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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	02 Oct 2023

Results information
Results version number	v2(current)
This version publication date	17 Apr 2024
First version publication date	13 Sep 2020
Other versions	v1
Version creation reason

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

Final

Date of interim/final analysis

02 Oct 2023

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

02 Oct 2023

Was the trial ended prematurely?

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

Türkiye: 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 in both Part 1 and 2 was up to 30 days prior to first dose.

Screening details

In Part 1 participants were initially enrolled by age and in a dose-escalating design; each group included participants on active and placebo treatment in a 2:1 ratio. After Part 2 dose selection the study enrolled additional participants in a 2:1 ratio in Part 2.

Period 1 title

Part 1 and 2 Placebo-Controlled

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 Cohort 1: Adolescents/Adults (3 mg Risdiplam)

Arm description

Adolescent and adult participants aged 12-25 years received risdiplam for at least 12 weeks. Once the placebo-controlled period was completed and Part 2 dose was selected, participants 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, 3 mg 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 Cohort 2: Adolescents/Adults (5 mg Risdiplam)

Arm description

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, 5 mg 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 Cohort 1: Adolescents/Adults (Placebo)

Arm description

Adolescent and adult participants aged 12-25 years received placebo matching to risdiplam for at least 12 weeks. Once the placebo-controlled period was completed, participants first switched to their cohort risdiplam dose (i.e. 3 mg). After the Part 2 dose was selected, participants switched to Part 2 dose and were treated in an open-label phase.

Arm type

Placebo

Investigational medicinal product name

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 A Cohort 2: Adolescents/Adults (Placebo)

Arm description

Adolescent and adult participants aged 12-25 years received placebo matching to risdiplam for at least 12 weeks. Once the placebo-controlled period was completed, participants first switched to their cohort risdiplam dose (i.e. 5 mg). After the Part 2 dose was selected, participants switched to Part 2 dose and were treated in an open-label phase.

Arm type

Placebo

Investigational medicinal product name

placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder for oral solution

Routes of administration

Oral use

Dosage and administration details

Part 1 Group B Cohort 1: Children (0.02 mg/kg Risdiplam)

Arm description

Children aged 2-11 years received risdiplam for at least 12 weeks. During the placebo-controlled period, participants escalated to 0.05 mg/kg and then to 0.15 mg/kg in two steps. Once the placebo-controlled period was completed, and after Part 2 dose was selected, participants 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, 0.02 mg/kg 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 Cohort 2: Children (0.05 mg/kg Risdiplam)

Arm description

Children aged 2-11 years received risdiplam for at least 12 weeks. During the placebo-controlled period, participants escalated to 0.15 mg/kg in one step. Once the placebo-controlled period was completed, and after Part 2 dose was selected, participants 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, 0.05 mg/kg 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 Cohort 3: Children (0.25 mg/kg Risdiplam)

Arm description

Children aged 2-11 years received risdiplam for at least 12 weeks. Once the placebo-controlled period was completed, and after Part 2 dose was selected, participants 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, 0.25 mg/kg 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 Cohort 1: 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, participants first switched to the final 0.15 mg/kg cohort risdiplam dose. After the Part 2 dose was selected, participants switched to Part 2 dose and were treated in an open-label phase.

Arm type

Placebo

Investigational medicinal product name

placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder for oral solution

Routes of administration

Oral use

Dosage and administration details

Part 1 Group B Cohort 2: Children (Placebo)

Arm description

Arm type

Placebo

Investigational medicinal product name

placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder for oral solution

Routes of administration

Oral use

Dosage and administration details

Part 1 Group B Cohort 3: 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, and after Part 2 dose was selected, participants switched to Part 2 dose and were treated in an open-label phase.

Arm type

Placebo

Investigational medicinal product name

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

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 12 months. Once the Part 2 placebo-controlled period was completed participants received risdiplam at the same dose level for another 12 months (Month 12-24) in the open-label treatment (OLT) phase. After Month 24 participants entered the Part 2 OLE phase and continued to receive risdiplam at the same dose level.

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

Participants aged 2-25 years received placebo matching to risdiplam for 12 months. After 12 months of treatment with placebo, participants switched to risdiplam (5 mg once daily for participants with a body weight (BW) >/=20kg or 0.25 mg/kg for participants with a BW <20) in a blinded manner in the OLT phase. After Month 24 participants entered the Part 2 OLE phase and continued to receive risdiplam at the same dose level.

Arm type

Placebo

Investigational medicinal product name

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 Cohort 1: Adolescents/Adults (3 mg Risdiplam)	Part 1 Group A Cohort 2: Adolescents/Adults (5 mg Risdiplam)	Part 1 Group A Cohort 1: Adolescents/Adults (Placebo)	Part 1 Group A Cohort 2: Adolescents/Adults (Placebo)	Part 1 Group B Cohort 1: Children (0.02 mg/kg Risdiplam)	Part 1 Group B Cohort 2: Children (0.05 mg/kg Risdiplam)	Part 1 Group B Cohort 3: Children (0.25 mg/kg Risdiplam)	Part 1 Group B Cohort 1: Children (Placebo)	Part 1 Group B Cohort 2: Children (Placebo)	Part 1 Group B Cohort 3: Children (Placebo)	Part 2: Risdiplam	Part 2: Placebo
Started	7	7	3	3	7	7	7	3	4	3	120	60
Completed	7	7	3	3	7	7	7	3	4	3	117	59
Not completed	0	0	0	0	0	0	0	0	0	0	3	1
Changed to other treatment	-	-	-	-	-	-	-	-	-	-	1	-
Changed to Spinraza	-	-	-	-	-	-	-	-	-	-	2	1

Period 2 title

Part 1 OLE and Part 2 OLT

Is this the baseline period?

Allocation method

Not applicable

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Part 1 Group A: OLE

Arm description

Once the placebo-controlled period was completed and Part 2 dose was selected, adolescents and adults switched to Part 2 dose and were treated in an open-label extension (OLE) 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 Group B: OLE

Arm description

Once the placebo-controlled period was completed and Part 2 dose was selected, children switched to Part 2 dose and were treated in an open-label extension (OLE) 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 2: Risdiplam/Risdiplam OLT

Arm description

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 2: Placebo/Risdiplam OLT

Arm description

Arm type

Experimental

Investigational medicinal product name

risdiplam

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder for oral solution, Powder for oral solution

Routes of administration

Oral use, Oral use

Dosage and administration details

Number of subjects in period 2	Part 1 Group A: OLE	Part 1 Group B: OLE	Part 2: Risdiplam/Risdiplam OLT	Part 2: Placebo/Risdiplam OLT
Started	20	31	117	59
Completed	18	30	116	59
Not completed	2	1	1	0
Consent withdrawn by subject	2	1	1	-

Period 3 title

Part 2 OLE

Is this the baseline period?

Allocation method

Not applicable

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Part 2: RisdiplamRisdiplam OLE

Arm description

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 2: Placebo/Risdiplam OLE

Arm description

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

Number of subjects in period 3 ^[1]	Part 2: RisdiplamRisdiplam OLE	Part 2: Placebo/Risdiplam OLE
Started	116	59
Completed	103	53
Not completed	13	6
Consent withdrawn by subject	10	5
Death	1	-
Reason not specified	2	1

Notes
[1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
Justification: Only Part 2 participants progressed to the final period.

Baseline characteristics

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Reporting group title

Part 1 Group A Cohort 1: Adolescents/Adults (3 mg Risdiplam)

Reporting group description

Reporting group title

Part 1 Group A Cohort 2: Adolescents/Adults (5 mg Risdiplam)

Reporting group description

Reporting group title

Part 1 Group A Cohort 1: Adolescents/Adults (Placebo)

Reporting group description

Reporting group title

Part 1 Group A Cohort 2: Adolescents/Adults (Placebo)

Reporting group description

Adolescent and adult participants aged 12-25 years received placebo matching to risdiplam for at least 12 weeks. Once the placebo-controlled period was completed, participants first switched to their cohort risdiplam dose (i.e. 5 mg). After the Part 2 dose was selected, participants switched to Part 2 dose and were treated in an open-label phase.

Reporting group title

Part 1 Group B Cohort 1: Children (0.02 mg/kg Risdiplam)

Reporting group description

Reporting group title

Part 1 Group B Cohort 2: Children (0.05 mg/kg Risdiplam)

Reporting group description

Reporting group title

Part 1 Group B Cohort 3: Children (0.25 mg/kg Risdiplam)

Reporting group description

Reporting group title

Part 1 Group B Cohort 1: Children (Placebo)

Reporting group description

Reporting group title

Part 1 Group B Cohort 2: Children (Placebo)

Reporting group description

Reporting group title

Part 1 Group B Cohort 3: Children (Placebo)

Reporting group description

Reporting group title

Part 2: Risdiplam

Reporting group description

Reporting group title

Part 2: Placebo

Reporting group description

Reporting group values	Part 1 Group A Cohort 1: Adolescents/Adults (3 mg Risdiplam)	Part 1 Group A Cohort 2: Adolescents/Adults (5 mg Risdiplam)	Part 1 Group A Cohort 1: Adolescents/Adults (Placebo)	Part 1 Group A Cohort 2: Adolescents/Adults (Placebo)	Part 1 Group B Cohort 1: Children (0.02 mg/kg Risdiplam)	Part 1 Group B Cohort 2: Children (0.05 mg/kg Risdiplam)	Part 1 Group B Cohort 3: Children (0.25 mg/kg Risdiplam)	Part 1 Group B Cohort 1: Children (Placebo)	Part 1 Group B Cohort 2: Children (Placebo)	Part 1 Group B Cohort 3: Children (Placebo)	Part 2: Risdiplam	Part 2: Placebo	Total
Number of subjects	7	7	3	3	7	7	7	3	4	3	120	60	231
Age categorical
Units: Subjects
Age Continuous
Units: Years
arithmetic mean (standard deviation)	13.3 ( 1.1 )	18.1 ( 4.6 )	14.7 ( 1.5 )	17.3 ( 5.1 )	6.1 ( 2.9 )	4.3 ( 1.7 )	6.0 ( 2.7 )	5.3 ( 2.1 )	3.5 ( 0.6 )	5.3 ( 2.9 )	9.9 ( 5.8 )	10.3 ( 6.0 )	-
Sex: Female, Male
Units: Participants
Female	5	5	1	2	5	3	4	0	2	0	61	30	118
Male	2	2	2	1	2	4	3	3	2	3	59	30	113

End points

Top of page

Reporting group title

Part 1 Group A Cohort 1: Adolescents/Adults (3 mg Risdiplam)

Reporting group description

Reporting group title

Part 1 Group A Cohort 2: Adolescents/Adults (5 mg Risdiplam)

Reporting group description

Reporting group title

Part 1 Group A Cohort 1: Adolescents/Adults (Placebo)

Reporting group description

Reporting group title

Part 1 Group A Cohort 2: Adolescents/Adults (Placebo)

Reporting group description

Adolescent and adult participants aged 12-25 years received placebo matching to risdiplam for at least 12 weeks. Once the placebo-controlled period was completed, participants first switched to their cohort risdiplam dose (i.e. 5 mg). After the Part 2 dose was selected, participants switched to Part 2 dose and were treated in an open-label phase.

Reporting group title

Part 1 Group B Cohort 1: Children (0.02 mg/kg Risdiplam)

Reporting group description

Reporting group title

Part 1 Group B Cohort 2: Children (0.05 mg/kg Risdiplam)

Reporting group description

Reporting group title

Part 1 Group B Cohort 3: Children (0.25 mg/kg Risdiplam)

Reporting group description

Reporting group title

Part 1 Group B Cohort 1: Children (Placebo)

Reporting group description

Reporting group title

Part 1 Group B Cohort 2: Children (Placebo)

Reporting group description

Reporting group title

Part 1 Group B Cohort 3: Children (Placebo)

Reporting group description

Reporting group title

Part 2: Risdiplam

Reporting group description

Reporting group title

Part 2: Placebo

Reporting group description

Reporting group title

Part 1 Group A: OLE

Reporting group description

Once the placebo-controlled period was completed and Part 2 dose was selected, adolescents and adults switched to Part 2 dose and were treated in an open-label extension (OLE) phase.

Reporting group title

Part 1 Group B: OLE

Reporting group description

Once the placebo-controlled period was completed and Part 2 dose was selected, children switched to Part 2 dose and were treated in an open-label extension (OLE) phase.

Reporting group title

Part 2: Risdiplam/Risdiplam OLT

Reporting group description

Reporting group title

Part 2: Placebo/Risdiplam OLT

Reporting group description

Reporting group title

Part 2: RisdiplamRisdiplam OLE

Reporting group description

Reporting group title

Part 2: Placebo/Risdiplam OLE

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 participants aged 12-25 years received risdiplam or risdiplam matching placebo.

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 participants aged 12-25 years received risdiplam or risdiplam matching placebo.

Subject analysis set title

Part 2: All Risdiplam

Subject analysis set type

Sub-group analysis

Subject analysis set description

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

Subject analysis set title

Part 2: All Risdiplam

Subject analysis set type

Sub-group analysis

Subject analysis set description

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

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 participants aged 12-25 years received risdiplam or risdiplam matching placebo.

Subject analysis set title

Part 2: All Risdiplam

Subject analysis set type

Sub-group analysis

Subject analysis set description

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

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

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End point title

Part 1: Selected Part 2 Dose of Risdiplam for Participants 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: No statistical analyses can be provided for this primary end point.

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 Participants with BW of <20kg

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End point title

Part 1: Selected Part 2 Dose of Risdiplam for Participants 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: No statistical analyses can be provided for this primary end point.

End point values	Part 1: All Risdiplam
Number of subjects analysed	51
Units: milligram/kilogram (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 for 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 task or maintain starting position; 1 - performs task partially; 2 - performs task incompletely or imperfectly; 3 - performs 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. Positive change from Baseline indicates improvement. MMRM analysis was performed based on primary efficacy hypothetical estimand, which included participants data assuming no prohibited medication intended for treatment of SMA was received and subjects continued on randomized treatment until the analysis time point. ITT population except subjects without MFM32 total score at Baseline.

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: Only Part 2 arms were included in this end point.

End point values	Part 2: Risdiplam	Part 2: Placebo
Number of subjects analysed	115	59
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)

Part 2: Risdiplam versus Placebo

Comparison groups

Part 2: Placebo v Part 2: Risdiplam

Number of subjects included in analysis

174

Analysis specification

Pre-specified

Analysis type

superiority ^[4]

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

Notes
[4] - 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.

Secondary: Part 2: Percentage of Participants 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 Participants with Marked Improvement (Defined as >= 3) in the Total Motor Function Measure (MFM32) Score at Month 12 ^[5]

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 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. ITT population defined as all randomized participants in Part 2. Subjects with missing MFM32 total score at Baseline not included in the analysis. Missing results at Month 12 are considered as non-responders.

End point type

Secondary

End point timeframe

At Month 12

Notes
[5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only Part 2 arms were included in this end point.

End point values	Part 2: Risdiplam	Part 2: Placebo
Number of subjects analysed	115	59
Units: Percentage of Participants
number (confidence interval 95%)	38.3 (28.94 to 47.58)	23.7 (12.03 to 35.43)

Part 2: Risdiplam versus Placebo

Comparison groups

Part 2: Risdiplam v Part 2: Placebo

Number of subjects included in analysis

174

Analysis specification

Pre-specified

Analysis type

superiority ^[6]

P-value

= 0.0469 ^[7]

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
[6] - 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.
[7] - 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 ^[8]

End point description

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 a 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. 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. Positive change from Baseline indicates improvement. MMRM analysis was performed based on the 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. Subjects with missing RULM total score at Baseline not included in analysis.

End point type

Secondary

End point timeframe

Baseline (Day-1) and Month 12

Notes
[8] - 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: Only Part 2 arms were included in this end point.

End point values	Part 2: Risdiplam	Part 2: Placebo
Number of subjects analysed	119	58
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)

Part 2: Risdiplam versus Placebo

Comparison groups

Part 2: Risdiplam v Part 2: Placebo

Number of subjects included in analysis

177

Analysis specification

Pre-specified

Analysis type

superiority ^[9]

P-value

= 0.0469 ^[10]

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
[9] - 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.
[10] - 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 Participants 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 Participants Aged 6-25 Years ^[11]

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 participants 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 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. ITT population defined as all randomized participants in Part 2. Subjects with missing FVC data at Baseline were not included in the analysis.

End point type

Secondary

End point timeframe

Baseline (Day-1) and Month 12

Notes
[11] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only Part 2 arms were included in this end point.

End point values	Part 2: Risdiplam	Part 2: Placebo
Number of subjects analysed	83	40
Units: Percentage Predicted
least squares mean (confidence interval 95%)	-5.16 (-7.93 to -2.39)	-3.11 (-6.59 to 0.74)

Part 2: Risdiplam versus Placebo

Comparison groups

Part 2: Risdiplam v Part 2: Placebo

Number of subjects included in analysis

123

Analysis specification

Pre-specified

Analysis type

superiority ^[12]

P-value

= 0.3902 ^[13]

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
[12] - 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.
[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 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. ITT population defined as all randomized participants in Part 2.

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: Only Part 2 arms were included in this end point.

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)

Part 2: Risdiplam versus Placebo

Comparison groups

Part 2: Risdiplam v Part 2: Placebo

Number of subjects included in analysis

180

Analysis specification

Pre-specified

Analysis type

superiority ^[15]

P-value

= 0.3902 ^[16]

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] - 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.
[16] - 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

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End point title

Part 2: Change from Baseline in the Caregiver-Reported SMA Independence Scale (SMAIS) Total Score at Month 12 ^[17]

End point description

SMA Independence Scale (SMAIS) was developed specifically for SMA participants in order to assess function-related independence. SMAIS contains 29 items, assessing the amount of assistance required from another individual to perform daily activities. Each item is scored on a 0-4 scale (or as non-applicable). SMAIS total score ranging from 0-44 is obtained based on 22 items with each item on a 0-2 scale. Lower scores indicate greater dependence on another individual. SMAIS was completed by participants aged 12 years or older and caregivers of participants aged 2-25 years. MMRM 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. ITT population: all randomized participants in Part 2. Subjects with missing SMAIS total score at Baseline not included in the analysis.

End point type

Secondary

End point timeframe

Baseline (Day-1) and Month 12

Notes
[17] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only Part 2 arms were included in this end point.

End point values	Part 2: Risdiplam	Part 2: Placebo
Number of subjects analysed	116	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)

Part 2: Risdiplam versus Placebo

Comparison groups

Part 2: Risdiplam v Part 2: Placebo

Number of subjects included in analysis

176

Analysis specification

Pre-specified

Analysis type

superiority ^[18]

P-value

= 0.3902 ^[19]

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
[18] - 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.
[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: Percentage of Participants Rated by Clinicians as 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 Participants Rated by Clinicians as Improved in the Clinical Global Impression of Change (CGI-C) Scale Ratings at Month 12 ^[20]

End point description

The Clinical Global Impression of Change (CGI-C) is used to score a clinician’s impression of a participant’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”. Participants 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 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. ITT population: all randomized participants in Part 2. Missing results at Month 12 are considered as non-responders.

End point type

Secondary

End point timeframe

At 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: Only Part 2 arms were included in this end point.

End point values	Part 2: Risdiplam	Part 2: Placebo
Number of subjects analysed	120	60
Units: Percentage of Participants
number (confidence interval 95%)	47.5 (38.15 to 56.86)	40.0 (26.77 to 53.23)

Part 2: Risdiplam versus Placebo

Statistical analysis description

CGI Improved

Comparison groups

Part 2: Risdiplam v Part 2: Placebo

Number of subjects included in analysis

180

Analysis specification

Pre-specified

Analysis type

superiority ^[21]

P-value

= 0.3902 ^[22]

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
[21] - 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.
[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 Participants who Achieve Stabilization or Improvement (Defined as >= 0) in the Total Motor Function Measure (MFM-32) Score at Month 12

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End point title

Part 2: Percentage of Participants who Achieve Stabilization or Improvement (Defined as >= 0) in the Total Motor Function Measure (MFM-32) Score at Month 12 ^[23]

End point description

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: Only Part 2 arms were included in this end point.

End point values	Part 2: Risdiplam	Part 2: Placebo
Number of subjects analysed	115	59
Units: Percentage of Participants
number (confidence interval 95%)	69.6 (60.72 to 78.41)	54.2 (40.68 to 67.80)

Part 2: Risdiplam versus Placebo

Comparison groups

Part 2: Risdiplam v Part 2: Placebo

Number of subjects included in analysis

174

Analysis specification

Pre-specified

Analysis type

superiority ^[24]

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

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

Secondary: Part 2: Percentage of Participants who Achieve an Improvement of at Least One Standard Error of Measurement on the Total MFM-32 Score at Month 12

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End point title

Part 2: Percentage of Participants who Achieve an Improvement of at Least One Standard Error of Measurement on the Total MFM-32 Score at Month 12 ^[25]

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 starting position; 1-performs task partially; 2-performs task incompletely or imperfectly; 3-performs 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 based on efficacy hypothetical estimand included participants data assuming no prohibited medication intended for treatment of SMA was received and subjects continued on randomized treatment until the analysis time point. ITT population except subjects without MFM32 total score at Baseline.

End point type

Secondary

End point timeframe

At Month 12

Notes
[25] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only Part 2 arms were included in this end point.

End point values	Part 2: Risdiplam	Part 2: Placebo
Number of subjects analysed	115	59
Units: Percentage of Participants
number (confidence interval 95%)	28.7 (20.65 to 37.88)	16.9 (8.44 to 28.97)

No statistical analyses for this end point

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

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End point title

Part 2: Change from Baseline in the Best Sniff Nasal Inspiratory Pressure (SNIP) at Month 12 ^[26]

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 participants 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 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. . ITT population except subjects without SNIP data at Baseline.

End point type

Secondary

End point timeframe

Baseline (Day-1) and Month 12

Notes
[26] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only Part 2 arms were included in this end point.

End point values	Part 2: Risdiplam	Part 2: Placebo
Number of subjects analysed	118	59
Units: Percentage Predicted
least squares mean (confidence interval 95%)	3.42 (0.22 to 6.62)	1.07 (-3.42 to 5.57)

Part 2: Risdiplam versus Placebo

Comparison groups

Part 2: Risdiplam v Part 2: Placebo

Number of subjects included in analysis

177

Analysis specification

Pre-specified

Analysis type

superiority ^[27]

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

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

Secondary: Part 2: Change from Baseline in the MFM-32 Domain 1 (D1) Score at Month 12

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End point title

Part 2: Change from Baseline in the MFM-32 Domain 1 (D1) Score at Month 12 ^[28]

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 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. . ITT population except subjects without MFM32 data at Baseline.

End point type

Secondary

End point timeframe

Baseline (Day-1) and Month 12

Notes
[28] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only Part 2 arms were included in this end point.

End point values	Part 2: Risdiplam	Part 2: Placebo
Number of subjects analysed	118	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)

Part 2: Risdiplam versus Placebo

Comparison groups

Part 2: Risdiplam v Part 2: Placebo

Number of subjects included in analysis

178

Analysis specification

Pre-specified

Analysis type

superiority ^[29]

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

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

Secondary: Part 2: Change from Baseline in the MFM-32 Domain 2 (D2) Score at Month 12

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End point title

Part 2: Change from Baseline in the MFM-32 Domain 2 (D2) Score at Month 12 ^[30]

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 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. . ITT population except subjects without MFM32 data at Baseline.

End point type

Secondary

End point timeframe

Baseline (Day-1) and 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: Only Part 2 arms were included in this end point.

End point values	Part 2: Risdiplam	Part 2: Placebo
Number of subjects analysed	118	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)

Part 2: Risdiplam versus Placebo

Comparison groups

Part 2: Risdiplam v Part 2: Placebo

Number of subjects included in analysis

178

Analysis specification

Pre-specified

Analysis type

superiority ^[31]

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

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

Secondary: Part 2: Change from Baseline in the MFM-32 Domain 3 (D3) Score at Month 12

Top of page

End point title

Part 2: Change from Baseline in the MFM-32 Domain 3 (D3) Score at Month 12 ^[32]

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 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. . ITT population except subjects without MFM32 data at Baseline.

End point type

Secondary

End point timeframe

Baseline (Day-1) and Month 12

Notes
[32] - 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: Only Part 2 arms were included in this end point.

End point values	Part 2: Risdiplam	Part 2: Placebo
Number of subjects analysed	115	59
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)

Part 2: Risdiplam versus Placebo

Comparison groups

Part 2: Risdiplam v Part 2: Placebo

Number of subjects included in analysis

174

Analysis specification

Pre-specified

Analysis type

superiority ^[33]

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

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

Secondary: Part 2: Change from Baseline in the Total Combined Scores of MFM-32 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-32 Domains 1 and 2 at Month 12 ^[34]

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 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. . ITT population except subjects without MFM32 data at Baseline.

End point type

Secondary

End point timeframe

Baseline (Day-1) and Month 12

Notes
[34] - 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: Only Part 2 arms were included in this end point.

End point values	Part 2: Risdiplam	Part 2: Placebo
Number of subjects analysed	118	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)

Part 2: Risdiplam versus Placebo

Comparison groups

Part 2: Risdiplam v Part 2: Placebo

Number of subjects included in analysis

178

Analysis specification

Pre-specified

Analysis type

superiority ^[35]

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

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

Secondary: Part 2: Change from Baseline in the Total Combined Scores of MFM-32 Domains 2 and 3 at Month 12

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End point title

Part 2: Change from Baseline in the Total Combined Scores of MFM-32 Domains 2 and 3 at Month 12 ^[36]

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+D3 items score are summed and expressed on 0-100 scale for the MFM D2+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 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. . ITT population except subjects without MFM32 data at Baseline.

End point type

Secondary

End point timeframe

Baseline (Day-1) and Month 12

Notes
[36] - 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: Only Part 2 arms were included in this end point.

End point values	Part 2: Risdiplam	Part 2: Placebo
Number of subjects analysed	115	59
Units: Scores on a Scale
least squares mean (confidence interval 95%)	2.02 (0.84 to 3.20)	-0.14 (-1.76 to 1.48)

Part 2: Risdiplam versus Placebo

Comparison groups

Part 2: Risdiplam v Part 2: Placebo

Number of subjects included in analysis

174

Analysis specification

Pre-specified

Analysis type

superiority ^[37]

P-value

= 0.0326

Method

Mixed Model Repeated Measure Analysis

Parameter type

Least Square Mean Difference

Point estimate

2.16

Confidence interval

level

95%

sides

2-sided

lower limit

0.18

upper limit

4.14

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

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

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End point title

Part 2: Change from Baseline in Forced Expiratory Volume in 1 Second (FEV1) at Month 12 in Participants Aged 6-25 Years ^[38]

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 participants 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 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. . ITT population except subjects without FEV1 data at Baseline.

End point type

Secondary

End point timeframe

Baseline (Day-1) and Month 12

Notes
[38] - 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: Only Part 2 arms were included in this end point.

End point values	Part 2: Risdiplam	Part 2: Placebo
Number of subjects analysed	83	40
Units: Percentage Predicted
least squares mean (confidence interval 95%)	-4.22 (-7.49 to -0.96)	-1.35 (-5.91 to 3.20)

Part 2: Risdiplam versus Placebo

Comparison groups

Part 2: Risdiplam v Part 2: Placebo

Number of subjects included in analysis

123

Analysis specification

Pre-specified

Analysis type

superiority ^[39]

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

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

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

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End point title

Part 2: Change from Baseline in the Peak Cough Flow (PCF) at Month 12 in Participants Aged 6-25 Years ^[40]

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 participants 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 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. . ITT population except subjects without PCF data at Baseline.

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: Only Part 2 arms were included in this end point.

End point values	Part 2: Risdiplam	Part 2: Placebo
Number of subjects analysed	83	42
Units: Percent Predicted
least squares mean (confidence interval 95%)	1.06 (-1.18 to 3.31)	-0.22 (-3.27 to 2.83)

Part 2: Risdiplam versus Placebo

Comparison groups

Part 2: Risdiplam v Part 2: Placebo

Number of subjects included in analysis

125

Analysis specification

Pre-specified

Analysis type

superiority ^[41]

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

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

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

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End point title

Part 2: Change from Baseline in Maximal Inspiratory Pressure (MIP) at Month 12 in Participants Aged 6-25 Years ^[42]

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 participants aged 6 or older. Participants 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 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. . ITT population except subjects without MIP data at Baseline.

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: Only Part 2 arms were included in this end point.

End point values	Part 2: Risdiplam	Part 2: Placebo
Number of subjects analysed	81	40
Units: Percentage Predicted
least squares mean (confidence interval 95%)	1.99 (-6.13 to 10.11)	-0.97 (-12.33 to 10.38)

Part 2: Risdiplam versus Placebo

Comparison groups

Part 2: Risdiplam v Part 2: Placebo

Number of subjects included in analysis

121

Analysis specification

Pre-specified

Analysis type

superiority ^[43]

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

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

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

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End point title

Part 2: Change from Baseline in Maximal Expiratory Pressure (MEP) at Month 12 in Participants Aged 6-25 Years ^[44]

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 participants aged 6 or older. Participants 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 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. . ITT population except subjects without MEP data at Baseline.

End point type

Secondary

End point timeframe

Baseline (Day-1) and Month 12

Notes
[44] - 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: Only Part 2 arms were included in this end point.

End point values	Part 2: Risdiplam	Part 2: Placebo
Number of subjects analysed	83	41
Units: Percentage Predicted
least squares mean (confidence interval 95%)	-2.75 (-6.22 to 0.72)	-2.33 (-7.21 to 2.56)

Part 2: Risdiplam versus Placebo

Comparison groups

Part 2: Risdiplam v Part 2: Placebo

Number of subjects included in analysis

124

Analysis specification

Pre-specified

Analysis type

superiority ^[45]

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

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

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

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End point title

Part 2: Change from Baseline in the Participant-Reported SMA Independence Scale (SMAIS) Total Score at Month 12 ^[46]

End point description

The SMAIS was developed specifically for SMA participants 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 participants aged 12 years or older and caregivers of participants aged 2-25 years. MMRM 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. . ITT population except subjects without SMAIS total score at Baseline.

End point type

Secondary

End point timeframe

Baseline (Day-1) and Month 12

Notes
[46] - 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: Only Part 2 arms were included in this end point.

End point values	Part 2: Risdiplam	Part 2: Placebo
Number of subjects analysed	43	23
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)

Part 2: Risdiplam versus Placebo

Comparison groups

Part 2: Risdiplam v Part 2: Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[47]

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

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

Secondary: Part 2: Percentage of Participants 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 Participants Rated by Clinicians as No Change or Improved in the Clinical Global Impression of Change (CGI-C) Scale Ratings at Month 12 ^[48]

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. ITT population: all randomized participants in Part 2. Missing results at Month 12 are considered as non-responders.

End point type

Secondary

End point timeframe

At 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: Only Part 2 arms were included in this end point.

End point values	Part 2: Risdiplam	Part 2: Placebo
Number of subjects analysed	120	60
Units: Percentage of Participants
number (confidence interval 95%)	85.8 (79.18 to 92.49)	83.3 (73.07 to 93.60)

Part 2: Risdiplam versus Placebo

Statistical analysis description

CGI No Change or Improved

Comparison groups

Part 2: Risdiplam v Part 2: Placebo

Number of subjects included in analysis

180

Analysis specification

Pre-specified

Analysis type

superiority ^[49]

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

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

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

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End point title

Part 2: Percentage of Participants who Experience at Least One Disease-Related Adverse Event at Month 12 ^[50]

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 participants 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
[50] - 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: Only Part 2 arms were included in this end point.

End point values	Part 2: Risdiplam	Part 2: Placebo
Number of subjects analysed	120	60
Units: Percentage of Participants
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

Top of page

End point title

Part 2: Number of disease-related adverse events per patient-years at Month 12 ^[51]

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
[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: Only Part 2 arms were included in this end point.

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

Top of page

End point title

Part 2: Percentage of Participants with Adverse Events (AEs) and Serious Adverse Events (SAEs) in the Placebo-Controlled Period ^[52]

End point description

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

End point type

Secondary

End point timeframe

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

Notes
[52] - 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: Only Part 2 arms were included in this end point.

End point values	Part 2: Risdiplam	Part 2: Placebo
Number of subjects analysed	120	60
Units: Percentage of Participants
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 Participants with Treatment Discontinuation due to Adverse Events (AEs) and Serious Adverse Events (SAEs) in the Placebo-Controlled Period

Top of page

End point title

Part 2: Percentage of Participants with Treatment Discontinuation due to Adverse Events (AEs) and Serious Adverse Events (SAEs) in the Placebo-Controlled Period ^[53]

End point description

End point type

Secondary

End point timeframe

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

Notes
[53] - 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: Only Part 2 arms were included in this end point.

End point values	Part 2: Risdiplam	Part 2: Placebo
Number of subjects analysed	120	60
Units: Percentage of Participants
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 Participants 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 Participants Aged 6-25 Years with Suicidal Ideation Based on Columbia-Suicide Severity Rating Scale (C-SSRS) in the Placebo-Controlled Period ^[54]

End point description

The Columbia Suicide Severity Rating Scale (C-SSRS) is used to assess the lifetime suicidality of a participant (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 participants aged 6 years and older.

End point type

Secondary

End point timeframe

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

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: Only Part 2 arms were included in this end point.

End point values	Part 2: Risdiplam	Part 2: Placebo
Number of subjects analysed	83	42
Units: Number of Participants
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

No statistical analyses for this end point

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

Top of page

End point title

Part 2: Number of Participants Aged 6-25 Years with Suicidal Behavior Based on Columbia-Suicide Severity Rating Scale (C-SSRS) in the Placebo-Controlled Period ^[55]

End point description

End point type

Secondary

End point timeframe

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

Notes
[55] - 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: Only Part 2 arms were included in this end point.

End point values	Part 2: Risdiplam	Part 2: Placebo
Number of subjects analysed	83	42
Units: Number of Participants
Preparatory Acts or Behavior	0	0
Aborted Attempt	0	0
Interrupted Attempt	0	0
Actual Attempt (non-fatal)	0	0
Completed Suicide	0	0

No statistical analyses for this end point

Secondary: Median Fold Change from Baseline in Survival of Motor Neuron (SMN) Protein Levels in Blood

Top of page

End point title

Median Fold Change from Baseline in Survival of Motor Neuron (SMN) Protein Levels in Blood

End point description

End point type

Secondary

End point timeframe

Part 1: Day -1, pre-dose of Weeks 1, 2 (>/= 12 years only), 17, 35 and 104, and at 4h post-dose of Weeks 4 and 52. Part 2: Day -1, pre-dose of Weeks 1, 17, 35 and 104, and at 4h post-dose of Weeks 4 and 52.

End point values	Part 1: All Risdiplam	Part 2: All Risdiplam
Number of subjects analysed	51	169
Units: unitless
median (full range (min-max))	2.91 (2.14 to 4.18)	1.96 (0.2 to 4.48)

No statistical analyses for this end point

Secondary: Part 1 and 2: Maximum Plasma Concentration (Cmax) of Risdiplam at Year 5

Top of page

End point title

Part 1 and 2: Maximum Plasma Concentration (Cmax) of Risdiplam at Year 5

End point description

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

End point type

Secondary

End point timeframe

Day 1: 1, 2, 4, 6 h postdose, Weeks 4, 8 (Part 1 only), 52, 87: pre-dose, 1, 2, 4, 6 h post-dose and Weeks 1 (Day 7), 2, 8 (Part 2 only) 17, 35, 70, 104: predose

End point values	Part 1: All Risdiplam	Part 2: All Risdiplam
Number of subjects analysed	51	179
Units: nanograms/milliliter (ng/mL)
median (full range (min-max))	137 (58.2 to 242)	140 (42.7 to 313)

No statistical analyses for this end point

Secondary: Part 1 and 2: Area Under the Curve (AUC) from 0 to 24 Hours of Risdiplam at Year 5 Visit

Top of page

End point title

Part 1 and 2: Area Under the Curve (AUC) from 0 to 24 Hours of Risdiplam at Year 5 Visit

End point description

End point type

Secondary

End point timeframe

Year 5 visit pre-dose, 1, 2, 4, 6, 24 hours post-dose

End point values	Part 1: All Risdiplam	Part 2: All Risdiplam
Number of subjects analysed	49	160
Units: ng*h/mL
median (full range (min-max))	1700 (1160 to 2590)	1880 (1200 to 2890)

No statistical analyses for this end point

Secondary: Part 1 and 2: Concentration at the End of a Dosing Interval (Ctrough) of Risdiplam at Year 5

Top of page

End point title

Part 1 and 2: Concentration at the End of a Dosing Interval (Ctrough) of Risdiplam at Year 5

End point description

End point type

Secondary

End point timeframe

The last predose sample collected from each participant who had at least 1400 days of risdiplam treatment duration.

End point values	Part 1: All Risdiplam	Part 2: All Risdiplam
Number of subjects analysed	49	107
Units: ng/mL
median (full range (min-max))	54.1 (21.3 to 108)	57.2 (4.50 to 229)

No statistical analyses for this end point

Adverse events

Top of page

Timeframe for reporting adverse events

Part 1 and Part 2: Up to approximately 5 years

Adverse event reporting additional description

The safety population included all participants who received at least one dose of study medication (risdiplam or placebo) whether prematurely withdrawn or not.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

26.1

Reporting group title

Part 1 Group A: Adolescents/Adults (3 mg Risdiplam)

Reporting group description

Adolescent and adult participants aged 12-25 years received risdiplam for at least 12 weeks during the placebo-controlled period.

Reporting group title

Part 1 Group A: OLE

Reporting group description

Once the placebo-controlled period was completed and Part 2 dose was selected, adolescents and adults switched to Part 2 dose and were treated in an open-label extension (OLE) phase.

Reporting group title

Part 1 Group B: Children (Placebo-Control Period Pooled)

Reporting group description

Children aged 2-11 years received placebo matching to risdiplam for at least 12 weeks during the placebo-controlled period.

Reporting group title

Part 1 Group B: Children (0.25 mg/kg Risdiplam)

Reporting group description

Children aged 2-11 years received risdiplam for at least 12 weeks during the placebo-controlled period.

Reporting group title

Part 1 Group B: Children (0.15 mg/kg Risdiplam)

Reporting group description

Children aged 2-11 years received risdiplam for at least 12 weeks during the placebo-controlled period.

Reporting group title

Part 1 Group B: Children (0.05 mg/kg Risdiplam)

Reporting group description

Children aged 2-11 years received risdiplam for at least 12 weeks during the placebo-controlled period.

Reporting group title

Part 1 Group A: Adolescents/Adults (5 mg Risdiplam)

Reporting group description

Adolescent and adult participants aged 12-25 years received risdiplam for at least 12 weeks during the placebo-controlled period.

Reporting group title

Part 1 Group A: Adolescents/Adults (Placebo-Control Pooled)

Reporting group description

Adolescent and adult participants aged 12-25 years received placebo matching to risdiplam for at least 12 weeks during the placebo-controlled period.

Reporting group title

Part 1 Group B: Children (0.02 mg/kg Risdiplam)

Reporting group description

Children aged 2-11 years received risdiplam for at least 12 weeks during the placebo-controlled period.

Reporting group title

Part 2 OLT: Risdiplam/Risdiplam

Reporting group description

Once the Part 2 placebo-controlled period was completed participants 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 another 12 months (Month 12-24) in the open-label treatment (OLT) phase.

Reporting group title

Part 2 Placebo-Controlled: Placebo

Reporting group description

Participants aged 2-25 years received placebo matching to risdiplam for 12 months during the placebo-controlled period.

Reporting group title

Part 2 Placebo-Controlled: Risdiplam

Reporting group description

Reporting group title

Part 1 Group B: OLE

Reporting group description

Once the placebo-controlled period was completed and Part 2 dose was selected, children switched to Part 2 dose and were treated in an open-label extension (OLE) phase.

Reporting group title

Part 2 OLT: Placebo/Risdiplam

Reporting group description

Once the Part 2 placebo-controlled period was completed participants switched to 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 12 months (Month 12-24) in the open-label treatment (OLT) phase.

Reporting group title

Part 2 OLE: Risdiplam

Reporting group description

Once the Part 2 OLT period ended participants entered the open-label extension period and continued to receive 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.

Part 1 Group A: Adolescents/Adults (3 mg Risdiplam)

Part 1 Group A: OLE

Part 1 Group B: Children (Placebo-Control Period Pooled)

Part 1 Group B: Children (0.25 mg/kg Risdiplam)

Part 1 Group B: Children (0.15 mg/kg Risdiplam)

Part 1 Group B: Children (0.05 mg/kg Risdiplam)

Part 1 Group A: Adolescents/Adults (5 mg Risdiplam)

Part 1 Group A: Adolescents/Adults (Placebo-Control Pooled)

Part 1 Group B: Children (0.02 mg/kg Risdiplam)

Part 2 OLT: Risdiplam/Risdiplam

Part 2 Placebo-Controlled: Placebo

Part 2 Placebo-Controlled: Risdiplam

Part 1 Group B: OLE

Part 2 OLT: Placebo/Risdiplam

Part 2 OLE: Risdiplam

Total subjects affected by serious adverse events

subjects affected / exposed

1 / 10 (10.00%)

5 / 20 (25.00%)

1 / 10 (10.00%)

0 / 7 (0.00%)

0 / 21 (0.00%)

0 / 14 (0.00%)

0 / 10 (0.00%)

0 / 6 (0.00%)

0 / 7 (0.00%)

25 / 117 (21.37%)

11 / 60 (18.33%)

24 / 120 (20.00%)

9 / 31 (29.03%)

4 / 59 (6.78%)

34 / 175 (19.43%)

number of deaths (all causes)

number of deaths resulting from adverse events

Vascular disorders

Haematoma

subjects affected / exposed

0 / 10 (0.00%)

0 / 20 (0.00%)

0 / 10 (0.00%)

0 / 7 (0.00%)

0 / 21 (0.00%)

0 / 14 (0.00%)

0 / 10 (0.00%)

0 / 6 (0.00%)

0 / 7 (0.00%)

0 / 117 (0.00%)

0 / 60 (0.00%)

0 / 120 (0.00%)

0 / 31 (0.00%)

0 / 59 (0.00%)

1 / 175 (0.57%)

occurrences causally related to treatment / all

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Superficial vein thrombosis

subjects affected / exposed

0 / 10 (0.00%)

0 / 20 (0.00%)

0 / 10 (0.00%)

0 / 7 (0.00%)

0 / 21 (0.00%)

0 / 14 (0.00%)

0 / 10 (0.00%)

0 / 6 (0.00%)

0 / 7 (0.00%)

0 / 117 (0.00%)

0 / 60 (0.00%)

0 / 120 (0.00%)

0 / 31 (0.00%)

0 / 59 (0.00%)

1 / 175 (0.57%)

occurrences causally related to treatment / all

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

General disorders and administration site conditions

Ill-defined disorder

subjects affected / exposed

0 / 10 (0.00%)

0 / 20 (0.00%)

0 / 10 (0.00%)

0 / 7 (0.00%)

0 / 21 (0.00%)

0 / 14 (0.00%)

0 / 10 (0.00%)

0 / 6 (0.00%)

0 / 7 (0.00%)

0 / 117 (0.00%)

0 / 60 (0.00%)

0 / 120 (0.00%)

0 / 31 (0.00%)

0 / 59 (0.00%)

1 / 175 (0.57%)

occurrences causally related to treatment / all

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Medical device pain

subjects affected / exposed

0 / 10 (0.00%)

0 / 20 (0.00%)

0 / 10 (0.00%)

0 / 7 (0.00%)

0 / 21 (0.00%)

0 / 14 (0.00%)

0 / 10 (0.00%)

0 / 6 (0.00%)

0 / 7 (0.00%)

0 / 117 (0.00%)

0 / 60 (0.00%)

1 / 120 (0.83%)

0 / 31 (0.00%)

0 / 59 (0.00%)

0 / 175 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Pyrexia

subjects affected / exposed

0 / 10 (0.00%)

0 / 20 (0.00%)

0 / 10 (0.00%)

0 / 7 (0.00%)

0 / 21 (0.00%)

0 / 14 (0.00%)

0 / 10 (0.00%)

0 / 6 (0.00%)

0 / 7 (0.00%)

0 / 117 (0.00%)

0 / 60 (0.00%)

2 / 120 (1.67%)

0 / 31 (0.00%)

1 / 59 (1.69%)

2 / 175 (1.14%)

occurrences causally related to treatment / all

0 / 0

0 / 2

0 / 0

0 / 1

0 / 2

deaths causally related to treatment / all

0 / 0

Respiratory, thoracic and mediastinal disorders

Chronic respiratory failure

subjects affected / exposed

0 / 10 (0.00%)

0 / 20 (0.00%)

0 / 10 (0.00%)

0 / 7 (0.00%)

0 / 21 (0.00%)

0 / 14 (0.00%)

0 / 10 (0.00%)

0 / 6 (0.00%)

0 / 7 (0.00%)

0 / 117 (0.00%)

0 / 60 (0.00%)

0 / 120 (0.00%)

1 / 31 (3.23%)

0 / 59 (0.00%)

0 / 175 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Acute respiratory failure

subjects affected / exposed

0 / 10 (0.00%)

0 / 20 (0.00%)

0 / 10 (0.00%)

0 / 7 (0.00%)

0 / 21 (0.00%)

0 / 14 (0.00%)

0 / 10 (0.00%)

0 / 6 (0.00%)

0 / 7 (0.00%)

0 / 117 (0.00%)

0 / 60 (0.00%)

0 / 120 (0.00%)

0 / 31 (0.00%)

0 / 59 (0.00%)

1 / 175 (0.57%)

occurrences causally related to treatment / all

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Aspiration

subjects affected / exposed

0 / 10 (0.00%)

0 / 20 (0.00%)

0 / 10 (0.00%)

0 / 7 (0.00%)

0 / 21 (0.00%)

0 / 14 (0.00%)

0 / 10 (0.00%)

0 / 6 (0.00%)

0 / 7 (0.00%)

0 / 117 (0.00%)

0 / 60 (0.00%)

1 / 120 (0.83%)

0 / 31 (0.00%)

0 / 59 (0.00%)

0 / 175 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Asthma

subjects affected / exposed

0 / 10 (0.00%)

0 / 20 (0.00%)

0 / 10 (0.00%)

0 / 7 (0.00%)

0 / 21 (0.00%)

0 / 14 (0.00%)

0 / 10 (0.00%)

0 / 6 (0.00%)

0 / 7 (0.00%)

0 / 117 (0.00%)

0 / 60 (0.00%)

1 / 120 (0.83%)

0 / 31 (0.00%)

0 / 59 (0.00%)

1 / 175 (0.57%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

1 / 4

deaths causally related to treatment / all

0 / 0

Atelectasis

subjects affected / exposed

0 / 10 (0.00%)

0 / 20 (0.00%)

0 / 10 (0.00%)

0 / 7 (0.00%)

0 / 21 (0.00%)

0 / 14 (0.00%)

0 / 10 (0.00%)

0 / 6 (0.00%)

0 / 7 (0.00%)

1 / 117 (0.85%)

0 / 60 (0.00%)

0 / 120 (0.00%)

0 / 31 (0.00%)

0 / 59 (0.00%)

1 / 175 (0.57%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Obstructive sleep apnoea syndrome

subjects affected / exposed

0 / 10 (0.00%)

0 / 20 (0.00%)

0 / 10 (0.00%)

0 / 7 (0.00%)

0 / 21 (0.00%)

0 / 14 (0.00%)

0 / 10 (0.00%)

0 / 6 (0.00%)

0 / 7 (0.00%)

0 / 117 (0.00%)

1 / 60 (1.67%)

0 / 120 (0.00%)

0 / 31 (0.00%)

0 / 59 (0.00%)

0 / 175 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Pleural effusion

subjects affected / exposed

0 / 10 (0.00%)

0 / 20 (0.00%)

0 / 10 (0.00%)

0 / 7 (0.00%)

0 / 21 (0.00%)

0 / 14 (0.00%)

0 / 10 (0.00%)

0 / 6 (0.00%)

0 / 7 (0.00%)

0 / 117 (0.00%)

0 / 60 (0.00%)

0 / 120 (0.00%)

0 / 31 (0.00%)

0 / 59 (0.00%)

1 / 175 (0.57%)

occurrences causally related to treatment / all

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Pneumonitis aspiration

subjects affected / exposed

0 / 10 (0.00%)

0 / 20 (0.00%)

0 / 10 (0.00%)

0 / 7 (0.00%)

0 / 21 (0.00%)

0 / 14 (0.00%)

0 / 10 (0.00%)

0 / 6 (0.00%)

0 / 7 (0.00%)

1 / 117 (0.85%)

0 / 60 (0.00%)

0 / 120 (0.00%)

0 / 31 (0.00%)

0 / 59 (0.00%)

0 / 175 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Pneumothorax

subjects affected / exposed

0 / 10 (0.00%)

0 / 20 (0.00%)

0 / 10 (0.00%)

0 / 7 (0.00%)

0 / 21 (0.00%)

0 / 14 (0.00%)

0 / 10 (0.00%)

0 / 6 (0.00%)

0 / 7 (0.00%)

1 / 117 (0.85%)

0 / 60 (0.00%)

0 / 120 (0.00%)

0 / 31 (0.00%)

0 / 59 (0.00%)

0 / 175 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Respiratory disorder

subjects affected / exposed

0 / 10 (0.00%)

0 / 20 (0.00%)

0 / 10 (0.00%)

0 / 7 (0.00%)

0 / 21 (0.00%)

0 / 14 (0.00%)

0 / 10 (0.00%)

0 / 6 (0.00%)

0 / 7 (0.00%)

0 / 117 (0.00%)

0 / 60 (0.00%)

0 / 120 (0.00%)

0 / 31 (0.00%)

1 / 59 (1.69%)

1 / 175 (0.57%)

occurrences causally related to treatment / all

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Respiratory failure

subjects affected / exposed

0 / 10 (0.00%)

0 / 20 (0.00%)

0 / 10 (0.00%)

0 / 7 (0.00%)

0 / 21 (0.00%)

0 / 14 (0.00%)

0 / 10 (0.00%)

0 / 6 (0.00%)

0 / 7 (0.00%)

0 / 117 (0.00%)

1 / 60 (1.67%)

0 / 120 (0.00%)

0 / 31 (0.00%)

0 / 59 (0.00%)

1 / 175 (0.57%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Psychiatric disorders

Affective disorder

subjects affected / exposed

0 / 10 (0.00%)

0 / 20 (0.00%)

0 / 10 (0.00%)

0 / 7 (0.00%)

0 / 21 (0.00%)

0 / 14 (0.00%)

0 / 10 (0.00%)

0 / 6 (0.00%)

0 / 7 (0.00%)

0 / 117 (0.00%)

0 / 60 (0.00%)

0 / 120 (0.00%)

0 / 31 (0.00%)

0 / 59 (0.00%)

1 / 175 (0.57%)

occurrences causally related to treatment / all

0 / 0

0 / 2

deaths causally related to treatment / all

0 / 0

Encopresis

subjects affected / exposed

0 / 10 (0.00%)

0 / 20 (0.00%)

0 / 10 (0.00%)

0 / 7 (0.00%)

0 / 21 (0.00%)

0 / 14 (0.00%)

0 / 10 (0.00%)

0 / 6 (0.00%)

0 / 7 (0.00%)

0 / 117 (0.00%)

0 / 60 (0.00%)

0 / 120 (0.00%)

0 / 31 (0.00%)

0 / 59 (0.00%)

1 / 175 (0.57%)

occurrences causally related to treatment / all

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Product issues

Device breakage

subjects affected / exposed

0 / 10 (0.00%)

0 / 20 (0.00%)

0 / 10 (0.00%)

0 / 7 (0.00%)

0 / 21 (0.00%)

0 / 14 (0.00%)

0 / 10 (0.00%)

0 / 6 (0.00%)

0 / 7 (0.00%)

0 / 117 (0.00%)

0 / 60 (0.00%)

0 / 120 (0.00%)

0 / 31 (0.00%)

0 / 59 (0.00%)

1 / 175 (0.57%)

occurrences causally related to treatment / all

0 / 0

0 / 2

deaths causally related to treatment / all

0 / 0

Investigations

Oxygen saturation decreased

subjects affected / exposed

0 / 10 (0.00%)

0 / 20 (0.00%)

0 / 10 (0.00%)

0 / 7 (0.00%)

0 / 21 (0.00%)

0 / 14 (0.00%)

0 / 10 (0.00%)

0 / 6 (0.00%)

0 / 7 (0.00%)

0 / 117 (0.00%)

1 / 60 (1.67%)

0 / 120 (0.00%)

0 / 31 (0.00%)

0 / 59 (0.00%)

0 / 175 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Injury, poisoning and procedural complications

Concussion

subjects affected / exposed

0 / 10 (0.00%)

0 / 20 (0.00%)

0 / 10 (0.00%)

0 / 7 (0.00%)

0 / 21 (0.00%)

0 / 14 (0.00%)

0 / 10 (0.00%)

0 / 6 (0.00%)

0 / 7 (0.00%)

0 / 117 (0.00%)

0 / 60 (0.00%)

0 / 120 (0.00%)

1 / 31 (3.23%)

0 / 59 (0.00%)

0 / 175 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Femur fracture

subjects affected / exposed

0 / 10 (0.00%)

0 / 20 (0.00%)

0 / 10 (0.00%)

0 / 7 (0.00%)

0 / 21 (0.00%)

0 / 14 (0.00%)

0 / 10 (0.00%)

0 / 6 (0.00%)

0 / 7 (0.00%)

0 / 117 (0.00%)

1 / 60 (1.67%)

1 / 120 (0.83%)

2 / 31 (6.45%)

0 / 59 (0.00%)

3 / 175 (1.71%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 2

0 / 0

0 / 4

deaths causally related to treatment / all

0 / 0

Near drowning

subjects affected / exposed

0 / 10 (0.00%)

0 / 20 (0.00%)

0 / 10 (0.00%)

0 / 7 (0.00%)

0 / 21 (0.00%)

0 / 14 (0.00%)

0 / 10 (0.00%)

0 / 6 (0.00%)

0 / 7 (0.00%)

0 / 117 (0.00%)

0 / 60 (0.00%)

0 / 120 (0.00%)

1 / 31 (3.23%)

0 / 59 (0.00%)

0 / 175 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Brain contusion

subjects affected / exposed

0 / 10 (0.00%)

0 / 20 (0.00%)

0 / 10 (0.00%)

0 / 7 (0.00%)

0 / 21 (0.00%)

0 / 14 (0.00%)

0 / 10 (0.00%)

0 / 6 (0.00%)

0 / 7 (0.00%)

1 / 117 (0.85%)

0 / 60 (0.00%)

0 / 120 (0.00%)

0 / 31 (0.00%)

0 / 59 (0.00%)

0 / 175 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Fall

subjects affected / exposed

0 / 10 (0.00%)

0 / 20 (0.00%)

0 / 10 (0.00%)

0 / 7 (0.00%)

0 / 21 (0.00%)

0 / 14 (0.00%)

0 / 10 (0.00%)

0 / 6 (0.00%)

0 / 7 (0.00%)

0 / 117 (0.00%)

0 / 60 (0.00%)

1 / 120 (0.83%)

0 / 31 (0.00%)

0 / 59 (0.00%)

0 / 175 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Toxicity to various agents

subjects affected / exposed

0 / 10 (0.00%)

0 / 20 (0.00%)

0 / 10 (0.00%)

0 / 7 (0.00%)

0 / 21 (0.00%)

0 / 14 (0.00%)

0 / 10 (0.00%)

0 / 6 (0.00%)

0 / 7 (0.00%)

0 / 117 (0.00%)

0 / 60 (0.00%)

0 / 120 (0.00%)

0 / 31 (0.00%)

0 / 59 (0.00%)

1 / 175 (0.57%)

occurrences causally related to treatment / all

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

0 / 1

Musculoskeletal procedural complication

subjects affected / exposed

0 / 10 (0.00%)

0 / 20 (0.00%)

0 / 10 (0.00%)

0 / 7 (0.00%)

0 / 21 (0.00%)

0 / 14 (0.00%)

0 / 10 (0.00%)

0 / 6 (0.00%)

0 / 7 (0.00%)

0 / 117 (0.00%)

0 / 60 (0.00%)

0 / 120 (0.00%)

0 / 31 (0.00%)

0 / 59 (0.00%)

1 / 175 (0.57%)

occurrences causally related to treatment / all

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Humerus fracture

subjects affected / exposed

0 / 10 (0.00%)

0 / 20 (0.00%)

0 / 10 (0.00%)

0 / 7 (0.00%)

0 / 21 (0.00%)

0 / 14 (0.00%)

0 / 10 (0.00%)

0 / 6 (0.00%)

0 / 7 (0.00%)

0 / 117 (0.00%)

0 / 60 (0.00%)

0 / 120 (0.00%)

0 / 31 (0.00%)

0 / 59 (0.00%)

1 / 175 (0.57%)

occurrences causally related to treatment / all

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Wound dehiscence

subjects affected / exposed

0 / 10 (0.00%)

0 / 20 (0.00%)

0 / 10 (0.00%)

0 / 7 (0.00%)

0 / 21 (0.00%)

0 / 14 (0.00%)

0 / 10 (0.00%)

0 / 6 (0.00%)

0 / 7 (0.00%)

0 / 117 (0.00%)

0 / 60 (0.00%)

0 / 120 (0.00%)

0 / 31 (0.00%)

0 / 59 (0.00%)

1 / 175 (0.57%)

occurrences causally related to treatment / all

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Congenital, familial and genetic disorders

Cryptorchism

subjects affected / exposed

0 / 10 (0.00%)

0 / 20 (0.00%)

0 / 10 (0.00%)

0 / 7 (0.00%)

0 / 21 (0.00%)

0 / 14 (0.00%)

0 / 10 (0.00%)

0 / 6 (0.00%)

0 / 7 (0.00%)

0 / 117 (0.00%)

0 / 60 (0.00%)

0 / 120 (0.00%)

0 / 31 (0.00%)

0 / 59 (0.00%)

1 / 175 (0.57%)

occurrences causally related to treatment / all

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Nervous system disorders

Febrile convulsion

subjects affected / exposed

0 / 10 (0.00%)

0 / 20 (0.00%)

0 / 10 (0.00%)

0 / 7 (0.00%)

0 / 21 (0.00%)

0 / 14 (0.00%)

0 / 10 (0.00%)

0 / 6 (0.00%)

0 / 7 (0.00%)

0 / 117 (0.00%)

0 / 60 (0.00%)

1 / 120 (0.83%)

0 / 31 (0.00%)

0 / 59 (0.00%)

0 / 175 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Partial seizures

subjects affected / exposed

0 / 10 (0.00%)

0 / 20 (0.00%)

0 / 10 (0.00%)

0 / 7 (0.00%)

0 / 21 (0.00%)

0 / 14 (0.00%)

0 / 10 (0.00%)

0 / 6 (0.00%)

0 / 7 (0.00%)

1 / 117 (0.85%)

0 / 60 (0.00%)

0 / 120 (0.00%)

0 / 31 (0.00%)

0 / 59 (0.00%)

1 / 175 (0.57%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Syncope

subjects affected / exposed

0 / 10 (0.00%)

0 / 20 (0.00%)

0 / 10 (0.00%)

0 / 7 (0.00%)

0 / 21 (0.00%)

0 / 14 (0.00%)

0 / 10 (0.00%)

0 / 6 (0.00%)

0 / 7 (0.00%)

0 / 117 (0.00%)

0 / 60 (0.00%)

0 / 120 (0.00%)

0 / 31 (0.00%)

0 / 59 (0.00%)

1 / 175 (0.57%)

occurrences causally related to treatment / all

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Blood and lymphatic system disorders

Spontaneous haematoma

subjects affected / exposed

0 / 10 (0.00%)

0 / 20 (0.00%)

0 / 10 (0.00%)

0 / 7 (0.00%)

0 / 21 (0.00%)

0 / 14 (0.00%)

0 / 10 (0.00%)

0 / 6 (0.00%)

0 / 7 (0.00%)

0 / 117 (0.00%)

0 / 60 (0.00%)

0 / 120 (0.00%)

0 / 31 (0.00%)

0 / 59 (0.00%)

1 / 175 (0.57%)

occurrences causally related to treatment / all

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Gastrointestinal disorders

Oesophagitis

subjects affected / exposed

0 / 10 (0.00%)

1 / 20 (5.00%)

0 / 10 (0.00%)

0 / 7 (0.00%)

0 / 21 (0.00%)

0 / 14 (0.00%)

0 / 10 (0.00%)

0 / 6 (0.00%)

0 / 7 (0.00%)

0 / 117 (0.00%)

0 / 60 (0.00%)

0 / 120 (0.00%)

0 / 31 (0.00%)

0 / 59 (0.00%)

0 / 175 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Abdominal pain

subjects affected / exposed

0 / 10 (0.00%)

1 / 20 (5.00%)

0 / 10 (0.00%)

0 / 7 (0.00%)

0 / 21 (0.00%)

0 / 14 (0.00%)

0 / 10 (0.00%)

0 / 6 (0.00%)

0 / 7 (0.00%)

0 / 117 (0.00%)

0 / 60 (0.00%)

0 / 120 (0.00%)

0 / 31 (0.00%)

0 / 59 (0.00%)

0 / 175 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Vomiting

subjects affected / exposed

0 / 10 (0.00%)

0 / 20 (0.00%)

1 / 10 (10.00%)

0 / 7 (0.00%)

0 / 21 (0.00%)

0 / 14 (0.00%)

0 / 10 (0.00%)

0 / 6 (0.00%)

0 / 7 (0.00%)

1 / 117 (0.85%)

0 / 60 (0.00%)

0 / 120 (0.00%)

0 / 31 (0.00%)

0 / 59 (0.00%)

1 / 175 (0.57%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

0 / 4

deaths causally related to treatment / all

0 / 0

Colitis

subjects affected / exposed

0 / 10 (0.00%)

0 / 20 (0.00%)

0 / 10 (0.00%)

0 / 7 (0.00%)

0 / 21 (0.00%)

0 / 14 (0.00%)

0 / 10 (0.00%)

0 / 6 (0.00%)

0 / 7 (0.00%)

0 / 117 (0.00%)

0 / 60 (0.00%)

0 / 120 (0.00%)

0 / 31 (0.00%)

0 / 59 (0.00%)

1 / 175 (0.57%)

occurrences causally related to treatment / all

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Constipation

subjects affected / exposed

0 / 10 (0.00%)

0 / 20 (0.00%)

0 / 10 (0.00%)

0 / 7 (0.00%)

0 / 21 (0.00%)

0 / 14 (0.00%)

0 / 10 (0.00%)

0 / 6 (0.00%)

0 / 7 (0.00%)

0 / 117 (0.00%)

0 / 60 (0.00%)

1 / 120 (0.83%)

0 / 31 (0.00%)

0 / 59 (0.00%)

1 / 175 (0.57%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Dental caries

subjects affected / exposed

0 / 10 (0.00%)

0 / 20 (0.00%)

0 / 10 (0.00%)

0 / 7 (0.00%)

0 / 21 (0.00%)

0 / 14 (0.00%)

0 / 10 (0.00%)

0 / 6 (0.00%)

0 / 7 (0.00%)

0 / 117 (0.00%)

0 / 60 (0.00%)

0 / 120 (0.00%)

0 / 31 (0.00%)

0 / 59 (0.00%)

1 / 175 (0.57%)

occurrences causally related to treatment / all

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Duodenal obstruction

subjects affected / exposed

0 / 10 (0.00%)

0 / 20 (0.00%)

0 / 10 (0.00%)

0 / 7 (0.00%)

0 / 21 (0.00%)

0 / 14 (0.00%)

0 / 10 (0.00%)

0 / 6 (0.00%)

0 / 7 (0.00%)

0 / 117 (0.00%)

0 / 60 (0.00%)

0 / 120 (0.00%)

0 / 31 (0.00%)

0 / 59 (0.00%)

1 / 175 (0.57%)

occurrences causally related to treatment / all

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Gastrointestinal haemorrhage

subjects affected / exposed

0 / 10 (0.00%)

0 / 20 (0.00%)

0 / 10 (0.00%)

0 / 7 (0.00%)

0 / 21 (0.00%)

0 / 14 (0.00%)

0 / 10 (0.00%)

0 / 6 (0.00%)

0 / 7 (0.00%)

0 / 117 (0.00%)

0 / 60 (0.00%)

0 / 120 (0.00%)

0 / 31 (0.00%)

0 / 59 (0.00%)

1 / 175 (0.57%)

occurrences causally related to treatment / all

0 / 0

1 / 1

deaths causally related to treatment / all

0 / 0

Gastritis

subjects affected / exposed

0 / 10 (0.00%)

0 / 20 (0.00%)

0 / 10 (0.00%)

0 / 7 (0.00%)

0 / 21 (0.00%)

0 / 14 (0.00%)

0 / 10 (0.00%)

0 / 6 (0.00%)

0 / 7 (0.00%)

2 / 117 (1.71%)

0 / 60 (0.00%)

0 / 120 (0.00%)

0 / 31 (0.00%)

0 / 59 (0.00%)

1 / 175 (0.57%)

occurrences causally related to treatment / all

0 / 0

0 / 4

0 / 0

1 / 1

deaths causally related to treatment / all

0 / 0

Gastrooesophageal reflux disease

subjects affected / exposed

0 / 10 (0.00%)

0 / 20 (0.00%)

0 / 10 (0.00%)

0 / 7 (0.00%)

0 / 21 (0.00%)

0 / 14 (0.00%)

0 / 10 (0.00%)

0 / 6 (0.00%)

0 / 7 (0.00%)

0 / 117 (0.00%)

0 / 60 (0.00%)

0 / 120 (0.00%)

0 / 31 (0.00%)

0 / 59 (0.00%)

1 / 175 (0.57%)

occurrences causally related to treatment / all

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Malpositioned teeth

subjects affected / exposed

0 / 10 (0.00%)

0 / 20 (0.00%)

0 / 10 (0.00%)

0 / 7 (0.00%)

0 / 21 (0.00%)

0 / 14 (0.00%)

0 / 10 (0.00%)

0 / 6 (0.00%)

0 / 7 (0.00%)

0 / 117 (0.00%)

0 / 60 (0.00%)

0 / 120 (0.00%)

0 / 31 (0.00%)

0 / 59 (0.00%)

1 / 175 (0.57%)

occurrences causally related to treatment / all

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Hepatobiliary disorders

Hypertransaminasaemia

subjects affected / exposed

0 / 10 (0.00%)

0 / 20 (0.00%)

0 / 10 (0.00%)

0 / 7 (0.00%)

0 / 21 (0.00%)

0 / 14 (0.00%)

0 / 10 (0.00%)

0 / 6 (0.00%)

0 / 7 (0.00%)

0 / 117 (0.00%)

0 / 60 (0.00%)

0 / 120 (0.00%)

0 / 31 (0.00%)

0 / 59 (0.00%)

1 / 175 (0.57%)

occurrences causally related to treatment / all

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Renal and urinary disorders

Haematuria

subjects affected / exposed

0 / 10 (0.00%)

0 / 20 (0.00%)

0 / 10 (0.00%)

0 / 7 (0.00%)

0 / 21 (0.00%)

0 / 14 (0.00%)

0 / 10 (0.00%)

0 / 6 (0.00%)

0 / 7 (0.00%)

1 / 117 (0.85%)

0 / 60 (0.00%)

0 / 120 (0.00%)

0 / 31 (0.00%)

0 / 59 (0.00%)

0 / 175 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Hydronephrosis

subjects affected / exposed

0 / 10 (0.00%)

0 / 20 (0.00%)

0 / 10 (0.00%)

0 / 7 (0.00%)

0 / 21 (0.00%)

0 / 14 (0.00%)

0 / 10 (0.00%)

0 / 6 (0.00%)

0 / 7 (0.00%)

0 / 117 (0.00%)

0 / 60 (0.00%)

1 / 120 (0.83%)

0 / 31 (0.00%)

0 / 59 (0.00%)

0 / 175 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Nephrolithiasis

subjects affected / exposed

0 / 10 (0.00%)

0 / 20 (0.00%)

0 / 10 (0.00%)

0 / 7 (0.00%)

0 / 21 (0.00%)

0 / 14 (0.00%)

0 / 10 (0.00%)

0 / 6 (0.00%)

0 / 7 (0.00%)

1 / 117 (0.85%)

1 / 60 (1.67%)

1 / 120 (0.83%)

0 / 31 (0.00%)

0 / 59 (0.00%)

1 / 175 (0.57%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Renal colic

subjects affected / exposed

0 / 10 (0.00%)

0 / 20 (0.00%)

0 / 10 (0.00%)

0 / 7 (0.00%)

0 / 21 (0.00%)

0 / 14 (0.00%)

0 / 10 (0.00%)

0 / 6 (0.00%)

0 / 7 (0.00%)

0 / 117 (0.00%)

0 / 60 (0.00%)

0 / 120 (0.00%)

0 / 31 (0.00%)

0 / 59 (0.00%)

1 / 175 (0.57%)

occurrences causally related to treatment / all

0 / 0

0 / 3

deaths causally related to treatment / all

0 / 0

Musculoskeletal and connective tissue disorders

Arthralgia

subjects affected / exposed

0 / 10 (0.00%)

0 / 20 (0.00%)

0 / 10 (0.00%)

0 / 7 (0.00%)

0 / 21 (0.00%)

0 / 14 (0.00%)

0 / 10 (0.00%)

0 / 6 (0.00%)

0 / 7 (0.00%)

0 / 117 (0.00%)

0 / 60 (0.00%)

0 / 120 (0.00%)

0 / 31 (0.00%)

1 / 59 (1.69%)

0 / 175 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Back pain

subjects affected / exposed

0 / 10 (0.00%)

0 / 20 (0.00%)

0 / 10 (0.00%)

0 / 7 (0.00%)

0 / 21 (0.00%)

0 / 14 (0.00%)

0 / 10 (0.00%)

0 / 6 (0.00%)

0 / 7 (0.00%)

1 / 117 (0.85%)

0 / 60 (0.00%)

0 / 120 (0.00%)

0 / 31 (0.00%)

1 / 59 (1.69%)

1 / 175 (0.57%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Infections and infestations

Appendicitis

subjects affected / exposed

0 / 10 (0.00%)

1 / 20 (5.00%)

0 / 10 (0.00%)

0 / 7 (0.00%)

0 / 21 (0.00%)

0 / 14 (0.00%)

0 / 10 (0.00%)

0 / 6 (0.00%)

0 / 7 (0.00%)

0 / 117 (0.00%)

1 / 60 (1.67%)

0 / 120 (0.00%)

0 / 31 (0.00%)

0 / 59 (0.00%)

0 / 175 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Gastroenteritis

subjects affected / exposed

0 / 10 (0.00%)

0 / 20 (0.00%)

0 / 10 (0.00%)

0 / 7 (0.00%)

0 / 21 (0.00%)

0 / 14 (0.00%)

0 / 10 (0.00%)

0 / 6 (0.00%)

0 / 7 (0.00%)

0 / 117 (0.00%)

2 / 60 (3.33%)

2 / 120 (1.67%)

1 / 31 (3.23%)

0 / 59 (0.00%)

2 / 175 (1.14%)

occurrences causally related to treatment / all

0 / 0

0 / 2

0 / 3

0 / 1

0 / 0

2 / 4

deaths causally related to treatment / all

0 / 0

Pneumonia mycoplasmal

subjects affected / exposed

0 / 10 (0.00%)

0 / 20 (0.00%)

0 / 10 (0.00%)

0 / 7 (0.00%)

0 / 21 (0.00%)

0 / 14 (0.00%)

0 / 10 (0.00%)

0 / 6 (0.00%)

0 / 7 (0.00%)

1 / 117 (0.85%)

0 / 60 (0.00%)

0 / 120 (0.00%)

1 / 31 (3.23%)

0 / 59 (0.00%)

0 / 175 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Influenza

subjects affected / exposed

0 / 10 (0.00%)

0 / 20 (0.00%)

0 / 10 (0.00%)

0 / 7 (0.00%)

0 / 21 (0.00%)

0 / 14 (0.00%)

0 / 10 (0.00%)

0 / 6 (0.00%)

0 / 7 (0.00%)

1 / 117 (0.85%)

0 / 60 (0.00%)

2 / 120 (1.67%)

1 / 31 (3.23%)

0 / 59 (0.00%)

1 / 175 (0.57%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 2

0 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Pneumonia

subjects affected / exposed

1 / 10 (10.00%)

2 / 20 (10.00%)

0 / 10 (0.00%)

0 / 7 (0.00%)

0 / 21 (0.00%)

0 / 14 (0.00%)

0 / 10 (0.00%)

0 / 6 (0.00%)

0 / 7 (0.00%)

8 / 117 (6.84%)

2 / 60 (3.33%)

10 / 120 (8.33%)

1 / 31 (3.23%)

0 / 59 (0.00%)

8 / 175 (4.57%)

occurrences causally related to treatment / all

0 / 1

0 / 3

0 / 0

0 / 10

0 / 2

0 / 12

0 / 1

0 / 0

3 / 12

deaths causally related to treatment / all

0 / 0

Respiratory tract infection

subjects affected / exposed

0 / 10 (0.00%)

1 / 20 (5.00%)

0 / 10 (0.00%)

0 / 7 (0.00%)

0 / 21 (0.00%)

0 / 14 (0.00%)

0 / 10 (0.00%)

0 / 6 (0.00%)

0 / 7 (0.00%)

1 / 117 (0.85%)

0 / 60 (0.00%)

0 / 120 (0.00%)

0 / 31 (0.00%)

1 / 59 (1.69%)

0 / 175 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Upper respiratory tract infection

subjects affected / exposed

0 / 10 (0.00%)

0 / 20 (0.00%)

0 / 10 (0.00%)

0 / 7 (0.00%)

0 / 21 (0.00%)

0 / 14 (0.00%)

0 / 10 (0.00%)

0 / 6 (0.00%)

0 / 7 (0.00%)

1 / 117 (0.85%)

0 / 60 (0.00%)

1 / 120 (0.83%)

1 / 31 (3.23%)

1 / 59 (1.69%)

2 / 175 (1.14%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

1 / 2

deaths causally related to treatment / all

0 / 0

Adenovirus infection

subjects affected / exposed

0 / 10 (0.00%)

0 / 20 (0.00%)

0 / 10 (0.00%)

0 / 7 (0.00%)

0 / 21 (0.00%)

0 / 14 (0.00%)

0 / 10 (0.00%)

0 / 6 (0.00%)

0 / 7 (0.00%)

0 / 117 (0.00%)

0 / 60 (0.00%)

0 / 120 (0.00%)

0 / 31 (0.00%)

0 / 59 (0.00%)

1 / 175 (0.57%)

occurrences causally related to treatment / all

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Bacteraemia

subjects affected / exposed

0 / 10 (0.00%)

0 / 20 (0.00%)

0 / 10 (0.00%)

0 / 7 (0.00%)

0 / 21 (0.00%)

0 / 14 (0.00%)

0 / 10 (0.00%)

0 / 6 (0.00%)

0 / 7 (0.00%)

0 / 117 (0.00%)

0 / 60 (0.00%)

2 / 120 (1.67%)

0 / 31 (0.00%)

0 / 59 (0.00%)

0 / 175 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

Bronchitis

subjects affected / exposed

0 / 10 (0.00%)

0 / 20 (0.00%)

0 / 10 (0.00%)

0 / 7 (0.00%)

0 / 21 (0.00%)

0 / 14 (0.00%)

0 / 10 (0.00%)

0 / 6 (0.00%)

0 / 7 (0.00%)

0 / 117 (0.00%)

0 / 60 (0.00%)

1 / 120 (0.83%)

0 / 31 (0.00%)

0 / 59 (0.00%)

1 / 175 (0.57%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

1 / 4

deaths causally related to treatment / all

0 / 0

COVID-19

subjects affected / exposed

0 / 10 (0.00%)

0 / 20 (0.00%)

0 / 10 (0.00%)

0 / 7 (0.00%)

0 / 21 (0.00%)

0 / 14 (0.00%)

0 / 10 (0.00%)

0 / 6 (0.00%)

0 / 7 (0.00%)

0 / 117 (0.00%)

0 / 60 (0.00%)

0 / 120 (0.00%)

0 / 31 (0.00%)

0 / 59 (0.00%)

2 / 175 (1.14%)

occurrences causally related to treatment / all

0 / 0

0 / 2

deaths causally related to treatment / all

0 / 0

Encephalitis

subjects affected / exposed

0 / 10 (0.00%)

0 / 20 (0.00%)

0 / 10 (0.00%)

0 / 7 (0.00%)

0 / 21 (0.00%)

0 / 14 (0.00%)

0 / 10 (0.00%)

0 / 6 (0.00%)

0 / 7 (0.00%)

1 / 117 (0.85%)

0 / 60 (0.00%)

0 / 120 (0.00%)

0 / 31 (0.00%)

0 / 59 (0.00%)

0 / 175 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Device related infection

subjects affected / exposed

0 / 10 (0.00%)

0 / 20 (0.00%)

0 / 10 (0.00%)

0 / 7 (0.00%)

0 / 21 (0.00%)

0 / 14 (0.00%)

0 / 10 (0.00%)

0 / 6 (0.00%)

0 / 7 (0.00%)

1 / 117 (0.85%)

0 / 60 (0.00%)

0 / 120 (0.00%)

0 / 31 (0.00%)

0 / 59 (0.00%)

0 / 175 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

COVID-19 pneumonia

subjects affected / exposed

0 / 10 (0.00%)

0 / 20 (0.00%)

0 / 10 (0.00%)

0 / 7 (0.00%)

0 / 21 (0.00%)

0 / 14 (0.00%)

0 / 10 (0.00%)

0 / 6 (0.00%)

0 / 7 (0.00%)

0 / 117 (0.00%)

0 / 60 (0.00%)

0 / 120 (0.00%)

0 / 31 (0.00%)

0 / 59 (0.00%)

1 / 175 (0.57%)

occurrences causally related to treatment / all

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Gastrointestinal infection

subjects affected / exposed

0 / 10 (0.00%)

0 / 20 (0.00%)

0 / 10 (0.00%)

0 / 7 (0.00%)

0 / 21 (0.00%)

0 / 14 (0.00%)

0 / 10 (0.00%)

0 / 6 (0.00%)

0 / 7 (0.00%)

0 / 117 (0.00%)

0 / 60 (0.00%)

0 / 120 (0.00%)

0 / 31 (0.00%)

1 / 59 (1.69%)

0 / 175 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Helicobacter infection

subjects affected / exposed

0 / 10 (0.00%)

0 / 20 (0.00%)

0 / 10 (0.00%)

0 / 7 (0.00%)

0 / 21 (0.00%)

0 / 14 (0.00%)

0 / 10 (0.00%)

0 / 6 (0.00%)

0 / 7 (0.00%)

0 / 117 (0.00%)

0 / 60 (0.00%)

0 / 120 (0.00%)

0 / 31 (0.00%)

0 / 59 (0.00%)

1 / 175 (0.57%)

occurrences causally related to treatment / all

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Herpes zoster

subjects affected / exposed

0 / 10 (0.00%)

0 / 20 (0.00%)

0 / 10 (0.00%)

0 / 7 (0.00%)

0 / 21 (0.00%)

0 / 14 (0.00%)

0 / 10 (0.00%)

0 / 6 (0.00%)

0 / 7 (0.00%)

1 / 117 (0.85%)

0 / 60 (0.00%)

0 / 120 (0.00%)

0 / 31 (0.00%)

0 / 59 (0.00%)

0 / 175 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Infective thrombosis

subjects affected / exposed

0 / 10 (0.00%)

0 / 20 (0.00%)

0 / 10 (0.00%)

0 / 7 (0.00%)

0 / 21 (0.00%)

0 / 14 (0.00%)

0 / 10 (0.00%)

0 / 6 (0.00%)

0 / 7 (0.00%)

1 / 117 (0.85%)

0 / 60 (0.00%)

0 / 120 (0.00%)

0 / 31 (0.00%)

0 / 59 (0.00%)

0 / 175 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Laryngitis

subjects affected / exposed

0 / 10 (0.00%)

0 / 20 (0.00%)

0 / 10 (0.00%)

0 / 7 (0.00%)

0 / 21 (0.00%)

0 / 14 (0.00%)

0 / 10 (0.00%)

0 / 6 (0.00%)

0 / 7 (0.00%)

0 / 117 (0.00%)

0 / 60 (0.00%)

1 / 120 (0.83%)

0 / 31 (0.00%)

0 / 59 (0.00%)

0 / 175 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Lower respiratory tract infection

subjects affected / exposed

0 / 10 (0.00%)

0 / 20 (0.00%)

0 / 10 (0.00%)

0 / 7 (0.00%)

0 / 21 (0.00%)

0 / 14 (0.00%)

0 / 10 (0.00%)

0 / 6 (0.00%)

0 / 7 (0.00%)

0 / 117 (0.00%)

1 / 60 (1.67%)

0 / 120 (0.00%)

0 / 31 (0.00%)

0 / 59 (0.00%)

2 / 175 (1.14%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 2

deaths causally related to treatment / all

0 / 0

Lower respiratory tract infection viral

subjects affected / exposed

0 / 10 (0.00%)

0 / 20 (0.00%)

0 / 10 (0.00%)

0 / 7 (0.00%)

0 / 21 (0.00%)

0 / 14 (0.00%)

0 / 10 (0.00%)

0 / 6 (0.00%)

0 / 7 (0.00%)

0 / 117 (0.00%)

1 / 60 (1.67%)

1 / 120 (0.83%)

0 / 31 (0.00%)

0 / 59 (0.00%)

1 / 175 (0.57%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Lymph gland infection

subjects affected / exposed

0 / 10 (0.00%)

0 / 20 (0.00%)

0 / 10 (0.00%)

0 / 7 (0.00%)

0 / 21 (0.00%)

0 / 14 (0.00%)

0 / 10 (0.00%)

0 / 6 (0.00%)

0 / 7 (0.00%)

0 / 117 (0.00%)

1 / 60 (1.67%)

0 / 120 (0.00%)

0 / 31 (0.00%)

0 / 59 (0.00%)

0 / 175 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Pneumonia aspiration

subjects affected / exposed

0 / 10 (0.00%)

0 / 20 (0.00%)

0 / 10 (0.00%)

0 / 7 (0.00%)

0 / 21 (0.00%)

0 / 14 (0.00%)

0 / 10 (0.00%)

0 / 6 (0.00%)

0 / 7 (0.00%)

0 / 117 (0.00%)

0 / 60 (0.00%)

1 / 120 (0.83%)

0 / 31 (0.00%)

0 / 59 (0.00%)

1 / 175 (0.57%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Pneumonia bacterial

subjects affected / exposed

0 / 10 (0.00%)

0 / 20 (0.00%)

0 / 10 (0.00%)

0 / 7 (0.00%)

0 / 21 (0.00%)

0 / 14 (0.00%)

0 / 10 (0.00%)

0 / 6 (0.00%)

0 / 7 (0.00%)

0 / 117 (0.00%)

0 / 60 (0.00%)

1 / 120 (0.83%)

0 / 31 (0.00%)

0 / 59 (0.00%)

0 / 175 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Post procedural infection

subjects affected / exposed

0 / 10 (0.00%)

0 / 20 (0.00%)

0 / 10 (0.00%)

0 / 7 (0.00%)

0 / 21 (0.00%)

0 / 14 (0.00%)

0 / 10 (0.00%)

0 / 6 (0.00%)

0 / 7 (0.00%)

1 / 117 (0.85%)

0 / 60 (0.00%)

0 / 120 (0.00%)

0 / 31 (0.00%)

0 / 59 (0.00%)

0 / 175 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Postoperative wound infection

subjects affected / exposed

0 / 10 (0.00%)

0 / 20 (0.00%)

0 / 10 (0.00%)

0 / 7 (0.00%)

0 / 21 (0.00%)

0 / 14 (0.00%)

0 / 10 (0.00%)

0 / 6 (0.00%)

0 / 7 (0.00%)

0 / 117 (0.00%)

0 / 60 (0.00%)

0 / 120 (0.00%)

0 / 31 (0.00%)

1 / 59 (1.69%)

0 / 175 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Pyelonephritis

subjects affected / exposed

0 / 10 (0.00%)

0 / 20 (0.00%)

0 / 10 (0.00%)

0 / 7 (0.00%)

0 / 21 (0.00%)

0 / 14 (0.00%)

0 / 10 (0.00%)

0 / 6 (0.00%)

0 / 7 (0.00%)

1 / 117 (0.85%)

0 / 60 (0.00%)

0 / 120 (0.00%)

0 / 31 (0.00%)

0 / 59 (0.00%)

0 / 175 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

Respiratory tract infection viral

subjects affected / exposed

0 / 10 (0.00%)

0 / 20 (0.00%)

0 / 10 (0.00%)

0 / 7 (0.00%)

0 / 21 (0.00%)

0 / 14 (0.00%)

0 / 10 (0.00%)

0 / 6 (0.00%)

0 / 7 (0.00%)

0 / 117 (0.00%)

0 / 60 (0.00%)

0 / 120 (0.00%)

0 / 31 (0.00%)

0 / 59 (0.00%)

1 / 175 (0.57%)

occurrences causally related to treatment / all

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Skin infection

subjects affected / exposed

0 / 10 (0.00%)

0 / 20 (0.00%)

0 / 10 (0.00%)

0 / 7 (0.00%)

0 / 21 (0.00%)

0 / 14 (0.00%)

0 / 10 (0.00%)

0 / 6 (0.00%)

0 / 7 (0.00%)

0 / 117 (0.00%)

0 / 60 (0.00%)

0 / 120 (0.00%)

0 / 31 (0.00%)

0 / 59 (0.00%)

1 / 175 (0.57%)

occurrences causally related to treatment / all

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Tonsillitis

subjects affected / exposed

0 / 10 (0.00%)

0 / 20 (0.00%)

0 / 10 (0.00%)

0 / 7 (0.00%)

0 / 21 (0.00%)

0 / 14 (0.00%)

0 / 10 (0.00%)

0 / 6 (0.00%)

0 / 7 (0.00%)

1 / 117 (0.85%)

0 / 60 (0.00%)

0 / 120 (0.00%)

0 / 31 (0.00%)

0 / 59 (0.00%)

0 / 175 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Viral upper respiratory tract infection

subjects affected / exposed

0 / 10 (0.00%)

0 / 20 (0.00%)

0 / 10 (0.00%)

0 / 7 (0.00%)

0 / 21 (0.00%)

0 / 14 (0.00%)

0 / 10 (0.00%)

0 / 6 (0.00%)

0 / 7 (0.00%)

1 / 117 (0.85%)

0 / 60 (0.00%)

1 / 120 (0.83%)

0 / 31 (0.00%)

0 / 59 (0.00%)

0 / 175 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Wound infection

subjects affected / exposed

0 / 10 (0.00%)

0 / 20 (0.00%)

0 / 10 (0.00%)

0 / 7 (0.00%)

0 / 21 (0.00%)

0 / 14 (0.00%)

0 / 10 (0.00%)

0 / 6 (0.00%)

0 / 7 (0.00%)

0 / 117 (0.00%)

0 / 60 (0.00%)

0 / 120 (0.00%)

0 / 31 (0.00%)

0 / 59 (0.00%)

1 / 175 (0.57%)

occurrences causally related to treatment / all

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Metabolism and nutrition disorders

Decreased appetite

subjects affected / exposed

0 / 10 (0.00%)

0 / 20 (0.00%)

0 / 10 (0.00%)

0 / 7 (0.00%)

0 / 21 (0.00%)

0 / 14 (0.00%)

0 / 10 (0.00%)

0 / 6 (0.00%)

0 / 7 (0.00%)

0 / 117 (0.00%)

0 / 60 (0.00%)

0 / 120 (0.00%)

1 / 31 (3.23%)

0 / 59 (0.00%)

0 / 175 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Dehydration

subjects affected / exposed

0 / 10 (0.00%)

0 / 20 (0.00%)

0 / 10 (0.00%)

0 / 7 (0.00%)

0 / 21 (0.00%)

0 / 14 (0.00%)

0 / 10 (0.00%)

0 / 6 (0.00%)

0 / 7 (0.00%)

1 / 117 (0.85%)

1 / 60 (1.67%)

0 / 120 (0.00%)

1 / 31 (3.23%)

0 / 59 (0.00%)

1 / 175 (0.57%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Hypoglycaemia

subjects affected / exposed

0 / 10 (0.00%)

0 / 20 (0.00%)

0 / 10 (0.00%)

0 / 7 (0.00%)

0 / 21 (0.00%)

0 / 14 (0.00%)

0 / 10 (0.00%)

0 / 6 (0.00%)

0 / 7 (0.00%)

0 / 117 (0.00%)

0 / 60 (0.00%)

0 / 120 (0.00%)

0 / 31 (0.00%)

0 / 59 (0.00%)

1 / 175 (0.57%)

occurrences causally related to treatment / all

0 / 0

2 / 2

deaths causally related to treatment / all

0 / 0

Metabolic acidosis

subjects affected / exposed

0 / 10 (0.00%)

0 / 20 (0.00%)

0 / 10 (0.00%)

0 / 7 (0.00%)

0 / 21 (0.00%)

0 / 14 (0.00%)

0 / 10 (0.00%)

0 / 6 (0.00%)

0 / 7 (0.00%)

0 / 117 (0.00%)

0 / 60 (0.00%)

0 / 120 (0.00%)

0 / 31 (0.00%)

0 / 59 (0.00%)

1 / 175 (0.57%)

occurrences causally related to treatment / all

0 / 0

1 / 1

deaths causally related to treatment / all

0 / 0

Hypokalaemia

subjects affected / exposed

0 / 10 (0.00%)

0 / 20 (0.00%)

0 / 10 (0.00%)

0 / 7 (0.00%)

0 / 21 (0.00%)

0 / 14 (0.00%)

0 / 10 (0.00%)

0 / 6 (0.00%)

0 / 7 (0.00%)

0 / 117 (0.00%)

0 / 60 (0.00%)

0 / 120 (0.00%)

0 / 31 (0.00%)

0 / 59 (0.00%)

1 / 175 (0.57%)

occurrences causally related to treatment / all

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

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

Non-serious adverse events	Part 1 Group A: Adolescents/Adults (3 mg Risdiplam)	Part 1 Group A: OLE	Part 1 Group B: Children (Placebo-Control Period Pooled)	Part 1 Group B: Children (0.25 mg/kg Risdiplam)	Part 1 Group B: Children (0.15 mg/kg Risdiplam)	Part 1 Group B: Children (0.05 mg/kg Risdiplam)	Part 1 Group A: Adolescents/Adults (5 mg Risdiplam)	Part 1 Group A: Adolescents/Adults (Placebo-Control Pooled)	Part 1 Group B: Children (0.02 mg/kg Risdiplam)	Part 2 OLT: Risdiplam/Risdiplam	Part 2 Placebo-Controlled: Placebo	Part 2 Placebo-Controlled: Risdiplam	Part 1 Group B: OLE	Part 2 OLT: Placebo/Risdiplam	Part 2 OLE: Risdiplam
Total subjects affected by non serious adverse events
subjects affected / exposed	9 / 10 (90.00%)	17 / 20 (85.00%)	9 / 10 (90.00%)	6 / 7 (85.71%)	18 / 21 (85.71%)	12 / 14 (85.71%)	8 / 10 (80.00%)	4 / 6 (66.67%)	6 / 7 (85.71%)	88 / 117 (75.21%)	50 / 60 (83.33%)	101 / 120 (84.17%)	28 / 31 (90.32%)	40 / 59 (67.80%)	140 / 175 (80.00%)
Vascular disorders
Hypertension
subjects affected / exposed	1 / 10 (10.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 21 (0.00%)	0 / 14 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 117 (0.00%)	0 / 60 (0.00%)	0 / 120 (0.00%)	0 / 31 (0.00%)	0 / 59 (0.00%)	0 / 175 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	0	0	0	0	0	0
General disorders and administration site conditions
Asthenia
subjects affected / exposed	1 / 10 (10.00%)	2 / 20 (10.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 21 (0.00%)	0 / 14 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	1 / 117 (0.85%)	0 / 60 (0.00%)	0 / 120 (0.00%)	0 / 31 (0.00%)	0 / 59 (0.00%)	0 / 175 (0.00%)
occurrences all number	1	3	0	0	0	0	0	0	0	1	0	0	0	0	0
Catheter site extravasation
subjects affected / exposed	0 / 10 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	1 / 21 (4.76%)	1 / 14 (7.14%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 117 (0.00%)	0 / 60 (0.00%)	0 / 120 (0.00%)	0 / 31 (0.00%)	0 / 59 (0.00%)	0 / 175 (0.00%)
occurrences all number	0	0	0	0	1	1	0	0	0	0	0	0	0	0	0
Hyperpyrexia
subjects affected / exposed	1 / 10 (10.00%)	1 / 20 (5.00%)	1 / 10 (10.00%)	0 / 7 (0.00%)	0 / 21 (0.00%)	0 / 14 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 117 (0.00%)	0 / 60 (0.00%)	1 / 120 (0.83%)	0 / 31 (0.00%)	0 / 59 (0.00%)	1 / 175 (0.57%)
occurrences all number	1	1	2	0	0	0	0	0	0	0	0	1	0	0	1
Granuloma
subjects affected / exposed	0 / 10 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	1 / 21 (4.76%)	1 / 14 (7.14%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 117 (0.00%)	0 / 60 (0.00%)	0 / 120 (0.00%)	0 / 31 (0.00%)	0 / 59 (0.00%)	0 / 175 (0.00%)
occurrences all number	0	0	0	0	1	1	0	0	0	0	0	0	0	0	0
Fatigue
subjects affected / exposed	2 / 10 (20.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)	1 / 7 (14.29%)	1 / 21 (4.76%)	0 / 14 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 117 (0.00%)	1 / 60 (1.67%)	1 / 120 (0.83%)	3 / 31 (9.68%)	0 / 59 (0.00%)	4 / 175 (2.29%)
occurrences all number	2	0	0	1	1	0	0	0	0	0	1	1	5	0	4
Oedema
subjects affected / exposed	0 / 10 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	1 / 21 (4.76%)	1 / 14 (7.14%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 117 (0.00%)	0 / 60 (0.00%)	0 / 120 (0.00%)	0 / 31 (0.00%)	0 / 59 (0.00%)	0 / 175 (0.00%)
occurrences all number	0	0	0	0	2	2	0	0	0	0	0	0	0	0	0
Influenza like illness
subjects affected / exposed	0 / 10 (0.00%)	1 / 20 (5.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 21 (0.00%)	0 / 14 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	3 / 117 (2.56%)	0 / 60 (0.00%)	0 / 120 (0.00%)	0 / 31 (0.00%)	0 / 59 (0.00%)	6 / 175 (3.43%)
occurrences all number	0	1	0	0	0	0	0	0	0	3	0	0	0	0	6
Hyperthermia
subjects affected / exposed	0 / 10 (0.00%)	0 / 20 (0.00%)	1 / 10 (10.00%)	0 / 7 (0.00%)	0 / 21 (0.00%)	0 / 14 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 117 (0.00%)	0 / 60 (0.00%)	0 / 120 (0.00%)	0 / 31 (0.00%)	0 / 59 (0.00%)	1 / 175 (0.57%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	0	0	0	0	1
Pain
subjects affected / exposed	0 / 10 (0.00%)	1 / 20 (5.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 21 (0.00%)	0 / 14 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 117 (0.00%)	0 / 60 (0.00%)	0 / 120 (0.00%)	0 / 31 (0.00%)	0 / 59 (0.00%)	2 / 175 (1.14%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	0	0	0	0	2
Pyrexia
subjects affected / exposed	2 / 10 (20.00%)	9 / 20 (45.00%)	3 / 10 (30.00%)	1 / 7 (14.29%)	4 / 21 (19.05%)	3 / 14 (21.43%)	1 / 10 (10.00%)	0 / 6 (0.00%)	2 / 7 (28.57%)	15 / 117 (12.82%)	10 / 60 (16.67%)	25 / 120 (20.83%)	18 / 31 (58.06%)	6 / 59 (10.17%)	30 / 175 (17.14%)
occurrences all number	4	19	5	1	5	4	2	0	2	22	20	41	52	7	38
Immune system disorders
Hypersensitivity
subjects affected / exposed	0 / 10 (0.00%)	2 / 20 (10.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 21 (0.00%)	0 / 14 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	1 / 117 (0.85%)	1 / 60 (1.67%)	1 / 120 (0.83%)	2 / 31 (6.45%)	0 / 59 (0.00%)	4 / 175 (2.29%)
occurrences all number	0	3	0	0	0	0	0	0	0	1	1	1	2	0	4
Reproductive system and breast disorders
Dysmenorrhoea
subjects affected / exposed	1 / 10 (10.00%)	4 / 20 (20.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 21 (0.00%)	0 / 14 (0.00%)	2 / 10 (20.00%)	1 / 6 (16.67%)	0 / 7 (0.00%)	1 / 117 (0.85%)	0 / 60 (0.00%)	2 / 120 (1.67%)	0 / 31 (0.00%)	1 / 59 (1.69%)	1 / 175 (0.57%)
occurrences all number	1	27	0	0	0	0	7	3	0	1	0	2	0	2	1
Amenorrhoea
subjects affected / exposed	1 / 10 (10.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 21 (0.00%)	0 / 14 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	1 / 117 (0.85%)	0 / 60 (0.00%)	0 / 120 (0.00%)	0 / 31 (0.00%)	0 / 59 (0.00%)	1 / 175 (0.57%)
occurrences all number	1	0	0	0	0	0	0	0	0	1	0	0	0	0	1
Heavy menstrual bleeding
subjects affected / exposed	0 / 10 (0.00%)	1 / 20 (5.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 21 (0.00%)	0 / 14 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 117 (0.00%)	1 / 60 (1.67%)	0 / 120 (0.00%)	0 / 31 (0.00%)	0 / 59 (0.00%)	1 / 175 (0.57%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	1	0	0	0	1
Premenstrual pain
subjects affected / exposed	0 / 10 (0.00%)	1 / 20 (5.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 21 (0.00%)	0 / 14 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 117 (0.00%)	0 / 60 (0.00%)	0 / 120 (0.00%)	0 / 31 (0.00%)	0 / 59 (0.00%)	0 / 175 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	0	0	0	0	0
Respiratory, thoracic and mediastinal disorders
Oropharyngeal pain
subjects affected / exposed	2 / 10 (20.00%)	3 / 20 (15.00%)	1 / 10 (10.00%)	0 / 7 (0.00%)	1 / 21 (4.76%)	1 / 14 (7.14%)	3 / 10 (30.00%)	1 / 6 (16.67%)	1 / 7 (14.29%)	4 / 117 (3.42%)	7 / 60 (11.67%)	6 / 120 (5.00%)	6 / 31 (19.35%)	1 / 59 (1.69%)	11 / 175 (6.29%)
occurrences all number	2	6	2	0	2	2	4	1	2	4	8	6	8	1	16
Nasal congestion
subjects affected / exposed	0 / 10 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 21 (0.00%)	0 / 14 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	1 / 117 (0.85%)	1 / 60 (1.67%)	1 / 120 (0.83%)	2 / 31 (6.45%)	0 / 59 (0.00%)	1 / 175 (0.57%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	1	1	2	0	1
Lower respiratory tract inflammation
subjects affected / exposed	0 / 10 (0.00%)	1 / 20 (5.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 21 (0.00%)	0 / 14 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 117 (0.00%)	0 / 60 (0.00%)	0 / 120 (0.00%)	0 / 31 (0.00%)	0 / 59 (0.00%)	0 / 175 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	0	0	0	0	0
Dyspnoea
subjects affected / exposed	0 / 10 (0.00%)	1 / 20 (5.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 21 (0.00%)	0 / 14 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 117 (0.00%)	0 / 60 (0.00%)	1 / 120 (0.83%)	0 / 31 (0.00%)	0 / 59 (0.00%)	1 / 175 (0.57%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	0	1	0	0	2
Cough
subjects affected / exposed	1 / 10 (10.00%)	4 / 20 (20.00%)	2 / 10 (20.00%)	1 / 7 (14.29%)	3 / 21 (14.29%)	2 / 14 (14.29%)	0 / 10 (0.00%)	0 / 6 (0.00%)	1 / 7 (14.29%)	12 / 117 (10.26%)	12 / 60 (20.00%)	17 / 120 (14.17%)	11 / 31 (35.48%)	5 / 59 (8.47%)	14 / 175 (8.00%)
occurrences all number	1	5	4	2	4	2	0	0	1	16	19	27	31	7	19
Pleurisy
subjects affected / exposed	0 / 10 (0.00%)	1 / 20 (5.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 21 (0.00%)	0 / 14 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 117 (0.00%)	0 / 60 (0.00%)	0 / 120 (0.00%)	0 / 31 (0.00%)	0 / 59 (0.00%)	0 / 175 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	0	0	0	0	0
Respiratory tract inflammation
subjects affected / exposed	0 / 10 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 21 (0.00%)	0 / 14 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 117 (0.00%)	0 / 60 (0.00%)	0 / 120 (0.00%)	3 / 31 (9.68%)	0 / 59 (0.00%)	0 / 175 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	4	0	0
Rhinitis allergic
subjects affected / exposed	1 / 10 (10.00%)	2 / 20 (10.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 21 (0.00%)	0 / 14 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	1 / 117 (0.85%)	2 / 60 (3.33%)	1 / 120 (0.83%)	1 / 31 (3.23%)	1 / 59 (1.69%)	3 / 175 (1.71%)
occurrences all number	1	6	0	0	0	0	0	0	0	1	3	1	1	1	3
Rhinorrhoea
subjects affected / exposed	0 / 10 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)	1 / 7 (14.29%)	1 / 21 (4.76%)	0 / 14 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	3 / 117 (2.56%)	3 / 60 (5.00%)	6 / 120 (5.00%)	3 / 31 (9.68%)	1 / 59 (1.69%)	10 / 175 (5.71%)
occurrences all number	0	0	0	1	1	0	0	0	0	4	3	6	7	1	12
Upper respiratory tract inflammation
subjects affected / exposed	0 / 10 (0.00%)	3 / 20 (15.00%)	2 / 10 (20.00%)	1 / 7 (14.29%)	1 / 21 (4.76%)	0 / 14 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 117 (0.00%)	1 / 60 (1.67%)	0 / 120 (0.00%)	4 / 31 (12.90%)	0 / 59 (0.00%)	0 / 175 (0.00%)
occurrences all number	0	5	2	1	1	0	0	0	0	0	1	0	6	0	0
Asthma
subjects affected / exposed	0 / 10 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	1 / 21 (4.76%)	1 / 14 (7.14%)	0 / 10 (0.00%)	0 / 6 (0.00%)	1 / 7 (14.29%)	1 / 117 (0.85%)	1 / 60 (1.67%)	0 / 120 (0.00%)	0 / 31 (0.00%)	0 / 59 (0.00%)	1 / 175 (0.57%)
occurrences all number	0	0	0	0	1	1	0	0	1	1	1	0	0	0	2
Epistaxis
subjects affected / exposed	0 / 10 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 21 (0.00%)	0 / 14 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	1 / 117 (0.85%)	3 / 60 (5.00%)	3 / 120 (2.50%)	1 / 31 (3.23%)	3 / 59 (5.08%)	1 / 175 (0.57%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	5	4	2	4	1
Productive cough
subjects affected / exposed	0 / 10 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 21 (0.00%)	0 / 14 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	1 / 117 (0.85%)	3 / 60 (5.00%)	0 / 120 (0.00%)	0 / 31 (0.00%)	0 / 59 (0.00%)	1 / 175 (0.57%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	3	0	0	0	1
Psychiatric disorders
Depression
subjects affected / exposed	0 / 10 (0.00%)	1 / 20 (5.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 21 (0.00%)	0 / 14 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 117 (0.00%)	0 / 60 (0.00%)	0 / 120 (0.00%)	0 / 31 (0.00%)	0 / 59 (0.00%)	3 / 175 (1.71%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	0	0	0	0	3
Initial insomnia
subjects affected / exposed	0 / 10 (0.00%)	1 / 20 (5.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 21 (0.00%)	0 / 14 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 117 (0.00%)	0 / 60 (0.00%)	0 / 120 (0.00%)	0 / 31 (0.00%)	0 / 59 (0.00%)	0 / 175 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	0	0	0	0	0
Investigations
Gastric pH decreased
subjects affected / exposed	0 / 10 (0.00%)	1 / 20 (5.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 21 (0.00%)	0 / 14 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 117 (0.00%)	0 / 60 (0.00%)	0 / 120 (0.00%)	0 / 31 (0.00%)	0 / 59 (0.00%)	0 / 175 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	0	0	0	0	0
Hepatic enzyme increased
subjects affected / exposed	1 / 10 (10.00%)	1 / 20 (5.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 21 (0.00%)	0 / 14 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 117 (0.00%)	0 / 60 (0.00%)	0 / 120 (0.00%)	0 / 31 (0.00%)	0 / 59 (0.00%)	0 / 175 (0.00%)
occurrences all number	1	1	0	0	0	0	0	0	0	0	0	0	0	0	0
Injury, poisoning and procedural complications
Arthropod bite
subjects affected / exposed	0 / 10 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	2 / 21 (9.52%)	2 / 14 (14.29%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	2 / 117 (1.71%)	1 / 60 (1.67%)	3 / 120 (2.50%)	1 / 31 (3.23%)	1 / 59 (1.69%)	2 / 175 (1.14%)
occurrences all number	0	0	0	0	3	3	0	0	0	2	2	3	1	1	2
Contusion
subjects affected / exposed	0 / 10 (0.00%)	0 / 20 (0.00%)	1 / 10 (10.00%)	0 / 7 (0.00%)	1 / 21 (4.76%)	1 / 14 (7.14%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	2 / 117 (1.71%)	0 / 60 (0.00%)	5 / 120 (4.17%)	1 / 31 (3.23%)	1 / 59 (1.69%)	1 / 175 (0.57%)
occurrences all number	0	0	1	0	1	1	0	0	0	2	0	5	1	1	1
Face injury
subjects affected / exposed	0 / 10 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 21 (0.00%)	0 / 14 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 117 (0.00%)	0 / 60 (0.00%)	0 / 120 (0.00%)	2 / 31 (6.45%)	0 / 59 (0.00%)	0 / 175 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	2	0	0
Femur fracture
subjects affected / exposed	0 / 10 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 21 (0.00%)	0 / 14 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 117 (0.00%)	0 / 60 (0.00%)	1 / 120 (0.83%)	3 / 31 (9.68%)	0 / 59 (0.00%)	3 / 175 (1.71%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	1	3	0	3
Fall
subjects affected / exposed	0 / 10 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	1 / 21 (4.76%)	1 / 14 (7.14%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 117 (0.00%)	0 / 60 (0.00%)	2 / 120 (1.67%)	3 / 31 (9.68%)	0 / 59 (0.00%)	4 / 175 (2.29%)
occurrences all number	0	0	0	0	1	1	0	0	0	0	0	4	4	0	4
Foot fracture
subjects affected / exposed	0 / 10 (0.00%)	1 / 20 (5.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 21 (0.00%)	0 / 14 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 117 (0.00%)	0 / 60 (0.00%)	0 / 120 (0.00%)	0 / 31 (0.00%)	0 / 59 (0.00%)	1 / 175 (0.57%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	0	0	0	0	1
Limb injury
subjects affected / exposed	0 / 10 (0.00%)	1 / 20 (5.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 21 (0.00%)	0 / 14 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	3 / 117 (2.56%)	0 / 60 (0.00%)	1 / 120 (0.83%)	1 / 31 (3.23%)	1 / 59 (1.69%)	0 / 175 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	3	0	1	2	1	0
Ligament sprain
subjects affected / exposed	0 / 10 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)	1 / 7 (14.29%)	1 / 21 (4.76%)	0 / 14 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 117 (0.00%)	0 / 60 (0.00%)	2 / 120 (1.67%)	1 / 31 (3.23%)	1 / 59 (1.69%)	1 / 175 (0.57%)
occurrences all number	0	0	0	1	1	0	0	0	0	0	0	2	2	1	1
Tooth dislocation
subjects affected / exposed	0 / 10 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	1 / 21 (4.76%)	1 / 14 (7.14%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 117 (0.00%)	0 / 60 (0.00%)	0 / 120 (0.00%)	0 / 31 (0.00%)	0 / 59 (0.00%)	0 / 175 (0.00%)
occurrences all number	0	0	0	0	1	1	0	0	0	0	0	0	0	0	0
Cardiac disorders
Palpitations
subjects affected / exposed	0 / 10 (0.00%)	1 / 20 (5.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 21 (0.00%)	0 / 14 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 117 (0.00%)	0 / 60 (0.00%)	1 / 120 (0.83%)	0 / 31 (0.00%)	1 / 59 (1.69%)	1 / 175 (0.57%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	0	2	0	1	1
Sinus tachycardia
subjects affected / exposed	0 / 10 (0.00%)	1 / 20 (5.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 21 (0.00%)	0 / 14 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 117 (0.00%)	0 / 60 (0.00%)	0 / 120 (0.00%)	0 / 31 (0.00%)	0 / 59 (0.00%)	0 / 175 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	0	0	0	0	0
Supraventricular tachycardia
subjects affected / exposed	0 / 10 (0.00%)	1 / 20 (5.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 21 (0.00%)	0 / 14 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 117 (0.00%)	0 / 60 (0.00%)	0 / 120 (0.00%)	0 / 31 (0.00%)	0 / 59 (0.00%)	0 / 175 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	0	0	0	0	0
Tachycardia
subjects affected / exposed	3 / 10 (30.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 21 (0.00%)	0 / 14 (0.00%)	0 / 10 (0.00%)	1 / 6 (16.67%)	0 / 7 (0.00%)	1 / 117 (0.85%)	0 / 60 (0.00%)	0 / 120 (0.00%)	1 / 31 (3.23%)	1 / 59 (1.69%)	2 / 175 (1.14%)
occurrences all number	3	0	0	0	0	0	0	1	0	1	0	0	2	1	2
Nervous system disorders
Dizziness
subjects affected / exposed	0 / 10 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)	1 / 7 (14.29%)	1 / 21 (4.76%)	0 / 14 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	1 / 117 (0.85%)	2 / 60 (3.33%)	0 / 120 (0.00%)	0 / 31 (0.00%)	0 / 59 (0.00%)	7 / 175 (4.00%)
occurrences all number	0	0	0	1	1	0	0	0	0	1	2	0	0	0	7
Headache
subjects affected / exposed	1 / 10 (10.00%)	3 / 20 (15.00%)	0 / 10 (0.00%)	1 / 7 (14.29%)	2 / 21 (9.52%)	1 / 14 (7.14%)	1 / 10 (10.00%)	0 / 6 (0.00%)	1 / 7 (14.29%)	12 / 117 (10.26%)	10 / 60 (16.67%)	24 / 120 (20.00%)	6 / 31 (19.35%)	11 / 59 (18.64%)	20 / 175 (11.43%)
occurrences all number	3	60	0	2	20	18	3	0	18	76	23	88	47	32	84
Blood and lymphatic system disorders
Iron deficiency anaemia
subjects affected / exposed	0 / 10 (0.00%)	1 / 20 (5.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 21 (0.00%)	0 / 14 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 117 (0.00%)	0 / 60 (0.00%)	1 / 120 (0.83%)	0 / 31 (0.00%)	1 / 59 (1.69%)	0 / 175 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	0	1	0	1	0
Neutropenia
subjects affected / exposed	1 / 10 (10.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 21 (0.00%)	0 / 14 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 117 (0.00%)	1 / 60 (1.67%)	1 / 120 (0.83%)	0 / 31 (0.00%)	0 / 59 (0.00%)	2 / 175 (1.14%)
occurrences all number	1	0	0	0	0	0	0	0	0	0	1	1	0	0	2
Ear and labyrinth disorders
Ear pain
subjects affected / exposed	0 / 10 (0.00%)	1 / 20 (5.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 21 (0.00%)	0 / 14 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	5 / 117 (4.27%)	2 / 60 (3.33%)	3 / 120 (2.50%)	4 / 31 (12.90%)	2 / 59 (3.39%)	3 / 175 (1.71%)
occurrences all number	0	1	0	0	0	0	0	0	0	5	2	4	5	2	4
Vertigo
subjects affected / exposed	0 / 10 (0.00%)	1 / 20 (5.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 21 (0.00%)	0 / 14 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 117 (0.00%)	0 / 60 (0.00%)	0 / 120 (0.00%)	0 / 31 (0.00%)	0 / 59 (0.00%)	0 / 175 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	0	0	0	0	0
Motion sickness
subjects affected / exposed	0 / 10 (0.00%)	0 / 20 (0.00%)	1 / 10 (10.00%)	0 / 7 (0.00%)	0 / 21 (0.00%)	0 / 14 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 117 (0.00%)	0 / 60 (0.00%)	2 / 120 (1.67%)	0 / 31 (0.00%)	1 / 59 (1.69%)	0 / 175 (0.00%)
occurrences all number	0	0	2	0	0	0	0	0	0	0	0	2	0	1	0
Eye disorders
Conjunctival hyperaemia
subjects affected / exposed	0 / 10 (0.00%)	0 / 20 (0.00%)	1 / 10 (10.00%)	0 / 7 (0.00%)	0 / 21 (0.00%)	0 / 14 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 117 (0.00%)	0 / 60 (0.00%)	0 / 120 (0.00%)	0 / 31 (0.00%)	0 / 59 (0.00%)	0 / 175 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	0	0	0	0	0
Ocular hyperaemia
subjects affected / exposed	0 / 10 (0.00%)	1 / 20 (5.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 21 (0.00%)	0 / 14 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	1 / 117 (0.85%)	0 / 60 (0.00%)	1 / 120 (0.83%)	1 / 31 (3.23%)	0 / 59 (0.00%)	2 / 175 (1.14%)
occurrences all number	0	1	0	0	0	0	0	0	0	1	0	1	1	0	2
Eczema eyelids
subjects affected / exposed	0 / 10 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	1 / 21 (4.76%)	1 / 14 (7.14%)	0 / 10 (0.00%)	0 / 6 (0.00%)	1 / 7 (14.29%)	0 / 117 (0.00%)	0 / 60 (0.00%)	0 / 120 (0.00%)	1 / 31 (3.23%)	0 / 59 (0.00%)	0 / 175 (0.00%)
occurrences all number	0	0	0	0	1	1	0	0	1	0	0	0	1	0	0
Corneal infiltrates
subjects affected / exposed	0 / 10 (0.00%)	1 / 20 (5.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 21 (0.00%)	0 / 14 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 117 (0.00%)	0 / 60 (0.00%)	0 / 120 (0.00%)	0 / 31 (0.00%)	0 / 59 (0.00%)	0 / 175 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	0	0	0	0	0
Retinal dystrophy
subjects affected / exposed	0 / 10 (0.00%)	1 / 20 (5.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 21 (0.00%)	0 / 14 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 117 (0.00%)	0 / 60 (0.00%)	0 / 120 (0.00%)	0 / 31 (0.00%)	0 / 59 (0.00%)	0 / 175 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	0	0	0	0	0
Vision blurred
subjects affected / exposed	0 / 10 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	1 / 21 (4.76%)	1 / 14 (7.14%)	0 / 10 (0.00%)	0 / 6 (0.00%)	1 / 7 (14.29%)	0 / 117 (0.00%)	0 / 60 (0.00%)	1 / 120 (0.83%)	0 / 31 (0.00%)	0 / 59 (0.00%)	0 / 175 (0.00%)
occurrences all number	0	0	0	0	1	1	0	0	1	0	0	1	0	0	0
Gastrointestinal disorders
Constipation
subjects affected / exposed	0 / 10 (0.00%)	0 / 20 (0.00%)	1 / 10 (10.00%)	0 / 7 (0.00%)	0 / 21 (0.00%)	0 / 14 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	4 / 117 (3.42%)	3 / 60 (5.00%)	9 / 120 (7.50%)	4 / 31 (12.90%)	2 / 59 (3.39%)	8 / 175 (4.57%)
occurrences all number	0	0	1	0	0	0	0	0	0	4	3	10	12	4	9
Aphthous ulcer
subjects affected / exposed	1 / 10 (10.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 21 (0.00%)	0 / 14 (0.00%)	1 / 10 (10.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	1 / 117 (0.85%)	0 / 60 (0.00%)	3 / 120 (2.50%)	0 / 31 (0.00%)	0 / 59 (0.00%)	1 / 175 (0.57%)
occurrences all number	1	0	0	0	0	0	1	0	0	1	0	4	0	0	2
Abdominal pain upper
subjects affected / exposed	0 / 10 (0.00%)	3 / 20 (15.00%)	1 / 10 (10.00%)	0 / 7 (0.00%)	0 / 21 (0.00%)	0 / 14 (0.00%)	1 / 10 (10.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	1 / 117 (0.85%)	2 / 60 (3.33%)	7 / 120 (5.83%)	3 / 31 (9.68%)	1 / 59 (1.69%)	9 / 175 (5.14%)
occurrences all number	0	4	1	0	0	0	1	0	0	1	3	7	5	1	10
Abdominal pain
subjects affected / exposed	1 / 10 (10.00%)	2 / 20 (10.00%)	1 / 10 (10.00%)	1 / 7 (14.29%)	1 / 21 (4.76%)	0 / 14 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	7 / 117 (5.98%)	5 / 60 (8.33%)	8 / 120 (6.67%)	4 / 31 (12.90%)	4 / 59 (6.78%)	7 / 175 (4.00%)
occurrences all number	1	2	1	2	2	0	0	0	0	10	6	10	6	5	15
Diarrhoea
subjects affected / exposed	0 / 10 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)	1 / 7 (14.29%)	1 / 21 (4.76%)	0 / 14 (0.00%)	1 / 10 (10.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	10 / 117 (8.55%)	5 / 60 (8.33%)	21 / 120 (17.50%)	3 / 31 (9.68%)	6 / 59 (10.17%)	17 / 175 (9.71%)
occurrences all number	0	0	0	1	1	0	1	0	0	12	5	27	14	8	26
Faecaloma
subjects affected / exposed	1 / 10 (10.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 21 (0.00%)	0 / 14 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 117 (0.00%)	0 / 60 (0.00%)	1 / 120 (0.83%)	0 / 31 (0.00%)	0 / 59 (0.00%)	1 / 175 (0.57%)
occurrences all number	1	0	0	0	0	0	0	0	0	0	0	1	0	0	1
Gastrointestinal disorder
subjects affected / exposed	0 / 10 (0.00%)	1 / 20 (5.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 21 (0.00%)	0 / 14 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 117 (0.00%)	0 / 60 (0.00%)	0 / 120 (0.00%)	0 / 31 (0.00%)	0 / 59 (0.00%)	0 / 175 (0.00%)
occurrences all number	0	2	0	0	0	0	0	0	0	0	0	0	0	0	0
Lip pruritus
subjects affected / exposed	0 / 10 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	1 / 21 (4.76%)	1 / 14 (7.14%)	0 / 10 (0.00%)	0 / 6 (0.00%)	1 / 7 (14.29%)	0 / 117 (0.00%)	0 / 60 (0.00%)	0 / 120 (0.00%)	0 / 31 (0.00%)	0 / 59 (0.00%)	0 / 175 (0.00%)
occurrences all number	0	0	0	0	1	1	0	0	1	0	0	0	0	0	0
Nausea
subjects affected / exposed	0 / 10 (0.00%)	2 / 20 (10.00%)	1 / 10 (10.00%)	1 / 7 (14.29%)	2 / 21 (9.52%)	1 / 14 (7.14%)	0 / 10 (0.00%)	0 / 6 (0.00%)	1 / 7 (14.29%)	4 / 117 (3.42%)	3 / 60 (5.00%)	11 / 120 (9.17%)	3 / 31 (9.68%)	3 / 59 (5.08%)	8 / 175 (4.57%)
occurrences all number	0	3	1	1	2	1	0	0	1	5	4	13	4	6	10
Toothache
subjects affected / exposed	0 / 10 (0.00%)	1 / 20 (5.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 21 (0.00%)	0 / 14 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 117 (0.00%)	0 / 60 (0.00%)	1 / 120 (0.83%)	0 / 31 (0.00%)	2 / 59 (3.39%)	1 / 175 (0.57%)
occurrences all number	0	4	0	0	0	0	0	0	0	0	0	1	0	2	1
Tongue oedema
subjects affected / exposed	0 / 10 (0.00%)	1 / 20 (5.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 21 (0.00%)	0 / 14 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 117 (0.00%)	0 / 60 (0.00%)	0 / 120 (0.00%)	0 / 31 (0.00%)	0 / 59 (0.00%)	0 / 175 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	0	0	0	0	0
Swollen tongue
subjects affected / exposed	0 / 10 (0.00%)	1 / 20 (5.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 21 (0.00%)	0 / 14 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 117 (0.00%)	0 / 60 (0.00%)	0 / 120 (0.00%)	0 / 31 (0.00%)	0 / 59 (0.00%)	0 / 175 (0.00%)
occurrences all number	0	2	0	0	0	0	0	0	0	0	0	0	0	0	0
Oral mucosal erythema
subjects affected / exposed	0 / 10 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	1 / 21 (4.76%)	1 / 14 (7.14%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 117 (0.00%)	1 / 60 (1.67%)	0 / 120 (0.00%)	2 / 31 (6.45%)	0 / 59 (0.00%)	0 / 175 (0.00%)
occurrences all number	0	0	0	0	1	1	0	0	0	0	1	0	2	0	0
Vomiting
subjects affected / exposed	0 / 10 (0.00%)	4 / 20 (20.00%)	1 / 10 (10.00%)	1 / 7 (14.29%)	5 / 21 (23.81%)	4 / 14 (28.57%)	1 / 10 (10.00%)	0 / 6 (0.00%)	2 / 7 (28.57%)	15 / 117 (12.82%)	14 / 60 (23.33%)	17 / 120 (14.17%)	10 / 31 (32.26%)	9 / 59 (15.25%)	20 / 175 (11.43%)
occurrences all number	0	6	1	1	7	6	1	0	4	31	22	35	27	13	43
Skin and subcutaneous tissue disorders
Acne
subjects affected / exposed	0 / 10 (0.00%)	1 / 20 (5.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 21 (0.00%)	0 / 14 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	1 / 117 (0.85%)	0 / 60 (0.00%)	3 / 120 (2.50%)	0 / 31 (0.00%)	1 / 59 (1.69%)	5 / 175 (2.86%)
occurrences all number	0	1	0	0	0	0	0	0	0	1	0	3	0	1	6
Alopecia
subjects affected / exposed	0 / 10 (0.00%)	1 / 20 (5.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 21 (0.00%)	0 / 14 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	1 / 117 (0.85%)	0 / 60 (0.00%)	0 / 120 (0.00%)	0 / 31 (0.00%)	0 / 59 (0.00%)	2 / 175 (1.14%)
occurrences all number	0	1	0	0	0	0	0	0	0	1	0	0	0	0	2
Blister
subjects affected / exposed	0 / 10 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	1 / 21 (4.76%)	1 / 14 (7.14%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	1 / 117 (0.85%)	0 / 60 (0.00%)	1 / 120 (0.83%)	0 / 31 (0.00%)	0 / 59 (0.00%)	2 / 175 (1.14%)
occurrences all number	0	0	0	0	1	1	0	0	0	1	0	1	0	0	5
Dermatitis
subjects affected / exposed	1 / 10 (10.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 21 (0.00%)	0 / 14 (0.00%)	0 / 10 (0.00%)	1 / 6 (16.67%)	0 / 7 (0.00%)	1 / 117 (0.85%)	0 / 60 (0.00%)	0 / 120 (0.00%)	0 / 31 (0.00%)	1 / 59 (1.69%)	2 / 175 (1.14%)
occurrences all number	1	0	0	0	0	0	0	1	0	1	0	0	0	1	2
Hyperkeratosis
subjects affected / exposed	1 / 10 (10.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 21 (0.00%)	0 / 14 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 117 (0.00%)	0 / 60 (0.00%)	0 / 120 (0.00%)	0 / 31 (0.00%)	0 / 59 (0.00%)	0 / 175 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Eczema
subjects affected / exposed	0 / 10 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 21 (0.00%)	0 / 14 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	3 / 117 (2.56%)	1 / 60 (1.67%)	5 / 120 (4.17%)	3 / 31 (9.68%)	1 / 59 (1.69%)	5 / 175 (2.86%)
occurrences all number	0	0	0	0	0	0	0	0	0	3	1	5	3	1	6
Dry skin
subjects affected / exposed	2 / 10 (20.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 21 (0.00%)	0 / 14 (0.00%)	0 / 10 (0.00%)	1 / 6 (16.67%)	0 / 7 (0.00%)	2 / 117 (1.71%)	0 / 60 (0.00%)	2 / 120 (1.67%)	1 / 31 (3.23%)	1 / 59 (1.69%)	1 / 175 (0.57%)
occurrences all number	2	0	0	0	0	0	0	1	0	2	0	2	1	1	1
Dermatitis diaper
subjects affected / exposed	0 / 10 (0.00%)	0 / 20 (0.00%)	1 / 10 (10.00%)	0 / 7 (0.00%)	0 / 21 (0.00%)	0 / 14 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 117 (0.00%)	0 / 60 (0.00%)	0 / 120 (0.00%)	0 / 31 (0.00%)	0 / 59 (0.00%)	0 / 175 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	0	0	0	0	0
Palmar erythema
subjects affected / exposed	1 / 10 (10.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 21 (0.00%)	0 / 14 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 117 (0.00%)	0 / 60 (0.00%)	0 / 120 (0.00%)	1 / 31 (3.23%)	0 / 59 (0.00%)	0 / 175 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	0	0	0	1	0	0
Pruritus
subjects affected / exposed	1 / 10 (10.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	1 / 21 (4.76%)	1 / 14 (7.14%)	0 / 10 (0.00%)	1 / 6 (16.67%)	1 / 7 (14.29%)	2 / 117 (1.71%)	0 / 60 (0.00%)	1 / 120 (0.83%)	0 / 31 (0.00%)	0 / 59 (0.00%)	0 / 175 (0.00%)
occurrences all number	3	0	0	0	1	1	0	3	1	2	0	1	0	0	0
Rash
subjects affected / exposed	0 / 10 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)	1 / 7 (14.29%)	3 / 21 (14.29%)	2 / 14 (14.29%)	1 / 10 (10.00%)	0 / 6 (0.00%)	1 / 7 (14.29%)	6 / 117 (5.13%)	1 / 60 (1.67%)	9 / 120 (7.50%)	3 / 31 (9.68%)	0 / 59 (0.00%)	7 / 175 (4.00%)
occurrences all number	0	0	0	1	3	2	1	0	1	6	1	11	3	0	10
Rash papular
subjects affected / exposed	0 / 10 (0.00%)	0 / 20 (0.00%)	1 / 10 (10.00%)	0 / 7 (0.00%)	1 / 21 (4.76%)	1 / 14 (7.14%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 117 (0.00%)	0 / 60 (0.00%)	1 / 120 (0.83%)	0 / 31 (0.00%)	0 / 59 (0.00%)	0 / 175 (0.00%)
occurrences all number	0	0	1	0	1	1	0	0	0	0	0	1	0	0	0
Seborrhoeic dermatitis
subjects affected / exposed	1 / 10 (10.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 21 (0.00%)	0 / 14 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	1 / 117 (0.85%)	0 / 60 (0.00%)	1 / 120 (0.83%)	0 / 31 (0.00%)	0 / 59 (0.00%)	2 / 175 (1.14%)
occurrences all number	1	0	0	0	0	0	0	0	0	1	0	2	0	0	2
Erythema
subjects affected / exposed	0 / 10 (0.00%)	1 / 20 (5.00%)	1 / 10 (10.00%)	0 / 7 (0.00%)	0 / 21 (0.00%)	0 / 14 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	2 / 117 (1.71%)	0 / 60 (0.00%)	3 / 120 (2.50%)	3 / 31 (9.68%)	0 / 59 (0.00%)	1 / 175 (0.57%)
occurrences all number	0	1	1	0	0	0	0	0	0	2	0	4	5	0	1
Skin induration
subjects affected / exposed	1 / 10 (10.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 21 (0.00%)	0 / 14 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 117 (0.00%)	0 / 60 (0.00%)	0 / 120 (0.00%)	0 / 31 (0.00%)	0 / 59 (0.00%)	0 / 175 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Renal and urinary disorders
Urinary tract pain
subjects affected / exposed	0 / 10 (0.00%)	0 / 20 (0.00%)	1 / 10 (10.00%)	0 / 7 (0.00%)	0 / 21 (0.00%)	0 / 14 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 117 (0.00%)	0 / 60 (0.00%)	0 / 120 (0.00%)	0 / 31 (0.00%)	0 / 59 (0.00%)	0 / 175 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	0	0	0	0	0
Musculoskeletal and connective tissue disorders
Neck pain
subjects affected / exposed	0 / 10 (0.00%)	1 / 20 (5.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 21 (0.00%)	0 / 14 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	1 / 117 (0.85%)	0 / 60 (0.00%)	1 / 120 (0.83%)	1 / 31 (3.23%)	0 / 59 (0.00%)	1 / 175 (0.57%)
occurrences all number	0	13	0	0	0	0	0	0	0	1	0	1	1	0	1
Myalgia
subjects affected / exposed	1 / 10 (10.00%)	1 / 20 (5.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 21 (0.00%)	0 / 14 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 117 (0.00%)	0 / 60 (0.00%)	3 / 120 (2.50%)	1 / 31 (3.23%)	1 / 59 (1.69%)	3 / 175 (1.71%)
occurrences all number	1	1	0	0	0	0	0	0	0	0	0	3	1	1	3
Back pain
subjects affected / exposed	0 / 10 (0.00%)	4 / 20 (20.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 21 (0.00%)	0 / 14 (0.00%)	1 / 10 (10.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	3 / 117 (2.56%)	2 / 60 (3.33%)	3 / 120 (2.50%)	2 / 31 (6.45%)	1 / 59 (1.69%)	11 / 175 (6.29%)
occurrences all number	0	14	0	0	0	0	1	0	0	3	4	4	3	1	13
Arthralgia
subjects affected / exposed	0 / 10 (0.00%)	1 / 20 (5.00%)	1 / 10 (10.00%)	0 / 7 (0.00%)	0 / 21 (0.00%)	0 / 14 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	3 / 117 (2.56%)	0 / 60 (0.00%)	6 / 120 (5.00%)	5 / 31 (16.13%)	2 / 59 (3.39%)	13 / 175 (7.43%)
occurrences all number	0	1	2	0	0	0	0	0	0	3	0	9	6	2	21
Osteoporosis
subjects affected / exposed	0 / 10 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 21 (0.00%)	0 / 14 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 117 (0.00%)	0 / 60 (0.00%)	0 / 120 (0.00%)	2 / 31 (6.45%)	0 / 59 (0.00%)	2 / 175 (1.14%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	2	0	2
Pain in extremity
subjects affected / exposed	0 / 10 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	1 / 21 (4.76%)	1 / 14 (7.14%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	2 / 117 (1.71%)	1 / 60 (1.67%)	4 / 120 (3.33%)	4 / 31 (12.90%)	3 / 59 (5.08%)	10 / 175 (5.71%)
occurrences all number	0	0	0	0	1	1	0	0	0	2	3	4	6	3	12
Infections and infestations
Bronchitis
subjects affected / exposed	0 / 10 (0.00%)	0 / 20 (0.00%)	1 / 10 (10.00%)	0 / 7 (0.00%)	0 / 21 (0.00%)	0 / 14 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	6 / 117 (5.13%)	10 / 60 (16.67%)	7 / 120 (5.83%)	7 / 31 (22.58%)	4 / 59 (6.78%)	9 / 175 (5.14%)
occurrences all number	0	0	1	0	0	0	0	0	0	7	12	9	15	4	11
COVID-19
subjects affected / exposed	0 / 10 (0.00%)	3 / 20 (15.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 21 (0.00%)	0 / 14 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 117 (0.00%)	0 / 60 (0.00%)	0 / 120 (0.00%)	9 / 31 (29.03%)	1 / 59 (1.69%)	55 / 175 (31.43%)
occurrences all number	0	3	0	0	0	0	0	0	0	0	0	0	12	1	60
Conjunctivitis
subjects affected / exposed	0 / 10 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 21 (0.00%)	0 / 14 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	1 / 117 (0.85%)	3 / 60 (5.00%)	4 / 120 (3.33%)	3 / 31 (9.68%)	2 / 59 (3.39%)	0 / 175 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	3	6	3	3	0
Cystitis
subjects affected / exposed	0 / 10 (0.00%)	1 / 20 (5.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 21 (0.00%)	0 / 14 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	1 / 117 (0.85%)	0 / 60 (0.00%)	3 / 120 (2.50%)	1 / 31 (3.23%)	1 / 59 (1.69%)	1 / 175 (0.57%)
occurrences all number	0	2	0	0	0	0	0	0	0	2	0	5	1	1	3
Gastroenteritis
subjects affected / exposed	0 / 10 (0.00%)	4 / 20 (20.00%)	1 / 10 (10.00%)	1 / 7 (14.29%)	1 / 21 (4.76%)	0 / 14 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	9 / 117 (7.69%)	5 / 60 (8.33%)	7 / 120 (5.83%)	9 / 31 (29.03%)	5 / 59 (8.47%)	12 / 175 (6.86%)
occurrences all number	0	7	1	2	2	0	0	0	0	9	6	10	11	7	18
Ear infection fungal
subjects affected / exposed	0 / 10 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	1 / 21 (4.76%)	1 / 14 (7.14%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 117 (0.00%)	0 / 60 (0.00%)	0 / 120 (0.00%)	0 / 31 (0.00%)	0 / 59 (0.00%)	0 / 175 (0.00%)
occurrences all number	0	0	0	0	2	2	0	0	0	0	0	0	0	0	0
Ear infection
subjects affected / exposed	0 / 10 (0.00%)	2 / 20 (10.00%)	1 / 10 (10.00%)	0 / 7 (0.00%)	1 / 21 (4.76%)	1 / 14 (7.14%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	3 / 117 (2.56%)	2 / 60 (3.33%)	2 / 120 (1.67%)	3 / 31 (9.68%)	1 / 59 (1.69%)	3 / 175 (1.71%)
occurrences all number	0	2	1	0	1	1	0	0	0	3	2	2	3	1	3
Gastroenteritis viral
subjects affected / exposed	0 / 10 (0.00%)	1 / 20 (5.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 21 (0.00%)	0 / 14 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 117 (0.00%)	1 / 60 (1.67%)	4 / 120 (3.33%)	0 / 31 (0.00%)	0 / 59 (0.00%)	3 / 175 (1.71%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	1	4	0	0	5
Gastrointestinal infection
subjects affected / exposed	0 / 10 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)	1 / 7 (14.29%)	1 / 21 (4.76%)	0 / 14 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	2 / 117 (1.71%)	1 / 60 (1.67%)	0 / 120 (0.00%)	0 / 31 (0.00%)	0 / 59 (0.00%)	3 / 175 (1.71%)
occurrences all number	0	0	0	1	1	0	0	0	0	2	1	0	0	0	3
Groin infection
subjects affected / exposed	0 / 10 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	1 / 21 (4.76%)	1 / 14 (7.14%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	1 / 117 (0.85%)	1 / 60 (1.67%)	0 / 120 (0.00%)	0 / 31 (0.00%)	0 / 59 (0.00%)	0 / 175 (0.00%)
occurrences all number	0	0	0	0	1	1	0	0	0	1	1	0	0	0	0
Influenza
subjects affected / exposed	1 / 10 (10.00%)	4 / 20 (20.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 21 (0.00%)	0 / 14 (0.00%)	1 / 10 (10.00%)	1 / 6 (16.67%)	0 / 7 (0.00%)	3 / 117 (2.56%)	3 / 60 (5.00%)	3 / 120 (2.50%)	6 / 31 (19.35%)	2 / 59 (3.39%)	8 / 175 (4.57%)
occurrences all number	1	12	0	0	0	0	1	1	0	3	4	3	8	2	8
Laryngitis
subjects affected / exposed	0 / 10 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	1 / 21 (4.76%)	1 / 14 (7.14%)	0 / 10 (0.00%)	0 / 6 (0.00%)	1 / 7 (14.29%)	0 / 117 (0.00%)	1 / 60 (1.67%)	0 / 120 (0.00%)	0 / 31 (0.00%)	0 / 59 (0.00%)	1 / 175 (0.57%)
occurrences all number	0	0	0	0	1	1	0	0	1	0	1	0	0	0	1
Laryngitis viral
subjects affected / exposed	0 / 10 (0.00%)	0 / 20 (0.00%)	1 / 10 (10.00%)	0 / 7 (0.00%)	0 / 21 (0.00%)	0 / 14 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 117 (0.00%)	0 / 60 (0.00%)	0 / 120 (0.00%)	0 / 31 (0.00%)	0 / 59 (0.00%)	0 / 175 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	0	0	0	0	0
Nasopharyngitis
subjects affected / exposed	0 / 10 (0.00%)	3 / 20 (15.00%)	1 / 10 (10.00%)	1 / 7 (14.29%)	2 / 21 (9.52%)	1 / 14 (7.14%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	26 / 117 (22.22%)	15 / 60 (25.00%)	31 / 120 (25.83%)	12 / 31 (38.71%)	6 / 59 (10.17%)	34 / 175 (19.43%)
occurrences all number	0	7	1	1	2	1	0	0	0	34	21	54	23	7	48
Pharyngitis
subjects affected / exposed	1 / 10 (10.00%)	1 / 20 (5.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	2 / 21 (9.52%)	2 / 14 (14.29%)	0 / 10 (0.00%)	0 / 6 (0.00%)	2 / 7 (28.57%)	6 / 117 (5.13%)	3 / 60 (5.00%)	6 / 120 (5.00%)	4 / 31 (12.90%)	4 / 59 (6.78%)	7 / 175 (4.00%)
occurrences all number	1	3	0	0	2	2	0	0	2	6	3	8	4	4	7
Pneumonia
subjects affected / exposed	0 / 10 (0.00%)	1 / 20 (5.00%)	1 / 10 (10.00%)	0 / 7 (0.00%)	0 / 21 (0.00%)	0 / 14 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	2 / 117 (1.71%)	3 / 60 (5.00%)	5 / 120 (4.17%)	0 / 31 (0.00%)	0 / 59 (0.00%)	12 / 175 (6.86%)
occurrences all number	0	1	1	0	0	0	0	0	0	2	3	6	0	0	16
Respiratory tract infection
subjects affected / exposed	0 / 10 (0.00%)	1 / 20 (5.00%)	0 / 10 (0.00%)	2 / 7 (28.57%)	3 / 21 (14.29%)	1 / 14 (7.14%)	2 / 10 (20.00%)	1 / 6 (16.67%)	1 / 7 (14.29%)	7 / 117 (5.98%)	6 / 60 (10.00%)	8 / 120 (6.67%)	2 / 31 (6.45%)	1 / 59 (1.69%)	5 / 175 (2.86%)
occurrences all number	0	1	0	2	3	1	2	1	1	8	9	10	3	1	5
Skin infection
subjects affected / exposed	0 / 10 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 21 (0.00%)	0 / 14 (0.00%)	1 / 10 (10.00%)	1 / 6 (16.67%)	0 / 7 (0.00%)	0 / 117 (0.00%)	0 / 60 (0.00%)	0 / 120 (0.00%)	0 / 31 (0.00%)	0 / 59 (0.00%)	2 / 175 (1.14%)
occurrences all number	0	0	0	0	0	0	1	1	0	0	0	0	0	0	2
Scarlet fever
subjects affected / exposed	0 / 10 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 21 (0.00%)	0 / 14 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	1 / 117 (0.85%)	0 / 60 (0.00%)	0 / 120 (0.00%)	2 / 31 (6.45%)	1 / 59 (1.69%)	0 / 175 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	0	2	1	0
Rhinitis
subjects affected / exposed	1 / 10 (10.00%)	1 / 20 (5.00%)	1 / 10 (10.00%)	0 / 7 (0.00%)	0 / 21 (0.00%)	0 / 14 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	1 / 117 (0.85%)	3 / 60 (5.00%)	5 / 120 (4.17%)	3 / 31 (9.68%)	3 / 59 (5.08%)	7 / 175 (4.00%)
occurrences all number	1	1	1	0	0	0	0	0	0	1	4	10	3	3	7
Tonsillitis
subjects affected / exposed	0 / 10 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	1 / 21 (4.76%)	1 / 14 (7.14%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	1 / 117 (0.85%)	2 / 60 (3.33%)	3 / 120 (2.50%)	3 / 31 (9.68%)	2 / 59 (3.39%)	5 / 175 (2.86%)
occurrences all number	0	0	0	0	1	1	0	0	0	1	4	4	4	2	10
Tooth abscess
subjects affected / exposed	0 / 10 (0.00%)	1 / 20 (5.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 21 (0.00%)	0 / 14 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 117 (0.00%)	0 / 60 (0.00%)	0 / 120 (0.00%)	1 / 31 (3.23%)	0 / 59 (0.00%)	0 / 175 (0.00%)
occurrences all number	0	2	0	0	0	0	0	0	0	0	0	0	1	0	0
Upper respiratory tract infection
subjects affected / exposed	0 / 10 (0.00%)	3 / 20 (15.00%)	0 / 10 (0.00%)	2 / 7 (28.57%)	4 / 21 (19.05%)	2 / 14 (14.29%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	18 / 117 (15.38%)	18 / 60 (30.00%)	38 / 120 (31.67%)	14 / 31 (45.16%)	10 / 59 (16.95%)	49 / 175 (28.00%)
occurrences all number	0	10	0	3	5	2	0	0	0	24	27	54	47	18	99
Urinary tract infection
subjects affected / exposed	0 / 10 (0.00%)	2 / 20 (10.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 21 (0.00%)	0 / 14 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	2 / 117 (1.71%)	0 / 60 (0.00%)	6 / 120 (5.00%)	2 / 31 (6.45%)	2 / 59 (3.39%)	12 / 175 (6.86%)
occurrences all number	0	2	0	0	0	0	0	0	0	3	0	7	7	2	21
Viral infection
subjects affected / exposed	0 / 10 (0.00%)	1 / 20 (5.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 21 (0.00%)	0 / 14 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 117 (0.00%)	0 / 60 (0.00%)	1 / 120 (0.83%)	3 / 31 (9.68%)	0 / 59 (0.00%)	4 / 175 (2.29%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	0	1	3	0	4
Sinusitis
subjects affected / exposed	0 / 10 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 21 (0.00%)	0 / 14 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	2 / 117 (1.71%)	2 / 60 (3.33%)	4 / 120 (3.33%)	0 / 31 (0.00%)	5 / 59 (8.47%)	5 / 175 (2.86%)
occurrences all number	0	0	0	0	0	0	0	0	0	2	4	5	0	6	5
Varicella
subjects affected / exposed	0 / 10 (0.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 21 (0.00%)	0 / 14 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 117 (0.00%)	3 / 60 (5.00%)	3 / 120 (2.50%)	1 / 31 (3.23%)	2 / 59 (3.39%)	3 / 175 (1.71%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	3	3	1	2	3
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	1 / 10 (10.00%)	0 / 20 (0.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 21 (0.00%)	0 / 14 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	2 / 117 (1.71%)	0 / 60 (0.00%)	2 / 120 (1.67%)	0 / 31 (0.00%)	0 / 59 (0.00%)	2 / 175 (1.14%)
occurrences all number	2	0	0	0	0	0	0	0	0	2	0	2	0	0	2
Iron deficiency
subjects affected / exposed	0 / 10 (0.00%)	1 / 20 (5.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 21 (0.00%)	0 / 14 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 117 (0.00%)	0 / 60 (0.00%)	0 / 120 (0.00%)	0 / 31 (0.00%)	0 / 59 (0.00%)	0 / 175 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	0	0	0	0	0
Vitamin D deficiency
subjects affected / exposed	0 / 10 (0.00%)	1 / 20 (5.00%)	0 / 10 (0.00%)	0 / 7 (0.00%)	0 / 21 (0.00%)	0 / 14 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 117 (0.00%)	0 / 60 (0.00%)	0 / 120 (0.00%)	0 / 31 (0.00%)	0 / 59 (0.00%)	1 / 175 (0.57%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	0	0	0	0	1

More information

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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

22 Jun 2020

The number of ophthalmological assessments required during the open-label extension period was reduced. The study drug name was changed from RO7034067 to risdiplam. Cautionary language on the concomitant use of CYP3A4 substrates was removed. Given the absence of any risdiplam-induced ophthalmological findings to date, the frequency of ophthalmology assessments after completion of study visit Week 104 was reduced to every 6 months and intra ocular pressure assessment and fundus photography were removed from the schedule of assessments after completion of Week 104. The follow-up visits after study completion/early withdrawal visit were replaced with a phone call 30 days after this visit (i.e. at least 30 days after last dose of study medication) to capture adverse events. Risdiplam-related adverse events were not expected beyond this adverse event reporting period.

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

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

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

Primary: Part 1: Selected Part 2 Dose of Risdiplam for Participants 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 Participants with Marked Improvement (Defined as >= 3) in the Total Motor Function Measure (MFM32) Score at Month 12

Secondary: Part 2: Percentage of Participants 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 Forced Vital Capacity (FVC) at Month 12 in Participants Aged 6-25 Years

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

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 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 Participants Rated by Clinicians as Improved in the Clinical Global Impression of Change (CGI-C) Scale Ratings at Month 12

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

Secondary: Part 2: Percentage of Participants who Achieve Stabilization or Improvement (Defined as >= 0) in the Total Motor Function Measure (MFM-32) Score at Month 12

Secondary: Part 2: Percentage of Participants who Achieve Stabilization or Improvement (Defined as >= 0) in the Total Motor Function Measure (MFM-32) Score at Month 12

Secondary: Part 2: Percentage of Participants who Achieve an Improvement of at Least One Standard Error of Measurement on the Total MFM-32 Score at Month 12

Secondary: Part 2: Percentage of Participants who Achieve an Improvement of at Least One Standard Error of Measurement on the Total MFM-32 Score 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 the Best Sniff Nasal Inspiratory Pressure (SNIP) at Month 12

Secondary: Part 2: Change from Baseline in the MFM-32 Domain 1 (D1) Score at Month 12

Secondary: Part 2: Change from Baseline in the MFM-32 Domain 1 (D1) Score at Month 12

Secondary: Part 2: Change from Baseline in the MFM-32 Domain 2 (D2) Score at Month 12

Secondary: Part 2: Change from Baseline in the MFM-32 Domain 2 (D2) Score at Month 12

Secondary: Part 2: Change from Baseline in the MFM-32 Domain 3 (D3) Score at Month 12

Secondary: Part 2: Change from Baseline in the MFM-32 Domain 3 (D3) Score at Month 12

Secondary: Part 2: Change from Baseline in the Total Combined Scores of MFM-32 Domains 1 and 2 at Month 12

Secondary: Part 2: Change from Baseline in the Total Combined Scores of MFM-32 Domains 1 and 2 at Month 12

Secondary: Part 2: Change from Baseline in the Total Combined Scores of MFM-32 Domains 2 and 3 at Month 12

Secondary: Part 2: Change from Baseline in the Total Combined Scores of MFM-32 Domains 2 and 3 at Month 12

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Secondary: Median Fold Change from Baseline in Survival of Motor Neuron (SMN) Protein Levels in Blood

Secondary: Median Fold Change from Baseline in Survival of Motor Neuron (SMN) Protein Levels in Blood

Secondary: Part 1 and 2: Maximum Plasma Concentration (Cmax) of Risdiplam at Year 5

Secondary: Part 1 and 2: Maximum Plasma Concentration (Cmax) of Risdiplam at Year 5

Secondary: Part 1 and 2: Area Under the Curve (AUC) from 0 to 24 Hours of Risdiplam at Year 5 Visit

Secondary: Part 1 and 2: Area Under the Curve (AUC) from 0 to 24 Hours of Risdiplam at Year 5 Visit

Secondary: Part 1 and 2: Concentration at the End of a Dosing Interval (Ctrough) of Risdiplam at Year 5

Secondary: Part 1 and 2: Concentration at the End of a Dosing Interval (Ctrough) of Risdiplam at Year 5

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

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