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Clinical Trial Results:
Escalating Dose and Randomized, Controlled Study of Nusinersen (BIIB058) in Participants With Spinal Muscular Atrophy

Summary
EudraCT number	2019-002663-10
Trial protocol	LV IE HU PL ES GB DE FR GR IT NL
Global end of trial date	30 May 2024

Results information
Results version number	v1(current)
This version publication date	13 Dec 2024
First version publication date	13 Dec 2024
Other versions

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

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Trial information

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Sponsor protocol code

232SM203

ISRCTN number

US NCT number

NCT04089566

WHO universal trial number (UTN)

Sponsor organisation name

Biogen

Sponsor organisation address

225 Binney Street, Cambridge, Massachusetts, United States, 02142

Public contact

Study Medical Director, Biogen, clinicaltrials@biogen.com

Scientific contact

Study Medical Director, Biogen, clinicaltrials@biogen.com

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

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

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

Yes

Analysis stage

Final

Date of interim/final analysis

30 May 2024

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

30 May 2024

Was the trial ended prematurely?

Main objective of the trial

The primary objectives of this study are to examine the clinical efficacy of nusinersen administered intrathecally at higher doses to participants with spinal muscular atrophy (SMA), as measured by change in Children's Hospital of Philadelphia-Infant Test of Neuromuscular Disorders (CHOP-INTEND) total score (Part B); to examine the safety and tolerability of nusinersen administered intrathecally at higher doses to participants with SMA (Parts A and C).

Protection of trial subjects

Written informed consent was obtained from each subject’s parent or legal guardian prior to evaluations being performed for eligibility. Adequate time to review the information in the informed consent and ask questions concerning all portions of the conduct of the study was provided. Through the informed consent process, awareness of the purpose of the study, the procedures, the benefits and risks of the study, the discomforts and the precautions taken was made. Any side effects or other health issues occurring during the study were followed up by the study doctor. Subjects were able to stop taking part in the study at any time without giving any reason.

Background therapy

Evidence for comparator

Actual start date of recruitment

26 Mar 2020

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

United States: 23

Country: Number of subjects enrolled

Japan: 6

Country: Number of subjects enrolled

Germany: 4

Country: Number of subjects enrolled

Italy: 4

Country: Number of subjects enrolled

Spain: 19

Country: Number of subjects enrolled

Canada: 2

Country: Number of subjects enrolled

Taiwan: 9

Country: Number of subjects enrolled

Estonia: 1

Country: Number of subjects enrolled

Mexico: 15

Country: Number of subjects enrolled

Saudi Arabia: 15

Country: Number of subjects enrolled

China: 11

Country: Number of subjects enrolled

Chile: 7

Country: Number of subjects enrolled

Brazil: 10

Country: Number of subjects enrolled

Poland: 4

Country: Number of subjects enrolled

Russian Federation: 8

Country: Number of subjects enrolled

Lebanon: 3

Country: Number of subjects enrolled

Colombia: 2

Country: Number of subjects enrolled

Hungary: 2

Worldwide total number of subjects

145

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Participants took part at the investigative sites in the United States, Brazil, Canada, Chile, China, Colombia, Estonia, Germany, Hungary, Italy, Japan, Lebanon, Mexico, Poland, Russia, Saudi Arabia, Spain, and Taiwan from 26 March 2020 to 30 May 2024.

Screening details

A total of 145 participants diagnosed with spinal muscular atrophy (SMA)  were enrolled in the 3-parts (Parts A, B, and C). Of which, 117 of participants completed the study.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Carer, Assessor

Are arms mutually exclusive

Yes

Part A: 28/28 Milligrams (mg) Nusinersen

Arm description

Participants with later-onset SMA received 3 loading doses of 28 mg of nusinersen, intrathecally (IT), on Days 1, 15 and 29 followed by 2 maintenance doses of 28 mg on Days 149 and 269.

Arm type

Experimental

Investigational medicinal product name

Nusinersen

Investigational medicinal product code

BIIB058

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intrathecal use

Dosage and administration details

Administered as specified in the treatment arm.

Part B: Infantile-Onset SMA: 12/12 mg Nusinersen

Arm description

Participants with infantile-onset SMA in the control group received 4 loading doses of 12 mg of nusinersen, IT, on Days 1, 15, 29, and 64 followed by 2 maintenance doses of 12 mg on Days 183 and 279. Sham procedure was administered on Day 135.

Arm type

Experimental

Investigational medicinal product name

Nusinersen

Investigational medicinal product code

BIIB058

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intrathecal use

Dosage and administration details

Administered as specified in the treatment arm.

Part B: Infantile-Onset SMA: 50/28 mg Nusinersen

Arm description

Participants with infantile-onset SMA received 2 loading doses of 50 mg of nusinersen, IT, on Days 1 and 15 followed by 2 maintenance doses of 28 mg on Days 135 and 279. Sham procedure was administered on Days 29, 64 and 183.

Arm type

Experimental

Investigational medicinal product name

Nusinersen

Investigational medicinal product code

BIIB058

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intrathecal use

Dosage and administration details

Administered as specified in the treatment arm.

Part B: Later-Onset SMA: 12/12 mg Nusinersen

Arm description

Participants with later-onset SMA in the control group received 4 loading doses of 12 mg of nusinersen, IT, on Days 1, 15, 29, and 64 followed by 2 maintenance doses of 12 mg on Days 183 and 279. Sham procedure was administered on Day 135.

Arm type

Experimental

Investigational medicinal product name

Nusinersen

Investigational medicinal product code

BIIB058

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intrathecal use

Dosage and administration details

Administered as specified in the treatment arm.

Part B: Later-Onset SMA: 50/28 mg Nusinersen

Arm description

Participants with later-onset SMA received 2 loading doses of 50 mg of nusinersen, IT, on Days 1 and 15 followed by 2 maintenance doses of 28 mg on Days 135 and 279. Sham procedure was administered on Days 29, 64 and 183.

Arm type

Experimental

Investigational medicinal product name

Nusinersen

Investigational medicinal product code

BIIB058

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intrathecal use

Dosage and administration details

Administered as specified in the treatment arm.

Part C: 50/28 mg Nusinersen

Arm description

Participants with infantile and later-onset SMA who had been receiving the approved dose of 12 mg for at least 1 year prior to entry, received a single bolus dose of 50 mg of nusinersen, IT, on Day 1 (4 months after their most recent maintenance dose of 12 mg) followed by 2 maintenance doses of 28 mg on Days 121 and 241.

Arm type

Experimental

Investigational medicinal product name

Nusinersen

Investigational medicinal product code

BIIB058

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intrathecal use

Dosage and administration details

Administered as specified in the treatment arm.

Number of subjects in period 1	Part A: 28/28 Milligrams (mg) Nusinersen	Part B: Infantile-Onset SMA: 12/12 mg Nusinersen	Part B: Infantile-Onset SMA: 50/28 mg Nusinersen	Part B: Later-Onset SMA: 12/12 mg Nusinersen	Part B: Later-Onset SMA: 50/28 mg Nusinersen	Part C: 50/28 mg Nusinersen
Started	6	25	50	8	16	40
Completed	6	13	35	7	16	40
Not completed	0	12	15	1	0	0
Adverse event, serious fatal	-	6	10	-	-	-
Withdrawal by Parent or Guardian	-	2	1	-	-	-
Reason not Specified	-	4	4	1	-	-

Baseline characteristics

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Reporting group title

Part A: 28/28 Milligrams (mg) Nusinersen

Reporting group description

Participants with later-onset SMA received 3 loading doses of 28 mg of nusinersen, intrathecally (IT), on Days 1, 15 and 29 followed by 2 maintenance doses of 28 mg on Days 149 and 269.

Reporting group title

Part B: Infantile-Onset SMA: 12/12 mg Nusinersen

Reporting group description

Reporting group title

Part B: Infantile-Onset SMA: 50/28 mg Nusinersen

Reporting group description

Reporting group title

Part B: Later-Onset SMA: 12/12 mg Nusinersen

Reporting group description

Reporting group title

Part B: Later-Onset SMA: 50/28 mg Nusinersen

Reporting group description

Reporting group title

Part C: 50/28 mg Nusinersen

Reporting group description

Reporting group values	Part A: 28/28 Milligrams (mg) Nusinersen	Part B: Infantile-Onset SMA: 12/12 mg Nusinersen	Part B: Infantile-Onset SMA: 50/28 mg Nusinersen	Part B: Later-Onset SMA: 12/12 mg Nusinersen	Part B: Later-Onset SMA: 50/28 mg Nusinersen	Part C: 50/28 mg Nusinersen	Total
Number of subjects	6	25	50	8	16	40	145
Age categorical
Units: participants
In Utero	0	0	0	0	0	0	0
Preterm newborn infants(gestational age<37 wks)	0	0	0	0	0	0	0
Newborns (0-27 days)	0	1	3	0	0	0	4
Infants and toddlers (28 days - 23 months)	0	24	47	0	0	0	71
Children (2 - 11 years)	5	0	0	8	16	10	39
Adolescents (12 - 17 years)	1	0	0	0	0	6	7
Adults (18 - 64 years)	0	0	0	0	0	23	23
From 65 - 84 years	0	0	0	0	0	1	1
85 years and over	0	0	0	0	0	0	0
Gender categorical
Units: participants
Male	5	14	26	2	2	25	74
Female	1	11	24	6	14	15	71
Race
Units: Subjects
American Indian or Alaska Native	0	0	2	0	0	0	2
Asian	2	4	10	2	5	7	30
Black or African American	0	0	0	0	1	0	1
Native Hawaiian or other Pacific Islander	0	0	0	0	0	0	0
White	4	17	29	3	8	32	93
Not Reported Due to Confidentiality Regulations	0	0	2	0	0	0	2
Other	0	4	7	3	2	1	17
Multiple	0	0	0	0	0	0	0
Ethnicity
Units: Subjects
Hispanic or Latino	1	10	18	2	6	5	42
Not Hispanic or Latino	5	13	30	6	10	35	99
Not reported	0	2	2	0	0	0	4

Subject analysis set title

CS3B Matched Sham Control Group

Subject analysis set type

Full analysis

Subject analysis set description

Historical data of participants who received sham treatment, IT, on Days 1, 15, 29, 64, 183, and 302 in the double-blind, phase 3 study CS3B (2013-004422-29), was used as control in the current study.

Subject analysis sets values	CS3B Matched Sham Control Group
Number of subjects	20
Age categorical
Units: participants
In Utero	0
Preterm newborn infants(gestational age<37 wks)	0
Newborns (0-27 days)	0
Infants and toddlers (28 days - 23 months)	0
Children (2 - 11 years)	0
Adolescents (12 - 17 years)	0
Adults (18 - 64 years)	0
From 65 - 84 years	0
85 years and over	0
Age continuous
Units:
	( )
Gender categorical
Units: participants
Male	0
Female	0
Race
Units: Subjects
American Indian or Alaska Native	0
Asian	0
Black or African American	0
Native Hawaiian or other Pacific Islander	0
White	0
Not Reported Due to Confidentiality Regulations	0
Other	0
Multiple	0
Ethnicity
Units: Subjects
Hispanic or Latino	0
Not Hispanic or Latino	0
Not reported	0

End points

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Reporting group title

Part A: 28/28 Milligrams (mg) Nusinersen

Reporting group description

Participants with later-onset SMA received 3 loading doses of 28 mg of nusinersen, intrathecally (IT), on Days 1, 15 and 29 followed by 2 maintenance doses of 28 mg on Days 149 and 269.

Reporting group title

Part B: Infantile-Onset SMA: 12/12 mg Nusinersen

Reporting group description

Reporting group title

Part B: Infantile-Onset SMA: 50/28 mg Nusinersen

Reporting group description

Reporting group title

Part B: Later-Onset SMA: 12/12 mg Nusinersen

Reporting group description

Reporting group title

Part B: Later-Onset SMA: 50/28 mg Nusinersen

Reporting group description

Reporting group title

Part C: 50/28 mg Nusinersen

Reporting group description

Subject analysis set title

CS3B Matched Sham Control Group

Subject analysis set type

Full analysis

Subject analysis set description

Primary: Part B Infantile-onset SMA: Change From Baseline in CHOP-INTEND Total Score for 50/28mg Nusinersen Versus CS3B Matched Sham Control Group

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End point title

Part B Infantile-onset SMA: Change From Baseline in CHOP-INTEND Total Score for 50/28mg Nusinersen Versus CS3B Matched Sham Control Group ^[1]

End point description

The CHOP-INTEND test was designed to evaluate the motor skills of infants with signiﬁcant motor weakness. It included 16 items (capturing neck, trunk, and proximal and distal limb strength), nine of which were scored 0, 1, 2, 3, or 4, ﬁve were scored as 0, 2, or 4, one was scored as 0, 1, 2, or 4, and one as 0, 2, 3, or 4 with greater scores indicating greater muscle strength. Total score ranged from 0 (worst possible score) and 64 (best possible score). The change from baseline to Day 183 in the CHOP-INTEND total score was compared to CS3B study (2013-004422-29) sham control group using the joint-rank methodology to account for mortality. As stated in protocol a matched sham set was defined for the analysis of this outcome measure. Matched sham set comprised of sham control participants of the CS3B study (2013-004422-29) identified by a matching algorithm and all of 50/28 mg participants in the ITT set.

End point type

Primary

End point timeframe

Baseline, Day 183

Notes
[1] - 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: Part B Infantile-onset SMA arms were planned to be analysed for this end point.

End point values	Part B: Infantile-Onset SMA: 50/28 mg Nusinersen	CS3B Matched Sham Control Group
Number of subjects analysed	50	20
Units: score on scale
least squares mean (confidence interval 95%)	42.9 (38.7 to 47.2)	16.9 (10.1 to 23.7)

Change From Baseline in CHOP-INTEND Total Score

Comparison groups

Part B: Infantile-Onset SMA: 50/28 mg Nusinersen v CS3B Matched Sham Control Group

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[2]

Method

ANCOVA

Parameter type

Least square (LS) mean difference

Point estimate

26.06

Confidence interval

level

95%

sides

2-sided

lower limit

17.941

upper limit

34.172

Variability estimate

Standard error of the mean

Dispersion value

4.141

Notes
[2] - The Analysis of Covariance (ANCOVA) model used rank score as response, treatment as fixed effect and disease duration at screening, baseline HINE 2, baseline CHOP INTEND total score as covariates. Rank score of baseline covariates was used in model.

Primary: Parts A and C: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (TESAEs)

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End point title

Parts A and C: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (TESAEs) ^[3] ^[4]

End point description

An adverse event (AE):any unfavorable & unintended sign (including an abnormal assessment such as an abnormal laboratory value), symptom, or disease temporally associated with use of an investigational product, whether or not related to investigational product. SAE:any untoward medical occurrence that at any dose resulted in death, in view of Investigator, placed participant at immediate risk of death, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, resulted in a birth defect. AE and SAEs were regarded as treatment-emergent if it was present prior to receiving first dose of nusinersen in current study and subsequently worsened in severity or was not present prior to receiving first dose of nusinersen and subsequently appeared Part A: safety analysis set. Part C: ITT set. Safety set and ITT set included all participants who received at least one dose of nusinersen in the current study.

End point type

Primary

End point timeframe

Part A: From the first dose of the study drug up to Day 389, Part C: From the first dose of the study drug up to Day 361

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

End point values	Part A: 28/28 Milligrams (mg) Nusinersen	Part C: 50/28 mg Nusinersen
Number of subjects analysed	6	40
Units: participants
TEAEs	4	37
TESAEs	1	6

No statistical analyses for this end point

Primary: Parts A and C: Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Blood Chemistry Parameters)

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End point title

Parts A and C: Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Blood Chemistry Parameters) ^[5] ^[6]

End point description

Blood chemistry parameters included protein, albumin, creatinine, blood urea nitrogen, bilirubin (total and direct), alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transferase, glucose, calcium, phosphorus, bicarbonate, chloride, sodium, potassium, cystatin C, and creatine kinase. Parameters were flagged as low, normal/ high relative to normal range/ as unknown if no result was available, by Investigator. Here, shift to low indicates values that were normal, high/ unknown at baseline and shifted to low values postbaseline. Shift to high indicates values that were normal, low or unknown at baseline and shifted to high postbaseline. Categories with at least one participant with shift from baseline are reported. Part A: safety analysis set. Part C: ITT set. Safety and ITT set included all participants who received at least one dose of nusinersen. Number analyzed ‘n’ is number of participants evaluable for analysis of the specified parameter.

End point type

Primary

End point timeframe

Parts A and C: Baseline up to Day 302

Notes
[5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only descriptive statistics were planned for this endpoint.
[6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Parts A and C arms were planned to be analysed for this end point.

End point values	Part A: 28/28 Milligrams (mg) Nusinersen	Part C: 50/28 mg Nusinersen
Number of subjects analysed	6	40
Units: participants
Alkaline Phosphatase Shift to High (n=6,39)	1	2
Alanine Aminotransferase Shift to High(n=6,34)	0	6
Aspartate Aminotransferase Shift to High (n=6,37)	0	8
Bicarbonate Shift to Low (n=2,31)	1	6
Bicarbonate Shift to High (n=2,40)	0	2
Bilirubin Shift to High (n=6,40)	0	1
Indirect Bilirubin Shift to Low (n=4,26)	4	12
Indirect Bilirubin Shift to High (n=6,40)	0	1
Calcium Shift to High (n=6,39)	0	1
Creatine Kinase Shift to Low (n=6,39)	0	0
Creatine Kinase Shift to High (n=3,22)	0	1
Chloride Shift to Low (n=6,40)	0	1
Creatinine Shift to Low (n=1,2)	0	1
Glucose Shift to Low (n=6,37)	0	3
Glucose Shift to High (n=5,33)	3	9
Potassium Shift to High (n=6,39)	1	1
Phosphate Shift to High (n=5,36)	2	10
Sodium Shift to High (n=6,40)	0	1
Urea Nitrogen Shift to Low (n=6,39)	0	1
Urea Nitrogen Shift to High (n=6,39)	1	3

No statistical analyses for this end point

Primary: Parts A and C: Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Hematology Parameters)

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End point title

Parts A and C: Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Hematology Parameters) ^[7] ^[8]

End point description

Hematology parameters included complete blood cell count, with diﬀerential and platelet count, and absolute neutrophil count. These parameters were flagged as low, normal, or high relative to parameter’s normal range or as unknown if no result was available, by the Investigator. Here, shift to low indicates values that were normal, high or unknown at baseline and shifted to low values postbaseline. Shift to high indicates values that were normal, low or unknown at baseline and shifted to high postbaseline. The categories with at least one participant with shift from baseline in these parameters are reported. Part A: safety analysis set. Part C: ITT set. Safety set and ITT set included all participants who received at least one dose of nusinersen in the current study. ‘Number analysed (n)’ indicates the number of participants evaluable for the specified hematology parameter.

End point type

Primary

End point timeframe

Parts A and C: Baseline up to Day 302

Notes
[7] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only descriptive statistics were planned for this endpoint.
[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: Parts A and C arms were planned to be analysed for this end point.

End point values	Part A: 28/28 Milligrams (mg) Nusinersen	Part C: 50/28 mg Nusinersen
Number of subjects analysed	6	40
Units: participants
Basophils Shift to High (n=3,37)	2	6
Basophils/Leukocytes Shift to High(n=2,35)	2	6
Eosinophils Shift to High(n=5,39)	1	3
Eosinophils/Leukocytes Shift to High(n=4,36)	3	9
Hematocrit Shift to Low(n=5,40)	0	2
Hematocrit Shift to High(n=6,40)	1	0
Hemoglobin Shift to Low(n=6,40)	0	3
Lymphocytes Shift to High(n=5,39)	0	1
Lymphocytes/Leukocytes Shift to Low(n=6,39)	0	2
Lymphocytes/Leukocytes Shift to High(n=6,36)	0	3
Monocytes Shift to Low(n=4,39)	1	4
Monocytes/Leukocytes Shift to Low(n=4,35)	3	2
Monocytes/Leukocytes Shift to High(n=6,40)	0	2
Neutrophils Shift to Low(n=6,35)	0	5
Neutrophils Shift to High(n=6,40)	0	2
Neutrophils/Leukocytes Shift to Low (n=5,38)	1	4
Neutrophils/Leukocytes Shift to High(n=6,39)	0	2
Platelets Shift to Low(n=6,39)	0	1
Platelets Shift to High(n=6,40)	0	1
Leukocytes Shift to Low(n=6,36)	0	3
Leukocytes Shift to High(n=6,40)	0	3

No statistical analyses for this end point

Primary: Parts A and C: Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Urinalysis Parameters)

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End point title

Parts A and C: Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Urinalysis Parameters) ^[9] ^[10]

End point description

Urinalysis included assessments of urine total protein, specific gravity, pH, protein, glucose, ketones, bilirubin, blood, red blood cells, white blood cells, epithelial cells, bacteria, casts and crystals. These parameters were flagged as low, normal, or high relative to parameter’s normal range or as unknown if no result was available, by the Investigator. Here, shift to low indicates values that were normal, high or unknown at baseline and shifted to low values postbaseline. Shift to high indicates values that were normal, low or unknown at baseline and shifted to high postbaseline. The categories with at least one participant with shift from baseline in these parameters are reported. Part A: safety analysis set. Part C: ITT set. Safety set and ITT set included all participants who received at least one dose of nusinersen in the current study. ‘Number analysed (n)’ indicates the number of participants evaluable for the specified urinalysis parameter.

End point type

Primary

End point timeframe

Parts A and C: Baseline up to Day 302

Notes
[9] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only descriptive statistics were planned for this endpoint.
[10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Parts A and C arms were planned to be analysed for this end point.

End point values	Part A: 28/28 Milligrams (mg) Nusinersen	Part C: 50/28 mg Nusinersen
Number of subjects analysed	6	40
Units: participants
Specific Gravity Shift to High (n=5,40)	2	1
pH Shift to High (n=6,40)	0	2
Protein High/positive (n=5,38)	4	9
Glucose High/positive (n=6,40)	0	2
Ketones High/positive (n=5,36)	1	8
Occult Blood High/positive (n=6,38)	2	4
RBC High/positive (n=4,12)	1	1
WBC High/positive (n=2,23)	0	2
Epithelial Cells High/positive (n=1,4)	0	4
Bacteria High/positive (n=1,2)	1	2

No statistical analyses for this end point

Primary: Parts A and C: Number of Participants With Shifts From Baseline in Cerebrospinal Fluid (CSF) Parameters

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End point title

Parts A and C: Number of Participants With Shifts From Baseline in Cerebrospinal Fluid (CSF) Parameters ^[11] ^[12]

End point description

CSF parameters included cell count, total protein, and glucose. These parameters were flagged as low, normal, or high relative to parameter’s normal range or as unknown if no result was available, by the Investigator. Here, shift to low indicates values that were normal, high or unknown at baseline and shifted to low values postbaseline. Shift to high indicates values that were normal, low or unknown at baseline and shifted to high postbaseline. The categories with at least one participant with shift from baseline in these parameters are reported. Part A: safety analysis set. Part C: ITT set. Safety set and ITT set included all participants who received at least one dose of nusinersen in the current study. ‘Number analysed (n)’ indicates the number of participants evaluable for the specified urinalysis parameter.

End point type

Primary

End point timeframe

Parts A: Baseline up to Day 269 Parts C: Baseline up to Day 241

Notes
[11] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only descriptive statistics were planned for this endpoint.
[12] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Parts A and C arms were planned to be analysed for this end point.

End point values	Part A: 28/28 Milligrams (mg) Nusinersen	Part C: 50/28 mg Nusinersen
Number of subjects analysed	6	40
Units: participants
Glucose Shift to Low (n=5,38)	1	2
Glucose Shift to High (n=6,38)	0	2
Protein Shift to Low (n=6,39)	0	3
Protein Shift to High (n=6,37)	0	8
Erythrocytes Shift to High (n=5,34)	2	8
Leukocytes Shift to High (n=5,36)	1	6

No statistical analyses for this end point

Primary: Parts A and C: Number of Participants With Shifts From Baseline in Electrocardiograms (ECGs)

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End point title

Parts A and C: Number of Participants With Shifts From Baseline in Electrocardiograms (ECGs) ^[13] ^[14]

End point description

The ECGs were assessed by the investigator to be normal, abnormal and abnormal AE. The number of participants with ECG shifts from normal to each of the categorical values denoting an abnormal scan (abnormal not AE, abnormal AE) was assessed. Shift from baseline to worst post-baseline values were reported. The categories with at least one participant with shift from baseline in ECG are reported. Part A: safety analysis set. Part C: ITT set. Safety set and ITT set included all participants who received at least one dose of nusinersen in the current study.

End point type

Primary

End point timeframe

Parts A and C: Baseline up to Day 302

Notes
[13] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only descriptive statistics were planned for this endpoint.
[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: Parts A and C arms were planned to be analysed for this end point.

End point values	Part A: 28/28 Milligrams (mg) Nusinersen	Part C: 50/28 mg Nusinersen
Number of subjects analysed	6	40
Units: participants
Normal to Normal	0	10
Normal to Abnormal, not AE	3	12
Abnormal, not AE to Abnormal, not AE	3	17
Unknown to Abnormal, not AE	0	1

No statistical analyses for this end point

Primary: Parts A and C: Number of Participants With Abnormalities in Vital Sign Parameters

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End point title

Parts A and C: Number of Participants With Abnormalities in Vital Sign Parameters ^[15] ^[16]

End point description

Vital sign assessment included temperature, pulse rate systolic blood pressure, diastolic blood pressure, and respiratory rate. As pre-specified in protocol, the criteria for determining potentially clinically relevant abnormalities in vital signs included: temperature < 36 and > 38 degrees Celsius (C), pulse rate < 60 and > 100 beats per minute (bpm), systolic blood pressure [< 90, > 140 and > 160 millimeters of mercury (mmHg)], diastolic blood pressure < 50, > 90 and > 100 mmHg and respiratory rate < 12 and > 20 breaths per minute. The categories with at least one participant with clinically relevant vital sign abnormalities are reported. Part A: safety analysis set. Part C: ITT set. Safety set and ITT set included all participants who received at least one dose of nusinersen.

End point type

Primary

End point timeframe

Parts A and C: Baseline up to Day 302

Notes
[15] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only descriptive statistics were planned for this endpoint.
[16] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Parts A and C arms were planned to be analysed for this end point.

End point values	Part A: 28/28 Milligrams (mg) Nusinersen	Part C: 50/28 mg Nusinersen
Number of subjects analysed	6	40
Units: participants
Temperature <36.0 C	4	13
Pulse rate <60 bpm	1	14
Pulse rate >100 bpm	6	19
Systolic blood pressure <90 mmHg	4	13
Systolic blood pressure >140 mmHg	0	3
Diastolic blood pressure <50 mmHg	3	10
Diastolic blood pressure >90 mmHg	1	7
Respiratory rate <12 breaths/min	0	1
Respiratory rate >20 breaths/min	6	27

No statistical analyses for this end point

Primary: Parts A and C: Change From Baseline in Growth Parameters (Ulnar Length)

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End point title

Parts A and C: Change From Baseline in Growth Parameters (Ulnar Length) ^[17] ^[18]

End point description

As pre-specified in the protocol, ulnar length was measured for participants with later-onset SMA. Part A: Safety set included all participants who received at least one dose of nusinersen. Part C:ITT set included all participants who received at least one a dose of nusinersen in the current study. ‘Subjects analysed' signifies number of participants evaluable in this endpoint.

End point type

Primary

End point timeframe

Parts A and C: Baseline, Day 302

Notes
[17] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only descriptive statistics were planned for this endpoint.
[18] - 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: Parts A and C arms were planned to be analysed for this end point.

End point values	Part A: 28/28 Milligrams (mg) Nusinersen	Part C: 50/28 mg Nusinersen
Number of subjects analysed	6	27
Units: cm
arithmetic mean (standard deviation)	1.8 ( 1.43 )	0.0 ( 1.27 )

No statistical analyses for this end point

Primary: Part C: Change From Baseline in Growth Parameters (Arm Circumference)

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End point title

Part C: Change From Baseline in Growth Parameters (Arm Circumference) ^[19] ^[20]

End point description

As pre-specified in the protocol, arm circumference was measured for participants with infantile-onset SMA. ‘99999’ signiﬁes that since only one participant was evaluable, standard deviation (SD) was not estimated. ITT set included all participants who received at least one dose of nusinersen in the current study. ‘Subjects analysed' signifies number of participants evaluable in this endpoint.

End point type

Primary

End point timeframe

Baseline, Day 302

Notes
[19] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only descriptive statistics were planned for this endpoint.
[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: Part C arm was planned to be analysed for this end point.

End point values	Part C: 50/28 mg Nusinersen
Number of subjects analysed	1
Units: cm
arithmetic mean (standard deviation)	-1.0 ( 99999 )

No statistical analyses for this end point

Primary: Part C: Change From Baseline in Growth Parameters (Chest Circumference)

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End point title

Part C: Change From Baseline in Growth Parameters (Chest Circumference) ^[21] ^[22]

End point description

As pre-specified in protocol, chest circumference was measured for participants with infantile-onset SMA only. ‘99999’ signifies that since only one participant was evaluable, standard deviation (SD) was not estimated. ITT set included all participants who received at least one dose of nusinersen in the current study. ‘Subjects analysed' signifies number of participants evaluable in this endpoint.

End point type

Primary

End point timeframe

Baseline, Day 302

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

End point values	Part C: 50/28 mg Nusinersen
Number of subjects analysed	1
Units: cm
arithmetic mean (standard deviation)	2.5 ( 99999 )

No statistical analyses for this end point

Primary: Part C: Change From Baseline in Growth Parameters (Head Circumference)

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End point title

Part C: Change From Baseline in Growth Parameters (Head Circumference) ^[23] ^[24]

End point description

As pre-specified in the protocol, head circumference was measured for participants with infantile-onset SMA only. ITT set included all participants who received at least one a dose of nusinersen in the current study. ‘99999’ signiﬁes that since only one participant was evaluable, standard deviation (SD) was not estimated. ‘Subjects analysed' signifies number of participants evaluable in this endpoint.

End point type

Primary

End point timeframe

Baseline, Day 302

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

End point values	Part C: 50/28 mg Nusinersen
Number of subjects analysed	1
Units: cm
arithmetic mean (standard deviation)	2.0 ( 99999 )

No statistical analyses for this end point

Primary: Parts A and C: Change From Baseline in Growth Parameters (Body Height)

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End point title

Parts A and C: Change From Baseline in Growth Parameters (Body Height) ^[25] ^[26]

End point description

Part A: safety analysis set. Part C: ITT set. Safety set and ITT set included all participants who received at least one dose of nusinersen in the current study. ‘Subjects analysed' signifies number of participants evaluable in this endpoint.

End point type

Primary

End point timeframe

Parts A and C: Baseline, Day 302

Notes
[25] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only descriptive statistics were planned for this endpoint.
[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: Parts A and C arms were planned to be analysed for this end point.

End point values	Part A: 28/28 Milligrams (mg) Nusinersen	Part C: 50/28 mg Nusinersen
Number of subjects analysed	2	32
Units: centimeters (cm)
arithmetic mean (standard deviation)	7.2 ( 1.70 )	0.8 ( 3.12 )

No statistical analyses for this end point

Primary: Parts A and C: Number of Participants With Shifts from Baseline in Coagulation Parameters (Activated Partial Thromboplastin Time (aPTT))

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End point title

Parts A and C: Number of Participants With Shifts from Baseline in Coagulation Parameters (Activated Partial Thromboplastin Time (aPTT)) ^[27] ^[28]

End point description

Activated partial thromboplastin time was evaluated to assess safety. "Shift to low" measured change in normal, high and unknown values of aPTT at baseline to low values postbaseline. "Shift to high" measured change in normal, high and unknown values of aPTT at baseline to high values postbaseline. Part A: Safety set included all participants who received at least one dose of nusinersen. Part C:ITT set included all participants who received at least one a dose of nusinersen in the current study. ‘Number analysed (n)' signifies number of participants evaluable for this outcome measure

End point type

Primary

End point timeframe

Parts A and C: Baseline up to Day 269

Notes
[27] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only descriptive statistics were planned for this endpoint.
[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: Parts A and C arms were planned to be analysed for this end point.

End point values	Part A: 28/28 Milligrams (mg) Nusinersen	Part C: 50/28 mg Nusinersen
Number of subjects analysed	6	40
Units: participants
Shift to Low (n=6,40)	0	5
Shift to High (n=5,36)	0	1

No statistical analyses for this end point

Primary: Parts A and C: Change From Baseline in Growth Parameters (Weight for Age Percentile)

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End point title

Parts A and C: Change From Baseline in Growth Parameters (Weight for Age Percentile) ^[29] ^[30]

End point description

WHO child growth standards (WHO Child Growth Standards, 2006) was used to calculate the weight for age percentile in the infantile-onset participants. The 2000 CDC Growth Charts was used to calculate the weight for age percentile for later-onset participants. Part A: Safety set included all participants who received at least one dose of nusinersen. Part C:ITT set included all participants who received at least one dose of nusinersen in the current study. ‘Subjects analysed' signifies number of participants evaluable in this endpoint.

End point type

Primary

End point timeframe

Parts A and C: Baseline, Day 302

Notes
[29] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only descriptive statistics were planned for this endpoint.
[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: Parts A and C arms were planned to be analysed for this end point.

End point values	Part A: 28/28 Milligrams (mg) Nusinersen	Part C: 50/28 mg Nusinersen
Number of subjects analysed	6	17
Units: percentile
arithmetic mean (standard deviation)	12.2 ( 12.84 )	-2.7 ( 9.47 )

No statistical analyses for this end point

Primary: Parts A and C: Change From Baseline in Growth Parameters (Weight for Length Ratio)

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End point title

Parts A and C: Change From Baseline in Growth Parameters (Weight for Length Ratio) ^[31] ^[32]

End point description

Part A: Safety set included all participants who received at least one dose of nusinersen. Part C:ITT set included all participants who received at least one dose of nusinersen in the current study.

End point type

Primary

End point timeframe

Parts A and C: Baseline, Day 302

Notes
[31] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only descriptive statistics were planned for this endpoint.
[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: Parts A and C arms were planned to be analysed for this end point.

End point values	Part A: 28/28 Milligrams (mg) Nusinersen	Part C: 50/28 mg Nusinersen
Number of subjects analysed	0 ^[33]	0 ^[34]
Units: ratio
arithmetic mean (standard deviation)	( )	( )

Notes
[33] - As the number of subjects analyzed was zero, mean and SD was not calculated.
[34] - As the number of subjects analyzed was zero, mean and SD was not calculated.

No statistical analyses for this end point

Primary: Parts A and C: Number of Participants With Shifts From Baseline in Coagulation Parameters (Prothrombin Time (PT))

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End point title

Parts A and C: Number of Participants With Shifts From Baseline in Coagulation Parameters (Prothrombin Time (PT)) ^[35] ^[36]

End point description

 Prothrombin time was evaluated to assess safety. "Shift to low" measured change in normal, high and unknown values of  PT at baseline to low values postbaseline. "Shift to high" measured change in normal, high and unknown values of PT at baseline to high values postbaseline. Part A: Safety set included all participants who received at least one dose of nusinersen. Part C:ITT set included all participants who received at least one a dose of nusinersen in the current study. ‘Number analysed (n)' signifies number of participants evaluable for this outcome measure.

End point type

Primary

End point timeframe

Parts A and C: Baseline up to Day 269

Notes
[35] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only descriptive statistics were planned for this endpoint.
[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: Parts A and C arms were planned to be analysed for this end point.

End point values	Part A: 28/28 Milligrams (mg) Nusinersen	Part C: 50/28 mg Nusinersen
Number of subjects analysed	6	40
Units: participants
Shift to Low (n=6,34)	0	0
Shift to High (n=6,32)	0	1

No statistical analyses for this end point

Primary: Part C: Change From Baseline in Growth Parameters (Head-to-Chest Circumference Ratio)

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End point title

Part C: Change From Baseline in Growth Parameters (Head-to-Chest Circumference Ratio) ^[37] ^[38]

End point description

As pre-specified in the protocol, head to chest circumference ratio was assessed only for the participants with infantile-onset SMA. ‘99999’ signiﬁes that since one or no participant was evaluable, standard deviation (SD) was not estimated. ITT set included all participants who received at least one dose of nusinersen in the current study. ‘Subjects analysed' signifies number of participants evaluable in this endpoint.

End point type

Primary

End point timeframe

Baseline, Day 302

Notes
[37] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only descriptive statistics were planned for this endpoint.
[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: Part C arm was planned to be analysed for this end point.

End point values	Part C: 50/28 mg Nusinersen
Number of subjects analysed	1
Units: ratio
arithmetic mean (standard deviation)	0.0 ( 99999 )

No statistical analyses for this end point

Primary: Parts A and C: Number of Participants With Shifts From Baseline in Coagulation Parameters (International Normalized Ratio (INR))

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End point title

Parts A and C: Number of Participants With Shifts From Baseline in Coagulation Parameters (International Normalized Ratio (INR)) ^[39] ^[40]

End point description

INR was evaluated to assess safety. "Shift to low" measured change in normal, high and unknown values of INR at baseline to low values postbaseline. "Shift to high" measured change in normal, high and unknown values of  INR  at baseline to high values postbaseline. The category with at least one participant with shift from baseline in INR ratio is reported. Part A: Safety set included all participants who received at least one dose of nusinersen. Part C:ITT set included all participants who received at least one a dose of nusinersen in the current study. ‘Number analysed (n)' signifies number of participants evaluable for this outcome measure.

End point type

Primary

End point timeframe

Parts A and C: Baseline up to Day 269

Notes
[39] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only descriptive statistics were planned for this endpoint.
[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: Parts A and C arms were planned to be analysed for this end point.

End point values	Part A: 28/28 Milligrams (mg) Nusinersen	Part C: 50/28 mg Nusinersen
Number of subjects analysed	6	40
Units: participants
Shift to Low (n=6,40)	0	3
Shift to High (n=6,39)	0	0

No statistical analyses for this end point

Primary: Parts A and C: Change From Baseline in Urine Total Protein

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End point title

Parts A and C: Change From Baseline in Urine Total Protein ^[41] ^[42]

End point description

Part A: Safety set included all participants who received at least one dose of nusinersen. Part C:ITT set included all participants who received at least one dose of nusinersen in the current study. 'Subjects analysed' signifies number of participants evaluable in this endpoint.

End point type

Primary

End point timeframe

Parts A and C: Baseline, Day 302

Notes
[41] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only descriptive statistics were planned for this endpoint.
[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: Parts A and C arms were planned to be analysed for this end point.

End point values	Part A: 28/28 Milligrams (mg) Nusinersen	Part C: 50/28 mg Nusinersen
Number of subjects analysed	3	29
Units: grams per liter (g/L)
arithmetic mean (standard deviation)	0.010 ( 0.1235 )	-0.692 ( 3.7040 )

No statistical analyses for this end point

Primary: Parts A and C: Number of Participants With Neurological Examination Abnormalities Reported as AEs

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End point title

Parts A and C: Number of Participants With Neurological Examination Abnormalities Reported as AEs ^[43] ^[44]

End point description

Participants with abnormalities in neurological examinations recorded as AEs were reported.

End point type

Primary

End point timeframe

Parts A and C: Baseline up to Day 302

Notes
[43] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only descriptive statistics were planned for this endpoint.
[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: Parts A and C arms were planned to be analysed for this end point.

End point values	Part A: 28/28 Milligrams (mg) Nusinersen	Part C: 50/28 mg Nusinersen
Number of subjects analysed	6	40
Units: participants
number (not applicable)
Vestibular Disorder	0	1
Asthenia	0	1
Gait Disturbance	0	1
Balance Disorder	0	1
Disturbance in Attention	0	1
Paraesthesia	1	0

No statistical analyses for this end point

Primary: Parts A and C: Percentage of Participants With a Postbaseline Corrected QT Interval Using Fridericia's Formula (QTcF) of > 500 milliseconds (msec) and an Increase From Baseline to any Postbaseline Timepoint in QTcF of > 60 msec

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End point title

Parts A and C: Percentage of Participants With a Postbaseline Corrected QT Interval Using Fridericia's Formula (QTcF) of > 500 milliseconds (msec) and an Increase From Baseline to any Postbaseline Timepoint in QTcF of > 60 msec ^[45] ^[46]

End point description

As a part of safety assessment, QTcF was evaluated for determining the incidence of clinically relevant abnormalities. Post baseline QTcF of > 500 msec and maximum increase from baseline to post baseline QTcF > 60 msec was considered as a criteria for clinically relevant abnormality in ECG. Part A: Safety set included all participants who received at least one dose of nusinersen. Part C:ITT set included all participants who received at least one dose of nusinersen in the current study. 'Subjects analysed' signifies number of participants evaluable in this endpoint.

End point type

Primary

End point timeframe

Parts A and C: Baseline up to Day 302

Notes
[45] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only descriptive statistics were planned for this endpoint.
[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: Parts A and C arms were planned to be analysed for this end point.

End point values	Part A: 28/28 Milligrams (mg) Nusinersen	Part C: 50/28 mg Nusinersen
Number of subjects analysed	6	39
Units: percentage of participants
number (not applicable)
Maximum Increase from Baseline QTcF>60msec	0	0
Maximum Post Baseline QTcF > 500 msec	0	0

No statistical analyses for this end point

Primary: Parts A and C: Percentage of Participants With a Postbaseline Platelet Count Below the Lower Limit of Normal on at Least 2 Consecutive Measurements

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End point title

Parts A and C: Percentage of Participants With a Postbaseline Platelet Count Below the Lower Limit of Normal on at Least 2 Consecutive Measurements ^[47] ^[48]

End point description

Part A: Safety set included all participants who received at least one dose of nusinersen. Part C:ITT set included all participants who received at least one a dose of nusinersen in the current study.

End point type

Primary

End point timeframe

Parts A and C: Baseline up to Day 302

Notes
[47] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only descriptive statistics were planned for this endpoint.
[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: Parts A and C arms were planned to be analysed for this end point.

End point values	Part A: 28/28 Milligrams (mg) Nusinersen	Part C: 50/28 mg Nusinersen
Number of subjects analysed	6	40
Units: percentage of participants
number (not applicable)	0	2.5

No statistical analyses for this end point

Secondary: Part B Infantile-onset SMA: Percentage of Hammersmith Infant Neurological Examination (HINE) Section 2 Motor Milestone Responders for 50/28mg Nusinersen Versus CS3B Matched Sham Control Group

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End point title

Part B Infantile-onset SMA: Percentage of Hammersmith Infant Neurological Examination (HINE) Section 2 Motor Milestone Responders for 50/28mg Nusinersen Versus CS3B Matched Sham Control Group ^[49]

End point description

Section 2 of HINE was used to assess motor milestones of participants. It’s composed of 8 motor milestone categories: voluntary grasp, ability to kick in supine position, head control, rolling, sitting, crawling, standing, & walking. Motor milestone responder: a participant that demonstrated atleast a 2-point increase in ability to kick category or increase to maximal score on that category or a 1-point increase in motor milestones category of head control, rolling, sitting, crawling, standing, or walking & demonstrated improvement in more categories than worsening. Participants who died or withdrew from study were considered as non-responders. A matched sham set was defined per protocol for analysis of this outcome measure. Matched sham set comprised of sham control participants of CS3B study (2013-004422-29) identified by a matching algorithm& all of 50/28 mg participants in the ITT set.

End point type

Secondary

End point timeframe

Baseline up to Day 183

Notes
[49] - 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: Part B Infantile-onset SMA arms were planned to be analysed for this end point.

End point values	Part B: Infantile-Onset SMA: 50/28 mg Nusinersen	CS3B Matched Sham Control Group
Number of subjects analysed	41	9
Units: percentage of responders
number (not applicable)
Ability to kick: At least a 2-point increase	18	0
Ability to kick: Achievement of touching toes	8	0
Head control: at least a 1-point increase	46	0
Rolling: at least a 1-point increase	28	0
Sitting: at least a 1-point increase	30	0
Crawling: at least a 1-point increase	6	0
Standing: at least a 1-point increase	14	0
Walking: at least a 1-point increase	0	0
Improvement in more categories than worsening	58	0

No statistical analyses for this end point

Secondary: Part B Infantile-onset SMA: Change From Baseline in CHOP-INTEND Total Score for 50/28mg Nusinersen Versus 12/12mg Nusinersen

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End point title

Part B Infantile-onset SMA: Change From Baseline in CHOP-INTEND Total Score for 50/28mg Nusinersen Versus 12/12mg Nusinersen ^[50]

End point description

The CHOP-INTEND test was designed to evaluate the motor skills of infants with signiﬁcant motor weakness. It included 16 items (capturing neck, trunk, and proximal and distal limb strength), nine of which were scored 0, 1, 2, 3, or 4, ﬁve were scored as 0, 2, or 4, one was scored as 0, 1, 2, or 4, and one as 0, 2, 3, or 4 with greater scores indicating greater muscle strength. Total scores ranged from 0 (worst possible score) and 64 (best possible score). The change from baseline to Day 302 in the CHOP-INTEND total score was analyzed using the joint-rank methodology to account for mortality. ITT set included all participants who were randomized and received at least one dose of nusinersen.

End point type

Secondary

End point timeframe

Baseline, Day 302

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: Part B Infantile-onset SMA arms were planned to be analysed for this end point.

End point values	Part B: Infantile-Onset SMA: 12/12 mg Nusinersen	Part B: Infantile-Onset SMA: 50/28 mg Nusinersen
Number of subjects analysed	25	50
Units: score on scale
least squares mean (confidence interval 95%)	37.3 (29.1 to 45.5)	38.3 (32.7 to 44.0)

Change From Baseline in CHOP INTEND Total Score

Comparison groups

Part B: Infantile-Onset SMA: 12/12 mg Nusinersen v Part B: Infantile-Onset SMA: 50/28 mg Nusinersen

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.8484 ^[51]

Method

ANCOVA

Parameter type

Least squares mean difference

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-9.29

upper limit

11.299

Variability estimate

Standard error of the mean

Dispersion value

5.251

Notes
[51] - ANCOVA model used rank score as response, treatment as fixed effect and disease duration at screening, baseline HINE 2, baseline CHOP INTEND total score as covariates. Rank score of baseline covariates was used in model.

Secondary: Part B Infantile-onset SMA: Change From (Ratio to) Baseline in Plasma Concentration of Neurofilament Light Chain (NF-L) for 50/28mg Nusinersen Versus CS3B Matched Sham Control Group

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End point title

Part B Infantile-onset SMA: Change From (Ratio to) Baseline in Plasma Concentration of Neurofilament Light Chain (NF-L) for 50/28mg Nusinersen Versus CS3B Matched Sham Control Group ^[52]

End point description

The change from baseline in the plasma concentration of NF-L was compared to the study CS3B (2013-004422-29) matched sham control group. Joint rank methodology was used for the analysis to account for mortality. The change from baseline data was reported in terms of least square geometric mean ratio to baseline. Lower ratios to baseline represent greater reductions in concentrations of NF-L from baseline. As stated in protocol a matched sham set was defined for the analysis of this outcome measure. Matched sham set comprised of sham control participants of the CS3B study (2013-004422-29) identified by a matching algorithm and all of 50/28 mg participants in the ITT set.

End point type

Secondary

End point timeframe

Baseline, Day 183

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: Part B Infantile-onset SMA arms were planned to be analysed for this end point.

End point values	Part B: Infantile-Onset SMA: 50/28 mg Nusinersen	CS3B Matched Sham Control Group
Number of subjects analysed	50	20
Units: ratio
least squares mean (confidence interval 95%)	0.06 (0.05 to 0.06)	0.70 (0.43 to 1.12)

Change From Baseline in NF-L Plasma Concentration

Comparison groups

Part B: Infantile-Onset SMA: 50/28 mg Nusinersen v CS3B Matched Sham Control Group

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[53]

Method

ANCOVA

Parameter type

LS geometric mean ratio

Point estimate

0.08

Confidence interval

level

95%

sides

2-sided

lower limit

0.05

upper limit

0.14

Notes
[53] - ANCOVA model was used with treatment as a fixed effect and adjustment for each participant disease duration at screening, baseline log plasma NF-L and baseline CHOP INTEND total score.

Secondary: Part B Infantile-onset SMA: Change From Baseline in HINE Section 2 Motor Milestones Total Score for 50/28mg Nusinersen Versus CS3B Matched Sham Control Group

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End point title

Part B Infantile-onset SMA: Change From Baseline in HINE Section 2 Motor Milestones Total Score for 50/28mg Nusinersen Versus CS3B Matched Sham Control Group ^[54]

End point description

Section 2 of the HINE was used to assess motor milestones of the participants. It’s composed of 8 motor milestone categories: voluntary grasp, ability to kick in supine position, head control, rolling, sitting, crawling, standing, and walking. Within each category, 3 to 5 levels can be achieved. The total HINE section 2 motor milestones score was calculated as sum of each level & ranged from 0 to 26, higher score indicating improvement in motor milestones. A negative change from baseline indicates decline in motor milestones.Change from baseline in HINE section 2 motor milestones total score was compared to study CS3B (2013-004422-29) matched sham control group, was analysed using joint rank methodology. As stated in protocol a matched sham set was defined for analysis of this outcome measure. Matched sham set comprised of sham control participants of CS3B study (2013-004422-29) identified by a matching algorithm and all of 50/28 mg participants in ITT set.

End point type

Secondary

End point timeframe

Baseline, Day 183

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: Part B Infantile-onset SMA arms were planned to be analysed for this end point.

End point values	Part B: Infantile-Onset SMA: 50/28 mg Nusinersen	CS3B Matched Sham Control Group
Number of subjects analysed	50	20
Units: score on scale
least squares mean (confidence interval 95%)	43.1 (39.0 to 47.2)	16.5 (9.9 to 23.0)

Change From Baseline in HINE Section Total Score

Comparison groups

Part B: Infantile-Onset SMA: 50/28 mg Nusinersen v CS3B Matched Sham Control Group

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[55]

Method

ANCOVA

Parameter type

Least squares mean difference

Point estimate

26.67

Confidence interval

level

95%

sides

2-sided

lower limit

18.812

upper limit

34.526

Variability estimate

Standard error of the mean

Dispersion value

4.009

Notes
[55] - ANCOVA model was used, rank score as response, treatment as fixed effect and disease duration at screening, baseline HINE 2, baseline CHOP INTEND total score as covariates. Rank score of baseline covariates was used in model.

Secondary: Part B Infantile-onset SMA: Change From Baseline in HINE Section 2 Motor Milestones Total Score for 50/28mg Nusinersen Versus 12/12mg Nusinersen

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End point title

Part B Infantile-onset SMA: Change From Baseline in HINE Section 2 Motor Milestones Total Score for 50/28mg Nusinersen Versus 12/12mg Nusinersen ^[56]

End point description

Section 2 of the HINE was used to assess motor milestones of the participants. It’s composed of 8 motor milestone categories: voluntary grasp, ability to kick in supine position, head control, rolling, sitting, crawling, standing, and walking. Within each of these categories, participants can progress from complete absence of a motor ability (the lowest level in each category) through multiple milestones (2 to 4 levels in each category) to the highest level within the category. The total motor milestones score for HINE section was calculated as the sum of each level and ranged from 0 to a maximum score of 26, higher score indicating improvement in motor milestones. ITT set included all participants who were randomized and received at least one dose of nusinersen.

End point type

Secondary

End point timeframe

Baseline, Day 302

Notes
[56] - 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: Part B Infantile-onset SMA arms were planned to be analysed for this end point.

End point values	Part B: Infantile-Onset SMA: 12/12 mg Nusinersen	Part B: Infantile-Onset SMA: 50/28 mg Nusinersen
Number of subjects analysed	25	50
Units: score on scale
least squares mean (confidence interval 95%)	33.9 (26.9 to 41.0)	40.0 (35.1 to 44.9)

Change From Baseline in HINE Section Total Score

Comparison groups

Part B: Infantile-Onset SMA: 12/12 mg Nusinersen v Part B: Infantile-Onset SMA: 50/28 mg Nusinersen

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.1734 ^[57]

Method

ANCOVA

Parameter type

Least squares mean difference

Point estimate

6.12

Confidence interval

level

95%

sides

2-sided

lower limit

-2.693

upper limit

14.939

Variability estimate

Standard error of the mean

Dispersion value

4.497

Notes
[57] - ANCOVA model used rank score as response, treatment as fixed effect and disease duration at screening, baseline HINE 2, baseline CHOP INTEND total score as covariates. Rank score of baseline covariates was used in model.

Secondary: Part B Infantile-onset SMA: Time to Death or Permanent Ventilation for 50/28mg Nusinersen Versus CS3B Matched Sham Control Group

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End point title

Part B Infantile-onset SMA: Time to Death or Permanent Ventilation for 50/28mg Nusinersen Versus CS3B Matched Sham Control Group ^[58]

End point description

Permanent ventilation was deﬁned as tracheostomy or ≥ 16 hours of ventilation/day continuously for > 21 days in absence of an acute reversible event. An independent endpoint adjudication committee (EAC) determined date at which a participant was considered to have met protocol-specified criteria of an acute reversible event. Only events that were adjudicated by the EAC as meeting the criteria for permanent ventilation or death were included in analysis. As stated in protocol a matched sham set was defined for analysis of this outcome measure. Matched sham set comprised of sham control participants of the CS3B study (2013-004422-29) identified by a matching algorithm and all of 50/28 mg participants in the ITT set. ‘99999’ signifies that median and upper range of 95% confidence interval (CI) were not estimable due to low number events of permanent ventilation or death.

End point type

Secondary

End point timeframe

Screening up to Day 399

Notes
[58] - 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: Part B Infantile-onset SMA arms were planned to be analysed for this end point.

End point values	Part B: Infantile-Onset SMA: 50/28 mg Nusinersen	CS3B Matched Sham Control Group
Number of subjects analysed	50	20
Units: weeks
median (confidence interval 95%)	99999 (39.86 to 99999)	19.1 (10.00 to 31.29)

No statistical analyses for this end point

Secondary: Part B Infantile-onset SMA: Change From (Ratio to) Baseline in Plasma Concentration of NF-L for 50/28mg Nusinersen Versus 12/12mg Nusinersen

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End point title

Part B Infantile-onset SMA: Change From (Ratio to) Baseline in Plasma Concentration of NF-L for 50/28mg Nusinersen Versus 12/12mg Nusinersen ^[59]

End point description

The change from baseline in plasma concentration of NF-L was analysed using the joint rank methodology to account for mortality. The change from baseline data was reported in terms of LS geometric mean ratio to baseline. Lower ratios to baseline represent greater reductions in concentrations of NF-L from baseline. ITT set included all participants who were randomized and received at least one dose of nusinersen.

End point type

Secondary

End point timeframe

Baseline, Day 64

Notes
[59] - 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: Part B Infantile-onset SMA arms were planned to be analysed for this end point.

End point values	Part B: Infantile-Onset SMA: 12/12 mg Nusinersen	Part B: Infantile-Onset SMA: 50/28 mg Nusinersen
Number of subjects analysed	25	50
Units: ratio
least squares mean (confidence interval 95%)	0.23 (0.16 to 0.32)	0.12 (0.09 to 0.15)

Change From Baseline in NF-L Plasma Concentration

Comparison groups

Part B: Infantile-Onset SMA: 12/12 mg Nusinersen v Part B: Infantile-Onset SMA: 50/28 mg Nusinersen

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.002 ^[60]

Method

ANCOVA

Parameter type

LS geometric mean ratio

Point estimate

0.51

Confidence interval

level

95%

sides

2-sided

lower limit

0.33

upper limit

0.78

Notes
[60] - ANCOVA model was used with treatment as a fixed effect and adjustment for each participant disease duration at screening, baseline log plasma NF-L and baseline CHOP INTEND total score.

Secondary: Part B Infantile-onset SMA: Time to Death or Permanent Ventilation for 50/28mg Nusinersen Versus 12/12mg Nusinersen

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End point title

Part B Infantile-onset SMA: Time to Death or Permanent Ventilation for 50/28mg Nusinersen Versus 12/12mg Nusinersen ^[61]

End point description

Permanent ventilation was deﬁned as tracheostomy or ≥ 16 hours of ventilation/day continuously for > 21 days in the absence of an acute reversible event. An independent EAC determined the date at which a participant was considered to have met the protocol-specified criteria of an acute reversible event. Only events that were adjudicated by the EAC as meeting the protocol defined criteria for permanent ventilation or death was included in the analysis. ITT set included all participants who were randomized and received at least one dose of nusinersen. ‘ 99999’ signifies that median or upper range of 95% confidence interval (CI) were not estimable due to low number events of permanent ventilation or death.

End point type

Secondary

End point timeframe

Screening up to Day 399

Notes
[61] - 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: Part B Infantile-onset SMA arms were planned to be analysed for this end point.

End point values	Part B: Infantile-Onset SMA: 12/12 mg Nusinersen	Part B: Infantile-Onset SMA: 50/28 mg Nusinersen
Number of subjects analysed	25	50
Units: weeks
median (confidence interval 95%)	24.7 (14.43 to 99999)	99999 (39.86 to 99999)

No statistical analyses for this end point

Secondary: Part B Infantile-onset SMA: Time to Death (Overall Survival) for 50/28mg Nusinersen Versus CS3B Matched Sham Control Group

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End point title

Part B Infantile-onset SMA: Time to Death (Overall Survival) for 50/28mg Nusinersen Versus CS3B Matched Sham Control Group ^[62]

End point description

Time to death was determined by an independent EAC. Time to death (overall survival) was compared to the study CS3B (2013-004422-29) matched sham control group. As stated in protocol a matched sham set was defined for the analysis of this outcome measure. Matched sham set comprised of sham control participants of the CS3B study (2013-004422-29) identified by a matching algorithm and all of 50/28 mg participants in the ITT set. ‘99999’ signifies that median and 95% CI were not estimable due to low number of events of death.

End point type

Secondary

End point timeframe

Screening up to Day 399

Notes
[62] - 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: Part B Infantile-onset SMA arms were planned to be analysed for this end point.

End point values	Part B: Infantile-Onset SMA: 50/28 mg Nusinersen	CS3B Matched Sham Control Group
Number of subjects analysed	50	20
Units: weeks
median (confidence interval 95%)	99999 (99999 to 99999)	33.6 (11.29 to 99999)

No statistical analyses for this end point

Secondary: Part B Later-onset SMA: Change From Baseline in Hammersmith Functional Motor Scale Expanded (HFMSE) Score for 50/28mg Nusinersen Versus 12/12mg Nusinersen

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End point title

Part B Later-onset SMA: Change From Baseline in Hammersmith Functional Motor Scale Expanded (HFMSE) Score for 50/28mg Nusinersen Versus 12/12mg Nusinersen ^[63]

End point description

HFMSE scale was a tool used to assess motor function in children with later-onset SMA. The original 20 item Hammersmith Functional Motor Scale was expanded to include 13 additional adapted items from the Gross Motor Function Measure to improve sensitivity for the higher functioning ambulant population. Each item is scored 0 (unable), 1 (performs with modiﬁcation or adaptation) or 2 (able) and the total score was calculated by summing the 33 items and ranged from 0 to 66 with higher scores indicating greater motor function. ITT set included all participants who were randomized and received at least one dose of nusinersen. ‘Subjects analysed' signifies number of participants evaluable in this endpoint.

End point type

Secondary

End point timeframe

Baseline, Day 302

Notes
[63] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Part B Later-onset SMA arms were planned to be analysed for this end point.

End point values	Part B: Later-Onset SMA: 12/12 mg Nusinersen	Part B: Later-Onset SMA: 50/28 mg Nusinersen
Number of subjects analysed	7	15
Units: score on scale
least squares mean (confidence interval 95%)	2.6 (0.2 to 5.1)	3.3 (1.5 to 5.0)

No statistical analyses for this end point

Secondary: Part B Later-onset SMA: Change From Baseline in Revised Upper Limb Module (RULM) Score for 50/28mg Nusinersen Versus 12/12mg Nusinersen

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End point title

Part B Later-onset SMA: Change From Baseline in Revised Upper Limb Module (RULM) Score for 50/28mg Nusinersen Versus 12/12mg Nusinersen ^[64]

End point description

The RULM test was used in participants with later-onset SMA to assess upper limb functional ability items that are reﬂective of activities of daily living (i.e., raise a can to mouth as if drinking, take a coin and place it in a box, remove the lid of a container). The RULM test had a total of 20 items with an entry item that served as functional class identiﬁcation and did not contribute to the total score. The remaining 19 scorable items reflected different functional domains and were graded on a 3-point system with a score of 0 (unable), 1 (able, with modiﬁcation), and a maximum of 2 (able, no difficulty). Scorable items were summed for a total score range of 0-37, with higher scores indicating increased upper limb function. ITT set included all participants who were randomized and received at least one dose of nusinersen. ‘Subjects analysed' signifies number of participants evaluable at the specified timepoint.

End point type

Secondary

End point timeframe

Baseline, Day 302

Notes
[64] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Part B Later-onset SMA arms were planned to be analysed for this end point.

End point values	Part B: Later-Onset SMA: 12/12 mg Nusinersen	Part B: Later-Onset SMA: 50/28 mg Nusinersen
Number of subjects analysed	7	16
Units: score on scale
least squares mean (confidence interval 95%)	1.8 (-0.8 to 4.4)	2.5 (0.7 to 4.2)

No statistical analyses for this end point

Secondary: Part B Infantile-onset SMA: Time to Death (Overall Survival) for 50/28mg Nusinersen Versus 12/12mg Nusinersen

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End point title

Part B Infantile-onset SMA: Time to Death (Overall Survival) for 50/28mg Nusinersen Versus 12/12mg Nusinersen ^[65]

End point description

Time to death was determined by an independent EAC. ITT set included all participants who were randomized and received at least one dose of nusinersen. ‘99999’ signifies that median and 95% CI was not estimable due to low number events of death.

End point type

Secondary

End point timeframe

Screening up to Day 399

Notes
[65] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Part B Infantile-onset SMA arms were planned to be analysed for this end point.

End point values	Part B: Infantile-Onset SMA: 12/12 mg Nusinersen	Part B: Infantile-Onset SMA: 50/28 mg Nusinersen
Number of subjects analysed	25	50
Units: weeks
median (confidence interval 95%)	99999 (24.71 to 99999)	99999 (99999 to 99999)

No statistical analyses for this end point

Secondary: Part B Later-onset SMA: Number of New World Health Organization (WHO) Motor Milestones for 50/28mg Nusinersen Versus 12/12mg Nusinersen

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End point title

Part B Later-onset SMA: Number of New World Health Organization (WHO) Motor Milestones for 50/28mg Nusinersen Versus 12/12mg Nusinersen ^[66]

End point description

The WHO motor milestones were a set of six milestones in motor development: sitting without support, standing with assistance, hands and knees crawling, walking with assistance, standing alone and walking alone. The examiner recorded an overall rating of the participant’s emotional state and then for each milestone one of the following four classiﬁcations: no (inability) - child tried but failed to perform the milestone, no (refusal) - child refused to perform despite being calm and alert, yes - child was able to perform the milestone, unable to test - could not be tested because of irritability, drowsiness or sickness. Mean of number of new milestones achieved was calculated and reported in this outcome measure. ITT set included all participants who were randomized and received at least one dose of nusinersen. ‘Subjects analysed' signifies number of participants evaluable for this outcome measure.

End point type

Secondary

End point timeframe

Baseline up to Day 302

Notes
[66] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Part B Later-onset SMA arms were planned to be analysed for this end point.

End point values	Part B: Later-Onset SMA: 12/12 mg Nusinersen	Part B: Later-Onset SMA: 50/28 mg Nusinersen
Number of subjects analysed	7	16
Units: motor milestones
arithmetic mean (standard deviation)	0.0 ( 0.00 )	0.3 ( 1.00 )

No statistical analyses for this end point

Secondary: Part B Later-onset SMA: Change From Baseline in Assessment of Caregiver Experience with Neuromuscular Disease (ACEND) for 50/28mg Nusinersen Versus 12/12mg Nusinersen

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End point title

Part B Later-onset SMA: Change From Baseline in Assessment of Caregiver Experience with Neuromuscular Disease (ACEND) for 50/28mg Nusinersen Versus 12/12mg Nusinersen ^[67]

End point description

This assessment instrument was designed to quantify the caregiver impact experienced by parents/caregivers of children affected with severe neuromuscular diseases, including children with SMA. ACEND included domains assessing physical impact (including feeding/grooming/dressing, sitting/play, transfers, and mobility) and general caregiver impact (including time, emotion, and finance) and each domain comprises several items. The total score ranges from 0 to 100 with a higher score indicating decreased caregiver burden A negative change from baseline indicates an increase in impact on caregiver. ITT set included all participants who were randomized and received at least one dose of nusinersen. ‘Subjects analysed' signiﬁes number of participants evaluable for the specified parameter.

End point type

Secondary

End point timeframe

Baseline, Day 302

Notes
[67] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Part B Later-onset SMA arms were planned to be analysed for this end point.

End point values	Part B: Later-Onset SMA: 12/12 mg Nusinersen	Part B: Later-Onset SMA: 50/28 mg Nusinersen
Number of subjects analysed	7	16
Units: score on scale
least squares mean (confidence interval 95%)
Feeding/Grooming/Dressing Total Score	7.9 (-4.8 to 20.6)	8.3 (-0.2 to 16.7)
Sitting/Play Total Score	10.3 (0.6 to 20.0)	10.1 (3.6 to 16.6)
Transfers Total Score	-0.0 (-10.9 to 10.9)	9.9 (2.6 to 17.2)
Mobility Total Score	6.9 (-7.2 to 20.9)	8.1 (-0.9 to 17.0)
Time Total Score	-4.4 (-17.9 to 9.2)	11.9 (2.9 to 20.9)
Emotion Total Score	2.6 (-8.7 to 13.9)	2.5 (-5.0 to 10.0)
Finance Total Score	-7.7 (-20.9 to 5.6)	7.8 (-0.7 to 31.7)

No statistical analyses for this end point

Secondary: Part B Later-onset SMA: Change From (Ratio to) Baseline in CSF Concentration of NF-L for 50/28mg Nusinersen Versus 12/12mg Nusinersen

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End point title

Part B Later-onset SMA: Change From (Ratio to) Baseline in CSF Concentration of NF-L for 50/28mg Nusinersen Versus 12/12mg Nusinersen ^[68]

End point description

The change from baseline data was reported in terms of geometric mean ratio to baseline. Lower ratios to baseline represent greater reductions in concentrations of NF-L from baseline. ITT set included all participants who were randomized and received at least one dose of nusinersen. ‘Subjects analysed' signifies number of participants evaluable in this endpoint.

End point type

Secondary

End point timeframe

Baseline, Day 279

Notes
[68] - 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: Part B Later-onset SMA arms were planned to be analysed for this end point.

End point values	Part B: Later-Onset SMA: 12/12 mg Nusinersen	Part B: Later-Onset SMA: 50/28 mg Nusinersen
Number of subjects analysed	7	16
Units: pg/mL
geometric mean (confidence interval 95%)	0.34 (0.23 to 0.50)	0.34 (0.25 to 0.45)

No statistical analyses for this end point

Secondary: Part B Later-onset SMA: Change From (Ratio to) Baseline in Plasma Concentration of NF-L for 50/28mg Nusinersen Versus 12/12mg Nusinersen

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End point title

Part B Later-onset SMA: Change From (Ratio to) Baseline in Plasma Concentration of NF-L for 50/28mg Nusinersen Versus 12/12mg Nusinersen ^[69]

End point description

End point type

Secondary

End point timeframe

Baseline, Day 302

Notes
[69] - 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: Part B Later-onset SMA arms were planned to be analysed for this end point.

End point values	Part B: Later-Onset SMA: 12/12 mg Nusinersen	Part B: Later-Onset SMA: 50/28 mg Nusinersen
Number of subjects analysed	5	16
Units: pg/mL
geometric mean (confidence interval 95%)	0.28 (0.14 to 0.56)	0.35 (0.24 to 0.51)

No statistical analyses for this end point

Secondary: Part B Later-onset SMA: Change From Baseline in Pediatric Quality of Life Inventory™ (PedsQL) for 50/28mg Nusinersen Versus 12/12mg Nusinersen

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End point title

Part B Later-onset SMA: Change From Baseline in Pediatric Quality of Life Inventory™ (PedsQL) for 50/28mg Nusinersen Versus 12/12mg Nusinersen ^[70]

End point description

PedsQL was used to measure health related quality of life (HRQOL) in children & adolescents. PedsQL generic core scale included assessment of physical functioning, emotional functioning, social functioning, and school functioning [PedsQL Inventory total score (PQLI)] and PedsQL Neuromuscular Module [Neuromuscular total score (PQLN)] measured HRQOL dimensions specific to with neuromuscular disorders, including SMA. Four dimensions were collected,each item scored on a 5-point ordinal scale (0=Never to 4=Almost Always). Items were reversed scored and were linearly transformed to a 0-100 scale. Total scale score was calculated as sum of all items over number of items answered on all scales. If more than 50% of items or more were missing, scale score was not computed. Higher scores indicated better health related quality of life. ITT set. Subjects analysed: number of participants evaluable for this endpoint. ‘Number analysed (n)':number of participants evaluable for this endpoint.

End point type

Secondary

End point timeframe

Baseline, Day 302

Notes
[70] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Part B Later-onset SMA arms were planned to be analysed for this end point.

End point values	Part B: Later-Onset SMA: 12/12 mg Nusinersen	Part B: Later-Onset SMA: 50/28 mg Nusinersen
Number of subjects analysed	7	16
Units: score on scale
least squares mean (standard error)
PQLI-Total Score-Subject (n=4,12)	-5.1 ( 4.73 )	3.8 ( 2.61 )
PQLI-Total Score-Parent (n=7,14)	-9.6 ( 4.32 )	-6.9 ( 2.96 )
PQLN-Total Score-Subject (n=4,12)	-4.8 ( 3.41 )	10.4 ( 1.91 )
PQLN-Total Score-Parent (n=7,16)	-6.4 ( 4.25 )	-0.7 ( 2.81 )

No statistical analyses for this end point

Secondary: Part B: Number of Participants with Shifts from Baseline in Clinical Laboratory Parameters (Hematology Parameters)

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End point title

Part B: Number of Participants with Shifts from Baseline in Clinical Laboratory Parameters (Hematology Parameters) ^[71]

End point description

Hematology parameters included complete blood cell count, with diﬀerential and platelet count, and absolute neutrophil count. These parameters were flagged as low, normal, or high relative to parameter’s normal range or as unknown if no result was available, by the Investigator. Here, shift to low indicates values that were normal, high or unknown at baseline and shifted to low values postbaseline. Shift to high indicates values that were normal, low or unknown at baseline and shifted to high postbaseline. The categories with at least one participant with shift from baseline in these parameters are reported. ‘Number analysed (n)' signifies number of participants evaluable for analysis of the specified hematology parameter.

End point type

Secondary

End point timeframe

Baseline up to Day 302

Notes
[71] - 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: Part B Infantile-onset SMA and Part B Later-onset SMA arms were planned to be analysed for this end point.

End point values	Part B: Infantile-Onset SMA: 12/12 mg Nusinersen	Part B: Infantile-Onset SMA: 50/28 mg Nusinersen	Part B: Later-Onset SMA: 12/12 mg Nusinersen	Part B: Later-Onset SMA: 50/28 mg Nusinersen
Number of subjects analysed	25	50	8	16
Units: participants
Basophils Shift to Low (n=22,46,8,16)	0	2	0	0
Basophils Shift to High (n=12,24,5,13)	7	17	4	8
Basophils/Leukocytes Shift to High (n=11,21,4,9)	7	14	3	9
Eosinophils Shift to Low (n=20,47,7,16)	0	7	1	0
Eosinophils Shift to High (n=19,43,5,14)	6	15	0	1
Eosinophil/Leukocyte Shift toLow(n=21,47,8,16)	0	4	0	0
Eosinophil/Leukocyte Shift to High(n=15,28,5,12)	8	12	1	5
Hematocrit Shift to Low (n=20,43,8,16)	6	12	0	2
Hematocrit Shift to High (n=22,47,8,15)	4	10	2	1
Hemoglobin Shift to Low (n=22,45,7,14)	11	18	0	2
Hemoglobin Shift to High (n=23,46,8,16)	3	2	0	0
Lymphocytes Shift to Low (n=22,47,8,16)	3	6	1	1
Lymphocytes Shift to High (n=19,41,7,14)	4	14	2	2
Lymphocyte Atypical Shift to High(n=1,7,8,16)	0	5	0	0
LymphocyteAtypical/LeukocyteShifttoHighn=1,7,8,16	0	4	0	0
Lymphocyte/Leukocyte Shift to Low(n=22,45,8,16)	4	5	1	2
Lymphocyte/Leukocyte Shift to High(n=20,43,7,16)	4	7	3	1
Ery Mean Corpuscular Vol Shift to Lown=5,10,8,16	2	2	0	0
Ery Mean Corpuscular Vol Shift to Highn=4,8,8,16	1	2	0	0
Monocytes Shift to Low (n=22,46,7,15)	5	12	1	6
Monocytes Shift to High (n=20,42,8,16)	5	13	2	2
Monocytes/Leukocytes Shift to Low (n=21,44,6,14)	7	20	1	9
Monocytes/Leukocytes Shift to High n=20,45,8,16	3	9	1	1
Neutrophils Shift to Low (n=19,42,5,16)	5	9	1	2
Neutrophils Shift to High (n=21,46,8,16)	11	13	1	1
Neutrophils/Leukocytes Shift to Low n=19,39,7,16	4	13	4	0
Neutrophils/Leukocytes ShifttoHigh n=21,45,7,16	6	6	1	1
Platelets Shift to Low (n=23,47, 8,16)	1	2	0	1
Platelets Shift to High (n=10,28,6,15)	4	14	1	4
Erythrocytes Shift to Low (n=23,46,6,15	4	10	0	0
Erythrocytes Shift to High (n=22,47,8,13)	3	6	1	0
Leukocytes Shift to Low (n=21,44,8,16)	4	13	2	0
Leukocytes Shift to High (n=21,41,7,15)	10	15	1	2

No statistical analyses for this end point

Secondary: Part B: Number of Participants with TEAEs and TESAEs

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End point title

Part B: Number of Participants with TEAEs and TESAEs ^[72]

End point description

AE was any unfavorable and unintended sign (including an abnormal assessment such as an abnormal laboratory value), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product. An SAE was any untoward medical occurrence that at any dose resulted in death, in the view of the Investigator, placed the participant at immediate risk of death, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, resulted in a birth defect. AE was regarded as treatment-emergent if it was present prior to receiving the first dose of nusinersen in the current study and subsequently worsened in severity or was not present prior to receiving the first dose of nusinersen and subsequently appeared. Safety set included all participants who received at least one dose of nusinersen.

End point type

Secondary

End point timeframe

From the first dose of the study drug up to Day 399

Notes
[72] - 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: Part B Infantile-onset SMA and Part B Later-onset SMA arms were planned to be analysed for this end point.

End point values	Part B: Infantile-Onset SMA: 12/12 mg Nusinersen	Part B: Infantile-Onset SMA: 50/28 mg Nusinersen	Part B: Later-Onset SMA: 12/12 mg Nusinersen	Part B: Later-Onset SMA: 50/28 mg Nusinersen
Number of subjects analysed	25	50	8	16
Units: participants
TEAEs	22	45	7	14
TESAEs	18	30	4	2

No statistical analyses for this end point

Secondary: Part B: Number of Participants with Shifts from Baseline in Clinical Laboratory Parameters (Blood Chemistry Parameters)

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End point title

Part B: Number of Participants with Shifts from Baseline in Clinical Laboratory Parameters (Blood Chemistry Parameters) ^[73]

End point description

Blood chemistry parameters included protein, albumin, creatinine, blood urea nitrogen, bilirubin (total and direct), alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transferase, glucose, calcium, phosphorus, bicarbonate, chloride, sodium, potassium, cystatin C, and creatine kinase. Parameters were flagged as low, normal, or high relative to parameter’s normal range or as unknown if no result was available, by the Investigator. Here, shift to low indicates values that were normal, high or unknown at baseline and shifted to low values postbaseline. Shift to high indicates values that were normal, low or unknown at baseline and shifted to high postbaseline. Categories with at least one participant with shift from baseline in these parameters are reported. Safety set included all participants who received at least a dose of nusinersen. ‘Number analysed (n)' signifies number of participants evaluable for analysis of the specified parameter.

End point type

Secondary

End point timeframe

Baseline up to Day 302

Notes
[73] - 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: Part B Infantile-onset SMA and Part B Later-onset SMA arms were planned to be analysed for this end point.

End point values	Part B: Infantile-Onset SMA: 12/12 mg Nusinersen	Part B: Infantile-Onset SMA: 50/28 mg Nusinersen	Part B: Later-Onset SMA: 12/12 mg Nusinersen	Part B: Later-Onset SMA: 50/28 mg Nusinersen
Number of subjects analysed	25	50	8	16
Units: participants
Albumin Shift to Low (n=20,46,8,15)	6	13	1	1
Albumin Shift to High (n=23,50,8,16)	1	2	0	0
Alkaline Phosphatase Shift to Low (n=23,50,8,16)	0	3	0	0
Alkaline Phosphatase Shift to High (n=23,50,8,16)	3	3	0	0
Alanine AminotransferaseShift to Low n=23,50,8,16	0	0	0	1
Alanine AminotransferaseShift to Highn=14,39,6,15	4	14	0	3
AspartateAminotransferaseShifttoHigh n=21,45,7,16	5	9	0	1
Bicarbonate Shift to Low (n=5,14,3,4)	4	12	3	4
Bicarbonate Shift to High (n=22,49,8,16)	1	1	0	0
Direct Bilirubin Shift to Low (n=22,45,8,16)	1	0	0	0
Bilirubin Shift to Low (n=21,49,8,16)	2	2	0	1
Bilirubin Shift to High (n=20,45,8,16)	1	1	0	0
Indirect Bilirubin Shift to Low (n=22,46,2,4)	11	21	2	3
Calcium Shift to Low (n=23,50,8,15)	1	4	2	1
Calcium Shift to High (n=19,45,8,15)	8	17	0	0
Creatine Kinase Shift to High (n=14,27,6,10)	6	12	3	3
Chloride Shift to Low (n=23,50,8,16)	3	3	0	1
Chloride Shift to High (n=23,48,7,16)	3	6	1	1
Creatinine Shift to Low (n=2,5,0,1)	2	5	0	1
Creatinine Shift to High (n=23,50,8,16)	0	1	0	0
Cystatin C Shift to Low(n=23,48,8,16)	2	0	1	1
Cystatin C Shift to High(n=23,48,8,16)	2	1	0	0
Gamma GlutamylTransferase ShifttoLown=18,45,8,16	7	11	0	1
GammaGlutamylTransferase ShifttoHighn=23,49,8,16	2	5	0	3
Glucose Shift to Low(n=23,49,8,16)	0	2	0	1
Glucose Shift to High(n=20,44,7,15)	6	17	2	6
Potassium Shift to Low(n=23,50,8,16)	1	2	0	1
Potassium Shift to High(n=21,44,8,16)	5	15	3	4
Lactate Dehydrogenase Shift to High(n=0,1,8,16)	0	1	0	0
Magnesium Shift to High(n=3,5,8,16)	0	2	0	0
Phosphate Shift to Low(n=23,50,8,16)	3	2	0	0
Phosphate Shift to High(n=18,42,4,13)	5	16	2	10
Protein Shift to Low(n=21,48,7,15)	7	9	1	2
Protein Shift to High(n=23,47,8,16)	2	6	0	2
Sodium Shift to Low(n=20,47,7,15)	3	15	2	3
Sodium Shift to High(n=23,50,8,16)	0	0	0	1
Urea Nitrogen Shift to Low(n=23,44,8,16)	1	3	2	1
Urea Nitrogen Shift to High(n=23,50,8,15)	0	0	2	1

No statistical analyses for this end point

Secondary: Part B: Number of Participants with Shifts from Baseline in Urinalysis

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End point title

Part B: Number of Participants with Shifts from Baseline in Urinalysis ^[74]

End point description

Urinalysis included assessments of urine total protein, specific gravity, pH, protein, glucose, ketones, bilirubin, blood, RBC , WBC, epithelial cells, bacteria, casts and crystals. These parameters were flagged as low, normal, or high relative to parameter’s normal range or as unknown if no result was available, by the Investigator. Here, shift to low indicates values that were normal, high, positive, abnormal or unknown at baseline and shifted to low values postbaseline. Shift to high indicates values that were normal, negative, absent, low or unknown at baseline and shifted to high postbaseline. The categories with at least one participant with shift from baseline in these parameters are reported. Part A: safety analysis set. Safety set included all participants who received at least one dose of nusinersen. ‘Number analysed (n)' signifies number of participants evaluable for analysis of the specified parameter.

End point type

Secondary

End point timeframe

Baseline up to Day 302

Notes
[74] - 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: Part B Infantile-onset SMA and Part B Later-onset SMA arms were planned to be analysed for this end point.

End point values	Part B: Infantile-Onset SMA: 12/12 mg Nusinersen	Part B: Infantile-Onset SMA: 50/28 mg Nusinersen	Part B: Later-Onset SMA: 12/12 mg Nusinersen	Part B: Later-Onset SMA: 50/28 mg Nusinersen
Number of subjects analysed	25	50	8	16
Units: participants
Specific Gravity Shift to Low (n=20,47,8,16)	2	2	1	1
Specific Gravity Shift to High (n=22,50,7,15)	3	3	1	1
pH Shift to Low (n=21,48,8,16)	2	1	0	1
pH Shift to High (n=21,47,8,16)	5	8	1	1
Protein High/positive (n=18,45,5,13)	12	27	3	9
Glucose High/positive (n=21,46,8,16)	2	2	0	0
Ketones High/positive (n=20,44,8,14)	5	16	4	4
Occult Blood High/positive (n=16,43,7,14)	4	12	2	1
RBC High/positive (n=13,26,7,12)	0	3	0	0
WBC High/positive (n=15,25,6,10)	3	12	3	4
Epithelial Cells High/positive (n=2,7,5,3)	0	6	5	2
Bacteria High/positive (n=10,18,2,8)	10	18	2	8
Casts High/positive (n=3,3,8,16)	0	1	0	0
Crystals High/positive (n=5,4,8,16)	2	1	0	0

No statistical analyses for this end point

Secondary: Part B: Number of Participants With Shifts From Baseline in CSF Parameters

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End point title

Part B: Number of Participants With Shifts From Baseline in CSF Parameters ^[75]

End point description

CSF parameters included cell count, total protein, and glucose. These parameters were flagged as low, normal, or high relative to parameter’s normal range or as unknown if no result was available, by the Investigator. Here, shift to low indicates values that were normal, high or unknown at baseline and shifted to low values postbaseline. Shift to high indicates values that were normal, low or unknown at baseline and shifted to high postbaseline. The categories with at least one participant with shift from baseline in these parameters are reported. Safety set included all participants who received at least one dose of nusinersen. ‘Number analysed (n)' signifies number of participants evaluable for analysis of the specified parameter.

End point type

Secondary

End point timeframe

Baseline up to Day 302

Notes
[75] - 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: Part B Infantile-onset SMA and Part B Later-onset SMA arms were planned to be analysed for this end point.

End point values	Part B: Infantile-Onset SMA: 12/12 mg Nusinersen	Part B: Infantile-Onset SMA: 50/28 mg Nusinersen	Part B: Later-Onset SMA: 12/12 mg Nusinersen	Part B: Later-Onset SMA: 50/28 mg Nusinersen
Number of subjects analysed	25	50	8	16
Units: participants
Glucose Shift to Low (n=16,36,7,12)	4	3	1	0
Glucose Shift to High (n=19,46,8,16)	0	1	0	0
Protein Shift to Low (n=18,45,5,11)	2	6	0	4
Protein Shift to High (n=12,25,8,15)	4	7	2	2
Erythrocytes Shift to Low (n=18,47,8,15)	1	0	0	0
Erythrocytes Shift to High (n=14,37,5,11)	3	9	2	7
Leukocytes Shift to Low (n=17,47,8,11)	1	2	0	1
Leukocytes Shift to High (n=16,38,8,11)	1	5	0	4

No statistical analyses for this end point

Secondary: Part B: Number of Participants With Shift From Baseline in ECGs

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End point title

Part B: Number of Participants With Shift From Baseline in ECGs ^[76]

End point description

The ECGs were assessed by the investigator to be normal, abnormal and abnormal AE. The number of participants with ECG shifts from normal to each of the categorical values denoting an abnormal scan (abnormal not AE, abnormal AE) was assessed. Shift from baseline to worst post-baseline values were reported. The categories with at least one participant with shift from baseline in ECG are reported. Safety set included all participants who received at least one dose of nusinersen.

End point type

Secondary

End point timeframe

Baseline up to Day 302

Notes
[76] - 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: Part B Infantile-onset SMA and Part B Later-onset SMA arms were planned to be analysed for this end point.

End point values	Part B: Infantile-Onset SMA: 12/12 mg Nusinersen	Part B: Infantile-Onset SMA: 50/28 mg Nusinersen	Part B: Later-Onset SMA: 12/12 mg Nusinersen	Part B: Later-Onset SMA: 50/28 mg Nusinersen
Number of subjects analysed	25	50	8	16
Units: participants
Normal to Normal	2	7	0	0
Normal to Abnormal, not AE	9	10	2	4
Normal to Abnormal, AE	1	0	0	0
Abnormal, not AE to Abnormal, not AE	12	30	6	12
Abnormal, not AE to Abnormal, AE	1	2	0	0
Unknown to Abnormal, not AE	0	1	0	0

No statistical analyses for this end point

Secondary: Part B: Number of Participants With Abnormalities in Vital Sign Parameters

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End point title

Part B: Number of Participants With Abnormalities in Vital Sign Parameters ^[77]

End point description

Vital sign assessment included temperature, pulse rate systolic blood pressure, diastolic blood pressure, and respiratory rate. As pre-specified in protocol, the criteria for determining potentially clinically relevant abnormalities in vital signs included: temperature < 36 and > 38 degrees C, pulse rate < 60 and > 100 bpm, systolic blood pressure < 90, > 140 and > 160 mmHg, diastolic blood pressure < 50, > 90 and > 100 mmHg and respiratory rate < 12 and > 20 breaths per minute. The categories with at least one participant with clinically relevant vital sign abnormalities are reported. Safety set included all participants who received at least one dose of nusinersen. ‘Number analysed (n)' signifies number of participants evaluable for analysis of the specified parameter.

End point type

Secondary

End point timeframe

Baseline up to Day 302

Notes
[77] - 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: Part B Infantile-onset SMA and Part B Later-onset SMA arms were planned to be analysed for this end point.

End point values	Part B: Infantile-Onset SMA: 12/12 mg Nusinersen	Part B: Infantile-Onset SMA: 50/28 mg Nusinersen	Part B: Later-Onset SMA: 12/12 mg Nusinersen	Part B: Later-Onset SMA: 50/28 mg Nusinersen
Number of subjects analysed	25	50	8	16
Units: participants
Temperature <36.0 C (n=25,50,8,16)	6	23	3	7
Temperature >38.0 C (n=25,50,8,16)	0	6	0	1
Pulse Rate <60 bpm (n=25,50,8,16)	1	2	0	0
Pulse Rate >100 bpm (n=25,50,8,16)	25	50	8	16
Systolic Blood Pressure <90 mmHg (n=25,49,8,16)	24	47	7	10
Systolic Blood Pressure >140 mmHg (n=25,49,8,16)	3	0	0	0
Diastolic Blood Pressure <50 mmHg (n=25,49,8,16)	22	44	4	10
Diastolic Blood Pressure >90 mmHg(n=25,49,8,16)	5	8	1	2
Diastolic Blood Pressure >100 mmHg(n=25,49,8,16)	2	0	0	1
Respiratory Rate >20 breaths/min (n=25,50,8,16)	25	50	8	16

No statistical analyses for this end point

Secondary: Part B: Change From Baseline in Growth Parameters (Body Height)

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End point title

Part B: Change From Baseline in Growth Parameters (Body Height) ^[78]

End point description

Body height was measured for all participants (infantile-onset and later-onset SMA). Safety set included all participants who received at least one dose of nusinersen. ‘Subjects analysed' signifies number of participants evaluable in this endpoint.. ‘99999’ signifies that since only one participant was evaluable, standard deviation (SD) was not estimated.

End point type

Secondary

End point timeframe

Baseline, Day 302

Notes
[78] - 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: Part B Infantile-onset SMA and Part B Later-onset SMA arms were planned to be analysed for this end point.

End point values	Part B: Infantile-Onset SMA: 12/12 mg Nusinersen	Part B: Infantile-Onset SMA: 50/28 mg Nusinersen	Part B: Later-Onset SMA: 12/12 mg Nusinersen	Part B: Later-Onset SMA: 50/28 mg Nusinersen
Number of subjects analysed	1	4	1	8
Units: cm
arithmetic mean (standard deviation)	8.00 ( 99999 )	10.25 ( 2.217 )	11.2 ( 99999 )	6.9 ( 3.65 )

No statistical analyses for this end point

Secondary: Part B Infantile-onset SMA: Change From Baseline in Growth Parameters (Head Circumference)

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End point title

Part B Infantile-onset SMA: Change From Baseline in Growth Parameters (Head Circumference) ^[79]

End point description

Head circumference was measured in participants with infantile-onset SMA. Safety set included all participants who received at least one dose of nusinersen. ‘Subjects analysed’ signifies number of participants evaluable for this endpoint.

End point type

Secondary

End point timeframe

Baseline, Day 302

Notes
[79] - 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: Part B Infantile-onset SMA arms were planned to be analysed for this end point.

End point values	Part B: Infantile-Onset SMA: 12/12 mg Nusinersen	Part B: Infantile-Onset SMA: 50/28 mg Nusinersen
Number of subjects analysed	13	35
Units: cm
arithmetic mean (standard deviation)	4.52 ( 1.703 )	5.50 ( 2.766 )

No statistical analyses for this end point

Secondary: Part B Infantile-onset SMA: Change From Baseline in Growth Parameters (Chest Circumference)

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End point title

Part B Infantile-onset SMA: Change From Baseline in Growth Parameters (Chest Circumference) ^[80]

End point description

Chest circumference was measured in participants with infantile-onset SMA. Safety set included all participants who received at least one dose of nusinersen. ‘Subjects analysed’ signifies number of participants evaluable for this endpoint.

End point type

Secondary

End point timeframe

Baseline, Day 302

Notes
[80] - 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: Part B Infantile-onset SMA arms were planned to be analysed for this end point.

End point values	Part B: Infantile-Onset SMA: 12/12 mg Nusinersen	Part B: Infantile-Onset SMA: 50/28 mg Nusinersen
Number of subjects analysed	13	35
Units: cm
arithmetic mean (standard deviation)	5.67 ( 4.868 )	6.64 ( 6.362 )

No statistical analyses for this end point

Secondary: Part B Infantile-onset SMA: Change From Baseline in Growth Parameters (Arm Circumference)

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End point title

Part B Infantile-onset SMA: Change From Baseline in Growth Parameters (Arm Circumference) ^[81]

End point description

Arm circumference was measured in participants with infantile-onset SMA. Safety set included all participants who received at least one dose of nusinersen. ‘Subjects analysed’ signifies number of participants evaluable for this endpoint.

End point type

Secondary

End point timeframe

Baseline, Day 302

Notes
[81] - 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: Part B Infantile-onset SMA arms were planned to be analysed for this end point.

End point values	Part B: Infantile-Onset SMA: 12/12 mg Nusinersen	Part B: Infantile-Onset SMA: 50/28 mg Nusinersen
Number of subjects analysed	13	35
Units: cm
arithmetic mean (standard deviation)	0.45 ( 2.141 )	1.16 ( 2.144 )

No statistical analyses for this end point

Secondary: Part B: Change From Baseline in Growth Parameters (Weight for Length Percentile)

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End point title

Part B: Change From Baseline in Growth Parameters (Weight for Length Percentile) ^[82]

End point description

As pre-specified in the protocol, weight for length percentile was assessed only for the participants with infantile-onset SMA. Safety set included all participants who received at least one dose of nusinersen. 'Subjects analysed' signifies number of participants evaluable for this endpoint.

End point type

Secondary

End point timeframe

Baseline, Day 302

Notes
[82] - 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: Part B Infantile-onset SMA and Part B Later-onset SMA arms were planned to be analysed for this end point.

End point values	Part B: Infantile-Onset SMA: 12/12 mg Nusinersen	Part B: Infantile-Onset SMA: 50/28 mg Nusinersen	Part B: Later-Onset SMA: 12/12 mg Nusinersen	Part B: Later-Onset SMA: 50/28 mg Nusinersen
Number of subjects analysed	12	30	0 ^[83]	0 ^[84]
Units: percentile
arithmetic mean (standard deviation)	-4.23 ( 35.817 )	6.05 ( 40.119 )	( )	( )

Notes
[83] - As the number of subjects analyzed was zero, mean and SD was not calculated.
[84] - As the number of subjects analyzed was zero, mean and SD was not calculated.

No statistical analyses for this end point

Secondary: Part B: Change From Baseline in Growth Parameters (Weight for Age Percentile)

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End point title

Part B: Change From Baseline in Growth Parameters (Weight for Age Percentile) ^[85]

End point description

WHO child growth standards (WHO Child Growth Standards, 2006) was used to calculate the weight for age percentile in the infantile-onset participants. The 2000 CDC Growth Charts was used to calculate the weight for age percentile for later-onset participants. Safety set included all participants who received at least one dose of nusinersen. ‘Subjects analysed’ signifies number of participants evaluable for this endpoint.

End point type

Secondary

End point timeframe

Baseline, Day 302

Notes
[85] - 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: Part B Infantile-onset SMA and Part B Later-onset SMA arms were planned to be analysed for this end point.

End point values	Part B: Infantile-Onset SMA: 12/12 mg Nusinersen	Part B: Infantile-Onset SMA: 50/28 mg Nusinersen	Part B: Later-Onset SMA: 12/12 mg Nusinersen	Part B: Later-Onset SMA: 50/28 mg Nusinersen
Number of subjects analysed	13	35	7	16
Units: percentile
arithmetic mean (standard deviation)	-6.70 ( 23.133 )	-3.60 ( 35.202 )	9.1 ( 20.23 )	-0.3 ( 6.96 )

No statistical analyses for this end point

Secondary: Part B Later-onset SMA: Change From Baseline in Growth Parameters (Ulnar Length)

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End point title

Part B Later-onset SMA: Change From Baseline in Growth Parameters (Ulnar Length) ^[86]

End point description

Ulnar length was measured in participants with later-onset SMA. Safety set included all participants who received at least one dose of nusinersen. ‘Subjects analysed’ signifies number of participants evaluable for this endpoint.

End point type

Secondary

End point timeframe

Baseline, Day 302

Notes
[86] - 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: Part B Later-onset SMA arms were planned to be analysed for this end point.

End point values	Part B: Later-Onset SMA: 12/12 mg Nusinersen	Part B: Later-Onset SMA: 50/28 mg Nusinersen
Number of subjects analysed	5	16
Units: cm
arithmetic mean (standard deviation)	2.8 ( 4.16 )	1.2 ( 1.39 )

No statistical analyses for this end point

Secondary: Part B: Change From Baseline in Growth Parameters (Head-to-Chest Circumference Ratio)

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End point title

Part B: Change From Baseline in Growth Parameters (Head-to-Chest Circumference Ratio) ^[87]

End point description

As pre-specified in the protocol, head to chest circumference ratio was assessed only for the participants with infantile-onset SMA. Safety set included all participants who received at least one dose of nusinersen. Subjects analysed signifies number of participants evaluable for this endpoint. ‘99999’ signiﬁes that since one or no participant was evaluable, SD was not estimated.

End point type

Secondary

End point timeframe

Baseline, Day 302

Notes
[87] - 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: Part B Infantile-onset SMA and Part B Later-onset SMA arms were planned to be analysed for this end point.

End point values	Part B: Infantile-Onset SMA: 12/12 mg Nusinersen	Part B: Infantile-Onset SMA: 50/28 mg Nusinersen
Number of subjects analysed	13	35
Units: ratio
arithmetic mean (standard deviation)	-0.03 ( 0.085 )	-0.05 ( 0.269 )

No statistical analyses for this end point

Secondary: Part B: Number of Participants With Shifts From Baseline in Coagulation Parameters (PT)

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End point title

Part B: Number of Participants With Shifts From Baseline in Coagulation Parameters (PT) ^[88]

End point description

Prothrombin time was evaluated to assess safety. "Shift to low" measured change in normal, high and unknown values of PT at baseline to low values postbaseline. "Shift to high" measured change in normal, high and unknown values of PT at baseline to high values postbaseline. Safety set included all participants who received at least one dose of nusinersen. ‘Number analysed (n)' signifies number of participants evaluable for analysis of the specified parameter.

End point type

Secondary

End point timeframe

Baseline up to Day 279

Notes
[88] - 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: Part B Infantile-onset SMA and Part B Later-onset SMA arms were planned to be analysed for this end point.

End point values	Part B: Infantile-Onset SMA: 12/12 mg Nusinersen	Part B: Infantile-Onset SMA: 50/28 mg Nusinersen	Part B: Later-Onset SMA: 12/12 mg Nusinersen	Part B: Later-Onset SMA: 50/28 mg Nusinersen
Number of subjects analysed	25	50	8	16
Units: participants
Shift to Low (n=22,48,8,15)	3	6	1	1
Shift to High (n=20,45,8,14)	2	6	0	1

No statistical analyses for this end point

Secondary: Part B: Number of Participants With Shifts From Baseline in Coagulation Parameters (aPTT)

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End point title

Part B: Number of Participants With Shifts From Baseline in Coagulation Parameters (aPTT) ^[89]

End point description

aPTT was evaluated to assess safety. "Shift to low" measured change in normal, high and unknown values of aPTT at baseline to low values postbaseline. "Shift to high" measured change in normal, high and unknown values of aPTT at baseline to high values postbaseline. Safety set included all participants who received at least one dose of nusinersen. ‘Number analysed (n)' signifies number of participants evaluable for analysis of the specified parameter.

End point type

Secondary

End point timeframe

Baseline up to Day 279

Notes
[89] - 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: Part B Infantile-onset SMA and Part B Later-onset SMA arms were planned to be analysed for this end point.

End point values	Part B: Infantile-Onset SMA: 12/12 mg Nusinersen	Part B: Infantile-Onset SMA: 50/28 mg Nusinersen	Part B: Later-Onset SMA: 12/12 mg Nusinersen	Part B: Later-Onset SMA: 50/28 mg Nusinersen
Number of subjects analysed	25	50	8	16
Units: participants
Shift to Low (n=22,48,7,16)	4	14	2	2
Shift to High (n=17,40,8,15)	6	7	1	1

No statistical analyses for this end point

Secondary: Part B: Number of Participants With Shifts From Baseline in Coagulation Parameters (INR)

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End point title

Part B: Number of Participants With Shifts From Baseline in Coagulation Parameters (INR) ^[90]

End point description

INR was evaluated to assess safety. "Shift to low" measured change in normal, high and unknown values of INR at baseline to low values postbaseline. "Shift to high" measured change in normal, high and unknown values of INR  at baseline to high values postbaseline. The category with at least one participant with shift from baseline in INR ratio is reported. Safety set included all participants who received at least one dose of nusinersen. ‘Number analysed (n)' signifies number of participants evaluable for analysis of specified parameter.

End point type

Secondary

End point timeframe

Baseline up to Day 279

Notes
[90] - 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: Part B Infantile-onset SMA and Part B Later-onset SMA arms were planned to be analysed for this end point.

End point values	Part B: Infantile-Onset SMA: 12/12 mg Nusinersen	Part B: Infantile-Onset SMA: 50/28 mg Nusinersen	Part B: Later-Onset SMA: 12/12 mg Nusinersen	Part B: Later-Onset SMA: 50/28 mg Nusinersen
Number of subjects analysed	25	50	8	16
Units: participants
Shift to Low (n=22,49,8,16)	1	5	0	0
Shift to High (n=21,44,8,16)	2	6	1	0

No statistical analyses for this end point

Secondary: Part B: Change From Baseline in Urine Total Protein

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End point title

Part B: Change From Baseline in Urine Total Protein ^[91]

End point description

Safety set included all participants who received at least one dose of nusinersen. Subjects analysed signifies number of participants evaluable for this endpoint.

End point type

Secondary

End point timeframe

Baseline, Day 302

Notes
[91] - 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: Part B Infantile-onset SMA and Part B Later-onset SMA arms were planned to be analysed for this end point.

End point values	Part B: Infantile-Onset SMA: 12/12 mg Nusinersen	Part B: Infantile-Onset SMA: 50/28 mg Nusinersen	Part B: Later-Onset SMA: 12/12 mg Nusinersen	Part B: Later-Onset SMA: 50/28 mg Nusinersen
Number of subjects analysed	7	18	3	11
Units: g/L
arithmetic mean (standard deviation)	-0.130 ( 0.4126 )	-3.274 ( 14.1387 )	-0.213 ( 0.2873 )	0.004 ( 0.0608 )

No statistical analyses for this end point

Secondary: Part B: Number of Participants With Neurological Examination Abnormalities Reported as AEs

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End point title

Part B: Number of Participants With Neurological Examination Abnormalities Reported as AEs ^[92]

End point description

Participants with abnormalities in neurological examinations recorded as AEs were reported.

End point type

Secondary

End point timeframe

Baseline up to Day 302

Notes
[92] - 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: Part B Infantile-onset SMA and Part B Later-onset SMA arms were planned to be analysed for this end point.

End point values	Part B: Infantile-Onset SMA: 12/12 mg Nusinersen	Part B: Infantile-Onset SMA: 50/28 mg Nusinersen	Part B: Later-Onset SMA: 12/12 mg Nusinersen	Part B: Later-Onset SMA: 50/28 mg Nusinersen
Number of subjects analysed	25	50	8	16
Units: participants
number (not applicable)
Muscular Weakness	0	1	0	0
Bulbar Palsy	1	0	0	0
Tremor	0	0	0	1

No statistical analyses for this end point

Secondary: Part B: Percentage of Participants With a Postbaseline Platelet Count Below the Lower Limit of Normal on at Least 2 Consecutive Measurements

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End point title

Part B: Percentage of Participants With a Postbaseline Platelet Count Below the Lower Limit of Normal on at Least 2 Consecutive Measurements ^[93]

End point description

Safety set included all participants who received at least one dose of nusinersen.

End point type

Secondary

End point timeframe

Baseline up to Day 302

Notes
[93] - 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: Part B Infantile-onset SMA and Part B Later-onset SMA arms were planned to be analysed for this end point.

End point values	Part B: Infantile-Onset SMA: 12/12 mg Nusinersen	Part B: Infantile-Onset SMA: 50/28 mg Nusinersen	Part B: Later-Onset SMA: 12/12 mg Nusinersen	Part B: Later-Onset SMA: 50/28 mg Nusinersen
Number of subjects analysed	25	50	8	16
Units: percentage of participants
number (not applicable)	4	0	0	0

No statistical analyses for this end point

Secondary: Parts A, B and C: Duration of Hospitalizations

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End point title

Parts A, B and C: Duration of Hospitalizations

End point description

Parts A, B and C: ITT set included all participants who received at least one dose of nusinersen in the current study. ‘Subjects analysed' signifies number of participants evaluable for this endpoint.

End point type

Secondary

End point timeframe

Parts A, B, and C: Baseline up to Day 302

End point values	Part A: 28/28 Milligrams (mg) Nusinersen	Part B: Infantile-Onset SMA: 12/12 mg Nusinersen	Part B: Infantile-Onset SMA: 50/28 mg Nusinersen	Part B: Later-Onset SMA: 12/12 mg Nusinersen	Part B: Later-Onset SMA: 50/28 mg Nusinersen	Part C: 50/28 mg Nusinersen
Number of subjects analysed	6	25	50	8	16	12
Units: percentage of days
median (full range (min-max))	0 (0 to 2)	6.4 (0 to 100)	1.9 (0 to 100)	0.0 (0 to 8)	0.0 (0 to 10)	1.34 (0.3 to 10.4)

No statistical analyses for this end point

Secondary: Part B: Percentage of Participants With a Postbaseline QTcF of > 500 msec and an Increase from Baseline to any Postbaseline Timepoint in QTcF of > 60 msec

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End point title

Part B: Percentage of Participants With a Postbaseline QTcF of > 500 msec and an Increase from Baseline to any Postbaseline Timepoint in QTcF of > 60 msec ^[94]

End point description

As a part of safety assessment, QTcF was evaluated for determining the incidence of clinically relevant abnormalities. Post baseline QTcF of > 500 msec and maximum increase from baseline to post baseline QTcF > 60 msec was considered as a criteria for clinically relevant abnormality in ECG. Safety set included all participants who received at least one dose of nusinersen. 'Subjects analysed' signifies number of participants evaluable in this endpoint.

End point type

Secondary

End point timeframe

Baseline up to Day 302

Notes
[94] - 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: Part B Infantile-onset SMA and Part B Later-onset SMA arms were planned to be analysed for this end point.

End point values	Part B: Infantile-Onset SMA: 12/12 mg Nusinersen	Part B: Infantile-Onset SMA: 50/28 mg Nusinersen	Part B: Later-Onset SMA: 12/12 mg Nusinersen	Part B: Later-Onset SMA: 50/28 mg Nusinersen
Number of subjects analysed	25	49	8	15
Units: percentage of participants
number (not applicable)	8	0	0	0

No statistical analyses for this end point

Secondary: Parts A, B and C: Number of Participants With Hospitalizations

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End point title

Parts A, B and C: Number of Participants With Hospitalizations

End point description

Parts A, B and C: ITT set included all participants who received at least one dose of nusinersen in the current study.

End point type

Secondary

End point timeframe

Parts A, B, and C: Baseline up to Day 302

End point values	Part A: 28/28 Milligrams (mg) Nusinersen	Part B: Infantile-Onset SMA: 12/12 mg Nusinersen	Part B: Infantile-Onset SMA: 50/28 mg Nusinersen	Part B: Later-Onset SMA: 12/12 mg Nusinersen	Part B: Later-Onset SMA: 50/28 mg Nusinersen	Part C: 50/28 mg Nusinersen
Number of subjects analysed	6	25	50	8	16	40
Units: number of participants	1	19	26	3	6	12

No statistical analyses for this end point

Secondary: Parts A, B and C: Number of Participants With Clinical Global Impression of Change (CGIC)

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End point title

Parts A, B and C: Number of Participants With Clinical Global Impression of Change (CGIC)

End point description

The CGIC scale was a 7 point scale that required the clinician to assess how much the participant's illness had changed relative to a baseline state at the beginning of the intervention, where 1=very much improved, 2=much improved, 3=minimally improved, 4=no change, 5=minimally worse, 6=much worse, 7=very much worse. Higher rating indicates worsening of the condition. A separate CGIC assessment was performed by the Investigator (I) and caregiver (C). The categories with at least one participant having a CGIC score was reported. ITT set included all participants who received at least one dose of nusinersen in the current study. 'Subjects analysed' signifies number of participants evaluable for this endpoint.

End point type

Secondary

End point timeframe

Parts A, B, and C: Day 302

End point values	Part A: 28/28 Milligrams (mg) Nusinersen	Part B: Infantile-Onset SMA: 12/12 mg Nusinersen	Part B: Infantile-Onset SMA: 50/28 mg Nusinersen	Part B: Later-Onset SMA: 12/12 mg Nusinersen	Part B: Later-Onset SMA: 50/28 mg Nusinersen	Part C: 50/28 mg Nusinersen
Number of subjects analysed	6	13	25	7	16	24
Units: participants
CGIC-I-Very Much Improved	0	0	8	0	1	0
CGIC-I-Much Improved	1	10	20	3	5	5
CGIC-I-Minimally Improved	5	3	7	4	9	19
CGIC-I-No Change	0	0	0	0	1	14
CGIC-I-Minimally Worse	0	0	0	0	0	2
CGIC-C-Very Much Improved	1	3	18	1	0	2
CGIC-C-Much Improved	2	7	13	2	8	6
CGIC-C-Minimally Improved	2	3	3	4	7	9
CGIC-C-No Change	0	0	1	0	1	5
CGIC-C-Minimally Worse	1	0	0	0	0	2

No statistical analyses for this end point

Secondary: Parts A, B and C: Number of Serious Respiratory Events

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End point title

Parts A, B and C: Number of Serious Respiratory Events

End point description

ITT set included all participants who received at least one dose of nusinersen in the current study.

End point type

Secondary

End point timeframe

Parts A, B, and C: Baseline up to Day 399

End point values	Part A: 28/28 Milligrams (mg) Nusinersen	Part B: Infantile-Onset SMA: 12/12 mg Nusinersen	Part B: Infantile-Onset SMA: 50/28 mg Nusinersen	Part B: Later-Onset SMA: 12/12 mg Nusinersen	Part B: Later-Onset SMA: 50/28 mg Nusinersen	Part C: 50/28 mg Nusinersen
Number of subjects analysed	6	25	50	8	16	40
Units: number of events
number (not applicable)	0	34	60	6	2	0

No statistical analyses for this end point

Secondary: Part A: Change From Baseline in the Parent Assessment of Swallowing Ability (PASA) Scale

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End point title

Part A: Change From Baseline in the Parent Assessment of Swallowing Ability (PASA) Scale ^[95]

End point description

End point type

Secondary

End point timeframe

Baseline, Day 302

Notes
[95] - 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: Part A arm was planned to be analysed for this endpoint.

End point values	Part A: 28/28 Milligrams (mg) Nusinersen
Number of subjects analysed	6
Units: score on scale
arithmetic mean (standard deviation)
Had Difficulty Feeding Themselves	0.2 ( 0.41 )
Had to Suction Excess Saliva/Drool	0.0 ( 0.00 )
Not Able Eat as Much as Would Like	0.2 ( 0.41 )
Not Able Eat Food Variety Would Like	-0.2 ( 0.41 )
Been Tube-Fed	0.0 ( 0.00 )
Attempted to Drink Liquid Foods	0.0 ( 0.00 )
Refused Liquid Foods	0.0 ( 0.00 )
Difficulty Drinking Thin Liquids	0.0 ( 0.00 )
Difficulty Drinking Thick Liquids	0.0 ( 0.00 )
Cough/Clear Throat Swallow Liquid Food	0.0 ( 0.00 )
Gagged or Choked on Liquid Food	0.0 ( 0.00 )
Retching/Vomiting Drinking Liquids	0.0 ( 0.00 )
Taken > 30 Minutes Drink Liquids	0.0 ( 0.00 )
Attempted to Eat Solid Foods	0.0 ( 0.00 )
Refused Solid Foods	0.2 ( 0.41 )
Difficulty Swallowing Soft Foods	0.0 ( 0.00 )
Difficulty Swallowing Solid Foods	-0.2 ( 0.41 )
Had Difficulty Swallowing Pills	0.2 ( 0.98 )
Cough/Clear Throat Eat/Swallow Solid Food	0.2 ( 0.41 )
Had Food Stuck in Throat/Chest	0.0 ( 0.00 )
Gagged/Choked on Their Solid Food	0.2 ( 0.41 )
Retching/Vomiting Eating Solids	0.2 ( 0.41 )
Required Food to Be Cut Up	0.7 ( 1.21 )
Experienced/Shown Pain When Eating	0.0 ( 0.00 )
Has Taken > 30 Minutes Eat Solids	0.3 ( 0.52 )
Concern Child's Swallowing Ability	0.8 ( 1.72 )
Concerned About Child's Weight	1.2 ( 1.60 )
Concern Variety Foods Child Eats	0.7 ( 1.51 )
Concern Child Not Able Eat as Much	1.3 ( 1.51 )
Concern Child Unable Eat Variety	1.3 ( 1.37 )
Concern Not Get Goodness From Diet	1.8 ( 1.17 )
Concerned Child Aspirating Food	1.0 ( 1.55 )
Concern Child Choking When Eating	1.2 ( 1.60 )

No statistical analyses for this end point

Secondary: Parts A, B and C: Number of Participants With Ventilator Use

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End point title

Parts A, B and C: Number of Participants With Ventilator Use

End point description

ITT set included all participants who received at least a dose of nusinersen.

End point type

Secondary

End point timeframe

Parts A, B, and C: Screening up to Day 302

End point values	Part A: 28/28 Milligrams (mg) Nusinersen	Part B: Infantile-Onset SMA: 12/12 mg Nusinersen	Part B: Infantile-Onset SMA: 50/28 mg Nusinersen	Part B: Later-Onset SMA: 12/12 mg Nusinersen	Part B: Later-Onset SMA: 50/28 mg Nusinersen	Part C: 50/28 mg Nusinersen
Number of subjects analysed	6	25	50	8	16	40
Units: participants	0	9	22	4	5	8

No statistical analyses for this end point

Secondary: Part B Infantile-onset SMA: Percentage of Time on Ventilation

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End point title

Part B Infantile-onset SMA: Percentage of Time on Ventilation ^[96]

End point description

ITT set included all participants who received at least one dose of nusinersen.

End point type

Secondary

End point timeframe

Baseline up to Day 302

Notes
[96] - 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: Part B Infantile-onset SMA arms were planned to be analysed for this end point.

End point values	Part B: Infantile-Onset SMA: 12/12 mg Nusinersen	Part B: Infantile-Onset SMA: 50/28 mg Nusinersen
Number of subjects analysed	25	50
Units: percentage of hours
median (full range (min-max))	5.6 (0 to 100)	7.5 (0 to 100)

No statistical analyses for this end point

Secondary: Part B: Change From Baseline in the PASA Scale

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End point title

Part B: Change From Baseline in the PASA Scale ^[97]

End point description

PASA questionnaire was developed to assess the signs and symptoms of dysphagia. It included 33 items across 4 domains. General feeding, drinking liquids and eating solid foods were assessed with 5 levels of response (Never, Rarely, Sometimes, Often, and Always), and 2 items were assessed with 'Yes'/'No'. The assessment of swallowing concerns has 4 levels of response: Strongly Agree, Agree, Disagree, and Strongly Disagree. As pre-specified in statistical analysis plan (SAP), PASA scale was assessed for the domain General feeding only. ⁠Higher score indicates improvement. ITT set included all participants who received at least one a dose of nusinersen. 'Subjects analysed' signifies number of participants evaluable in this endpoint. 'Number analysed (n)', signifies the number of participants evaluable for the specified parameter.

End point type

Secondary

End point timeframe

Baseline, Day 302

Notes
[97] - 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: Part B Infantile-onset SMA and Part B Later-onset SMA arms were planned to be analysed for this end point.

End point values	Part B: Infantile-Onset SMA: 12/12 mg Nusinersen	Part B: Infantile-Onset SMA: 50/28 mg Nusinersen	Part B: Later-Onset SMA: 12/12 mg Nusinersen	Part B: Later-Onset SMA: 50/28 mg Nusinersen
Number of subjects analysed	7	32	7	14
Units: score on scale
arithmetic mean (standard deviation)
Had Difficulty Feeding Themselves (n=7,29)	-1.6 ( 1.81 )	-0.6 ( 1.55 )	-0.4 ( 0.53 )	0.3 ( 0.73 )
Had To Suction Excess Saliva or Drool(n=7,31)	-1.7 ( 1.38 )	-0.2 ( 1.58 )	0.1 ( 0.38 )	0.1 ( 0.36 )
Not Able To Eat As Much As Would Like(n=7,31)	-1.6 ( 1.72 )	-0.2 ( 1.45 )	0.3 ( 0.95 )	0.0 ( 0.39 )
Not Able To Eat Food Variety They Like(n=7,29)	-1.6 ( 1.72 )	-1.0 ( 1.18 )	0.1 ( 0.69 )	-0.4 ( 0.93 )
Been Tube-Fed	-1.8 ( 2.11 )	-0.9 ( 1.76 )	0.0 ( 0.00 )	0.0 ( 0.00 )

No statistical analyses for this end point

Secondary: Parts A and C: Change From Baseline in HFMSE Total Score

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End point title

Parts A and C: Change From Baseline in HFMSE Total Score ^[98]

End point description

HFMSE scale was a tool used to assess motor function in children with SMA. The original 20 item Hammersmith Functional Motor Scale was expanded to include 13 additional adapted items from the Gross Motor Function Measure to improve sensitivity for the higher functioning ambulant population. Each item is scored 0 (unable), 1 (performs with modification or adaptation) or 2 (able) and the total score was calculated by summing the 33 items and ranged from 0 to 66 with higher scores indicating greater motor function. ITT set included all participants who received at least one dose of nusinersen. ‘Subjects analysed' signifies number of participants evaluable in this endpoint.

End point type

Secondary

End point timeframe

Parts A and C: Baseline, Day 302

Notes
[98] - 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: Parts A and C arms were planned to be analysed for this end point.

End point values	Part A: 28/28 Milligrams (mg) Nusinersen	Part C: 50/28 mg Nusinersen
Number of subjects analysed	6	38
Units: score on scale
arithmetic mean (standard deviation)	-0.8 ( 3.76 )	1.8 ( 3.99 )

No statistical analyses for this end point

Secondary: Parts A and C: Change From Baseline in RULM Total Score

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End point title

Parts A and C: Change From Baseline in RULM Total Score ^[99]

End point description

The RULM Test was used in participants with SMA to assess upper limb functional ability items that are reflective of activities of daily living (i.e., raise a can to mouth as if drinking, take a coin and place it in a box, remove the lid of a container). The RULM test had a total of 20 items with an entry item that served as functional class identification and did not contribute to the total score. The remaining 19 scorable items reflected different functional domains and were graded on a 3-point system with a score of 0 (unable), 1 (able, with modification), and a maximum of 2 (able, no difficulty). Scorable items were summed for a total score range of 0-37, with higher scores indicating increased great upper limb function. ITT set included all participants who received at least one dose of nusinersen. ‘Subjects analysed' signifies number of participants evaluable for this endpoint.

End point type

Secondary

End point timeframe

Parts A and C: Baseline, Day 302

Notes
[99] - 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: Parts A and C arms were planned to be analysed for this end point.

End point values	Part A: 28/28 Milligrams (mg) Nusinersen	Part C: 50/28 mg Nusinersen
Number of subjects analysed	6	37
Units: score on scale
arithmetic mean (standard deviation)	1.5 ( 1.52 )	1.2 ( 2.14 )

No statistical analyses for this end point

Secondary: Part B: Infantile SMA-onset: Change From (Ratio to) Baseline in CSF Concentration of NF-L

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End point title

Part B: Infantile SMA-onset: Change From (Ratio to) Baseline in CSF Concentration of NF-L ^[100]

End point description

End point type

Secondary

End point timeframe

Baseline, Day 279

Notes
[100] - 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: Part B Infantile-onset SMA arms were planned to be analysed for this end point.

End point values	Part B: Infantile-Onset SMA: 12/12 mg Nusinersen	Part B: Infantile-Onset SMA: 50/28 mg Nusinersen
Number of subjects analysed	25	50
Units: pg/mL
geometric mean (confidence interval 95%)	0.06 (0.05 to 0.08)	0.05 (0.04 to 0.06)

Change From Baseline in NF-L CSF Concentration

Comparison groups

Part B: Infantile-Onset SMA: 12/12 mg Nusinersen v Part B: Infantile-Onset SMA: 50/28 mg Nusinersen

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.3785 ^[101]

Method

ANCOVA

Parameter type

LS geometric mean ratio

Point estimate

0.86

Confidence interval

level

95%

sides

2-sided

lower limit

0.62

upper limit

1.2

Notes
[101] - ANCOVA model was used with treatment as a fixed effect and adjustment for each participant disease duration at screening, baseline log CSF NF-L and baseline CHOP INTEND total score.

Secondary: Parts A and C: Change From Baseline in ACEND Total Score

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End point title

Parts A and C: Change From Baseline in ACEND Total Score ^[102]

End point description

This assessment instrument was designed to quantify the caregiver impact experienced by parents/caregivers of children affected with severe neuromuscular diseases, including children with SMA. ACEND included domains assessing physical impact (including feeding/grooming/dressing, sitting/play, transfers, and mobility) and general caregiver impact (including time, emotion, and finance) and each domain comprises several items. The total score ranges from 0 to 100 with a higher score indicating a greater impact on the caregiver. A negative change from baseline indicates an increase in impact on caregiver. ITT set included all participants who received at least one dose of nusinersen. Subjects analysed signifies number of participants evaluable for this endpoint.

End point type

Secondary

End point timeframe

Parts A and C: Baseline, Day 302

Notes
[102] - 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: Parts A and C arms were planned to be analysed for this end point.

End point values	Part A: 28/28 Milligrams (mg) Nusinersen	Part C: 50/28 mg Nusinersen
Number of subjects analysed	6	17
Units: score on scale
arithmetic mean (standard deviation)
Feeding/Grooming/Dressing Total Score	0.6 ( 2.51 )	0.8 ( 7.50 )
Sitting/Play Total Score	0.0 ( 11.03 )	-2.8 ( 14.48 )
Transfers Total Score	-8.0 ( 12.39 )	-2.0 ( 15.34 )
Mobility Total Score	7.1 ( 13.85 )	-0.8 ( 15.01 )
Time Total Score	6.3 ( 14.25 )	0.4 ( 10.47 )
Emotion Total Score	11.1 ( 7.66 )	-2.4 ( 9.44 )
Finance Total Score	15.8 ( 14.29 )	-2.4 ( 12.00 )

No statistical analyses for this end point

Secondary: Parts A and C: Total Number of New WHO Motor Milestones

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End point title

Parts A and C: Total Number of New WHO Motor Milestones ^[103]

End point description

The WHO motor milestones were a set of six milestones in motor development: sitting without support, standing with assistance, hands and knees crawling, walking with assistance, standing alone and walking alone. The examiner recorded an overall rating of the participant’s emotional state and then for each milestone one of the following four classifications: no (inability) - child tried but failed to perform the milestone, no (refusal) - child refused to perform despite being calm and alert, yes - child was able to perform the milestone, unable to test - could not be tested because of irritability, drowsiness or sickness. ITT set included all participants who received at least one dose of nusinersen. ‘Number analysed (n)' signifies number of participants evaluable for this outcome measure.

End point type

Secondary

End point timeframe

Parts A and C: Baseline up to Day 302

Notes
[103] - 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: Parts A and C arms were planned to be analysed for this end point.

End point values	Part A: 28/28 Milligrams (mg) Nusinersen	Part C: 50/28 mg Nusinersen
Number of subjects analysed	6	40
Units: motor milestones
Gain of one or More Motor Milestones (n=6,37)	0	3
No Change (n=6,37)	0	32
Loss of one or More Motor Milestones (n=6,37)	0	2

No statistical analyses for this end point

Secondary: Parts A and C: Change From Baseline in PedsQL™ Total Score

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End point title

Parts A and C: Change From Baseline in PedsQL™ Total Score ^[104]

End point description

End point type

Secondary

End point timeframe

Parts A and C: Baseline, Day 302

Notes
[104] - 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: Parts A and C arms were planned to be analysed for this end point.

End point values	Part A: 28/28 Milligrams (mg) Nusinersen	Part C: 50/28 mg Nusinersen
Number of subjects analysed	5	14
Units: score on scale
arithmetic mean (standard deviation)
PQLI-Total Score-Subject (n=5,12)	6.1 ( 18.28 )	1.1 ( 9.74 )
PQLI-Total Score-Parent (n=5,14)	3.3 ( 12.51 )	0.7 ( 8.15 )
PQLN-Total Score-Subject (n=5,12)	9.9 ( 6.94 )	6.7 ( 13.11 )
PQLN-Total Score-Parent (n=6,13)	4.7 ( 5.72 )	0.1 ( 9.65 )

No statistical analyses for this end point

Secondary: Part C: Change From Baseline in CHOP-INTEND Total Score

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End point title

Part C: Change From Baseline in CHOP-INTEND Total Score ^[105]

End point description

The CHOP-INTEND test was designed to evaluate the motor skills of infants with significant motor weakness. It included 16 items (capturing neck, trunk, and proximal and distal limb strength), nine of which were scored 0, 1, 2, 3, or 4, five were scored as 0, 2, or 4, one was scored as 0, 1, 2, or 4, and one as 0, 2, 3, or 4 with greater scores indicating greater muscle strength. Total score ranged from 0 (worst possible score) and 64 (best possible score). ITT set included all participants who received at least one dose of nusinersen in the current study. ‘99999’ signiﬁes that since only one participant was evaluable, standard deviation (SD) was not estimated. Subjects analysed signifies number of participants evaluable for this endpoint.

End point type

Secondary

End point timeframe

Baseline, Day 302

Notes
[105] - 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: Part C arm was planned to be analysed for this endpoint.

End point values	Part C: 50/28 mg Nusinersen
Number of subjects analysed	1
Units: score on scale
arithmetic mean (standard deviation)	0.0 ( 99999 )

No statistical analyses for this end point

Secondary: Part C: Change From Baseline in HINE Section 2 Motor Milestones Total Score

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End point title

Part C: Change From Baseline in HINE Section 2 Motor Milestones Total Score ^[106]

End point description

Section 2 of the HINE was used to assess motor milestones of the participants. Its composed of 8 motor milestone categories: voluntary grasp, ability to kick in supine position, head control, rolling, sitting, crawling, standing, and walking. Within each of these categories, participants can progress from complete absence of a motor ability (the lowest level in each category) through multiple milestones (2 to 4 levels in each category) to the highest level within the category. The 8 categories of HINE Section 2 can be summed to give a total score that ranges from 0 to 26. Safety set included all participants who received at least one dose of nusinersen. Subjects analysed signifies number of participants evaluable for this endpoint. ‘99999’ signifies that since only one participant was evaluable, standard deviation (SD) was not estimated.

End point type

Secondary

End point timeframe

Baseline, Day 302

Notes
[106] - 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: Part C arm was planned to be analysed for this endpoint.

End point values	Part C: 50/28 mg Nusinersen
Number of subjects analysed	1
Units: score on scale
arithmetic mean (standard deviation)	2.0 ( 99999 )

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

From first dose of study drug up to end of study (up to 1527 days)

Adverse event reporting additional description

Safety set included all participants who received at least a dose of nusinersen. MedDRA version 24.0 was applied for Part A, MedDRA version 26.1 was applied for Part B, and MedDRA version 26.0 was applied for Part C.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

24,26,26.1

Reporting group title

Part A: Nusinersen 28/28 Milligrams (mg)

Reporting group description

Participants with later-onset SMA received 3 loading doses of 28 mg of nusinersen, intrathecally (IT), on Days 1, 15 and 29 followed by 2 maintenance doses of 28 mg on Days 149 and 269.

Reporting group title

Part C: Nusinersen 50/28 mg

Reporting group description

Participants with infantile and later-onset SMA who had been receiving the approved dose of 12 mg for at least 1 year prior to entry, received a single bolus dose of 50 mg of nusinersen intrathecally on Day 1 (4 months after their most recent maintenance dose of 12 mg) followed by 2 maintenance doses of 28 mg on Days 121 and 241.

Reporting group title

Part B: Later-Onset SMA: 12/12 mg Nusinersen

Reporting group description

Participants with later-onset SMA received 4 loading doses of 12 mg of nusinersen intrathecally on Days 1, 15, 29, and 64 followed by 2 maintenance doses of 12 mg on Days 183 and 279. Sham procedure was administered on Day 135.

Reporting group title

Part B: Later-Onset SMA: 50/28 mg Nusinersen

Reporting group description

Participants with later-onset SMA received 2 loading doses of 50 mg of nusinersen intrathecally on Days 1 and 15 followed by 2 maintenance doses of 28 mg on Days 135 and 279. Sham procedure was administered on Days 29, 64 and 183.

Reporting group title

Part B: Infantile-Onset SMA: 12/12 mg Nusinersen

Reporting group description

Participants with infantile-onset SMA received 4 loading doses of 12 mg of nusinersen intrathecally on Days 1, 15, 29, and 64 followed by 2 maintenance doses of 12 mg on Days 183 and 279. Sham procedure was administered on Day 135.

Reporting group title

Part B: Infantile-Onset SMA: 50/28 mg Nusinersen

Reporting group description

Participants with infantile-onset SMA received 2 loading doses of 50 mg of nusinersen intrathecally on Days 1 and 15 followed by 2 maintenance doses of 28 mg on Days 135 and 279. Sham procedure was administered on Days 29, 64 and 183.

Serious adverse events	Part A: Nusinersen 28/28 Milligrams (mg)	Part C: Nusinersen 50/28 mg	Part B: Later-Onset SMA: 12/12 mg Nusinersen	Part B: Later-Onset SMA: 50/28 mg Nusinersen	Part B: Infantile-Onset SMA: 12/12 mg Nusinersen	Part B: Infantile-Onset SMA: 50/28 mg Nusinersen
Total subjects affected by serious adverse events
subjects affected / exposed	1 / 6 (16.67%)	6 / 40 (15.00%)	4 / 8 (50.00%)	2 / 16 (12.50%)	18 / 25 (72.00%)	30 / 50 (60.00%)
number of deaths (all causes)	0	0	0	0	6	10
number of deaths resulting from adverse events	0	0	0	0	6	10
Vascular disorders
Shock haemorrhagic
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	0 / 25 (0.00%)	1 / 50 (2.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pregnancy, puerperium and perinatal conditions
Abortion spontaneous
subjects affected / exposed	0 / 6 (0.00%)	1 / 40 (2.50%)	0 / 8 (0.00%)	0 / 16 (0.00%)	0 / 25 (0.00%)	0 / 50 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Pyrexia
subjects affected / exposed	0 / 6 (0.00%)	1 / 40 (2.50%)	0 / 8 (0.00%)	0 / 16 (0.00%)	0 / 25 (0.00%)	1 / 50 (2.00%)
occurrences causally related to treatment / all	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
Gait disturbance
subjects affected / exposed	0 / 6 (0.00%)	1 / 40 (2.50%)	0 / 8 (0.00%)	0 / 16 (0.00%)	0 / 25 (0.00%)	0 / 50 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Sudden infant death syndrome
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	1 / 25 (4.00%)	2 / 50 (4.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 2
Organ failure
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	0 / 25 (0.00%)	1 / 50 (2.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
Respiratory, thoracic and mediastinal disorders
Atelectasis
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	1 / 8 (12.50%)	0 / 16 (0.00%)	2 / 25 (8.00%)	0 / 50 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Aspiration
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	0 / 25 (0.00%)	1 / 50 (2.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
Acute respiratory failure
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	3 / 25 (12.00%)	2 / 50 (4.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 4	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
Chronic respiratory failure
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	0 / 25 (0.00%)	1 / 50 (2.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cough
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	1 / 25 (4.00%)	0 / 50 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Interstitial lung disease
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	0 / 25 (0.00%)	1 / 50 (2.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
Obstructive airways disorder
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	0 / 25 (0.00%)	1 / 50 (2.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory acidosis
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	1 / 25 (4.00%)	0 / 50 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
Respiratory arrest
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	1 / 25 (4.00%)	0 / 50 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory disorder
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	0 / 25 (0.00%)	1 / 50 (2.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory distress
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	1 / 25 (4.00%)	1 / 50 (2.00%)
occurrences causally related to treatment / all	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
Respiratory failure
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	4 / 25 (16.00%)	8 / 50 (16.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	2 / 5	0 / 11
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
Asthma
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	1 / 8 (12.50%)	0 / 16 (0.00%)	0 / 25 (0.00%)	0 / 50 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Investigations
Oxygen saturation decreased
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	0 / 25 (0.00%)	2 / 50 (4.00%)
occurrences causally related to treatment / all	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
Electrocardiogram qt prolonged
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	1 / 25 (4.00%)	0 / 50 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Fall
subjects affected / exposed	1 / 6 (16.67%)	2 / 40 (5.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	0 / 25 (0.00%)	0 / 50 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 2	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
Femur fracture
subjects affected / exposed	1 / 6 (16.67%)	2 / 40 (5.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	0 / 25 (0.00%)	0 / 50 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 2	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
Traumatic haemothorax
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	0 / 25 (0.00%)	1 / 50 (2.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Tracheostomy malfunction
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	0 / 25 (0.00%)	1 / 50 (2.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
Cardiac arrest
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	2 / 25 (8.00%)	3 / 50 (6.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2	0 / 1
Cardiomyopathy
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	1 / 25 (4.00%)	0 / 50 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
Cardio-respiratory arrest
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	2 / 25 (8.00%)	0 / 50 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Hypoglycaemic seizure
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	1 / 25 (4.00%)	0 / 50 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cerebral infarction
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	1 / 25 (4.00%)	0 / 50 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
Brain stem infarction
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	1 / 25 (4.00%)	0 / 50 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
Hypoxic-ischaemic encephalopathy
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	1 / 25 (4.00%)	0 / 50 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
Blood and lymphatic system disorders
Leukocytosis
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	1 / 25 (4.00%)	0 / 50 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Dysphagia
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	1 / 25 (4.00%)	1 / 50 (2.00%)
occurrences causally related to treatment / all	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
Musculoskeletal and connective tissue disorders
Acquired macrocephaly
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	0 / 25 (0.00%)	1 / 50 (2.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Muscular weakness
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	0 / 25 (0.00%)	1 / 50 (2.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Adenoviral upper respiratory infection
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	0 / 25 (0.00%)	1 / 50 (2.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Bronchiolitis
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	1 / 25 (4.00%)	3 / 50 (6.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
Covid-19
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	1 / 16 (6.25%)	0 / 25 (0.00%)	3 / 50 (6.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Enterovirus infection
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	0 / 25 (0.00%)	1 / 50 (2.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Escherichia urinary tract infection
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	1 / 25 (4.00%)	0 / 50 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastroenteritis adenovirus
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	1 / 25 (4.00%)	0 / 50 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastroenteritis bacterial
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	0 / 25 (0.00%)	1 / 50 (2.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastroenteritis escherichia coli
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	1 / 25 (4.00%)	0 / 50 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Human coronavirus OC43 infection
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	0 / 25 (0.00%)	1 / 50 (2.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lower respiratory tract infection viral
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	1 / 25 (4.00%)	1 / 50 (2.00%)
occurrences causally related to treatment / all	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
Measles
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	1 / 25 (4.00%)	0 / 50 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Norovirus infection
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	0 / 25 (0.00%)	1 / 50 (2.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	5 / 25 (20.00%)	7 / 50 (14.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 7	0 / 8
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2	0 / 1
Pneumonia acinetobacter
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	1 / 25 (4.00%)	0 / 50 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia aspiration
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	1 / 8 (12.50%)	0 / 16 (0.00%)	1 / 25 (4.00%)	7 / 50 (14.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1	0 / 9
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia bacterial
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	1 / 25 (4.00%)	1 / 50 (2.00%)
occurrences causally related to treatment / all	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
Pneumonia influenzal
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	1 / 25 (4.00%)	1 / 50 (2.00%)
occurrences causally related to treatment / all	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
Pneumonia mycoplasmal
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	1 / 8 (12.50%)	0 / 16 (0.00%)	0 / 25 (0.00%)	1 / 50 (2.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia pseudomonal
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	1 / 25 (4.00%)	0 / 50 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia respiratory syncytial viral
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	1 / 8 (12.50%)	1 / 16 (6.25%)	0 / 25 (0.00%)	1 / 50 (2.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia viral
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	1 / 25 (4.00%)	2 / 50 (4.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
Respiratory tract infection
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	2 / 25 (8.00%)	0 / 50 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Rhinovirus infection
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	0 / 25 (0.00%)	1 / 50 (2.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Urinary tract infection
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	1 / 25 (4.00%)	1 / 50 (2.00%)
occurrences causally related to treatment / all	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
Upper respiratory tract infection
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	1 / 25 (4.00%)	1 / 50 (2.00%)
occurrences causally related to treatment / all	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
Stoma site infection
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	0 / 25 (0.00%)	1 / 50 (2.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Sepsis
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	0 / 25 (0.00%)	1 / 50 (2.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Staphylococcal bacteraemia
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	1 / 25 (4.00%)	0 / 50 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Staphylococcal sepsis
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	0 / 25 (0.00%)	1 / 50 (2.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
Pneumonia pneumococcal
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	1 / 8 (12.50%)	0 / 16 (0.00%)	0 / 25 (0.00%)	0 / 50 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastroenteritis rotavirus
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	1 / 8 (12.50%)	0 / 16 (0.00%)	0 / 25 (0.00%)	0 / 50 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastroenteritis
subjects affected / exposed	0 / 6 (0.00%)	1 / 40 (2.50%)	0 / 8 (0.00%)	0 / 16 (0.00%)	0 / 25 (0.00%)	0 / 50 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Hypoglycaemia
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	1 / 25 (4.00%)	0 / 50 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 0%

Non-serious adverse events	Part A: Nusinersen 28/28 Milligrams (mg)	Part C: Nusinersen 50/28 mg	Part B: Later-Onset SMA: 12/12 mg Nusinersen	Part B: Later-Onset SMA: 50/28 mg Nusinersen	Part B: Infantile-Onset SMA: 12/12 mg Nusinersen	Part B: Infantile-Onset SMA: 50/28 mg Nusinersen
Total subjects affected by non serious adverse events
subjects affected / exposed	4 / 6 (66.67%)	36 / 40 (90.00%)	7 / 8 (87.50%)	14 / 16 (87.50%)	19 / 25 (76.00%)	37 / 50 (74.00%)
Vascular disorders
Lymphoedema
subjects affected / exposed	0 / 6 (0.00%)	1 / 40 (2.50%)	0 / 8 (0.00%)	0 / 16 (0.00%)	0 / 25 (0.00%)	0 / 50 (0.00%)
occurrences all number	0	1	0	0	0	0
Peripheral coldness
subjects affected / exposed	0 / 6 (0.00%)	1 / 40 (2.50%)	0 / 8 (0.00%)	0 / 16 (0.00%)	0 / 25 (0.00%)	0 / 50 (0.00%)
occurrences all number	0	1	0	0	0	0
Hypotension
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	0 / 25 (0.00%)	1 / 50 (2.00%)
occurrences all number	0	0	0	0	0	1
Hypertension
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	1 / 25 (4.00%)	1 / 50 (2.00%)
occurrences all number	0	0	0	0	1	1
Cyanosis
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	0 / 25 (0.00%)	2 / 50 (4.00%)
occurrences all number	0	0	0	0	0	2
General disorders and administration site conditions
Chills
subjects affected / exposed	1 / 6 (16.67%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	0 / 25 (0.00%)	0 / 50 (0.00%)
occurrences all number	2	0	0	0	0	0
Pyrexia
subjects affected / exposed	0 / 6 (0.00%)	3 / 40 (7.50%)	0 / 8 (0.00%)	1 / 16 (6.25%)	4 / 25 (16.00%)	9 / 50 (18.00%)
occurrences all number	0	3	0	2	6	12
Vaccination site haemorrhage
subjects affected / exposed	0 / 6 (0.00%)	1 / 40 (2.50%)	0 / 8 (0.00%)	0 / 16 (0.00%)	0 / 25 (0.00%)	0 / 50 (0.00%)
occurrences all number	0	1	0	0	0	0
Feeling hot
subjects affected / exposed	0 / 6 (0.00%)	1 / 40 (2.50%)	0 / 8 (0.00%)	0 / 16 (0.00%)	0 / 25 (0.00%)	0 / 50 (0.00%)
occurrences all number	0	1	0	0	0	0
Infusion site rash
subjects affected / exposed	0 / 6 (0.00%)	1 / 40 (2.50%)	0 / 8 (0.00%)	0 / 16 (0.00%)	0 / 25 (0.00%)	0 / 50 (0.00%)
occurrences all number	0	1	0	0	0	0
Medical device pain
subjects affected / exposed	0 / 6 (0.00%)	1 / 40 (2.50%)	0 / 8 (0.00%)	0 / 16 (0.00%)	0 / 25 (0.00%)	0 / 50 (0.00%)
occurrences all number	0	1	0	0	0	0
Medical device site discomfort
subjects affected / exposed	0 / 6 (0.00%)	1 / 40 (2.50%)	0 / 8 (0.00%)	0 / 16 (0.00%)	0 / 25 (0.00%)	0 / 50 (0.00%)
occurrences all number	0	1	0	0	0	0
Vaccination site erythema
subjects affected / exposed	0 / 6 (0.00%)	1 / 40 (2.50%)	0 / 8 (0.00%)	0 / 16 (0.00%)	0 / 25 (0.00%)	0 / 50 (0.00%)
occurrences all number	0	1	0	0	0	0
Asthenia
subjects affected / exposed	0 / 6 (0.00%)	1 / 40 (2.50%)	0 / 8 (0.00%)	10 / 16 (62.50%)	0 / 25 (0.00%)	0 / 50 (0.00%)
occurrences all number	0	1	0	0	0	0
Vessel puncture site haemorrhage
subjects affected / exposed	0 / 6 (0.00%)	1 / 40 (2.50%)	0 / 8 (0.00%)	0 / 16 (0.00%)	0 / 25 (0.00%)	0 / 50 (0.00%)
occurrences all number	0	1	0	0	0	0
Oedema
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	0 / 25 (0.00%)	1 / 50 (2.00%)
occurrences all number	0	0	0	0	0	0
Medical device site rash
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	0 / 25 (0.00%)	1 / 50 (2.00%)
occurrences all number	0	0	0	0	0	1
Medical device site hypersensitivity
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	0 / 25 (0.00%)	1 / 50 (2.00%)
occurrences all number	0	0	0	0	0	1
Oedema peripheral
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	0 / 25 (0.00%)	1 / 50 (2.00%)
occurrences all number	0	0	0	0	0	1
Respiratory complication associated with device
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	1 / 25 (4.00%)	0 / 50 (0.00%)
occurrences all number	0	0	0	0	1	0
Immune system disorders
Mite allergy
subjects affected / exposed	0 / 6 (0.00%)	1 / 40 (2.50%)	0 / 8 (0.00%)	0 / 16 (0.00%)	0 / 25 (0.00%)	0 / 50 (0.00%)
occurrences all number	0	1	0	0	0	0
Milk allergy
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	0 / 25 (0.00%)	1 / 50 (2.00%)
occurrences all number	0	0	0	0	0	1
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	0 / 6 (0.00%)	1 / 40 (2.50%)	0 / 8 (0.00%)	2 / 16 (12.50%)	2 / 25 (8.00%)	5 / 50 (10.00%)
occurrences all number	0	1	0	2	2	5
Rhinorrhoea
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	2 / 16 (12.50%)	0 / 25 (0.00%)	0 / 50 (0.00%)
occurrences all number	0	0	0	2	0	0
Epistaxis
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	1 / 16 (6.25%)	0 / 25 (0.00%)	0 / 50 (0.00%)
occurrences all number	0	0	0	1	0	0
Rhinitis allergic
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	1 / 16 (6.25%)	0 / 25 (0.00%)	0 / 50 (0.00%)
occurrences all number	0	0	0	1	0	0
Bronchial obstruction
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	1 / 8 (12.50%)	0 / 16 (0.00%)	0 / 25 (0.00%)	1 / 50 (2.00%)
occurrences all number	0	0	1	0	0	2
Respiratory failure
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	0 / 25 (0.00%)	3 / 50 (6.00%)
occurrences all number	0	0	0	0	0	3
Respiratory muscle weakness
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	0 / 25 (0.00%)	1 / 50 (2.00%)
occurrences all number	0	0	0	0	0	1
Productive cough
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	0 / 25 (0.00%)	1 / 50 (2.00%)
occurrences all number	0	0	0	0	0	1
Pleural effusion
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	0 / 25 (0.00%)	1 / 50 (2.00%)
occurrences all number	0	0	0	0	0	1
Interstitial lung disease
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	0 / 25 (0.00%)	1 / 50 (2.00%)
occurrences all number	0	0	0	0	0	1
Sneezing
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	0 / 25 (0.00%)	1 / 50 (2.00%)
occurrences all number	0	0	0	0	0	1
Acute respiratory failure
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	0 / 25 (0.00%)	1 / 50 (2.00%)
occurrences all number	0	0	0	0	0	1
Acute respiratory distress syndrome
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	0 / 25 (0.00%)	1 / 50 (2.00%)
occurrences all number	0	0	0	0	0	1
Respiratory distress
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	0 / 25 (0.00%)	2 / 50 (4.00%)
occurrences all number	0	0	0	0	0	3
Increased bronchial secretion
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	1 / 25 (4.00%)	2 / 50 (4.00%)
occurrences all number	0	0	0	0	1	2
Atelectasis
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	1 / 25 (4.00%)	2 / 50 (4.00%)
occurrences all number	0	0	0	0	1	4
Bronchospasm
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	0 / 25 (0.00%)	1 / 50 (2.00%)
occurrences all number	0	0	0	0	0	1
Pneumothorax
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	2 / 25 (8.00%)	0 / 50 (0.00%)
occurrences all number	0	0	0	0	2	0
Hypoxia
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	1 / 25 (4.00%)	0 / 50 (0.00%)
occurrences all number	0	0	0	0	1	0
Decreased bronchial secretion
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	1 / 25 (4.00%)	0 / 50 (0.00%)
occurrences all number	0	0	0	0	1	0
Psychiatric disorders
Dysphoria
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	0 / 25 (0.00%)	1 / 50 (2.00%)
occurrences all number	0	0	0	0	0	2
Investigations
CSF pressure increased
subjects affected / exposed	0 / 6 (0.00%)	2 / 40 (5.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	0 / 25 (0.00%)	0 / 50 (0.00%)
occurrences all number	0	2	0	0	0	0
Crystal urine present
subjects affected / exposed	0 / 6 (0.00%)	2 / 40 (5.00%)	0 / 8 (0.00%)	1 / 16 (6.25%)	0 / 25 (0.00%)	0 / 50 (0.00%)
occurrences all number	0	2	0	1	0	0
CSF protein increased
subjects affected / exposed	0 / 6 (0.00%)	1 / 40 (2.50%)	0 / 8 (0.00%)	0 / 16 (0.00%)	0 / 25 (0.00%)	0 / 50 (0.00%)
occurrences all number	0	1	0	0	0	0
Body height below normal
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	1 / 16 (6.25%)	0 / 25 (0.00%)	1 / 50 (2.00%)
occurrences all number	0	0	0	1	0	1
Weight decreased
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	1 / 16 (6.25%)	1 / 25 (4.00%)	0 / 50 (0.00%)
occurrences all number	0	0	0	1	1	0
Staphylococcus test positive
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	1 / 8 (12.50%)	0 / 16 (0.00%)	0 / 25 (0.00%)	0 / 50 (0.00%)
occurrences all number	0	0	1	0	0	0
Bacterial test positive
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	0 / 25 (0.00%)	1 / 50 (2.00%)
occurrences all number	0	0	0	0	0	1
Body temperature increased
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	0 / 25 (0.00%)	1 / 50 (2.00%)
occurrences all number	0	0	0	0	0	1
Electrocardiogram QT prolonged
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	0 / 25 (0.00%)	1 / 50 (2.00%)
occurrences all number	0	0	0	0	0	1
Oxygen saturation decreased
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	1 / 25 (4.00%)	1 / 50 (2.00%)
occurrences all number	0	0	0	0	1	1
Alanine aminotransferase increased
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	1 / 25 (4.00%)	0 / 50 (0.00%)
occurrences all number	0	0	0	0	1	0
Blood albumin decreased
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	1 / 25 (4.00%)	0 / 50 (0.00%)
occurrences all number	0	0	0	0	1	0
Myocardial necrosis marker increased
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	0 / 25 (0.00%)	3 / 50 (6.00%)
occurrences all number	0	0	0	0	0	3
Blood phosphorus increased
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	1 / 25 (4.00%)	0 / 50 (0.00%)
occurrences all number	0	0	0	0	1	0
Blood creatinine decreased
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	1 / 25 (4.00%)	0 / 50 (0.00%)
occurrences all number	0	0	0	0	1	0
Blood creatine phosphokinase increased
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	1 / 25 (4.00%)	0 / 50 (0.00%)
occurrences all number	0	0	0	0	1	0
Blood bicarbonate decreased
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	1 / 25 (4.00%)	0 / 50 (0.00%)
occurrences all number	0	0	0	0	1	0
Coronavirus test positive
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	1 / 25 (4.00%)	0 / 50 (0.00%)
occurrences all number	0	0	0	0	1	0
Gamma-glutamyltransferase increased
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	1 / 25 (4.00%)	0 / 50 (0.00%)
occurrences all number	0	0	0	0	1	0
Injury, poisoning and procedural complications
Procedural pain
subjects affected / exposed	2 / 6 (33.33%)	8 / 40 (20.00%)	3 / 8 (37.50%)	3 / 16 (18.75%)	0 / 25 (0.00%)	3 / 50 (6.00%)
occurrences all number	3	12	5	8	0	3
Procedural headache
subjects affected / exposed	1 / 6 (16.67%)	13 / 40 (32.50%)	0 / 8 (0.00%)	4 / 16 (25.00%)	0 / 25 (0.00%)	0 / 50 (0.00%)
occurrences all number	1	20	0	7	0	0
Anaesthetic complication neurological
subjects affected / exposed	0 / 6 (0.00%)	1 / 40 (2.50%)	0 / 8 (0.00%)	0 / 16 (0.00%)	0 / 25 (0.00%)	0 / 50 (0.00%)
occurrences all number	0	1	0	0	0	0
Fall
subjects affected / exposed	0 / 6 (0.00%)	4 / 40 (10.00%)	0 / 8 (0.00%)	1 / 16 (6.25%)	0 / 25 (0.00%)	2 / 50 (4.00%)
occurrences all number	0	5	0	1	0	2
Procedural vomiting
subjects affected / exposed	0 / 6 (0.00%)	3 / 40 (7.50%)	0 / 8 (0.00%)	1 / 16 (6.25%)	0 / 25 (0.00%)	0 / 50 (0.00%)
occurrences all number	0	4	0	1	0	0
Post procedural discomfort
subjects affected / exposed	0 / 6 (0.00%)	1 / 40 (2.50%)	0 / 8 (0.00%)	0 / 16 (0.00%)	0 / 25 (0.00%)	1 / 50 (2.00%)
occurrences all number	0	2	0	0	0	3
Road traffic accident
subjects affected / exposed	0 / 6 (0.00%)	2 / 40 (5.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	0 / 25 (0.00%)	0 / 50 (0.00%)
occurrences all number	0	2	0	0	0	0
Anaesthetic complication
subjects affected / exposed	0 / 6 (0.00%)	1 / 40 (2.50%)	0 / 8 (0.00%)	0 / 16 (0.00%)	0 / 25 (0.00%)	0 / 50 (0.00%)
occurrences all number	0	1	0	0	0	0
Craniocerebral injury
subjects affected / exposed	0 / 6 (0.00%)	1 / 40 (2.50%)	0 / 8 (0.00%)	0 / 16 (0.00%)	0 / 25 (0.00%)	0 / 50 (0.00%)
occurrences all number	0	1	0	0	0	0
Procedural nausea
subjects affected / exposed	0 / 6 (0.00%)	1 / 40 (2.50%)	0 / 8 (0.00%)	1 / 16 (6.25%)	0 / 25 (0.00%)	0 / 50 (0.00%)
occurrences all number	0	1	0	1	0	0
Skin abrasion
subjects affected / exposed	0 / 6 (0.00%)	1 / 40 (2.50%)	0 / 8 (0.00%)	0 / 16 (0.00%)	0 / 25 (0.00%)	0 / 50 (0.00%)
occurrences all number	0	1	0	0	0	0
Foreign body ingestion
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	1 / 16 (6.25%)	0 / 25 (0.00%)	0 / 50 (0.00%)
occurrences all number	0	0	0	1	0	0
Post procedural fever
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	1 / 16 (6.25%)	0 / 25 (0.00%)	0 / 50 (0.00%)
occurrences all number	0	0	0	1	0	0
Traumatic haematoma
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	1 / 16 (6.25%)	0 / 25 (0.00%)	0 / 50 (0.00%)
occurrences all number	0	0	0	1	0	0
Head injury
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	0 / 25 (0.00%)	1 / 50 (2.00%)
occurrences all number	0	0	0	0	0	1
Femur fracture
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	0 / 25 (0.00%)	1 / 50 (2.00%)
occurrences all number	0	0	0	0	0	1
Periorbital haemorrhage
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	0 / 25 (0.00%)	1 / 50 (2.00%)
occurrences all number	0	0	0	0	0	1
Post procedural swelling
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	0 / 25 (0.00%)	1 / 50 (2.00%)
occurrences all number	0	0	0	0	0	1
Neurological procedural complication
subjects affected / exposed	0 / 6 (0.00%)	1 / 40 (2.50%)	0 / 8 (0.00%)	0 / 16 (0.00%)	1 / 25 (4.00%)	0 / 50 (0.00%)
occurrences all number	0	1	0	0	1	0
Post procedural haemorrhage
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	1 / 16 (6.25%)	1 / 25 (4.00%)	0 / 50 (0.00%)
occurrences all number	0	0	0	1	1	0
Congenital, familial and genetic disorders
Cryptorchism
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	0 / 25 (0.00%)	1 / 50 (2.00%)
occurrences all number	0	0	0	0	0	1
Developmental hip dysplasia
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	0 / 25 (0.00%)	2 / 50 (4.00%)
occurrences all number	0	0	0	0	0	2
Cardiac disorders
Sinus tachycardia
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	1 / 16 (6.25%)	0 / 25 (0.00%)	0 / 50 (0.00%)
occurrences all number	0	0	0	1	0	0
Tachycardia
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	0 / 25 (0.00%)	1 / 50 (2.00%)
occurrences all number	0	0	0	0	0	1
Nervous system disorders
Headache
subjects affected / exposed	2 / 6 (33.33%)	5 / 40 (12.50%)	0 / 8 (0.00%)	0 / 16 (0.00%)	0 / 25 (0.00%)	0 / 50 (0.00%)
occurrences all number	3	7	0	0	0	0
Paraesthesia
subjects affected / exposed	1 / 6 (16.67%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	0 / 25 (0.00%)	0 / 50 (0.00%)
occurrences all number	2	0	0	0	0	0
Balance disorder
subjects affected / exposed	0 / 6 (0.00%)	1 / 40 (2.50%)	0 / 8 (0.00%)	0 / 16 (0.00%)	0 / 25 (0.00%)	0 / 50 (0.00%)
occurrences all number	0	2	0	0	0	0
Dizziness
subjects affected / exposed	0 / 6 (0.00%)	2 / 40 (5.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	0 / 25 (0.00%)	0 / 50 (0.00%)
occurrences all number	0	2	0	0	0	0
Disturbance in attention
subjects affected / exposed	0 / 6 (0.00%)	1 / 40 (2.50%)	0 / 8 (0.00%)	0 / 16 (0.00%)	0 / 25 (0.00%)	0 / 50 (0.00%)
occurrences all number	0	1	0	0	0	0
Dizziness postural
subjects affected / exposed	0 / 6 (0.00%)	1 / 40 (2.50%)	0 / 8 (0.00%)	0 / 16 (0.00%)	0 / 25 (0.00%)	0 / 50 (0.00%)
occurrences all number	0	1	0	0	0	0
Intracranial pressure increased
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	1 / 16 (6.25%)	0 / 25 (0.00%)	0 / 50 (0.00%)
occurrences all number	0	0	0	1	0	0
Tremor
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	1 / 16 (6.25%)	0 / 25 (0.00%)	0 / 50 (0.00%)
occurrences all number	0	0	0	1	0	0
Febrile convulsion
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	1 / 25 (4.00%)	0 / 50 (0.00%)
occurrences all number	0	0	0	0	1	0
Bulbar palsy
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	1 / 25 (4.00%)	0 / 50 (0.00%)
occurrences all number	0	0	0	0	1	0
Blood and lymphatic system disorders
Eosinophilia
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	1 / 16 (6.25%)	0 / 25 (0.00%)	1 / 50 (2.00%)
occurrences all number	0	0	0	1	0	1
Anaemia
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	1 / 25 (4.00%)	3 / 50 (6.00%)
occurrences all number	0	0	0	0	1	3
Leukocytosis
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	2 / 25 (8.00%)	0 / 50 (0.00%)
occurrences all number	0	0	0	0	2	0
Iron deficiency anaemia
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	1 / 25 (4.00%)	0 / 50 (0.00%)
occurrences all number	0	0	0	0	1	0
Deficiency anaemia
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	1 / 25 (4.00%)	0 / 50 (0.00%)
occurrences all number	0	0	0	0	2	0
Hypofibrinogenaemia
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	0 / 25 (0.00%)	1 / 50 (2.00%)
occurrences all number	0	0	0	0	0	1
Normochromic normocytic anaemia
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	1 / 25 (4.00%)	0 / 50 (0.00%)
occurrences all number	0	0	0	0	1	0
Thrombocytosis
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	1 / 25 (4.00%)	0 / 50 (0.00%)
occurrences all number	0	0	0	0	1	0
Secondary thrombocytosis
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	1 / 25 (4.00%)	0 / 50 (0.00%)
occurrences all number	0	0	0	0	1	0
Ear and labyrinth disorders
Vestibular disorder
subjects affected / exposed	0 / 6 (0.00%)	1 / 40 (2.50%)	0 / 8 (0.00%)	0 / 16 (0.00%)	0 / 25 (0.00%)	0 / 50 (0.00%)
occurrences all number	0	1	0	0	0	0
Eye disorders
Myopia
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	1 / 16 (6.25%)	0 / 25 (0.00%)	0 / 50 (0.00%)
occurrences all number	0	0	0	1	0	0
Eye discharge
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	0 / 25 (0.00%)	1 / 50 (2.00%)
occurrences all number	0	0	0	0	0	2
Gastrointestinal disorders
Vomiting
subjects affected / exposed	2 / 6 (33.33%)	1 / 40 (2.50%)	1 / 8 (12.50%)	2 / 16 (12.50%)	2 / 25 (8.00%)	4 / 50 (8.00%)
occurrences all number	2	2	1	2	3	6
Diarrhoea
subjects affected / exposed	0 / 6 (0.00%)	1 / 40 (2.50%)	0 / 8 (0.00%)	2 / 16 (12.50%)	0 / 25 (0.00%)	2 / 50 (4.00%)
occurrences all number	0	2	0	2	0	2
Nausea
subjects affected / exposed	0 / 6 (0.00%)	2 / 40 (5.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	1 / 25 (4.00%)	0 / 50 (0.00%)
occurrences all number	0	2	0	0	1	0
Constipation
subjects affected / exposed	0 / 6 (0.00%)	2 / 40 (5.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	1 / 25 (4.00%)	7 / 50 (14.00%)
occurrences all number	0	2	0	0	2	8
Abdominal pain
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	1 / 16 (6.25%)	0 / 25 (0.00%)	0 / 50 (0.00%)
occurrences all number	0	0	0	1	0	0
Gastrooesophageal reflux disease
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	1 / 25 (4.00%)	2 / 50 (4.00%)
occurrences all number	0	0	0	0	1	2
Dysphagia
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	2 / 25 (8.00%)	5 / 50 (10.00%)
occurrences all number	0	0	0	0	2	6
Dysbiosis
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	0 / 25 (0.00%)	1 / 50 (2.00%)
occurrences all number	0	0	0	0	0	1
Salivary hypersecretion
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	0 / 25 (0.00%)	1 / 50 (2.00%)
occurrences all number	0	0	0	0	0	1
Infantile diarrhoea
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	0 / 25 (0.00%)	1 / 50 (2.00%)
occurrences all number	0	0	0	0	0	1
Functional gastrointestinal disorder
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	0 / 25 (0.00%)	1 / 50 (2.00%)
occurrences all number	0	0	0	0	0	1
Hepatobiliary disorders
Hyperbilirubinaemia
subjects affected / exposed	0 / 6 (0.00%)	1 / 40 (2.50%)	0 / 8 (0.00%)	0 / 16 (0.00%)	0 / 25 (0.00%)	0 / 50 (0.00%)
occurrences all number	0	1	0	0	0	0
Hepatic function abnormal
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	0 / 25 (0.00%)	2 / 50 (4.00%)
occurrences all number	0	0	0	0	0	3
Skin and subcutaneous tissue disorders
Urticaria
subjects affected / exposed	1 / 6 (16.67%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	0 / 25 (0.00%)	0 / 50 (0.00%)
occurrences all number	1	0	0	0	0	0
Dermatitis allergic
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	1 / 16 (6.25%)	0 / 25 (0.00%)	0 / 50 (0.00%)
occurrences all number	0	0	0	1	0	0
Rash
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	1 / 8 (12.50%)	0 / 16 (0.00%)	0 / 25 (0.00%)	3 / 50 (6.00%)
occurrences all number	0	0	1	0	0	3
Dermatitis contact
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	2 / 25 (8.00%)	0 / 50 (0.00%)
occurrences all number	0	0	0	0	2	0
Acne infantile
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	1 / 25 (4.00%)	0 / 50 (0.00%)
occurrences all number	0	0	0	0	1	0
Rash erythematous
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	0 / 25 (0.00%)	1 / 50 (2.00%)
occurrences all number	0	0	0	0	0	1
Eczema infantile
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	0 / 25 (0.00%)	1 / 50 (2.00%)
occurrences all number	0	0	0	0	0	1
Dermatitis
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	0 / 25 (0.00%)	1 / 50 (2.00%)
occurrences all number	0	0	0	0	0	1
Eczema
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	0 / 25 (0.00%)	2 / 50 (4.00%)
occurrences all number	0	0	0	0	0	3
Dermatitis diaper
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	0 / 25 (0.00%)	3 / 50 (6.00%)
occurrences all number	0	0	0	0	0	3
Renal and urinary disorders
Nephrolithiasis
subjects affected / exposed	0 / 6 (0.00%)	1 / 40 (2.50%)	0 / 8 (0.00%)	0 / 16 (0.00%)	0 / 25 (0.00%)	0 / 50 (0.00%)
occurrences all number	0	1	0	0	0	0
Proteinuria
subjects affected / exposed	0 / 6 (0.00%)	1 / 40 (2.50%)	0 / 8 (0.00%)	1 / 16 (6.25%)	0 / 25 (0.00%)	0 / 50 (0.00%)
occurrences all number	0	1	0	1	0	0
Leukocyturia
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	1 / 25 (4.00%)	0 / 50 (0.00%)
occurrences all number	0	0	0	0	1	0
Musculoskeletal and connective tissue disorders
Foot deformity
subjects affected / exposed	1 / 6 (16.67%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	0 / 25 (0.00%)	0 / 50 (0.00%)
occurrences all number	2	0	0	0	0	0
Myalgia
subjects affected / exposed	0 / 6 (0.00%)	3 / 40 (7.50%)	0 / 8 (0.00%)	0 / 16 (0.00%)	0 / 25 (0.00%)	0 / 50 (0.00%)
occurrences all number	0	5	0	0	0	0
Muscle contracture
subjects affected / exposed	0 / 6 (0.00%)	3 / 40 (7.50%)	0 / 8 (0.00%)	0 / 16 (0.00%)	0 / 25 (0.00%)	1 / 50 (2.00%)
occurrences all number	0	3	0	0	0	1
Pain in extremity
subjects affected / exposed	0 / 6 (0.00%)	3 / 40 (7.50%)	0 / 8 (0.00%)	0 / 16 (0.00%)	0 / 25 (0.00%)	0 / 50 (0.00%)
occurrences all number	0	3	0	0	0	0
Osteopenia
subjects affected / exposed	0 / 6 (0.00%)	1 / 40 (2.50%)	0 / 8 (0.00%)	0 / 16 (0.00%)	0 / 25 (0.00%)	0 / 50 (0.00%)
occurrences all number	0	1	0	0	0	0
Joint contracture
subjects affected / exposed	0 / 6 (0.00%)	1 / 40 (2.50%)	0 / 8 (0.00%)	1 / 16 (6.25%)	0 / 25 (0.00%)	0 / 50 (0.00%)
occurrences all number	0	2	0	1	0	0
Neck pain
subjects affected / exposed	0 / 6 (0.00%)	2 / 40 (5.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	0 / 25 (0.00%)	0 / 50 (0.00%)
occurrences all number	0	2	0	0	0	0
Limb discomfort
subjects affected / exposed	0 / 6 (0.00%)	1 / 40 (2.50%)	0 / 8 (0.00%)	0 / 16 (0.00%)	0 / 25 (0.00%)	0 / 50 (0.00%)
occurrences all number	0	1	0	0	0	0
Musculoskeletal stiffness
subjects affected / exposed	0 / 6 (0.00%)	1 / 40 (2.50%)	0 / 8 (0.00%)	0 / 16 (0.00%)	0 / 25 (0.00%)	0 / 50 (0.00%)
occurrences all number	0	1	0	0	0	0
Myalgia intercostal
subjects affected / exposed	0 / 6 (0.00%)	1 / 40 (2.50%)	0 / 8 (0.00%)	0 / 16 (0.00%)	0 / 25 (0.00%)	0 / 50 (0.00%)
occurrences all number	0	1	0	0	0	0
Arthralgia
subjects affected / exposed	0 / 6 (0.00%)	2 / 40 (5.00%)	1 / 8 (12.50%)	0 / 16 (0.00%)	0 / 25 (0.00%)	0 / 50 (0.00%)
occurrences all number	0	2	1	0	0	0
Osteoporosis
subjects affected / exposed	0 / 6 (0.00%)	1 / 40 (2.50%)	0 / 8 (0.00%)	0 / 16 (0.00%)	0 / 25 (0.00%)	0 / 50 (0.00%)
occurrences all number	0	1	0	0	0	0
Scoliosis
subjects affected / exposed	0 / 6 (0.00%)	1 / 40 (2.50%)	0 / 8 (0.00%)	1 / 16 (6.25%)	0 / 25 (0.00%)	2 / 50 (4.00%)
occurrences all number	0	1	0	1	0	2
Short stature
subjects affected / exposed	0 / 6 (0.00%)	1 / 40 (2.50%)	0 / 8 (0.00%)	0 / 16 (0.00%)	0 / 25 (0.00%)	0 / 50 (0.00%)
occurrences all number	0	1	0	0	0	0
Tendinous contracture
subjects affected / exposed	0 / 6 (0.00%)	1 / 40 (2.50%)	0 / 8 (0.00%)	0 / 16 (0.00%)	0 / 25 (0.00%)	0 / 50 (0.00%)
occurrences all number	0	1	0	0	0	0
Acquired plagiocephaly
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	0 / 25 (0.00%)	1 / 50 (2.00%)
occurrences all number	0	0	0	0	0	1
Joint range of motion decreased
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	0 / 25 (0.00%)	1 / 50 (2.00%)
occurrences all number	0	0	0	0	0	1
Muscular weakness
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	0 / 25 (0.00%)	1 / 50 (2.00%)
occurrences all number	0	0	0	0	0	1
Extremity contracture
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	1 / 25 (4.00%)	0 / 50 (0.00%)
occurrences all number	0	0	0	0	1	0
Infections and infestations
Upper respiratory tract infection
subjects affected / exposed	1 / 6 (16.67%)	2 / 40 (5.00%)	2 / 8 (25.00%)	2 / 16 (12.50%)	3 / 25 (12.00%)	8 / 50 (16.00%)
occurrences all number	2	3	3	2	3	9
Gingivitis
subjects affected / exposed	1 / 6 (16.67%)	0 / 40 (0.00%)	0 / 8 (0.00%)	1 / 16 (6.25%)	0 / 25 (0.00%)	0 / 50 (0.00%)
occurrences all number	1	0	0	1	0	0
Tonsillitis
subjects affected / exposed	1 / 6 (16.67%)	0 / 40 (0.00%)	1 / 8 (12.50%)	2 / 16 (12.50%)	0 / 25 (0.00%)	0 / 50 (0.00%)
occurrences all number	1	0	1	2	0	0
COVID-19
subjects affected / exposed	0 / 6 (0.00%)	11 / 40 (27.50%)	1 / 8 (12.50%)	0 / 16 (0.00%)	2 / 25 (8.00%)	5 / 50 (10.00%)
occurrences all number	0	12	1	0	2	6
Cystitis
subjects affected / exposed	0 / 6 (0.00%)	1 / 40 (2.50%)	0 / 8 (0.00%)	0 / 16 (0.00%)	0 / 25 (0.00%)	0 / 50 (0.00%)
occurrences all number	0	1	0	0	0	0
Bronchitis
subjects affected / exposed	0 / 6 (0.00%)	1 / 40 (2.50%)	0 / 8 (0.00%)	1 / 16 (6.25%)	3 / 25 (12.00%)	2 / 50 (4.00%)
occurrences all number	0	2	0	1	3	2
Gastroenteritis
subjects affected / exposed	0 / 6 (0.00%)	2 / 40 (5.00%)	0 / 8 (0.00%)	1 / 16 (6.25%)	0 / 25 (0.00%)	1 / 50 (2.00%)
occurrences all number	0	2	0	1	0	2
Urinary tract infection
subjects affected / exposed	0 / 6 (0.00%)	2 / 40 (5.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	0 / 25 (0.00%)	0 / 50 (0.00%)
occurrences all number	0	2	0	0	0	0
Nasopharyngitis
subjects affected / exposed	0 / 6 (0.00%)	4 / 40 (10.00%)	0 / 8 (0.00%)	2 / 16 (12.50%)	1 / 25 (4.00%)	2 / 50 (4.00%)
occurrences all number	0	6	0	2	1	2
Influenza
subjects affected / exposed	0 / 6 (0.00%)	1 / 40 (2.50%)	1 / 8 (12.50%)	1 / 16 (6.25%)	1 / 25 (4.00%)	2 / 50 (4.00%)
occurrences all number	0	1	1	1	1	3
Sinusitis
subjects affected / exposed	0 / 6 (0.00%)	1 / 40 (2.50%)	0 / 8 (0.00%)	0 / 16 (0.00%)	0 / 25 (0.00%)	0 / 50 (0.00%)
occurrences all number	0	1	0	0	0	0
Respiratory tract infection
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	1 / 16 (6.25%)	1 / 25 (4.00%)	1 / 50 (2.00%)
occurrences all number	0	0	0	1	1	1
Asymptomatic bacteriuria
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	1 / 16 (6.25%)	0 / 25 (0.00%)	0 / 50 (0.00%)
occurrences all number	0	0	0	1	0	0
Hand-foot-and-mouth disease
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	1 / 16 (6.25%)	0 / 25 (0.00%)	1 / 50 (2.00%)
occurrences all number	0	0	0	1	0	1
Lice infestation
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	1 / 16 (6.25%)	0 / 25 (0.00%)	0 / 50 (0.00%)
occurrences all number	0	0	0	1	0	0
Otitis media acute
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	1 / 16 (6.25%)	0 / 25 (0.00%)	0 / 50 (0.00%)
occurrences all number	0	0	0	1	0	0
Suspected COVID-19
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	1 / 16 (6.25%)	0 / 25 (0.00%)	0 / 50 (0.00%)
occurrences all number	0	0	0	1	0	0
Vulvovaginal candidiasis
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	1 / 16 (6.25%)	0 / 25 (0.00%)	0 / 50 (0.00%)
occurrences all number	0	0	0	1	0	0
Vulvovaginitis
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	1 / 16 (6.25%)	0 / 25 (0.00%)	0 / 50 (0.00%)
occurrences all number	0	0	0	1	0	0
Gastroenteritis rotavirus
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	1 / 8 (12.50%)	0 / 16 (0.00%)	0 / 25 (0.00%)	0 / 50 (0.00%)
occurrences all number	0	0	1	0	0	0
Otitis media
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	1 / 8 (12.50%)	0 / 16 (0.00%)	0 / 25 (0.00%)	2 / 50 (4.00%)
occurrences all number	0	0	1	0	0	2
Pneumonia
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	1 / 8 (12.50%)	0 / 16 (0.00%)	0 / 25 (0.00%)	3 / 50 (6.00%)
occurrences all number	0	0	1	0	0	3
Bronchiolitis
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	0 / 25 (0.00%)	2 / 50 (4.00%)
occurrences all number	0	0	0	0	0	2
Pneumonia klebsiella
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	0 / 25 (0.00%)	2 / 50 (4.00%)
occurrences all number	0	0	0	0	0	2
Stoma site infection
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	0 / 25 (0.00%)	2 / 50 (4.00%)
occurrences all number	0	0	0	0	0	4
Herpangina
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	1 / 25 (4.00%)	1 / 50 (2.00%)
occurrences all number	0	0	0	0	1	1
Bronchitis viral
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	0 / 25 (0.00%)	1 / 50 (2.00%)
occurrences all number	0	0	0	0	0	1
Cystitis bacterial
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	0 / 25 (0.00%)	1 / 50 (2.00%)
occurrences all number	0	0	0	0	0	1
Enterovirus infection
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	0 / 25 (0.00%)	1 / 50 (2.00%)
occurrences all number	0	0	0	0	0	1
Eye infection
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	0 / 25 (0.00%)	1 / 50 (2.00%)
occurrences all number	0	0	0	0	0	1
Helminthic infection
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	0 / 25 (0.00%)	1 / 50 (2.00%)
occurrences all number	0	0	0	0	0	1
Viral infection
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	0 / 25 (0.00%)	2 / 50 (4.00%)
occurrences all number	0	0	0	0	0	3
Otitis externa
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	0 / 25 (0.00%)	1 / 50 (2.00%)
occurrences all number	0	0	0	0	0	1
Pharyngitis
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	0 / 25 (0.00%)	1 / 50 (2.00%)
occurrences all number	0	0	0	0	0	1
Pneumonia moraxella
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	0 / 25 (0.00%)	1 / 50 (2.00%)
occurrences all number	0	0	0	0	0	1
Pneumonia pseudomonal
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	1 / 25 (4.00%)	1 / 50 (2.00%)
occurrences all number	0	0	0	0	1	1
Respiratory syncytial virus bronchiolitis
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	0 / 25 (0.00%)	1 / 50 (2.00%)
occurrences all number	0	0	0	0	0	1
Respiratory tract infection viral
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	0 / 25 (0.00%)	1 / 50 (2.00%)
occurrences all number	0	0	0	0	0	1
Rhinovirus infection
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	1 / 25 (4.00%)	1 / 50 (2.00%)
occurrences all number	0	0	0	0	1	1
Sepsis
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	1 / 25 (4.00%)	1 / 50 (2.00%)
occurrences all number	0	0	0	0	1	1
Septic shock
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	0 / 25 (0.00%)	1 / 50 (2.00%)
occurrences all number	0	0	0	0	0	1
Varicella
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	1 / 25 (4.00%)	1 / 50 (2.00%)
occurrences all number	0	0	0	0	1	1
Vascular device infection
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	0 / 25 (0.00%)	1 / 50 (2.00%)
occurrences all number	0	0	0	0	0	1
Viral upper respiratory tract infection
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	2 / 25 (8.00%)	1 / 50 (2.00%)
occurrences all number	0	0	0	0	2	1
Gastroenteritis adenovirus
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	1 / 25 (4.00%)	0 / 50 (0.00%)
occurrences all number	0	0	0	0	1	0
Gastroenteritis Escherichia coli
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	1 / 25 (4.00%)	0 / 50 (0.00%)
occurrences all number	0	0	0	0	1	0
Urinary tract infection enterococcal
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	1 / 25 (4.00%)	0 / 50 (0.00%)
occurrences all number	0	0	0	0	1	0
Staphylococcal infection
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	1 / 25 (4.00%)	0 / 50 (0.00%)
occurrences all number	0	0	0	0	2	0
Pneumonia respiratory syncytial viral
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	1 / 25 (4.00%)	0 / 50 (0.00%)
occurrences all number	0	0	0	0	1	0
Klebsiella urinary tract infection
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	1 / 25 (4.00%)	0 / 50 (0.00%)
occurrences all number	0	0	0	0	1	0
Klebsiella infection
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	2 / 25 (8.00%)	0 / 50 (0.00%)
occurrences all number	0	0	0	0	2	0
Gastroenteritis viral
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	1 / 25 (4.00%)	0 / 50 (0.00%)
occurrences all number	0	0	0	0	1	0
Gastroenteritis norovirus
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	1 / 25 (4.00%)	0 / 50 (0.00%)
occurrences all number	0	0	0	0	1	0
Acinetobacter infection
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	1 / 25 (4.00%)	0 / 50 (0.00%)
occurrences all number	0	0	0	0	1	0
Conjunctivitis
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	1 / 25 (4.00%)	0 / 50 (0.00%)
occurrences all number	0	0	0	0	1	0
Enterobacter infection
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	1 / 25 (4.00%)	0 / 50 (0.00%)
occurrences all number	0	0	0	0	1	0
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	1 / 6 (16.67%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	0 / 25 (0.00%)	0 / 50 (0.00%)
occurrences all number	1	0	0	0	0	0
Hyponatraemia
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	0 / 25 (0.00%)	1 / 50 (2.00%)
occurrences all number	0	0	0	0	0	1
Dairy intolerance
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	0 / 25 (0.00%)	1 / 50 (2.00%)
occurrences all number	0	0	0	0	0	1
Malnutrition
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	2 / 25 (8.00%)	5 / 50 (10.00%)
occurrences all number	0	0	0	0	3	5
Hypoalbuminaemia
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	1 / 25 (4.00%)	0 / 50 (0.00%)
occurrences all number	0	0	0	0	1	0
Hypoglycaemia
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	1 / 25 (4.00%)	0 / 50 (0.00%)
occurrences all number	0	0	0	0	1	0
Hypokalaemia
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	1 / 25 (4.00%)	0 / 50 (0.00%)
occurrences all number	0	0	0	0	1	0
Lactose intolerance
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	1 / 25 (4.00%)	0 / 50 (0.00%)
occurrences all number	0	0	0	0	1	0
Protein deficiency
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	1 / 25 (4.00%)	0 / 50 (0.00%)
occurrences all number	0	0	0	0	1	0
Hyperglycaemia
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	1 / 25 (4.00%)	0 / 50 (0.00%)
occurrences all number	0	0	0	0	1	0
Electrolyte imbalance
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	1 / 25 (4.00%)	0 / 50 (0.00%)
occurrences all number	0	0	0	0	1	0
Underweight
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	0 / 25 (0.00%)	1 / 50 (2.00%)
occurrences all number	0	0	0	0	0	1
Iron deficiency
subjects affected / exposed	0 / 6 (0.00%)	0 / 40 (0.00%)	0 / 8 (0.00%)	0 / 16 (0.00%)	0 / 25 (0.00%)	1 / 50 (2.00%)
occurrences all number	0	0	0	0	0	1

More information

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Were there any global substantial amendments to the protocol? Yes

03 Dec 2019

- Clarified that the primary objective for Part B was to examine efficacy, as measured by the change from baseline in CHOP INTEND total score. - Clarified that the remaining assessments that were used to evaluate the clinical efficacy of nusinersen for participants in Part B were secondary endpoints related to a secondary objective. - A separate table for Parts A and C objectives and endpoints was added to emphasize the differences between Part B and Parts A and C, and to clarify that safety was the primary objective for Parts A and C.

05 Jun 2020

- Made revision to the study stopping rules to clarify that they only apply to the primary safety portions of the study. - The footnotes regarding ECG monitoring in schedule of activities (SoA) tables were revised to adjust the postdose ECG timing and address abnormal ECG results. - The loading dose visit windows for Parts A and B of Study 232SM203 were clarified and revised. - A footnote was added to SoA tables to ensure that efficacy assessments (CHOP INTEND, HFMSE, and RULM) were conducted twice prior to the first dose of study treatment. - Guidance was added on the number of participants with scoliosis and/or severe contractures to be included in Part C of the study. - The study duration was extended, in order to align the requirements of contraception use and reporting, the follow-up period of the study was extended for those participants who require contraception use and an assessment was added on Day 410, Day 420, and Day 382 for Part A, Part B, and Part C, respectively. - Inclusion and exclusion criteria was updated. - A new section was added to the protocol to provide additional details on ventilation use.

05 Aug 2020

- Made revision to the study stopping rules so that they apply to all participants in Parts A and B of the study. - Language was added to the protocol regarding remote monitoring of study sites during the global coronavirus disease (COVID-19) pandemic.

01 Oct 2021

- Increased the sample size by including an additional cohort of up to approximately 20 adult participants in Part C to allow collection of clinical data in adults transitioning from the currently approved nusinersen dosing regimen to a higher dose. - The timepoints for collection of vital signs, neurological examinations, and ECGs and the collection windows for plasma PK samples were updated for Parts B and C. - A schedule of activities table specifically for Part C Cohort 2 was added. - A new table was added for participants in Part B who discontinued study treatment but agreed to remain in the study for follow-up. - Inclusion and exclusion criteria was updated for Parts A,B and C. - Added details on contracture assessment, to update the information on PedsQL for the adult participants who enrolled in Cohort 2 of Part C. - Updated growth parameters to allow for measurement of length for participants with later-onset SMA who were not able to have height measured.

05 May 2022

- Reduced the sample size for Part B infantile onset participants to 75. As a result, the total sample size for the study was adjusted to 145 participants. - Part B exclusion criteria was updated. - The PedsQL Measurement 4.0 Generic Core Scales and 3.0 Neuromuscular Module for participants ≥ 26 years of age were added. - Language was updated in laboratory safety assessments to further specify that total protein would be measured for the CSF local laboratory sample. - All references to an interim analysis being performed to assess the feasibility of borrowing participant data from Study CS3B were removed

Were there any global interruptions to the trial? No

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

None reported

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Clinical trials

Clinical Trial Results: Escalating Dose and Randomized, Controlled Study of Nusinersen (BIIB058) in Participants With Spinal Muscular Atrophy

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Part B Infantile-onset SMA: Change From Baseline in CHOP-INTEND Total Score for 50/28mg Nusinersen Versus CS3B Matched Sham Control Group

Primary: Part B Infantile-onset SMA: Change From Baseline in CHOP-INTEND Total Score for 50/28mg Nusinersen Versus CS3B Matched Sham Control Group

Primary: Parts A and C: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (TESAEs)

Primary: Parts A and C: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (TESAEs)

Primary: Parts A and C: Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Blood Chemistry Parameters)

Primary: Parts A and C: Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Blood Chemistry Parameters)

Primary: Parts A and C: Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Hematology Parameters)

Primary: Parts A and C: Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Hematology Parameters)

Primary: Parts A and C: Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Urinalysis Parameters)

Primary: Parts A and C: Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Urinalysis Parameters)

Primary: Parts A and C: Number of Participants With Shifts From Baseline in Cerebrospinal Fluid (CSF) Parameters

Primary: Parts A and C: Number of Participants With Shifts From Baseline in Cerebrospinal Fluid (CSF) Parameters

Primary: Parts A and C: Number of Participants With Shifts From Baseline in Electrocardiograms (ECGs)

Primary: Parts A and C: Number of Participants With Shifts From Baseline in Electrocardiograms (ECGs)

Primary: Parts A and C: Number of Participants With Abnormalities in Vital Sign Parameters

Primary: Parts A and C: Number of Participants With Abnormalities in Vital Sign Parameters

Primary: Parts A and C: Change From Baseline in Growth Parameters (Ulnar Length)

Primary: Parts A and C: Change From Baseline in Growth Parameters (Ulnar Length)

Primary: Part C: Change From Baseline in Growth Parameters (Arm Circumference)

Primary: Part C: Change From Baseline in Growth Parameters (Arm Circumference)

Primary: Part C: Change From Baseline in Growth Parameters (Chest Circumference)

Primary: Part C: Change From Baseline in Growth Parameters (Chest Circumference)

Primary: Part C: Change From Baseline in Growth Parameters (Head Circumference)

Primary: Part C: Change From Baseline in Growth Parameters (Head Circumference)

Primary: Parts A and C: Change From Baseline in Growth Parameters (Body Height)

Primary: Parts A and C: Change From Baseline in Growth Parameters (Body Height)

Primary: Parts A and C: Number of Participants With Shifts from Baseline in Coagulation Parameters (Activated Partial Thromboplastin Time (aPTT))

Primary: Parts A and C: Number of Participants With Shifts from Baseline in Coagulation Parameters (Activated Partial Thromboplastin Time (aPTT))

Primary: Parts A and C: Change From Baseline in Growth Parameters (Weight for Age Percentile)

Primary: Parts A and C: Change From Baseline in Growth Parameters (Weight for Age Percentile)

Primary: Parts A and C: Change From Baseline in Growth Parameters (Weight for Length Ratio)

Primary: Parts A and C: Change From Baseline in Growth Parameters (Weight for Length Ratio)

Primary: Parts A and C: Number of Participants With Shifts From Baseline in Coagulation Parameters (Prothrombin Time (PT))

Primary: Parts A and C: Number of Participants With Shifts From Baseline in Coagulation Parameters (Prothrombin Time (PT))

Primary: Part C: Change From Baseline in Growth Parameters (Head-to-Chest Circumference Ratio)

Primary: Part C: Change From Baseline in Growth Parameters (Head-to-Chest Circumference Ratio)

Primary: Parts A and C: Number of Participants With Shifts From Baseline in Coagulation Parameters (International Normalized Ratio (INR))

Primary: Parts A and C: Number of Participants With Shifts From Baseline in Coagulation Parameters (International Normalized Ratio (INR))

Primary: Parts A and C: Change From Baseline in Urine Total Protein

Primary: Parts A and C: Change From Baseline in Urine Total Protein

Primary: Parts A and C: Number of Participants With Neurological Examination Abnormalities Reported as AEs

Primary: Parts A and C: Number of Participants With Neurological Examination Abnormalities Reported as AEs

Primary: Parts A and C: Percentage of Participants With a Postbaseline Corrected QT Interval Using Fridericia's Formula (QTcF) of > 500 milliseconds (msec) and an Increase From Baseline to any Postbaseline Timepoint in QTcF of > 60 msec

Primary: Parts A and C: Percentage of Participants With a Postbaseline Corrected QT Interval Using Fridericia's Formula (QTcF) of > 500 milliseconds (msec) and an Increase From Baseline to any Postbaseline Timepoint in QTcF of > 60 msec

Primary: Parts A and C: Percentage of Participants With a Postbaseline Platelet Count Below the Lower Limit of Normal on at Least 2 Consecutive Measurements

Primary: Parts A and C: Percentage of Participants With a Postbaseline Platelet Count Below the Lower Limit of Normal on at Least 2 Consecutive Measurements

Secondary: Part B Infantile-onset SMA: Percentage of Hammersmith Infant Neurological Examination (HINE) Section 2 Motor Milestone Responders for 50/28mg Nusinersen Versus CS3B Matched Sham Control Group

Secondary: Part B Infantile-onset SMA: Percentage of Hammersmith Infant Neurological Examination (HINE) Section 2 Motor Milestone Responders for 50/28mg Nusinersen Versus CS3B Matched Sham Control Group

Secondary: Part B Infantile-onset SMA: Change From Baseline in CHOP-INTEND Total Score for 50/28mg Nusinersen Versus 12/12mg Nusinersen

Secondary: Part B Infantile-onset SMA: Change From Baseline in CHOP-INTEND Total Score for 50/28mg Nusinersen Versus 12/12mg Nusinersen

Secondary: Part B Infantile-onset SMA: Change From (Ratio to) Baseline in Plasma Concentration of Neurofilament Light Chain (NF-L) for 50/28mg Nusinersen Versus CS3B Matched Sham Control Group

Secondary: Part B Infantile-onset SMA: Change From (Ratio to) Baseline in Plasma Concentration of Neurofilament Light Chain (NF-L) for 50/28mg Nusinersen Versus CS3B Matched Sham Control Group

Secondary: Part B Infantile-onset SMA: Change From Baseline in HINE Section 2 Motor Milestones Total Score for 50/28mg Nusinersen Versus CS3B Matched Sham Control Group

Secondary: Part B Infantile-onset SMA: Change From Baseline in HINE Section 2 Motor Milestones Total Score for 50/28mg Nusinersen Versus CS3B Matched Sham Control Group

Secondary: Part B Infantile-onset SMA: Change From Baseline in HINE Section 2 Motor Milestones Total Score for 50/28mg Nusinersen Versus 12/12mg Nusinersen

Secondary: Part B Infantile-onset SMA: Change From Baseline in HINE Section 2 Motor Milestones Total Score for 50/28mg Nusinersen Versus 12/12mg Nusinersen

Secondary: Part B Infantile-onset SMA: Time to Death or Permanent Ventilation for 50/28mg Nusinersen Versus CS3B Matched Sham Control Group

Secondary: Part B Infantile-onset SMA: Time to Death or Permanent Ventilation for 50/28mg Nusinersen Versus CS3B Matched Sham Control Group

Secondary: Part B Infantile-onset SMA: Change From (Ratio to) Baseline in Plasma Concentration of NF-L for 50/28mg Nusinersen Versus 12/12mg Nusinersen

Secondary: Part B Infantile-onset SMA: Change From (Ratio to) Baseline in Plasma Concentration of NF-L for 50/28mg Nusinersen Versus 12/12mg Nusinersen

Secondary: Part B Infantile-onset SMA: Time to Death or Permanent Ventilation for 50/28mg Nusinersen Versus 12/12mg Nusinersen

Secondary: Part B Infantile-onset SMA: Time to Death or Permanent Ventilation for 50/28mg Nusinersen Versus 12/12mg Nusinersen

Secondary: Part B Infantile-onset SMA: Time to Death (Overall Survival) for 50/28mg Nusinersen Versus CS3B Matched Sham Control Group

Secondary: Part B Infantile-onset SMA: Time to Death (Overall Survival) for 50/28mg Nusinersen Versus CS3B Matched Sham Control Group

Secondary: Part B Later-onset SMA: Change From Baseline in Hammersmith Functional Motor Scale Expanded (HFMSE) Score for 50/28mg Nusinersen Versus 12/12mg Nusinersen

Secondary: Part B Later-onset SMA: Change From Baseline in Hammersmith Functional Motor Scale Expanded (HFMSE) Score for 50/28mg Nusinersen Versus 12/12mg Nusinersen

Secondary: Part B Later-onset SMA: Change From Baseline in Revised Upper Limb Module (RULM) Score for 50/28mg Nusinersen Versus 12/12mg Nusinersen

Secondary: Part B Later-onset SMA: Change From Baseline in Revised Upper Limb Module (RULM) Score for 50/28mg Nusinersen Versus 12/12mg Nusinersen

Secondary: Part B Infantile-onset SMA: Time to Death (Overall Survival) for 50/28mg Nusinersen Versus 12/12mg Nusinersen

Secondary: Part B Infantile-onset SMA: Time to Death (Overall Survival) for 50/28mg Nusinersen Versus 12/12mg Nusinersen

Clinical Trial Results:
Escalating Dose and Randomized, Controlled Study of Nusinersen (BIIB058) in Participants With Spinal Muscular Atrophy