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Clinical Trial Results:
A Two Part Seamless, Open-Label, Multicenter Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Efficacy of Risdiplam in Infants with Type 1 Spinal Muscular Atrophy

Summary
EudraCT number	2016-000778-40
Trial protocol	DE ES IT BE FR PL HR
Global end of trial date

Results information
Results version number	v1
This version publication date	26 Nov 2020
First version publication date	26 Nov 2020
Other versions	v2 , v3

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

BP39056

ISRCTN number

US NCT number

NCT02913482

WHO universal trial number (UTN)

Sponsor organisation name

F. Hoffmann-La Roche AG

Sponsor organisation address

Grenzacherstrasse 124., Basel, Switzerland, CH-4070

Public contact

F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, 41 616878333, global.trial_information@roche.com

Scientific contact

F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, 41 616878333, global.trial_information@roche.com

Is trial part of an agreed paediatric investigation plan (PIP)

Yes

EMA paediatric investigation plan number(s)

EMEA-002070-PIP01-16

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Interim

Date of interim/final analysis

14 Nov 2019

Is this the analysis of the primary completion data?

Yes

Primary completion date

14 Nov 2019

Global end of trial reached?

Main objective of the trial

Part 1: To evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of risdiplam in infants with Type 1 SMA and to select the dose for Part 2. Part 2: To assess the efficacy of risdiplam measured as the proportion of infants sitting without support after 12 months of treatment, as assessed in the gross motor scale of the Bayley Scales of Infant and Toddler Development -Third Edition (BSID-III) (defined as sitting without support for 5 seconds).

Protection of trial subjects

All study subjects, parent or legal guardian were required to read and sign an Informed Consent Form.

Background therapy

Evidence for comparator

Actual start date of recruitment

23 Dec 2016

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Switzerland: 1

Country: Number of subjects enrolled

France: 8

Country: Number of subjects enrolled

Italy: 21

Country: Number of subjects enrolled

United States: 4

Country: Number of subjects enrolled

Belgium: 2

Country: Number of subjects enrolled

Brazil: 3

Country: Number of subjects enrolled

China: 11

Country: Number of subjects enrolled

Croatia: 1

Country: Number of subjects enrolled

Japan: 1

Country: Number of subjects enrolled

Poland: 4

Country: Number of subjects enrolled

Russian Federation: 5

Country: Number of subjects enrolled

Turkey: 1

Worldwide total number of subjects

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

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

Screening details

The Screening in both Part 1 and 2 was up to 30 days prior to first dose.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Not applicable

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Exploratory Part 1 - Cohort 1

Arm description

Subjects 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.

Arm type

Experimental

Investigational medicinal product name

risdiplam

Investigational medicinal product code

Other name

Evrysdi

Pharmaceutical forms

Powder and solvent for oral solution

Routes of administration

Oral use

Dosage and administration details

Throughout the study, risdiplam should be taken orally once daily. In the case of breastfeeding, the subject should be fed prior to dosing, winded, and risdiplam administered. In subjects able to swallow, risdiplam is administered with a syringe inserted between baby's gum and cheek. Thereafter, water (approx. 10–20 mL) should be administered with a baby’s bottle to prevent prolonged contact of study drug with buccal mucosa. Similarly, the peribuccal- area of the SMA infant is washed with water in case of drug drooling or spitting. Subjects unable to swallow the study medication and who have a naso-gastric or gastrostomy tube in situ should receive the study medication by bolus via the tube. This should be followed by a bolus flush of water through the tube.

Exploratory Part 1 - Cohort 2

Arm description

Subjects received risdiplam in a staggered, dose-escalation manner once daily at Dose Level 2 for a minimum of 4 weeks to select the dose for Part 2. Dose Level 2 was targeting an exposure of mean AUC0-24h,ss </= 2000 ng*h/mL. Cohort 2 included one infant who started at Dose Level 1 and was escalated to Dose Level 2 on Day 83.

Arm type

Experimental

Investigational medicinal product name

risdiplam

Investigational medicinal product code

Other name

Evrysdi

Pharmaceutical forms

Powder and solvent for oral solution

Routes of administration

Oral use

Dosage and administration details

Confirmatory Part 2 - Risdiplam

Arm description

Subjects received risdiplam orally once daily at a dose of target exposure cap of a mean AUC0-24h,ss of 2000 ng*h/mL, for a duration of 24 months with a primary analysis after 12 months. Starting doses were either 0.04mg/kg, 0.08mg/kg or 0.2mg/kg depending on the subject’s age. All subjects had their dose adjusted to 0.2mg/kg within a few months of starting treatment. The dose was adjusted to 0.25mg/kg when subject reached 2 years of age.

Arm type

Experimental

Investigational medicinal product name

risdiplam

Investigational medicinal product code

Other name

Evrysdi

Pharmaceutical forms

Powder and solvent for oral solution

Routes of administration

Oral use

Dosage and administration details

Number of subjects in period 1	Exploratory Part 1 - Cohort 1	Exploratory Part 1 - Cohort 2	Confirmatory Part 2 - Risdiplam
Started	4	17	41
Completed	3	15	38
Not completed	1	2	3
Adverse event, serious fatal	1	1	2
Progressive Disease	-	1	1

Baseline characteristics

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Reporting group title

Exploratory Part 1 - Cohort 1

Reporting group description

Reporting group title

Exploratory Part 1 - Cohort 2

Reporting group description

Reporting group title

Confirmatory Part 2 - Risdiplam

Reporting group description

Reporting group values	Exploratory Part 1 - Cohort 1	Exploratory Part 1 - Cohort 2	Confirmatory Part 2 - Risdiplam	Total
Number of subjects	4	17	41	62
Age categorical
Units: Subjects
In utero	0	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0	0
Newborns (0-27 days)	0	0	0	0
Infants and toddlers (28 days-23 months)	4	17	41	62
Children (2-11 years)	0	0	0	0
Adolescents (12-17 years)	0	0	0	0
Adults (18-64 years)	0	0	0	0
From 65-84 years	0	0	0	0
85 years and over	0	0	0	0
Age Continuous
Units: months
arithmetic mean (standard deviation)	6.84 ± 0.10	5.56 ± 1.43	5.20 ± 1.47	-
Sex: Female, Male
Units:
Male	0	6	19	25
Female	4	11	22	37
Race/Ethnicity, Customized
Units: Subjects
Not Hispanic or Latino	4	17	36	57
Hispanic or Latino	0	0	5	5
Race/Ethnicity, Customized
Units: Subjects
Asian	0	4	14	18
White	4	13	22	39
Unknown	0	0	5	5

End points

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Reporting group title

Exploratory Part 1 - Cohort 1

Reporting group description

Reporting group title

Exploratory Part 1 - Cohort 2

Reporting group description

Reporting group title

Confirmatory Part 2 - Risdiplam

Reporting group description

Subject analysis set title

Part 1: Intent-to-Treat (ITT)

Subject analysis set type

Intention-to-treat

Subject analysis set description

The intent-to-treat (ITT) population was defined as all subjects enrolled in Part 1 of the study, regardless of whether they received treatment or not.

Subject analysis set title

Part 1: Safety Population

Subject analysis set type

Safety analysis

Subject analysis set description

All subjects in Part 1 who received at least one dose of study medication (risdiplam) were included in the safety population.

Subject analysis set title

Part 2: ITT

Subject analysis set type

Intention-to-treat

Subject analysis set description

The intent-to-treat (ITT) population for Part 2 was defined as all subjects enrolled in Part 2 of the study, regardless of whether they received treatment or not. The ITT population was the primary analysis population for all efficacy analyses, with the exception of weight-for-age and length/height-for-age percentiles, which were analyzed based on the safety population.

Subject analysis set title

Part 2: Safety Population

Subject analysis set type

Safety analysis

Subject analysis set description

All subjects in Part 2 who received at least one dose of study medication (risdiplam) were included in the safety population.

Subject analysis set title

Exploratory Part 1 - Risdiplam

Subject analysis set type

Sub-group analysis

Subject analysis set description

Infants aged between 28 days (1 month) of life and 210 days (7 months) received at least one dose of risdiplam orally or by bolus via naso-gastric or gastrostomy tube, and had available data at the time of the data snapshot for selecting the Part 2 dose.

Primary: Part 1: Selected Part 2 Dose of Risdiplam

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End point title

Part 1: Selected Part 2 Dose of Risdiplam ^[1]

End point description

All safety, tolerability, PK and PD data available up to the clinical cut-off date of 5 January 2018, plus data that became available prior to the database snapshot on 6 February 2018 were included in the Internal Monitoring Committee (IMC) review. The IMC was responsible for selecting the dose for Part 2 of the study (pivotal dose). An external Independent Data Monitoring Committee (iDMC) reviewed data from Part 1 and confirmed the dose-selection decision of the IMC. The dose for Part 2 selected by the IMC was a dose that: 1.Was judged to be safe and well-tolerated, based on all available safety data from Part 1 and as confirmed by the iDMC; 2. Resulted in an exposure at steady-state below the exposure cap (mean value) of AUC0-24h,ss 2000 ng*h/mL (adjusted for free-fraction, if required); 3. Resulted in an SMN protein increase that was expected to be clinically relevant.

End point type

Primary

End point timeframe

Minimum of 2 weeks at steady state exposure

Notes
[1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only descriptive statistics was planned to be reported in the endpoint.

End point values	Exploratory Part 1 - Risdiplam
Number of subjects analysed	18
Units: mg/kg
number (not applicable)	0.2

No statistical analyses for this end point

Primary: 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

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End point title

Part 2: Percentage of Infants who are Sitting Without Support for at least 5 Seconds as Assessed by Item 22 of the Gross Motor Scale of the Bayley Scales of Infant and Toddler development Third Edition (BSID-III) at Month 12 ^[2] ^[3]

End point description

The BSID-III is a standardized assessment commonly used to evaluate development across five domains in infants and young children aged between 1 and 42 months. The gross motor subscale of the BSID-III is evaluated based on the linear and hierarchical obtainment of motor skills, as seen in typically developing children. The gross motor scale consists of 72 items scored at 0 (unable to perform the activity) or 1 (criteria for item achieved). Item 22 is not considered achieved if the infant sits alone for less than 5 seconds before losing balance and falling over, or if the infant uses his or her arms to prop him- or herself up. The assessment was video recorded at study sites and reviewed/scored by two independent raters. 90% CI for one sample binomial was computed using Clopper-Pearson (exact) method. The result was compared to a performance criterion of 5% derived from natural history data (p<0.0001).

End point type

Primary

End point timeframe

At Month 12 (Up to the Clinical Cut-off Date (CCOD) of 14 November 2019)

Notes
[2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only descriptive statistics was planned to be reported in the endpoint.
[3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Data for this endpoint was provided only for those arms which were planned to be reported.

End point values	Confirmatory Part 2 - Risdiplam
Number of subjects analysed	41
Units: Percentage of Subjects
number (confidence interval 90%)	29.3 (17.84 to 43.07)

No statistical analyses for this end point

Secondary: 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

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End point title

Part 2: Percentage of Infants who Achieve a Score of 40 or Higher in the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND) at Month 12 ^[4]

End point description

The CHOP-INTEND instrument was developed to evaluate motor function in infants with SMA from the ages of 1.4 to 37.9 months. It consists of 16 items, where each item assesses a specific motor task graded on a scale of 0 to 4, where zero is no response and 4 is a complete response. The total score ranges from 0 to 64, with higher scores consistent with better motor function. 90% CI for one sample binomial was computed using Clopper-Pearson (exact) method. The result was compared to a performance criterion of 17% derived from natural history data (p<0.0001).

End point type

Secondary

End point timeframe

At Month 12 (Up to the Clinical Cut-off Date (CCOD) of 14 November 2019)

Notes
[4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Data for this endpoint was provided only for those arms which were planned to be reported.

End point values	Confirmatory Part 2 - Risdiplam
Number of subjects analysed	41
Units: Percentage of Subjects
number (confidence interval 90%)	56.1 (42.13 to 69.38)

No statistical analyses for this end point

Secondary: Part 2: Percentage of Infants Achieving an Increase of >/= 4 Points in their CHOP-INTEND Score from Baseline at Month 8 and 12

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End point title

Part 2: Percentage of Infants Achieving an Increase of >/= 4 Points in their CHOP-INTEND Score from Baseline at Month 8 and 12 ^[5]

End point description

End point type

Secondary

End point timeframe

At Month 8 and Month 12 (Up to the CCOD of 14 November 2019)

Notes
[5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Data for this endpoint was provided only for those arms which were planned to be reported.

End point values	Confirmatory Part 2 - Risdiplam
Number of subjects analysed	41
Units: Percentage of Subjects
number (confidence interval 90%)
Month 8	87.8 (76.05 to 95.07)
Month 12	90.2 (79.05 to 96.60)

No statistical analyses for this end point

Secondary: Part 2: Percentage of Infants Achieving Head Control (Defined as a Score of >/= 3 for CHOP-INTEND Item 12) at Month 8 and 12

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End point title

Part 2: Percentage of Infants Achieving Head Control (Defined as a Score of >/= 3 for CHOP-INTEND Item 12) at Month 8 and 12 ^[6]

End point description

End point type

Secondary

End point timeframe

At Month 8 and Month 12 (Up to the CCOD of 14 November 2019)

Notes
[6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Data for this endpoint was provided only for those arms which were planned to be reported.

End point values	Confirmatory Part 2 - Risdiplam
Number of subjects analysed	41
Units: Percentage of Subjects
number (confidence interval 90%)
Month 8	46.3 (32.87 to 60.23)
Month 12	53.7 (39.77 to 67.13)

No statistical analyses for this end point

Secondary: Part 2: Change From Baseline in the Total Raw Score of the BSID-III Gross Motor Scale at Month 12

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End point title

Part 2: Change From Baseline in the Total Raw Score of the BSID-III Gross Motor Scale at Month 12 ^[7]

End point description

The BSID-III is a standardized assessment commonly used to evaluate development across five domains in infants and young children aged between 1 and 42 months. The gross motor subscale of the BSID-III is evaluated based on the linear and hierarchical obtainment of motor skills, as seen in typically developing children. The gross motor scale consists of 72 items scored at 0 (unable to perform the activity) or 1 (criteria for item achieved). In this study the gross motor scale was assessed in a modified way compared with the standard administration. A total raw score was calculated by summing the item scores to give a maximum possible score of 72.

End point type

Secondary

End point timeframe

At Month 12 (Up to the CCOD of 14 November 2019)

Notes
[7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Data for this endpoint was provided only for those arms which were planned to be reported.

End point values	Confirmatory Part 2 - Risdiplam
Number of subjects analysed	38 ^[8]
Units: Scores on a Scale
arithmetic mean (standard deviation)
Month 12	7.21 ± 5.71

Notes
[8] - Only subjects for whom data were collected are included in the analysis.

No statistical analyses for this end point

Secondary: 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

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End point title

Part 2: Percentage of Infants who Achieve the Attainment Levels of a Subset of Motor Milestones Assessed in the Hammersmith Infant Neurological Examination Module 2 (HINE-2) at Month 8 ^[9]

End point description

The HINE was designed to evaluate infants between 2 months and 24 months of age. It is a simple and standardized instrument that includes 26 items assessing different aspects of neurological examinations, such as cranial nerves, posture, movements, tone, and reflexes. In this study, Module 2 of the HINE (HINE-2) was assessed. The HINE-2 evaluates 8 developmental milestones (head control, sitting, voluntary grasp, ability to kick, rolling, crawling, standing, and walking) scored on a 3, 4, or 5-point scale, with 0 indicating inability to perform a task and a score of 2, 3, or 4 (depending on the task) indicating full milestone development. The total score is calculated by summing the item scores to give a maximum possible score of 26. This measure represents subset numbers at Month 8 for head control, ability to kick and rolling milestones only.

End point type

Secondary

End point timeframe

At Month 8 (Up to the CCOD of 14 November 2019)

Notes
[9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Data for this endpoint was provided only for those arms which were planned to be reported.

End point values	Confirmatory Part 2 - Risdiplam
Number of subjects analysed	41
Units: Percentage of Subjects
number (not applicable)
Unable to maintain head upright (Head Control)	36.6
Wobbles (Head Control)	14.6
All the time maintained upright (Head Control)	39.0
No kicking (Ability to Kick (supine))	24.4
Kicks horizontally;legs don’t lift (Kick (supine))	58.5
Upward (vertically) (Ability to Kick (supine))	7.3
Touches leg (Ability to Kick (supine))	0
Touches toes (Ability to Kick (supine))	0
No rolling (Rolling)	56.1
Rolling to side (Rolling)	29.3
Prone to supine (Rolling)	2.4
Supine to prone (Rolling)	2.4

No statistical analyses for this end point

Secondary: 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

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End point title

Part 2: Percentage of Infants who Achieve the Attainment Levels of the Motor Milestones Assessed in the Hammersmith Infant Neurological Examination Module 2 (HINE-2) at Month 12 ^[10]

End point description

End point type

Secondary

End point timeframe

At Month 12 (Up to the CCOD of 14 November 2019)

Notes
[10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Data for this endpoint was provided only for those arms which were planned to be reported.

End point values	Confirmatory Part 2 - Risdiplam
Number of subjects analysed	41
Units: Percentage of Subjects
number (not applicable)
Unable to maintain head upright (Head Control)	17.1
Wobbles (Head Control)	31.7
All the time maintained upright (Head Control)	43.9
Cannot sit (Sitting)	31.7
Sits with support at hips (Sitting)	17.1
Props (Sitting)	19.5
Stable sit (Sitting)	14.6
Pivots (rotates) (Sitting)	9.8
No grasp (Voluntary Grasp)	2.4
Uses whole hand (Voluntary Grasp)	29.3
Index finger & thumb, immature (Voluntary Grasp)	48.8
Pincer grasp (Voluntary Grasp)	12.2
No kicking (Ability to Kick (supine))	12.2
Kicks horizontally;legs don’t lift (Kick (supine))	58.5
Upward (vertically) (Ability to Kick (supine))	7.3
Touches leg (Ability to Kick (supine))	4.9
Touches toes (Ability to Kick (supine))	9.8
No rolling (Rolling)	36.6
Rolling to side (Rolling)	31.7
Prone to supine (Rolling)	14.6
Supine to prone (Rolling)	9.8
Does not lift head (Crawling)	85.4
On elbow (Crawling)	2.4
On outstretched hand (Crawling)	2.4
Crawling flat on abdomen (Crawling)	0
Crawling on hands and knees (Crawling)	0
Cannot test (Crawling)	2.4
Does not support weight (Standing)	61.0
Supports weight (Standing)	17.1
Stands with support (Standing)	4.9
Stands unaided (Standing)	0
Cannot test (Standing)	4.9
Not done (Standing)	4.9
Bouncing (Walking)	2.4
Cruising (walks holding on) (Walking)	0
Walking independently (Walking)	0
Cannot test (Walking)	82.9
Not Done (Walking)	7.3

No statistical analyses for this end point

Secondary: Part 2: Percentage of Motor Milestone Responders as Assessed by HINE-2 at Month 12

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End point title

Part 2: Percentage of Motor Milestone Responders as Assessed by HINE-2 at Month 12 ^[11]

End point description

The HINE-2 evaluates 8 developmental milestones scored on a 3, 4, or 5-point scale, with 0 indicating inability to perform a task and a score of 2, 3, or 4 (depending on the task) indicating full milestone development. 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. The result was compared to a performance criterion of 12% derived from natural history data (p<0.0001).

End point type

Secondary

End point timeframe

At Month 12 (Up to the CCOD of 14 November 2019)

Notes
[11] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Data for this endpoint was provided only for those arms which were planned to be reported.

End point values	Confirmatory Part 2 - Risdiplam
Number of subjects analysed	41
Units: Percentage of Subjects
number (confidence interval 90%)	78.0 (64.82 to 88.04)

No statistical analyses for this end point

Secondary: Part 2: Highest Motor Milestone Achieved by Month 12 as Assessed in the BSID-III Gross Motor Scale

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End point title

Part 2: Highest Motor Milestone Achieved by Month 12 as Assessed in the BSID-III Gross Motor Scale ^[12]

End point description

The BSID-III is a standardized assessment commonly used to evaluate development across five domains in infants and young children aged between 1 and 42 months. The gross motor subscale of the BSID-III is evaluated based on the linear and hierarchical obtainment of motor skills, as seen in typically developing children. The gross motor scale consists of 72 items scored at 0 (unable to perform the activity) or 1 (criteria for item achieved). This measure included 6 milestones: Item 9 ‘Controls head while upright for 15 seconds’, Item 14 ‘Rolls from side to back’, Item 22 ‘Sits without support for 5 seconds’, Item 30 ‘Crawls on stomach’, Item 40 ‘Stands alone’ and Item 42 ‘Walks alone’.

End point type

Secondary

End point timeframe

At Month 12 (Up to the CCOD of 14 November 2019)

Notes
[12] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Data for this endpoint was provided only for those arms which were planned to be reported.

End point values	Confirmatory Part 2 - Risdiplam
Number of subjects analysed	41
Units: Percentage of Subjects
number (not applicable)
Item 9: Controls Head While Upright for 15 sec	0
Item 14: Rolls from Side to Back	56.1
Item 22: Sits Without Support for 5 sec	29.3
Item 30: Crawls on Stomach	0
Item 40: Stands Alone	0
Item 42: Walks Alone	0

No statistical analyses for this end point

Secondary: Part 2: Time to Death

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End point title

Part 2: Time to Death ^[13]

End point description

The median time to event was estimated using Kaplan-Meier methodology. 90% CI was estimated using the method of Brookmeyer and Crowley. The median time to death was not estimable as few subjects had an event. 9999=not estimable

End point type

Secondary

End point timeframe

Baseline up to 12 Months (Up to the CCOD of 14 November 2019)

Notes
[13] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Data for this endpoint was provided only for those arms which were planned to be reported.

End point values	Confirmatory Part 2 - Risdiplam
Number of subjects analysed	41 ^[14]
Units: Months
median (confidence interval 90%)
Month 12	9999 (9999 to 9999)

Notes
[14] - The median time to death was not estimable as few subjects had an event.

No statistical analyses for this end point

Secondary: Part 2: Time to Death or Permanent Ventilation

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End point title

Part 2: Time to Death or Permanent Ventilation ^[15]

End point description

Permanent ventilation is defined as >/=16 hours of non-invasive ventilation per day or intubation for >21 consecutive days in the absence of, or following the resolution of, an acute reversible event; or tracheostomy. Permanent ventilation events were reviewed and confirmed by an independent adjudication committee. The median time to event was estimated using Kaplan-Meier methodology. 90% CI was estimated using the method of Brookmeyer and Crowley. The median time to death or permanent ventilation was not estimable as few subjects had an event. 9999=not estimable

End point type

Secondary

End point timeframe

Baseline up to 12 Months (Up to the CCOD of 14 November 2019)

Notes
[15] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Data for this endpoint was provided only for those arms which were planned to be reported.

End point values	Confirmatory Part 2 - Risdiplam
Number of subjects analysed	41 ^[16]
Units: Months
median (confidence interval 90%)
Month 12	9999 (9999 to 9999)

Notes
[16] - The median time to death or permanent ventilation was not estimable as few subjects had an event.

No statistical analyses for this end point

Secondary: Part 2: Time to Permanent Ventilation

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End point title

Part 2: Time to Permanent Ventilation ^[17]

End point description

Permanent ventilation is defined as >/=16 hours of non-invasive ventilation per day or intubation for >21 consecutive days in the absence of, or following the resolution of, an acute reversible event; or tracheostomy. Permanent ventilation events were reviewed and confirmed by an independent adjudication committee. The median time to event was estimated using Kaplan-Meier methodology. 90% CI was estimated using the method of Brookmeyer and Crowley. The median time to permanent ventilation was not estimable as few subjects had an event. 9999=not estimable

End point type

Secondary

End point timeframe

Baseline up to 12 Months (Up to the CCOD of 14 November 2019)

Notes
[17] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Data for this endpoint was provided only for those arms which were planned to be reported.

End point values	Confirmatory Part 2 - Risdiplam
Number of subjects analysed	41 ^[18]
Units: Months
median (confidence interval 90%)
Month 12	9999 (9999 to 9999)

Notes
[18] - The median time to permanent ventilation was not estimable as few subjects had an event.

No statistical analyses for this end point

Secondary: Part 2: Percentage of Infants who are Alive Without Permanent Ventilation at Month 12

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End point title

Part 2: Percentage of Infants who are Alive Without Permanent Ventilation at Month 12 ^[19]

End point description

Permanent ventilation is defined as >/=16 hours of non-invasive ventilation per day or intubation for >21 consecutive days in the absence of, or following the resolution of, an acute reversible event; or tracheostomy. Permanent ventilation events were reviewed and confirmed by an independent adjudication committee. Kaplan-Meier methodology was used to estimate the percentages. 90% CI was computed using the complementary log-log transformation. The result was compared to a performance criterion of 42% derived from natural history data (p<0.0001).

End point type

Secondary

End point timeframe

At Month 12 (Up to the CCOD of 14 November 2019)

Notes
[19] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Data for this endpoint was provided only for those arms which were planned to be reported.

End point values	Confirmatory Part 2 - Risdiplam
Number of subjects analysed	41
Units: Percentage of Subjects
number (confidence interval 90%)
Month 12	85.4 (73.35 to 92.24)

No statistical analyses for this end point

Secondary: Part 2: Percentage of Infants Who Are Alive at Month 12

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End point title

Part 2: Percentage of Infants Who Are Alive at Month 12 ^[20]

End point description

Kaplan-Meier methodology was used to estimate the percentages. 90% CI was computed using the complementary log-log transformation. The result was compared to a performance criterion of 60% derived from natural history data (p=0.0005).

End point type

Secondary

End point timeframe

At Month 12 (Up to the CCOD of 14 November 2019)

Notes
[20] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Data for this endpoint was provided only for those arms which were planned to be reported.

End point values	Confirmatory Part 2 - Risdiplam
Number of subjects analysed	41
Units: Percentage of Subjects
number (confidence interval 90%)	92.7 (82.16 to 97.10)

No statistical analyses for this end point

Secondary: Part 2: Percentage of Infants Who Are Without Permanent Ventilation at Month 12

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End point title

Part 2: Percentage of Infants Who Are Without Permanent Ventilation at Month 12 ^[21]

End point description

Permanent ventilation is defined as >/=16 hours of non-invasive ventilation per day or intubation for >21 consecutive days in the absence of, or following the resolution of, an acute reversible event; or tracheostomy. Permanent ventilation events were reviewed and confirmed by an independent adjudication committee. Kaplan-Meier methodology was used to estimate the percentages. 90% CI was computed using the complementary log-log transformation. The result was compared to a performance criterion of 89% derived from natural history data (p=0.2595).

End point type

Secondary

End point timeframe

At Month 12 (Up to the CCOD of 14 November 2019)

Notes
[21] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Data for this endpoint was provided only for those arms which were planned to be reported.

End point values	Confirmatory Part 2 - Risdiplam
Number of subjects analysed	41
Units: Percentage of Subjects
number (confidence interval 90%)
Month 12	92.3 (81.24 to 96.95)

No statistical analyses for this end point

Secondary: 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

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End point title

Part 2: Percentage of Infants who Achieve a Reduction of At Least 30 Degrees in Phase Angle From Baseline, as Measured by Respiratory Plethysmography (RP) at Month 12 ^[22]

End point description

RP measures the degree of synchrony between abdominal and thoracic cage-driven breathing. The weakness of intercostal muscles leads to asynchrony of the thorax with the diaphragm, resulting in inefficient and paradoxical breathing patterns. The degree of synchrony between the movement of the chest wall and abdomen during the respiratory cycle can be expressed as the phase angle between the two compartments and measured by placing two RP bands around the thorax and abdomen. In paradoxical breathing, the phase angle is reversed compared with the normal ventilation cycle. A phase angle of 0° indicates perfect in-phase movement, while a value of 180° indicates completely out-of-phase movement between the two compartments. In this measure, 8 or more valid breaths were used to determine the phase angle at each visit; the calculation was not performed if fewer than 8 valid breaths had been measured. 90% CI for one sample binomial was computed using Clopper-Pearson (exact) method.

End point type

Secondary

End point timeframe

At Month 12 (Up to the CCOD of 14 November 2019)

Notes
[22] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Data for this endpoint was provided only for those arms which were planned to be reported.

End point values	Confirmatory Part 2 - Risdiplam
Number of subjects analysed	41
Units: Percentage of Subjects
number (confidence interval 90%)	34.1 (21.96 to 48.13)

No statistical analyses for this end point

Secondary: Part 2: Percentage of Infants not Requiring Respiratory Support (Invasive or Non-Invasive) at Month 12

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End point title

Part 2: Percentage of Infants not Requiring Respiratory Support (Invasive or Non-Invasive) at Month 12 ^[23]

End point description

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

End point type

Secondary

End point timeframe

At Month 12 (Up to the CCOD of 14 November 2019)

Notes
[23] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Data for this endpoint was provided only for those arms which were planned to be reported.

End point values	Confirmatory Part 2 - Risdiplam
Number of subjects analysed	41
Units: Percentage of Subjects
number (confidence interval 90%)
Month 12	24.4 (13.87 to 37.85)

No statistical analyses for this end point

Secondary: Part 2: Percentage of Infants Able to Feed Orally at Month 12

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End point title

Part 2: Percentage of Infants Able to Feed Orally at Month 12 ^[24]

End point description

Able to feed orally includes subjects fed orally and subjects fed via a combination of oral and tube feeding. 90% CI for one sample binomial was computed using Clopper-Pearson (exact) method

End point type

Secondary

End point timeframe

At Month 12 (Up to the CCOD of 14 November 2019)

Notes
[24] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Data for this endpoint was provided only for those arms which were planned to be reported.

End point values	Confirmatory Part 2 - Risdiplam
Number of subjects analysed	41
Units: Percentage of Subjects
number (confidence interval 90%)
Month 12	82.9 (70.31 to 91.70)

No statistical analyses for this end point

Secondary: Part 1: Percentage of Subjects With Adverse Events (AE) and Serious Adverse Events (SAEs)

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End point title

Part 1: Percentage of Subjects With Adverse Events (AE) and Serious Adverse Events (SAEs) ^[25]

End point description

An adverse event (AE) is any untoward medical occurrence in a subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as adverse events.

End point type

Secondary

End point timeframe

From first dose of risdiplam up to a minimum of 12 months (Up to CCOD 27 February 2019)

Notes
[25] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Data for this endpoint was provided only for those arms which were planned to be reported.

End point values	Exploratory Part 1 - Cohort 1	Exploratory Part 1 - Cohort 2
Number of subjects analysed	4	17
Units: Percentage of Subjects
number (not applicable)
With at least one AE	100.0	100.0
With at least one SAE	75.0	41.2

No statistical analyses for this end point

Secondary: Part 2: Percentage of Subjects With Adverse Events (AE) and Serious Adverse Events (SAEs)

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End point title

Part 2: Percentage of Subjects With Adverse Events (AE) and Serious Adverse Events (SAEs) ^[26]

End point description

End point type

Secondary

End point timeframe

From first dose of risdiplam up to a minimum of 12 months (Up to the CCOD of 14 November 2019)

Notes
[26] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Data for this endpoint was provided only for those arms which were planned to be reported.

End point values	Confirmatory Part 2 - Risdiplam
Number of subjects analysed	41
Units: Percentage of Subjects
number (not applicable)
With al least one AE	100.0
With at least one SAE	58.5

No statistical analyses for this end point

Secondary: Part 2: Percentage of Subjects With AEs and SAEs Leading to Treatment Discontinuation

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End point title

Part 2: Percentage of Subjects With AEs and SAEs Leading to Treatment Discontinuation ^[27]

End point description

End point type

Secondary

End point timeframe

From first dose of risdiplam up to a minimum of 12 months (Up to the CCOD of 14 November 2019)

Notes
[27] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Data for this endpoint was provided only for those arms which were planned to be reported.

End point values	Confirmatory Part 2 - Risdiplam
Number of subjects analysed	41
Units: Percentage of Subjects
number (not applicable)
Due to AE	0
Due to SAE	0

No statistical analyses for this end point

Secondary: Part 2: Percentage of Subjects With AEs and SAEs Leading to Treatment Modification/Interruption

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End point title

Part 2: Percentage of Subjects With AEs and SAEs Leading to Treatment Modification/Interruption ^[28]

End point description

End point type

Secondary

End point timeframe

From first dose of risdiplam up to a minimum of 12 months (Up to the CCOD of 14 November 2019)

Notes
[28] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Data for this endpoint was provided only for those arms which were planned to be reported.

End point values	Confirmatory Part 2 - Risdiplam
Number of subjects analysed	41
Units: Percentage of Subjects
number (not applicable)
Due to AE	4.9
Due to SAE	2.4

No statistical analyses for this end point

Secondary: Part 2: Anthropometric Examination of Weight Measured in Kilograms

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End point title

Part 2: Anthropometric Examination of Weight Measured in Kilograms ^[29]

End point description

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

End point type

Secondary

End point timeframe

At Month 12 (Up to the CCOD of 14 November 2019)

Notes
[29] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Data for this endpoint was provided only for those arms which were planned to be reported.

End point values	Confirmatory Part 2 - Risdiplam
Number of subjects analysed	38 ^[30]
Units: kilogram (kg)
arithmetic mean (standard deviation)
Month 12	9.59 ± 1.40

Notes
[30] - Only subjects for whom data were collected are included in the analysis.

No statistical analyses for this end point

Secondary: Part 2: Anthropometric Examination of Height, Head Circumference and Chest Circumference Measured in Centimeter

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End point title

Part 2: Anthropometric Examination of Height, Head Circumference and Chest Circumference Measured in Centimeter ^[31]

End point description

End point type

Secondary

End point timeframe

At Month 12 (Up to the CCOD of 14 November 2019)

Notes
[31] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Data for this endpoint was provided only for those arms which were planned to be reported.

End point values	Confirmatory Part 2 - Risdiplam
Number of subjects analysed	38 ^[32]
Units: centimeter (cm)
arithmetic mean (standard deviation)
Month 12 (Height)	80.47 ± 4.00
Month 12 (Head Circumference)	47.09 ± 1.72
Month 12 (Chest Circumference)	45.77 ± 2.31

Notes
[32] - Only subjects for whom data were collected are included in the analysis.

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Part 1: From first dose of risdiplam up to a minimum of 12 months (Up to CCOD 27 February 2019) Part 2: From first dose of risdiplam up to a minimum of 12 months (Up to the CCOD of 14 November 2019)

Adverse event reporting additional description

Part 1 and Part 2 of the study were independent trials with different safety populations. Serious and Non-Serious Adverse Event collection were managed independently. Adverse Events NOT occurring at the 5% threshold in one part of the study does not mean that the event didn’t occur, however, it may have occurred at a different frequency threshold.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

21.1; 22.1

Reporting group title

Exploratory Part 1 - Cohort 1

Reporting group description

Reporting group title

Exploratory Part 1 - Cohort 2

Reporting group description

Reporting group title

Confirmatory Part 2 - Risdiplam

Reporting group description

Serious adverse events	Exploratory Part 1 - Cohort 1	Exploratory Part 1 - Cohort 2	Confirmatory Part 2 - Risdiplam
Total subjects affected by serious adverse events
subjects affected / exposed	3 / 4 (75.00%)	7 / 17 (41.18%)	24 / 41 (58.54%)
number of deaths (all causes)	1	2	3
number of deaths resulting from adverse events
Investigations
Weight decreased
subjects affected / exposed	0 / 4 (0.00%)	1 / 17 (5.88%)	0 / 41 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Congenital, familial and genetic disorders
Cryptorchism
subjects affected / exposed	0 / 4 (0.00%)	0 / 17 (0.00%)	1 / 41 (2.44%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cardiac disorders
Cardiac arrest
subjects affected / exposed	0 / 4 (0.00%)	1 / 17 (5.88%)	1 / 41 (2.44%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Sinus tachycardia
subjects affected / exposed	0 / 4 (0.00%)	0 / 17 (0.00%)	1 / 41 (2.44%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Nervous system disorders
Hydrocephalus
subjects affected / exposed	0 / 4 (0.00%)	0 / 17 (0.00%)	1 / 41 (2.44%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hypotonia
subjects affected / exposed	0 / 4 (0.00%)	0 / 17 (0.00%)	2 / 41 (4.88%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Neutropenia
subjects affected / exposed	1 / 4 (25.00%)	0 / 17 (0.00%)	0 / 41 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Vomiting
subjects affected / exposed	0 / 4 (0.00%)	0 / 17 (0.00%)	1 / 41 (2.44%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Acute respiratory failure
subjects affected / exposed	1 / 4 (25.00%)	1 / 17 (5.88%)	1 / 41 (2.44%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1
Atelectasis
subjects affected / exposed	0 / 4 (0.00%)	1 / 17 (5.88%)	1 / 41 (2.44%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hypoxia
subjects affected / exposed	0 / 4 (0.00%)	1 / 17 (5.88%)	0 / 41 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pneumonia aspiration
subjects affected / exposed	0 / 4 (0.00%)	1 / 17 (5.88%)	0 / 41 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pneumothorax
subjects affected / exposed	0 / 4 (0.00%)	1 / 17 (5.88%)	0 / 41 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Respiratory distress
subjects affected / exposed	0 / 4 (0.00%)	2 / 17 (11.76%)	1 / 41 (2.44%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Respiratory failure
subjects affected / exposed	0 / 4 (0.00%)	1 / 17 (5.88%)	2 / 41 (4.88%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Aspiration
subjects affected / exposed	0 / 4 (0.00%)	0 / 17 (0.00%)	1 / 41 (2.44%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Respiratory tract inflammation
subjects affected / exposed	0 / 4 (0.00%)	0 / 17 (0.00%)	1 / 41 (2.44%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Sleep apnoea syndrome
subjects affected / exposed	0 / 4 (0.00%)	0 / 17 (0.00%)	1 / 41 (2.44%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Infections and infestations
Influenza
subjects affected / exposed	1 / 4 (25.00%)	0 / 17 (0.00%)	1 / 41 (2.44%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	2 / 4 (50.00%)	1 / 17 (5.88%)	13 / 41 (31.71%)
occurrences causally related to treatment / all	0 / 3	0 / 1	0 / 16
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 2
Respiratory tract infection
subjects affected / exposed	1 / 4 (25.00%)	1 / 17 (5.88%)	1 / 41 (2.44%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Respiratory tract infection viral
subjects affected / exposed	1 / 4 (25.00%)	1 / 17 (5.88%)	1 / 41 (2.44%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Upper respiratory tract infection
subjects affected / exposed	0 / 4 (0.00%)	1 / 17 (5.88%)	0 / 41 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Bronchiolitis
subjects affected / exposed	0 / 4 (0.00%)	0 / 17 (0.00%)	2 / 41 (4.88%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Bronchitis
subjects affected / exposed	0 / 4 (0.00%)	0 / 17 (0.00%)	1 / 41 (2.44%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Escherichia urinary tract infection
subjects affected / exposed	0 / 4 (0.00%)	0 / 17 (0.00%)	1 / 41 (2.44%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastroenteritis
subjects affected / exposed	0 / 4 (0.00%)	0 / 17 (0.00%)	1 / 41 (2.44%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Lower respiratory tract infection
subjects affected / exposed	0 / 4 (0.00%)	0 / 17 (0.00%)	1 / 41 (2.44%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pharyngitis
subjects affected / exposed	0 / 4 (0.00%)	0 / 17 (0.00%)	1 / 41 (2.44%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pneumonia bacterial
subjects affected / exposed	0 / 4 (0.00%)	0 / 17 (0.00%)	1 / 41 (2.44%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pneumonia viral
subjects affected / exposed	0 / 4 (0.00%)	0 / 17 (0.00%)	1 / 41 (2.44%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Tracheitis
subjects affected / exposed	0 / 4 (0.00%)	0 / 17 (0.00%)	1 / 41 (2.44%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Tracheobronchitis
subjects affected / exposed	0 / 4 (0.00%)	0 / 17 (0.00%)	1 / 41 (2.44%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Failure to thrive
subjects affected / exposed	0 / 4 (0.00%)	1 / 17 (5.88%)	0 / 41 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Dehydration
subjects affected / exposed	0 / 4 (0.00%)	0 / 17 (0.00%)	1 / 41 (2.44%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Exploratory Part 1 - Cohort 1	Exploratory Part 1 - Cohort 2	Confirmatory Part 2 - Risdiplam
Total subjects affected by non serious adverse events
subjects affected / exposed	3 / 4 (75.00%)	17 / 17 (100.00%)	36 / 41 (87.80%)
Injury, poisoning and procedural complications
Fall
subjects affected / exposed	0 / 4 (0.00%)	2 / 17 (11.76%)	0 / 41 (0.00%)
occurrences all number	0	2	0
Head injury
subjects affected / exposed	0 / 4 (0.00%)	1 / 17 (5.88%)	0 / 41 (0.00%)
occurrences all number	0	1	0
Incorrect dose administered
subjects affected / exposed	0 / 4 (0.00%)	1 / 17 (5.88%)	0 / 41 (0.00%)
occurrences all number	0	1	0
Joint dislocation
subjects affected / exposed	0 / 4 (0.00%)	1 / 17 (5.88%)	0 / 41 (0.00%)
occurrences all number	0	1	0
Stoma site hypergranulation
subjects affected / exposed	0 / 4 (0.00%)	1 / 17 (5.88%)	0 / 41 (0.00%)
occurrences all number	0	1	0
Thermal burn
subjects affected / exposed	0 / 4 (0.00%)	1 / 17 (5.88%)	0 / 41 (0.00%)
occurrences all number	0	1	0
Surgical and medical procedures
Mechanical ventilation
subjects affected / exposed	0 / 4 (0.00%)	1 / 17 (5.88%)	0 / 41 (0.00%)
occurrences all number	0	1	0
Nervous system disorders
Loss of consciousness
subjects affected / exposed	0 / 4 (0.00%)	1 / 17 (5.88%)	0 / 41 (0.00%)
occurrences all number	0	1	0
Blood and lymphatic system disorders
Leukocytosis
subjects affected / exposed	0 / 4 (0.00%)	1 / 17 (5.88%)	0 / 41 (0.00%)
occurrences all number	0	1	0
Lymphadenopathy
subjects affected / exposed	0 / 4 (0.00%)	1 / 17 (5.88%)	0 / 41 (0.00%)
occurrences all number	0	1	0
General disorders and administration site conditions
Discomfort
subjects affected / exposed	0 / 4 (0.00%)	1 / 17 (5.88%)	0 / 41 (0.00%)
occurrences all number	0	1	0
Ill-defined disorder
subjects affected / exposed	0 / 4 (0.00%)	1 / 17 (5.88%)	0 / 41 (0.00%)
occurrences all number	0	1	0
Pyrexia
subjects affected / exposed	3 / 4 (75.00%)	8 / 17 (47.06%)	16 / 41 (39.02%)
occurrences all number	16	14	39
Eye disorders
Conjunctival hyperaemia
subjects affected / exposed	1 / 4 (25.00%)	1 / 17 (5.88%)	0 / 41 (0.00%)
occurrences all number	1	1	0
Macular cyst
subjects affected / exposed	0 / 4 (0.00%)	1 / 17 (5.88%)	0 / 41 (0.00%)
occurrences all number	0	1	0
Gastrointestinal disorders
Abdominal distension
subjects affected / exposed	1 / 4 (25.00%)	0 / 17 (0.00%)	0 / 41 (0.00%)
occurrences all number	1	0	0
Abnormal faeces
subjects affected / exposed	0 / 4 (0.00%)	1 / 17 (5.88%)	0 / 41 (0.00%)
occurrences all number	0	1	0
Aphthous ulcer
subjects affected / exposed	1 / 4 (25.00%)	0 / 17 (0.00%)	0 / 41 (0.00%)
occurrences all number	1	0	0
Constipation
subjects affected / exposed	1 / 4 (25.00%)	3 / 17 (17.65%)	8 / 41 (19.51%)
occurrences all number	1	3	8
Diarrhoea
subjects affected / exposed	0 / 4 (0.00%)	6 / 17 (35.29%)	4 / 41 (9.76%)
occurrences all number	0	7	4
Dysphagia
subjects affected / exposed	0 / 4 (0.00%)	1 / 17 (5.88%)	0 / 41 (0.00%)
occurrences all number	0	1	0
Faeces discoloured
subjects affected / exposed	0 / 4 (0.00%)	1 / 17 (5.88%)	0 / 41 (0.00%)
occurrences all number	0	1	0
Flatulence
subjects affected / exposed	1 / 4 (25.00%)	1 / 17 (5.88%)	0 / 41 (0.00%)
occurrences all number	1	1	0
Gastrooesophageal reflux disease
subjects affected / exposed	0 / 4 (0.00%)	2 / 17 (11.76%)	0 / 41 (0.00%)
occurrences all number	0	3	0
Haematochezia
subjects affected / exposed	0 / 4 (0.00%)	1 / 17 (5.88%)	0 / 41 (0.00%)
occurrences all number	0	1	0
Infrequent bowel movements
subjects affected / exposed	0 / 4 (0.00%)	1 / 17 (5.88%)	0 / 41 (0.00%)
occurrences all number	0	1	0
Salivary hypersecretion
subjects affected / exposed	0 / 4 (0.00%)	1 / 17 (5.88%)	0 / 41 (0.00%)
occurrences all number	0	1	0
Teething
subjects affected / exposed	0 / 4 (0.00%)	3 / 17 (17.65%)	3 / 41 (7.32%)
occurrences all number	0	4	5
Toothache
subjects affected / exposed	0 / 4 (0.00%)	1 / 17 (5.88%)	0 / 41 (0.00%)
occurrences all number	0	1	0
Vomiting
subjects affected / exposed	1 / 4 (25.00%)	4 / 17 (23.53%)	3 / 41 (7.32%)
occurrences all number	1	10	8
Respiratory, thoracic and mediastinal disorders
Atelectasis
subjects affected / exposed	0 / 4 (0.00%)	1 / 17 (5.88%)	0 / 41 (0.00%)
occurrences all number	0	4	0
Bronchial secretion retention
subjects affected / exposed	0 / 4 (0.00%)	1 / 17 (5.88%)	0 / 41 (0.00%)
occurrences all number	0	1	0
Cough
subjects affected / exposed	0 / 4 (0.00%)	5 / 17 (29.41%)	0 / 41 (0.00%)
occurrences all number	0	7	0
Epistaxis
subjects affected / exposed	0 / 4 (0.00%)	1 / 17 (5.88%)	0 / 41 (0.00%)
occurrences all number	0	1	0
Hypoxia
subjects affected / exposed	0 / 4 (0.00%)	1 / 17 (5.88%)	0 / 41 (0.00%)
occurrences all number	0	1	0
Nasal congestion
subjects affected / exposed	0 / 4 (0.00%)	2 / 17 (11.76%)	0 / 41 (0.00%)
occurrences all number	0	2	0
Respiratory tract congestion
subjects affected / exposed	0 / 4 (0.00%)	2 / 17 (11.76%)	0 / 41 (0.00%)
occurrences all number	0	2	0
Rhinorrhoea
subjects affected / exposed	0 / 4 (0.00%)	1 / 17 (5.88%)	0 / 41 (0.00%)
occurrences all number	0	1	0
Sleep apnoea syndrome
subjects affected / exposed	0 / 4 (0.00%)	1 / 17 (5.88%)	0 / 41 (0.00%)
occurrences all number	0	1	0
Upper respiratory tract congestion
subjects affected / exposed	0 / 4 (0.00%)	1 / 17 (5.88%)	0 / 41 (0.00%)
occurrences all number	0	1	0
Upper respiratory tract inflammation
subjects affected / exposed	2 / 4 (50.00%)	1 / 17 (5.88%)	0 / 41 (0.00%)
occurrences all number	2	2	0
Skin and subcutaneous tissue disorders
Dermatitis
subjects affected / exposed	1 / 4 (25.00%)	0 / 17 (0.00%)	0 / 41 (0.00%)
occurrences all number	1	0	0
Dermatitis allergic
subjects affected / exposed	0 / 4 (0.00%)	1 / 17 (5.88%)	0 / 41 (0.00%)
occurrences all number	0	1	0
Dermatitis atopic
subjects affected / exposed	0 / 4 (0.00%)	1 / 17 (5.88%)	0 / 41 (0.00%)
occurrences all number	0	2	0
Eczema
subjects affected / exposed	0 / 4 (0.00%)	3 / 17 (17.65%)	0 / 41 (0.00%)
occurrences all number	0	3	0
Erythema
subjects affected / exposed	2 / 4 (50.00%)	1 / 17 (5.88%)	0 / 41 (0.00%)
occurrences all number	3	1	0
Macule
subjects affected / exposed	1 / 4 (25.00%)	0 / 17 (0.00%)	0 / 41 (0.00%)
occurrences all number	1	0	0
Petechiae
subjects affected / exposed	0 / 4 (0.00%)	1 / 17 (5.88%)	0 / 41 (0.00%)
occurrences all number	0	2	0
Rash
subjects affected / exposed	0 / 4 (0.00%)	2 / 17 (11.76%)	3 / 41 (7.32%)
occurrences all number	0	3	3
Miliaria
subjects affected / exposed	0 / 4 (0.00%)	0 / 17 (0.00%)	3 / 41 (7.32%)
occurrences all number	0	0	3
Rash maculo-papular
subjects affected / exposed	0 / 4 (0.00%)	0 / 17 (0.00%)	4 / 41 (9.76%)
occurrences all number	0	0	4
Musculoskeletal and connective tissue disorders
Kyphosis
subjects affected / exposed	0 / 4 (0.00%)	1 / 17 (5.88%)	0 / 41 (0.00%)
occurrences all number	0	1	0
Scoliosis
subjects affected / exposed	0 / 4 (0.00%)	1 / 17 (5.88%)	0 / 41 (0.00%)
occurrences all number	0	1	0
Infections and infestations
Conjunctivitis
subjects affected / exposed	0 / 4 (0.00%)	1 / 17 (5.88%)	0 / 41 (0.00%)
occurrences all number	0	1	0
Ear infection
subjects affected / exposed	1 / 4 (25.00%)	2 / 17 (11.76%)	0 / 41 (0.00%)
occurrences all number	1	3	0
Exanthema subitum
subjects affected / exposed	1 / 4 (25.00%)	0 / 17 (0.00%)	0 / 41 (0.00%)
occurrences all number	1	0	0
Folliculitis
subjects affected / exposed	0 / 4 (0.00%)	1 / 17 (5.88%)	0 / 41 (0.00%)
occurrences all number	0	1	0
Gastroenteritis
subjects affected / exposed	0 / 4 (0.00%)	1 / 17 (5.88%)	0 / 41 (0.00%)
occurrences all number	0	2	0
Lower respiratory tract infection
subjects affected / exposed	0 / 4 (0.00%)	1 / 17 (5.88%)	0 / 41 (0.00%)
occurrences all number	0	1	0
Nasopharyngitis
subjects affected / exposed	0 / 4 (0.00%)	3 / 17 (17.65%)	5 / 41 (12.20%)
occurrences all number	0	5	9
Oral candidiasis
subjects affected / exposed	0 / 4 (0.00%)	1 / 17 (5.88%)	0 / 41 (0.00%)
occurrences all number	0	1	0
Otitis media
subjects affected / exposed	0 / 4 (0.00%)	1 / 17 (5.88%)	0 / 41 (0.00%)
occurrences all number	0	1	0
Pharyngitis
subjects affected / exposed	1 / 4 (25.00%)	0 / 17 (0.00%)	0 / 41 (0.00%)
occurrences all number	1	0	0
Pneumonia
subjects affected / exposed	0 / 4 (0.00%)	1 / 17 (5.88%)	4 / 41 (9.76%)
occurrences all number	0	1	4
Pneumonia staphylococcal
subjects affected / exposed	0 / 4 (0.00%)	1 / 17 (5.88%)	0 / 41 (0.00%)
occurrences all number	0	1	0
Respiratory tract infection
subjects affected / exposed	0 / 4 (0.00%)	1 / 17 (5.88%)	0 / 41 (0.00%)
occurrences all number	0	4	0
Rhinitis
subjects affected / exposed	0 / 4 (0.00%)	3 / 17 (17.65%)	5 / 41 (12.20%)
occurrences all number	0	3	7
Upper respiratory tract infection
subjects affected / exposed	1 / 4 (25.00%)	7 / 17 (41.18%)	19 / 41 (46.34%)
occurrences all number	2	11	33
Urinary tract infection
subjects affected / exposed	1 / 4 (25.00%)	0 / 17 (0.00%)	3 / 41 (7.32%)
occurrences all number	1	0	4
Varicella post vaccine
subjects affected / exposed	0 / 4 (0.00%)	1 / 17 (5.88%)	0 / 41 (0.00%)
occurrences all number	0	1	0
Viral infection
subjects affected / exposed	0 / 4 (0.00%)	1 / 17 (5.88%)	0 / 41 (0.00%)
occurrences all number	0	1	0
Viral upper respiratory tract infection
subjects affected / exposed	0 / 4 (0.00%)	1 / 17 (5.88%)	0 / 41 (0.00%)
occurrences all number	0	1	0
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	0 / 4 (0.00%)	2 / 17 (11.76%)	0 / 41 (0.00%)
occurrences all number	0	3	0
Iron deficiency
subjects affected / exposed	0 / 4 (0.00%)	1 / 17 (5.88%)	0 / 41 (0.00%)
occurrences all number	0	1	0

More information

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Were there any global substantial amendments to the protocol? Yes

10 Feb 2017

The protocol was updated to clarify the nature of the decisions to be taken by the IMC and the meeting schedule of the IMC; Exclusion criterion #3 was updated to reflect the fact that some subjects may have taken the recently approved drug, Spinraza™, as part of medical care, rather than only in a study; Exclusion criterion #22 was updated to clarify the term ‘use’ (in relation to prohibited medication use within 90 days prior to enrollment) as administration for at least 8 weeks within 90 days of beginning the study; Details on dilution factors for drug preparation were removed from the protocol as they are provided in the pharmacy manual (referenced in the protocol); The protocol was updated to clarify that subjects could be breastfed and winded if needed, followed by study drug administration.

22 May 2017

A new, optimized formulation was introduced. Subjects participating in the Part 1 extension of the study continued to use the Part 1 clinical formulation until they switched to the Part 2 clinical formulation upon availability of the new formulation. Subjects in Part 2 of the study receive the Part 2 formulation throughout their participation in the study; In Part 2, CMAP acquired from below the elbow stimulation was included following suggestions from different therapeutic area experts. This technical change was expected to give better wave forms in smaller infants, as the size of the hand may be too small for consistent placement of electrodes on the hand and wrist, and ultimately more consistent results.

06 Apr 2018

The Part 2 dose was incorporated into the protocol based on the Part 1 data, as reviewed by the IMC and the iDMC in February 2018. In addition, the protocol was updated to allow all subjects in Part 1 to receive the dose selected for Part 2, including the first enrolled subject who per protocol thus far remained at the low target exposure of AUC 700 ng*h/mL; Following experience gained in Part 1, some ophthalmology assessments were modified to decrease unnecessary burden to subjects while optimizing quality of the main assessment (OCT); An option to enroll subjects in a specifically extended China enrollment phase after the global enrollment phase at CFDA-recognized sites, was added to ensure approximately 10 subjects are included in the China subpopulation; The definition of permanent ventilation was changed to >/= 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. This definition better reflects the clinical situation in which an acute but reversible event could necessitate the use of non-invasive ventilation for several hours a day after which the subjects could be weaned, thus not truly meeting the original definition; An independent Permanent Ventilation Adjudication Committee was added to review all pertinent data for subjects who may have met the definition of permanent ventilation. This committee has been added to address the change in the definition of permanent ventilation described above and to provide greater transparency if a patient met this endpoint;

06 Apr 2018

PK monitoring and dose adjustments as required were added to ensure subjects are within the targeted exposure and are in compliance with the exposure cap; The secondary objective to investigate muscle electrophysiology, as assessed by CMAP was changed to an exploratory objective as it is less well defined with regards to clinical meaningfulness than the multiple motor assessments already being performed; An efficacy outcome measure of ability to swallow and feed orally was added because these data are an important clinical outcome for subjects with SMA Type 1, who in the natural history of the disease lose the ability to swallow; In the context of the independent safety surveillance provided by the iDMC once Part 2 was initiated, AEs of skin or subcutaneous reaction, pharyngeal/laryngeal or mucosal reaction; and clinically relevant retinal abnormalities on OCT/fundus photography were removed from the list of non-serious AEs of special interest (AESI).

27 Jan 2019

Results from in vitro studies characterizing the inhibition of CYP3A4 by risdiplam were added. This inhibition has the potential to increase the concentration of concomitant medications predominantly metabolized by the CYP3A4 enzyme; The permitted therapy section was updated to state that concomitant medications that are CYP3A4 substrates are permitted if required; however, as per usual clinical practice, potential toxicities should be monitored carefully, in particular for medications with a narrow therapeutic window. If possible, a different concomitant medication should be chosen; The Clinical Domain Level Global Impression assessment was added to collect information on the respiratory function and swallowing ability of subjects which will be compared with their abilities at baseline, with untreated patients with Type 1 SMA, and with typically developing infants. Exploring the effect of treatment with risdiplam on respiratory function and the ability to swallow, as assessed by the clinical domain level items, was added as an exploratory efficacy objective; Evaluation of the change from baseline in weight and height at 12 and 24 months was added as an exploratory efficacy objective; Text was added to clarify that the dose of risdiplam administered may be higher than the dose levels explicitly listed in the protocol in order to maintain the exposure level over time in an individual growing subject.

18 May 2020

Protocol was released but is not effective.

17 Jun 2020

Given the absence of any risdiplam-induced ophthalmological findings to date in 471 subjects exposed to risdiplam for up to 3 years, the frequency of ophthalmology assessments has been reduced to every 6 months and colour fundus photography will no longer be performed; The length of the open-label extension phase has been defined as 3 years for each subject to allow for a longer safety follow-up period. Continued access to risdiplam will be provided until the end of study, provided that risdiplam is not commercially available in the subject's country. The length of the study has been modified and will not exceed 5 years after the last subject is enrolled in the study; Cautionary language on the concomitant use of CYP3A4 substrates has been removed, based on the recent results of the clinical drug-drug interaction Study BP41361 and subsequent physiologically-based pharmacokinetic modelling for extrapolation to children and infants. The study showed that coadministration with risdiplam led to only a small increase in exposure of the sensitive CYP3A substrate midazolam, which is not considered to be clinically relevant;

17 Jun 2020

The safety monitoring period has been modified to extend from screening through the open-label extension, the study completion/early withdrawal visit, and follow-up (phone call). Language related to the study completion/early withdrawal visit and follow-up has been clarified to ensure that all assessments are performed at the last visit for each subject, and that the follow-up should occur 30 days after that visit; Safety monitoring and stopping rules for adverse events affecting the skin, mouth, pharynx, and larynx have been removed to align with current data on potential risks updated in the Risdiplam Investigator's Brochure, Version 7; The adverse event reporting period has been reduced to 30 days after the study completion/early withdrawal visit (i.e., at least 30 days after the last dose of study drug), to reflect that adverse events are not expected beyond this reporting period; the elimination half-life of risdiplam will not exceed 30 days.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Clinical trials

Clinical Trial Results: A Two Part Seamless, Open-Label, Multicenter Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Efficacy of Risdiplam in Infants with Type 1 Spinal Muscular Atrophy

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Part 1: Selected Part 2 Dose of Risdiplam

Primary: Part 1: Selected Part 2 Dose of Risdiplam

Primary: 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

Primary: 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

Secondary: 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

Secondary: 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

Secondary: Part 2: Percentage of Infants Achieving an Increase of >/= 4 Points in their CHOP-INTEND Score from Baseline at Month 8 and 12

Secondary: Part 2: Percentage of Infants Achieving an Increase of >/= 4 Points in their CHOP-INTEND Score from Baseline at Month 8 and 12

Secondary: Part 2: Percentage of Infants Achieving Head Control (Defined as a Score of >/= 3 for CHOP-INTEND Item 12) at Month 8 and 12

Secondary: Part 2: Percentage of Infants Achieving Head Control (Defined as a Score of >/= 3 for CHOP-INTEND Item 12) at Month 8 and 12

Secondary: Part 2: Change From Baseline in the Total Raw Score of the BSID-III Gross Motor Scale at Month 12

Secondary: Part 2: Change From Baseline in the Total Raw Score of the BSID-III Gross Motor Scale at Month 12

Secondary: 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

Secondary: 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

Secondary: 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

Secondary: 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

Secondary: Part 2: Percentage of Motor Milestone Responders as Assessed by HINE-2 at Month 12

Secondary: Part 2: Percentage of Motor Milestone Responders as Assessed by HINE-2 at Month 12

Secondary: Part 2: Highest Motor Milestone Achieved by Month 12 as Assessed in the BSID-III Gross Motor Scale

Secondary: Part 2: Highest Motor Milestone Achieved by Month 12 as Assessed in the BSID-III Gross Motor Scale

Secondary: Part 2: Time to Death

Secondary: Part 2: Time to Death

Secondary: Part 2: Time to Death or Permanent Ventilation

Secondary: Part 2: Time to Death or Permanent Ventilation

Secondary: Part 2: Time to Permanent Ventilation

Secondary: Part 2: Time to Permanent Ventilation

Secondary: Part 2: Percentage of Infants who are Alive Without Permanent Ventilation at Month 12

Secondary: Part 2: Percentage of Infants who are Alive Without Permanent Ventilation at Month 12

Secondary: Part 2: Percentage of Infants Who Are Alive at Month 12

Secondary: Part 2: Percentage of Infants Who Are Alive at Month 12

Secondary: Part 2: Percentage of Infants Who Are Without Permanent Ventilation at Month 12

Secondary: Part 2: Percentage of Infants Who Are Without Permanent Ventilation at Month 12

Secondary: 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

Secondary: 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

Secondary: Part 2: Percentage of Infants not Requiring Respiratory Support (Invasive or Non-Invasive) at Month 12

Secondary: Part 2: Percentage of Infants not Requiring Respiratory Support (Invasive or Non-Invasive) at Month 12

Secondary: Part 2: Percentage of Infants Able to Feed Orally at Month 12

Secondary: Part 2: Percentage of Infants Able to Feed Orally at Month 12

Secondary: Part 1: Percentage of Subjects With Adverse Events (AE) and Serious Adverse Events (SAEs)

Secondary: Part 1: Percentage of Subjects With Adverse Events (AE) and Serious Adverse Events (SAEs)

Secondary: Part 2: Percentage of Subjects With Adverse Events (AE) and Serious Adverse Events (SAEs)

Secondary: Part 2: Percentage of Subjects With Adverse Events (AE) and Serious Adverse Events (SAEs)

Secondary: Part 2: Percentage of Subjects With AEs and SAEs Leading to Treatment Discontinuation

Secondary: Part 2: Percentage of Subjects With AEs and SAEs Leading to Treatment Discontinuation

Secondary: Part 2: Percentage of Subjects With AEs and SAEs Leading to Treatment Modification/Interruption

Secondary: Part 2: Percentage of Subjects With AEs and SAEs Leading to Treatment Modification/Interruption

Secondary: Part 2: Anthropometric Examination of Weight Measured in Kilograms

Secondary: Part 2: Anthropometric Examination of Weight Measured in Kilograms

Secondary: Part 2: Anthropometric Examination of Height, Head Circumference and Chest Circumference Measured in Centimeter

Secondary: Part 2: Anthropometric Examination of Height, Head Circumference and Chest Circumference Measured in Centimeter

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
A Two Part Seamless, Open-Label, Multicenter Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Efficacy of Risdiplam in Infants with Type 1 Spinal Muscular Atrophy