Trial Outcomes & Findings for Investigate Safety, Tolerability, PK, PD and Efficacy of Risdiplam (RO7034067) in Infants With Type1 Spinal Muscular Atrophy (NCT NCT02913482)

Last Updated: 2024-08-07

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

62 participants

Primary outcome timeframe

Minimum of 2 weeks at steady state exposure

Results posted on

2024-08-07

Participant Flow

Part 1 was conducted at 7 investigational sites across 5 countries; Part 2 was conducted at 14 investigational sites across 10 countries.

Participant milestones

Participant milestones
Measure	Exploratory Part 1 - Cohort 1 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.	Exploratory Part 1 - Cohort 2 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.	Confirmatory Part 2 - Risdiplam Participants received risdiplam orally once daily at a dose targeting an exposure of mean AUC0-24h,ss \</= 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 5 mg when the participant reached 20 kg body weight.
Overall Study STARTED	4	17	41
Overall Study COMPLETED	3	13	36
Overall Study NOT COMPLETED	1	4	5

Reasons for withdrawal

Reasons for withdrawal
Measure	Exploratory Part 1 - Cohort 1 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.	Exploratory Part 1 - Cohort 2 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.	Confirmatory Part 2 - Risdiplam Participants received risdiplam orally once daily at a dose targeting an exposure of mean AUC0-24h,ss \</= 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 5 mg when the participant reached 20 kg body weight.
Overall Study Death	0	2	2
Overall Study Progressive Disease	1	1	1
Overall Study Reason not specified	0	0	1
Overall Study Withdrawal by Subject	0	1	1

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Exploratory Part 1 - Cohort 1 n=4 Participants 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.	Exploratory Part 1 - Cohort 2 n=17 Participants 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.	Confirmatory Part 2 - Risdiplam n=41 Participants Participants received risdiplam orally once daily at a dose targeting an exposure of mean AUC0-24h,ss \</= 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 5 mg when the participant reached 20 kg body weight.	Total n=62 Participants Total of all reporting groups
Age, Continuous	6.84 Months STANDARD_DEVIATION 0.10 • n=5 Participants	5.56 Months STANDARD_DEVIATION 1.43 • n=7 Participants	5.20 Months STANDARD_DEVIATION 1.47 • n=5 Participants	5.41 Months STANDARD_DEVIATION 1.46 • n=4 Participants
Sex: Female, Male Female	4 Participants n=5 Participants	11 Participants n=7 Participants	22 Participants n=5 Participants	37 Participants n=4 Participants
Sex: Female, Male Male	0 Participants n=5 Participants	6 Participants n=7 Participants	19 Participants n=5 Participants	25 Participants n=4 Participants
Race/Ethnicity, Customized Not Hispanic or Latino	4 Participants n=5 Participants	17 Participants n=7 Participants	36 Participants n=5 Participants	57 Participants n=4 Participants
Race/Ethnicity, Customized Hispanic or Latino	0 Participants n=5 Participants	0 Participants n=7 Participants	5 Participants n=5 Participants	5 Participants n=4 Participants
Race/Ethnicity, Customized Asian	0 Participants n=5 Participants	4 Participants n=7 Participants	14 Participants n=5 Participants	18 Participants n=4 Participants
Race/Ethnicity, Customized White	4 Participants n=5 Participants	9 Participants n=7 Participants	22 Participants n=5 Participants	35 Participants n=4 Participants
Race/Ethnicity, Customized Unknown	0 Participants n=5 Participants	4 Participants n=7 Participants	5 Participants n=5 Participants	9 Participants n=4 Participants

PRIMARY outcome

Timeframe: Minimum of 2 weeks at steady state exposure

Population: 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.

Outcome measures

Outcome measures
Measure	Exploratory Part 1 - Risdiplam n=18 Participants 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.	Exploratory Part 1 - Cohort 2 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.	Confirmatory Part 2 - Risdiplam Participants received risdiplam orally once daily at a dose targeting an exposure of mean AUC0-24h,ss \</= 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 5 mg when the participant reached 20 kg body weight.
Part 1: Selected Part 2 Dose of Risdiplam	0.2 mg/kg	—	—

PRIMARY outcome

Timeframe: Month 12

Population: 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.

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.

Outcome measures

Outcome measures
Measure	Exploratory Part 1 - Risdiplam n=41 Participants 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.	Exploratory Part 1 - Cohort 2 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.	Confirmatory Part 2 - Risdiplam Participants received risdiplam orally once daily at a dose targeting an exposure of mean AUC0-24h,ss \</= 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 5 mg when the participant reached 20 kg body weight.
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	29.3 Percentage of Participants Interval 17.84 to 43.07	—	—

SECONDARY outcome

Timeframe: Month 12

Population: 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.

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.

Outcome measures

Outcome measures
Measure	Exploratory Part 1 - Risdiplam n=41 Participants 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.	Exploratory Part 1 - Cohort 2 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.	Confirmatory Part 2 - Risdiplam Participants received risdiplam orally once daily at a dose targeting an exposure of mean AUC0-24h,ss \</= 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 5 mg when the participant reached 20 kg body weight.
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	56.1 Percentage of Participants Interval 42.13 to 69.38	—	—

SECONDARY outcome

Timeframe: Month 8, Month 12

Population: 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.

Outcome measures

Outcome measures
Measure	Exploratory Part 1 - Risdiplam n=41 Participants 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.	Exploratory Part 1 - Cohort 2 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.	Confirmatory Part 2 - Risdiplam Participants received risdiplam orally once daily at a dose targeting an exposure of mean AUC0-24h,ss \</= 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 5 mg when the participant reached 20 kg body weight.
Part 2: Percentage of Infants Achieving an Increase of >/= 4 Points in Their CHOP-INTEND Score From Baseline at Months 8 and 12 Month 8	87.8 Percentage of Participants Interval 76.05 to 95.07	—	—
Part 2: Percentage of Infants Achieving an Increase of >/= 4 Points in Their CHOP-INTEND Score From Baseline at Months 8 and 12 Month 12	90.2 Percentage of Participants Interval 79.05 to 96.6	—	—

SECONDARY outcome

Timeframe: Month 8, Month 12, Month 24

Population: 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.

Outcome measures

Outcome measures
Measure	Exploratory Part 1 - Risdiplam n=41 Participants 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.	Exploratory Part 1 - Cohort 2 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.	Confirmatory Part 2 - Risdiplam Participants received risdiplam orally once daily at a dose targeting an exposure of mean AUC0-24h,ss \</= 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 5 mg when the participant reached 20 kg body weight.
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 Month 8	46.3 Percentage of Participants Interval 32.87 to 60.23	—	—
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 Month 12	53.7 Percentage of Participants Interval 39.77 to 67.13	—	—
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 Month 24	70.7 Percentage of Participants Interval 56.93 to 82.16	—	—

SECONDARY outcome

Timeframe: Baseline, Month 12, Month 24

Population: 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.

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.

Outcome measures

Outcome measures
Measure	Exploratory Part 1 - Risdiplam n=41 Participants 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.	Exploratory Part 1 - Cohort 2 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.	Confirmatory Part 2 - Risdiplam Participants received risdiplam orally once daily at a dose targeting an exposure of mean AUC0-24h,ss \</= 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 5 mg when the participant reached 20 kg body weight.
Part 2: Change From Baseline in the Total Raw Score of the BSID-III Gross Motor Scale at Months 12 and 24 Baseline	1.85 Scores on a Scale Standard Deviation 1.61	—	—
Part 2: Change From Baseline in the Total Raw Score of the BSID-III Gross Motor Scale at Months 12 and 24 Change from Baseline at Month 12	7.21 Scores on a Scale Standard Deviation 5.71	—	—
Part 2: Change From Baseline in the Total Raw Score of the BSID-III Gross Motor Scale at Months 12 and 24 Change from Baseline at Month 24	12.89 Scores on a Scale Standard Deviation 6.89	—	—

SECONDARY outcome

Timeframe: Month 8

Population: 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.

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.

Outcome measures

Outcome measures
Measure	Exploratory Part 1 - Risdiplam n=41 Participants 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.	Exploratory Part 1 - Cohort 2 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.	Confirmatory Part 2 - Risdiplam Participants received risdiplam orally once daily at a dose targeting an exposure of mean AUC0-24h,ss \</= 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 5 mg when the participant reached 20 kg body weight.
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 Unable to maintain head upright (Head Control) at Month 8	36.6 Percentage of Participants	—	—
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 Wobbles (Head Control) at Month 8	14.6 Percentage of Participants	—	—
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 All the time maintained upright (Head Control) at Month 8	39.0 Percentage of Participants	—	—
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 No kicking (Ability to Kick [supine]) at Month 8	24.4 Percentage of Participants	—	—
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 Kicks horizontally; legs do not lift (Ability to Kick [supine]) at Month 8	58.5 Percentage of Participants	—	—
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 Upward (vertically) (Ability to Kick [supine]) at Month 8	7.3 Percentage of Participants	—	—
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 Touches leg (Ability to Kick [supine]) at Month 8	0 Percentage of Participants	—	—
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 Touches toes (Ability to Kick [supine]) at Month 8	0 Percentage of Participants	—	—
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 No rolling (Rolling) at Month 8	56.1 Percentage of Participants	—	—
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 Rolling to side (Rolling) at Month 8	29.3 Percentage of Participants	—	—
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 Prone to supine (Rolling) at Month 8	2.4 Percentage of Participants	—	—
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 Supine to prone (Rolling) at Month 8	2.4 Percentage of Participants	—	—

SECONDARY outcome

Timeframe: Month 12

Population: 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.

Outcome measures

Outcome measures
Measure	Exploratory Part 1 - Risdiplam n=41 Participants 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.	Exploratory Part 1 - Cohort 2 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.	Confirmatory Part 2 - Risdiplam Participants received risdiplam orally once daily at a dose targeting an exposure of mean AUC0-24h,ss \</= 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 5 mg when the participant reached 20 kg body weight.
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 Unable to maintain head upright (Head Control) at Month 12	17.1 Percentage of Participants	—	—
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 Wobbles (Head Control) at Month 12	31.7 Percentage of Participants	—	—
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 All the time maintained upright (Head Control) at Month 12	43.9 Percentage of Participants	—	—
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 Cannot sit (Sitting) at Month 12	31.7 Percentage of Participants	—	—
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 Sits with support at hips (Sitting) at Month 12	17.1 Percentage of Participants	—	—
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 Props (Sitting) at Month 12	19.5 Percentage of Participants	—	—
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 Stable sit (Sitting) at Month 12	14.6 Percentage of Participants	—	—
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 Pivots (rotates) (Sitting) at Month 12	9.8 Percentage of Participants	—	—
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 No grasp (Voluntary Grasp) at Month 12	2.4 Percentage of Participants	—	—
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 Uses whole hand (Voluntary Grasp) at Month 12	29.3 Percentage of Participants	—	—
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 Index finger and thumb but immature grasp (Voluntary Grasp) at Month 12	48.8 Percentage of Participants	—	—
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 Pincer grasp (Voluntary Grasp) at Month 12	12.2 Percentage of Participants	—	—
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 No kicking (Ability to Kick [supine]) at Month 12	12.2 Percentage of Participants	—	—
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 Kicks horizontally; legs do not lift (Ability to Kick [supine]) at Month 12	58.5 Percentage of Participants	—	—
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 Upward (vertically) (Ability to Kick [supine]) at Month 12	7.3 Percentage of Participants	—	—
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 Touches leg (Ability to Kick [supine]) at Month 12	4.9 Percentage of Participants	—	—
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 Touches toes (Ability to Kick [supine]) at Month 12	9.8 Percentage of Participants	—	—
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 No rolling (Rolling) at Month 12	36.6 Percentage of Participants	—	—
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 Rolling to side (Rolling) at Month 12	31.7 Percentage of Participants	—	—
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 Prone to supine (Rolling) at Month 12	14.6 Percentage of Participants	—	—
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 Supine to prone (Rolling) at Month 12	9.8 Percentage of Participants	—	—
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 Does not lift head (Crawling) at Month 12	85.4 Percentage of Participants	—	—
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 On elbow (Crawling) at Month 12	2.4 Percentage of Participants	—	—
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 On outstretched hand (Crawling) at Month 12	2.4 Percentage of Participants	—	—
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 Crawling flat on abdomen (Crawling) at Month 12	0 Percentage of Participants	—	—
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 Crawling on hands and knees (Crawling) at Month 12	0 Percentage of Participants	—	—
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 Cannot test (Crawling) at Month 12	2.4 Percentage of Participants	—	—
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 Does not support weight (Standing) at Month 12	61.0 Percentage of Participants	—	—
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 Supports weight (Standing) at Month 12	17.1 Percentage of Participants	—	—
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 Stands with support (Standing) at Month 12	4.9 Percentage of Participants	—	—
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 Stands unaided (Standing) at Month 12	0 Percentage of Participants	—	—
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 Cannot test (Standing) at Month 12	4.9 Percentage of Participants	—	—
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 Not done (Standing) at Month 12	4.9 Percentage of Participants	—	—
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 Bouncing (Walking) at Month 12	2.4 Percentage of Participants	—	—
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 Cruising (walks holding on) (Walking) at Month 12	0 Percentage of Participants	—	—
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 Walking independently (Walking) at Month 12	0 Percentage of Participants	—	—
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 Cannot test (Walking) at Month 12	82.9 Percentage of Participants	—	—
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 Not Done (Walking) at Month 12	7.3 Percentage of Participants	—	—

SECONDARY outcome

Timeframe: Month 24

Population: 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.

Outcome measures

Outcome measures
Measure	Exploratory Part 1 - Risdiplam n=41 Participants 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.	Exploratory Part 1 - Cohort 2 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.	Confirmatory Part 2 - Risdiplam Participants received risdiplam orally once daily at a dose targeting an exposure of mean AUC0-24h,ss \</= 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 5 mg when the participant reached 20 kg body weight.
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 Unable to maintain head upright (Head Control) at Month 24	7.3 Percentage of Participants	—	—
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 Wobbles (Head Control) at Month 24	19.5 Percentage of Participants	—	—
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 All the time maintained upright (Head Control) at Month 24	63.4 Percentage of Participants	—	—
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 Not done (Head Control) at Month 24	2.4 Percentage of Participants	—	—
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 Cannot sit (Sitting) at Month 24	19.5 Percentage of Participants	—	—
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 Sits with support at hips (Sitting) at Month 24	7.3 Percentage of Participants	—	—
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 Props (Sitting) at Month 24	9.8 Percentage of Participants	—	—
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 Stable sit (Sitting) at Month 24	24.4 Percentage of Participants	—	—
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 Pivots (rotates) (Sitting) at Month 24	29.3 Percentage of Participants	—	—
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 Not done (Sitting) at Month 24	2.4 Percentage of Participants	—	—
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 No grasp (Voluntary Grasp) at Month 24	2.4 Percentage of Participants	—	—
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 Uses whole hand (Voluntary Grasp) at Month 24	4.9 Percentage of Participants	—	—
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 Index finger and thumb but immature grasp (Voluntary Grasp) at Month 24	39.0 Percentage of Participants	—	—
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 Pincer grasp (Voluntary Grasp) at Month 24	41.5 Percentage of Participants	—	—
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 Not done (Voluntary Grasp) at Month 24	4.9 Percentage of Participants	—	—
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 No kicking (Ability to Kick [supine]) at Month 24	7.3 Percentage of Participants	—	—
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 Kicks horizontally; legs do not lift (Ability to Kick [supine]) at Month 24	31.7 Percentage of Participants	—	—
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 Upward (vertically) (Ability to Kick [supine]) at Month 24	9.8 Percentage of Participants	—	—
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 Touches leg (Ability to Kick [supine]) at Month 24	9.8 Percentage of Participants	—	—
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 Touches toes (Ability to Kick [supine]) at Month 24	31.7 Percentage of Participants	—	—
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 Not Done (Ability to Kick [supine]) at Month 24	2.4 Percentage of Participants	—	—
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 No rolling (Rolling) at Month 24	9.8 Percentage of Participants	—	—
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 Rolling to side (Rolling) at Month 24	29.3 Percentage of Participants	—	—
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 Prone to supine (Rolling) at Month 24	7.3 Percentage of Participants	—	—
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 Supine to prone (Rolling) at Month 24	43.9 Percentage of Participants	—	—
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 Not Done (Rolling) at Month 24	2.4 Percentage of Participants	—	—
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 Does not lift head (Crawling) at Month 24	75.6 Percentage of Participants	—	—
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 On elbow (Crawling) at Month 24	7.3 Percentage of Participants	—	—
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 On outstretched hand (Crawling) at Month 24	2.4 Percentage of Participants	—	—
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 Crawling flat on abdomen (Crawling) at Month 24	0 Percentage of Participants	—	—
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 Crawling on hands and knees (Crawling) at Month 24	4.9 Percentage of Participants	—	—
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 Not done (Crawling) at Month 24	2.4 Percentage of Participants	—	—
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 Does not support weight (Standing) at Month 24	63.4 Percentage of Participants	—	—
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 Supports weight (Standing) at Month 24	12.2 Percentage of Participants	—	—
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 Stands with support (Standing) at Month 24	14.6 Percentage of Participants	—	—
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 Stands unaided (Standing) at Month 24	0 Percentage of Participants	—	—
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 Not done (Standing) at Month 24	2.4 Percentage of Participants	—	—
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 Bouncing (Walking) at Month 24	2.4 Percentage of Participants	—	—
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 Cruising (walks holding on) (Walking) at Month 24	2.4 Percentage of Participants	—	—
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 Walking independently (Walking) at Month 24	0 Percentage of Participants	—	—
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 Cannot test (Walking) at Month 24	75.6 Percentage of Participants	—	—
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 Not Done (Walking) at Month 24	12.2 Percentage of Participants	—	—

SECONDARY outcome

Timeframe: Month 12, Month 24

Population: 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.

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.

Outcome measures

Outcome measures
Measure	Exploratory Part 1 - Risdiplam n=41 Participants 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.	Exploratory Part 1 - Cohort 2 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.	Confirmatory Part 2 - Risdiplam Participants received risdiplam orally once daily at a dose targeting an exposure of mean AUC0-24h,ss \</= 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 5 mg when the participant reached 20 kg body weight.
Part 2: Percentage of Motor Milestone Responders as Assessed by HINE-2 at Months 12 and 24 Month 12	78.0 Percentage of Participants Interval 64.82 to 88.04	—	—
Part 2: Percentage of Motor Milestone Responders as Assessed by HINE-2 at Months 12 and 24 Month 24	85.4 Percentage of Participants Interval 73.15 to 93.43	—	—

SECONDARY outcome

Timeframe: Month 12, Month 24

Population: 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.

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.

Outcome measures

Outcome measures
Measure	Exploratory Part 1 - Risdiplam n=41 Participants 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.	Exploratory Part 1 - Cohort 2 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.	Confirmatory Part 2 - Risdiplam Participants received risdiplam orally once daily at a dose targeting an exposure of mean AUC0-24h,ss \</= 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 5 mg when the participant reached 20 kg body weight.
Part 2: Highest Motor Milestone Achieved of Six Specified Milestones Assessed in the BSID-III Gross Motor Scale by Months 12 and 24 Item 9: Controls Head While Upright for 15 sec at Month 12	0 Percentage of Participants	—	—
Part 2: Highest Motor Milestone Achieved of Six Specified Milestones Assessed in the BSID-III Gross Motor Scale by Months 12 and 24 Item 14: Rolls from Side to Back at Month 12	56.1 Percentage of Participants	—	—
Part 2: Highest Motor Milestone Achieved of Six Specified Milestones Assessed in the BSID-III Gross Motor Scale by Months 12 and 24 Item 22: Sits Without Support for 5 sec at Month 12	29.3 Percentage of Participants	—	—
Part 2: Highest Motor Milestone Achieved of Six Specified Milestones Assessed in the BSID-III Gross Motor Scale by Months 12 and 24 Item 30: Crawls on Stomach at Month 12	0 Percentage of Participants	—	—
Part 2: Highest Motor Milestone Achieved of Six Specified Milestones Assessed in the BSID-III Gross Motor Scale by Months 12 and 24 Item 40: Stands Alone at Month 12	0 Percentage of Participants	—	—
Part 2: Highest Motor Milestone Achieved of Six Specified Milestones Assessed in the BSID-III Gross Motor Scale by Months 12 and 24 Item 42: Walks Alone at Month 12	0 Percentage of Participants	—	—
Part 2: Highest Motor Milestone Achieved of Six Specified Milestones Assessed in the BSID-III Gross Motor Scale by Months 12 and 24 Item 9: Controls Head While Upright for 15 sec at Month 24	0 Percentage of Participants	—	—
Part 2: Highest Motor Milestone Achieved of Six Specified Milestones Assessed in the BSID-III Gross Motor Scale by Months 12 and 24 Item 14: Rolls from Side to Back at Month 24	29.3 Percentage of Participants	—	—
Part 2: Highest Motor Milestone Achieved of Six Specified Milestones Assessed in the BSID-III Gross Motor Scale by Months 12 and 24 Item 22: Sits Without Support for 5 sec at Month 24	61.0 Percentage of Participants	—	—
Part 2: Highest Motor Milestone Achieved of Six Specified Milestones Assessed in the BSID-III Gross Motor Scale by Months 12 and 24 Item 30: Crawls on Stomach at Month 24	0 Percentage of Participants	—	—
Part 2: Highest Motor Milestone Achieved of Six Specified Milestones Assessed in the BSID-III Gross Motor Scale by Months 12 and 24 Item 40: Stands Alone at Month 24	0 Percentage of Participants	—	—
Part 2: Highest Motor Milestone Achieved of Six Specified Milestones Assessed in the BSID-III Gross Motor Scale by Months 12 and 24 Item 42: Walks Alone at Month 24	0 Percentage of Participants	—	—

SECONDARY outcome

Timeframe: Month 24

Population: 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.

Outcome measures

Outcome measures
Measure	Exploratory Part 1 - Risdiplam n=41 Participants 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.	Exploratory Part 1 - Cohort 2 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.	Confirmatory Part 2 - Risdiplam Participants received risdiplam orally once daily at a dose targeting an exposure of mean AUC0-24h,ss \</= 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 5 mg when the participant reached 20 kg body weight.
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	61.0 Percentage of Participants Interval 46.94 to 73.77	—	—

SECONDARY outcome

Timeframe: Month 24

Population: 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.

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.

Outcome measures

Outcome measures
Measure	Exploratory Part 1 - Risdiplam n=41 Participants 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.	Exploratory Part 1 - Cohort 2 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.	Confirmatory Part 2 - Risdiplam Participants received risdiplam orally once daily at a dose targeting an exposure of mean AUC0-24h,ss \</= 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 5 mg when the participant reached 20 kg body weight.
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	43.9 Percentage of Participants Interval 30.62 to 57.87	—	—

SECONDARY outcome

Timeframe: Month 24

Population: 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.

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.

Outcome measures

Outcome measures
Measure	Exploratory Part 1 - Risdiplam n=41 Participants 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.	Exploratory Part 1 - Cohort 2 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.	Confirmatory Part 2 - Risdiplam Participants received risdiplam orally once daily at a dose targeting an exposure of mean AUC0-24h,ss \</= 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 5 mg when the participant reached 20 kg body weight.
Part 2: Percentage of Infants Who Are Standing Alone as Assessed by Item 40 of the BSID-III Gross Motor Scale at Month 24	0 Percentage of Participants Interval 0.0 to 7.05	—	—

SECONDARY outcome

Timeframe: Month 24

Population: 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.

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.

Outcome measures

Outcome measures
Measure	Exploratory Part 1 - Risdiplam n=41 Participants 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.	Exploratory Part 1 - Cohort 2 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.	Confirmatory Part 2 - Risdiplam Participants received risdiplam orally once daily at a dose targeting an exposure of mean AUC0-24h,ss \</= 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 5 mg when the participant reached 20 kg body weight.
Part 2: Percentage of Infants Who Are Walking Alone as Assessed by Item 42 of the BSID-III Gross Motor Scale at Month 24	0 Percentage of Participants Interval 0.0 to 7.05	—	—

SECONDARY outcome

Timeframe: Up to 24 months

Population: 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.

The median time to event was estimated using Kaplan-Meier methodology. 90% CI was estimated using the method of Brookmeyer and Crowley.

Outcome measures

Outcome measures
Measure	Exploratory Part 1 - Risdiplam n=41 Participants 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.	Exploratory Part 1 - Cohort 2 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.	Confirmatory Part 2 - Risdiplam Participants received risdiplam orally once daily at a dose targeting an exposure of mean AUC0-24h,ss \</= 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 5 mg when the participant reached 20 kg body weight.
Part 2: Time to Death	NA Months The median time to death was not estimable as few participants had an event.	—	—

SECONDARY outcome

Timeframe: Up to 24 months

Population: 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.

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.

Outcome measures

Outcome measures
Measure	Exploratory Part 1 - Risdiplam n=41 Participants 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.	Exploratory Part 1 - Cohort 2 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.	Confirmatory Part 2 - Risdiplam Participants received risdiplam orally once daily at a dose targeting an exposure of mean AUC0-24h,ss \</= 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 5 mg when the participant reached 20 kg body weight.
Part 2: Time to Death or Permanent Ventilation	NA Months The median time to death or permanent ventilation was not estimable as few participants had an event.	—	—

SECONDARY outcome

Timeframe: Up to 24 months

Population: 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.

Outcome measures

Outcome measures
Measure	Exploratory Part 1 - Risdiplam n=41 Participants 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.	Exploratory Part 1 - Cohort 2 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.	Confirmatory Part 2 - Risdiplam Participants received risdiplam orally once daily at a dose targeting an exposure of mean AUC0-24h,ss \</= 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 5 mg when the participant reached 20 kg body weight.
Part 2: Time to Permanent Ventilation	NA Months The median time to permanent ventilation was not estimable as few participants had an event.	—	—

SECONDARY outcome

Timeframe: Month 12, Month 24

Population: 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.

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.

Outcome measures

Outcome measures
Measure	Exploratory Part 1 - Risdiplam n=41 Participants 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.	Exploratory Part 1 - Cohort 2 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.	Confirmatory Part 2 - Risdiplam Participants received risdiplam orally once daily at a dose targeting an exposure of mean AUC0-24h,ss \</= 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 5 mg when the participant reached 20 kg body weight.
Part 2: Percentage of Infants Who Are Alive Without Permanent Ventilation at Months 12 and 24 Month 12	85.37 Percentage of Participants Interval 73.35 to 92.24	—	—
Part 2: Percentage of Infants Who Are Alive Without Permanent Ventilation at Months 12 and 24 Month 24	82.93 Percentage of Participants Interval 70.54 to 90.44	—	—

SECONDARY outcome

Timeframe: Month 12, Month 24

Population: 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.

Kaplan-Meier methodology was used to estimate the percentages. 90% CI was computed using the complementary log-log transformation.

Outcome measures

Outcome measures
Measure	Exploratory Part 1 - Risdiplam n=41 Participants 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.	Exploratory Part 1 - Cohort 2 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.	Confirmatory Part 2 - Risdiplam Participants received risdiplam orally once daily at a dose targeting an exposure of mean AUC0-24h,ss \</= 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 5 mg when the participant reached 20 kg body weight.
Part 2: Percentage of Infants Who Are Alive at Months 12 and 24 Month 12	92.68 Percentage of Participants Interval 82.16 to 97.1	—	—
Part 2: Percentage of Infants Who Are Alive at Months 12 and 24 Month 24	92.68 Percentage of Participants Interval 82.16 to 97.1	—	—

SECONDARY outcome

Timeframe: Month 12, Month 24

Population: 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.

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.

Outcome measures

Outcome measures
Measure	Exploratory Part 1 - Risdiplam n=41 Participants 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.	Exploratory Part 1 - Cohort 2 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.	Confirmatory Part 2 - Risdiplam Participants received risdiplam orally once daily at a dose targeting an exposure of mean AUC0-24h,ss \</= 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 5 mg when the participant reached 20 kg body weight.
Part 2: Percentage of Infants Who Are Without Permanent Ventilation at Months 12 and 24 Month 12	92.29 Percentage of Participants Interval 81.24 to 96.95	—	—
Part 2: Percentage of Infants Who Are Without Permanent Ventilation at Months 12 and 24 Month 24	89.65 Percentage of Participants Interval 77.96 to 95.32	—	—

SECONDARY outcome

Timeframe: Month 12

Population: 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.

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.

Outcome measures

Outcome measures
Measure	Exploratory Part 1 - Risdiplam n=41 Participants 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.	Exploratory Part 1 - Cohort 2 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.	Confirmatory Part 2 - Risdiplam Participants received risdiplam orally once daily at a dose targeting an exposure of mean AUC0-24h,ss \</= 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 5 mg when the participant reached 20 kg body weight.
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	34.1 Percentage of Participants Interval 21.96 to 48.13	—	—

SECONDARY outcome

Timeframe: Month 12, Month 24

Population: 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.

90% CI for one sample binomial was computed using Clopper-Pearson (exact) method.

Outcome measures

Outcome measures
Measure	Exploratory Part 1 - Risdiplam n=41 Participants 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.	Exploratory Part 1 - Cohort 2 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.	Confirmatory Part 2 - Risdiplam Participants received risdiplam orally once daily at a dose targeting an exposure of mean AUC0-24h,ss \</= 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 5 mg when the participant reached 20 kg body weight.
Part 2: Percentage of Infants Not Requiring Respiratory Support (Invasive or Non-Invasive) at Months 12 and 24 Month 12	24.4 Percentage of Participants Interval 13.87 to 37.85	—	—
Part 2: Percentage of Infants Not Requiring Respiratory Support (Invasive or Non-Invasive) at Months 12 and 24 Month 24	19.5 Percentage of Participants Interval 10.1 to 32.46	—	—

SECONDARY outcome

Timeframe: Month 12, Month 24

Population: 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.

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.

Outcome measures

Outcome measures
Measure	Exploratory Part 1 - Risdiplam n=41 Participants 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.	Exploratory Part 1 - Cohort 2 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.	Confirmatory Part 2 - Risdiplam Participants received risdiplam orally once daily at a dose targeting an exposure of mean AUC0-24h,ss \</= 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 5 mg when the participant reached 20 kg body weight.
Part 2: Percentage of Infants Able to Feed Orally at Months 12 and 24 Month 12	82.9 Percentage of Participants Interval 70.31 to 91.7	—	—
Part 2: Percentage of Infants Able to Feed Orally at Months 12 and 24 Month 24	85.4 Percentage of Participants Interval 73.15 to 93.43	—	—

SECONDARY outcome

Timeframe: From first dose up to 30 days after last dose of risdiplam (up to 60 months)

Population: All infants who received at least one dose of study medication (risdiplam) were included in the safety population.

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.

Outcome measures

Outcome measures
Measure	Exploratory Part 1 - Risdiplam n=4 Participants 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.	Exploratory Part 1 - Cohort 2 n=17 Participants 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.	Confirmatory Part 2 - Risdiplam n=41 Participants Participants received risdiplam orally once daily at a dose targeting an exposure of mean AUC0-24h,ss \</= 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 5 mg when the participant reached 20 kg body weight.
Part 1 and Part 2: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) With at least one AE	4 Participants	17 Participants	41 Participants
Part 1 and Part 2: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) With at least one SAE	4 Participants	13 Participants	34 Participants

SECONDARY outcome

Timeframe: From first dose up to 30 days after last dose of risdiplam (up to 60 months)

Population: All infants who received at least one dose of study medication (risdiplam) were included in the safety population.

Outcome measures

Outcome measures
Measure	Exploratory Part 1 - Risdiplam n=41 Participants 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.	Exploratory Part 1 - Cohort 2 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.	Confirmatory Part 2 - Risdiplam Participants received risdiplam orally once daily at a dose targeting an exposure of mean AUC0-24h,ss \</= 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 5 mg when the participant reached 20 kg body weight.
Part 2: Number of Participants With AEs and SAEs Leading to Treatment Discontinuation Due to AE	0 Participants	—	—
Part 2: Number of Participants With AEs and SAEs Leading to Treatment Discontinuation Due to SAE	0 Participants	—	—

SECONDARY outcome

Timeframe: From first dose up to 30 days after last dose of risdiplam (up to 60 months)

Population: All infants who received at least one dose of study medication (risdiplam) were included in the safety population.

Outcome measures

Outcome measures
Measure	Exploratory Part 1 - Risdiplam n=41 Participants 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.	Exploratory Part 1 - Cohort 2 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.	Confirmatory Part 2 - Risdiplam Participants received risdiplam orally once daily at a dose targeting an exposure of mean AUC0-24h,ss \</= 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 5 mg when the participant reached 20 kg body weight.
Part 2: Number of Participants With AEs and SAEs Leading to Treatment Modification/Interruption Due to AE	4 Participants	—	—
Part 2: Number of Participants With AEs and SAEs Leading to Treatment Modification/Interruption Due to SAE	2 Participants	—	—

SECONDARY outcome

Timeframe: Month 12, Month 24

Population: 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.

Anthropometric examination included weight, height, head circumference and chest circumference.

Outcome measures

Outcome measures
Measure	Exploratory Part 1 - Risdiplam n=38 Participants 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.	Exploratory Part 1 - Cohort 2 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.	Confirmatory Part 2 - Risdiplam Participants received risdiplam orally once daily at a dose targeting an exposure of mean AUC0-24h,ss \</= 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 5 mg when the participant reached 20 kg body weight.
Part 2: Anthropometric Examination of Weight Measured in Kilograms Month 12	9.59 kilogram (kg) Standard Deviation 1.40	—	—
Part 2: Anthropometric Examination of Weight Measured in Kilograms Month 24	11.28 kilogram (kg) Standard Deviation 1.91	—	—

SECONDARY outcome

Timeframe: Month 12, Month 24

Anthropometric examination included weight, height, head circumference and chest circumference.

Outcome measures

Outcome measures
Measure	Exploratory Part 1 - Risdiplam n=38 Participants 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.	Exploratory Part 1 - Cohort 2 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.	Confirmatory Part 2 - Risdiplam Participants received risdiplam orally once daily at a dose targeting an exposure of mean AUC0-24h,ss \</= 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 5 mg when the participant reached 20 kg body weight.
Part 2: Anthropometric Examination of Height, Head Circumference and Chest Circumference Measured in Centimeters Height at Month 24	89.13 centimeter (cm) Standard Deviation 5.12	—	—
Part 2: Anthropometric Examination of Height, Head Circumference and Chest Circumference Measured in Centimeters Head Circumference at Month 12	47.09 centimeter (cm) Standard Deviation 1.72	—	—
Part 2: Anthropometric Examination of Height, Head Circumference and Chest Circumference Measured in Centimeters Height at Month 12	80.47 centimeter (cm) Standard Deviation 4.00	—	—
Part 2: Anthropometric Examination of Height, Head Circumference and Chest Circumference Measured in Centimeters Head Circumference at Month 24	49.28 centimeter (cm) Standard Deviation 2.13	—	—
Part 2: Anthropometric Examination of Height, Head Circumference and Chest Circumference Measured in Centimeters Chest Circumference at Month 12	45.77 centimeter (cm) Standard Deviation 2.31	—	—
Part 2: Anthropometric Examination of Height, Head Circumference and Chest Circumference Measured in Centimeters Chest Circumference at Month 24	48.35 centimeter (cm) Standard Deviation 3.10	—	—

SECONDARY outcome

Timeframe: Day 1: 2, 4, 6, 24 hours post dose; Days 14, 119, 245, 364, 427, 490, 609, 728: predose ; Days 28, 56, 182, 301, 546, 672: predose, 2, 4, 6 hours post dose

Population: All participants with at least one time point with a risdiplam concentration measurement were included in the PK analysis data set.

Reported here is the maximum observed concentration throughout the observation period.

Outcome measures

Outcome measures
Measure	Exploratory Part 1 - Risdiplam n=41 Participants 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.	Exploratory Part 1 - Cohort 2 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.	Confirmatory Part 2 - Risdiplam Participants received risdiplam orally once daily at a dose targeting an exposure of mean AUC0-24h,ss \</= 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 5 mg when the participant reached 20 kg body weight.
Part 2: Maximum Plasma Concentration (Cmax) of Risdiplam	195 nanograms/milliliter (ng/mL) Interval 67.7 to 296.0	—	—

SECONDARY outcome

Timeframe: Year 5 visit: pre-dose

Population: All participants with at least one time point with a risdiplam concentration measurement were included in the PK analysis data set. Only participants for whom data were collected are included in the analysis.

The AUC was derived by modelling \& simulation via the population pharmacokinetics (PPK) method based on the Year 5 pre-dose concentration measurement only. Hence, no other timepoints have been reported.

Outcome measures

Outcome measures
Measure	Exploratory Part 1 - Risdiplam n=35 Participants 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.	Exploratory Part 1 - Cohort 2 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.	Confirmatory Part 2 - Risdiplam Participants received risdiplam orally once daily at a dose targeting an exposure of mean AUC0-24h,ss \</= 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 5 mg when the participant reached 20 kg body weight.
Part 2: Area Under the Curve (AUC) From 0 to 24 Hours of Risdiplam at Year 5 Visit	2560 ng*h/mL Interval 1820.0 to 3670.0	—	—

SECONDARY outcome

Timeframe: Predose at Year 5

Ctrough at Year 5 was the last predose sample collected from each participant who had at least 1400 days of risdiplam treatment duration.

Outcome measures

Outcome measures
Measure	Exploratory Part 1 - Risdiplam n=33 Participants 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.	Exploratory Part 1 - Cohort 2 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.	Confirmatory Part 2 - Risdiplam Participants received risdiplam orally once daily at a dose targeting an exposure of mean AUC0-24h,ss \</= 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 5 mg when the participant reached 20 kg body weight.
Part 2: Concentration at the End of a Dosing Interval (Ctrough) of Risdiplam at Year 5	63.1 ng/mL Interval 15.1 to 134.0	—	—

SECONDARY outcome

Timeframe: Days 1, 28, 119, 245, 364, 609, 728, 819 and 1820

Population: All participants with at least one time point with a protein measurement were included in the pharmacodynamic (PD) analysis data set. Only participants for whom data were collected are included in the analysis.

Outcome measures

Outcome measures
Measure	Exploratory Part 1 - Risdiplam n=40 Participants 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.	Exploratory Part 1 - Cohort 2 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.	Confirmatory Part 2 - Risdiplam Participants received risdiplam orally once daily at a dose targeting an exposure of mean AUC0-24h,ss \</= 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 5 mg when the participant reached 20 kg body weight.
Part 2: Median Fold Change From Baseline in Survival of Motor Neuron (SMN) Protein Levels in Blood Day 1	1.00 ng/mL Interval 1.0 to 1.0	—	—
Part 2: Median Fold Change From Baseline in Survival of Motor Neuron (SMN) Protein Levels in Blood Day 28	2.13 ng/mL Interval 0.75 to 4.66	—	—
Part 2: Median Fold Change From Baseline in Survival of Motor Neuron (SMN) Protein Levels in Blood Day 119	2.21 ng/mL Interval 0.6 to 6.33	—	—
Part 2: Median Fold Change From Baseline in Survival of Motor Neuron (SMN) Protein Levels in Blood Day 245	2.26 ng/mL Interval 0.58 to 4.54	—	—
Part 2: Median Fold Change From Baseline in Survival of Motor Neuron (SMN) Protein Levels in Blood Day 364	1.99 ng/mL Interval 0.9 to 4.06	—	—
Part 2: Median Fold Change From Baseline in Survival of Motor Neuron (SMN) Protein Levels in Blood Day 609	1.69 ng/mL Interval 1.02 to 3.67	—	—
Part 2: Median Fold Change From Baseline in Survival of Motor Neuron (SMN) Protein Levels in Blood Day 728	1.84 ng/mL Interval 0.95 to 4.25	—	—
Part 2: Median Fold Change From Baseline in Survival of Motor Neuron (SMN) Protein Levels in Blood Day 819	2.05 ng/mL Interval 1.87 to 2.23	—	—
Part 2: Median Fold Change From Baseline in Survival of Motor Neuron (SMN) Protein Levels in Blood Day 1820	1.69 ng/mL Interval 0.72 to 4.74	—	—

Adverse Events

Exploratory Part 1 - Cohort 1

Serious events: 4 serious events

Other events: 3 other events

Deaths: 1 deaths

Exploratory Part 1 - Cohort 2

Serious events: 13 serious events

Other events: 17 other events

Deaths: 3 deaths

Confirmatory Part 2 - Risdiplam

Serious events: 34 serious events

Other events: 40 other events

Deaths: 3 deaths

Serious adverse events

Other adverse events

Additional Information

Medical Communications

Hoffmann-La Roche

Phone: 800 821-8590

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee 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.
Publication restrictions are in place

Restriction type: OTHER