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

• ClinicalTrials.gov Identifier: NCT02913482
• Recruitment Status: Completed
• First Posted: September 23, 2016
• Results First Posted: January 8, 2021
• Last Update Posted: January 5, 2024
• Sponsor: Hoffmann-La Roche
• 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

Participant Flow

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
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]	14 [1]	38 [1]
Not Completed	1	3	3
Reason Not Completed
Death	0	2	2
Progressive Disease	1	1	1
[1] Participants remaining in the study at CCOD of 12 Nov 2020

Baseline Characteristics

Arm/Group Title		Exploratory Part 1 - Cohort 1	Exploratory Part 1 - Cohort 2	Confirmatory Part 2 - Risdiplam	Total
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
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%

Outcome Measures

1. Primary Outcome

Title	Part 1: Selected Part 2 Dose of Risdiplam
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

Outcome Measure Data

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
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
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	Month 12

Outcome Measure Data

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
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)

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
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	Month 12

Outcome Measure Data

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
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)

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 Months 8 and 12
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	Month 8, Month 12

Outcome Measure Data

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
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)

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 Months 8, 12 and 24
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	Month 8, Month 12, Month 24

Outcome Measure Data

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
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)
Month 24	70.7; (56.93 to 82.16)

6. Secondary Outcome

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

Outcome Measure Data

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
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
Mean (Standard Deviation); Unit of Measure: Scores on a Scale
Baseline	Number Analyzed	41 participants
		1.85 (1.61)
Change from Baseline at Month 12	Number Analyzed	38 participants
		7.21 (5.71)
Change from Baseline at Month 24	Number Analyzed	38 participants
		12.89 (6.89)

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
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	Month 8

Outcome Measure Data

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
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) at Month 8	36.6
Wobbles (Head Control) at Month 8	14.6
All the time maintained upright (Head Control) at Month 8	39.0
No kicking (Ability to Kick [supine]) at Month 8	24.4
Kicks horizontally; legs do not lift (Ability to Kick [supine]) at Month 8	58.5
Upward (vertically) (Ability to Kick [supine]) at Month 8	7.3
Touches leg (Ability to Kick [supine]) at Month 8	0
Touches toes (Ability to Kick [supine]) at Month 8	0
No rolling (Rolling) at Month 8	56.1
Rolling to side (Rolling) at Month 8	29.3
Prone to supine (Rolling) at Month 8	2.4
Supine to prone (Rolling) at Month 8	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
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	Month 12

Outcome Measure Data

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
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) at Month 12	17.1
Wobbles (Head Control) at Month 12	31.7
All the time maintained upright (Head Control) at Month 12	43.9
Cannot sit (Sitting) at Month 12	31.7
Sits with support at hips (Sitting) at Month 12	17.1
Props (Sitting) at Month 12	19.5
Stable sit (Sitting) at Month 12	14.6
Pivots (rotates) (Sitting) at Month 12	9.8
No grasp (Voluntary Grasp) at Month 12	2.4
Uses whole hand (Voluntary Grasp) at Month 12	29.3
Index finger and thumb but immature grasp (Voluntary Grasp) at Month 12	48.8
Pincer grasp (Voluntary Grasp) at Month 12	12.2
No kicking (Ability to Kick [supine]) at Month 12	12.2
Kicks horizontally; legs do not lift (Ability to Kick [supine]) at Month 12	58.5
Upward (vertically) (Ability to Kick [supine]) at Month 12	7.3
Touches leg (Ability to Kick [supine]) at Month 12	4.9
Touches toes (Ability to Kick [supine]) at Month 12	9.8
No rolling (Rolling) at Month 12	36.6
Rolling to side (Rolling) at Month 12	31.7
Prone to supine (Rolling) at Month 12	14.6
Supine to prone (Rolling) at Month 12	9.8
Does not lift head (Crawling) at Month 12	85.4
On elbow (Crawling) at Month 12	2.4
On outstretched hand (Crawling) at Month 12	2.4
Crawling flat on abdomen (Crawling) at Month 12	0
Crawling on hands and knees (Crawling) at Month 12	0
Cannot test (Crawling) at Month 12	2.4
Does not support weight (Standing) at Month 12	61.0
Supports weight (Standing) at Month 12	17.1
Stands with support (Standing) at Month 12	4.9
Stands unaided (Standing) at Month 12	0
Cannot test (Standing) at Month 12	4.9
Not done (Standing) at Month 12	4.9
Bouncing (Walking) at Month 12	2.4
Cruising (walks holding on) (Walking) at Month 12	0
Walking independently (Walking) at Month 12	0
Cannot test (Walking) at Month 12	82.9
Not Done (Walking) at Month 12	7.3

9. 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 24
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	Month 24

Outcome Measure Data

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
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) at Month 24	7.3
Wobbles (Head Control) at Month 24	19.5
All the time maintained upright (Head Control) at Month 24	63.4
Not done (Head Control) at Month 24	2.4
Cannot sit (Sitting) at Month 24	19.5
Sits with support at hips (Sitting) at Month 24	7.3
Props (Sitting) at Month 24	9.8
Stable sit (Sitting) at Month 24	24.4
Pivots (rotates) (Sitting) at Month 24	29.3
Not done (Sitting) at Month 24	2.4
No grasp (Voluntary Grasp) at Month 24	2.4
Uses whole hand (Voluntary Grasp) at Month 24	4.9
Index finger and thumb but immature grasp (Voluntary Grasp) at Month 24	39.0
Pincer grasp (Voluntary Grasp) at Month 24	41.5
Not done (Voluntary Grasp) at Month 24	4.9
No kicking (Ability to Kick [supine]) at Month 24	7.3
Kicks horizontally; legs do not lift (Ability to Kick [supine]) at Month 24	31.7
Upward (vertically) (Ability to Kick [supine]) at Month 24	9.8
Touches leg (Ability to Kick [supine]) at Month 24	9.8
Touches toes (Ability to Kick [supine]) at Month 24	31.7
Not Done (Ability to Kick [supine]) at Month 24	2.4
No rolling (Rolling) at Month 24	9.8
Rolling to side (Rolling) at Month 24	29.3
Prone to supine (Rolling) at Month 24	7.3
Supine to prone (Rolling) at Month 24	43.9
Not Done (Rolling) at Month 24	2.4
Does not lift head (Crawling) at Month 24	75.6
On elbow (Crawling) at Month 24	7.3
On outstretched hand (Crawling) at Month 24	2.4
Crawling flat on abdomen (Crawling) at Month 24	0
Crawling on hands and knees (Crawling) at Month 24	4.9
Not done (Crawling) at Month 24	2.4
Does not support weight (Standing) at Month 24	63.4
Supports weight (Standing) at Month 24	12.2
Stands with support (Standing) at Month 24	14.6
Stands unaided (Standing) at Month 24	0
Not done (Standing) at Month 24	2.4
Bouncing (Walking) at Month 24	2.4
Cruising (walks holding on) (Walking) at Month 24	2.4
Walking independently (Walking) at Month 24	0
Cannot test (Walking) at Month 24	75.6
Not Done (Walking) at Month 24	12.2

10. Secondary Outcome

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

Outcome Measure Data

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
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 12	78.0; (64.82 to 88.04)
Month 24	85.4; (73.15 to 93.43)

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 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]

11. Secondary Outcome

Title	Part 2: Highest Motor Milestone Achieved of Six Specified Milestones Assessed in the BSID-III Gross Motor Scale by Months 12 and 24
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 specific 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'. Reported here is the percentage of participants for whom the reported item was the highest item achieved out of these six items by Months 12 and 24.
Time Frame	Month 12, Month 24

Outcome Measure Data

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
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 at Month 12	0
Item 14: Rolls from Side to Back at Month 12	56.1
Item 22: Sits Without Support for 5 sec at Month 12	29.3
Item 30: Crawls on Stomach at Month 12	0
Item 40: Stands Alone at Month 12	0
Item 42: Walks Alone at Month 12	0
Item 9: Controls Head While Upright for 15 sec at Month 24	0
Item 14: Rolls from Side to Back at Month 24	29.3
Item 22: Sits Without Support for 5 sec at Month 24	61.0
Item 30: Crawls on Stomach at Month 24	0
Item 40: Stands Alone at Month 24	0
Item 42: Walks Alone at Month 24	0

12. 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
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	Month 24

Outcome Measure Data

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
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
	61.0; (46.94 to 73.77)

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]

13. 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
Description	The BSID-III is a standardized assessment commonly used to evaluate development across five domains in infants and young children aged between 1 and 42 months. The gross motor subscale of the BSID-III is evaluated based on the linear and hierarchical obtainment of motor skills, as seen in typically developing children. The gross motor scale consists of 72 items scored at 0 (unable to perform the activity) or 1 (criteria for item achieved). Item 26 is not considered achieved if the infant sits alone for less than 30 seconds before losing balance and falling over, or if the infant uses his or her arms to prop him- or herself up. The assessment was video recorded at study sites and reviewed/scored by two independent raters. 90% CI for one sample binomial was computed using Clopper-Pearson (exact) method.
Time Frame	Month 24

Outcome Measure Data

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
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
	43.9; (30.62 to 57.87)

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]

14. 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
Description	The BSID-III is a standardized assessment commonly used to evaluate development across five domains in infants and young children aged between 1 and 42 months. The gross motor subscale of the BSID-III is evaluated based on the linear and hierarchical obtainment of motor skills, as seen in typically developing children. The gross motor scale consists of 72 items scored at 0 (unable to perform the activity) or 1 (criteria for item achieved). Reported here is the percentage of participants who achieved item 40 'Stands alone' at Month 24. The assessment was video recorded at study sites and reviewed/scored by two independent raters. 90% CI for one sample binomial was computed using Clopper-Pearson (exact) method.
Time Frame	Month 24

Outcome Measure Data

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
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
	0; (0.00 to 7.05)

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	1.0000
	Comments	[Not Specified]
	Method	One-sided Exact Binomial Test
	Comments	[Not Specified]

15. 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
Description	The BSID-III is a standardized assessment commonly used to evaluate development across five domains in infants and young children aged between 1 and 42 months. The gross motor subscale of the BSID-III is evaluated based on the linear and hierarchical obtainment of motor skills, as seen in typically developing children. The gross motor scale consists of 72 items scored at 0 (unable to perform the activity) or 1 (criteria for item achieved). Reported here is the percentage of participants who achieved item 42 'Walks alone' at Month 24. The assessment was video recorded at study sites and reviewed/scored by two independent raters. 90% CI for one sample binomial was computed using Clopper-Pearson (exact) method.
Time Frame	Month 24

Outcome Measure Data

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
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
	0; (0.00 to 7.05)

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	1.0000
	Comments	[Not Specified]
	Method	One-sided Exact Binomial Test
	Comments	[Not Specified]

16. Secondary Outcome

Title	Part 2: Time to Death
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	Up to 24 months (up to the Clinical Cut-off Date [CCOD] of 12 November 2020)

Outcome Measure Data

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
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.

17. Secondary Outcome

Title	Part 2: Time to Death or Permanent Ventilation
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	Up to 24 months (up to the CCOD of 12 November 2020)

Outcome Measure Data

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
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.

18. Secondary Outcome

Title	Part 2: Time to Permanent Ventilation
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	Up to 24 months (up to the CCOD of 12 November 2020)

Outcome Measure Data

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
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.

19. Secondary Outcome

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

Outcome Measure Data

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
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 12	85.37; (73.35 to 92.24)
Month 24	82.93; (70.54 to 90.44)

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 analysis was only performed for Month 12 data.
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	[Not Specified]
	Method	One-sided Z-test
	Comments	[Not Specified]

20. Secondary Outcome

Title	Part 2: Percentage of Infants Who Are Alive at Months 12 and 24
Description	Kaplan-Meier methodology was used to estimate the percentages. 90% CI was computed using the complementary log-log transformation.
Time Frame	Month 12, Month 24

Outcome Measure Data

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
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 12	92.68; (82.16 to 97.10)
Month 24	92.68; (82.16 to 97.10)

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 analysis was only performed for Month 12 data.
Statistical Test of Hypothesis	P-Value	0.0005
	Comments	[Not Specified]
	Method	One-sided Z-test
	Comments	[Not Specified]

21. Secondary Outcome

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

Outcome Measure Data

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
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 12	92.29; (81.24 to 96.95)
Month 24	89.65; (77.96 to 95.32)

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 analysis was only performed for Month 12 data.
Statistical Test of Hypothesis	P-Value	0.2595
	Comments	[Not Specified]
	Method	One-sided Z-test
	Comments	[Not Specified]

22. 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
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	Month 12

Outcome Measure Data

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
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)

23. Secondary Outcome

Title	Part 2: Percentage of Infants Not Requiring Respiratory Support (Invasive or Non-Invasive) at Months 12 and 24
Description	90% CI for one sample binomial was computed using Clopper-Pearson (exact) method.
Time Frame	Month 12, Month 24

Outcome Measure Data

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
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 12	24.4; (13.87 to 37.85)
Month 24	19.5; (10.10 to 32.46)

24. Secondary Outcome

Title	Part 2: Percentage of Infants Able to Feed Orally at Months 12 and 24
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	Month 12, Month 24

Outcome Measure Data

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
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 12	82.9; (70.31 to 91.70)
Month 24	85.4; (73.15 to 93.43)

25. Secondary Outcome

Title	Part 1 and Part 2: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
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 24 months (CCOD of 12 November 2020)

Outcome Measure Data

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	Confirmatory Part 2 - Risdiplam
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.
Overall Number of Participants Analyzed	4	17	41
Measure Type: Count of Participants; Unit of Measure: Participants
With at least one AE	4 100.0%	17 100.0%	41 100.0%
With at least one SAE	4 100.0%	12 70.6%	28 68.3%

26. Secondary Outcome

Title	Part 2: Number of Participants With AEs and SAEs Leading to Treatment Discontinuation
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 24 months (CCOD of 12 November 2020)

Outcome Measure Data

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
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: Count of Participants; Unit of Measure: Participants
Due to AE	0 0.0%
Due to SAE	0 0.0%

27. Secondary Outcome

Title	Part 2: Number of Participants With AEs and SAEs Leading to Treatment Modification/Interruption
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 24 months (CCOD of 12 November 2020)

Outcome Measure Data

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
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: Count of Participants; Unit of Measure: Participants
Due to AE	2 4.9%
Due to SAE	1 2.4%

28. Secondary Outcome

Title	Part 2: Anthropometric Examination of Weight Measured in Kilograms
Description	Anthropometric examination included weight, height, head circumference and chest circumference.
Time Frame	Month 12, Month 24

Outcome Measure Data

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
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)
Month 12	Number Analyzed	38 participants
		9.59 (1.40)
Month 24	Number Analyzed	36 participants
		11.28 (1.91)

29. Secondary Outcome

Title	Part 2: Anthropometric Examination of Height, Head Circumference and Chest Circumference Measured in Centimeters
Description	Anthropometric examination included weight, height, head circumference and chest circumference.
Time Frame	Month 12, Month 24

Outcome Measure Data

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
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)
Height at Month 12	Number Analyzed	38 participants
		80.47 (4.00)
Height at Month 24	Number Analyzed	36 participants
		89.13 (5.12)
Head Circumference at Month 12	Number Analyzed	38 participants
		47.09 (1.72)
Head Circumference at Month 24	Number Analyzed	35 participants
		49.28 (2.13)
Chest Circumference at Month 12	Number Analyzed	38 participants
		45.77 (2.31)
Chest Circumference at Month 24	Number Analyzed	34 participants
		48.35 (3.10)

30. Secondary Outcome

Title	Part 2: Maximum Plasma Concentration (Cmax) of Risdiplam
Description	[Not Specified]
Time Frame	Day 1: predose, 2, 4, 6, 24 hours; Days 14, 119, 245, 364, 427, 490, 609, 728: predose, 4 hours; Days 28, 56, 182, 301, 546, 672: predose, 2, 4, 6 hours

Outcome Measure Data Not Reported

31. Secondary Outcome

Title	Part 2: Area Under the Curve (AUC) of Risdiplam
Description	[Not Specified]
Time Frame	Day 1: predose, 2, 4, 6, 24 hours; Days 14, 119, 245, 364, 427, 490, 609, 728: predose, 4 hours; Days 28, 56, 182, 301, 546, 672: predose, 2, 4, 6 hours

Outcome Measure Data Not Reported

32. Secondary Outcome

Title	Part 2: Concentration at the End of a Dosing Interval (Ctrough) of Risdiplam
Description	[Not Specified]
Time Frame	Predose on Days 2, 14, 28, 56, 119, 182, 301, 546, 672

Outcome Measure Data Not Reported

33. Secondary Outcome

Title	Survival Motor Neuron (SMN) Protein Levels in Blood
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
Description	[Not Specified]
Time Frame	Days 1, 14 (Part 1 only), 28, 245, 364, 609, 728

Outcome Measure Data Not Reported

Adverse Events

Time Frame	This interim report covers adverse events from first dose of risdiplam up to a minimum of 24 months (CCOD of 12 November 2020).
Adverse Event Reporting Description	All infants who received at least one dose of risdiplam were included in the safety population.
Arm/Group Title	Exploratory Part 1 - Cohort 1		Exploratory Part 1 - Cohort 2		Confirmatory Part 2 - Risdiplam
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%)		3/17 (17.65%)		3/41 (7.32%)
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	4/4 (100.00%)		12/17 (70.59%)		28/41 (68.29%)
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	2/17 (11.76%)	2	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
Intestinal malrotation † 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
Constipation † 1	0/4 (0.00%)	0	0/17 (0.00%)	0	1/41 (2.44%)	1
Diarrhoea † 1	0/4 (0.00%)	0	0/17 (0.00%)	0	1/41 (2.44%)	1
Gastrooesophageal reflux disease † 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	4/17 (23.53%)	4	16/41 (39.02%)	20
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	0/17 (0.00%)	0	0/41 (0.00%)	0
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	1/4 (25.00%)	1	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	1/17 (5.88%)	1	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	1/17 (5.88%)	1	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
Gastroenteritis rotavirus † 1	0/4 (0.00%)	0	0/17 (0.00%)	0	1/41 (2.44%)	1
Respiratory syncytial virus bronchiolitis † 1	0/4 (0.00%)	0	1/17 (5.88%)	1	0/41 (0.00%)	0
Sepsis † 1	0/4 (0.00%)	0	0/17 (0.00%)	0	1/41 (2.44%)	1
Viral upper respiratory tract infection † 1	0/4 (0.00%)	0	1/17 (5.88%)	1	1/41 (2.44%)	1
Injury, poisoning and procedural complications
Near drowning † 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
Oxygen saturation abnormal † 1	0/4 (0.00%)	0	0/17 (0.00%)	0	1/41 (2.44%)	1
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	1/4 (25.00%)	1	0/17 (0.00%)	0	2/41 (4.88%)	2
Decreased appetite † 1	0/4 (0.00%)	0	1/17 (5.88%)	1	0/41 (0.00%)	0
Hypoglycaemia † 1	1/4 (25.00%)	1	1/17 (5.88%)	1	0/41 (0.00%)	0
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	2/41 (4.88%)	2
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%)	2	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	3/41 (7.32%)	3
Respiratory failure † 1	0/4 (0.00%)	0	1/17 (5.88%)	1	2/41 (4.88%)	3
Aspiration † 1	0/4 (0.00%)	0	0/17 (0.00%)	0	2/41 (4.88%)	3
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
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	0/17 (0.00%)	0	1/41 (2.44%)	1
Obstructive airways disorder † 1	0/4 (0.00%)	0	1/17 (5.88%)	1	0/41 (0.00%)	0
1 Term from vocabulary, MedDRA 23.1; † Indicates events were collected by systematic assessment
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%)		16/17 (94.12%)		38/41 (92.68%)
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	1/41 (2.44%)	1
Congenital, familial and genetic disorders
Cryptorchism † 1	0/4 (0.00%)	0	2/17 (11.76%)	2	2/41 (4.88%)	2
Phimosis † 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
Retinal exudates † 1	0/4 (0.00%)	0	1/17 (5.88%)	1	0/41 (0.00%)	0
Strabismus † 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%)	4	12/41 (29.27%)	19
Diarrhoea † 1	0/4 (0.00%)	0	6/17 (35.29%)	8	5/41 (12.20%)	5
Dysphagia † 1	0/4 (0.00%)	0	2/17 (11.76%)	2	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	3/17 (17.65%)	5	1/41 (2.44%)	2
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	2/17 (11.76%)	2	1/41 (2.44%)	1
Teething † 1	0/4 (0.00%)	0	5/17 (29.41%)	7	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	6/17 (35.29%)	12	4/41 (9.76%)	10
Dental caries † 1	0/4 (0.00%)	0	1/17 (5.88%)	1	0/41 (0.00%)	0
Intestinal dilatation † 1	0/4 (0.00%)	0	1/17 (5.88%)	1	0/41 (0.00%)	0
General disorders
Discomfort † 1	0/4 (0.00%)	0	1/17 (5.88%)	1	1/41 (2.44%)	1
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%)	23	13/17 (76.47%)	37	18/41 (43.90%)	47
No coding available † 1	0/4 (0.00%)	0	1/17 (5.88%)	1	1/41 (2.44%)	1
Infections and infestations
Conjunctivitis † 1	0/4 (0.00%)	0	1/17 (5.88%)	1	1/41 (2.44%)	1
Ear infection † 1	1/4 (25.00%)	1	3/17 (17.65%)	4	0/41 (0.00%)	0
Exanthema subitum † 1	1/4 (25.00%)	1	0/17 (0.00%)	0	2/41 (4.88%)	2
Folliculitis † 1	0/4 (0.00%)	0	1/17 (5.88%)	1	0/41 (0.00%)	0
Gastroenteritis † 1	0/4 (0.00%)	0	3/17 (17.65%)	4	1/41 (2.44%)	1
Lower respiratory tract infection † 1	0/4 (0.00%)	0	2/17 (11.76%)	5	0/41 (0.00%)	0
Nasopharyngitis † 1	0/4 (0.00%)	0	5/17 (29.41%)	12	7/41 (17.07%)	13
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	2/41 (4.88%)	2
Pharyngitis † 1	1/4 (25.00%)	1	0/17 (0.00%)	0	2/41 (4.88%)	2
Pneumonia † 1	0/4 (0.00%)	0	0/17 (0.00%)	0	6/41 (14.63%)	6
Pneumonia staphylococcal † 1	0/4 (0.00%)	0	1/17 (5.88%)	1	0/41 (0.00%)	0
Rhinitis † 1	1/4 (25.00%)	1	5/17 (29.41%)	8	5/41 (12.20%)	7
Upper respiratory tract infection † 1	1/4 (25.00%)	4	10/17 (58.82%)	21	22/41 (53.66%)	47
Urinary tract infection † 1	1/4 (25.00%)	2	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	2/17 (11.76%)	2	1/41 (2.44%)	1
Viral upper respiratory tract infection † 1	0/4 (0.00%)	0	1/17 (5.88%)	1	1/41 (2.44%)	1
Bronchitis † 1	0/4 (0.00%)	0	0/17 (0.00%)	0	5/41 (12.20%)	6
Gastroenteritis adenovirus † 1	0/4 (0.00%)	0	1/17 (5.88%)	1	0/41 (0.00%)	0
Influenza † 1	1/4 (25.00%)	1	1/17 (5.88%)	1	2/41 (4.88%)	2
Stoma site cellulitis † 1	0/4 (0.00%)	0	1/17 (5.88%)	1	0/41 (0.00%)	0
Upper respiratory tract infection bacterial † 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	1/41 (2.44%)	1
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	2/17 (11.76%)	2	3/41 (7.32%)	3
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
Humerus fracture † 1	0/4 (0.00%)	0	1/17 (5.88%)	1	0/41 (0.00%)	0
Investigations
Weight decreased † 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	1/41 (2.44%)	1
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	1/41 (2.44%)	1
Joint instability † 1	0/4 (0.00%)	0	1/17 (5.88%)	1	0/41 (0.00%)	0
Kyphoscoliosis † 1	0/4 (0.00%)	0	1/17 (5.88%)	1	0/41 (0.00%)	0
Osteoporosis † 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	1/41 (2.44%)	1
Cough † 1	0/4 (0.00%)	0	7/17 (41.18%)	10	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	3/17 (17.65%)	4	0/41 (0.00%)	0
Respiratory tract congestion † 1	0/4 (0.00%)	0	2/17 (11.76%)	2	1/41 (2.44%)	1
Rhinorrhoea † 1	0/4 (0.00%)	0	2/17 (11.76%)	3	1/41 (2.44%)	2
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	1/41 (2.44%)	1
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	1/41 (2.44%)	1
Dermatitis allergic † 1	0/4 (0.00%)	0	1/17 (5.88%)	1	1/41 (2.44%)	1
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	1/41 (2.44%)	1
Erythema † 1	2/4 (50.00%)	3	1/17 (5.88%)	2	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	1/41 (2.44%)	1
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
Vascular disorders
Haematoma † 1	0/4 (0.00%)	0	1/17 (5.88%)	1	0/41 (0.00%)	0
1 Term from vocabulary, MedDRA 23.1; † Indicates events were collected by systematic assessment

Limitations and Caveats

[Not Specified]

More Information

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

• Name/Title: Medical Communications
• Organization: Hoffmann-La Roche
• Phone: 800 821-8590
• EMail: genentech@druginfo.com

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Masson R, Mazurkiewicz-Beldzinska M, Rose K, Servais L, Xiong H, Zanoteli E, Baranello G, Bruno C, Day JW, Deconinck N, Klein A, Mercuri E, Vlodavets D, Wang Y, Dodman A, El-Khairi M, Gorni K, Jaber B, Kletzl H, Gaki E, Fontoura P, Darras BT; FIREFISH Study Group. Safety and efficacy of risdiplam in patients with type 1 spinal muscular atrophy (FIREFISH part 2): secondary analyses from an open-label trial. Lancet Neurol. 2022 Dec;21(12):1110-1119. doi: 10.1016/S1474-4422(22)00339-8. Epub 2022 Oct 14.

Cances C, Vlodavets D, Comi GP, Masson R, Mazurkiewicz-Beldzinska M, Saito K, Zanoteli E, Dodman A, El-Khairi M, Gorni K, Gravestock I, Hoffart J, Scalco RS, Darras BT; ANCHOVY Working Group. Natural history of Type 1 spinal muscular atrophy: a retrospective, global, multicenter study. Orphanet J Rare Dis. 2022 Jul 29;17(1):300. doi: 10.1186/s13023-022-02455-x.

Darras BT, Masson R, Mazurkiewicz-Beldzinska M, Rose K, Xiong H, Zanoteli E, Baranello G, Bruno C, Vlodavets D, Wang Y, El-Khairi M, Gerber M, Gorni K, Khwaja O, Kletzl H, Scalco RS, Fontoura P, Servais L; FIREFISH Working Group. Risdiplam-Treated Infants with Type 1 Spinal Muscular Atrophy versus Historical Controls. N Engl J Med. 2021 Jul 29;385(5):427-435. doi: 10.1056/NEJMoa2102047.

Baranello G, Darras BT, Day JW, Deconinck N, Klein A, Masson R, Mercuri E, Rose K, El-Khairi M, Gerber M, Gorni K, Khwaja O, Kletzl H, Scalco RS, Seabrook T, Fontoura P, Servais L; FIREFISH Working Group. Risdiplam in Type 1 Spinal Muscular Atrophy. N Engl J Med. 2021 Mar 11;384(10):915-923. doi: 10.1056/NEJMoa2009965. Epub 2021 Feb 24.

• 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: January 5, 2024