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Clinical Trial Results:
A Two-Part Seamless, Multi-Center, Randomized, Placebo-Controlled, Double Blind Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Efficacy of Risdiplam (RO7034067) in Type 2 and 3 Spinal Muscular Atrophy Patients

Summary
EudraCT number	2016-000750-35
Trial protocol	ES GB IT BE DE FR PL HR BG
Global end of trial date

Results information
Results version number	v1
This version publication date	13 Sep 2020
First version publication date	13 Sep 2020
Other versions	v2

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

BP39055

ISRCTN number

US NCT number

NCT02908685

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?

Yes

Analysis stage

Interim

Date of interim/final analysis

06 Sep 2019

Is this the analysis of the primary completion data?

Yes

Primary completion date

06 Sep 2019

Global end of trial reached?

Main objective of the trial

Part 1: To evaluate the safety, tolerability, Pharmacokinetics (PK) and Pharmacodynamics (PD) of risdiplam in subjects with Type 2 and Type 3 (ambulant or non-ambulant) SMA, and to select the dose for Part 2 of the study; Part 2: To evaluate efficacy of risdiplam compared to placebo in terms of motor function in Type 2 and non-ambulant Type 3 SMA subjects, as assessed by the change from baseline in the total score of the Motor Function Measure (MFM) at 12 months

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

19 Oct 2016

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Belgium: 19

Country: Number of subjects enrolled

Germany: 4

Country: Number of subjects enrolled

France: 25

Country: Number of subjects enrolled

Italy: 51

Country: Number of subjects enrolled

Brazil: 2

Country: Number of subjects enrolled

Canada: 18

Country: Number of subjects enrolled

China: 16

Country: Number of subjects enrolled

Spain: 21

Country: Number of subjects enrolled

Croatia: 11

Country: Number of subjects enrolled

Japan: 15

Country: Number of subjects enrolled

Poland: 32

Country: Number of subjects enrolled

Russian Federation: 4

Country: Number of subjects enrolled

Serbia: 8

Country: Number of subjects enrolled

Turkey: 1

Country: Number of subjects enrolled

United States: 4

Worldwide total number of subjects

231

EEA total number of subjects

163

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)

143

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

Study Part 1 was conducted at 5 investigational sites across 4 countries, and Part 2 was conducted at 42 investigational sites across 14 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

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Monitor, Carer, Data analyst, Assessor

Are arms mutually exclusive

Yes

Part 1 Group A: Adolescents and Adults (Risdiplam)

Arm description

Adolescent and adult subjects aged 12-25 years received risdiplam for at least 12 weeks. Once the placebo-controlled period was completed and Part 2 dose was selected, subjects switched to Part 2 dose and were treated in an open-label phase.

Arm type

Experimental

Investigational medicinal product name

risdiplam

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder for oral solution

Routes of administration

Oral use

Dosage and administration details

Part 1 was a does-finding exploratory part. Risdiplam was administered once daily with meal orally or through gastric tube. Subjects receiving risdiplam orally followed this by rinsing their mouth with water and swallowing. Subjects unable to swallow were to receive risdiplam by bolus via their naso-gastric or gastrostomy tube. This was followed by a bolus flush of water through the tube.

Part 1 Group A: Adolescents and Adults (Placebo)

Arm description

Adolescent and adult subjects aged 12-25 years received placebo matching to risdiplam for at least 12 weeks. Once the placebo-controlled period was completed, subjects first switched to their cohort risdiplam dose. After the Part 2 dose was selected, subjects switched to Part 2 dose and were treated in an open-label phase.

Arm type

Placebo

Investigational medicinal product name

risdiplam matching placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder for oral solution

Routes of administration

Oral use

Dosage and administration details

Part 1 was a dose-finding exploratory part. Risdiplam matching placebo was administered once daily with meal orally or through gastric tube. Subjects receiving risdiplam matching placebo orally followed this by rinsing their mouth with water and swallowing. Subjects unable to swallow were to receive risdiplam matching placebo by bolus via their naso-gastric or gastrostomy tube. This was followed by a bolus flush of water through the tube.

Part 1 Group B: Children (Risdiplam)

Arm description

Children aged 2-11 years received risdiplam for at least 12 weeks. Once the placebo-controlled period was completed and Part 2 dose was selected, subjects switched to Part 2 dose and were treated in an open-label phase.

Arm type

Experimental

Investigational medicinal product name

risdiplam

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder for oral solution

Routes of administration

Oral use

Dosage and administration details

Part 1 was a dose-finding exploratory part. Risdiplam was administered once daily with meal orally or through gastric tube. Subjects receiving risdiplam orally followed this by rinsing their mouth with water and swallowing. Subjects unable to swallow were to receive risdiplam by bolus via their naso-gastric or gastrostomy tube. This was followed by a bolus flush of water through the tube.

Part 1 Group B: Children (Placebo)

Arm description

Children aged 2-11 years received placebo matching to risdiplam for at least 12 weeks. Once the placebo-controlled period was completed, subjects first switched to their cohort risdiplam dose. After the Part 2 dose was selected, subjects switched to Part 2 dose and were treated in an open-label phase.

Arm type

Placebo

Investigational medicinal product name

risdiplam matching placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder for oral solution

Routes of administration

Oral use

Dosage and administration details

Part 2: Risdiplam

Arm description

Subjects aged 2-25 years received risdiplam at the dose of 5 mg once daily for subjects with a body weight (BW) >/=20kg or 0.25 mg/kg for subjects with a BW <20 kg for 12 months.

Arm type

Experimental

Investigational medicinal product name

risdiplam

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder for oral solution

Routes of administration

Oral use

Dosage and administration details

Risdiplam was administered once daily with meal orally or through gastric tube at 5 mg for subjects with body weight (BW) >/=20 kg and 0.25 mg/kg for subjects with BW <20 kg. Subjects receiving risdiplam orally followed this by rinsing their mouth with water and swallowing. Subjects unable to swallow were to receive risdiplam by bolus via their naso-gastric or gastrostomy tube. This was followed by a bolus flush of water through the tube.

Part 2: Placebo

Arm description

Subjects aged 2-25 years received placebo matching to risdiplam for 12 months. After 12 months of treatment with placebo, subjects switched to risdiplam (5 mg once daily for subjects with a body weight (BW) >/=20kg or 0.25 mg/kg for subjects with a BW <20) in a blinded manner and subjects will continue with treatment and observations.

Arm type

Placebo

Investigational medicinal product name

risdiplam matching placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder for oral solution

Routes of administration

Oral use

Dosage and administration details

Risdiplam matching placebo was administered once daily with meal orally or through gastric tube. Subjects receiving risdiplam matching placebo orally followed this by rinsing their mouth with water and swallowing. Subjects unable to swallow were to receive risdiplam matching placebo by bolus via their naso-gastric or gastrostomy tube. This was followed by a bolus flush of water through the tube.

Number of subjects in period 1	Part 1 Group A: Adolescents and Adults (Risdiplam)	Part 1 Group A: Adolescents and Adults (Placebo)	Part 1 Group B: Children (Risdiplam)	Part 1 Group B: Children (Placebo)	Part 2: Risdiplam	Part 2: Placebo
Started	14	6	21	10	120	60
Completed	13	6	21	10	117	59
Not completed	1	0	0	0	3	1
Consent withdrawn by subject	1	-	-	-	-	-
Changed to other treatment	-	-	-	-	1	-
Changed to Spinraza	-	-	-	-	2	1

Baseline characteristics

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Reporting group title

Part 1 Group A: Adolescents and Adults (Risdiplam)

Reporting group description

Reporting group title

Part 1 Group A: Adolescents and Adults (Placebo)

Reporting group description

Reporting group title

Part 1 Group B: Children (Risdiplam)

Reporting group description

Reporting group title

Part 1 Group B: Children (Placebo)

Reporting group description

Reporting group title

Part 2: Risdiplam

Reporting group description

Subjects aged 2-25 years received risdiplam at the dose of 5 mg once daily for subjects with a body weight (BW) >/=20kg or 0.25 mg/kg for subjects with a BW <20 kg for 12 months.

Reporting group title

Part 2: Placebo

Reporting group description

Reporting group values	Part 1 Group A: Adolescents and Adults (Risdiplam)	Part 1 Group A: Adolescents and Adults (Placebo)	Part 1 Group B: Children (Risdiplam)	Part 1 Group B: Children (Placebo)	Part 2: Risdiplam	Part 2: Placebo	Total
Number of subjects	14	6	21	10	120	60	231
Age categorical
Units: Subjects
In utero	0	0	0	0	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0	0	0	0	0
Newborns (0-27 days)	0	0	0	0	0	0	0
Infants and toddlers (28 days-23 months)	0	0	0	0	0	0	0
Children (2-11 years)	0	0	21	10	76	36	143
Adolescents (12-17 years)	11	5	0	0	30	16	62
Adults (18-64 years)	3	1	0	0	14	8	26
From 65-84 years	0	0	0	0	0	0	0
85 years and over	0	0	0	0	0	0	0
Age Continuous
Units: Years
arithmetic mean (standard deviation)	15.7 ± 4.1	16.0 ± 3.7	5.5 ± 2.5	4.6 ± 2.0	9.9 ± 5.8	10.3 ± 6.1	-
Sex: Female, Male
Units: Participants
Female	10	3	12	2	61	30	118
Male	4	3	9	8	59	30	113
Race/Ethnicity, Customized
Units: Subjects
Asian	0	0	1	0	23	12	36
White	14	6	19	9	80	41	169
Multiple	0	0	1	1	1	0	3
Black or African American	0	0	0	0	2	0	2
Not stated	0	0	0	0	14	7	21
Race/Ethnicity, Customized
Units: Subjects
Hispanic or Latino	0	0	0	0	5	2	7
Not Hispanic or Latino	14	6	20	10	114	57	221
Unknown	0	0	1	0	1	1	3

End points

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Reporting group title

Part 1 Group A: Adolescents and Adults (Risdiplam)

Reporting group description

Reporting group title

Part 1 Group A: Adolescents and Adults (Placebo)

Reporting group description

Reporting group title

Part 1 Group B: Children (Risdiplam)

Reporting group description

Reporting group title

Part 1 Group B: Children (Placebo)

Reporting group description

Reporting group title

Part 2: Risdiplam

Reporting group description

Subjects aged 2-25 years received risdiplam at the dose of 5 mg once daily for subjects with a body weight (BW) >/=20kg or 0.25 mg/kg for subjects with a BW <20 kg for 12 months.

Reporting group title

Part 2: Placebo

Reporting group description

Subject analysis set title

Part 1: All Risdiplam

Subject analysis set type

Sub-group analysis

Subject analysis set description

Children aged 2-11 years and adolescent and adult subjects aged 12-25 years received risdiplam or risdiplam matching placebo.

Subject analysis set title

Part 1 Intent-to Treat (ITT)

Subject analysis set type

Intention-to-treat

Subject analysis set description

The ITT population in Part 1 is defined as all randomized subjects. Subjects were grouped by treatment and by age group of 2-11 or 12-25 years old.

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 or placebo) whether prematurely withdrawn or not 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 ITT population defined as all randomized subjects in Part 2 are the primary analysis population for all efficacy analyses. Subjects under the ITT population are reported according to the treatment they were randomized to.

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 or placebo) were included in the safety population. Subjects were grouped according to the treatment received.

Primary: Part 1: Selected Part 2 Dose of Risdiplam for Subjects with a Body Weight (BW) of >/=20kg

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End point title

Part 1: Selected Part 2 Dose of Risdiplam for Subjects with a Body Weight (BW) of >/=20kg ^[1]

End point description

The Internal Monitoring Committee (IMC) was responsible for selecting the dose for Part 2 of the study (pivotal dose). An external Independent Data Monitoring Committee (iDMC) reviewed data from Part 1 and confirmed the dose-selection decision of the IMC. The dose for Part 2 selected by the IMC was a dose that: 1.Was judged to be safe and well-tolerated, based on all available safety data from Part 1 and as confirmed by the iDMC; 2. Resulted in an exposure at steady-state below the exposure cap (mean value) of AUC0-24h,ss 2000 ng*h/mL (adjusted for free-fraction, if required); 3. Resulted in an SMN protein increase that was expected to be clinically relevant.

End point type

Primary

End point timeframe

Day 1 up to at least 4 weeks on study (Up to CCOD of 25 July 2017)

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	Part 1: All Risdiplam
Number of subjects analysed	51
Units: milligram (mg)	5

No statistical analyses for this end point

Primary: Part 1: Selected Part 2 Dose of Risdiplam for Subjects with BW of <20kg

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End point title

Part 1: Selected Part 2 Dose of Risdiplam for Subjects with BW of <20kg ^[2]

End point description

End point type

Primary

End point timeframe

Day 1 up to at least 4 weeks on study (Up to CCOD of 25 July 2017)

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.

End point values	Part 1: All Risdiplam
Number of subjects analysed	51
Units: milligram/kilogramm (mg/kg)
number (not applicable)	0.25

No statistical analyses for this end point

Primary: Part 2: Change from Baseline in the Total Motor Function Measure 32 (MFM-32) Total Score at Month 12

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End point title

Part 2: Change from Baseline in the Total Motor Function Measure 32 (MFM-32) Total Score at Month 12 ^[3]

End point description

The Motor Function Measure 32 (MFM32) is a scale constructed for use in neuromuscular disorders. It comprises 32 items that evaluate physical function in three dimensions: D1 function related to standing and transfer; D2 axial and proximal function; D3 distal motor function. Tasks are scored with a 4-point Likert scale: 0 - cannot initiate the task or maintain the starting position; 1 - performs the task partially; 2 - performs the task incompletely or imperfectly; 3 - performs the task fully and “normally”. The 32 scores are summed and expressed on a 0-100 scale for the MFM32 total score. Higher scores indicate increased motor function. A positive change from Baseline indicates improvement. MMRM analysis was performed based on primary efficacy hypothetical estimand, which included subjects data assuming no prohibited medication intended for treatment of SMA was received and subjects continued on their randomized treatment until the analysis time point at Month 12.

End point type

Primary

End point timeframe

Baseline (Day -1) and Month 12

Notes
[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	Part 2: Risdiplam	Part 2: Placebo
Number of subjects analysed	115 ^[4]	59 ^[5]
Units: Scores on a Scale
least squares mean (confidence interval 95%)	1.36 (0.61 to 2.11)	-0.19 (-1.22 to 0.84)

Notes
[4] - Subjects with missing MFM32 total score at Baseline were not included in the analysis.
[5] - Subjects with missing MFM32 total score at Baseline were not included in the analysis.

Risdiplam vs Placebo

Statistical analysis description

This is the first end point and first family tested in the hierarchical testing. The variables included in the MMRM model are: baseline total score, treatment, age group, visit, treatment-by-visit and baseline score-by-visit interaction.

Comparison groups

Part 2: Risdiplam v Part 2: Placebo

Number of subjects included in analysis

174

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0156

Method

Mixed Model Repeated Measure Analysis

Parameter type

Least Square Mean Difference

Point estimate

1.55

Confidence interval

level

95%

sides

2-sided

lower limit

0.3

upper limit

2.81

Secondary: Part 2: Percentage of Subjects with Marked Improvement (Defined as >= 3) in the Total Motor Function Measure (MFM32) Score at Month 12

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End point title

Part 2: Percentage of Subjects with Marked Improvement (Defined as >= 3) in the Total Motor Function Measure (MFM32) Score at Month 12 ^[6]

End point description

The MFM32 comprises 32 items that evaluate physical function. The scoring of each task uses a 4-point Likert scale: 0 - cannot initiate the task or maintain the starting position; 1 - performs the task partially; 2 - performs the task incompletely or imperfectly; 3 - performs the task fully and “normally”. The 32 scores are summed and expressed on a 0-100 scale for the MFM32 total score. A change in MFM32 total score of threshold >/=3 represents marked improvement in this measure. Logistic regression analysis was performed based on efficacy hypothetical estimand, which included subjects data assuming no prohibited medication intended for treatment of SMA was received and subjects continued on their randomized treatment until the analysis time point at Month 12. Missing results at Month 12 are considered as non-responders.

End point type

Secondary

End point timeframe

At Month 12

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	Part 2: Risdiplam	Part 2: Placebo
Number of subjects analysed	115 ^[7]	59 ^[8]
Units: Percentage of Subjects
least squares mean (confidence interval 95%)	38.3 (28.94 to 47.58)	23.7 (12.03 to 35.43)

Notes
[7] - Subjects with missing MFM32 total score at Baseline were not included in the analysis.
[8] - Subjects with missing MFM32 total score at Baseline were not included in the analysis.

Risdiplam vs Placebo

Statistical analysis description

This is the second end point and second family tested in the hierarchical testing. Logistic Regression Model.The variables included in the logistic regression are: baseline total score, treatment and age group.

Comparison groups

Part 2: Risdiplam v Part 2: Placebo

Number of subjects included in analysis

174

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0469 ^[9]

Method

Wald test

Parameter type

Odds ratio (OR)

Point estimate

2.35

Confidence interval

level

95%

sides

2-sided

lower limit

1.01

upper limit

5.44

Notes
[9] - Adjusted p-Value The adjusted p-values were derived based on all the p-values from end points in order of the hierarchical testing up to the current endpoint.

Secondary: Part 2: Change from Baseline in the Total Score of the Revised Upper Limb Module (RULM) at Month 12

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End point title

Part 2: Change from Baseline in the Total Score of the Revised Upper Limb Module (RULM) at Month 12 ^[10]

End point description

The RULM is a 20 items scale that assesses the proximal and distal motor functions of the arm. There is an entry item and the remaining 18 items are scored on the 3 point scale of : 0: cannot complete task independently; 1: modified method but can complete task independently; 2: completes task without any assistance, and with 1 item scored on a 2 point scale of as a can/cannot score with 1 as the highest score. The RULM total score is the sum of 19 items scores with range of 0-37, and the entry item does not contribute to the total score. Higher scores indicate greater upper limb function. A positive change from Baseline indicates improvement. MMRM analysis was performed based on the efficacy hypothetical estimand, which included subjects data assuming no prohibited medication intended for treatment of SMA was received and subjects continued on their randomized treatment until the analysis time point at Month 12.

End point type

Secondary

End point timeframe

Baseline (Day-1) and Month 12

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	Part 2: Risdiplam	Part 2: Placebo
Number of subjects analysed	119 ^[11]	58 ^[12]
Units: Scores on a Scale
least squares mean (confidence interval 95%)	1.61 (1.00 to 2.22)	0.02 (-0.83 to 0.87)

Notes
[11] - Subjects with missing RULM total score at Baseline were not included in the analysis.
[12] - Subjects with missing RULM total score at Baseline were not included in the analysis.

Risdiplam vs Placebo

Statistical analysis description

This is the third end point and third family tested in the hierarchical testing. The variables included in the MMRM model are: baseline total score, treatment, age group, visit, treatment-by-visit and baseline score-by-visit interaction.

Comparison groups

Part 2: Risdiplam v Part 2: Placebo

Number of subjects included in analysis

177

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0469 ^[13]

Method

Mixed Model Repeated Measure Analysis

Parameter type

Least Square Mean Difference

Point estimate

1.59

Confidence interval

level

95%

sides

2-sided

lower limit

0.55

upper limit

2.62

Notes
[13] - Adjusted p-Value The adjusted p-values were derived based on all the p-values from end points in order of the hierarchical testing up to the current endpoint.

Secondary: Part 2: Change from Baseline in Total Score of Hammersmith Functional Motor Scale Expanded (HFMSE) at Month 12

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End point title

Part 2: Change from Baseline in Total Score of Hammersmith Functional Motor Scale Expanded (HFMSE) at Month 12 ^[14]

End point description

The HFMSE scale contains 33 items, which are scored on a 3-point Likert-type scale (0-2) and summed to derive the total score, with lower scores indicating greater impairment. The HFMSE contains a series of assessments designed to assess important functional abilities, including standing, transfers, ambulation, and proximal and axial function. The overall score is the sum of the scores for all activities with a maximum achievable score of 66. Higher scores indicate greater motor function. A positive change from Baseline indicates improvement. MMRM analysis was performed based on the efficacy hypothetical estimand, which included subjects data assuming no prohibited medication intended for treatment of SMA was received and subjects continued on their randomized treatment until the analysis time point at Month 12.

End point type

Secondary

End point timeframe

Baseline (Day-1) and Month 12

Notes
[14] - 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	Part 2: Risdiplam	Part 2: Placebo
Number of subjects analysed	120	60
Units: Scores on a Scale
least squares mean (confidence interval 95%)	0.95 (0.29 to 1.61)	0.37 (-0.54 to 1.28)

Risdiplam vs Placebo

Statistical analysis description

This is one of the two end points in family four in the hierarchical testing. The variables included in the MMRM model are: baseline total score, treatment, age group, visit, treatment-by-visit and baseline score-by-visit interaction.

Comparison groups

Part 2: Risdiplam v Part 2: Placebo

Number of subjects included in analysis

180

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.3902 ^[15]

Method

Mixed Model Repeated Measure Analysis

Parameter type

Least Square Mean Difference

Point estimate

0.58

Confidence interval

level

95%

sides

2-sided

lower limit

-0.53

upper limit

1.69

Notes
[15] - Adjusted p-Value The adjusted p-values were derived based on all the p-values from end points in order of the hierarchical testing up to the current endpoint.

Secondary: Part 2: Change from Baseline in Forced Vital Capacity (FVC) at Month 12 in Subjects Aged 6-25 Years

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End point title

Part 2: Change from Baseline in Forced Vital Capacity (FVC) at Month 12 in Subjects Aged 6-25 Years ^[16]

End point description

Spirometry is a pulmonary function test that assesses how the lungs work by measuring how much air moves through the airways. Spirometry was performed by all subjects aged 6 or older. Forced vital capacity (FVC) is the total volume that can be exhaled after inhaling maximally. The best % predicted value out of all attempts were used for the analysis. MMRM analysis was performed based on the efficacy hypothetical estimand, which included subjects data assuming no prohibited medication intended for treatment of SMA was received and subjects continued on their randomized treatment until the analysis time point at Month 12.

End point type

Secondary

End point timeframe

Baseline (Day-1) and Month 12

Notes
[16] - 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	Part 2: Risdiplam	Part 2: Placebo
Number of subjects analysed	83 ^[17]	40 ^[18]
Units: Percentage Predicted
least squares mean (confidence interval 95%)	-5.16 (-7.93 to -2.39)	-3.11 (-6.59 to 0.74)

Notes
[17] - Subjects with missing FVC data at Baseline were not included in the analysis.
[18] - Subjects with missing FVC data at Baseline were not included in the analysis.

Risdiplam vs Placebo

Statistical analysis description

Comparison groups

Part 2: Risdiplam v Part 2: Placebo

Number of subjects included in analysis

123

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.3902 ^[19]

Method

Mixed Model Repeated Measure Analysis

Parameter type

Least Square Mean Difference

Point estimate

-2.05

Confidence interval

level

95%

sides

2-sided

lower limit

-6.67

upper limit

2.56

Notes
[19] - Adjusted p-Value The adjusted p-values were derived based on all the p-values from end points in order of the hierarchical testing up to the current endpoint.

Secondary: Part 2: Change from Baseline in the Caregiver-Reported SMA Independence Scale (SMAIS) Total Score at Month 12

Top of page

End point title

Part 2: Change from Baseline in the Caregiver-Reported SMA Independence Scale (SMAIS) Total Score at Month 12 ^[20]

End point description

The SMA Independence Scale (SMAIS) was developed specifically for SMA subjects in order to assess function-related independence. The SMAIS contains 29 items, assessing the amount of assistance required from another individual to perform daily activities such as eating, or bathing. Each item is scored on a 0-4 scale (with an additional option to indicate that an item is non-applicable). The SMAIS total score ranging from 0-44 is obtained based on 22 items with each item on the 0-2 scale. Lower scores indicate greater dependence on another individual. The SMAIS was completed by subjects aged 12 years or older and caregivers of subjects aged 2-25 years. MMRM analysis was performed based on efficacy hypothetical estimand, which included subjects data assuming no prohibited medication intended for treatment of SMA was received and subjects continued on their randomized treatment until the analysis time point at Month 12.

End point type

Secondary

End point timeframe

Baseline (Day-1) and Month 12

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	Part 2: Risdiplam	Part 2: Placebo
Number of subjects analysed	116 ^[21]	60
Units: Scores on a Scale
least squares mean (confidence interval 95%)	1.65 (0.66 to 2.63)	-0.91 (-2.23 to 0.42)

Notes
[21] - Subjects with missing SMAIS total score at Baseline were not included in the analysis.

Risdiplam vs Placebo

Statistical analysis description

This is the sixth endpoint and the fifth family tested in the hierarchical testing. The variables included in the MMRM model are: baseline total score, treatment, age group, visit, treatment-by-visit and baseline score-by-visit interaction.

Comparison groups

Part 2: Risdiplam v Part 2: Placebo

Number of subjects included in analysis

176

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.3902 ^[22]

Method

Mixed Model Repeated Measure Analysis

Parameter type

Least Square Mean Difference

Point estimate

2.55

Confidence interval

level

95%

sides

2-sided

lower limit

0.93

upper limit

4.17

Notes
[22] - Adjusted p-Value The adjusted p-values were derived based on all the p-values from end points in order of the hierarchical testing up to the current endpoint.

Secondary: Part 2: Percentage of Subjects Rated by Clinicians as Improved in the Clinical Global Impression of Change (CGI-C) Scale Ratings at Month 12

Top of page

End point title

Part 2: Percentage of Subjects Rated by Clinicians as Improved in the Clinical Global Impression of Change (CGI-C) Scale Ratings at Month 12 ^[23]

End point description

The Clinical Global Impression of Change (CGI-C) is used to score a clinician’s impression of a subject’s change in global health. The CGI-C is a single item measure of change in global health, using seven response options: “very much improved”, “much improved”, “minimally improved”, “no change”, “minimally worse”, “much worse”, and “very much worse”. Subjects considered as "improved" included responses of "very much improved, "much improved" and "minimally improved". Logistic regression analysis was performed based on efficacy hypothetical estimand, which included subjects data assuming no prohibited medication intended for treatment of SMA was received and subjects continued on their randomized treatment until the analysis time point at Month 12.

End point type

Secondary

End point timeframe

At Month 12

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	Part 2: Risdiplam	Part 2: Placebo
Number of subjects analysed	120 ^[24]	60 ^[25]
Units: Percentage of Subjects
number (confidence interval 95%)	47.5 (38.15 to 56.86)	40.0 (26.77 to 53.23)

Notes
[24] - Missing results at Month 12 are considered as non-responders.
[25] - Missing results at Month 12 are considered as non-responders.

CGI Improved

Statistical analysis description

This is the seventh endpoint and the sixth family tested in the hierarchical testing. Logistic Regression Model. The variables included in the logistic regression are: baseline total score, treatment and age group.

Comparison groups

Part 2: Risdiplam v Part 2: Placebo

Number of subjects included in analysis

180

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.3902 ^[26]

Method

Wald-test

Parameter type

Odds ratio (OR)

Point estimate

1.38

Confidence interval

level

95%

sides

2-sided

lower limit

0.7

upper limit

2.74

Notes
[26] - Adjusted p-Value The adjusted p-values were derived based on all the p-values from end points in order of the hierarchical testing up to the current endpoint.

Secondary: Part 2: Percentage of Subjects who Achieve Stabilization or Improvement (Defined as >= 0) in the Total Motor Function Measure (MFM) Score at Month 12

Top of page

End point title

Part 2: Percentage of Subjects who Achieve Stabilization or Improvement (Defined as >= 0) in the Total Motor Function Measure (MFM) Score at Month 12 ^[27]

End point description

The MFM32 comprises 32 items that evaluate physical function in three dimensions: D1 function related to standing and transfer; D2 axial and proximal function; D3 distal motor function. Tasks are scored with a 4-point Likert scale: 0 - cannot initiate the task or maintain the starting position; 1 - performs the task partially; 2 - performs the task incompletely or imperfectly; 3 - performs the task fully and “normally”. The 32 scores are summed and expressed on a 0-100 scale for the MFM32 total score. Higher scores indicate increased motor function. Logistic regression analysis was performed based on efficacy hypothetical estimand, which included subjects data assuming no prohibited medication intended for treatment of SMA was received and subjects continued on their randomized treatment until the analysis time point at Month 12. Missing results at Month 12 are considered as non-responders.

End point type

Secondary

End point timeframe

At Month 12

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	Part 2: Risdiplam	Part 2: Placebo
Number of subjects analysed	115 ^[28]	59 ^[29]
Units: Percentage of Subjects
number (confidence interval 95%)	69.6 (60.72 to 78.41)	54.2 (40.68 to 67.80)

Notes
[28] - Subjects with missing MFM32 total score at Baseline were not included in the analysis.
[29] - Subjects with missing MFM32 total score at Baseline were not included in the analysis.

Risdiplam vs Placebo

Statistical analysis description

Logistic Regression Model. The variables included in the logistic regression are: baseline total score, treatment and age group.

Comparison groups

Part 2: Risdiplam v Part 2: Placebo

Number of subjects included in analysis

174

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.043

Method

Wald test

Parameter type

Odds ratio (OR)

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

1.02

upper limit

3.93

Secondary: Part 2: Percentage of Subjects who Achieve an Improvement of at Least One Standard Error of Measurement (SEM) on the Total MFM Score at Month 12

Top of page

End point title

Part 2: Percentage of Subjects who Achieve an Improvement of at Least One Standard Error of Measurement (SEM) on the Total MFM Score at Month 12 ^[30]

End point description

The MFM32 comprises 32 items that evaluate physical function in three dimensions: D1 standing and transfer; D2 axial and proximal function; D3 distal motor function. Tasks are scored with a 4-point Likert scale: 0-cannot initiate the task or maintain the starting position; 1-performs the task partially; 2-performs the task incompletely or imperfectly; 3-performs the task fully and “normally”. The 32 scores are summed and expressed on a 0-100 scale for the total score. Higher scores indicate increased motor function. Standard error of measurement (SEM) is derived using 32 items scores and total scores at baseline. Change from baseline >= one SEM is equivalent to a change >= 4. Logistic regression analysis was performed based on efficacy hypothetical estimand included subjects data assuming no prohibited medication intended for treatment of SMA was received and subjects continued on their randomized treatment until the analysis time point at Month 12.

End point type

Secondary

End point timeframe

At Month 12

Notes
[30] - 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	Part 2: Risdiplam	Part 2: Placebo
Number of subjects analysed	115 ^[31]	59 ^[32]
Units: Percentage of Subjects
number (confidence interval 95%)
Week 52	28.7 (20.65 to 37.88)	16.9 (8.44 to 28.97)

Notes
[31] - Subjects with missing MFM32 total score at Baseline were not included in the analysis.
[32] - Subjects with missing MFM32 total score at Baseline were not included in the analysis.

No statistical analyses for this end point

Secondary: Part 2: Change from Baseline in the MFM Domain 1 (D1) Score at Month 12

Top of page

End point title

Part 2: Change from Baseline in the MFM Domain 1 (D1) Score at Month 12 ^[33]

End point description

The MFM32 comprises 32 items that evaluate physical function in three dimensions: D1 function related to standing and transfer; D2 axial and proximal function; D3 distal motor function. Tasks are scored with a 4-point Likert scale: 0 - cannot initiate the task or maintain the starting position; 1 - performs the task partially; 2 - performs the task incompletely or imperfectly; 3 - performs the task fully and “normally”. The D1 items score are summed and expressed on 0-100 scale for the MFM D1 total score. Higher scores indicate increased motor function. A positive change from Baseline indicates improvement. MMRM analysis was performed based on efficacy hypothetical estimand, which included subjects data assuming no prohibited medication intended for treatment of SMA was received and subjects continued on their randomized treatment until the analysis time point at Month 12.

End point type

Secondary

End point timeframe

Baseline (Day-1) and Month 12

Notes
[33] - 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	Part 2: Risdiplam	Part 2: Placebo
Number of subjects analysed	118 ^[34]	60
Units: Scores on a Scale
least squares mean (confidence interval 95%)	0.37 (-0.12 to 0.87)	-0.26 (-0.94 to 0.42)

Notes
[34] - Subjects with missing MFM32 D1 score at Baseline were not included in the analysis.

Risdiplam vs Placebo

Statistical analysis description

The variables included in the MMRM model are: baseline total score, treatment, age group, visit, treatment-by-visit and baseline score-by-visit interaction.

Comparison groups

Part 2: Risdiplam v Part 2: Placebo

Number of subjects included in analysis

178

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.1328

Method

Mixed Model Repeated Measure Analysis

Parameter type

Least Square Mean Difference

Point estimate

0.64

Confidence interval

level

95%

sides

2-sided

lower limit

-0.2

upper limit

1.47

Secondary: Part 2: Change from Baseline in the MFM Domain 2 (D2) Score at Month 12

Top of page

End point title

Part 2: Change from Baseline in the MFM Domain 2 (D2) Score at Month 12 ^[35]

End point description

The MFM32 comprises 32 items that evaluate physical function in three dimensions: D1 function related to standing and transfer; D2 axial and proximal function; D3 distal motor function. Tasks are scored with a 4-point Likert scale: 0 - cannot initiate the task or maintain the starting position; 1 - performs the task partially; 2 - performs the task incompletely or imperfectly; 3 - performs the task fully and “normally”. The D2 items score are summed and expressed on 0-100 scale for the MFM D2 total score. Higher scores indicate increased motor function. A positive change from Baseline indicates improvement. MMRM analysis was performed based on efficacy hypothetical estimand, which included subjects data assuming no prohibited medication intended for treatment of SMA was received and subjects continued on their randomized treatment until the analysis time point at Month 12.

End point type

Secondary

End point timeframe

Baseline (Day-1) and Month 12

Notes
[35] - 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	Part 2: Risdiplam	Part 2: Placebo
Number of subjects analysed	118 ^[36]	60
Units: Scores on a Scale
least squares mean (confidence interval 95%)	1.04 (-0.38 to 2.46)	-0.93 (-2.87 to 1.02)

Notes
[36] - Subjects with missing MFM32 D2 total score at Baseline were not included in the analysis.

Risdiplam vs Placebo

Statistical analysis description

The variables included in the MMRM model are: baseline total score, treatment, age group, visit, treatment-by-visit and baseline score-by-visit interaction.

Comparison groups

Part 2: Risdiplam v Part 2: Placebo

Number of subjects included in analysis

178

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.103

Method

Mixed Model Repeated Measure Analysis

Parameter type

Least Square Mean Difference

Point estimate

1.97

Confidence interval

level

95%

sides

2-sided

lower limit

-0.4

upper limit

4.34

Secondary: Part 2: Change from Baseline in the MFM Domain 3 (D3) Score at Month 12

Top of page

End point title

Part 2: Change from Baseline in the MFM Domain 3 (D3) Score at Month 12 ^[37]

End point description

The MFM32 comprises 32 items that evaluate physical function in three dimensions: D1 function related to standing and transfer; D2 axial and proximal function; D3 distal motor function. Tasks are scored with a 4-point Likert scale: 0 - cannot initiate the task or maintain the starting position; 1 - performs the task partially; 2 - performs the task incompletely or imperfectly; 3 - performs the task fully and “normally”. The D3 items score are summed and expressed on 0-100 scale for the MFM D3 total score. Higher scores indicate increased motor function. A positive change from Baseline indicates improvement. MMRM analysis was performed based on efficacy hypothetical estimand, which included subjects data assuming no prohibited medication intended for treatment of SMA was received and subjects continued on their randomized treatment until the analysis time point at Month 12.

End point type

Secondary

End point timeframe

Baseline (Day-1) and Month 12

Notes
[37] - 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	Part 2: Risdiplam	Part 2: Placebo
Number of subjects analysed	115 ^[38]	59 ^[39]
Units: Scores on a Scale
least squares mean (confidence interval 95%)	3.68 (2.31 to 5.04)	1.34 (-0.54 to 3.22)

Notes
[38] - Subjects with missing MFM32 D3 total score at Baseline were not included in the analysis.
[39] - Subjects with missing MFM32 D3 total score at Baseline were not included in the analysis.

Risdiplam vs Placebo

Statistical analysis description

The variables included in the MMRM model are: baseline total score, treatment, age group, visit, treatment-by-visit and baseline score-by-visit interaction.

Comparison groups

Part 2: Risdiplam v Part 2: Placebo

Number of subjects included in analysis

174

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0451

Method

Mixed Model Repeated Measure Analysis

Parameter type

Least Square Mean Difference

Point estimate

2.34

Confidence interval

level

95%

sides

2-sided

lower limit

0.05

upper limit

4.62

Secondary: Part 2: Change from Baseline in the Total Combined Scores of MFM Domains 1 and 2 at Month 12

Top of page

End point title

Part 2: Change from Baseline in the Total Combined Scores of MFM Domains 1 and 2 at Month 12 ^[40]

End point description

The MFM32 comprises 32 items that evaluate physical function in three dimensions: D1 function related to standing and transfer; D2 axial and proximal function; D3 distal motor function. Tasks are scored with a 4-point Likert scale: 0 - cannot initiate the task or maintain the starting position; 1 - performs the task partially; 2 - performs the task incompletely or imperfectly; 3 - performs the task fully and “normally”. The D1+D2 items score are summed and expressed on 0-100 scale for the MFM D1+D2 total score. Higher scores indicate increased motor function. A positive change from Baseline indicates improvement. MMRM analysis was performed based on efficacy hypothetical estimand, which included subjects data assuming no prohibited medication intended for treatment of SMA was received and subjects continued on their randomized treatment until the analysis time point at Month 12.

End point type

Secondary

End point timeframe

Baseline (Day-1) and Month 12

Notes
[40] - 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	Part 2: Risdiplam	Part 2: Placebo
Number of subjects analysed	118 ^[41]	60
Units: Scores on a Scale
least squares mean (confidence interval 95%)	0.69 (-0.07 to 1.45)	-0.59 (-1.64 to 0.45)

Notes
[41] - Subjects with missing MFM32 D1+D2 total score at Baseline were not included in the analysis.

Risdiplam vs Placebo

Statistical analysis description

The variables included in the MMRM model are: baseline total score, treatment, age group, visit, treatment-by-visit and baseline score-by-visit interaction.

Comparison groups

Part 2: Risdiplam v Part 2: Placebo

Number of subjects included in analysis

178

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0489

Method

Mixed Model Repeated Measure Analysis

Parameter type

Least Square Mean Difference

Point estimate

1.28

Confidence interval

level

95%

sides

2-sided

lower limit

0.01

upper limit

2.56

Secondary: Part 2: Change from Baseline in Forced Expiratory Volume in 1 Second (FEV1) at Month 12 in Subjects Aged 6-25 Years

Top of page

End point title

Part 2: Change from Baseline in Forced Expiratory Volume in 1 Second (FEV1) at Month 12 in Subjects Aged 6-25 Years ^[42]

End point description

Spirometry is a pulmonary function test that assesses how the lungs work by measuring how much air moves through the airways. Spirometry was performed by all subjects aged 6 or older. Forced expiratory volume (FEV1) is the volume forcefully exhaled in the first second of the forced vital capacity test. The best % predicted value out of all attempts were used for the analysis. MMRM analysis was performed based on efficacy hypothetical estimand, which included subjects data assuming no prohibited medication intended for treatment of SMA was received and subjects continued on their randomized treatment until the analysis time point at Month 12.

End point type

Secondary

End point timeframe

Baseline (Day-1) and Month 12

Notes
[42] - 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	Part 2: Risdiplam	Part 2: Placebo
Number of subjects analysed	83 ^[43]	40 ^[44]
Units: Percentage Predicted
least squares mean (confidence interval 95%)	-4.22 (-7.49 to -0.96)	-1.35 (-5.91 to 3.20)

Notes
[43] - Subjects with missing FEV1 data at Baseline were not included in the analysis.
[44] - Subjects with missing FEV1 data at Baseline were not included in the analysis.

Risdiplam vs Placebo

Statistical analysis description

The variables included in the MMRM model are: baseline total score, treatment, age group, visit, treatment-by-visit and baseline score-by-visit interaction.

Comparison groups

Part 2: Risdiplam v Part 2: Placebo

Number of subjects included in analysis

123

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.3029

Method

Mixed Model Repeated Measure Analysis

Parameter type

Least Square Mean Difference

Point estimate

-2.87

Confidence interval

level

95%

sides

2-sided

lower limit

-8.36

upper limit

2.62

Secondary: Part 2: Change from Baseline in the Peak Cough Flow (PCF) at Month 12 in Subjects Aged 6-25 Years

Top of page

End point title

Part 2: Change from Baseline in the Peak Cough Flow (PCF) at Month 12 in Subjects Aged 6-25 Years ^[45]

End point description

Spirometry is a pulmonary function test that assesses how the lungs work by measuring how much air moves through the airways. Spirometry was performed by all subjects aged 6 or older. Peak cough flow (PCF) is an assessment of cough strength. The best % predicted value out of all attempts were used for the analysis MMRM analysis was performed based on efficacy hypothetical estimand, which included subjects data assuming no prohibited medication intended for treatment of SMA was received and subjects continued on their randomized treatment until the analysis time point at Month 12.

End point type

Secondary

End point timeframe

Baseline (Day-1) and Month 12

Notes
[45] - 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	Part 2: Risdiplam	Part 2: Placebo
Number of subjects analysed	83 ^[46]	42 ^[47]
Units: Percent Predicted
least squares mean (confidence interval 95%)	1.06 (-1.18 to 3.31)	-0.22 (-3.27 to 2.83)

Notes
[46] - Subjects with missing PCF data at Baseline were not included in the analysis.
[47] - Subjects with missing PCF data at Baseline were not included in the analysis.

Risdiplam vs Placebo

Statistical analysis description

The variables included in the MMRM model are: baseline total score, treatment, age group, visit, treatment-by-visit and baseline score-by-visit interaction.

Comparison groups

Part 2: Risdiplam v Part 2: Placebo

Number of subjects included in analysis

125

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.4937

Method

Mixed Model Repeated Measure Analysis

Parameter type

Least Square Mean Difference

Point estimate

1.28

Confidence interval

level

95%

sides

2-sided

lower limit

-2.42

upper limit

4.99

Secondary: Part 2: Change from Baseline in the Best Sniff Nasal Inspiratory Pressure (SNIP) at Month 12

Top of page

End point title

Part 2: Change from Baseline in the Best Sniff Nasal Inspiratory Pressure (SNIP) at Month 12 ^[48]

End point description

The Sniff Nasal Inspiratory Pressure (SNIP) is a volitional, non-invasive test of inspiratory muscle strength that has been successfully applied to children > 2 years of age. Advantages include the simplicity of the maneuver and the absence of a mouthpiece, which is particularly helpful for subjects with SMA, who may have bulbar weakness. SNIP also has the advantage of measuring inspiratory pressure during a natural maneuver that is easily performed even by young children with neuromuscular disorders. The best % predicted value out of all attempts were used for the analysis. MMRM analysis was performed based on efficacy hypothetical estimand, which included subjects data assuming no prohibited medication intended for treatment of SMA was received and subjects continued on their randomized treatment until the analysis time point at Month 12.

End point type

Secondary

End point timeframe

Baseline (Day-1) and Month 12

Notes
[48] - 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	Part 2: Risdiplam	Part 2: Placebo
Number of subjects analysed	118 ^[49]	59 ^[50]
Units: Percentage Predicted
least squares mean (confidence interval 95%)	3.42 (0.22 to 6.62)	1.07 (-3.42 to 5.57)

Notes
[49] - Subjects with missing SNIP data at Baseline were not included in the analysis.
[50] - Subjects with missing SNIP data at Baseline were not included in the analysis.

Risdiplam vs Placebo

Statistical analysis description

The variables included in the MMRM model are: baseline total score, treatment, age group, visit, treatment-by-visit and baseline score-by-visit interaction.

Comparison groups

Part 2: Risdiplam v Part 2: Placebo

Number of subjects included in analysis

177

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.3967

Method

Mixed Model Repeated Measure Analysis

Parameter type

Least Square Mean Difference

Point estimate

2.35

Confidence interval

level

95%

sides

2-sided

lower limit

-3.11

upper limit

7.8

Secondary: Part 2: Change from Baseline in Maximal Inspiratory Pressure (MIP) at Month 12 in Subjects Aged 6-25 Years

Top of page

End point title

Part 2: Change from Baseline in Maximal Inspiratory Pressure (MIP) at Month 12 in Subjects Aged 6-25 Years ^[51]

End point description

The maximal inspiratory pressure (MIP) is a non-invasive test of muscle strength, which measures the maximum strength of the diaphragm and other inspiratory muscles. MIP was measured in subjects aged 6 or older. Subjects were asked to perform a forceful inspiration against an occluded mouth piece. The best % predicted value out of all attempts were used for the analysis. MMRM analysis was performed based on efficacy hypothetical estimand, which included subjects data assuming no prohibited medication intended for treatment of SMA was received and subjects continued on their randomized treatment until the analysis time point at Month 12.

End point type

Secondary

End point timeframe

Baseline (Day-1) and Month 12

Notes
[51] - 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	Part 2: Risdiplam	Part 2: Placebo
Number of subjects analysed	81 ^[52]	40 ^[53]
Units: Percentage Predicted
least squares mean (confidence interval 95%)	1.99 (-6.13 to 10.11)	-0.97 (-12.33 to 10.38)

Notes
[52] - Subjects with missing MIP data at Baseline were not included in the analysis.
[53] - Subjects with missing MIP data at Baseline were not included in the analysis.

Risdiplam vs Placebo

Statistical analysis description

The variables included in the MMRM model are: baseline total score, treatment, age group, visit, treatment-by-visit and baseline score-by-visit interaction.

Comparison groups

Part 2: Risdiplam v Part 2: Placebo

Number of subjects included in analysis

121

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.6704

Method

Mixed Model Repeated Measure Analysis

Parameter type

Least Square Mean Difference

Point estimate

2.96

Confidence interval

level

95%

sides

2-sided

lower limit

-10.78

upper limit

16.7

Secondary: Part 2: Change from Baseline in Maximal Expiratory Pressure (MEP) at Month 12 in Subjects Aged 6-25 Years

Top of page

End point title

Part 2: Change from Baseline in Maximal Expiratory Pressure (MEP) at Month 12 in Subjects Aged 6-25 Years ^[54]

End point description

The maximal expiratory pressure (MEP) is a non-invasive test of muscle strength, which measures the maximum strength of the abdominal muscles and other expiratory muscles. MEP was measured in subjects aged 6 or older. Subjects were asked to perform a forceful inspiration against an occluded mouth piece. The best % predicted value out of all attempts were used for the analysis. MMRM analysis was performed based on efficacy hypothetical estimand, which included subjects data assuming no prohibited medication intended for treatment of SMA was received and subjects continued on their randomized treatment until the analysis time point at Month 12.

End point type

Secondary

End point timeframe

Baseline (Day-1) and Month 12

Notes
[54] - 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	Part 2: Risdiplam	Part 2: Placebo
Number of subjects analysed	83 ^[55]	41 ^[56]
Units: Percentage Predicted
least squares mean (confidence interval 95%)	-2.75 (-6.22 to 0.72)	-2.33 (-7.21 to 2.56)

Notes
[55] - Subjects with missing MEP data at Baseline were not included in the analysis.
[56] - Subjects with missing MEP data at Baseline were not included in the analysis.

Risdiplam vs Placebo

Statistical analysis description

The variables included in the MMRM model are: baseline total score, treatment, age group, visit, treatment-by-visit and baseline score-by-visit interaction.

Comparison groups

Part 2: Risdiplam v Part 2: Placebo

Number of subjects included in analysis

124

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.8856

Method

Mixed Model Repeated Measure Analysis

Parameter type

Least Square Mean Difference

Point estimate

-0.43

Confidence interval

level

95%

sides

2-sided

lower limit

-6.3

upper limit

5.45

Secondary: Part 2: Change from Baseline in the Subject-Reported SMA Independence Scale (SMAIS) Total Score at Month 12

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End point title

Part 2: Change from Baseline in the Subject-Reported SMA Independence Scale (SMAIS) Total Score at Month 12 ^[57]

End point description

The SMAIS was developed specifically for SMA subjects in order to assess function-related independence. It contains 29 items, assessing the amount of assistance required from another individual to perform daily activities such as eating, or bathing. Each item is scored on a 0-4 scale (with an additional option to indicate that an item is non-applicable). The SMAIS total score ranging from 0-44 is obtained based on 22 items with each item on the 0-2 scale. Lower scores indicate greater dependence on another individual. The SMAIS was completed by subjects aged 12 years or older and caregivers of subjects aged 2-25 years. MMRM analysis was performed based on efficacy hypothetical estimand, which included subjects data assuming no prohibited medication intended for treatment of SMA was received and subjects continued on their randomized treatment until the analysis time point at Month 12.

End point type

Secondary

End point timeframe

Baseline (Day-1) and Month 12

Notes
[57] - 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	Part 2: Risdiplam	Part 2: Placebo
Number of subjects analysed	43 ^[58]	23 ^[59]
Units: Scores on a Scale
least squares mean (confidence interval 95%)	1.04 (-0.26 to 2.35)	-0.40 (-2.13 to 1.32)

Notes
[58] - Subjects with missing SMAIS total score at Baseline were not included in the analysis.
[59] - Subjects with missing SMAIS total score at Baseline were not included in the analysis.

Risdiplam vs Placebo

Statistical analysis description

The variables included in the MMRM model are: baseline total score, treatment, age group, visit, treatment-by-visit and baseline score-by-visit interaction.

Comparison groups

Part 2: Risdiplam v Part 2: Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.1778

Method

Mixed Model Repeated Measure Analysis

Parameter type

Least Square Mean Difference

Point estimate

1.45

Confidence interval

level

95%

sides

2-sided

lower limit

-0.68

upper limit

3.57

Secondary: Part 2: Percentage of Subjects Rated by Clinicians as No Change or Improved in the Clinical Global Impression of Change (CGI-C) Scale Ratings at Month 12

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End point title

Part 2: Percentage of Subjects Rated by Clinicians as No Change or Improved in the Clinical Global Impression of Change (CGI-C) Scale Ratings at Month 12 ^[60]

End point description

The CGI-C is used to score a clinician’s impression of a participant’s change in global health. It is a single item measure of change in global health, using seven response options: “very much improved”, “much improved”, “minimally improved”, “no change”, “minimally worse”, “much worse”, and “very much worse”. Participants considered as "no change or improved" included responses of "no change", "very much improved", "much improved" and "minimally improved". Logistic regression analysis was performed based on efficacy hypothetical estimand, which included participants data assuming no prohibited medication intended for treatment of SMA was received and participants continued on their randomized treatment until the analysis time point at Month 12.

End point type

Secondary

End point timeframe

At Month 12

Notes
[60] - 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	Part 2: Risdiplam	Part 2: Placebo
Number of subjects analysed	120 ^[61]	60 ^[62]
Units: Percentage of Subjects
number (confidence interval 95%)	85.8 (79.18 to 92.49)	83.3 (73.07 to 93.60)

Notes
[61] - Missing results at Month 12 are considered as non-responders.
[62] - Missing results at Month 12 are considered as non-responders.

CGI No Change or Improved

Statistical analysis description

Logistic Regression Model. The variables included in the logistic regression are: baseline total score, treatment and age group.

Comparison groups

Part 2: Risdiplam v Part 2: Placebo

Number of subjects included in analysis

180

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.6636

Method

Wald-test

Parameter type

Odds ratio (OR)

Point estimate

1.21

Confidence interval

level

95%

sides

2-sided

lower limit

0.52

upper limit

2.83

Secondary: Part 2: Percentage of Subjects who Experience at Least One Disease-Related Adverse Event at Month 12

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End point title

Part 2: Percentage of Subjects who Experience at Least One Disease-Related Adverse Event at Month 12 ^[63]

End point description

Disease-related adverse events (AEs) were identified by applying two different types of baskets to the AE dataset: Narrow prospectively defined baskets of MedDRA lowest level terms. This basket was defined based on a group of CDC terms selected from an age and gender matched case control study comparing CDC code rates observed in subjects with and without SMA using commercially available insurance claim data (CLAIMS and Market scan data). The lowest level terms included in each basket, coded using the latest version of MedDRA; Broad prospectively defined basket with events selected at preferred term level from all AEs reported in ongoing clinical trials up to January 2019, i.e., prior to unblinding of Part 2 of Study BP39055.

End point type

Secondary

End point timeframe

Baseline up to Month 12 (Week 52; up to CCOD of 06 September 2019)

Notes
[63] - 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	Part 2: Risdiplam	Part 2: Placebo
Number of subjects analysed	120	60
Units: Percentage of Subjects
number (confidence interval 95%)
Narrow Basket AEs	46.7 (37.51 to 55.99)	53.3 (40.00 to 66.33)
Broad Basket AEs	65.0 (55.76 to 73.48)	60.0 (46.54 to 72.44)

No statistical analyses for this end point

Secondary: Part 2: Number of Disease-Related Adverse Events Per Patient-Years at Month 12

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End point title

Part 2: Number of Disease-Related Adverse Events Per Patient-Years at Month 12 ^[64]

End point description

Disease-related AEs were collected through the AE reporting of the study, and the disease-related AE rate was adjusted for patient years (AE rate per 100 patient-years). They were identified by applying two different types of baskets to the AE dataset: Narrow prospectively defined baskets of MedDRA lowest level terms and Broad prospectively defined basket with events selected at preferred term level from all AEs reported in ongoing clinical trials up to January 2019, i.e., prior to unblinding of Part 2 of Study BP39055.

End point type

Secondary

End point timeframe

Baseline up to Month 12 (Week 52; up to CCOD of 06 September 2019)

Notes
[64] - 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	Part 2: Risdiplam	Part 2: Placebo
Number of subjects analysed	120	60
Units: Number of Events per 100 Patient-Years
number (confidence interval 95%)
Narrow Basket AEs	101.51 (84.23 to 121.29)	119.77 (93.71 to 150.82)
Broad Basket AEs	217.29 (191.63 to 245.42)	199.61 (165.50 to 238.68)

No statistical analyses for this end point

Secondary: Part 1: Percentage of Subjects with Adverse Events (AEs) and Serious Adverse Events (SAEs)

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End point title

Part 1: Percentage of Subjects with Adverse Events (AEs) and Serious Adverse Events (SAEs)

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. All subjects in Part 1 who received at least one dose of study medication (risdiplam or placebo) whether prematurely withdrawn or not were included in the safety population.

End point type

Secondary

End point timeframe

Day 1 on risdiplam up to at least 12 months (up to CCOD of 09 January 2019)

End point values	Part 1: All Risdiplam
Number of subjects analysed	51
Units: Percentage of Subjects
number (not applicable)
With at Least One AE	94.1
With at Least One SAE	17.6

No statistical analyses for this end point

Secondary: Part 2: Percentage of Subjects with Adverse Events (AEs) and Serious Adverse Events (SAEs) in the Placebo-Controlled Period

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End point title

Part 2: Percentage of Subjects with Adverse Events (AEs) and Serious Adverse Events (SAEs) in the Placebo-Controlled Period ^[65]

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

End point type

Secondary

End point timeframe

Day 1 up to 12 months of the placebo-controlled period

Notes
[65] - 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	Part 2: Risdiplam	Part 2: Placebo
Number of subjects analysed	120	60
Units: Percentage of Subjects
number (not applicable)
With at Least One AE	92.5	91.7
With at Least One SAE	20.0	18.3

No statistical analyses for this end point

Secondary: Part 2: Percentage of Subjects with Treatment Discontinuation due to Adverse Events (AEs) and Serious Adverse Events (SAEs) in the Placebo-Controlled Period

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End point title

Part 2: Percentage of Subjects with Treatment Discontinuation due to Adverse Events (AEs) and Serious Adverse Events (SAEs) in the Placebo-Controlled Period ^[66]

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

End point type

Secondary

End point timeframe

Day 1 up to 12 months of the placebo-controlled period

Notes
[66] - 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	Part 2: Risdiplam	Part 2: Placebo
Number of subjects analysed	120	60
Units: Percentage of Subjects
number (not applicable)
Due to AE	0.0	0.0
Due to SAE	0.0	0.0

No statistical analyses for this end point

Secondary: Part 2: Number of Subjects Aged 6-25 Years with Suicidal Ideation Based on Columbia-Suicide Severity Rating Scale (C-SSRS) in the Placebo-Controlled Period

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End point title

Part 2: Number of Subjects Aged 6-25 Years with Suicidal Ideation Based on Columbia-Suicide Severity Rating Scale (C-SSRS) in the Placebo-Controlled Period ^[67]

End point description

The Columbia Suicide Severity Rating Scale (C-SSRS) is used to assess the lifetime suicidality of a subject (C-SSRS baseline) as well as any new instances of suicidality (C-SSRS since last visit). The structured interview prompts recollection of suicidal ideation, including the intensity of the ideation, behavior, and attempts with actual/potential lethality. The C-SSRS assessments results were collected for subjects aged 6 years and older.

End point type

Secondary

End point timeframe

Day 1 up to 12 months of the placebo-controlled period

Notes
[67] - 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	Part 2: Risdiplam	Part 2: Placebo
Number of subjects analysed	83 ^[68]	42 ^[69]
Units: Number of Subjects
number (not applicable)
Wish to be Dead	1	1
Non-specific Active Suicidal Thoughts	1	1
Ideation with Any Methods, No Intent to Act	1	1
Ideation with Some Intent to Act, No Plan	0	1
Ideation with Specific Plan and Intent	0	1

Notes
[68] - Data were collected for subjects aged 6-25 years.
[69] - Data were collected for subjects aged 6-25 years.

No statistical analyses for this end point

Secondary: Part 2: Number of Subjects Aged 6-25 Years with Suicidal Behavior Based on Columbia-Suicide Severity Rating Scale (C-SSRS) in the Placebo-Controlled Period

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End point title

Part 2: Number of Subjects Aged 6-25 Years with Suicidal Behavior Based on Columbia-Suicide Severity Rating Scale (C-SSRS) in the Placebo-Controlled Period ^[70]

End point description

End point type

Secondary

End point timeframe

Day 1 up to 12 months of the placebo-controlled period

Notes
[70] - 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	Part 2: Risdiplam	Part 2: Placebo
Number of subjects analysed	83 ^[71]	42 ^[72]
Units: Number of Subjects
number (not applicable)
Preparatory Acts or Behavior	0	0
Aborted Attempt	0	0
Interrupted Attempt	0	0
Actual Attempt (non-fatal)	0	0
Completed Suicide	0	0

Notes
[71] - Data were collected for subjects aged 6-25 years.
[72] - Data were collected for subjects aged 6-25 years.

No statistical analyses for this end point

Adverse events

Top of page

Timeframe for reporting adverse events

Part 1: Day 1 up to at least 12 months (up to CCOD of 09 January 2019); Part 2: At least 12 months (up to CCOD of 06 September 2019)

Adverse event reporting additional description

All subjects in Part 1 who received at least one dose of study medication (risdiplam or placebo) whether prematurely withdrawn or not were included in the safety population. All subjects in Part 2 who receive at least one dose of study medication (risdiplam or placebo) were included in the safety population.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

22.0

Reporting group title

Part 1 Group A: Adolescents and Adults (Risdiplam)

Reporting group description

Adolescent and adult participants aged 12-25 years received Risdiplam for 12 weeks. Once 12-week treatment was completed and Part 2 dose was selected, participants switched to Part 2 dose and were followed up in open-label extension (OLE) phase.

Reporting group title

Part 1 Group A: Adolescents and Adults (Placebo)

Reporting group description

Adolescent and adult participants aged 12-25 years received placebo matching to Risdiplam for 12 weeks. Once 12-week treatment was completed and Part 2 dose was selected, participants switched to Part 2 dose and were followed up in OLE phase.

Reporting group title

Part 1 Group B: Children (Risdiplam)

Reporting group description

Children aged 2-11 years received Risdiplam for 12 weeks. Once 12-week treatment was completed and Part 2 dose was selected, participants switched to Part 2 dose and were followed up in OLE phase.

Reporting group title

Part 2: Risdiplam

Reporting group description

Participants aged 2-25 years received Risdiplam at the dose of 5 mg once daily for participants with a body weight (BW) >/=20kg or 0.25 mg/kg for participants with a BW <20 kg, for 24 months. After 24-month treatment, participants were offered the opportunity to enter the OLE phase.

Reporting group title

Part 1 Group B: Children (Placebo)

Reporting group description

Children aged 2-11 years received placebo matching to Risdiplam for 12 weeks. Once 12-week treatment was completed and Part 2 dose was selected, participants switched to Part 2 dose and were followed up in OLE phase.

Reporting group title

Part 2: Placebo

Reporting group description

Participants aged 2-25 years received placebo matching to Risdiplam. After 12 months of treatment with placebo, participants switched to Risdiplam in a blinded manner and treatment then continued until Month 24. After 24-month treatment, participants were offered the opportunity to enter the OLE phase.

Serious adverse events	Part 1 Group A: Adolescents and Adults (Risdiplam)	Part 1 Group A: Adolescents and Adults (Placebo)	Part 1 Group B: Children (Risdiplam)	Part 2: Risdiplam	Part 1 Group B: Children (Placebo)	Part 2: Placebo
Total subjects affected by serious adverse events
subjects affected / exposed	2 / 14 (14.29%)	2 / 6 (33.33%)	3 / 21 (14.29%)	26 / 120 (21.67%)	2 / 10 (20.00%)	11 / 60 (18.33%)
number of deaths (all causes)	0	0	0	0	0	0
number of deaths resulting from adverse events
Investigations
Oxygen saturation decreased
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	0 / 21 (0.00%)	0 / 120 (0.00%)	0 / 10 (0.00%)	1 / 60 (1.67%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Fall
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	0 / 21 (0.00%)	1 / 120 (0.83%)	0 / 10 (0.00%)	0 / 60 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Femur fracture
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	0 / 21 (0.00%)	1 / 120 (0.83%)	1 / 10 (10.00%)	1 / 60 (1.67%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Surgical and medical procedures
Lung operation
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	0 / 21 (0.00%)	1 / 120 (0.83%)	0 / 10 (0.00%)	0 / 60 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Renal stone removal
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	0 / 21 (0.00%)	0 / 120 (0.00%)	0 / 10 (0.00%)	1 / 60 (1.67%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
Atrial fibrillation
subjects affected / exposed	0 / 14 (0.00%)	1 / 6 (16.67%)	0 / 21 (0.00%)	0 / 120 (0.00%)	0 / 10 (0.00%)	0 / 60 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Febrile convulsion
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	0 / 21 (0.00%)	1 / 120 (0.83%)	0 / 10 (0.00%)	0 / 60 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Partial seizures
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	0 / 21 (0.00%)	1 / 120 (0.83%)	0 / 10 (0.00%)	0 / 60 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Medical device pain
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	0 / 21 (0.00%)	1 / 120 (0.83%)	0 / 10 (0.00%)	0 / 60 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pyrexia
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	0 / 21 (0.00%)	2 / 120 (1.67%)	0 / 10 (0.00%)	0 / 60 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Constipation
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	0 / 21 (0.00%)	1 / 120 (0.83%)	0 / 10 (0.00%)	0 / 60 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nausea
subjects affected / exposed	1 / 14 (7.14%)	0 / 6 (0.00%)	0 / 21 (0.00%)	0 / 120 (0.00%)	0 / 10 (0.00%)	0 / 60 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vomiting
subjects affected / exposed	1 / 14 (7.14%)	0 / 6 (0.00%)	0 / 21 (0.00%)	0 / 120 (0.00%)	1 / 10 (10.00%)	0 / 60 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Aspiration
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	0 / 21 (0.00%)	1 / 120 (0.83%)	0 / 10 (0.00%)	0 / 60 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Asthma
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	0 / 21 (0.00%)	1 / 120 (0.83%)	0 / 10 (0.00%)	0 / 60 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Atelectasis
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	0 / 21 (0.00%)	1 / 120 (0.83%)	0 / 10 (0.00%)	0 / 60 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia aspiration
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	0 / 21 (0.00%)	1 / 120 (0.83%)	0 / 10 (0.00%)	0 / 60 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory failure
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	0 / 21 (0.00%)	0 / 120 (0.00%)	0 / 10 (0.00%)	1 / 60 (1.67%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Sleep apnoea syndrome
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	0 / 21 (0.00%)	0 / 120 (0.00%)	0 / 10 (0.00%)	1 / 60 (1.67%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Chronic respiratory failure
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	1 / 21 (4.76%)	0 / 120 (0.00%)	0 / 10 (0.00%)	0 / 60 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Hydronephrosis
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	0 / 21 (0.00%)	1 / 120 (0.83%)	0 / 10 (0.00%)	0 / 60 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nephrolithiasis
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	0 / 21 (0.00%)	1 / 120 (0.83%)	0 / 10 (0.00%)	1 / 60 (1.67%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Back pain
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	0 / 21 (0.00%)	1 / 120 (0.83%)	0 / 10 (0.00%)	0 / 60 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Appendicitis
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	0 / 21 (0.00%)	0 / 120 (0.00%)	0 / 10 (0.00%)	1 / 60 (1.67%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Bacteraemia
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	0 / 21 (0.00%)	2 / 120 (1.67%)	0 / 10 (0.00%)	0 / 60 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Bronchitis
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	0 / 21 (0.00%)	1 / 120 (0.83%)	0 / 10 (0.00%)	0 / 60 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastroenteritis
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	1 / 21 (4.76%)	2 / 120 (1.67%)	0 / 10 (0.00%)	2 / 60 (3.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 3	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal infection
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	0 / 21 (0.00%)	0 / 120 (0.00%)	0 / 10 (0.00%)	1 / 60 (1.67%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Influenza
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	0 / 21 (0.00%)	2 / 120 (1.67%)	0 / 10 (0.00%)	0 / 60 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Laryngitis
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	0 / 21 (0.00%)	1 / 120 (0.83%)	0 / 10 (0.00%)	0 / 60 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lower respiratory tract infection viral
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	0 / 21 (0.00%)	1 / 120 (0.83%)	0 / 10 (0.00%)	0 / 60 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lung infection
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	0 / 21 (0.00%)	1 / 120 (0.83%)	0 / 10 (0.00%)	1 / 60 (1.67%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lymph gland infection
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	0 / 21 (0.00%)	0 / 120 (0.00%)	0 / 10 (0.00%)	1 / 60 (1.67%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	1 / 14 (7.14%)	1 / 6 (16.67%)	0 / 21 (0.00%)	9 / 120 (7.50%)	0 / 10 (0.00%)	1 / 60 (1.67%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 12	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia bacterial
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	0 / 21 (0.00%)	1 / 120 (0.83%)	0 / 10 (0.00%)	0 / 60 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia mycoplasmal
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	0 / 21 (0.00%)	1 / 120 (0.83%)	0 / 10 (0.00%)	0 / 60 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory tract infection
subjects affected / exposed	0 / 14 (0.00%)	1 / 6 (16.67%)	0 / 21 (0.00%)	1 / 120 (0.83%)	0 / 10 (0.00%)	0 / 60 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory tract infection viral
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	0 / 21 (0.00%)	0 / 120 (0.00%)	0 / 10 (0.00%)	1 / 60 (1.67%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Upper respiratory tract infection
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	1 / 21 (4.76%)	1 / 120 (0.83%)	0 / 10 (0.00%)	0 / 60 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Viral upper respiratory tract infection
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	0 / 21 (0.00%)	1 / 120 (0.83%)	0 / 10 (0.00%)	0 / 60 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Dehydration
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	1 / 21 (4.76%)	0 / 120 (0.00%)	0 / 10 (0.00%)	1 / 60 (1.67%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Decreased appetite
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	0 / 21 (0.00%)	0 / 120 (0.00%)	1 / 10 (10.00%)	0 / 60 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0

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

Non-serious adverse events	Part 1 Group A: Adolescents and Adults (Risdiplam)	Part 1 Group A: Adolescents and Adults (Placebo)	Part 1 Group B: Children (Risdiplam)	Part 2: Risdiplam	Part 1 Group B: Children (Placebo)	Part 2: Placebo
Total subjects affected by non serious adverse events
subjects affected / exposed	13 / 14 (92.86%)	5 / 6 (83.33%)	20 / 21 (95.24%)	102 / 120 (85.00%)	9 / 10 (90.00%)	50 / 60 (83.33%)
Vascular disorders
Hypertension
subjects affected / exposed	1 / 14 (7.14%)	0 / 6 (0.00%)	0 / 21 (0.00%)	0 / 120 (0.00%)	0 / 10 (0.00%)	0 / 60 (0.00%)
occurrences all number	1	0	0	0	0	0
General disorders and administration site conditions
Malaise
subjects affected / exposed	0 / 14 (0.00%)	1 / 6 (16.67%)	1 / 21 (4.76%)	1 / 120 (0.83%)	0 / 10 (0.00%)	3 / 60 (5.00%)
occurrences all number	0	1	1	1	0	3
Pyrexia
subjects affected / exposed	3 / 14 (21.43%)	2 / 6 (33.33%)	13 / 21 (61.90%)	27 / 120 (22.50%)	6 / 10 (60.00%)	11 / 60 (18.33%)
occurrences all number	13	2	16	45	16	21
Asthenia
subjects affected / exposed	1 / 14 (7.14%)	0 / 6 (0.00%)	0 / 21 (0.00%)	0 / 120 (0.00%)	0 / 10 (0.00%)	0 / 60 (0.00%)
occurrences all number	2	0	0	0	0	0
Fatigue
subjects affected / exposed	2 / 14 (14.29%)	0 / 6 (0.00%)	1 / 21 (4.76%)	0 / 120 (0.00%)	1 / 10 (10.00%)	0 / 60 (0.00%)
occurrences all number	2	0	3	0	2	0
Hyperpyrexia
subjects affected / exposed	2 / 14 (14.29%)	0 / 6 (0.00%)	0 / 21 (0.00%)	0 / 120 (0.00%)	1 / 10 (10.00%)	0 / 60 (0.00%)
occurrences all number	2	0	0	0	2	0
Hyperthermia
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	0 / 21 (0.00%)	0 / 120 (0.00%)	1 / 10 (10.00%)	0 / 60 (0.00%)
occurrences all number	0	0	0	0	1	0
Pain
subjects affected / exposed	1 / 14 (7.14%)	0 / 6 (0.00%)	0 / 21 (0.00%)	0 / 120 (0.00%)	0 / 10 (0.00%)	0 / 60 (0.00%)
occurrences all number	1	0	0	0	0	0
Reproductive system and breast disorders
Amenorrhoea
subjects affected / exposed	1 / 14 (7.14%)	0 / 6 (0.00%)	0 / 21 (0.00%)	0 / 120 (0.00%)	0 / 10 (0.00%)	0 / 60 (0.00%)
occurrences all number	1	0	0	0	0	0
Dysmenorrhoea
subjects affected / exposed	2 / 14 (14.29%)	1 / 6 (16.67%)	0 / 21 (0.00%)	0 / 120 (0.00%)	0 / 10 (0.00%)	0 / 60 (0.00%)
occurrences all number	12	9	0	0	0	0
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	3 / 14 (21.43%)	1 / 6 (16.67%)	7 / 21 (33.33%)	17 / 120 (14.17%)	7 / 10 (70.00%)	13 / 60 (21.67%)
occurrences all number	3	1	9	29	21	21
Epistaxis
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	0 / 21 (0.00%)	3 / 120 (2.50%)	0 / 10 (0.00%)	3 / 60 (5.00%)
occurrences all number	0	0	0	4	0	5
Oropharyngeal pain
subjects affected / exposed	5 / 14 (35.71%)	1 / 6 (16.67%)	3 / 21 (14.29%)	6 / 120 (5.00%)	3 / 10 (30.00%)	8 / 60 (13.33%)
occurrences all number	8	1	4	6	5	9
Productive cough
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	0 / 21 (0.00%)	0 / 120 (0.00%)	0 / 10 (0.00%)	3 / 60 (5.00%)
occurrences all number	0	0	0	0	0	3
Rhinorrhoea
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	3 / 21 (14.29%)	5 / 120 (4.17%)	0 / 10 (0.00%)	3 / 60 (5.00%)
occurrences all number	0	0	8	6	0	3
Catarrh
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	0 / 21 (0.00%)	0 / 120 (0.00%)	1 / 10 (10.00%)	0 / 60 (0.00%)
occurrences all number	0	0	0	0	1	0
Dyspnoea
subjects affected / exposed	0 / 14 (0.00%)	1 / 6 (16.67%)	0 / 21 (0.00%)	0 / 120 (0.00%)	0 / 10 (0.00%)	0 / 60 (0.00%)
occurrences all number	0	1	0	0	0	0
Respiratory tract inflammation
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	3 / 21 (14.29%)	0 / 120 (0.00%)	0 / 10 (0.00%)	0 / 60 (0.00%)
occurrences all number	0	0	4	0	0	0
Rhinitis allergic
subjects affected / exposed	1 / 14 (7.14%)	1 / 6 (16.67%)	0 / 21 (0.00%)	0 / 120 (0.00%)	0 / 10 (0.00%)	0 / 60 (0.00%)
occurrences all number	5	1	0	0	0	0
Upper respiratory tract inflammation
subjects affected / exposed	2 / 14 (14.29%)	1 / 6 (16.67%)	3 / 21 (14.29%)	0 / 120 (0.00%)	3 / 10 (30.00%)	0 / 60 (0.00%)
occurrences all number	4	2	5	0	5	0
Psychiatric disorders
Initial insomnia
subjects affected / exposed	1 / 14 (7.14%)	0 / 6 (0.00%)	0 / 21 (0.00%)	0 / 120 (0.00%)	0 / 10 (0.00%)	0 / 60 (0.00%)
occurrences all number	1	0	0	0	0	0
Investigations
Hepatic enzyme increased
subjects affected / exposed	1 / 14 (7.14%)	0 / 6 (0.00%)	0 / 21 (0.00%)	0 / 120 (0.00%)	0 / 10 (0.00%)	0 / 60 (0.00%)
occurrences all number	1	0	0	0	0	0
Injury, poisoning and procedural complications
Arthropod bite
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	2 / 21 (9.52%)	0 / 120 (0.00%)	0 / 10 (0.00%)	0 / 60 (0.00%)
occurrences all number	0	0	4	0	0	0
Contusion
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	2 / 21 (9.52%)	0 / 120 (0.00%)	1 / 10 (10.00%)	0 / 60 (0.00%)
occurrences all number	0	0	2	0	1	0
Fall
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	1 / 21 (4.76%)	0 / 120 (0.00%)	1 / 10 (10.00%)	0 / 60 (0.00%)
occurrences all number	0	0	1	0	1	0
Foot fracture
subjects affected / exposed	1 / 14 (7.14%)	0 / 6 (0.00%)	0 / 21 (0.00%)	0 / 120 (0.00%)	0 / 10 (0.00%)	0 / 60 (0.00%)
occurrences all number	1	0	0	0	0	0
Ligament sprain
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	2 / 21 (9.52%)	0 / 120 (0.00%)	0 / 10 (0.00%)	0 / 60 (0.00%)
occurrences all number	0	0	2	0	0	0
Muscle rupture
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	0 / 21 (0.00%)	0 / 120 (0.00%)	1 / 10 (10.00%)	0 / 60 (0.00%)
occurrences all number	0	0	0	0	1	0
Cardiac disorders
Tachycardia
subjects affected / exposed	2 / 14 (14.29%)	1 / 6 (16.67%)	0 / 21 (0.00%)	0 / 120 (0.00%)	1 / 10 (10.00%)	0 / 60 (0.00%)
occurrences all number	2	1	0	0	2	0
Nervous system disorders
Headache
subjects affected / exposed	3 / 14 (21.43%)	1 / 6 (16.67%)	3 / 21 (14.29%)	25 / 120 (20.83%)	2 / 10 (20.00%)	11 / 60 (18.33%)
occurrences all number	13	8	38	139	3	46
Dizziness
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	1 / 21 (4.76%)	0 / 120 (0.00%)	1 / 10 (10.00%)	0 / 60 (0.00%)
occurrences all number	0	0	1	0	1	0
Blood and lymphatic system disorders
Iron deficiency anaemia
subjects affected / exposed	0 / 14 (0.00%)	1 / 6 (16.67%)	0 / 21 (0.00%)	0 / 120 (0.00%)	0 / 10 (0.00%)	0 / 60 (0.00%)
occurrences all number	0	1	0	0	0	0
Neutropenia
subjects affected / exposed	1 / 14 (7.14%)	0 / 6 (0.00%)	0 / 21 (0.00%)	0 / 120 (0.00%)	0 / 10 (0.00%)	0 / 60 (0.00%)
occurrences all number	1	0	0	0	0	0
Ear and labyrinth disorders
Ear pain
subjects affected / exposed	1 / 14 (7.14%)	1 / 6 (16.67%)	2 / 21 (9.52%)	0 / 120 (0.00%)	1 / 10 (10.00%)	0 / 60 (0.00%)
occurrences all number	1	1	2	0	1	0
Motion sickness
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	0 / 21 (0.00%)	0 / 120 (0.00%)	1 / 10 (10.00%)	0 / 60 (0.00%)
occurrences all number	0	0	0	0	2	0
Vertigo
subjects affected / exposed	0 / 14 (0.00%)	1 / 6 (16.67%)	0 / 21 (0.00%)	0 / 120 (0.00%)	0 / 10 (0.00%)	0 / 60 (0.00%)
occurrences all number	0	1	0	0	0	0
Eye disorders
Conjunctival hyperaemia
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	0 / 21 (0.00%)	0 / 120 (0.00%)	1 / 10 (10.00%)	0 / 60 (0.00%)
occurrences all number	0	0	0	0	1	0
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	3 / 14 (21.43%)	0 / 6 (0.00%)	2 / 21 (9.52%)	9 / 120 (7.50%)	2 / 10 (20.00%)	5 / 60 (8.33%)
occurrences all number	3	0	3	12	2	8
Abdominal pain upper
subjects affected / exposed	2 / 14 (14.29%)	1 / 6 (16.67%)	2 / 21 (9.52%)	7 / 120 (5.83%)	1 / 10 (10.00%)	2 / 60 (3.33%)
occurrences all number	4	1	3	7	1	3
Constipation
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	2 / 21 (9.52%)	9 / 120 (7.50%)	1 / 10 (10.00%)	5 / 60 (8.33%)
occurrences all number	0	0	3	11	1	7
Diarrhoea
subjects affected / exposed	1 / 14 (7.14%)	0 / 6 (0.00%)	2 / 21 (9.52%)	22 / 120 (18.33%)	1 / 10 (10.00%)	8 / 60 (13.33%)
occurrences all number	1	0	3	29	4	8
Nausea
subjects affected / exposed	1 / 14 (7.14%)	0 / 6 (0.00%)	3 / 21 (14.29%)	11 / 120 (9.17%)	1 / 10 (10.00%)	4 / 60 (6.67%)
occurrences all number	3	0	4	13	1	6
Vomiting
subjects affected / exposed	2 / 14 (14.29%)	2 / 6 (33.33%)	8 / 21 (38.10%)	18 / 120 (15.00%)	3 / 10 (30.00%)	15 / 60 (25.00%)
occurrences all number	2	3	14	38	6	29
Aphthous ulcer
subjects affected / exposed	2 / 14 (14.29%)	0 / 6 (0.00%)	0 / 21 (0.00%)	0 / 120 (0.00%)	0 / 10 (0.00%)	0 / 60 (0.00%)
occurrences all number	2	0	0	0	0	0
Faecaloma
subjects affected / exposed	1 / 14 (7.14%)	0 / 6 (0.00%)	0 / 21 (0.00%)	0 / 120 (0.00%)	0 / 10 (0.00%)	0 / 60 (0.00%)
occurrences all number	1	0	0	0	0	0
Hyperchlorhydria
subjects affected / exposed	1 / 14 (7.14%)	1 / 6 (16.67%)	0 / 21 (0.00%)	0 / 120 (0.00%)	0 / 10 (0.00%)	0 / 60 (0.00%)
occurrences all number	2	1	0	0	0	0
Oral mucosal erythema
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	1 / 21 (4.76%)	0 / 120 (0.00%)	1 / 10 (10.00%)	0 / 60 (0.00%)
occurrences all number	0	0	1	0	1	0
Tongue oedema
subjects affected / exposed	0 / 14 (0.00%)	1 / 6 (16.67%)	0 / 21 (0.00%)	0 / 120 (0.00%)	0 / 10 (0.00%)	0 / 60 (0.00%)
occurrences all number	0	1	0	0	0	0
Skin and subcutaneous tissue disorders
Eczema
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	2 / 21 (9.52%)	6 / 120 (5.00%)	0 / 10 (0.00%)	1 / 60 (1.67%)
occurrences all number	0	0	2	6	0	1
Rash
subjects affected / exposed	2 / 14 (14.29%)	0 / 6 (0.00%)	5 / 21 (23.81%)	9 / 120 (7.50%)	0 / 10 (0.00%)	1 / 60 (1.67%)
occurrences all number	2	0	6	11	0	1
Acne
subjects affected / exposed	1 / 14 (7.14%)	0 / 6 (0.00%)	0 / 21 (0.00%)	0 / 120 (0.00%)	0 / 10 (0.00%)	0 / 60 (0.00%)
occurrences all number	1	0	0	0	0	0
Alopecia
subjects affected / exposed	1 / 14 (7.14%)	0 / 6 (0.00%)	0 / 21 (0.00%)	0 / 120 (0.00%)	0 / 10 (0.00%)	0 / 60 (0.00%)
occurrences all number	1	0	0	0	0	0
Dermatitis
subjects affected / exposed	0 / 14 (0.00%)	1 / 6 (16.67%)	0 / 21 (0.00%)	0 / 120 (0.00%)	0 / 10 (0.00%)	0 / 60 (0.00%)
occurrences all number	0	1	0	0	0	0
Dermatitis diaper
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	0 / 21 (0.00%)	0 / 120 (0.00%)	1 / 10 (10.00%)	0 / 60 (0.00%)
occurrences all number	0	0	0	0	1	0
Dry skin
subjects affected / exposed	1 / 14 (7.14%)	1 / 6 (16.67%)	1 / 21 (4.76%)	0 / 120 (0.00%)	0 / 10 (0.00%)	0 / 60 (0.00%)
occurrences all number	1	1	1	0	0	0
Erythema
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	2 / 21 (9.52%)	0 / 120 (0.00%)	2 / 10 (20.00%)	0 / 60 (0.00%)
occurrences all number	0	0	2	0	4	0
Hyperhidrosis
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	0 / 21 (0.00%)	0 / 120 (0.00%)	1 / 10 (10.00%)	0 / 60 (0.00%)
occurrences all number	0	0	0	0	1	0
Hyperkeratosis
subjects affected / exposed	1 / 14 (7.14%)	0 / 6 (0.00%)	0 / 21 (0.00%)	0 / 120 (0.00%)	0 / 10 (0.00%)	0 / 60 (0.00%)
occurrences all number	1	0	0	0	0	0
Palmar erythema
subjects affected / exposed	1 / 14 (7.14%)	0 / 6 (0.00%)	1 / 21 (4.76%)	0 / 120 (0.00%)	0 / 10 (0.00%)	0 / 60 (0.00%)
occurrences all number	1	0	1	0	0	0
Pruritus
subjects affected / exposed	0 / 14 (0.00%)	1 / 6 (16.67%)	0 / 21 (0.00%)	0 / 120 (0.00%)	0 / 10 (0.00%)	0 / 60 (0.00%)
occurrences all number	0	3	0	0	0	0
Rash papular
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	1 / 21 (4.76%)	0 / 120 (0.00%)	1 / 10 (10.00%)	0 / 60 (0.00%)
occurrences all number	0	0	1	0	1	0
Seborrhoeic dermatitis
subjects affected / exposed	1 / 14 (7.14%)	0 / 6 (0.00%)	0 / 21 (0.00%)	0 / 120 (0.00%)	0 / 10 (0.00%)	0 / 60 (0.00%)
occurrences all number	1	0	0	0	0	0
Skin induration
subjects affected / exposed	1 / 14 (7.14%)	0 / 6 (0.00%)	0 / 21 (0.00%)	0 / 120 (0.00%)	0 / 10 (0.00%)	0 / 60 (0.00%)
occurrences all number	1	0	0	0	0	0
Renal and urinary disorders
Urinary tract pain
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	0 / 21 (0.00%)	0 / 120 (0.00%)	1 / 10 (10.00%)	0 / 60 (0.00%)
occurrences all number	0	0	0	0	1	0
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	2 / 21 (9.52%)	7 / 120 (5.83%)	1 / 10 (10.00%)	0 / 60 (0.00%)
occurrences all number	0	0	3	10	2	0
Pain in extremity
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	3 / 21 (14.29%)	4 / 120 (3.33%)	3 / 10 (30.00%)	3 / 60 (5.00%)
occurrences all number	0	0	5	4	3	5
Back pain
subjects affected / exposed	3 / 14 (21.43%)	0 / 6 (0.00%)	1 / 21 (4.76%)	0 / 120 (0.00%)	0 / 10 (0.00%)	0 / 60 (0.00%)
occurrences all number	16	0	1	0	0	0
Fracture pain
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	0 / 21 (0.00%)	0 / 120 (0.00%)	1 / 10 (10.00%)	0 / 60 (0.00%)
occurrences all number	0	0	0	0	1	0
Groin pain
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	0 / 21 (0.00%)	0 / 120 (0.00%)	1 / 10 (10.00%)	0 / 60 (0.00%)
occurrences all number	0	0	0	0	1	0
Myalgia
subjects affected / exposed	1 / 14 (7.14%)	0 / 6 (0.00%)	1 / 21 (4.76%)	0 / 120 (0.00%)	0 / 10 (0.00%)	0 / 60 (0.00%)
occurrences all number	1	0	1	0	0	0
Neck pain
subjects affected / exposed	0 / 14 (0.00%)	1 / 6 (16.67%)	0 / 21 (0.00%)	0 / 120 (0.00%)	1 / 10 (10.00%)	0 / 60 (0.00%)
occurrences all number	0	1	0	0	1	0
Infections and infestations
Bronchitis
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	4 / 21 (19.05%)	7 / 120 (5.83%)	2 / 10 (20.00%)	10 / 60 (16.67%)
occurrences all number	0	0	7	9	4	12
Conjunctivitis
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	0 / 21 (0.00%)	4 / 120 (3.33%)	2 / 10 (20.00%)	4 / 60 (6.67%)
occurrences all number	0	0	0	6	2	5
Gastroenteritis
subjects affected / exposed	1 / 14 (7.14%)	0 / 6 (0.00%)	3 / 21 (14.29%)	8 / 120 (6.67%)	2 / 10 (20.00%)	5 / 60 (8.33%)
occurrences all number	1	0	4	11	2	7
Influenza
subjects affected / exposed	2 / 14 (14.29%)	2 / 6 (33.33%)	1 / 21 (4.76%)	3 / 120 (2.50%)	1 / 10 (10.00%)	3 / 60 (5.00%)
occurrences all number	2	4	1	3	1	4
Nasopharyngitis
subjects affected / exposed	1 / 14 (7.14%)	1 / 6 (16.67%)	5 / 21 (23.81%)	32 / 120 (26.67%)	3 / 10 (30.00%)	16 / 60 (26.67%)
occurrences all number	1	1	8	57	8	22
Pharyngitis
subjects affected / exposed	2 / 14 (14.29%)	1 / 6 (16.67%)	2 / 21 (9.52%)	7 / 120 (5.83%)	2 / 10 (20.00%)	3 / 60 (5.00%)
occurrences all number	2	1	2	9	2	3
Pneumonia
subjects affected / exposed	1 / 14 (7.14%)	0 / 6 (0.00%)	0 / 21 (0.00%)	4 / 120 (3.33%)	1 / 10 (10.00%)	3 / 60 (5.00%)
occurrences all number	1	0	0	5	1	3
Respiratory tract infection
subjects affected / exposed	2 / 14 (14.29%)	1 / 6 (16.67%)	3 / 21 (14.29%)	9 / 120 (7.50%)	0 / 10 (0.00%)	7 / 60 (11.67%)
occurrences all number	2	1	5	12	0	10
Rhinitis
subjects affected / exposed	1 / 14 (7.14%)	1 / 6 (16.67%)	1 / 21 (4.76%)	5 / 120 (4.17%)	1 / 10 (10.00%)	3 / 60 (5.00%)
occurrences all number	1	1	1	9	2	4
Tonsillitis
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	1 / 21 (4.76%)	3 / 120 (2.50%)	1 / 10 (10.00%)	3 / 60 (5.00%)
occurrences all number	0	0	1	4	1	5
Upper respiratory tract infection
subjects affected / exposed	1 / 14 (7.14%)	1 / 6 (16.67%)	7 / 21 (33.33%)	39 / 120 (32.50%)	3 / 10 (30.00%)	20 / 60 (33.33%)
occurrences all number	1	2	15	58	7	31
Urinary tract infection
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	0 / 21 (0.00%)	6 / 120 (5.00%)	0 / 10 (0.00%)	1 / 60 (1.67%)
occurrences all number	0	0	0	7	0	1
Varicella
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	0 / 21 (0.00%)	3 / 120 (2.50%)	0 / 10 (0.00%)	3 / 60 (5.00%)
occurrences all number	0	0	0	3	0	3
Cystitis
subjects affected / exposed	1 / 14 (7.14%)	0 / 6 (0.00%)	0 / 21 (0.00%)	0 / 120 (0.00%)	0 / 10 (0.00%)	0 / 60 (0.00%)
occurrences all number	1	0	0	0	0	0
Ear infection
subjects affected / exposed	1 / 14 (7.14%)	0 / 6 (0.00%)	1 / 21 (4.76%)	0 / 120 (0.00%)	2 / 10 (20.00%)	0 / 60 (0.00%)
occurrences all number	1	0	1	0	3	0
Fungal skin infection
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	0 / 21 (0.00%)	0 / 120 (0.00%)	1 / 10 (10.00%)	0 / 60 (0.00%)
occurrences all number	0	0	0	0	1	0
Gastroenteritis viral
subjects affected / exposed	1 / 14 (7.14%)	0 / 6 (0.00%)	0 / 21 (0.00%)	0 / 120 (0.00%)	0 / 10 (0.00%)	0 / 60 (0.00%)
occurrences all number	1	0	0	0	0	0
Gastrointestinal viral infection
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	0 / 21 (0.00%)	0 / 120 (0.00%)	1 / 10 (10.00%)	0 / 60 (0.00%)
occurrences all number	0	0	0	0	1	0
Infection
subjects affected / exposed	1 / 14 (7.14%)	0 / 6 (0.00%)	0 / 21 (0.00%)	0 / 120 (0.00%)	0 / 10 (0.00%)	0 / 60 (0.00%)
occurrences all number	1	0	0	0	0	0
Laryngitis
subjects affected / exposed	1 / 14 (7.14%)	0 / 6 (0.00%)	1 / 21 (4.76%)	0 / 120 (0.00%)	0 / 10 (0.00%)	0 / 60 (0.00%)
occurrences all number	1	0	1	0	0	0
Laryngitis viral
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	0 / 21 (0.00%)	0 / 120 (0.00%)	1 / 10 (10.00%)	0 / 60 (0.00%)
occurrences all number	0	0	0	0	1	0
Paronychia
subjects affected / exposed	1 / 14 (7.14%)	0 / 6 (0.00%)	0 / 21 (0.00%)	0 / 120 (0.00%)	0 / 10 (0.00%)	0 / 60 (0.00%)
occurrences all number	1	0	0	0	0	0
Scarlet fever
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	2 / 21 (9.52%)	0 / 120 (0.00%)	0 / 10 (0.00%)	0 / 60 (0.00%)
occurrences all number	0	0	2	0	0	0
Skin infection
subjects affected / exposed	0 / 14 (0.00%)	1 / 6 (16.67%)	0 / 21 (0.00%)	0 / 120 (0.00%)	0 / 10 (0.00%)	0 / 60 (0.00%)
occurrences all number	0	1	0	0	0	0
Tracheitis
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	0 / 21 (0.00%)	0 / 120 (0.00%)	1 / 10 (10.00%)	0 / 60 (0.00%)
occurrences all number	0	0	0	0	1	0
Viral infection
subjects affected / exposed	0 / 14 (0.00%)	0 / 6 (0.00%)	0 / 21 (0.00%)	0 / 120 (0.00%)	1 / 10 (10.00%)	0 / 60 (0.00%)
occurrences all number	0	0	0	0	1	0
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	1 / 14 (7.14%)	0 / 6 (0.00%)	0 / 21 (0.00%)	0 / 120 (0.00%)	1 / 10 (10.00%)	0 / 60 (0.00%)
occurrences all number	2	0	0	0	1	0
Iron deficiency
subjects affected / exposed	0 / 14 (0.00%)	1 / 6 (16.67%)	0 / 21 (0.00%)	0 / 120 (0.00%)	0 / 10 (0.00%)	0 / 60 (0.00%)
occurrences all number	0	1	0	0	0	0

More information

Top of page

Were there any global substantial amendments to the protocol? Yes

05 Oct 2016

Details were added regarding neurological examinations specified in the protocol; Urine and blood pregnancy tests were added to the schedule of assessments for both Part 1 and Part 2 of the study; Stopping rules for cohorts in the dose-escalation part of the study were changed to allow the decision to terminate a cohort to be made by the iDMC

07 Mar 2017

The randomization ratio was changed from 1:1 to 2 (active):1 (placebo), and the sample size increased to maintain the same statistical power; Subjects initially randomized to placebo were switched to active treatment after 12 months; Age group stratification was subdivided: in place of one group of subjects aged 6 to 17 years, two groups were specified, aged 6 to 11 and 12 to 17 years; A new market formulation was introduced; Clarification that following the dose selection for Part 2, data from the exploratory Part 1 of this study (and the Part 1 extension phase) could be locked at intervals in order to analyze and report the safety, PK/PD and exploratory efficacy of those subjects enrolled into Part 1 only, which does not impact the integrity of Part 2 of the study; Two new scales were added, the SMAIS and CGI-C; The respiratory measures MEP and MIP were added; Based on Study BP29840, no interaction with CYP3A inducers or inhibitors was expected; therefore, some prohibited drugs were removed from the exclusion criteria and prohibited therapy; A summary of Part 1 data was provided. The pivotal dose was incorporated into the protocol; PedsQL subject-reported outcome measurements were included in Part 1 for up to 12 months of risdiplam treatment; Home nursing visits were removed (for U.S. only) as these were not utilized by the sites except to deliver study drug. These visits were replaced with a study drug service; The age limit at time of randomization was clarified for the completion of pulmonary function testing required for the study

01 Mar 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; Studies in animals have shown that risdiplam is teratogenic and fetotoxic. The “Background on RO7034067” and “Safety Precautions” sections were updated accordingly; Responder analyses for the Hammersmith Functional Motor Scale Expanded (HFMSE) and Revised Upper Limb Module (RULM) were added as secondary objectives; The end of the study was revised. A subject’s treatment in the open-label extension phase of the study may continue for 3 years. Thereafter, treatment will continue until the drug is available commercially in the subject’s country. The end of the study is when the last patient completes 5 years into the study; An exclusion criterion was added for the use of inhibitors or inducers of FMO1 or FMO3. FMO1 and FMO3 inhibitors and inducers was added to the prohibited therapy section; Chronic treatment was defined as a minimum of 8 weeks to ensure that all sites in the study are applying the same definition;

01 Mar 2019

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; Adverse events of skin or subcutaneous reaction, pharyngeal/laryngeal or mucosal reaction, and clinically relevant retinal abnormalities on optical coherence tomography/fundus photography were removed from the list of non-serious adverse events of special interest (AESI) as the independent data monitoring committee (iDMC) provided independent safety surveillance; Blood samples for SMN protein every 26 weeks following the Week 104 visit were added in order to assess whether any increase in SMN protein observed in the first 104 weeks is sustained over the long term

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, Multi-Center, Randomized, Placebo-Controlled, Double Blind Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Efficacy of Risdiplam (RO7034067) in Type 2 and 3 Spinal Muscular Atrophy Patients

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 for Subjects with a Body Weight (BW) of >/=20kg

Primary: Part 1: Selected Part 2 Dose of Risdiplam for Subjects with a Body Weight (BW) of >/=20kg

Primary: Part 1: Selected Part 2 Dose of Risdiplam for Subjects with BW of <20kg

Primary: Part 1: Selected Part 2 Dose of Risdiplam for Subjects with BW of <20kg

Primary: Part 2: Change from Baseline in the Total Motor Function Measure 32 (MFM-32) Total Score at Month 12

Primary: Part 2: Change from Baseline in the Total Motor Function Measure 32 (MFM-32) Total Score at Month 12

Secondary: Part 2: Percentage of Subjects with Marked Improvement (Defined as >= 3) in the Total Motor Function Measure (MFM32) Score at Month 12

Secondary: Part 2: Percentage of Subjects with Marked Improvement (Defined as >= 3) in the Total Motor Function Measure (MFM32) Score at Month 12

Secondary: Part 2: Change from Baseline in the Total Score of the Revised Upper Limb Module (RULM) at Month 12

Secondary: Part 2: Change from Baseline in the Total Score of the Revised Upper Limb Module (RULM) at Month 12

Secondary: Part 2: Change from Baseline in Total Score of Hammersmith Functional Motor Scale Expanded (HFMSE) at Month 12

Secondary: Part 2: Change from Baseline in Total Score of Hammersmith Functional Motor Scale Expanded (HFMSE) at Month 12

Secondary: Part 2: Change from Baseline in Forced Vital Capacity (FVC) at Month 12 in Subjects Aged 6-25 Years

Secondary: Part 2: Change from Baseline in Forced Vital Capacity (FVC) at Month 12 in Subjects Aged 6-25 Years

Secondary: Part 2: Change from Baseline in the Caregiver-Reported SMA Independence Scale (SMAIS) Total Score at Month 12

Secondary: Part 2: Change from Baseline in the Caregiver-Reported SMA Independence Scale (SMAIS) Total Score at Month 12

Secondary: Part 2: Percentage of Subjects Rated by Clinicians as Improved in the Clinical Global Impression of Change (CGI-C) Scale Ratings at Month 12

Secondary: Part 2: Percentage of Subjects Rated by Clinicians as Improved in the Clinical Global Impression of Change (CGI-C) Scale Ratings at Month 12

Secondary: Part 2: Percentage of Subjects who Achieve Stabilization or Improvement (Defined as >= 0) in the Total Motor Function Measure (MFM) Score at Month 12

Secondary: Part 2: Percentage of Subjects who Achieve Stabilization or Improvement (Defined as >= 0) in the Total Motor Function Measure (MFM) Score at Month 12

Secondary: Part 2: Percentage of Subjects who Achieve an Improvement of at Least One Standard Error of Measurement (SEM) on the Total MFM Score at Month 12

Secondary: Part 2: Percentage of Subjects who Achieve an Improvement of at Least One Standard Error of Measurement (SEM) on the Total MFM Score at Month 12

Secondary: Part 2: Change from Baseline in the MFM Domain 1 (D1) Score at Month 12

Secondary: Part 2: Change from Baseline in the MFM Domain 1 (D1) Score at Month 12

Secondary: Part 2: Change from Baseline in the MFM Domain 2 (D2) Score at Month 12

Secondary: Part 2: Change from Baseline in the MFM Domain 2 (D2) Score at Month 12

Secondary: Part 2: Change from Baseline in the MFM Domain 3 (D3) Score at Month 12

Secondary: Part 2: Change from Baseline in the MFM Domain 3 (D3) Score at Month 12

Secondary: Part 2: Change from Baseline in the Total Combined Scores of MFM Domains 1 and 2 at Month 12

Secondary: Part 2: Change from Baseline in the Total Combined Scores of MFM Domains 1 and 2 at Month 12

Secondary: Part 2: Change from Baseline in Forced Expiratory Volume in 1 Second (FEV1) at Month 12 in Subjects Aged 6-25 Years

Secondary: Part 2: Change from Baseline in Forced Expiratory Volume in 1 Second (FEV1) at Month 12 in Subjects Aged 6-25 Years

Secondary: Part 2: Change from Baseline in the Peak Cough Flow (PCF) at Month 12 in Subjects Aged 6-25 Years

Secondary: Part 2: Change from Baseline in the Peak Cough Flow (PCF) at Month 12 in Subjects Aged 6-25 Years

Secondary: Part 2: Change from Baseline in the Best Sniff Nasal Inspiratory Pressure (SNIP) at Month 12

Secondary: Part 2: Change from Baseline in the Best Sniff Nasal Inspiratory Pressure (SNIP) at Month 12

Secondary: Part 2: Change from Baseline in Maximal Inspiratory Pressure (MIP) at Month 12 in Subjects Aged 6-25 Years

Secondary: Part 2: Change from Baseline in Maximal Inspiratory Pressure (MIP) at Month 12 in Subjects Aged 6-25 Years

Secondary: Part 2: Change from Baseline in Maximal Expiratory Pressure (MEP) at Month 12 in Subjects Aged 6-25 Years

Secondary: Part 2: Change from Baseline in Maximal Expiratory Pressure (MEP) at Month 12 in Subjects Aged 6-25 Years

Secondary: Part 2: Change from Baseline in the Subject-Reported SMA Independence Scale (SMAIS) Total Score at Month 12

Secondary: Part 2: Change from Baseline in the Subject-Reported SMA Independence Scale (SMAIS) Total Score at Month 12

Secondary: Part 2: Percentage of Subjects Rated by Clinicians as No Change or Improved in the Clinical Global Impression of Change (CGI-C) Scale Ratings at Month 12

Secondary: Part 2: Percentage of Subjects Rated by Clinicians as No Change or Improved in the Clinical Global Impression of Change (CGI-C) Scale Ratings at Month 12

Secondary: Part 2: Percentage of Subjects who Experience at Least One Disease-Related Adverse Event at Month 12

Secondary: Part 2: Percentage of Subjects who Experience at Least One Disease-Related Adverse Event at Month 12

Secondary: Part 2: Number of Disease-Related Adverse Events Per Patient-Years at Month 12

Secondary: Part 2: Number of Disease-Related Adverse Events Per Patient-Years at Month 12

Secondary: Part 1: Percentage of Subjects with Adverse Events (AEs) and Serious Adverse Events (SAEs)

Secondary: Part 1: Percentage of Subjects with Adverse Events (AEs) and Serious Adverse Events (SAEs)

Secondary: Part 2: Percentage of Subjects with Adverse Events (AEs) and Serious Adverse Events (SAEs) in the Placebo-Controlled Period

Secondary: Part 2: Percentage of Subjects with Adverse Events (AEs) and Serious Adverse Events (SAEs) in the Placebo-Controlled Period

Secondary: Part 2: Percentage of Subjects with Treatment Discontinuation due to Adverse Events (AEs) and Serious Adverse Events (SAEs) in the Placebo-Controlled Period

Secondary: Part 2: Percentage of Subjects with Treatment Discontinuation due to Adverse Events (AEs) and Serious Adverse Events (SAEs) in the Placebo-Controlled Period

Secondary: Part 2: Number of Subjects Aged 6-25 Years with Suicidal Ideation Based on Columbia-Suicide Severity Rating Scale (C-SSRS) in the Placebo-Controlled Period

Secondary: Part 2: Number of Subjects Aged 6-25 Years with Suicidal Ideation Based on Columbia-Suicide Severity Rating Scale (C-SSRS) in the Placebo-Controlled Period

Secondary: Part 2: Number of Subjects Aged 6-25 Years with Suicidal Behavior Based on Columbia-Suicide Severity Rating Scale (C-SSRS) in the Placebo-Controlled Period

Secondary: Part 2: Number of Subjects Aged 6-25 Years with Suicidal Behavior Based on Columbia-Suicide Severity Rating Scale (C-SSRS) in the Placebo-Controlled Period

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
A Two-Part Seamless, Multi-Center, Randomized, Placebo-Controlled, Double Blind Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Efficacy of Risdiplam (RO7034067) in Type 2 and 3 Spinal Muscular Atrophy Patients