Trial Outcomes & Findings for A Study of Multiple Doses of Nusinersen (ISIS 396443) Delivered to Infants With Genetically Diagnosed and Presymptomatic Spinal Muscular Atrophy (NCT NCT02386553)

Last Updated: 2025-10-20

Results Overview

The time was the age of the participant at the first occurrence of either a respiratory intervention or death. Respiratory intervention was defined as invasive or noninvasive ventilation for ≥6 hours/day continuously for 7 or more days OR tracheostomy.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

25 participants

Primary outcome timeframe

Screening up to Day 2891

Results posted on

2025-10-20

Participant Flow

Participants took part in the multiple investigative sites from 18 May 2015 to 17 Dec 2024.

A total of 25 participants diagnosed with Spinal Muscular Atrophy (SMA) were enrolled in the study.

Participant milestones

Participant milestones
Measure	ISIS 396443 2 SMN2 Copies Participants with 2 survival motor neuron 2 (SMN2) copies received 12 milligrams (mg) nusinersen, intrathecally (IT) on Days 1, 15, 29, 64, 183, 302, 421, 540, 659, 778, 897, 1016, 1135, 1254, 1373, 1492, 1611, 1730, 1849, 1968, 2087, 2206, 2325, 2444, 2563, 2682, and 2801.	ISIS 396443 3 SMN2 Copies Participants with 3 SMN2 copies received 12 mg nusinersen, IT on Days 1, 15, 29, 64, 183, 302, 421, 540, 659, 778, 897, 1016, 1135, 1254, 1373, 1492, 1611, 1730, 1849, 1968, 2087, 2206, 2325, 2444, 2563, 2682, and 2801.
Overall Study STARTED	15	10
Overall Study COMPLETED	13	9
Overall Study NOT COMPLETED	2	1

Reasons for withdrawal

Reasons for withdrawal
Measure	ISIS 396443 2 SMN2 Copies Participants with 2 survival motor neuron 2 (SMN2) copies received 12 milligrams (mg) nusinersen, intrathecally (IT) on Days 1, 15, 29, 64, 183, 302, 421, 540, 659, 778, 897, 1016, 1135, 1254, 1373, 1492, 1611, 1730, 1849, 1968, 2087, 2206, 2325, 2444, 2563, 2682, and 2801.	ISIS 396443 3 SMN2 Copies Participants with 3 SMN2 copies received 12 mg nusinersen, IT on Days 1, 15, 29, 64, 183, 302, 421, 540, 659, 778, 897, 1016, 1135, 1254, 1373, 1492, 1611, 1730, 1849, 1968, 2087, 2206, 2325, 2444, 2563, 2682, and 2801.
Overall Study Reason Not Specified	1	1
Overall Study Withdrawal by parent/Guardian	1	0

Baseline Characteristics

A Study of Multiple Doses of Nusinersen (ISIS 396443) Delivered to Infants With Genetically Diagnosed and Presymptomatic Spinal Muscular Atrophy

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	ISIS 396443 2 SMN2 Copies n=15 Participants Participants with 2 SMN2 copies received 12 mg nusinersen, IT on Days 1, 15, 29, 64, 183, 302, 421, 540, 659, 778, 897, 1016, 1135, 1254, 1373, 1492, 1611, 1730, 1849, 1968, 2087, 2206, 2325, 2444, 2563, 2682, and 2801.	ISIS 396443 3 SMN2 Copies n=10 Participants Participants with 3 SMN2 copies received 12 mg nusinersen, IT on Days 1, 15, 29, 64, 183, 302, 421, 540, 659, 778, 897, 1016, 1135, 1254, 1373, 1492, 1611, 1730, 1849, 1968, 2087, 2206, 2325, 2444, 2563, 2682, and 2801.	Total n=25 Participants Total of all reporting groups
Age, Continuous	19.5 days STANDARD_DEVIATION 9.29 • n=5 Participants	22.3 days STANDARD_DEVIATION 12.45 • n=7 Participants	20.6 days STANDARD_DEVIATION 10.51 • n=5 Participants
Sex: Female, Male Female	7 Participants n=5 Participants	6 Participants n=7 Participants	13 Participants n=5 Participants
Sex: Female, Male Male	8 Participants n=5 Participants	4 Participants n=7 Participants	12 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	2 Participants n=5 Participants	0 Participants n=7 Participants	2 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	10 Participants n=5 Participants	9 Participants n=7 Participants	19 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	3 Participants n=5 Participants	1 Participants n=7 Participants	4 Participants n=5 Participants
Race/Ethnicity, Customized Race · American Indian or Alaska Native	1 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants
Race/Ethnicity, Customized Race · Asian	1 Participants n=5 Participants	2 Participants n=7 Participants	3 Participants n=5 Participants
Race/Ethnicity, Customized Race · White	8 Participants n=5 Participants	6 Participants n=7 Participants	14 Participants n=5 Participants
Race/Ethnicity, Customized Race · Other	2 Participants n=5 Participants	1 Participants n=7 Participants	3 Participants n=5 Participants
Race/Ethnicity, Customized Race · Not Reported Due to Confidentiality Regulations	3 Participants n=5 Participants	1 Participants n=7 Participants	4 Participants n=5 Participants

PRIMARY outcome

Timeframe: Screening up to Day 2891

Outcome measures

Outcome measures
Measure	ISIS 396443 2 SMN2 Copies n=5 Participants Participants with 2 SMN2 copies received 12 mg nusinersen, IT on Days 1, 15, 29, 64, 183, 302, 421, 540, 659, 778, 897, 1016, 1135, 1254, 1373, 1492, 1611, 1730, 1849, 1968, 2087, 2206, 2325, 2444, 2563, 2682, and 2801.	ISIS 396443 3 SMN2 Copies Participants with 3 SMN2 copies received 12 mg nusinersen, IT on Days 1, 15, 29, 64, 183, 302, 421, 540, 659, 778, 897, 1016, 1135, 1254, 1373, 1492, 1611, 1730, 1849, 1968, 2087, 2206, 2325, 2444, 2563, 2682, and 2801.
Time to Death or Respiratory Intervention	NA months Interval 19.1 to Median or upper 95% CI not estimable are due to low number of events (i.e. death or respiratory events described above) within the assessed time frame.	—

SECONDARY outcome

Timeframe: At 13 and 24 months of age

Population: The ITT set included all participants who received at least 1 dose of ISIS 396443.

A participant was considered having clinically manifested SMA if any of the following occurred: * Age-adjusted weight \<5th percentile or decrease of ≥2 major weight growth curve percentiles (3rd, 5th, 10th, 25th, or 50th) or a percutaneous gastric tube placement for nutritional support * Failure to achieve the ability to sit without support * Failure to achieve standing with assistance * Failure to achieve hands-and-knees crawling * Failure to achieve walking with assistance by 24 months of age * Failure to achieve standing alone by 24 months of age * Failure to achieve walking alone by 24 months of age

Outcome measures

Outcome measures
Measure	ISIS 396443 2 SMN2 Copies n=15 Participants Participants with 2 SMN2 copies received 12 mg nusinersen, IT on Days 1, 15, 29, 64, 183, 302, 421, 540, 659, 778, 897, 1016, 1135, 1254, 1373, 1492, 1611, 1730, 1849, 1968, 2087, 2206, 2325, 2444, 2563, 2682, and 2801.	ISIS 396443 3 SMN2 Copies n=10 Participants Participants with 3 SMN2 copies received 12 mg nusinersen, IT on Days 1, 15, 29, 64, 183, 302, 421, 540, 659, 778, 897, 1016, 1135, 1254, 1373, 1492, 1611, 1730, 1849, 1968, 2087, 2206, 2325, 2444, 2563, 2682, and 2801.
Proportion of Participants Developing Clinically Manifested Spinal Muscular Atrophy (SMA) 13 months of age	0.67 proportion of participants Interval 0.39 to 0.87	0.20 proportion of participants Interval 0.04 to 0.56
Proportion of Participants Developing Clinically Manifested Spinal Muscular Atrophy (SMA) 24 months of age	0.47 proportion of participants Interval 0.22 to 0.73	0 proportion of participants Interval 0.0 to 0.34

SECONDARY outcome

Timeframe: Up to 8 years of age

Population: The ITT set included all participants who received at least 1 dose of ISIS 396443.

Outcome measures

Outcome measures
Measure	ISIS 396443 2 SMN2 Copies n=15 Participants Participants with 2 SMN2 copies received 12 mg nusinersen, IT on Days 1, 15, 29, 64, 183, 302, 421, 540, 659, 778, 897, 1016, 1135, 1254, 1373, 1492, 1611, 1730, 1849, 1968, 2087, 2206, 2325, 2444, 2563, 2682, and 2801.	ISIS 396443 3 SMN2 Copies n=10 Participants Participants with 3 SMN2 copies received 12 mg nusinersen, IT on Days 1, 15, 29, 64, 183, 302, 421, 540, 659, 778, 897, 1016, 1135, 1254, 1373, 1492, 1611, 1730, 1849, 1968, 2087, 2206, 2325, 2444, 2563, 2682, and 2801.
Percentage of Participants Alive	100 percentage of participants	100 percentage of participants

SECONDARY outcome

Timeframe: Day 700

Population: The ITT set included all participants who received at least 1 dose of ISIS 396443.

HINE is evaluated in infants between 2-24 months of age. It's a simple, standardized instrument including 26 items assessing different aspects of neurological examinations, such as cranial nerves, posture, movements, tone, and reflexes. In this study, Module 2 of HINE (HINE-2) was assessed, which evaluates 8 developmental milestones (head control, sitting, voluntary grasp, ability to kick, rolling, crawling, standing, and walking) scored on a 3, 4, or 5-point scale, with 0 indicating inability to perform task and score of 2, 3, or 4 indicating full milestone development. Total score is calculated by summing item scores to give maximum possible score of 26. Higher score indicates good neurological function.

Outcome measures

Outcome measures
Measure	ISIS 396443 2 SMN2 Copies n=15 Participants Participants with 2 SMN2 copies received 12 mg nusinersen, IT on Days 1, 15, 29, 64, 183, 302, 421, 540, 659, 778, 897, 1016, 1135, 1254, 1373, 1492, 1611, 1730, 1849, 1968, 2087, 2206, 2325, 2444, 2563, 2682, and 2801.	ISIS 396443 3 SMN2 Copies n=10 Participants Participants with 3 SMN2 copies received 12 mg nusinersen, IT on Days 1, 15, 29, 64, 183, 302, 421, 540, 659, 778, 897, 1016, 1135, 1254, 1373, 1492, 1611, 1730, 1849, 1968, 2087, 2206, 2325, 2444, 2563, 2682, and 2801.
Percentage of Participants Who Attained Motor Milestones Assessed as Part of the Hammersmith Infant Neurological Examination (HINE) First achievement of sitting milestone - Stable sit or Pivots (Rotates)	100 percentage of participants	100 percentage of participants
Percentage of Participants Who Attained Motor Milestones Assessed as Part of the Hammersmith Infant Neurological Examination (HINE) First achievement of standing with support milestone - Stands with support or Stands unaided	93 percentage of participants	100 percentage of participants
Percentage of Participants Who Attained Motor Milestones Assessed as Part of the Hammersmith Infant Neurological Examination (HINE) First achievement of standing unaided milestone - Stands unaided	73 percentage of participants	100 percentage of participants
Percentage of Participants Who Attained Motor Milestones Assessed as Part of the Hammersmith Infant Neurological Examination (HINE) First achievement of walking cruising milestone - Cruising (walks holding on)/Walking independently	87 percentage of participants	100 percentage of participants
Percentage of Participants Who Attained Motor Milestones Assessed as Part of the Hammersmith Infant Neurological Examination (HINE) First achievement of walking milestone - Walking independently	67 percentage of participants	100 percentage of participants
Percentage of Participants Who Attained Motor Milestones Assessed as Part of the Hammersmith Infant Neurological Examination (HINE) First achievement of head control - All the time maintained upright	100 percentage of participants	100 percentage of participants
Percentage of Participants Who Attained Motor Milestones Assessed as Part of the Hammersmith Infant Neurological Examination (HINE) First achievement of voluntary grasp - Pincer grasp	100 percentage of participants	100 percentage of participants
Percentage of Participants Who Attained Motor Milestones Assessed as Part of the Hammersmith Infant Neurological Examination (HINE) First achievement of ability to kick - Touches toes	100 percentage of participants	100 percentage of participants
Percentage of Participants Who Attained Motor Milestones Assessed as Part of the Hammersmith Infant Neurological Examination (HINE) First achievement of crawling - Crawling on hands and knees	73 percentage of participants	100 percentage of participants
Percentage of Participants Who Attained Motor Milestones Assessed as Part of the Hammersmith Infant Neurological Examination (HINE) First achievement of rolling - Prone to supine or Supine to prone	100 percentage of participants	100 percentage of participants

SECONDARY outcome

Timeframe: Baseline up to Day 2891

Population: The ITT set included all participants who received at least 1 dose of ISIS 396443.

The WHO motor milestones are a set of six milestones in motor development, all of which would be expected to be attained by 24 months of age in healthy children. The individual milestones are: sitting without support, standing with assistance, hands and knees crawling, walking with assistance, standing alone and walking alone.

Outcome measures

Outcome measures
Measure	ISIS 396443 2 SMN2 Copies n=15 Participants Participants with 2 SMN2 copies received 12 mg nusinersen, IT on Days 1, 15, 29, 64, 183, 302, 421, 540, 659, 778, 897, 1016, 1135, 1254, 1373, 1492, 1611, 1730, 1849, 1968, 2087, 2206, 2325, 2444, 2563, 2682, and 2801.	ISIS 396443 3 SMN2 Copies n=10 Participants Participants with 3 SMN2 copies received 12 mg nusinersen, IT on Days 1, 15, 29, 64, 183, 302, 421, 540, 659, 778, 897, 1016, 1135, 1254, 1373, 1492, 1611, 1730, 1849, 1968, 2087, 2206, 2325, 2444, 2563, 2682, and 2801.
Percentage of Participants Who Attained Motor Milestones as Assessed by World Health Organization (WHO) Criteria First standing alone milestone achieved using caregiver or site reported dates	93 percentage of participants	100 percentage of participants
Percentage of Participants Who Attained Motor Milestones as Assessed by World Health Organization (WHO) Criteria First sitting without support milestone achieved using caregiver or site reported dates	100 percentage of participants	100 percentage of participants
Percentage of Participants Who Attained Motor Milestones as Assessed by World Health Organization (WHO) Criteria First hands-and-knees crawling milestone achieved using caregiver or site reported dates	93 percentage of participants	100 percentage of participants
Percentage of Participants Who Attained Motor Milestones as Assessed by World Health Organization (WHO) Criteria First standing with assistance milestone achieved using caregiver or site reported dates	100 percentage of participants	100 percentage of participants
Percentage of Participants Who Attained Motor Milestones as Assessed by World Health Organization (WHO) Criteria First walking with assistance milestone achieved using caregiver or site reported dates	93 percentage of participants	100 percentage of participants
Percentage of Participants Who Attained Motor Milestones as Assessed by World Health Organization (WHO) Criteria First walking alone milestone achieved using caregiver or site reported dates	87 percentage of participants	100 percentage of participants

SECONDARY outcome

Timeframe: Baseline, Day 2891

Population: The ITT set included all participants who received at least 1 dose of ISIS 396443. Here 'number analyzed' signifies the number of participants available for analysis at a specified time point.

The CHOP-INTEND test was designed to evaluate the motor skills of infants with signiﬁcant motor weakness. Participants who were ≥2 years were continued to be assessed until a CHOP INTEND maximum score of 64 was achieved. 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 higher scores indicating greater muscle strength and function. Total score was calculated as the sum of scores for each item. Total score ranged from 0 (worst possible score) and 64 (best possible score). CHOP-INTEND assessments were discontinued once participants achieved a maximum score of 64, so the number of participants with available data points decreased over time.

Outcome measures

Outcome measures
Measure	ISIS 396443 2 SMN2 Copies n=15 Participants Participants with 2 SMN2 copies received 12 mg nusinersen, IT on Days 1, 15, 29, 64, 183, 302, 421, 540, 659, 778, 897, 1016, 1135, 1254, 1373, 1492, 1611, 1730, 1849, 1968, 2087, 2206, 2325, 2444, 2563, 2682, and 2801.	ISIS 396443 3 SMN2 Copies n=10 Participants Participants with 3 SMN2 copies received 12 mg nusinersen, IT on Days 1, 15, 29, 64, 183, 302, 421, 540, 659, 778, 897, 1016, 1135, 1254, 1373, 1492, 1611, 1730, 1849, 1968, 2087, 2206, 2325, 2444, 2563, 2682, and 2801.
Change From Baseline in the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) Motor Function Scale Baseline	47.0 score on a scale Standard Deviation 10.04	51.9 score on a scale Standard Deviation 6.10
Change From Baseline in the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) Motor Function Scale Change at Day 2891	29.0 score on a scale Standard Deviation 11.31	—

SECONDARY outcome

Timeframe: Baseline, Day 2160

The HFMSE consists of 33 scored activities used to assess motor function in children with SMA. Participants were asked to do a specific activity (such as rolling) and they were then graded on the quality and execution of that movement on a scale of 0=being unable, 1=performed with some compensation, and 2=unaided. The overall score is the sum of the scores for all activities and ranged from 0 to 66. Higher scores indicate increased motor function. Baseline was defined as the time of first HFMSE score after Day 700.

Outcome measures

Outcome measures
Measure	ISIS 396443 2 SMN2 Copies n=15 Participants Participants with 2 SMN2 copies received 12 mg nusinersen, IT on Days 1, 15, 29, 64, 183, 302, 421, 540, 659, 778, 897, 1016, 1135, 1254, 1373, 1492, 1611, 1730, 1849, 1968, 2087, 2206, 2325, 2444, 2563, 2682, and 2801.	ISIS 396443 3 SMN2 Copies n=10 Participants Participants with 3 SMN2 copies received 12 mg nusinersen, IT on Days 1, 15, 29, 64, 183, 302, 421, 540, 659, 778, 897, 1016, 1135, 1254, 1373, 1492, 1611, 1730, 1849, 1968, 2087, 2206, 2325, 2444, 2563, 2682, and 2801.
Change From Baseline in Hammersmith Functional Motor Scale - Expanded (HFMSE) Baseline	34.5 score on a scale Standard Deviation 12.15	46.4 score on a scale Standard Deviation 7.44
Change From Baseline in Hammersmith Functional Motor Scale - Expanded (HFMSE) Change at Day 2160	23.5 score on a scale Standard Deviation 5.34	22.5 score on a scale Standard Deviation 5.68

SECONDARY outcome

Timeframe: Baseline, Day 2891

The World Health Organization (WHO) child growth standards for participants aged up to 10 years was used to determine the percentiles. WHO Anthro software was used to calculate the percentiles for the given weights of each child. Negative change from baseline indicates low weight for age percentile.

Outcome measures

Outcome measures
Measure	ISIS 396443 2 SMN2 Copies n=15 Participants Participants with 2 SMN2 copies received 12 mg nusinersen, IT on Days 1, 15, 29, 64, 183, 302, 421, 540, 659, 778, 897, 1016, 1135, 1254, 1373, 1492, 1611, 1730, 1849, 1968, 2087, 2206, 2325, 2444, 2563, 2682, and 2801.	ISIS 396443 3 SMN2 Copies n=10 Participants Participants with 3 SMN2 copies received 12 mg nusinersen, IT on Days 1, 15, 29, 64, 183, 302, 421, 540, 659, 778, 897, 1016, 1135, 1254, 1373, 1492, 1611, 1730, 1849, 1968, 2087, 2206, 2325, 2444, 2563, 2682, and 2801.
Change From Baseline in Weight for Age Baseline	44.04 percentile Standard Deviation 31.197	34.76 percentile Standard Deviation 16.054
Change From Baseline in Weight for Age Change at Day 2891	-1.46 percentile Standard Deviation 48.041	24.49 percentile Standard Deviation 40.263

SECONDARY outcome

Timeframe: Baseline, Day 1849

Population: The ITT set included all participants who received at least 1 dose of ISIS 396443. Here, 'overall number of participants analyzed' signifies the number of participants with data available for outcome measure analysis. 'number analyzed' signifies the number of participants available for analysis at a specified time point.

The WHO child growth standards for participants aged up to 10 years was used to determine the percentiles. WHO Anthro software was used to calculate the percentiles for the given weights of each child.

Outcome measures

Outcome measures
Measure	ISIS 396443 2 SMN2 Copies n=10 Participants Participants with 2 SMN2 copies received 12 mg nusinersen, IT on Days 1, 15, 29, 64, 183, 302, 421, 540, 659, 778, 897, 1016, 1135, 1254, 1373, 1492, 1611, 1730, 1849, 1968, 2087, 2206, 2325, 2444, 2563, 2682, and 2801.	ISIS 396443 3 SMN2 Copies n=6 Participants Participants with 3 SMN2 copies received 12 mg nusinersen, IT on Days 1, 15, 29, 64, 183, 302, 421, 540, 659, 778, 897, 1016, 1135, 1254, 1373, 1492, 1611, 1730, 1849, 1968, 2087, 2206, 2325, 2444, 2563, 2682, and 2801.
Change From Baseline in Weight for Length Baseline	21.63 percentile Standard Deviation 22.806	45.26 percentile Standard Deviation 28.039
Change From Baseline in Weight for Length Change at Day 1849	38.94 percentile Standard Deviation NA Since only one participant was evaluable at Day 1849, the standard deviation (SD) could not be estimated.	—

SECONDARY outcome

Timeframe: Baseline, Day 2891

Outcome measures

Outcome measures
Measure	ISIS 396443 2 SMN2 Copies n=15 Participants Participants with 2 SMN2 copies received 12 mg nusinersen, IT on Days 1, 15, 29, 64, 183, 302, 421, 540, 659, 778, 897, 1016, 1135, 1254, 1373, 1492, 1611, 1730, 1849, 1968, 2087, 2206, 2325, 2444, 2563, 2682, and 2801.	ISIS 396443 3 SMN2 Copies n=10 Participants Participants with 3 SMN2 copies received 12 mg nusinersen, IT on Days 1, 15, 29, 64, 183, 302, 421, 540, 659, 778, 897, 1016, 1135, 1254, 1373, 1492, 1611, 1730, 1849, 1968, 2087, 2206, 2325, 2444, 2563, 2682, and 2801.
Change From Baseline in Head Circumference Baseline	35.59 centimeter (cm) Standard Deviation 2.285	36.11 centimeter (cm) Standard Deviation 2.198
Change From Baseline in Head Circumference Change at Day 2891	—	19.00 centimeter (cm) Standard Deviation NA Since only one participant was evaluable at Day 2891, the SD could not be estimated.

SECONDARY outcome

Timeframe: Baseline, Day 2891

Outcome measures

Outcome measures
Measure	ISIS 396443 2 SMN2 Copies n=15 Participants Participants with 2 SMN2 copies received 12 mg nusinersen, IT on Days 1, 15, 29, 64, 183, 302, 421, 540, 659, 778, 897, 1016, 1135, 1254, 1373, 1492, 1611, 1730, 1849, 1968, 2087, 2206, 2325, 2444, 2563, 2682, and 2801.	ISIS 396443 3 SMN2 Copies n=10 Participants Participants with 3 SMN2 copies received 12 mg nusinersen, IT on Days 1, 15, 29, 64, 183, 302, 421, 540, 659, 778, 897, 1016, 1135, 1254, 1373, 1492, 1611, 1730, 1849, 1968, 2087, 2206, 2325, 2444, 2563, 2682, and 2801.
Change From Baseline in Chest Circumference Baseline	34.43 cm Standard Deviation 2.724	35.25 cm Standard Deviation 2.551
Change From Baseline in Chest Circumference Change at Day 2891	—	28.20 cm Standard Deviation NA Since only one participant was evaluable at Day 2891, the SD could not be estimated.

SECONDARY outcome

Timeframe: Baseline, Day 2891

Negative change from baseline indicates reduction in head-to-chest circumference ratio.

Outcome measures

Outcome measures
Measure	ISIS 396443 2 SMN2 Copies n=15 Participants Participants with 2 SMN2 copies received 12 mg nusinersen, IT on Days 1, 15, 29, 64, 183, 302, 421, 540, 659, 778, 897, 1016, 1135, 1254, 1373, 1492, 1611, 1730, 1849, 1968, 2087, 2206, 2325, 2444, 2563, 2682, and 2801.	ISIS 396443 3 SMN2 Copies n=10 Participants Participants with 3 SMN2 copies received 12 mg nusinersen, IT on Days 1, 15, 29, 64, 183, 302, 421, 540, 659, 778, 897, 1016, 1135, 1254, 1373, 1492, 1611, 1730, 1849, 1968, 2087, 2206, 2325, 2444, 2563, 2682, and 2801.
Change From Baseline in Head to Chest Circumference Ratio Baseline	1.036 ratio Standard Deviation 0.0537	1.027 ratio Standard Deviation 0.0595
Change From Baseline in Head to Chest Circumference Ratio Change at Day 2891	—	-0.186 ratio Standard Deviation NA Since only one participant was evaluable at Day 2891, the SD could not be estimated.

SECONDARY outcome

Timeframe: Baseline, Day 2891

Outcome measures

Outcome measures
Measure	ISIS 396443 2 SMN2 Copies n=15 Participants Participants with 2 SMN2 copies received 12 mg nusinersen, IT on Days 1, 15, 29, 64, 183, 302, 421, 540, 659, 778, 897, 1016, 1135, 1254, 1373, 1492, 1611, 1730, 1849, 1968, 2087, 2206, 2325, 2444, 2563, 2682, and 2801.	ISIS 396443 3 SMN2 Copies n=10 Participants Participants with 3 SMN2 copies received 12 mg nusinersen, IT on Days 1, 15, 29, 64, 183, 302, 421, 540, 659, 778, 897, 1016, 1135, 1254, 1373, 1492, 1611, 1730, 1849, 1968, 2087, 2206, 2325, 2444, 2563, 2682, and 2801.
Change From Baseline in Arm Circumference Baseline	10.85 cm Standard Deviation 1.251	10.77 cm Standard Deviation 1.656
Change From Baseline in Arm Circumference Change at Day 2891	—	9.40 cm Standard Deviation NA Since only one participant was evaluable at Day 2891, the SD could not be estimated.

SECONDARY outcome

Timeframe: From the signing of the informed consent form (ICF) up to the end of the study (up to Day 2891)

Population: The ITT set included all participants who received at least 1 dose of ISIS 396443.

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.

Outcome measures

Outcome measures
Measure	ISIS 396443 2 SMN2 Copies n=15 Participants Participants with 2 SMN2 copies received 12 mg nusinersen, IT on Days 1, 15, 29, 64, 183, 302, 421, 540, 659, 778, 897, 1016, 1135, 1254, 1373, 1492, 1611, 1730, 1849, 1968, 2087, 2206, 2325, 2444, 2563, 2682, and 2801.	ISIS 396443 3 SMN2 Copies n=10 Participants Participants with 3 SMN2 copies received 12 mg nusinersen, IT on Days 1, 15, 29, 64, 183, 302, 421, 540, 659, 778, 897, 1016, 1135, 1254, 1373, 1492, 1611, 1730, 1849, 1968, 2087, 2206, 2325, 2444, 2563, 2682, and 2801.
Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) AEs	15 Participants	10 Participants
Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) SAEs	10 Participants	4 Participants

SECONDARY outcome

Timeframe: Baseline up to Day 2891

Hematology parameters included hemoglobin, hematocrit, erythrocytes, platelets, leukocytes, neutrophils, eosinophils, basophils, lymphocytes, and monocytes count. These parameters were flagged as low, normal, or high relative to parameter's normal range or as unknown if no result was available. Here, shift to low indicated 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 values.

Outcome measures

Outcome measures
Measure	ISIS 396443 2 SMN2 Copies n=15 Participants Participants with 2 SMN2 copies received 12 mg nusinersen, IT on Days 1, 15, 29, 64, 183, 302, 421, 540, 659, 778, 897, 1016, 1135, 1254, 1373, 1492, 1611, 1730, 1849, 1968, 2087, 2206, 2325, 2444, 2563, 2682, and 2801.	ISIS 396443 3 SMN2 Copies n=10 Participants Participants with 3 SMN2 copies received 12 mg nusinersen, IT on Days 1, 15, 29, 64, 183, 302, 421, 540, 659, 778, 897, 1016, 1135, 1254, 1373, 1492, 1611, 1730, 1849, 1968, 2087, 2206, 2325, 2444, 2563, 2682, and 2801.
Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Hematology Parameters) Hemoglobin Shift to Low	10 Participants	5 Participants
Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Hematology Parameters) Hemoglobin Shift to High	3 Participants	4 Participants
Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Hematology Parameters) Hematocrit Shift to Low	7 Participants	7 Participants
Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Hematology Parameters) Hematocrit Shift to High	4 Participants	4 Participants
Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Hematology Parameters) Erythrocytes Shift to Low	3 Participants	5 Participants
Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Hematology Parameters) Erythrocytes Shift to High	9 Participants	3 Participants
Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Hematology Parameters) Leukocytes Shift to Low	5 Participants	6 Participants
Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Hematology Parameters) Leukocytes Shift to High	11 Participants	4 Participants
Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Hematology Parameters) Neutrophils/Leukocytes Shift to Low	4 Participants	2 Participants
Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Hematology Parameters) Neutrophils/Leukocytes Shift to High	4 Participants	0 Participants
Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Hematology Parameters) Eosinophils/Leukocytes Shift to Low	0 Participants	0 Participants
Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Hematology Parameters) Eosinophils/Leukocytes Shift to High	7 Participants	8 Participants
Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Hematology Parameters) Basophils/Leukocytes Shift to Low	0 Participants	0 Participants
Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Hematology Parameters) Basophils/Leukocytes Shift to High	10 Participants	9 Participants
Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Hematology Parameters) Lymphocytes/Leukocytes Shift to Low	4 Participants	1 Participants
Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Hematology Parameters) Monocytes/Leukocytes Shift to Low	11 Participants	7 Participants
Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Hematology Parameters) Lymphocytes/Leukocytes Shift to High	6 Participants	4 Participants
Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Hematology Parameters) Monocytes/Leukocytes Shift to High	4 Participants	1 Participants
Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Hematology Parameters) Neutrophils Shift to Low	2 Participants	1 Participants
Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Hematology Parameters) Neutrophils Shift to High	3 Participants	0 Participants
Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Hematology Parameters) Neutrophils, Segmented Shift to Low	6 Participants	4 Participants
Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Hematology Parameters) Neutrophils, Segmented Shift to High	9 Participants	1 Participants
Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Hematology Parameters) Eosinophils Shift to Low	0 Participants	0 Participants
Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Hematology Parameters) Eosinophils Shift to High	11 Participants	8 Participants
Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Hematology Parameters) Basophils Shift to Low	0 Participants	0 Participants
Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Hematology Parameters) Basophils Shift to High	4 Participants	2 Participants
Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Hematology Parameters) Lymphocytes Shift to Low	2 Participants	1 Participants
Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Hematology Parameters) Lymphocytes Shift to High	11 Participants	8 Participants
Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Hematology Parameters) Monocytes Shift to Low	14 Participants	10 Participants
Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Hematology Parameters) Monocytes Shift to High	4 Participants	0 Participants
Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Hematology Parameters) Platelets Shift to Low	3 Participants	5 Participants
Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Hematology Parameters) Platelets Shift to High	9 Participants	7 Participants

SECONDARY outcome

Timeframe: Baseline up to Day 2891

Blood chemistry parameters included bilirubin (direct and indirect), alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transferase, creatinine, sodium, potassium, chloride, protein, albumin, calcium, phosphate, glucose, cystatin C, creatine kinase. These parameters were flagged as low, normal, or high relative to parameter's normal range or as unknown if no result was available. Here, shift to low indicated 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 values.

Outcome measures

Outcome measures
Measure	ISIS 396443 2 SMN2 Copies n=15 Participants Participants with 2 SMN2 copies received 12 mg nusinersen, IT on Days 1, 15, 29, 64, 183, 302, 421, 540, 659, 778, 897, 1016, 1135, 1254, 1373, 1492, 1611, 1730, 1849, 1968, 2087, 2206, 2325, 2444, 2563, 2682, and 2801.	ISIS 396443 3 SMN2 Copies n=10 Participants Participants with 3 SMN2 copies received 12 mg nusinersen, IT on Days 1, 15, 29, 64, 183, 302, 421, 540, 659, 778, 897, 1016, 1135, 1254, 1373, 1492, 1611, 1730, 1849, 1968, 2087, 2206, 2325, 2444, 2563, 2682, and 2801.
Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Blood Chemistry Parameters) Indirect Bilirubin Shift to High	1 Participants	1 Participants
Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Blood Chemistry Parameters) Chloride Shift to Low	0 Participants	1 Participants
Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Blood Chemistry Parameters) Direct Bilirubin Shift to Low	14 Participants	10 Participants
Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Blood Chemistry Parameters) Direct Bilirubin Shift to High	0 Participants	1 Participants
Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Blood Chemistry Parameters) Alkaline Phosphatase Shift to Low	3 Participants	0 Participants
Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Blood Chemistry Parameters) Alkaline Phosphatase Shift to High	2 Participants	5 Participants
Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Blood Chemistry Parameters) Alanine Aminotransferase Shift to Low	0 Participants	0 Participants
Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Blood Chemistry Parameters) Alanine Aminotransferase Shift to High	7 Participants	2 Participants
Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Blood Chemistry Parameters) Aspartate Aminotransferase Shift to Low	0 Participants	0 Participants
Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Blood Chemistry Parameters) Aspartate Aminotransferase Shift to High	6 Participants	2 Participants
Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Blood Chemistry Parameters) Gamma Glutamyl Transferase Shift to Low	1 Participants	0 Participants
Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Blood Chemistry Parameters) Gamma Glutamyl Transferase Shift to High	1 Participants	0 Participants
Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Blood Chemistry Parameters) Urea Nitrogen Shift to Low	6 Participants	0 Participants
Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Blood Chemistry Parameters) Urea Nitrogen Shift to High	0 Participants	2 Participants
Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Blood Chemistry Parameters) Creatinine Shift to Low	5 Participants	2 Participants
Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Blood Chemistry Parameters) Creatinine Shift to High	1 Participants	4 Participants
Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Blood Chemistry Parameters) Sodium Shift to Low	2 Participants	0 Participants
Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Blood Chemistry Parameters) Sodium Shift to High	0 Participants	1 Participants
Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Blood Chemistry Parameters) Bilirubin Shift to Low	14 Participants	10 Participants
Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Blood Chemistry Parameters) Bilirubin Shift to High	2 Participants	1 Participants
Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Blood Chemistry Parameters) Indirect Bilirubin Shift to Low	0 Participants	0 Participants
Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Blood Chemistry Parameters) Potassium Shift to Low	0 Participants	1 Participants
Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Blood Chemistry Parameters) Potassium Shift to High	8 Participants	3 Participants
Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Blood Chemistry Parameters) Chloride Shift to High	0 Participants	2 Participants
Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Blood Chemistry Parameters) Protein Shift to Low	2 Participants	5 Participants
Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Blood Chemistry Parameters) Protein Shift to High	13 Participants	6 Participants
Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Blood Chemistry Parameters) Albumin Shift to Low	0 Participants	0 Participants
Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Blood Chemistry Parameters) Albumin Shift to High	10 Participants	8 Participants
Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Blood Chemistry Parameters) Bicarbonate Shift to Low	8 Participants	7 Participants
Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Blood Chemistry Parameters) Bicarbonate Shift to High	1 Participants	0 Participants
Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Blood Chemistry Parameters) Calcium Shift to Low	3 Participants	3 Participants
Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Blood Chemistry Parameters) Calcium Shift to High	6 Participants	8 Participants
Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Blood Chemistry Parameters) Phosphate Shift to Low	0 Participants	0 Participants
Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Blood Chemistry Parameters) Phosphate Shift to High	9 Participants	4 Participants
Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Blood Chemistry Parameters) Glucose Shift to Low	7 Participants	6 Participants
Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Blood Chemistry Parameters) Glucose Shift to High	11 Participants	7 Participants
Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Blood Chemistry Parameters) Cystatin C Shift to Low	6 Participants	4 Participants
Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Blood Chemistry Parameters) Cystatin C Shift to High	2 Participants	0 Participants
Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Blood Chemistry Parameters) Creatine Kinase Shift to Low	0 Participants	0 Participants
Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Blood Chemistry Parameters) Creatine Kinase Shift to High	8 Participants	6 Participants

SECONDARY outcome

Timeframe: Baseline up to Day 2891

Urinalysis included assessments of specific gravity, pH, protein, glucose, ketones, bilirubin, occult blood, erythrocytes, leukocytes, 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. Here, shift to low indicated 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 values.

Outcome measures

Outcome measures
Measure	ISIS 396443 2 SMN2 Copies n=15 Participants Participants with 2 SMN2 copies received 12 mg nusinersen, IT on Days 1, 15, 29, 64, 183, 302, 421, 540, 659, 778, 897, 1016, 1135, 1254, 1373, 1492, 1611, 1730, 1849, 1968, 2087, 2206, 2325, 2444, 2563, 2682, and 2801.	ISIS 396443 3 SMN2 Copies n=10 Participants Participants with 3 SMN2 copies received 12 mg nusinersen, IT on Days 1, 15, 29, 64, 183, 302, 421, 540, 659, 778, 897, 1016, 1135, 1254, 1373, 1492, 1611, 1730, 1849, 1968, 2087, 2206, 2325, 2444, 2563, 2682, and 2801.
Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Urinalysis Parameters) Specific Gravity Shift to Low	3 Participants	1 Participants
Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Urinalysis Parameters) Specific Gravity Shift to High	6 Participants	5 Participants
Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Urinalysis Parameters) pH Shift to Low	0 Participants	1 Participants
Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Urinalysis Parameters) pH Shift to High	3 Participants	3 Participants
Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Urinalysis Parameters) Protein Shift to High/positive	13 Participants	8 Participants
Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Urinalysis Parameters) Glucose Shift to High/positive	1 Participants	0 Participants
Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Urinalysis Parameters) Ketones Shift to High/positive	9 Participants	6 Participants
Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Urinalysis Parameters) Bilirubin Shift to High/positive	0 Participants	0 Participants
Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Urinalysis Parameters) Occult Blood Shift to High/positive	4 Participants	2 Participants
Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Urinalysis Parameters) Erythrocytes Shift to High/positive	7 Participants	1 Participants
Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Urinalysis Parameters) Leukocytes Shift to High/positive	5 Participants	4 Participants
Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Urinalysis Parameters) Epithelial Cells Shift to High/positive	5 Participants	0 Participants
Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Urinalysis Parameters) Bacteria Shift to High/positive	7 Participants	6 Participants
Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Urinalysis Parameters) Casts Shift to High/positive	1 Participants	2 Participants
Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Urinalysis Parameters) Crystals Shift to High/positive	1 Participants	2 Participants

SECONDARY outcome

Timeframe: Baseline up to Day 2891

aPTT was evaluated to assess safety. Shift to high measured change in normal, low and unknown values at baseline to high values postbaseline.

Outcome measures

Outcome measures
Measure	ISIS 396443 2 SMN2 Copies n=9 Participants Participants with 2 SMN2 copies received 12 mg nusinersen, IT on Days 1, 15, 29, 64, 183, 302, 421, 540, 659, 778, 897, 1016, 1135, 1254, 1373, 1492, 1611, 1730, 1849, 1968, 2087, 2206, 2325, 2444, 2563, 2682, and 2801.	ISIS 396443 3 SMN2 Copies n=8 Participants Participants with 3 SMN2 copies received 12 mg nusinersen, IT on Days 1, 15, 29, 64, 183, 302, 421, 540, 659, 778, 897, 1016, 1135, 1254, 1373, 1492, 1611, 1730, 1849, 1968, 2087, 2206, 2325, 2444, 2563, 2682, and 2801.
Number of Participants With Shifts From Baseline in Coagulation Parameters [Activated Partial Thromboplastin Time (aPTT)]	4 Participants	2 Participants

SECONDARY outcome

Timeframe: Baseline up to Day 2891

PT was evaluated to assess safety. Shift to high measured change in normal, low and unknown values at baseline to high values postbaseline.

Outcome measures

Outcome measures
Measure	ISIS 396443 2 SMN2 Copies n=11 Participants Participants with 2 SMN2 copies received 12 mg nusinersen, IT on Days 1, 15, 29, 64, 183, 302, 421, 540, 659, 778, 897, 1016, 1135, 1254, 1373, 1492, 1611, 1730, 1849, 1968, 2087, 2206, 2325, 2444, 2563, 2682, and 2801.	ISIS 396443 3 SMN2 Copies n=8 Participants Participants with 3 SMN2 copies received 12 mg nusinersen, IT on Days 1, 15, 29, 64, 183, 302, 421, 540, 659, 778, 897, 1016, 1135, 1254, 1373, 1492, 1611, 1730, 1849, 1968, 2087, 2206, 2325, 2444, 2563, 2682, and 2801.
Number of Participants With Shifts From Baseline in Coagulation Parameters [Prothrombin Time (PT)]	7 Participants	5 Participants

SECONDARY outcome

Timeframe: Baseline up to Day 2891

INR was evaluated to assess safety. Shift to high measured change in normal, low and unknown values at baseline to high values postbaseline.

Outcome measures

Outcome measures
Measure	ISIS 396443 2 SMN2 Copies n=11 Participants Participants with 2 SMN2 copies received 12 mg nusinersen, IT on Days 1, 15, 29, 64, 183, 302, 421, 540, 659, 778, 897, 1016, 1135, 1254, 1373, 1492, 1611, 1730, 1849, 1968, 2087, 2206, 2325, 2444, 2563, 2682, and 2801.	ISIS 396443 3 SMN2 Copies n=7 Participants Participants with 3 SMN2 copies received 12 mg nusinersen, IT on Days 1, 15, 29, 64, 183, 302, 421, 540, 659, 778, 897, 1016, 1135, 1254, 1373, 1492, 1611, 1730, 1849, 1968, 2087, 2206, 2325, 2444, 2563, 2682, and 2801.
Number of Participants With Shifts From Baseline in Coagulation Parameters [International Normalized Ratio (INR)]	4 Participants	4 Participants

SECONDARY outcome

Timeframe: Baseline up to Day 2891

Population: The ITT set included all participants who received at least 1 dose of ISIS 396443. Overall number of participants analyzed signifies the number of participants with post-baseline ECG abnormalities.

Clinical significance of abnormalities in ECG was determined based on the investigator's discretion. Shift to abnormal indicated values that were normal or unknown at baseline and shifted to abnormal values post-baseline.

Outcome measures

Outcome measures
Measure	ISIS 396443 2 SMN2 Copies n=12 Participants Participants with 2 SMN2 copies received 12 mg nusinersen, IT on Days 1, 15, 29, 64, 183, 302, 421, 540, 659, 778, 897, 1016, 1135, 1254, 1373, 1492, 1611, 1730, 1849, 1968, 2087, 2206, 2325, 2444, 2563, 2682, and 2801.	ISIS 396443 3 SMN2 Copies n=8 Participants Participants with 3 SMN2 copies received 12 mg nusinersen, IT on Days 1, 15, 29, 64, 183, 302, 421, 540, 659, 778, 897, 1016, 1135, 1254, 1373, 1492, 1611, 1730, 1849, 1968, 2087, 2206, 2325, 2444, 2563, 2682, and 2801.
Percentage of Participants With Clinically Significant Shifts in Electrocardiograms (ECG) Abnormalities	0 percentage of participants	0 percentage of participants

SECONDARY outcome

Timeframe: Baseline, Day 2891

Negative change from baseline indicates reduction in temperature.

Outcome measures

Outcome measures
Measure	ISIS 396443 2 SMN2 Copies n=15 Participants Participants with 2 SMN2 copies received 12 mg nusinersen, IT on Days 1, 15, 29, 64, 183, 302, 421, 540, 659, 778, 897, 1016, 1135, 1254, 1373, 1492, 1611, 1730, 1849, 1968, 2087, 2206, 2325, 2444, 2563, 2682, and 2801.	ISIS 396443 3 SMN2 Copies n=10 Participants Participants with 3 SMN2 copies received 12 mg nusinersen, IT on Days 1, 15, 29, 64, 183, 302, 421, 540, 659, 778, 897, 1016, 1135, 1254, 1373, 1492, 1611, 1730, 1849, 1968, 2087, 2206, 2325, 2444, 2563, 2682, and 2801.
Change From Baseline in Vital Signs (Temperature) Baseline	36.7 degree Celsius Standard Deviation 0.39	36.8 degree Celsius Standard Deviation 0.44
Change From Baseline in Vital Signs (Temperature) Change at Day 2891	0.0 degree Celsius Standard Deviation 0.54	-0.1 degree Celsius Standard Deviation 0.52

SECONDARY outcome

Timeframe: Baseline, Day 2891

Outcome measures

Outcome measures
Measure	ISIS 396443 2 SMN2 Copies n=15 Participants Participants with 2 SMN2 copies received 12 mg nusinersen, IT on Days 1, 15, 29, 64, 183, 302, 421, 540, 659, 778, 897, 1016, 1135, 1254, 1373, 1492, 1611, 1730, 1849, 1968, 2087, 2206, 2325, 2444, 2563, 2682, and 2801.	ISIS 396443 3 SMN2 Copies n=10 Participants Participants with 3 SMN2 copies received 12 mg nusinersen, IT on Days 1, 15, 29, 64, 183, 302, 421, 540, 659, 778, 897, 1016, 1135, 1254, 1373, 1492, 1611, 1730, 1849, 1968, 2087, 2206, 2325, 2444, 2563, 2682, and 2801.
Change From Baseline in Vital Signs (Blood Pressure) Baseline-Systolic Blood Pressure	83.4 millimeters of mercury (mmHg) Standard Deviation 16.40	88.1 millimeters of mercury (mmHg) Standard Deviation 17.84
Change From Baseline in Vital Signs (Blood Pressure) Change at Day 2891-Systolic Blood Pressure	22.9 millimeters of mercury (mmHg) Standard Deviation 15.29	13.6 millimeters of mercury (mmHg) Standard Deviation 15.24
Change From Baseline in Vital Signs (Blood Pressure) Baseline-Diastolic Blood Pressure	51.1 millimeters of mercury (mmHg) Standard Deviation 17.46	50.8 millimeters of mercury (mmHg) Standard Deviation 12.30
Change From Baseline in Vital Signs (Blood Pressure) Change at Day 2891-Diastolic Blood Pressure	12.8 millimeters of mercury (mmHg) Standard Deviation 17.16	11.0 millimeters of mercury (mmHg) Standard Deviation 13.07

SECONDARY outcome

Timeframe: Baseline, Day 2891

Negative change from baseline indicates reduction in heart rate.

Outcome measures

Outcome measures
Measure	ISIS 396443 2 SMN2 Copies n=15 Participants Participants with 2 SMN2 copies received 12 mg nusinersen, IT on Days 1, 15, 29, 64, 183, 302, 421, 540, 659, 778, 897, 1016, 1135, 1254, 1373, 1492, 1611, 1730, 1849, 1968, 2087, 2206, 2325, 2444, 2563, 2682, and 2801.	ISIS 396443 3 SMN2 Copies n=9 Participants Participants with 3 SMN2 copies received 12 mg nusinersen, IT on Days 1, 15, 29, 64, 183, 302, 421, 540, 659, 778, 897, 1016, 1135, 1254, 1373, 1492, 1611, 1730, 1849, 1968, 2087, 2206, 2325, 2444, 2563, 2682, and 2801.
Change From Baseline in Vital Signs (Heart Rate) Baseline	141.5 beats per minute (beats/min) Standard Deviation 14.71	154.2 beats per minute (beats/min) Standard Deviation 16.55
Change From Baseline in Vital Signs (Heart Rate) Change at Day 2891	-47.2 beats per minute (beats/min) Standard Deviation 20.86	-62.4 beats per minute (beats/min) Standard Deviation 25.16

SECONDARY outcome

Timeframe: Baseline, Day 2891

Negative change from baseline indicates reduction in respiratory rate.

Outcome measures

Outcome measures
Measure	ISIS 396443 2 SMN2 Copies n=15 Participants Participants with 2 SMN2 copies received 12 mg nusinersen, IT on Days 1, 15, 29, 64, 183, 302, 421, 540, 659, 778, 897, 1016, 1135, 1254, 1373, 1492, 1611, 1730, 1849, 1968, 2087, 2206, 2325, 2444, 2563, 2682, and 2801.	ISIS 396443 3 SMN2 Copies n=10 Participants Participants with 3 SMN2 copies received 12 mg nusinersen, IT on Days 1, 15, 29, 64, 183, 302, 421, 540, 659, 778, 897, 1016, 1135, 1254, 1373, 1492, 1611, 1730, 1849, 1968, 2087, 2206, 2325, 2444, 2563, 2682, and 2801.
Change From Baseline in Vital Signs (Respiratory Rate) Baseline	42.1 breaths per minute (breaths/min) Standard Deviation 12.17	39.8 breaths per minute (breaths/min) Standard Deviation 13.87
Change From Baseline in Vital Signs (Respiratory Rate) Change at Day 2891	-21.0 breaths per minute (breaths/min) Standard Deviation 12.39	-20.6 breaths per minute (breaths/min) Standard Deviation 14.43

SECONDARY outcome

Timeframe: From the signing of the ICF up to the end of the study (up to Day 2891)

Population: The ITT set included all participants who received at least 1 dose of ISIS 396443.

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

Outcome measures

Outcome measures
Measure	ISIS 396443 2 SMN2 Copies n=15 Participants Participants with 2 SMN2 copies received 12 mg nusinersen, IT on Days 1, 15, 29, 64, 183, 302, 421, 540, 659, 778, 897, 1016, 1135, 1254, 1373, 1492, 1611, 1730, 1849, 1968, 2087, 2206, 2325, 2444, 2563, 2682, and 2801.	ISIS 396443 3 SMN2 Copies n=10 Participants Participants with 3 SMN2 copies received 12 mg nusinersen, IT on Days 1, 15, 29, 64, 183, 302, 421, 540, 659, 778, 897, 1016, 1135, 1254, 1373, 1492, 1611, 1730, 1849, 1968, 2087, 2206, 2325, 2444, 2563, 2682, and 2801.
Number of Participants With Neurological Examination Abnormalities Reported as AEs Muscle contractions involuntary	8 Participants	1 Participants
Number of Participants With Neurological Examination Abnormalities Reported as AEs Dysarthria	7 Participants	1 Participants
Number of Participants With Neurological Examination Abnormalities Reported as AEs Tremor	8 Participants	0 Participants
Number of Participants With Neurological Examination Abnormalities Reported as AEs Hypotonia	4 Participants	0 Participants
Number of Participants With Neurological Examination Abnormalities Reported as AEs Areflexia	2 Participants	1 Participants
Number of Participants With Neurological Examination Abnormalities Reported as AEs Facial paresis	2 Participants	0 Participants
Number of Participants With Neurological Examination Abnormalities Reported as AEs Hyperreflexia	1 Participants	1 Participants
Number of Participants With Neurological Examination Abnormalities Reported as AEs Myoclonus	2 Participants	0 Participants
Number of Participants With Neurological Examination Abnormalities Reported as AEs Clonus	1 Participants	0 Participants
Number of Participants With Neurological Examination Abnormalities Reported as AEs Extensor plantar response	1 Participants	0 Participants
Number of Participants With Neurological Examination Abnormalities Reported as AEs Peripheral sensory neuropathy	1 Participants	0 Participants
Number of Participants With Neurological Examination Abnormalities Reported as AEs Unresponsive to stimuli	1 Participants	0 Participants
Number of Participants With Neurological Examination Abnormalities Reported as AEs Muscular weakness	9 Participants	1 Participants
Number of Participants With Neurological Examination Abnormalities Reported as AEs Torticollis	1 Participants	1 Participants
Number of Participants With Neurological Examination Abnormalities Reported as AEs Muscle spasms	0 Participants	1 Participants
Number of Participants With Neurological Examination Abnormalities Reported as AEs Muscle twitching	0 Participants	1 Participants
Number of Participants With Neurological Examination Abnormalities Reported as AEs Trismus	1 Participants	0 Participants
Number of Participants With Neurological Examination Abnormalities Reported as AEs Winged scapula	1 Participants	0 Participants
Number of Participants With Neurological Examination Abnormalities Reported as AEs Anisocoria	0 Participants	1 Participants
Number of Participants With Neurological Examination Abnormalities Reported as AEs Heterophoria	1 Participants	0 Participants
Number of Participants With Neurological Examination Abnormalities Reported as AEs Strabismus	0 Participants	1 Participants
Number of Participants With Neurological Examination Abnormalities Reported as AEs Vision blurred	0 Participants	1 Participants
Number of Participants With Neurological Examination Abnormalities Reported as AEs Automatism	1 Participants	0 Participants

SECONDARY outcome

Timeframe: Predose on Days 1, 15, 29, 64, 183, 302, 421, 540, 659, 778, 897, 1016, 1135, 1254, 1373, 1492, 1611, 1730, 1849, 1968, 2087, 2206, 2325, 2444, 2563, 2682, 2801

Outcome measures

SECONDARY outcome

Timeframe: Predose on Days 64, 183, 302, 421, 540, 659, 778, 897, 1016, 1135, 1254, 1373, 1492, 1611, 1730, 1849, 1968, 2087, 2206, 2325, 2444, 2563, 2682, 2801 and 4-hour post-dose on Day 1

Outcome measures

Adverse Events

ISIS 396443 2 SMN2 Copies

Serious events: 10 serious events

Other events: 15 other events

Deaths: 0 deaths

ISIS 396443 3 SMN2 Copies

Serious events: 4 serious events

Other events: 10 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

US Biogen Clinical Trial Center

Biogen

Phone: 866-633-4636

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee Our agreement is subject to confidentiality but generally the PI can publish, for non-commercial purposes only, results and methods of the trial, but no other Sponsor Confidential Information. PI must give Sponsor no less than 60 days to review any manuscript for a proposed publication and must delay publication for up to an additional 90 days thereafter if Sponsor needs to file any patent application to protect any of Sponsor's intellectual property contained in the proposed publication.
Publication restrictions are in place

Restriction type: OTHER

Measure	ISIS 396443 2 SMN2 Copies n=15 Participants Participants with 2 SMN2 copies received 12 mg nusinersen, IT on Days 1, 15, 29, 64, 183, 302, 421, 540, 659, 778, 897, 1016, 1135, 1254, 1373, 1492, 1611, 1730, 1849, 1968, 2087, 2206, 2325, 2444, 2563, 2682, and 2801.	ISIS 396443 3 SMN2 Copies n=10 Participants Participants with 3 SMN2 copies received 12 mg nusinersen, IT on Days 1, 15, 29, 64, 183, 302, 421, 540, 659, 778, 897, 1016, 1135, 1254, 1373, 1492, 1611, 1730, 1849, 1968, 2087, 2206, 2325, 2444, 2563, 2682, and 2801.
Cerebrospinal Fluid (CSF) Concentration of Nusinersen Day 1, Pre-dose	0.03 nanograms per milliliter (ng/mL) Geometric Coefficient of Variation 0.00	0.03 nanograms per milliliter (ng/mL) Geometric Coefficient of Variation 0.00
Cerebrospinal Fluid (CSF) Concentration of Nusinersen Day 15, Pre-dose	7.52 nanograms per milliliter (ng/mL) Geometric Coefficient of Variation 189.00	10.22 nanograms per milliliter (ng/mL) Geometric Coefficient of Variation 285.47
Cerebrospinal Fluid (CSF) Concentration of Nusinersen Day 29, Pre-dose	23.41 nanograms per milliliter (ng/mL) Geometric Coefficient of Variation 72.04	24.56 nanograms per milliliter (ng/mL) Geometric Coefficient of Variation 85.78
Cerebrospinal Fluid (CSF) Concentration of Nusinersen Day 64, Pre-dose	14.95 nanograms per milliliter (ng/mL) Geometric Coefficient of Variation 58.06	21.33 nanograms per milliliter (ng/mL) Geometric Coefficient of Variation 63.00
Cerebrospinal Fluid (CSF) Concentration of Nusinersen Day 183, Pre-dose	11.66 nanograms per milliliter (ng/mL) Geometric Coefficient of Variation 69.60	13.85 nanograms per milliliter (ng/mL) Geometric Coefficient of Variation 54.32
Cerebrospinal Fluid (CSF) Concentration of Nusinersen Day 302, Pre-dose	11.34 nanograms per milliliter (ng/mL) Geometric Coefficient of Variation 54.67	10.06 nanograms per milliliter (ng/mL) Geometric Coefficient of Variation 27.29
Cerebrospinal Fluid (CSF) Concentration of Nusinersen Day 421, Pre-dose	12.20 nanograms per milliliter (ng/mL) Geometric Coefficient of Variation 66.72	10.53 nanograms per milliliter (ng/mL) Geometric Coefficient of Variation 67.48
Cerebrospinal Fluid (CSF) Concentration of Nusinersen Day 540, Pre-dose	10.23 nanograms per milliliter (ng/mL) Geometric Coefficient of Variation 38.84	9.42 nanograms per milliliter (ng/mL) Geometric Coefficient of Variation 51.04
Cerebrospinal Fluid (CSF) Concentration of Nusinersen Day 659, Pre-dose	11.91 nanograms per milliliter (ng/mL) Geometric Coefficient of Variation 42.32	10.30 nanograms per milliliter (ng/mL) Geometric Coefficient of Variation 38.34
Cerebrospinal Fluid (CSF) Concentration of Nusinersen Day 778, Pre-dose	10.87 nanograms per milliliter (ng/mL) Geometric Coefficient of Variation 54.28	11.77 nanograms per milliliter (ng/mL) Geometric Coefficient of Variation 61.01
Cerebrospinal Fluid (CSF) Concentration of Nusinersen Day 897, Pre-dose	11.03 nanograms per milliliter (ng/mL) Geometric Coefficient of Variation 43.91	10.72 nanograms per milliliter (ng/mL) Geometric Coefficient of Variation 35.90
Cerebrospinal Fluid (CSF) Concentration of Nusinersen Day 1016, Pre-dose	12.06 nanograms per milliliter (ng/mL) Geometric Coefficient of Variation 58.41	10.65 nanograms per milliliter (ng/mL) Geometric Coefficient of Variation 39.34
Cerebrospinal Fluid (CSF) Concentration of Nusinersen Day 1135, Pre-dose	10.49 nanograms per milliliter (ng/mL) Geometric Coefficient of Variation 46.05	10.87 nanograms per milliliter (ng/mL) Geometric Coefficient of Variation 36.62
Cerebrospinal Fluid (CSF) Concentration of Nusinersen Day 1254, Pre-dose	12.88 nanograms per milliliter (ng/mL) Geometric Coefficient of Variation 47.06	11.29 nanograms per milliliter (ng/mL) Geometric Coefficient of Variation 33.29
Cerebrospinal Fluid (CSF) Concentration of Nusinersen Day 1373, Pre-dose	11.94 nanograms per milliliter (ng/mL) Geometric Coefficient of Variation 61.51	10.19 nanograms per milliliter (ng/mL) Geometric Coefficient of Variation 52.12
Cerebrospinal Fluid (CSF) Concentration of Nusinersen Day 1492, Pre-dose	15.04 nanograms per milliliter (ng/mL) Geometric Coefficient of Variation 51.20	12.71 nanograms per milliliter (ng/mL) Geometric Coefficient of Variation 92.23
Cerebrospinal Fluid (CSF) Concentration of Nusinersen Day 1611, Pre-dose	13.46 nanograms per milliliter (ng/mL) Geometric Coefficient of Variation 40.19	13.90 nanograms per milliliter (ng/mL) Geometric Coefficient of Variation 36.31
Cerebrospinal Fluid (CSF) Concentration of Nusinersen Day 1730, Pre-dose	13.63 nanograms per milliliter (ng/mL) Geometric Coefficient of Variation 57.76	15.14 nanograms per milliliter (ng/mL) Geometric Coefficient of Variation 42.12
Cerebrospinal Fluid (CSF) Concentration of Nusinersen Day 1849, Pre-dose	15.14 nanograms per milliliter (ng/mL) Geometric Coefficient of Variation 63.15	14.19 nanograms per milliliter (ng/mL) Geometric Coefficient of Variation 42.87
Cerebrospinal Fluid (CSF) Concentration of Nusinersen Day 1968, Pre-dose	16.52 nanograms per milliliter (ng/mL) Geometric Coefficient of Variation 67.05	17.46 nanograms per milliliter (ng/mL) Geometric Coefficient of Variation 48.67
Cerebrospinal Fluid (CSF) Concentration of Nusinersen Day 2087, Pre-dose	15.57 nanograms per milliliter (ng/mL) Geometric Coefficient of Variation 47.34	17.07 nanograms per milliliter (ng/mL) Geometric Coefficient of Variation 58.91
Cerebrospinal Fluid (CSF) Concentration of Nusinersen Day 2206, Pre-dose	16.95 nanograms per milliliter (ng/mL) Geometric Coefficient of Variation 45.86	17.16 nanograms per milliliter (ng/mL) Geometric Coefficient of Variation 46.34
Cerebrospinal Fluid (CSF) Concentration of Nusinersen Day 2325, Pre-dose	18.27 nanograms per milliliter (ng/mL) Geometric Coefficient of Variation 59.23	20.02 nanograms per milliliter (ng/mL) Geometric Coefficient of Variation 37.41
Cerebrospinal Fluid (CSF) Concentration of Nusinersen Day 2444, Pre-dose	16.92 nanograms per milliliter (ng/mL) Geometric Coefficient of Variation 49.19	17.01 nanograms per milliliter (ng/mL) Geometric Coefficient of Variation 40.87
Cerebrospinal Fluid (CSF) Concentration of Nusinersen Day 2563, Pre-dose	16.74 nanograms per milliliter (ng/mL) Geometric Coefficient of Variation 53.14	13.37 nanograms per milliliter (ng/mL) Geometric Coefficient of Variation 85.72
Cerebrospinal Fluid (CSF) Concentration of Nusinersen Day 2682, Pre-dose	17.42 nanograms per milliliter (ng/mL) Geometric Coefficient of Variation 44.34	16.05 nanograms per milliliter (ng/mL) Geometric Coefficient of Variation 41.83
Cerebrospinal Fluid (CSF) Concentration of Nusinersen Day 2801, Pre-dose	17.44 nanograms per milliliter (ng/mL) Geometric Coefficient of Variation 45.60	17.85 nanograms per milliliter (ng/mL) Geometric Coefficient of Variation 36.35

Measure	ISIS 396443 2 SMN2 Copies n=15 Participants Participants with 2 SMN2 copies received 12 mg nusinersen, IT on Days 1, 15, 29, 64, 183, 302, 421, 540, 659, 778, 897, 1016, 1135, 1254, 1373, 1492, 1611, 1730, 1849, 1968, 2087, 2206, 2325, 2444, 2563, 2682, and 2801.	ISIS 396443 3 SMN2 Copies n=10 Participants Participants with 3 SMN2 copies received 12 mg nusinersen, IT on Days 1, 15, 29, 64, 183, 302, 421, 540, 659, 778, 897, 1016, 1135, 1254, 1373, 1492, 1611, 1730, 1849, 1968, 2087, 2206, 2325, 2444, 2563, 2682, and 2801.
Plasma Concentration of Nusinersen Day 2801, Pre-dose	0.39 ng/ml Geometric Coefficient of Variation 36.16	0.35 ng/ml Geometric Coefficient of Variation 65.12
Plasma Concentration of Nusinersen Day 1, 4 hours post-dose	391.66 ng/ml Geometric Coefficient of Variation 113.16	406.69 ng/ml Geometric Coefficient of Variation 82.92
Plasma Concentration of Nusinersen Day 64, Pre-dose	1.60 ng/ml Geometric Coefficient of Variation 34.52	1.56 ng/ml Geometric Coefficient of Variation 46.54
Plasma Concentration of Nusinersen Day 183, Pre-dose	0.73 ng/ml Geometric Coefficient of Variation 27.03	0.81 ng/ml Geometric Coefficient of Variation 19.82
Plasma Concentration of Nusinersen Day 302, Pre-dose	0.82 ng/ml Geometric Coefficient of Variation 54.28	0.81 ng/ml Geometric Coefficient of Variation 21.12
Plasma Concentration of Nusinersen Day 421, Pre-dose	0.78 ng/ml Geometric Coefficient of Variation 39.94	0.82 ng/ml Geometric Coefficient of Variation 29.31
Plasma Concentration of Nusinersen Day 540, Pre-dose	0.72 ng/ml Geometric Coefficient of Variation 29.72	0.72 ng/ml Geometric Coefficient of Variation 19.16
Plasma Concentration of Nusinersen Day 659, Pre-dose	0.74 ng/ml Geometric Coefficient of Variation 26.78	0.78 ng/ml Geometric Coefficient of Variation 32.51
Plasma Concentration of Nusinersen Day 778, Pre-dose	0.68 ng/ml Geometric Coefficient of Variation 48.37	0.81 ng/ml Geometric Coefficient of Variation 23.52
Plasma Concentration of Nusinersen Day 897, Pre-dose	0.71 ng/ml Geometric Coefficient of Variation 34.77	0.63 ng/ml Geometric Coefficient of Variation 40.31
Plasma Concentration of Nusinersen Day 1016, Pre-dose	0.69 ng/ml Geometric Coefficient of Variation 38.47	0.74 ng/ml Geometric Coefficient of Variation 21.97
Plasma Concentration of Nusinersen Day 1135, Pre-dose	0.67 ng/ml Geometric Coefficient of Variation 33.70	0.58 ng/ml Geometric Coefficient of Variation 33.78
Plasma Concentration of Nusinersen Day 1254, Pre-dose	0.63 ng/ml Geometric Coefficient of Variation 27.16	0.60 ng/ml Geometric Coefficient of Variation 24.10
Plasma Concentration of Nusinersen Day 1373, Pre-dose	0.60 ng/ml Geometric Coefficient of Variation 39.79	0.59 ng/ml Geometric Coefficient of Variation 17.98
Plasma Concentration of Nusinersen Day 1492, Pre-dose	0.69 ng/ml Geometric Coefficient of Variation 40.55	0.68 ng/ml Geometric Coefficient of Variation 43.50
Plasma Concentration of Nusinersen Day 1611, Pre-dose	0.62 ng/ml Geometric Coefficient of Variation 38.14	0.53 ng/ml Geometric Coefficient of Variation 43.12
Plasma Concentration of Nusinersen Day 1730, Pre-dose	0.54 ng/ml Geometric Coefficient of Variation 16.13	0.53 ng/ml Geometric Coefficient of Variation 30.84
Plasma Concentration of Nusinersen Day 1849, Pre-dose	0.47 ng/ml Geometric Coefficient of Variation 52.05	0.49 ng/ml Geometric Coefficient of Variation 36.37
Plasma Concentration of Nusinersen Day 1968, Pre-dose	0.53 ng/ml Geometric Coefficient of Variation 25.66	0.43 ng/ml Geometric Coefficient of Variation 22.96
Plasma Concentration of Nusinersen Day 2087, Pre-dose	0.55 ng/ml Geometric Coefficient of Variation 40.43	0.47 ng/ml Geometric Coefficient of Variation 31.50
Plasma Concentration of Nusinersen Day 2206, Pre-dose	0.43 ng/ml Geometric Coefficient of Variation 43.01	0.40 ng/ml Geometric Coefficient of Variation 32.58
Plasma Concentration of Nusinersen Day 2325, Pre-dose	0.46 ng/ml Geometric Coefficient of Variation 56.98	0.45 ng/ml Geometric Coefficient of Variation 35.19
Plasma Concentration of Nusinersen Day 2444, Pre-dose	0.43 ng/ml Geometric Coefficient of Variation 35.15	0.51 ng/ml Geometric Coefficient of Variation 17.26
Plasma Concentration of Nusinersen Day 2563, Pre-dose	0.38 ng/ml Geometric Coefficient of Variation 61.73	0.42 ng/ml Geometric Coefficient of Variation 31.10
Plasma Concentration of Nusinersen Day 2682, Pre-dose	0.36 ng/ml Geometric Coefficient of Variation 55.66	0.40 ng/ml Geometric Coefficient of Variation 24.48

Measure	ISIS 396443 2 SMN2 Copies n=15 participants at risk Participants with 2 SMN2 copies received 12 mg nusinersen, IT on Days 1, 15, 29, 64, 183, 302, 421, 540, 659, 778, 897, 1016, 1135, 1254, 1373, 1492, 1611, 1730, 1849, 1968, 2087, 2206, 2325, 2444, 2563, 2682, and 2801.	ISIS 396443 3 SMN2 Copies n=10 participants at risk Participants with 3 SMN2 copies received 12 mg nusinersen, IT on Days 1, 15, 29, 64, 183, 302, 421, 540, 659, 778, 897, 1016, 1135, 1254, 1373, 1492, 1611, 1730, 1849, 1968, 2087, 2206, 2325, 2444, 2563, 2682, and 2801.
Cardiac disorders Tachycardia	6.7% 1/15 • From the signing of the ICF up to the end of the study (up to Day 2891) The ITT set included all participants who received at least 1 dose of ISIS 396443.	0.00% 0/10 • From the signing of the ICF up to the end of the study (up to Day 2891) The ITT set included all participants who received at least 1 dose of ISIS 396443.
Gastrointestinal disorders Abdominal distension	6.7% 1/15 • From the signing of the ICF up to the end of the study (up to Day 2891) The ITT set included all participants who received at least 1 dose of ISIS 396443.	0.00% 0/10 • From the signing of the ICF up to the end of the study (up to Day 2891) The ITT set included all participants who received at least 1 dose of ISIS 396443.
Gastrointestinal disorders Diarrhoea	0.00% 0/15 • From the signing of the ICF up to the end of the study (up to Day 2891) The ITT set included all participants who received at least 1 dose of ISIS 396443.	10.0% 1/10 • From the signing of the ICF up to the end of the study (up to Day 2891) The ITT set included all participants who received at least 1 dose of ISIS 396443.
Gastrointestinal disorders Faecaloma	6.7% 1/15 • From the signing of the ICF up to the end of the study (up to Day 2891) The ITT set included all participants who received at least 1 dose of ISIS 396443.	0.00% 0/10 • From the signing of the ICF up to the end of the study (up to Day 2891) The ITT set included all participants who received at least 1 dose of ISIS 396443.
Gastrointestinal disorders Vomiting	6.7% 1/15 • From the signing of the ICF up to the end of the study (up to Day 2891) The ITT set included all participants who received at least 1 dose of ISIS 396443.	0.00% 0/10 • From the signing of the ICF up to the end of the study (up to Day 2891) The ITT set included all participants who received at least 1 dose of ISIS 396443.
General disorders Pyrexia	13.3% 2/15 • From the signing of the ICF up to the end of the study (up to Day 2891) The ITT set included all participants who received at least 1 dose of ISIS 396443.	0.00% 0/10 • From the signing of the ICF up to the end of the study (up to Day 2891) The ITT set included all participants who received at least 1 dose of ISIS 396443.
Hepatobiliary disorders Hypertransaminasaemia	6.7% 1/15 • From the signing of the ICF up to the end of the study (up to Day 2891) The ITT set included all participants who received at least 1 dose of ISIS 396443.	0.00% 0/10 • From the signing of the ICF up to the end of the study (up to Day 2891) The ITT set included all participants who received at least 1 dose of ISIS 396443.
Immune system disorders Anaphylactic reaction	6.7% 1/15 • From the signing of the ICF up to the end of the study (up to Day 2891) The ITT set included all participants who received at least 1 dose of ISIS 396443.	0.00% 0/10 • From the signing of the ICF up to the end of the study (up to Day 2891) The ITT set included all participants who received at least 1 dose of ISIS 396443.
Infections and infestations Bronchitis	6.7% 1/15 • From the signing of the ICF up to the end of the study (up to Day 2891) The ITT set included all participants who received at least 1 dose of ISIS 396443.	0.00% 0/10 • From the signing of the ICF up to the end of the study (up to Day 2891) The ITT set included all participants who received at least 1 dose of ISIS 396443.
Infections and infestations Coronavirus infection	6.7% 1/15 • From the signing of the ICF up to the end of the study (up to Day 2891) The ITT set included all participants who received at least 1 dose of ISIS 396443.	0.00% 0/10 • From the signing of the ICF up to the end of the study (up to Day 2891) The ITT set included all participants who received at least 1 dose of ISIS 396443.
Infections and infestations Enterovirus infection	6.7% 1/15 • From the signing of the ICF up to the end of the study (up to Day 2891) The ITT set included all participants who received at least 1 dose of ISIS 396443.	0.00% 0/10 • From the signing of the ICF up to the end of the study (up to Day 2891) The ITT set included all participants who received at least 1 dose of ISIS 396443.
Infections and infestations Gastroenteritis viral	6.7% 1/15 • From the signing of the ICF up to the end of the study (up to Day 2891) The ITT set included all participants who received at least 1 dose of ISIS 396443.	0.00% 0/10 • From the signing of the ICF up to the end of the study (up to Day 2891) The ITT set included all participants who received at least 1 dose of ISIS 396443.
Infections and infestations Pneumonia	33.3% 5/15 • From the signing of the ICF up to the end of the study (up to Day 2891) The ITT set included all participants who received at least 1 dose of ISIS 396443.	0.00% 0/10 • From the signing of the ICF up to the end of the study (up to Day 2891) The ITT set included all participants who received at least 1 dose of ISIS 396443.
Infections and infestations Pneumonia aspiration	6.7% 1/15 • From the signing of the ICF up to the end of the study (up to Day 2891) The ITT set included all participants who received at least 1 dose of ISIS 396443.	0.00% 0/10 • From the signing of the ICF up to the end of the study (up to Day 2891) The ITT set included all participants who received at least 1 dose of ISIS 396443.
Infections and infestations Pneumonia bacterial	6.7% 1/15 • From the signing of the ICF up to the end of the study (up to Day 2891) The ITT set included all participants who received at least 1 dose of ISIS 396443.	0.00% 0/10 • From the signing of the ICF up to the end of the study (up to Day 2891) The ITT set included all participants who received at least 1 dose of ISIS 396443.
Infections and infestations Pneumonia mycoplasmal	6.7% 1/15 • From the signing of the ICF up to the end of the study (up to Day 2891) The ITT set included all participants who received at least 1 dose of ISIS 396443.	0.00% 0/10 • From the signing of the ICF up to the end of the study (up to Day 2891) The ITT set included all participants who received at least 1 dose of ISIS 396443.
Infections and infestations Pneumonia pneumococcal	6.7% 1/15 • From the signing of the ICF up to the end of the study (up to Day 2891) The ITT set included all participants who received at least 1 dose of ISIS 396443.	0.00% 0/10 • From the signing of the ICF up to the end of the study (up to Day 2891) The ITT set included all participants who received at least 1 dose of ISIS 396443.
Infections and infestations Pneumonia pseudomonal	6.7% 1/15 • From the signing of the ICF up to the end of the study (up to Day 2891) The ITT set included all participants who received at least 1 dose of ISIS 396443.	0.00% 0/10 • From the signing of the ICF up to the end of the study (up to Day 2891) The ITT set included all participants who received at least 1 dose of ISIS 396443.
Infections and infestations Pneumonia respiratory syncytial viral	6.7% 1/15 • From the signing of the ICF up to the end of the study (up to Day 2891) The ITT set included all participants who received at least 1 dose of ISIS 396443.	0.00% 0/10 • From the signing of the ICF up to the end of the study (up to Day 2891) The ITT set included all participants who received at least 1 dose of ISIS 396443.
Infections and infestations Respiratory syncytial virus bronchiolitis	13.3% 2/15 • From the signing of the ICF up to the end of the study (up to Day 2891) The ITT set included all participants who received at least 1 dose of ISIS 396443.	0.00% 0/10 • From the signing of the ICF up to the end of the study (up to Day 2891) The ITT set included all participants who received at least 1 dose of ISIS 396443.
Infections and infestations Respiratory syncytial virus infection	13.3% 2/15 • From the signing of the ICF up to the end of the study (up to Day 2891) The ITT set included all participants who received at least 1 dose of ISIS 396443.	10.0% 1/10 • From the signing of the ICF up to the end of the study (up to Day 2891) The ITT set included all participants who received at least 1 dose of ISIS 396443.
Infections and infestations Tonsillitis	0.00% 0/15 • From the signing of the ICF up to the end of the study (up to Day 2891) The ITT set included all participants who received at least 1 dose of ISIS 396443.	10.0% 1/10 • From the signing of the ICF up to the end of the study (up to Day 2891) The ITT set included all participants who received at least 1 dose of ISIS 396443.
Infections and infestations Upper respiratory tract infection	6.7% 1/15 • From the signing of the ICF up to the end of the study (up to Day 2891) The ITT set included all participants who received at least 1 dose of ISIS 396443.	10.0% 1/10 • From the signing of the ICF up to the end of the study (up to Day 2891) The ITT set included all participants who received at least 1 dose of ISIS 396443.
Infections and infestations Urinary tract infection	6.7% 1/15 • From the signing of the ICF up to the end of the study (up to Day 2891) The ITT set included all participants who received at least 1 dose of ISIS 396443.	0.00% 0/10 • From the signing of the ICF up to the end of the study (up to Day 2891) The ITT set included all participants who received at least 1 dose of ISIS 396443.
Infections and infestations Viral upper respiratory tract infection	0.00% 0/15 • From the signing of the ICF up to the end of the study (up to Day 2891) The ITT set included all participants who received at least 1 dose of ISIS 396443.	10.0% 1/10 • From the signing of the ICF up to the end of the study (up to Day 2891) The ITT set included all participants who received at least 1 dose of ISIS 396443.
Investigations Influenza a virus test positive	6.7% 1/15 • From the signing of the ICF up to the end of the study (up to Day 2891) The ITT set included all participants who received at least 1 dose of ISIS 396443.	0.00% 0/10 • From the signing of the ICF up to the end of the study (up to Day 2891) The ITT set included all participants who received at least 1 dose of ISIS 396443.
Investigations Respirovirus test positive	6.7% 1/15 • From the signing of the ICF up to the end of the study (up to Day 2891) The ITT set included all participants who received at least 1 dose of ISIS 396443.	0.00% 0/10 • From the signing of the ICF up to the end of the study (up to Day 2891) The ITT set included all participants who received at least 1 dose of ISIS 396443.
Metabolism and nutrition disorders Dehydration	13.3% 2/15 • From the signing of the ICF up to the end of the study (up to Day 2891) The ITT set included all participants who received at least 1 dose of ISIS 396443.	0.00% 0/10 • From the signing of the ICF up to the end of the study (up to Day 2891) The ITT set included all participants who received at least 1 dose of ISIS 396443.
Metabolism and nutrition disorders Failure to thrive	6.7% 1/15 • From the signing of the ICF up to the end of the study (up to Day 2891) The ITT set included all participants who received at least 1 dose of ISIS 396443.	0.00% 0/10 • From the signing of the ICF up to the end of the study (up to Day 2891) The ITT set included all participants who received at least 1 dose of ISIS 396443.
Metabolism and nutrition disorders Feeding disorder	6.7% 1/15 • From the signing of the ICF up to the end of the study (up to Day 2891) The ITT set included all participants who received at least 1 dose of ISIS 396443.	0.00% 0/10 • From the signing of the ICF up to the end of the study (up to Day 2891) The ITT set included all participants who received at least 1 dose of ISIS 396443.
Musculoskeletal and connective tissue disorders Tendon disorder	6.7% 1/15 • From the signing of the ICF up to the end of the study (up to Day 2891) The ITT set included all participants who received at least 1 dose of ISIS 396443.	0.00% 0/10 • From the signing of the ICF up to the end of the study (up to Day 2891) The ITT set included all participants who received at least 1 dose of ISIS 396443.
Nervous system disorders Hyperreflexia	6.7% 1/15 • From the signing of the ICF up to the end of the study (up to Day 2891) The ITT set included all participants who received at least 1 dose of ISIS 396443.	0.00% 0/10 • From the signing of the ICF up to the end of the study (up to Day 2891) The ITT set included all participants who received at least 1 dose of ISIS 396443.
Respiratory, thoracic and mediastinal disorders Acute respiratory failure	6.7% 1/15 • From the signing of the ICF up to the end of the study (up to Day 2891) The ITT set included all participants who received at least 1 dose of ISIS 396443.	0.00% 0/10 • From the signing of the ICF up to the end of the study (up to Day 2891) The ITT set included all participants who received at least 1 dose of ISIS 396443.
Respiratory, thoracic and mediastinal disorders Choking	20.0% 3/15 • From the signing of the ICF up to the end of the study (up to Day 2891) The ITT set included all participants who received at least 1 dose of ISIS 396443.	0.00% 0/10 • From the signing of the ICF up to the end of the study (up to Day 2891) The ITT set included all participants who received at least 1 dose of ISIS 396443.
Respiratory, thoracic and mediastinal disorders Obstructive sleep apnoea syndrome	6.7% 1/15 • From the signing of the ICF up to the end of the study (up to Day 2891) The ITT set included all participants who received at least 1 dose of ISIS 396443.	0.00% 0/10 • From the signing of the ICF up to the end of the study (up to Day 2891) The ITT set included all participants who received at least 1 dose of ISIS 396443.
Respiratory, thoracic and mediastinal disorders Respiratory distress	13.3% 2/15 • From the signing of the ICF up to the end of the study (up to Day 2891) The ITT set included all participants who received at least 1 dose of ISIS 396443.	0.00% 0/10 • From the signing of the ICF up to the end of the study (up to Day 2891) The ITT set included all participants who received at least 1 dose of ISIS 396443.
Respiratory, thoracic and mediastinal disorders Respiratory failure	13.3% 2/15 • From the signing of the ICF up to the end of the study (up to Day 2891) The ITT set included all participants who received at least 1 dose of ISIS 396443.	0.00% 0/10 • From the signing of the ICF up to the end of the study (up to Day 2891) The ITT set included all participants who received at least 1 dose of ISIS 396443.
Surgical and medical procedures Medical device change	6.7% 1/15 • From the signing of the ICF up to the end of the study (up to Day 2891) The ITT set included all participants who received at least 1 dose of ISIS 396443.	0.00% 0/10 • From the signing of the ICF up to the end of the study (up to Day 2891) The ITT set included all participants who received at least 1 dose of ISIS 396443.
Surgical and medical procedures Tonsillectomy	13.3% 2/15 • From the signing of the ICF up to the end of the study (up to Day 2891) The ITT set included all participants who received at least 1 dose of ISIS 396443.	0.00% 0/10 • From the signing of the ICF up to the end of the study (up to Day 2891) The ITT set included all participants who received at least 1 dose of ISIS 396443.