participants had their dose adjusted to 0.2mg/kg within a few months of starting treatment. The dose was adjusted to 0.25mg/kg when participant reached 2 years of age.
Period Title: Overall Study
Started 4 17 41
Completed 3 [1] 15 [1] 38 [2]
Not Completed 1 2 3
Reason Not Completed
Death             1             1             2
Progressive Disease             0             1             1
[1]
Participants remaining in the study at CCOD of 27 Feb 2019
[2]
Participants remaining in the study at CCOD of 14 Nov 2019
Arm/Group Title Exploratory Part 1 - Cohort 1 Exploratory Part 1 - Cohort 2 Confirmatory Part 2 - Risdiplam Total
Hide Arm/Group Description Participants received risdiplam in a staggered, dose-escalation manner once daily at Dose Level 1 for a minimum of 4 weeks to select the dose for Part 2. Dose Level 1 was targeting an exposure of mean AUC0-24h,ss 700 ng*h/mL. Participants received risdiplam in a staggered, dose-escalation manner once daily at Dose Level 2 for a minimum of 4 weeks to select the dose for Part 2. Dose Level 2 was targeting an exposure of mean AUC0-24h,ss </= 2000 ng*h/mL. Cohort 2 included one infant who started at Dose Level 1 and was escalated to Dose Level 2 on Day 83. Participants received risdiplam orally once daily at a dose of target exposure cap of a mean AUC0-24h,ss of 2000 ng*h/mL, for a duration of 24 months with a primary analysis after 12 months. Starting doses were either 0.04mg/kg, 0.08mg/kg or 0.2mg/kg depending on the participant's age. All participants had their dose adjusted to 0.2mg/kg within a few months of starting treatment. The dose was adjusted to 0.25mg/kg when participant reached 2 years of age. Total of all reporting groups
Overall Number of Baseline Participants 4 17 41 62
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Months
Number Analyzed 4 participants 17 participants 41 participants 62 participants
6.84  (0.10) 5.56  (1.43) 5.20  (1.47) 5.41  (1.46)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 4 participants 17 participants 41 participants 62 participants
Female
4
 100.0%
11
  64.7%
22
  53.7%
37
  59.7%
Male
0
   0.0%
6
  35.3%
19
  46.3%
25
  40.3%
Race/Ethnicity, Customized  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 4 participants 17 participants 41 participants 62 participants
Not Hispanic or Latino
4
 100.0%
17
 100.0%
36
  87.8%
57
  91.9%
Hispanic or Latino
0
   0.0%
0
   0.0%
5
  12.2%
5
   8.1%
Race/Ethnicity, Customized  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 4 participants 17 participants 41 participants 62 participants
Asian
0
   0.0%
4
  23.5%
14
  34.1%
18
  29.0%
White
4
 100.0%
9
  52.9%
22
  53.7%
35
  56.5%
Unknown
0
   0.0%
4
  23.5%
5
  12.2%
9
  14.5%
1.Primary Outcome
Title Part 1: Selected Part 2 Dose of Risdiplam
Hide Description All safety, tolerability, PK and PD data available up to the clinical cut-off date of 5 January 2018, plus data that became available prior to the database snapshot on 6 February 2018 were included in the Internal Monitoring Committee (IMC) review. The IMC was responsible for selecting the dose for Part 2 of the study (pivotal dose). An external Independent Data Monitoring Committee (iDMC) reviewed data from Part 1 and confirmed the dose-selection decision of the IMC. The dose for Part 2 selected by the IMC was a dose that: 1.Was judged to be safe and well-tolerated, based on all available safety data from Part 1 and as confirmed by the iDMC; 2. Resulted in an exposure at steady-state below the exposure cap (mean value) of AUC0-24h,ss 2000 ng*h/mL (adjusted for free-fraction, if required); 3. Resulted in an SMN protein increase that was expected to be clinically relevant.
Time Frame Minimum of 2 weeks at steady state exposure
Hide Outcome Measure Data
Hide Analysis Population Description
All participants in Part 1 who received at least one dose of risdiplam and had available data at the time of the data snapshot for selecting the Part 2 dose.
Arm/Group Title Exploratory Part 1 - Risdiplam
Hide Arm/Group Description:
Infants aged between 28 days (1 month) of life and 210 days (7 months) received risdiplam orally or by bolus via naso-gastric or gastrostomy tube.
Overall Number of Participants Analyzed 18
Measure Type: Number
Unit of Measure: mg/kg
0.2
2.Primary Outcome
Title Part 2: Percentage of Infants Who Are Sitting Without Support for at Least 5 Seconds as Assessed by Item 22 of the Gross Motor Scale of the Bayley Scales of Infant and Toddler Development Third Edition (BSID-III) at Month 12
Hide Description The BSID-III is a standardized assessment commonly used to evaluate development across five domains in infants and young children aged between 1 and 42 months. The gross motor subscale of the BSID-III is evaluated based on the linear and hierarchical obtainment of motor skills, as seen in typically developing children. The gross motor scale consists of 72 items scored at 0 (unable to perform the activity) or 1 (criteria for item achieved). Item 22 is not considered achieved if the infant sits alone for less than 5 seconds before losing balance and falling over, or if the infant uses his or her arms to prop him- or herself up. The assessment was video recorded at study sites and reviewed/scored by two independent raters. 90% CI for one sample binomial was computed using Clopper-Pearson (exact) method.
Time Frame At Month 12 (Up to the Clinical Cut-off Date (CCOD) of 14 November 2019)
Hide Outcome Measure Data
Hide Analysis Population Description
The intent-to-treat (ITT) population is defined as all infants enrolled in Part 2 of the study, regardless of whether they received treatment or not.
Arm/Group Title Confirmatory Part 2 - Risdiplam
Hide Arm/Group Description:
Participants received risdiplam orally once daily at a dose of target exposure cap of a mean AUC0-24h,ss of 2000 ng*h/mL, for a duration of 24 months with a primary analysis after 12 months. Starting doses were either 0.04mg/kg, 0.08mg/kg or 0.2mg/kg depending on the participant's age. All participants had their dose adjusted to 0.2mg/kg within a few months of starting treatment. The dose was adjusted to 0.25mg/kg when participant reached 2 years of age.
Overall Number of Participants Analyzed 41
Measure Type: Number
Number (90% Confidence Interval)
Unit of Measure: Percentage of Participants
29.3
(17.84 to 43.07)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Confirmatory Part 2 - Risdiplam
Comments [Not Specified]
Type of Statistical Test Superiority
Comments Result compared to a performance criterion of 5% derived from natural history data.
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method One-sided Exact Binomial Test
Comments [Not Specified]
3.Secondary Outcome
Title Part 2: Percentage of Infants Who Achieve a Score of 40 or Higher in the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND) at Month 12
Hide Description The CHOP-INTEND instrument was developed to evaluate motor function in infants with SMA from the ages of 1.4 to 37.9 months. It consists of 16 items, where each item assesses a specific motor task graded on a scale of 0 to 4, where zero is no response and 4 is a complete response. The total score ranges from 0 to 64, with higher scores consistent with better motor function. 90% CI for one sample binomial was computed using Clopper-Pearson (exact) method.
Time Frame At Month 12 (Up to the Clinical Cut-off Date (CCOD) of 14 November 2019)
Hide Outcome Measure Data
Hide Analysis Population Description
The intent-to-treat (ITT) population is defined as all infants enrolled in Part 2 of the study, regardless of whether they received treatment or not.
Arm/Group Title Confirmatory Part 2 - Risdiplam
Hide Arm/Group Description:
Participants received risdiplam orally once daily at a dose of target exposure cap of a mean AUC0-24h,ss of 2000 ng*h/mL, for a duration of 24 months with a primary analysis after 12 months. Starting doses were either 0.04mg/kg, 0.08mg/kg or 0.2mg/kg depending on the participant's age. All participants had their dose adjusted to 0.2mg/kg within a few months of starting treatment. The dose was adjusted to 0.25mg/kg when participant reached 2 years of age.
Overall Number of Participants Analyzed 41
Measure Type: Number
Number (90% Confidence Interval)
Unit of Measure: Percentage of Participants
56.1
(42.13 to 69.38)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Confirmatory Part 2 - Risdiplam
Comments [Not Specified]
Type of Statistical Test Superiority
Comments Result compared to a performance criterion of 17% derived from natural history data.
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method One-sided Exact Binomial Test
Comments [Not Specified]
4.Secondary Outcome
Title Part 2: Percentage of Infants Achieving an Increase of >/= 4 Points in Their CHOP-INTEND Score From Baseline at Month 8 and 12
Hide Description The CHOP-INTEND instrument was developed to evaluate motor function in infants with SMA from the ages of 1.4 to 37.9 months. It consists of 16 items, where each item assesses a specific motor task graded on a scale of 0 to 4, where zero is no response and 4 is a complete response. The total score ranges from 0 to 64, with higher scores consistent with better motor function. 90% CI for one sample binomial was computed using Clopper-Pearson (exact) method.
Time Frame At Month 8 and Month 12 (Up to the CCOD of 14 November 2019)
Hide Outcome Measure Data
Hide Analysis Population Description
The intent-to-treat (ITT) population is defined as all infants enrolled in Part 2 of the study, regardless of whether they received treatment or not.
Arm/Group Title Confirmatory Part 2 - Risdiplam
Hide Arm/Group Description:
Participants received risdiplam orally once daily at a dose of target exposure cap of a mean AUC0-24h,ss of 2000 ng*h/mL, for a duration of 24 months with a primary analysis after 12 months. Starting doses were either 0.04mg/kg, 0.08mg/kg or 0.2mg/kg depending on the participant's age. All participants had their dose adjusted to 0.2mg/kg within a few months of starting treatment. The dose was adjusted to 0.25mg/kg when participant reached 2 years of age.
Overall Number of Participants Analyzed 41
Measure Type: Number
Number (90% Confidence Interval)
Unit of Measure: Percentage of Participants
Month 8
87.8
(76.05 to 95.07)
Month 12
90.2
(79.05 to 96.60)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Confirmatory Part 2 - Risdiplam
Comments [Not Specified]
Type of Statistical Test Superiority
Comments Result compared to a performance criterion of 17% derived from natural history data. Statistical analysis was only performed for Month 12 data.
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method One-sided Exact Binomial Test
Comments [Not Specified]
5.Secondary Outcome
Title Part 2: Percentage of Infants Achieving Head Control (Defined as a Score of >/= 3 for CHOP-INTEND Item 12) at Month 8 and 12
Hide Description The CHOP-INTEND instrument was developed to evaluate motor function in infants with SMA from the ages of 1.4 to 37.9 months. It consists of 16 items, where each item assesses a specific motor task graded on a scale of 0 to 4, where zero is no response and 4 is a complete response. The total score ranges from 0 to 64, with higher scores consistent with better motor function. 90% CI for one sample binomial was computed using Clopper-Pearson (exact) method.
Time Frame At Month 8 and Month 12 (Up to the CCOD of 14 November 2019)
Hide Outcome Measure Data
Hide Analysis Population Description
The intent-to-treat (ITT) population is defined as all infants enrolled in Part 2 of the study, regardless of whether they received treatment or not.
Arm/Group Title Confirmatory Part 2 - Risdiplam
Hide Arm/Group Description:
Participants received risdiplam orally once daily at a dose of target exposure cap of a mean AUC0-24h,ss of 2000 ng*h/mL, for a duration of 24 months with a primary analysis after 12 months. Starting doses were either 0.04mg/kg, 0.08mg/kg or 0.2mg/kg depending on the participant's age. All participants had their dose adjusted to 0.2mg/kg within a few months of starting treatment. The dose was adjusted to 0.25mg/kg when participant reached 2 years of age.
Overall Number of Participants Analyzed 41
Measure Type: Number
Number (90% Confidence Interval)
Unit of Measure: Percentage of Participants
Month 8
46.3
(32.87 to 60.23)
Month 12
53.7
(39.77 to 67.13)
6.Secondary Outcome
Title Part 2: Change From Baseline in the Total Raw Score of the BSID-III Gross Motor Scale at Month 12
Hide Description The BSID-III is a standardized assessment commonly used to evaluate development across five domains in infants and young children aged between 1 and 42 months. The gross motor subscale of the BSID-III is evaluated based on the linear and hierarchical obtainment of motor skills, as seen in typically developing children. The gross motor scale consists of 72 items scored at 0 (unable to perform the activity) or 1 (criteria for item achieved). In this study the gross motor scale was assessed in a modified way compared with the standard administration. A total raw score was calculated by summing the item scores to give a maximum possible score of 72.
Time Frame At Month 12 (Up to the CCOD of 14 November 2019)
Hide Outcome Measure Data
Hide Analysis Population Description
The intent-to-treat (ITT) population is defined as all infants enrolled in Part 2 of the study, regardless of whether they received treatment or not. Only participants for whom data were collected are included in the analysis.
Arm/Group Title Confirmatory Part 2 - Risdiplam
Hide Arm/Group Description:
Participants received risdiplam orally once daily at a dose of target exposure cap of a mean AUC0-24h,ss of 2000 ng*h/mL, for a duration of 24 months with a primary analysis after 12 months. Starting doses were either 0.04mg/kg, 0.08mg/kg or 0.2mg/kg depending on the participant's age. All participants had their dose adjusted to 0.2mg/kg within a few months of starting treatment. The dose was adjusted to 0.25mg/kg when participant reached 2 years of age.
Overall Number of Participants Analyzed 38
Mean (Standard Deviation)
Unit of Measure: Scores on a Scale
7.21  (5.71)
7.Secondary Outcome
Title Part 2: Percentage of Infants Who Achieve the Attainment Levels of a Subset of Motor Milestones Assessed in the Hammersmith Infant Neurological Examination Module 2 (HINE-2) at Month 8
Hide Description The HINE was designed to evaluate infants between 2 months and 24 months of age. It is a simple and standardized instrument that includes 26 items assessing different aspects of neurological examinations, such as cranial nerves, posture, movements, tone, and reflexes. In this study, Module 2 of the HINE (HINE-2) was assessed. The HINE-2 evaluates 8 developmental milestones (head control, sitting, voluntary grasp, ability to kick, rolling, crawling, standing, and walking) scored on a 3, 4, or 5-point scale, with 0 indicating inability to perform a task and a score of 2, 3, or 4 (depending on the task) indicating full milestone development. The total score is calculated by summing the item scores to give a maximum possible score of 26. This measure represents subset numbers at Month 8 for head control, ability to kick and rolling milestones only.
Time Frame At Month 8 (Up to the CCOD of 14 November 2019)
Hide Outcome Measure Data
Hide Analysis Population Description
The intent-to-treat (ITT) population is defined as all infants enrolled in Part 2 of the study, regardless of whether they received treatment or not.
Arm/Group Title Confirmatory Part 2 - Risdiplam
Hide Arm/Group Description:
Participants received risdiplam orally once daily at a dose of target exposure cap of a mean AUC0-24h,ss of 2000 ng*h/mL, for a duration of 24 months with a primary analysis after 12 months. Starting doses were either 0.04mg/kg, 0.08mg/kg or 0.2mg/kg depending on the participant's age. All participants had their dose adjusted to 0.2mg/kg within a few months of starting treatment. The dose was adjusted to 0.25mg/kg when participant reached 2 years of age.
Overall Number of Participants Analyzed 41
Measure Type: Number
Unit of Measure: Percentage of Participants
Unable to maintain head upright (Head Control) 36.6
Wobbles (Head Control) 14.6
All the time maintained upright (Head Control) 39.0
No kicking (Ability to Kick (supine)) 24.4
Kicks horizontally; legs do not lift (Ability to Kick (supine)) 58.5
Upward (vertically) (Ability to Kick (supine)) 7.3
Touches leg (Ability to Kick (supine)) 0
Touches toes (Ability to Kick (supine)) 0
No rolling (Rolling) 56.1
Rolling to side (Rolling) 29.3
Prone to supine (Rolling) 2.4
Supine to prone (Rolling) 2.4
8.Secondary Outcome
Title Part 2: Percentage of Infants Who Achieve the Attainment Levels of the Motor Milestones Assessed in the Hammersmith Infant Neurological Examination Module 2 (HINE-2) at Month 12
Hide Description The HINE was designed to evaluate infants between 2 months and 24 months of age. It is a simple and standardized instrument that includes 26 items assessing different aspects of neurological examinations, such as cranial nerves, posture, movements, tone, and reflexes. In this study, Module 2 of the HINE (HINE-2) was assessed. The HINE-2 evaluates 8 developmental milestones (head control, sitting, voluntary grasp, ability to kick, rolling, crawling, standing, and walking) scored on a 3, 4, or 5-point scale, with 0 indicating inability to perform a task and a score of 2, 3, or 4 (depending on the task) indicating full milestone development. The total score is calculated by summing the item scores to give a maximum possible score of 26.
Time Frame At Month 12 (Up to the CCOD of 14 November 2019)
Hide Outcome Measure Data
Hide Analysis Population Description
The intent-to-treat (ITT) population is defined as all infants enrolled in Part 2 of the study, regardless of whether they received treatment or not.
Arm/Group Title Confirmatory Part 2 - Risdiplam
Hide Arm/Group Description:
Participants received risdiplam orally once daily at a dose of target exposure cap of a mean AUC0-24h,ss of 2000 ng*h/mL, for a duration of 24 months with a primary analysis after 12 months. Starting doses were either 0.04mg/kg, 0.08mg/kg or 0.2mg/kg depending on the participant's age. All participants had their dose adjusted to 0.2mg/kg within a few months of starting treatment. The dose was adjusted to 0.25mg/kg when participant reached 2 years of age.
Overall Number of Participants Analyzed 41
Measure Type: Number
Unit of Measure: Percentage of Participants
Unable to maintain head upright (Head Control) 17.1
Wobbles (Head Control) 31.7
All the time maintained upright (Head Control) 43.9
Cannot sit (Sitting) 31.7
Sits with support at hips (Sitting) 17.1
Props (Sitting) 19.5
Stable sit (Sitting) 14.6
Pivots (rotates) (Sitting) 9.8
No grasp (Voluntary Grasp) 2.4
Uses whole hand (Voluntary Grasp) 29.3
Index finger and thumb but immature grasp (Voluntary Grasp) 48.8
Pincer grasp (Voluntary Grasp) 12.2
No kicking (Ability to Kick (supine)) 12.2
Kicks horizontally; legs do not lift (Ability to Kick (supine)) 58.5
Upward (vertically) (Ability to Kick (supine)) 7.3
Touches leg (Ability to Kick (supine)) 4.9
Touches toes (Ability to Kick (supine)) 9.8
No rolling (Rolling) 36.6
Rolling to side (Rolling) 31.7
Prone to supine (Rolling) 14.6
Supine to prone (Rolling) 9.8
Does not lift head (Crawling) 85.4
On elbow (Crawling) 2.4
On outstretched hand (Crawling) 2.4
Crawling flat on abdomen (Crawling) 0
Crawling on hands and knees (Crawling) 0
Cannot test (Crawling) 2.4
Does not support weight (Standing) 61.0
Supports weight (Standing) 17.1
Stands with support (Standing) 4.9
Stands unaided (Standing) 0
Cannot test (Standing) 4.9
Not done (Standing) 4.9
Bouncing (Walking) 2.4
Cruising (walks holding on) (Walking) 0
Walking independently (Walking) 0
Cannot test (Walking) 82.9
Not Done (Walking) 7.3
9.Secondary Outcome
Title Part 2: Percentage of Motor Milestone Responders as Assessed by HINE-2 at Month 12
Hide Description The HINE-2 evaluates 8 developmental milestones scored on a 3, 4, or 5-point scale, with 0 indicating inability to perform a task and a score of 2, 3, or 4 (depending on the task) indicating full milestone development. The total score is calculated by summing the item scores to give a maximum possible score of 26. For the motor milestone responder definition, an improvement in a motor milestone is defined as at least a 2-point increase in ability to kick (or maximal score) or a 1-point increase in head control, rolling, sitting, crawling, standing, or walking. Worsening is similarly defined as a 2-point decrease in ability to kick (or lowest score) or a 1-point decrease in head control, rolling, sitting, crawling, standing, or walking. Voluntary grasp is excluded from the definition. An infant is classified as a responder if more motor milestones show improvement than show worsening. 90% CI for one sample binomial was computed using Clopper-Pearson (exact) method.
Time Frame At Month 12 (Up to the CCOD of 14 November 2019)
Hide Outcome Measure Data
Hide Analysis Population Description
The intent-to-treat (ITT) population is defined as all infants enrolled in Part 2 of the study, regardless of whether they received treatment or not.
Arm/Group Title Confirmatory Part 2 - Risdiplam
Hide Arm/Group Description:
Participants received risdiplam orally once daily at a dose of target exposure cap of a mean AUC0-24h,ss of 2000 ng*h/mL, for a duration of 24 months with a primary analysis after 12 months. Starting doses were either 0.04mg/kg, 0.08mg/kg or 0.2mg/kg depending on the participant's age. All participants had their dose adjusted to 0.2mg/kg within a few months of starting treatment. The dose was adjusted to 0.25mg/kg when participant reached 2 years of age.
Overall Number of Participants Analyzed 41
Measure Type: Number
Number (90% Confidence Interval)
Unit of Measure: Percentage of Participants
78.0
(64.82 to 88.04)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Confirmatory Part 2 - Risdiplam
Comments [Not Specified]
Type of Statistical Test Superiority
Comments Result compared to a performance criterion of 12% derived from natural history data.
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method One-sided Exact Binomial Test
Comments [Not Specified]
10.Secondary Outcome
Title Part 2: Highest Motor Milestone Achieved by Month 12 as Assessed in the BSID-III Gross Motor Scale
Hide Description The BSID-III is a standardized assessment commonly used to evaluate development across five domains in infants and young children aged between 1 and 42 months. The gross motor subscale of the BSID-III is evaluated based on the linear and hierarchical obtainment of motor skills, as seen in typically developing children. The gross motor scale consists of 72 items scored at 0 (unable to perform the activity) or 1 (criteria for item achieved). This measure included 6 milestones: Item 9 'Controls head while upright for 15 seconds', Item 14 'Rolls from side to back', Item 22 'Sits without support for 5 seconds', Item 30 'Crawls on stomach', Item 40 'Stands alone' and Item 42 'Walks alone'.
Time Frame At Month 12 (Up to the CCOD of 14 November 2019)
Hide Outcome Measure Data
Hide Analysis Population Description
The intent-to-treat (ITT) population is defined as all infants enrolled in Part 2 of the study, regardless of whether they received treatment or not.
Arm/Group Title Confirmatory Part 2 - Risdiplam
Hide Arm/Group Description:
Participants received risdiplam orally once daily at a dose of target exposure cap of a mean AUC0-24h,ss of 2000 ng*h/mL, for a duration of 24 months with a primary analysis after 12 months. Starting doses were either 0.04mg/kg, 0.08mg/kg or 0.2mg/kg depending on the participant's age. All participants had their dose adjusted to 0.2mg/kg within a few months of starting treatment. The dose was adjusted to 0.25mg/kg when participant reached 2 years of age.
Overall Number of Participants Analyzed 41
Measure Type: Number
Unit of Measure: Percentage of Participants
Item 9: Controls Head While Upright for 15 sec 0
Item 14: Rolls from Side to Back 56.1
Item 22: Sits Without Support for 5 sec 29.3
Item 30: Crawls on Stomach 0
Item 40: Stands Alone 0
Item 42: Walks Alone 0
11.Secondary Outcome
Title Part 2: Percentage of Infants Who Are Sitting Without Support for at Least 5 Seconds as Assessed by Item 22 of the BSID-III Gross Motor Scale at Month 24
Hide Description [Not Specified]
Time Frame Month 24
Outcome Measure Data Not Reported
12.Secondary Outcome
Title Part 2: Percentage of Infants Who Are Sitting Without Support for at Least 30 Seconds as Assessed by Item 26 of the BSID-III Gross Motor Scale at Month 24
Hide Description [Not Specified]
Time Frame Month 24
Outcome Measure Data Not Reported
13.Secondary Outcome
Title Part 2: Percentage of Infants Who Are Standing Alone as Assessed by Item 40 of the BSID-III Gross Motor Scale at Month 24
Hide Description [Not Specified]
Time Frame Month 24
Outcome Measure Data Not Reported
14.Secondary Outcome
Title Part 2: Percentage of Infants Who Are Walking Alone as Assessed by Item 42 of the BSID-III Gross Motor Scale at Month 24
Hide Description [Not Specified]
Time Frame Month 24
Outcome Measure Data Not Reported
15.Secondary Outcome
Title Part 2: Time to Death
Hide Description The median time to event was estimated using Kaplan-Meier methodology. 90% CI was estimated using the method of Brookmeyer and Crowley.
Time Frame Baseline up to 12 Months (Up to the CCOD of 14 November 2019)
Hide Outcome Measure Data
Hide Analysis Population Description
The intent-to-treat (ITT) population is defined as all infants enrolled in Part 2 of the study, regardless of whether they received treatment or not.
Arm/Group Title Confirmatory Part 2 - Risdiplam
Hide Arm/Group Description:
Participants received risdiplam orally once daily at a dose of target exposure cap of a mean AUC0-24h,ss of 2000 ng*h/mL, for a duration of 24 months with a primary analysis after 12 months. Starting doses were either 0.04mg/kg, 0.08mg/kg or 0.2mg/kg depending on the participant's age. All participants had their dose adjusted to 0.2mg/kg within a few months of starting treatment. The dose was adjusted to 0.25mg/kg when participant reached 2 years of age.
Overall Number of Participants Analyzed 41
Median (90% Confidence Interval)
Unit of Measure: Months
NA [1] 
(NA to NA)
[1]
The median time to death was not estimable as few participants had an event.
16.Secondary Outcome
Title Part 2: Time to Death or Permanent Ventilation
Hide Description Permanent ventilation is defined as >/=16 hours of non-invasive ventilation per day or intubation for >21 consecutive days in the absence of, or following the resolution of, an acute reversible event; or tracheostomy. Permanent ventilation events were reviewed and confirmed by an independent adjudication committee. The median time to event was estimated using Kaplan-Meier methodology. 90% CI was estimated using the method of Brookmeyer and Crowley.
Time Frame Baseline up to 12 Months (Up to the CCOD of 14 November 2019)
Hide Outcome Measure Data
Hide Analysis Population Description
The intent-to-treat (ITT) population is defined as all infants enrolled in Part 2 of the study, regardless of whether they received treatment or not.
Arm/Group Title Confirmatory Part 2 - Risdiplam
Hide Arm/Group Description:
Participants received risdiplam orally once daily at a dose of target exposure cap of a mean AUC0-24h,ss of 2000 ng*h/mL, for a duration of 24 months with a primary analysis after 12 months. Starting doses were either 0.04mg/kg, 0.08mg/kg or 0.2mg/kg depending on the participant's age. All participants had their dose adjusted to 0.2mg/kg within a few months of starting treatment. The dose was adjusted to 0.25mg/kg when participant reached 2 years of age.
Overall Number of Participants Analyzed 41
Median (90% Confidence Interval)
Unit of Measure: Months
NA [1] 
(NA to NA)
[1]
The median time to death or permanent ventilation was not estimable as few participants had an event.
17.Secondary Outcome
Title Part 2: Time to Permanent Ventilation
Hide Description Permanent ventilation is defined as >/=16 hours of non-invasive ventilation per day or intubation for >21 consecutive days in the absence of, or following the resolution of, an acute reversible event; or tracheostomy. Permanent ventilation events were reviewed and confirmed by an independent adjudication committee. The median time to event was estimated using Kaplan-Meier methodology. 90% CI was estimated using the method of Brookmeyer and Crowley.
Time Frame Baseline up to 12 Months (Up to the CCOD of 14 November 2019)
Hide Outcome Measure Data
Hide Analysis Population Description
The intent-to-treat (ITT) population is defined as all infants enrolled in Part 2 of the study, regardless of whether they received treatment or not.
Arm/Group Title Confirmatory Part 2 - Risdiplam
Hide Arm/Group Description:
Participants received risdiplam orally once daily at a dose of target exposure cap of a mean AUC0-24h,ss of 2000 ng*h/mL, for a duration of 24 months with a primary analysis after 12 months. Starting doses were either 0.04mg/kg, 0.08mg/kg or 0.2mg/kg depending on the participant's age. All participants had their dose adjusted to 0.2mg/kg within a few months of starting treatment. The dose was adjusted to 0.25mg/kg when participant reached 2 years of age.
Overall Number of Participants Analyzed 41
Median (90% Confidence Interval)
Unit of Measure: Months
NA [1] 
(NA to NA)
[1]
The median time to permanent ventilation was not estimable as few participants had an event.
18.Secondary Outcome
Title Part 2: Percentage of Infants Who Are Alive Without Permanent Ventilation at Month 12
Hide Description Permanent ventilation is defined as >/=16 hours of non-invasive ventilation per day or intubation for >21 consecutive days in the absence of, or following the resolution of, an acute reversible event; or tracheostomy. Permanent ventilation events were reviewed and confirmed by an independent adjudication committee. Kaplan-Meier methodology was used to estimate the percentages. 90% CI was computed using the complementary log-log transformation.
Time Frame At Month 12 (Up to the CCOD of 14 November 2019)
Hide Outcome Measure Data
Hide Analysis Population Description
The intent-to-treat (ITT) population is defined as all infants enrolled in Part 2 of the study, regardless of whether they received treatment or not.
Arm/Group Title Confirmatory Part 2 - Risdiplam
Hide Arm/Group Description:
Participants received risdiplam orally once daily at a dose of target exposure cap of a mean AUC0-24h,ss of 2000 ng*h/mL, for a duration of 24 months with a primary analysis after 12 months. Starting doses were either 0.04mg/kg, 0.08mg/kg or 0.2mg/kg depending on the participant's age. All participants had their dose adjusted to 0.2mg/kg within a few months of starting treatment. The dose was adjusted to 0.25mg/kg when participant reached 2 years of age.
Overall Number of Participants Analyzed 41
Measure Type: Number
Number (90% Confidence Interval)
Unit of Measure: Percentage of Participants
85.4
(73.35 to 92.24)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Confirmatory Part 2 - Risdiplam
Comments [Not Specified]
Type of Statistical Test Superiority
Comments Result compared to a performance criterion of 42% derived from natural history data.
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method One-sided Z-test
Comments [Not Specified]
19.Secondary Outcome
Title Part 2: Percentage of Infants Who Are Alive at Month 12
Hide Description Kaplan-Meier methodology was used to estimate the percentages. 90% CI was computed using the complementary log-log transformation.
Time Frame At Month 12 (Up to the CCOD of 14 November 2019)
Hide Outcome Measure Data
Hide Analysis Population Description
The intent-to-treat (ITT) population is defined as all infants enrolled in Part 2 of the study, regardless of whether they received treatment or not.
Arm/Group Title Confirmatory Part 2 - Risdiplam
Hide Arm/Group Description:
Participants received risdiplam orally once daily at a dose of target exposure cap of a mean AUC0-24h,ss of 2000 ng*h/mL, for a duration of 24 months with a primary analysis after 12 months. Starting doses were either 0.04mg/kg, 0.08mg/kg or 0.2mg/kg depending on the participant's age. All participants had their dose adjusted to 0.2mg/kg within a few months of starting treatment. The dose was adjusted to 0.25mg/kg when participant reached 2 years of age.
Overall Number of Participants Analyzed 41
Measure Type: Number
Number (90% Confidence Interval)
Unit of Measure: Percentage of Participants
92.7
(82.16 to 97.10)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Confirmatory Part 2 - Risdiplam
Comments [Not Specified]
Type of Statistical Test Superiority
Comments Result compared to a performance criterion of 60% derived from natural history data.
Statistical Test of Hypothesis P-Value 0.0005
Comments [Not Specified]
Method One-sided Z-test
Comments [Not Specified]
20.Secondary Outcome
Title Part 2: Percentage of Infants Who Are Without Permanent Ventilation at Month 12
Hide Description Permanent ventilation is defined as >/=16 hours of non-invasive ventilation per day or intubation for >21 consecutive days in the absence of, or following the resolution of, an acute reversible event; or tracheostomy. Permanent ventilation events were reviewed and confirmed by an independent adjudication committee. Kaplan-Meier methodology was used to estimate the percentages. 90% CI was computed using the complementary log-log transformation.
Time Frame At Month 12 (Up to the CCOD of 14 November 2019)
Hide Outcome Measure Data
Hide Analysis Population Description
The intent-to-treat (ITT) population is defined as all infants enrolled in Part 2 of the study, regardless of whether they received treatment or not.
Arm/Group Title Confirmatory Part 2 - Risdiplam
Hide Arm/Group Description:
Participants received risdiplam orally once daily at a dose of target exposure cap of a mean AUC0-24h,ss of 2000 ng*h/mL, for a duration of 24 months with a primary analysis after 12 months. Starting doses were either 0.04mg/kg, 0.08mg/kg or 0.2mg/kg depending on the participant's age. All participants had their dose adjusted to 0.2mg/kg within a few months of starting treatment. The dose was adjusted to 0.25mg/kg when participant reached 2 years of age.
Overall Number of Participants Analyzed 41
Measure Type: Number
Number (90% Confidence Interval)
Unit of Measure: Percentage of Participants
92.3
(81.24 to 96.95)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Confirmatory Part 2 - Risdiplam
Comments [Not Specified]
Type of Statistical Test Superiority
Comments Result compared to a performance criterion of 89% derived from natural history data.
Statistical Test of Hypothesis P-Value 0.2595
Comments [Not Specified]
Method One-sided Z-test
Comments [Not Specified]
21.Secondary Outcome
Title Part 2: Percentage of Infants Who Achieve a Reduction of At Least 30 Degrees in Phase Angle From Baseline, as Measured by Respiratory Plethysmography (RP) at Month 12
Hide Description RP measures the degree of synchrony between abdominal and thoracic cage-driven breathing. The weakness of intercostal muscles leads to asynchrony of the thorax with the diaphragm, resulting in inefficient and paradoxical breathing patterns. The degree of synchrony between the movement of the chest wall and abdomen during the respiratory cycle can be expressed as the phase angle between the two compartments and measured by placing two RP bands around the thorax and abdomen. In paradoxical breathing, the phase angle is reversed compared with the normal ventilation cycle. A phase angle of 0° indicates perfect in-phase movement, while a value of 180° indicates completely out-of-phase movement between the two compartments. In this measure, 8 or more valid breaths were used to determine the phase angle at each visit; the calculation was not performed if fewer than 8 valid breaths had been measured. 90% CI for one sample binomial was computed using Clopper-Pearson (exact) method.
Time Frame At Month 12 (Up to the CCOD of 14 November 2019)
Hide Outcome Measure Data
Hide Analysis Population Description
The intent-to-treat (ITT) population is defined as all infants enrolled in Part 2 of the study, regardless of whether they received treatment or not.
Arm/Group Title Confirmatory Part 2 - Risdiplam
Hide Arm/Group Description:
Participants received risdiplam orally once daily at a dose of target exposure cap of a mean AUC0-24h,ss of 2000 ng*h/mL, for a duration of 24 months with a primary analysis after 12 months. Starting doses were either 0.04mg/kg, 0.08mg/kg or 0.2mg/kg depending on the participant's age. All participants had their dose adjusted to 0.2mg/kg within a few months of starting treatment. The dose was adjusted to 0.25mg/kg when participant reached 2 years of age.
Overall Number of Participants Analyzed 41
Measure Type: Number
Number (90% Confidence Interval)
Unit of Measure: Percentage of Participants
34.1
(21.96 to 48.13)
22.Secondary Outcome
Title Part 2: Percentage of Infants Not Requiring Respiratory Support (Invasive or Non-Invasive) at Month 12
Hide Description 90% CI for one sample binomial was computed using Clopper-Pearson (exact) method.
Time Frame At Month 12 (Up to the CCOD of 14 November 2019)
Hide Outcome Measure Data
Hide Analysis Population Description
The intent-to-treat (ITT) population is defined as all infants enrolled in Part 2 of the study, regardless of whether they received treatment or not.
Arm/Group Title Confirmatory Part 2 - Risdiplam
Hide Arm/Group Description:
Participants received risdiplam orally once daily at a dose of target exposure cap of a mean AUC0-24h,ss of 2000 ng*h/mL, for a duration of 24 months with a primary analysis after 12 months. Starting doses were either 0.04mg/kg, 0.08mg/kg or 0.2mg/kg depending on the participant's age. All participants had their dose adjusted to 0.2mg/kg within a few months of starting treatment. The dose was adjusted to 0.25mg/kg when participant reached 2 years of age.
Overall Number of Participants Analyzed 41
Measure Type: Number
Number (90% Confidence Interval)
Unit of Measure: Percentage of Participants
24.4
(13.87 to 37.85)
23.Secondary Outcome
Title Part 2: Percentage of Infants Able to Feed Orally at Month 12
Hide Description Able to feed orally includes participants fed orally and participants fed via a combination of oral and tube feeding. 90% CI for one sample binomial was computed using Clopper-Pearson (exact) method.
Time Frame At Month 12 (Up to the CCOD of 14 November 2019)
Hide Outcome Measure Data
Hide Analysis Population Description
The intent-to-treat (ITT) population is defined as all infants enrolled in Part 2 of the study, regardless of whether they received treatment or not.
Arm/Group Title Confirmatory Part 2 - Risdiplam
Hide Arm/Group Description:
Participants received risdiplam orally once daily at a dose of target exposure cap of a mean AUC0-24h,ss of 2000 ng*h/mL, for a duration of 24 months with a primary analysis after 12 months. Starting doses were either 0.04mg/kg, 0.08mg/kg or 0.2mg/kg depending on the participant's age. All participants had their dose adjusted to 0.2mg/kg within a few months of starting treatment. The dose was adjusted to 0.25mg/kg when participant reached 2 years of age.
Overall Number of Participants Analyzed 41
Measure Type: Number
Number (90% Confidence Interval)
Unit of Measure: Percentage of Participants
82.9
(70.31 to 91.70)
24.Secondary Outcome
Title Part 1: Percentage of Participants With Adverse Events (AE) 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 From first dose of risdiplam up to a minimum of 12 months (Up to CCOD 27 February 2019)
Hide Outcome Measure Data
Hide Analysis Population Description
All infants who received at least one dose of study medication (risdiplam) were included in the safety population.
Arm/Group Title Exploratory Part 1 - Cohort 1 Exploratory Part 1 - Cohort 2
Hide Arm/Group Description:
Participants received risdiplam in a staggered, dose-escalation manner once daily at Dose Level 1 for a minimum of 4 weeks to select the dose for Part 2. Dose Level 1 was targeting an exposure of mean AUC0-24h,ss 700 ng*h/mL.
Participants received risdiplam in a staggered, dose-escalation manner once daily at Dose Level 2 for a minimum of 4 weeks to select the dose for Part 2. Dose Level 2 was targeting an exposure of mean AUC0-24h,ss </= 2000 ng*h/mL. Cohort 2 included one infant who started at Dose Level 1 and was escalated to Dose Level 2 on Day 83.
Overall Number of Participants Analyzed 4 17
Measure Type: Number
Unit of Measure: Percentage of Participants
With at least one AE 100.0 100.0
With at least one SAE 75.0 41.2
25.Secondary Outcome
Title Part 2: Percentage of Participants With Adverse Events (AE) 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 From first dose of risdiplam up to a minimum of 12 months (Up to the CCOD of 14 November 2019)
Hide Outcome Measure Data
Hide Analysis Population Description
All infants who received at least one dose of study medication (risdiplam) were included in the safety population.
Arm/Group Title Confirmatory Part 2 - Risdiplam
Hide Arm/Group Description:
Participants received risdiplam orally once daily at a dose of target exposure cap of a mean AUC0-24h,ss of 2000 ng*h/mL, for a duration of 24 months with a primary analysis after 12 months. Starting doses were either 0.04mg/kg, 0.08mg/kg or 0.2mg/kg depending on the participant's age. All participants had their dose adjusted to 0.2mg/kg within a few months of starting treatment. The dose was adjusted to 0.25mg/kg when participant reached 2 years of age.
Overall Number of Participants Analyzed 41
Measure Type: Number
Unit of Measure: Percentage of Participants
With al least one AE 100.0
With at least one SAE 58.5
26.Secondary Outcome
Title Part 2: Percentage of Participants With AEs and SAEs Leading to Treatment Discontinuation
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 From first dose of risdiplam up to a minimum of 12 months (Up to the CCOD of 14 November 2019)
Hide Outcome Measure Data
Hide Analysis Population Description
All infants who received at least one dose of study medication (risdiplam) were included in the safety population.
Arm/Group Title Confirmatory Part 2 - Risdiplam
Hide Arm/Group Description:
Participants received risdiplam orally once daily at a dose of target exposure cap of a mean AUC0-24h,ss of 2000 ng*h/mL, for a duration of 24 months with a primary analysis after 12 months. Starting doses were either 0.04mg/kg, 0.08mg/kg or 0.2mg/kg depending on the participant's age. All participants had their dose adjusted to 0.2mg/kg within a few months of starting treatment. The dose was adjusted to 0.25mg/kg when participant reached 2 years of age.
Overall Number of Participants Analyzed 41
Measure Type: Number
Unit of Measure: Percentage of Participants
Due to AE 0
Due to SAE 0
27.Secondary Outcome
Title Part 2: Percentage of Participants With AEs and SAEs Leading to Treatment Modification/Interruption
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 From first dose of risdiplam up to a minimum of 12 months (Up to the CCOD of 14 November 2019)
Hide Outcome Measure Data
Hide Analysis Population Description
All infants who received at least one dose of study medication (risdiplam) were included in the safety population.
Arm/Group Title Confirmatory Part 2 - Risdiplam
Hide Arm/Group Description:
Participants received risdiplam orally once daily at a dose of target exposure cap of a mean AUC0-24h,ss of 2000 ng*h/mL, for a duration of 24 months with a primary analysis after 12 months. Starting doses were either 0.04mg/kg, 0.08mg/kg or 0.2mg/kg depending on the participant's age. All participants had their dose adjusted to 0.2mg/kg within a few months of starting treatment. The dose was adjusted to 0.25mg/kg when participant reached 2 years of age.
Overall Number of Participants Analyzed 41
Measure Type: Number
Unit of Measure: Percentage of Participants
Due to AE 4.9
Due to SAE 2.4
28.Secondary Outcome
Title Part 2: Anthropometric Examination of Weight Measured in Kilograms
Hide Description Anthropometric examination included weight, height, head circumference and chest circumference.
Time Frame At Month 12 (Up to the CCOD of 14 November 2019)
Hide Outcome Measure Data
Hide Analysis Population Description
All infants who received at least one dose of study medication (risdiplam) were included in the safety population. Only participants for whom data were collected are included in the analysis.
Arm/Group Title Confirmatory Part 2 - Risdiplam
Hide Arm/Group Description:
Participants received risdiplam orally once daily at a dose of target exposure cap of a mean AUC0-24h,ss of 2000 ng*h/mL, for a duration of 24 months with a primary analysis after 12 months. Starting doses were either 0.04mg/kg, 0.08mg/kg or 0.2mg/kg depending on the participant's age. All participants had their dose adjusted to 0.2mg/kg within a few months of starting treatment. The dose was adjusted to 0.25mg/kg when participant reached 2 years of age.
Overall Number of Participants Analyzed 38
Mean (Standard Deviation)
Unit of Measure: kilogram (kg)
9.59  (1.40)
29.Secondary Outcome
Title Part 2: Anthropometric Examination of Height, Head Circumference and Chest Circumference Measured in Centimeter
Hide Description Anthropometric examination included weight, height, head circumference and chest circumference.
Time Frame At Month 12 (Up to the CCOD of 14 November 2019)
Hide Outcome Measure Data
Hide Analysis Population Description
All infants who received at least one dose of study medication (risdiplam) were included in the safety population. Only participants for whom data were collected are included in the analysis.
Arm/Group Title Confirmatory Part 2 - Risdiplam
Hide Arm/Group Description:
Participants received risdiplam orally once daily at a dose of target exposure cap of a mean AUC0-24h,ss of 2000 ng*h/mL, for a duration of 24 months with a primary analysis after 12 months. Starting doses were either 0.04mg/kg, 0.08mg/kg or 0.2mg/kg depending on the participant's age. All participants had their dose adjusted to 0.2mg/kg within a few months of starting treatment. The dose was adjusted to 0.25mg/kg when participant reached 2 years of age.
Overall Number of Participants Analyzed 38
Mean (Standard Deviation)
Unit of Measure: centimeter (cm)
Month 12 (Height) 80.47  (4.00)
Month 12 (Head Circumference) 47.09  (1.72)
Month 12 (Chest Circumference) 45.77  (2.31)
30.Secondary Outcome
Title Part 2: Maximum Plasma Concentration (Cmax) of Risdiplam
Hide Description [Not Specified]
Time Frame 2, 4, 6, hours PoD on Day 1; PrD (Hour 0) on Days 2, 14, 119, 245, 364, 427, 490, 609, 728; PrD and 2, 4, 6 hours PoD on Days 28, 56, 182, 301, 546, 672
Outcome Measure Data Not Reported
31.Secondary Outcome
Title Part 2: Area Under the Curve (AUC) of Risdiplam
Hide Description [Not Specified]
Time Frame 2, 4, 6, hours PoD on Day 1; PrD (Hour 0) on Days 2, 14, 119, 245, 364, 427, 490, 609, 728; PrD and 2, 4, 6 hours PoD on Days 28, 56, 182, 301, 546, 672
Outcome Measure Data Not Reported
32.Secondary Outcome
Title Part 2: Concentration at the End of a Dosing Interval (Ctrough) of Risdiplam
Hide Description [Not Specified]
Time Frame PrD (Hour 0) on Days 2, 14, 28, 56, 119, 182, 301, 546, 672
Outcome Measure Data Not Reported
33.Secondary Outcome
Title Survival of Motor Neuron (SMN) Protein Levels in Blood
Hide Description [Not Specified]
Time Frame Days 1, 14 (Part 1 only), 28, 119, 245, 364, 609, 728
Outcome Measure Data Not Reported
34.Secondary Outcome
Title Survival Motor Neuron (SMN) Messenger Ribonucleic Acid (mRNA) Levels in Blood
Hide Description [Not Specified]
Time Frame Days 1, 14 (Part 1 only), 28, 245, 364, 609, 728
Outcome Measure Data Not Reported
Time Frame Part 1: From first dose of risdiplam up to a minimum of 12 months (Up to CCOD 27 February 2019) Part 2: From first dose of risdiplam up to a minimum of 12 months (Up to the CCOD of 14 November 2019)
Adverse Event Reporting Description All infants who received at least one dose of risdiplam were included in the safety population. Part 1 and Part 2 of the study were independent trials with different safety populations. SAE and AE collection were managed independently. AEs not occurring at the 5% threshold in one part of the study does not mean that the event didn't occur, however, it may have occurred at a different frequency threshold. Part 1 used MedDRA 21.1, Part 2 used MedDRA 22.1 for coding.
 
Arm/Group Title Exploratory Part 1 - Cohort 1 Exploratory Part 1 - Cohort 2 Confirmatory Part 2 - Risdiplam
Hide Arm/Group Description Participants received risdiplam in a staggered, dose-escalation manner once daily at Dose Level 1 for a minimum of 4 weeks to select the dose for Part 2. Dose Level 1 was targeting an exposure of mean AUC0-24h,ss 700 ng*h/mL. Participants received risdiplam in a staggered, dose-escalation manner once daily at Dose Level 2 for a minimum of 4 weeks to select the dose for Part 2. Dose Level 2 was targeting an exposure of mean AUC0-24h,ss </= 2000 ng*h/mL. Cohort 2 included one infant who started at Dose Level 1 and was escalated to Dose Level 2 on Day 83. Participants received risdiplam orally once daily at a dose of target exposure cap of a mean AUC0-24h,ss of 2000 ng*h/mL, for a duration of 24 months with a primary analysis after 12 months. Starting doses were either 0.04mg/kg, 0.08mg/kg or 0.2mg/kg depending on the participant's age. All participants had their dose adjusted to 0.2mg/kg within a few months of starting treatment. The dose was adjusted to 0.25mg/kg when participant reached 2 years of age.
All-Cause Mortality
Exploratory Part 1 - Cohort 1 Exploratory Part 1 - Cohort 2 Confirmatory Part 2 - Risdiplam
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   1/4 (25.00%)      2/17 (11.76%)      3/41 (7.32%)    
Hide Serious Adverse Events
Exploratory Part 1 - Cohort 1 Exploratory Part 1 - Cohort 2 Confirmatory Part 2 - Risdiplam
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   3/4 (75.00%)      7/17 (41.18%)      24/41 (58.54%)    
Blood and lymphatic system disorders       
Neutropenia  1  1/4 (25.00%)  1 0/17 (0.00%)  0 0/41 (0.00%)  0
Cardiac disorders       
Cardiac arrest  1  0/4 (0.00%)  0 1/17 (5.88%)  1 1/41 (2.44%)  1
Sinus tachycardia  1  0/4 (0.00%)  0 0/17 (0.00%)  0 1/41 (2.44%)  1
Congenital, familial and genetic disorders       
Cryptorchism  1  0/4 (0.00%)  0 0/17 (0.00%)  0 1/41 (2.44%)  1
Gastrointestinal disorders       
Vomiting  1  0/4 (0.00%)  0 0/17 (0.00%)  0 1/41 (2.44%)  1
Infections and infestations       
Influenza  1  1/4 (25.00%)  1 0/17 (0.00%)  0 1/41 (2.44%)  1
Pneumonia  1  2/4 (50.00%)  3 1/17 (5.88%)  1 13/41 (31.71%)  16
Respiratory tract infection  1  1/4 (25.00%)  1 1/17 (5.88%)  1 1/41 (2.44%)  1
Respiratory tract infection viral  1  1/4 (25.00%)  1 1/17 (5.88%)  1 1/41 (2.44%)  1
Upper respiratory tract infection  1  0/4 (0.00%)  0 1/17 (5.88%)  1 0/41 (0.00%)  0
Bronchiolitis  1  0/4 (0.00%)  0 0/17 (0.00%)  0 2/41 (4.88%)  3
Bronchitis  1  0/4 (0.00%)  0 0/17 (0.00%)  0 1/41 (2.44%)  1
Escherichia urinary tract infection  1  0/4 (0.00%)  0 0/17 (0.00%)  0 1/41 (2.44%)  1
Gastroenteritis  1  0/4 (0.00%)  0 0/17 (0.00%)  0 1/41 (2.44%)  1
Lower respiratory tract infection  1  0/4 (0.00%)  0 0/17 (0.00%)  0 1/41 (2.44%)  1
Pharyngitis  1  0/4 (0.00%)  0 0/17 (0.00%)  0 1/41 (2.44%)  1
Pneumonia bacterial  1  0/4 (0.00%)  0 0/17 (0.00%)  0 1/41 (2.44%)  1
Pneumonia viral  1  0/4 (0.00%)  0 0/17 (0.00%)  0 1/41 (2.44%)  1
Tracheitis  1  0/4 (0.00%)  0 0/17 (0.00%)  0 1/41 (2.44%)  1
Tracheobronchitis  1  0/4 (0.00%)  0 0/17 (0.00%)  0 1/41 (2.44%)  1
Investigations       
Weight decreased  1  0/4 (0.00%)  0 1/17 (5.88%)  1 0/41 (0.00%)  0
Metabolism and nutrition disorders       
Failure to thrive  1  0/4 (0.00%)  0 1/17 (5.88%)  1 0/41 (0.00%)  0
Dehydration  1  0/4 (0.00%)  0 0/17 (0.00%)  0 1/41 (2.44%)  1
Nervous system disorders       
Hydrocephalus  1  0/4 (0.00%)  0 0/17 (0.00%)  0 1/41 (2.44%)  1
Hypotonia  1  0/4 (0.00%)  0 0/17 (0.00%)  0 2/41 (4.88%)  2
Respiratory, thoracic and mediastinal disorders       
Acute respiratory failure  1  1/4 (25.00%)  1 1/17 (5.88%)  1 1/41 (2.44%)  1
Atelectasis  1  0/4 (0.00%)  0 1/17 (5.88%)  2 1/41 (2.44%)  2
Hypoxia  1  0/4 (0.00%)  0 1/17 (5.88%)  1 0/41 (0.00%)  0
Pneumonia aspiration  1  0/4 (0.00%)  0 1/17 (5.88%)  1 0/41 (0.00%)  0
Pneumothorax  1  0/4 (0.00%)  0 1/17 (5.88%)  1 0/41 (0.00%)  0
Respiratory distress  1  0/4 (0.00%)  0 2/17 (11.76%)  2 1/41 (2.44%)  1
Respiratory failure  1  0/4 (0.00%)  0 1/17 (5.88%)  1 2/41 (4.88%)  2
Aspiration  1  0/4 (0.00%)  0 0/17 (0.00%)  0 1/41 (2.44%)  1
Respiratory tract inflammation  1  0/4 (0.00%)  0 0/17 (0.00%)  0 1/41 (2.44%)  1
Sleep apnoea syndrome  1  0/4 (0.00%)  0 0/17 (0.00%)  0 1/41 (2.44%)  1
1
Term from vocabulary, MedDRA 21.1
Indicates events were collected by systematic assessment
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Exploratory Part 1 - Cohort 1 Exploratory Part 1 - Cohort 2 Confirmatory Part 2 - Risdiplam
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   3/4 (75.00%)      17/17 (100.00%)      36/41 (87.80%)    
Blood and lymphatic system disorders       
Leukocytosis  1  0/4 (0.00%)  0 1/17 (5.88%)  1 0/41 (0.00%)  0
Lymphadenopathy  1  0/4 (0.00%)  0 1/17 (5.88%)  1 0/41 (0.00%)  0
Eye disorders       
Conjunctival hyperaemia  1  1/4 (25.00%)  1 1/17 (5.88%)  1 0/41 (0.00%)  0
Macular cyst  1  0/4 (0.00%)  0 1/17 (5.88%)  1 0/41 (0.00%)  0
Gastrointestinal disorders       
Abdominal distension  1  1/4 (25.00%)  1 0/17 (0.00%)  0 0/41 (0.00%)  0
Abnormal faeces  1  0/4 (0.00%)  0 1/17 (5.88%)  1 0/41 (0.00%)  0
Aphthous ulcer  1  1/4 (25.00%)  1 0/17 (0.00%)  0 0/41 (0.00%)  0
Constipation  1  1/4 (25.00%)  1 3/17 (17.65%)  3 8/41 (19.51%)  8
Diarrhoea  1  0/4 (0.00%)  0 6/17 (35.29%)  7 4/41 (9.76%)  4
Dysphagia  1  0/4 (0.00%)  0 1/17 (5.88%)  1 0/41 (0.00%)  0
Faeces discoloured  1  0/4 (0.00%)  0 1/17 (5.88%)  1 0/41 (0.00%)  0
Flatulence  1  1/4 (25.00%)  1 1/17 (5.88%)  1 0/41 (0.00%)  0
Gastrooesophageal reflux disease  1  0/4 (0.00%)  0 2/17 (11.76%)  3 0/41 (0.00%)  0
Haematochezia  1  0/4 (0.00%)  0 1/17 (5.88%)  1 0/41 (0.00%)  0
Infrequent bowel movements  1  0/4 (0.00%)  0 1/17 (5.88%)  1 0/41 (0.00%)  0
Salivary hypersecretion  1  0/4 (0.00%)  0 1/17 (5.88%)  1 0/41 (0.00%)  0
Teething  1  0/4 (0.00%)  0 3/17 (17.65%)  4 3/41 (7.32%)  5
Toothache  1  0/4 (0.00%)  0 1/17 (5.88%)  1 0/41 (0.00%)  0
Vomiting  1  1/4 (25.00%)  1 4/17 (23.53%)  10 3/41 (7.32%)  8
General disorders       
Discomfort  1  0/4 (0.00%)  0 1/17 (5.88%)  1 0/41 (0.00%)  0
Ill-defined disorder  1  0/4 (0.00%)  0 1/17 (5.88%)  1 0/41 (0.00%)  0
Pyrexia  1  3/4 (75.00%)  16 8/17 (47.06%)  14 16/41 (39.02%)  39
Infections and infestations       
Conjunctivitis  1  0/4 (0.00%)  0 1/17 (5.88%)  1 0/41 (0.00%)  0
Ear infection  1  1/4 (25.00%)  1 2/17 (11.76%)  3 0/41 (0.00%)  0
Exanthema subitum  1  1/4 (25.00%)  1 0/17 (0.00%)  0 0/41 (0.00%)  0
Folliculitis  1  0/4 (0.00%)  0 1/17 (5.88%)  1 0/41 (0.00%)  0
Gastroenteritis  1  0/4 (0.00%)  0 1/17 (5.88%)  2 0/41 (0.00%)  0
Lower respiratory tract infection  1  0/4 (0.00%)  0 1/17 (5.88%)  1 0/41 (0.00%)  0
Nasopharyngitis  1  0/4 (0.00%)  0 3/17 (17.65%)  5 5/41 (12.20%)  9
Oral candidiasis  1  0/4 (0.00%)  0 1/17 (5.88%)  1 0/41 (0.00%)  0
Otitis media  1  0/4 (0.00%)  0 1/17 (5.88%)  1 0/41 (0.00%)  0
Pharyngitis  1  1/4 (25.00%)  1 0/17 (0.00%)  0 0/41 (0.00%)  0
Pneumonia  1  0/4 (0.00%)  0 1/17 (5.88%)  1 4/41 (9.76%)  4
Pneumonia staphylococcal  1  0/4 (0.00%)  0 1/17 (5.88%)  1 0/41 (0.00%)  0
Respiratory tract infection  1  0/4 (0.00%)  0 1/17 (5.88%)  4 0/41 (0.00%)  0
Rhinitis  1  0/4 (0.00%)  0 3/17 (17.65%)  3 5/41 (12.20%)  7
Upper respiratory tract infection  1  1/4 (25.00%)  2 7/17 (41.18%)  11 19/41 (46.34%)  33
Urinary tract infection  1  1/4 (25.00%)  1 0/17 (0.00%)  0 3/41 (7.32%)  4
Varicella post vaccine  1  0/4 (0.00%)  0 1/17 (5.88%)  1 0/41 (0.00%)  0
Viral infection  1  0/4 (0.00%)  0 1/17 (5.88%)  1 0/41 (0.00%)  0
Viral upper respiratory tract infection  1  0/4 (0.00%)  0 1/17 (5.88%)  1 0/41 (0.00%)  0
Injury, poisoning and procedural complications       
Fall  1  0/4 (0.00%)  0 2/17 (11.76%)  2 0/41 (0.00%)  0
Head injury  1  0/4 (0.00%)  0 1/17 (5.88%)  1 0/41 (0.00%)  0
Incorrect dose administered  1  0/4 (0.00%)  0 1/17 (5.88%)  1 0/41 (0.00%)  0
Joint dislocation  1  0/4 (0.00%)  0 1/17 (5.88%)  1 0/41 (0.00%)  0
Stoma site hypergranulation  1  0/4 (0.00%)  0 1/17 (5.88%)  1 0/41 (0.00%)  0
Thermal burn  1  0/4 (0.00%)  0 1/17 (5.88%)  1 0/41 (0.00%)  0
Metabolism and nutrition disorders       
Decreased appetite  1  0/4 (0.00%)  0 2/17 (11.76%)  3 0/41 (0.00%)  0
Iron deficiency  1  0/4 (0.00%)  0 1/17 (5.88%)  1 0/41 (0.00%)  0
Musculoskeletal and connective tissue disorders       
Kyphosis  1  0/4 (0.00%)  0 1/17 (5.88%)  1 0/41 (0.00%)  0
Scoliosis  1  0/4 (0.00%)  0 1/17 (5.88%)  1 0/41 (0.00%)  0
Nervous system disorders       
Loss of consciousness  1  0/4 (0.00%)  0 1/17 (5.88%)  1 0/41 (0.00%)  0
Respiratory, thoracic and mediastinal disorders       
Atelectasis  1  0/4 (0.00%)  0 1/17 (5.88%)  4 0/41 (0.00%)  0
Bronchial secretion retention  1  0/4 (0.00%)  0 1/17 (5.88%)  1 0/41 (0.00%)  0
Cough  1  0/4 (0.00%)  0 5/17 (29.41%)  7 0/41 (0.00%)  0
Epistaxis  1  0/4 (0.00%)  0 1/17 (5.88%)  1 0/41 (0.00%)  0
Hypoxia  1  0/4 (0.00%)  0 1/17 (5.88%)  1 0/41 (0.00%)  0
Nasal congestion  1  0/4 (0.00%)  0 2/17 (11.76%)  2 0/41 (0.00%)  0
Respiratory tract congestion  1  0/4 (0.00%)  0 2/17 (11.76%)  2 0/41 (0.00%)  0
Rhinorrhoea  1  0/4 (0.00%)  0 1/17 (5.88%)  1 0/41 (0.00%)  0
Sleep apnoea syndrome  1  0/4 (0.00%)  0 1/17 (5.88%)  1 0/41 (0.00%)  0
Upper respiratory tract congestion  1  0/4 (0.00%)  0 1/17 (5.88%)  1 0/41 (0.00%)  0
Upper respiratory tract inflammation  1  2/4 (50.00%)  2 1/17 (5.88%)  2 0/41 (0.00%)  0
Skin and subcutaneous tissue disorders       
Dermatitis  1  1/4 (25.00%)  1 0/17 (0.00%)  0 0/41 (0.00%)  0
Dermatitis allergic  1  0/4 (0.00%)  0 1/17 (5.88%)  1 0/41 (0.00%)  0
Dermatitis atopic  1  0/4 (0.00%)  0 1/17 (5.88%)  2 0/41 (0.00%)  0
Eczema  1  0/4 (0.00%)  0 3/17 (17.65%)  3 0/41 (0.00%)  0
Erythema  1  2/4 (50.00%)  3 1/17 (5.88%)  1 0/41 (0.00%)  0
Macule  1  1/4 (25.00%)  1 0/17 (0.00%)  0 0/41 (0.00%)  0
Petechiae  1  0/4 (0.00%)  0 1/17 (5.88%)  2 0/41 (0.00%)  0
Rash  1  0/4 (0.00%)  0 2/17 (11.76%)  3 3/41 (7.32%)  3
Miliaria  1  0/4 (0.00%)  0 0/17 (0.00%)  0 3/41 (7.32%)  3
Rash maculo-papular  1  0/4 (0.00%)  0 0/17 (0.00%)  0 4/41 (9.76%)  4
Surgical and medical procedures       
Mechanical ventilation  1  0/4 (0.00%)  0 1/17 (5.88%)  1 0/41 (0.00%)  0
1
Term from vocabulary, MedDRA 21.1
Indicates events were collected by systematic assessment
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
The Study being conducted under this Agreement is part of the Overall Study. Investigator is free to publish in reputable journals or to present at professional conferences the results of the Study, but only after the first publication or presentation that involves the Overall Study. The Sponsor may request that Confidential Information be deleted and/or the publication be postponed in order to protect the Sponsor's intellectual property rights.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Medical Communications
Organization: Hoffmann-La Roche
Phone: 800 821-8590
EMail: genentech@druginfo.com
Layout table for additonal information
Responsible Party: Hoffmann-La Roche
ClinicalTrials.gov Identifier: NCT02913482    
Other Study ID Numbers: BP39056
2016-000778-40 ( EudraCT Number )
First Submitted: September 21, 2016
First Posted: September 23, 2016
Results First Submitted: November 10, 2020
Results First Posted: January 8, 2021
Last Update Posted: March 16, 2021