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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

    Close Top of page
    Trial identification
    Sponsor protocol code
    BP39055
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02908685
    WHO universal trial number (UTN)
    -
    Sponsors
    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
    Paediatric regulatory details
    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?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    02 Oct 2023
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    02 Oct 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    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
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    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
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    143
    Adolescents (12-17 years)
    62
    Adults (18-64 years)
    26
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

    Close Top of page
    Recruitment
    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.

    Pre-assignment
    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
    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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    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.

    Arm title
    Part 1 Group A Cohort 2: Adolescents/Adults (5 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, 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.

    Arm title
    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.

    Arm title
    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 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.

    Arm title
    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.

    Arm title
    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.

    Arm title
    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.

    Arm title
    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 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.

    Arm title
    Part 1 Group B Cohort 2: 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 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.

    Arm title
    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 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.

    Arm title
    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.

    Arm title
    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
    Period 2 title
    Part 1 OLE and Part 2 OLT
    Is this the baseline period?
    No
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    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
    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.

    Arm title
    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
    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.

    Arm title
    Part 2: Risdiplam/Risdiplam OLT
    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.

    Arm title
    Part 2: Placebo/Risdiplam OLT
    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
    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
    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.

    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
    Period 3 title
    Part 2 OLE
    Is this the baseline period?
    No
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Part 2: RisdiplamRisdiplam OLE
    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.

    Arm title
    Part 2: Placebo/Risdiplam OLE
    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
    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.

    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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    Baseline characteristics reporting groups
    Reporting group title
    Part 1 Group A Cohort 1: Adolescents/Adults (3 mg Risdiplam)
    Reporting group 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.

    Reporting group title
    Part 1 Group A Cohort 2: Adolescents/Adults (5 mg Risdiplam)
    Reporting group 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.

    Reporting group title
    Part 1 Group A Cohort 1: 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. 3 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 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
    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.

    Reporting group title
    Part 1 Group B Cohort 2: 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, 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.

    Reporting group title
    Part 1 Group B Cohort 3: Children (0.25 mg/kg Risdiplam)
    Reporting group 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.

    Reporting group title
    Part 1 Group B Cohort 1: Children (Placebo)
    Reporting group 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.

    Reporting group title
    Part 1 Group B Cohort 2: Children (Placebo)
    Reporting group 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.

    Reporting group title
    Part 1 Group B Cohort 3: Children (Placebo)
    Reporting group 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.

    Reporting group title
    Part 2: Risdiplam
    Reporting group description
    Participants aged 2-25 years received risdiplam at the dose of 5 mg once daily for participants with a body weight (BW) >/=20kg or 0.25 mg/kg for participants with a BW <20 kg for 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.

    Reporting group title
    Part 2: Placebo
    Reporting group 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.

    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

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    End points reporting groups
    Reporting group title
    Part 1 Group A Cohort 1: Adolescents/Adults (3 mg Risdiplam)
    Reporting group 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.

    Reporting group title
    Part 1 Group A Cohort 2: Adolescents/Adults (5 mg Risdiplam)
    Reporting group 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.

    Reporting group title
    Part 1 Group A Cohort 1: 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. 3 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 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
    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.

    Reporting group title
    Part 1 Group B Cohort 2: 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, 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.

    Reporting group title
    Part 1 Group B Cohort 3: Children (0.25 mg/kg Risdiplam)
    Reporting group 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.

    Reporting group title
    Part 1 Group B Cohort 1: Children (Placebo)
    Reporting group 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.

    Reporting group title
    Part 1 Group B Cohort 2: Children (Placebo)
    Reporting group 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.

    Reporting group title
    Part 1 Group B Cohort 3: Children (Placebo)
    Reporting group 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.

    Reporting group title
    Part 2: Risdiplam
    Reporting group description
    Participants aged 2-25 years received risdiplam at the dose of 5 mg once daily for participants with a body weight (BW) >/=20kg or 0.25 mg/kg for participants with a BW <20 kg for 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.

    Reporting group title
    Part 2: Placebo
    Reporting group 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.
    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
    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.

    Reporting group title
    Part 2: Placebo/Risdiplam OLT
    Reporting group 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.
    Reporting group title
    Part 2: RisdiplamRisdiplam OLE
    Reporting group description
    Participants aged 2-25 years received risdiplam at the dose of 5 mg once daily for participants with a body weight (BW) >/=20kg or 0.25 mg/kg for participants with a BW <20 kg for 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.

    Reporting group title
    Part 2: Placebo/Risdiplam OLE
    Reporting group 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.

    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
    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
    [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)
    Statistical analysis title
    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)
    Statistical analysis title
    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)
    Statistical analysis title
    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)
    Statistical analysis title
    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)
    Statistical analysis title
    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)
    Statistical analysis title
    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)
    Statistical analysis title
    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
    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
    [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)
    Statistical analysis title
    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
    2
    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)
    Statistical analysis title
    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)
    Statistical analysis title
    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)
    Statistical analysis title
    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

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    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)
    Statistical analysis title
    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

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    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)
    Statistical analysis title
    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)
    Statistical analysis title
    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)
    Statistical analysis title
    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)
    Statistical analysis title
    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)
    Statistical analysis title
    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)
    Statistical analysis title
    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)
    Statistical analysis title
    Part 2: Risdiplam versus Placebo
    Comparison groups
    Part 2: Risdiplam v Part 2: Placebo
    Number of subjects included in analysis
    66
    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)
    Statistical analysis title
    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

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    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

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    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

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    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
    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
    [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

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    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
    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
    [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

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    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

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    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

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    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

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    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

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    Adverse events information
    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 used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    26.1
    Reporting groups
    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
    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 during the placebo-controlled period..

    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.

    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 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)
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
         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 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 2
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 4
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 3
    0 / 1
    0 / 0
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 2
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 10
    0 / 2
    0 / 12
    0 / 1
    0 / 0
    3 / 12
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 1
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Wound infection
         subjects affected / exposed