Spinal Muscular Atrophy
Conditions
Keywords
NURTURE
Brief summary
The primary objective of the study is to examine the efficacy of multiple doses of Nusinersen administered intrathecally in preventing or delaying the need for respiratory intervention or death in infants with genetically diagnosed and presymptomatic spinal muscular atrophy (SMA). Secondary objectives of this study are to examine the effects of Nusinersen in infants with genetically diagnosed and presymptomatic SMA.
Interventions
DRUGNusinersen
Solution for intrathecal injection
Sponsors
Biogen
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
PREVENTION
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
0 Weeks to 6 Weeks
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * Age ≤ 6 weeks at first dose. * Genetic documentation of 5q SMA homozygous gene deletion or mutation or compound heterozygous mutation. * Genetic documentation of 2 or 3 copies of survival motor neuron 2 (SMN2). * Ulnar compound muscle action potential (CMAP) ≥ 1 mV at Baseline. * Gestational age of 37 to 42 weeks for singleton births; gestational age of 34 to 42 weeks for twins. * Meet additional study related criteria. Key
Exclusion criteria
* Hypoxemia (oxygen saturation \<96% awake or asleep without any supplemental oxygen or respiratory support). * Any clinical signs or symptoms at Screening or immediately prior to the first dosing (Day 1) that are, in the opinion of the Investigator, strongly suggestive of SMA. * Clinically significant abnormalities in hematology or clinical chemistry parameters. * Treatment with an investigational drug given for the treatment of SMA biological agent, or device. Any history of gene therapy, prior antisense oligonucleotide (ASO) treatment, or cell transplantation. * Meet additional study related criteria. Note: Other protocol defined Inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time to Death or Respiratory Intervention | Screening up to Day 2891 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Alive | Up to 8 years of age | — |
| Change From Baseline in Weight for Length | Baseline, Day 1849 | 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. |
| Change From Baseline in Head Circumference | Baseline, Day 2891 | — |
| Change From Baseline in Chest Circumference | Baseline, Day 2891 | — |
| Percentage of Participants Who Attained Motor Milestones Assessed as Part of the Hammersmith Infant Neurological Examination (HINE) | Day 700 | 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. |
| Percentage of Participants Who Attained Motor Milestones as Assessed by World Health Organization (WHO) Criteria | Baseline up to Day 2891 | 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. |
| Change From Baseline in the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) Motor Function Scale | Baseline, Day 2891 | 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. |
| Change From Baseline in Hammersmith Functional Motor Scale - Expanded (HFMSE) | 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. |
| Change From Baseline in Weight for Age | 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. |
| Change From Baseline in Head to Chest Circumference Ratio | Baseline, Day 2891 | Negative change from baseline indicates reduction in head-to-chest circumference ratio. |
| Change From Baseline in Arm Circumference | Baseline, Day 2891 | — |
| Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | From the signing of the informed consent form (ICF) up to the end of the study (up to Day 2891) | 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. |
| Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Hematology Parameters) | 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. |
| Proportion of Participants Developing Clinically Manifested Spinal Muscular Atrophy (SMA) | At 13 and 24 months of age | 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 |
| Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Urinalysis Parameters) | 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. |
| Number of Participants With Shifts From Baseline in Coagulation Parameters [Activated Partial Thromboplastin Time (aPTT)] | 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. |
| Number of Participants With Shifts From Baseline in Coagulation Parameters [Prothrombin Time (PT)] | 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. |
| Number of Participants With Shifts From Baseline in Coagulation Parameters [International Normalized Ratio (INR)] | 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. |
| Percentage of Participants With Clinically Significant Shifts in Electrocardiograms (ECG) Abnormalities | Baseline up to Day 2891 | 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. |
| Change From Baseline in Vital Signs (Temperature) | Baseline, Day 2891 | Negative change from baseline indicates reduction in temperature. |
| Change From Baseline in Vital Signs (Blood Pressure) | Baseline, Day 2891 | — |
| Change From Baseline in Vital Signs (Heart Rate) | Baseline, Day 2891 | Negative change from baseline indicates reduction in heart rate. |
| Change From Baseline in Vital Signs (Respiratory Rate) | Baseline, Day 2891 | Negative change from baseline indicates reduction in respiratory rate. |
| Number of Participants With Neurological Examination Abnormalities Reported as AEs | From the signing of the ICF up to the end of the study (up to Day 2891) | Participants with abnormalities in neurological examinations recorded as AEs were reported. |
| Cerebrospinal Fluid (CSF) Concentration of Nusinersen | 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 | — |
| Plasma Concentration of Nusinersen | 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 | — |
| Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Blood Chemistry Parameters) | 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. |
Countries
Australia, Germany, Italy, Qatar, Taiwan, Turkey (Türkiye), United States
Participant flow
Recruitment details
Participants took part in the multiple investigative sites from 18 May 2015 to 17 Dec 2024.
Pre-assignment details
A total of 25 participants diagnosed with Spinal Muscular Atrophy (SMA) were enrolled in the study.
Participants by arm
| Arm | Count |
|---|---|
| ISIS 396443 2 SMN2 Copies 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. | 15 |
| 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. | 10 |
| Total | 25 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Reason Not Specified | 1 | 1 |
| Overall Study | Withdrawal by parent/Guardian | 1 | 0 |
Baseline characteristics
| Characteristic | ISIS 396443 2 SMN2 Copies | ISIS 396443 3 SMN2 Copies | Total |
|---|---|---|---|
| Age, Continuous | 19.5 days STANDARD_DEVIATION 9.29 | 22.3 days STANDARD_DEVIATION 12.45 | 20.6 days STANDARD_DEVIATION 10.51 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 0 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 10 Participants | 9 Participants | 19 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 3 Participants | 1 Participants | 4 Participants |
| Race/Ethnicity, Customized Race American Indian or Alaska Native | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Race Asian | 1 Participants | 2 Participants | 3 Participants |
| Race/Ethnicity, Customized Race Not Reported Due to Confidentiality Regulations | 3 Participants | 1 Participants | 4 Participants |
| Race/Ethnicity, Customized Race Other | 2 Participants | 1 Participants | 3 Participants |
| Race/Ethnicity, Customized Race White | 8 Participants | 6 Participants | 14 Participants |
| Sex: Female, Male Female | 7 Participants | 6 Participants | 13 Participants |
| Sex: Female, Male Male | 8 Participants | 4 Participants | 12 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 15 | 0 / 10 |
| other Total, other adverse events | 15 / 15 | 10 / 10 |
| serious Total, serious adverse events | 10 / 15 | 4 / 10 |
Outcome results
Primary
Time to Death or Respiratory Intervention
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.
Time frame: Screening up to Day 2891
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.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| ISIS 396443 2 SMN2 Copies | Time to Death or Respiratory Intervention | NA months |
Secondary
Cerebrospinal Fluid (CSF) Concentration of Nusinersen
Time frame: 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
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.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| ISIS 396443 2 SMN2 Copies | Cerebrospinal Fluid (CSF) Concentration of Nusinersen | Day 540, Pre-dose | 10.23 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 38.84 |
| ISIS 396443 2 SMN2 Copies | Cerebrospinal Fluid (CSF) Concentration of Nusinersen | Day 1373, Pre-dose | 11.94 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 61.51 |
| ISIS 396443 2 SMN2 Copies | Cerebrospinal Fluid (CSF) Concentration of Nusinersen | Day 183, Pre-dose | 11.66 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 69.6 |
| ISIS 396443 2 SMN2 Copies | Cerebrospinal Fluid (CSF) Concentration of Nusinersen | Day 1492, Pre-dose | 15.04 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 51.2 |
| ISIS 396443 2 SMN2 Copies | Cerebrospinal Fluid (CSF) Concentration of Nusinersen | Day 659, Pre-dose | 11.91 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 42.32 |
| ISIS 396443 2 SMN2 Copies | Cerebrospinal Fluid (CSF) Concentration of Nusinersen | Day 1611, Pre-dose | 13.46 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 40.19 |
| ISIS 396443 2 SMN2 Copies | Cerebrospinal Fluid (CSF) Concentration of Nusinersen | Day 15, Pre-dose | 7.52 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 189 |
| ISIS 396443 2 SMN2 Copies | Cerebrospinal Fluid (CSF) Concentration of Nusinersen | Day 1730, Pre-dose | 13.63 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 57.76 |
| ISIS 396443 2 SMN2 Copies | Cerebrospinal Fluid (CSF) Concentration of Nusinersen | Day 778, Pre-dose | 10.87 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 54.28 |
| ISIS 396443 2 SMN2 Copies | Cerebrospinal Fluid (CSF) Concentration of Nusinersen | Day 1849, Pre-dose | 15.14 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 63.15 |
| ISIS 396443 2 SMN2 Copies | Cerebrospinal Fluid (CSF) Concentration of Nusinersen | Day 302, Pre-dose | 11.34 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 54.67 |
| ISIS 396443 2 SMN2 Copies | Cerebrospinal Fluid (CSF) Concentration of Nusinersen | Day 1968, Pre-dose | 16.52 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 67.05 |
| ISIS 396443 2 SMN2 Copies | Cerebrospinal Fluid (CSF) Concentration of Nusinersen | Day 897, Pre-dose | 11.03 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 43.91 |
| ISIS 396443 2 SMN2 Copies | Cerebrospinal Fluid (CSF) Concentration of Nusinersen | Day 2087, Pre-dose | 15.57 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 47.34 |
| ISIS 396443 2 SMN2 Copies | Cerebrospinal Fluid (CSF) Concentration of Nusinersen | Day 64, Pre-dose | 14.95 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 58.06 |
| ISIS 396443 2 SMN2 Copies | Cerebrospinal Fluid (CSF) Concentration of Nusinersen | Day 2206, Pre-dose | 16.95 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 45.86 |
| ISIS 396443 2 SMN2 Copies | Cerebrospinal Fluid (CSF) Concentration of Nusinersen | Day 1016, Pre-dose | 12.06 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 58.41 |
| ISIS 396443 2 SMN2 Copies | Cerebrospinal Fluid (CSF) Concentration of Nusinersen | Day 2325, Pre-dose | 18.27 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 59.23 |
| ISIS 396443 2 SMN2 Copies | Cerebrospinal Fluid (CSF) Concentration of Nusinersen | Day 421, Pre-dose | 12.20 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 66.72 |
| ISIS 396443 2 SMN2 Copies | Cerebrospinal Fluid (CSF) Concentration of Nusinersen | Day 2444, Pre-dose | 16.92 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 49.19 |
| ISIS 396443 2 SMN2 Copies | Cerebrospinal Fluid (CSF) Concentration of Nusinersen | Day 1135, Pre-dose | 10.49 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 46.05 |
| ISIS 396443 2 SMN2 Copies | Cerebrospinal Fluid (CSF) Concentration of Nusinersen | Day 2563, Pre-dose | 16.74 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 53.14 |
| ISIS 396443 2 SMN2 Copies | Cerebrospinal Fluid (CSF) Concentration of Nusinersen | Day 29, Pre-dose | 23.41 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 72.04 |
| ISIS 396443 2 SMN2 Copies | Cerebrospinal Fluid (CSF) Concentration of Nusinersen | Day 2682, Pre-dose | 17.42 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 44.34 |
| ISIS 396443 2 SMN2 Copies | Cerebrospinal Fluid (CSF) Concentration of Nusinersen | Day 1254, Pre-dose | 12.88 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 47.06 |
| ISIS 396443 2 SMN2 Copies | Cerebrospinal Fluid (CSF) Concentration of Nusinersen | Day 2801, Pre-dose | 17.44 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 45.6 |
| ISIS 396443 2 SMN2 Copies | Cerebrospinal Fluid (CSF) Concentration of Nusinersen | Day 1, Pre-dose | 0.03 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 0 |
| ISIS 396443 3 SMN2 Copies | Cerebrospinal Fluid (CSF) Concentration of Nusinersen | Day 2801, Pre-dose | 17.85 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 36.35 |
| ISIS 396443 3 SMN2 Copies | Cerebrospinal Fluid (CSF) Concentration of Nusinersen | Day 1, Pre-dose | 0.03 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 0 |
| ISIS 396443 3 SMN2 Copies | Cerebrospinal Fluid (CSF) Concentration of Nusinersen | Day 15, Pre-dose | 10.22 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 285.47 |
| ISIS 396443 3 SMN2 Copies | Cerebrospinal Fluid (CSF) Concentration of Nusinersen | Day 29, Pre-dose | 24.56 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 85.78 |
| ISIS 396443 3 SMN2 Copies | Cerebrospinal Fluid (CSF) Concentration of Nusinersen | Day 64, Pre-dose | 21.33 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 63 |
| ISIS 396443 3 SMN2 Copies | Cerebrospinal Fluid (CSF) Concentration of Nusinersen | Day 183, Pre-dose | 13.85 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 54.32 |
| ISIS 396443 3 SMN2 Copies | Cerebrospinal Fluid (CSF) Concentration of Nusinersen | Day 302, Pre-dose | 10.06 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 27.29 |
| ISIS 396443 3 SMN2 Copies | Cerebrospinal Fluid (CSF) Concentration of Nusinersen | Day 421, Pre-dose | 10.53 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 67.48 |
| ISIS 396443 3 SMN2 Copies | Cerebrospinal Fluid (CSF) Concentration of Nusinersen | Day 540, Pre-dose | 9.42 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 51.04 |
| ISIS 396443 3 SMN2 Copies | Cerebrospinal Fluid (CSF) Concentration of Nusinersen | Day 659, Pre-dose | 10.30 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 38.34 |
| ISIS 396443 3 SMN2 Copies | Cerebrospinal Fluid (CSF) Concentration of Nusinersen | Day 778, Pre-dose | 11.77 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 61.01 |
| ISIS 396443 3 SMN2 Copies | Cerebrospinal Fluid (CSF) Concentration of Nusinersen | Day 897, Pre-dose | 10.72 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 35.9 |
| ISIS 396443 3 SMN2 Copies | Cerebrospinal Fluid (CSF) Concentration of Nusinersen | Day 1016, Pre-dose | 10.65 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 39.34 |
| ISIS 396443 3 SMN2 Copies | Cerebrospinal Fluid (CSF) Concentration of Nusinersen | Day 1135, Pre-dose | 10.87 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 36.62 |
| ISIS 396443 3 SMN2 Copies | Cerebrospinal Fluid (CSF) Concentration of Nusinersen | Day 1254, Pre-dose | 11.29 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 33.29 |
| ISIS 396443 3 SMN2 Copies | Cerebrospinal Fluid (CSF) Concentration of Nusinersen | Day 1373, Pre-dose | 10.19 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 52.12 |
| ISIS 396443 3 SMN2 Copies | Cerebrospinal Fluid (CSF) Concentration of Nusinersen | Day 1492, Pre-dose | 12.71 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 92.23 |
| ISIS 396443 3 SMN2 Copies | Cerebrospinal Fluid (CSF) Concentration of Nusinersen | Day 1611, Pre-dose | 13.90 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 36.31 |
| ISIS 396443 3 SMN2 Copies | Cerebrospinal Fluid (CSF) Concentration of Nusinersen | Day 1730, Pre-dose | 15.14 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 42.12 |
| ISIS 396443 3 SMN2 Copies | Cerebrospinal Fluid (CSF) Concentration of Nusinersen | Day 1849, Pre-dose | 14.19 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 42.87 |
| ISIS 396443 3 SMN2 Copies | Cerebrospinal Fluid (CSF) Concentration of Nusinersen | Day 1968, Pre-dose | 17.46 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 48.67 |
| ISIS 396443 3 SMN2 Copies | Cerebrospinal Fluid (CSF) Concentration of Nusinersen | Day 2087, Pre-dose | 17.07 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 58.91 |
| ISIS 396443 3 SMN2 Copies | Cerebrospinal Fluid (CSF) Concentration of Nusinersen | Day 2206, Pre-dose | 17.16 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 46.34 |
| ISIS 396443 3 SMN2 Copies | Cerebrospinal Fluid (CSF) Concentration of Nusinersen | Day 2325, Pre-dose | 20.02 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 37.41 |
| ISIS 396443 3 SMN2 Copies | Cerebrospinal Fluid (CSF) Concentration of Nusinersen | Day 2444, Pre-dose | 17.01 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 40.87 |
| ISIS 396443 3 SMN2 Copies | Cerebrospinal Fluid (CSF) Concentration of Nusinersen | Day 2563, Pre-dose | 13.37 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 85.72 |
| ISIS 396443 3 SMN2 Copies | Cerebrospinal Fluid (CSF) Concentration of Nusinersen | Day 2682, Pre-dose | 16.05 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 41.83 |
Secondary
Change From Baseline in Arm Circumference
Time frame: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| ISIS 396443 2 SMN2 Copies | Change From Baseline in Arm Circumference | Baseline | 10.85 cm | Standard Deviation 1.251 |
| ISIS 396443 3 SMN2 Copies | Change From Baseline in Arm Circumference | Baseline | 10.77 cm | Standard Deviation 1.656 |
| ISIS 396443 3 SMN2 Copies | Change From Baseline in Arm Circumference | Change at Day 2891 | 9.40 cm | — |
Secondary
Change From Baseline in Chest Circumference
Time frame: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| ISIS 396443 2 SMN2 Copies | Change From Baseline in Chest Circumference | Baseline | 34.43 cm | Standard Deviation 2.724 |
| ISIS 396443 3 SMN2 Copies | Change From Baseline in Chest Circumference | Baseline | 35.25 cm | Standard Deviation 2.551 |
| ISIS 396443 3 SMN2 Copies | Change From Baseline in Chest Circumference | Change at Day 2891 | 28.20 cm | — |
Secondary
Change From Baseline in Hammersmith Functional Motor Scale - Expanded (HFMSE)
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.
Time frame: Baseline, Day 2160
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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| ISIS 396443 2 SMN2 Copies | Change From Baseline in Hammersmith Functional Motor Scale - Expanded (HFMSE) | Baseline | 34.5 score on a scale | Standard Deviation 12.15 |
| ISIS 396443 2 SMN2 Copies | Change From Baseline in Hammersmith Functional Motor Scale - Expanded (HFMSE) | Change at Day 2160 | 23.5 score on a scale | Standard Deviation 5.34 |
| ISIS 396443 3 SMN2 Copies | Change From Baseline in Hammersmith Functional Motor Scale - Expanded (HFMSE) | Baseline | 46.4 score on a scale | Standard Deviation 7.44 |
| ISIS 396443 3 SMN2 Copies | Change From Baseline in Hammersmith Functional Motor Scale - Expanded (HFMSE) | Change at Day 2160 | 22.5 score on a scale | Standard Deviation 5.68 |
Secondary
Change From Baseline in Head Circumference
Time frame: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| ISIS 396443 2 SMN2 Copies | Change From Baseline in Head Circumference | Baseline | 35.59 centimeter (cm) | Standard Deviation 2.285 |
| ISIS 396443 3 SMN2 Copies | Change From Baseline in Head Circumference | Baseline | 36.11 centimeter (cm) | Standard Deviation 2.198 |
| ISIS 396443 3 SMN2 Copies | Change From Baseline in Head Circumference | Change at Day 2891 | 19.00 centimeter (cm) | — |
Secondary
Change From Baseline in Head to Chest Circumference Ratio
Negative change from baseline indicates reduction in head-to-chest circumference ratio.
Time frame: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| ISIS 396443 2 SMN2 Copies | Change From Baseline in Head to Chest Circumference Ratio | Baseline | 1.036 ratio | Standard Deviation 0.0537 |
| ISIS 396443 3 SMN2 Copies | Change From Baseline in Head to Chest Circumference Ratio | Baseline | 1.027 ratio | Standard Deviation 0.0595 |
| ISIS 396443 3 SMN2 Copies | Change From Baseline in Head to Chest Circumference Ratio | Change at Day 2891 | -0.186 ratio | — |
Secondary
Change From Baseline in the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) Motor Function Scale
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.
Time frame: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| ISIS 396443 2 SMN2 Copies | 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 |
| ISIS 396443 2 SMN2 Copies | 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 |
| ISIS 396443 3 SMN2 Copies | Change From Baseline in the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) Motor Function Scale | Baseline | 51.9 score on a scale | Standard Deviation 6.1 |
Secondary
Change From Baseline in Vital Signs (Blood Pressure)
Time frame: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| ISIS 396443 2 SMN2 Copies | Change From Baseline in Vital Signs (Blood Pressure) | Baseline-Systolic Blood Pressure | 83.4 millimeters of mercury (mmHg) | Standard Deviation 16.4 |
| ISIS 396443 2 SMN2 Copies | 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 |
| ISIS 396443 2 SMN2 Copies | Change From Baseline in Vital Signs (Blood Pressure) | Baseline-Diastolic Blood Pressure | 51.1 millimeters of mercury (mmHg) | Standard Deviation 17.46 |
| ISIS 396443 2 SMN2 Copies | 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 |
| ISIS 396443 3 SMN2 Copies | Change From Baseline in Vital Signs (Blood Pressure) | Change at Day 2891-Diastolic Blood Pressure | 11.0 millimeters of mercury (mmHg) | Standard Deviation 13.07 |
| ISIS 396443 3 SMN2 Copies | Change From Baseline in Vital Signs (Blood Pressure) | Baseline-Systolic Blood Pressure | 88.1 millimeters of mercury (mmHg) | Standard Deviation 17.84 |
| ISIS 396443 3 SMN2 Copies | Change From Baseline in Vital Signs (Blood Pressure) | Baseline-Diastolic Blood Pressure | 50.8 millimeters of mercury (mmHg) | Standard Deviation 12.3 |
| ISIS 396443 3 SMN2 Copies | Change From Baseline in Vital Signs (Blood Pressure) | Change at Day 2891-Systolic Blood Pressure | 13.6 millimeters of mercury (mmHg) | Standard Deviation 15.24 |
Secondary
Change From Baseline in Vital Signs (Heart Rate)
Negative change from baseline indicates reduction in heart rate.
Time frame: Baseline, Day 2891
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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| ISIS 396443 2 SMN2 Copies | Change From Baseline in Vital Signs (Heart Rate) | Baseline | 141.5 beats per minute (beats/min) | Standard Deviation 14.71 |
| ISIS 396443 2 SMN2 Copies | Change From Baseline in Vital Signs (Heart Rate) | Change at Day 2891 | -47.2 beats per minute (beats/min) | Standard Deviation 20.86 |
| ISIS 396443 3 SMN2 Copies | Change From Baseline in Vital Signs (Heart Rate) | Baseline | 154.2 beats per minute (beats/min) | Standard Deviation 16.55 |
| ISIS 396443 3 SMN2 Copies | Change From Baseline in Vital Signs (Heart Rate) | Change at Day 2891 | -62.4 beats per minute (beats/min) | Standard Deviation 25.16 |
Secondary
Change From Baseline in Vital Signs (Respiratory Rate)
Negative change from baseline indicates reduction in respiratory rate.
Time frame: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| ISIS 396443 2 SMN2 Copies | Change From Baseline in Vital Signs (Respiratory Rate) | Baseline | 42.1 breaths per minute (breaths/min) | Standard Deviation 12.17 |
| ISIS 396443 2 SMN2 Copies | Change From Baseline in Vital Signs (Respiratory Rate) | Change at Day 2891 | -21.0 breaths per minute (breaths/min) | Standard Deviation 12.39 |
| ISIS 396443 3 SMN2 Copies | Change From Baseline in Vital Signs (Respiratory Rate) | Baseline | 39.8 breaths per minute (breaths/min) | Standard Deviation 13.87 |
| ISIS 396443 3 SMN2 Copies | Change From Baseline in Vital Signs (Respiratory Rate) | Change at Day 2891 | -20.6 breaths per minute (breaths/min) | Standard Deviation 14.43 |
Secondary
Change From Baseline in Vital Signs (Temperature)
Negative change from baseline indicates reduction in temperature.
Time frame: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| ISIS 396443 2 SMN2 Copies | Change From Baseline in Vital Signs (Temperature) | Baseline | 36.7 degree Celsius | Standard Deviation 0.39 |
| ISIS 396443 2 SMN2 Copies | Change From Baseline in Vital Signs (Temperature) | Change at Day 2891 | 0.0 degree Celsius | Standard Deviation 0.54 |
| ISIS 396443 3 SMN2 Copies | Change From Baseline in Vital Signs (Temperature) | Baseline | 36.8 degree Celsius | Standard Deviation 0.44 |
| ISIS 396443 3 SMN2 Copies | Change From Baseline in Vital Signs (Temperature) | Change at Day 2891 | -0.1 degree Celsius | Standard Deviation 0.52 |
Secondary
Change From Baseline in Weight for Age
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.
Time frame: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| ISIS 396443 2 SMN2 Copies | Change From Baseline in Weight for Age | Baseline | 44.04 percentile | Standard Deviation 31.197 |
| ISIS 396443 2 SMN2 Copies | Change From Baseline in Weight for Age | Change at Day 2891 | -1.46 percentile | Standard Deviation 48.041 |
| ISIS 396443 3 SMN2 Copies | Change From Baseline in Weight for Age | Baseline | 34.76 percentile | Standard Deviation 16.054 |
| ISIS 396443 3 SMN2 Copies | Change From Baseline in Weight for Age | Change at Day 2891 | 24.49 percentile | Standard Deviation 40.263 |
Secondary
Change From Baseline in Weight for Length
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.
Time frame: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| ISIS 396443 2 SMN2 Copies | Change From Baseline in Weight for Length | Baseline | 21.63 percentile | Standard Deviation 22.806 |
| ISIS 396443 2 SMN2 Copies | Change From Baseline in Weight for Length | Change at Day 1849 | 38.94 percentile | — |
| ISIS 396443 3 SMN2 Copies | Change From Baseline in Weight for Length | Baseline | 45.26 percentile | Standard Deviation 28.039 |
Secondary
Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
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.
Time frame: 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.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| ISIS 396443 2 SMN2 Copies | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | AEs | 15 Participants |
| ISIS 396443 2 SMN2 Copies | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | SAEs | 10 Participants |
| ISIS 396443 3 SMN2 Copies | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | AEs | 10 Participants |
| ISIS 396443 3 SMN2 Copies | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | SAEs | 4 Participants |
Secondary
Number of Participants With Neurological Examination Abnormalities Reported as AEs
Participants with abnormalities in neurological examinations recorded as AEs were reported.
Time frame: 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.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| ISIS 396443 2 SMN2 Copies | Number of Participants With Neurological Examination Abnormalities Reported as AEs | Myoclonus | 2 Participants |
| ISIS 396443 2 SMN2 Copies | Number of Participants With Neurological Examination Abnormalities Reported as AEs | Strabismus | 0 Participants |
| ISIS 396443 2 SMN2 Copies | Number of Participants With Neurological Examination Abnormalities Reported as AEs | Clonus | 1 Participants |
| ISIS 396443 2 SMN2 Copies | Number of Participants With Neurological Examination Abnormalities Reported as AEs | Tremor | 8 Participants |
| ISIS 396443 2 SMN2 Copies | Number of Participants With Neurological Examination Abnormalities Reported as AEs | Extensor plantar response | 1 Participants |
| ISIS 396443 2 SMN2 Copies | Number of Participants With Neurological Examination Abnormalities Reported as AEs | Automatism | 1 Participants |
| ISIS 396443 2 SMN2 Copies | Number of Participants With Neurological Examination Abnormalities Reported as AEs | Peripheral sensory neuropathy | 1 Participants |
| ISIS 396443 2 SMN2 Copies | Number of Participants With Neurological Examination Abnormalities Reported as AEs | Hypotonia | 4 Participants |
| ISIS 396443 2 SMN2 Copies | Number of Participants With Neurological Examination Abnormalities Reported as AEs | Unresponsive to stimuli | 1 Participants |
| ISIS 396443 2 SMN2 Copies | Number of Participants With Neurological Examination Abnormalities Reported as AEs | Heterophoria | 1 Participants |
| ISIS 396443 2 SMN2 Copies | Number of Participants With Neurological Examination Abnormalities Reported as AEs | Muscular weakness | 9 Participants |
| ISIS 396443 2 SMN2 Copies | Number of Participants With Neurological Examination Abnormalities Reported as AEs | Areflexia | 2 Participants |
| ISIS 396443 2 SMN2 Copies | Number of Participants With Neurological Examination Abnormalities Reported as AEs | Torticollis | 1 Participants |
| ISIS 396443 2 SMN2 Copies | Number of Participants With Neurological Examination Abnormalities Reported as AEs | Muscle contractions involuntary | 8 Participants |
| ISIS 396443 2 SMN2 Copies | Number of Participants With Neurological Examination Abnormalities Reported as AEs | Muscle spasms | 0 Participants |
| ISIS 396443 2 SMN2 Copies | Number of Participants With Neurological Examination Abnormalities Reported as AEs | Facial paresis | 2 Participants |
| ISIS 396443 2 SMN2 Copies | Number of Participants With Neurological Examination Abnormalities Reported as AEs | Muscle twitching | 0 Participants |
| ISIS 396443 2 SMN2 Copies | Number of Participants With Neurological Examination Abnormalities Reported as AEs | Vision blurred | 0 Participants |
| ISIS 396443 2 SMN2 Copies | Number of Participants With Neurological Examination Abnormalities Reported as AEs | Trismus | 1 Participants |
| ISIS 396443 2 SMN2 Copies | Number of Participants With Neurological Examination Abnormalities Reported as AEs | Hyperreflexia | 1 Participants |
| ISIS 396443 2 SMN2 Copies | Number of Participants With Neurological Examination Abnormalities Reported as AEs | Winged scapula | 1 Participants |
| ISIS 396443 2 SMN2 Copies | Number of Participants With Neurological Examination Abnormalities Reported as AEs | Dysarthria | 7 Participants |
| ISIS 396443 2 SMN2 Copies | Number of Participants With Neurological Examination Abnormalities Reported as AEs | Anisocoria | 0 Participants |
| ISIS 396443 3 SMN2 Copies | Number of Participants With Neurological Examination Abnormalities Reported as AEs | Extensor plantar response | 0 Participants |
| ISIS 396443 3 SMN2 Copies | Number of Participants With Neurological Examination Abnormalities Reported as AEs | Heterophoria | 0 Participants |
| ISIS 396443 3 SMN2 Copies | Number of Participants With Neurological Examination Abnormalities Reported as AEs | Strabismus | 1 Participants |
| ISIS 396443 3 SMN2 Copies | Number of Participants With Neurological Examination Abnormalities Reported as AEs | Vision blurred | 1 Participants |
| ISIS 396443 3 SMN2 Copies | Number of Participants With Neurological Examination Abnormalities Reported as AEs | Automatism | 0 Participants |
| ISIS 396443 3 SMN2 Copies | Number of Participants With Neurological Examination Abnormalities Reported as AEs | Muscle contractions involuntary | 1 Participants |
| ISIS 396443 3 SMN2 Copies | Number of Participants With Neurological Examination Abnormalities Reported as AEs | Dysarthria | 1 Participants |
| ISIS 396443 3 SMN2 Copies | Number of Participants With Neurological Examination Abnormalities Reported as AEs | Tremor | 0 Participants |
| ISIS 396443 3 SMN2 Copies | Number of Participants With Neurological Examination Abnormalities Reported as AEs | Hypotonia | 0 Participants |
| ISIS 396443 3 SMN2 Copies | Number of Participants With Neurological Examination Abnormalities Reported as AEs | Areflexia | 1 Participants |
| ISIS 396443 3 SMN2 Copies | Number of Participants With Neurological Examination Abnormalities Reported as AEs | Facial paresis | 0 Participants |
| ISIS 396443 3 SMN2 Copies | Number of Participants With Neurological Examination Abnormalities Reported as AEs | Hyperreflexia | 1 Participants |
| ISIS 396443 3 SMN2 Copies | Number of Participants With Neurological Examination Abnormalities Reported as AEs | Myoclonus | 0 Participants |
| ISIS 396443 3 SMN2 Copies | Number of Participants With Neurological Examination Abnormalities Reported as AEs | Clonus | 0 Participants |
| ISIS 396443 3 SMN2 Copies | Number of Participants With Neurological Examination Abnormalities Reported as AEs | Anisocoria | 1 Participants |
| ISIS 396443 3 SMN2 Copies | Number of Participants With Neurological Examination Abnormalities Reported as AEs | Peripheral sensory neuropathy | 0 Participants |
| ISIS 396443 3 SMN2 Copies | Number of Participants With Neurological Examination Abnormalities Reported as AEs | Unresponsive to stimuli | 0 Participants |
| ISIS 396443 3 SMN2 Copies | Number of Participants With Neurological Examination Abnormalities Reported as AEs | Muscular weakness | 1 Participants |
| ISIS 396443 3 SMN2 Copies | Number of Participants With Neurological Examination Abnormalities Reported as AEs | Torticollis | 1 Participants |
| ISIS 396443 3 SMN2 Copies | Number of Participants With Neurological Examination Abnormalities Reported as AEs | Muscle spasms | 1 Participants |
| ISIS 396443 3 SMN2 Copies | Number of Participants With Neurological Examination Abnormalities Reported as AEs | Muscle twitching | 1 Participants |
| ISIS 396443 3 SMN2 Copies | Number of Participants With Neurological Examination Abnormalities Reported as AEs | Trismus | 0 Participants |
| ISIS 396443 3 SMN2 Copies | Number of Participants With Neurological Examination Abnormalities Reported as AEs | Winged scapula | 0 Participants |
Secondary
Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Blood Chemistry Parameters)
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.
Time frame: Baseline up to 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 of the specified blood chemistry parameter.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| ISIS 396443 2 SMN2 Copies | Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Blood Chemistry Parameters) | Aspartate Aminotransferase Shift to Low | 0 Participants |
| ISIS 396443 2 SMN2 Copies | Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Blood Chemistry Parameters) | Bilirubin Shift to High | 2 Participants |
| ISIS 396443 2 SMN2 Copies | Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Blood Chemistry Parameters) | Indirect Bilirubin Shift to Low | 0 Participants |
| ISIS 396443 2 SMN2 Copies | Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Blood Chemistry Parameters) | Indirect Bilirubin Shift to High | 1 Participants |
| ISIS 396443 2 SMN2 Copies | Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Blood Chemistry Parameters) | Direct Bilirubin Shift to Low | 14 Participants |
| ISIS 396443 2 SMN2 Copies | Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Blood Chemistry Parameters) | Direct Bilirubin Shift to High | 0 Participants |
| ISIS 396443 2 SMN2 Copies | Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Blood Chemistry Parameters) | Alkaline Phosphatase Shift to Low | 3 Participants |
| ISIS 396443 2 SMN2 Copies | Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Blood Chemistry Parameters) | Alkaline Phosphatase Shift to High | 2 Participants |
| ISIS 396443 2 SMN2 Copies | Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Blood Chemistry Parameters) | Alanine Aminotransferase Shift to Low | 0 Participants |
| ISIS 396443 2 SMN2 Copies | Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Blood Chemistry Parameters) | Alanine Aminotransferase Shift to High | 7 Participants |
| ISIS 396443 2 SMN2 Copies | Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Blood Chemistry Parameters) | Bilirubin Shift to Low | 14 Participants |
| ISIS 396443 2 SMN2 Copies | Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Blood Chemistry Parameters) | Aspartate Aminotransferase Shift to High | 6 Participants |
| ISIS 396443 2 SMN2 Copies | Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Blood Chemistry Parameters) | Gamma Glutamyl Transferase Shift to Low | 1 Participants |
| ISIS 396443 2 SMN2 Copies | Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Blood Chemistry Parameters) | Gamma Glutamyl Transferase Shift to High | 1 Participants |
| ISIS 396443 2 SMN2 Copies | Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Blood Chemistry Parameters) | Urea Nitrogen Shift to Low | 6 Participants |
| ISIS 396443 2 SMN2 Copies | Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Blood Chemistry Parameters) | Urea Nitrogen Shift to High | 0 Participants |
| ISIS 396443 2 SMN2 Copies | Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Blood Chemistry Parameters) | Creatinine Shift to Low | 5 Participants |
| ISIS 396443 2 SMN2 Copies | Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Blood Chemistry Parameters) | Creatinine Shift to High | 1 Participants |
| ISIS 396443 2 SMN2 Copies | Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Blood Chemistry Parameters) | Sodium Shift to Low | 2 Participants |
| ISIS 396443 2 SMN2 Copies | Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Blood Chemistry Parameters) | Sodium Shift to High | 0 Participants |
| ISIS 396443 2 SMN2 Copies | Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Blood Chemistry Parameters) | Potassium Shift to Low | 0 Participants |
| ISIS 396443 2 SMN2 Copies | Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Blood Chemistry Parameters) | Potassium Shift to High | 8 Participants |
| ISIS 396443 2 SMN2 Copies | Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Blood Chemistry Parameters) | Chloride Shift to Low | 0 Participants |
| ISIS 396443 2 SMN2 Copies | Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Blood Chemistry Parameters) | Chloride Shift to High | 0 Participants |
| ISIS 396443 2 SMN2 Copies | Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Blood Chemistry Parameters) | Protein Shift to Low | 2 Participants |
| ISIS 396443 2 SMN2 Copies | Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Blood Chemistry Parameters) | Protein Shift to High | 13 Participants |
| ISIS 396443 2 SMN2 Copies | Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Blood Chemistry Parameters) | Albumin Shift to Low | 0 Participants |
| ISIS 396443 2 SMN2 Copies | Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Blood Chemistry Parameters) | Albumin Shift to High | 10 Participants |
| ISIS 396443 2 SMN2 Copies | Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Blood Chemistry Parameters) | Bicarbonate Shift to Low | 8 Participants |
| ISIS 396443 2 SMN2 Copies | Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Blood Chemistry Parameters) | Bicarbonate Shift to High | 1 Participants |
| ISIS 396443 2 SMN2 Copies | Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Blood Chemistry Parameters) | Calcium Shift to Low | 3 Participants |
| ISIS 396443 2 SMN2 Copies | Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Blood Chemistry Parameters) | Calcium Shift to High | 6 Participants |
| ISIS 396443 2 SMN2 Copies | Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Blood Chemistry Parameters) | Phosphate Shift to Low | 0 Participants |
| ISIS 396443 2 SMN2 Copies | Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Blood Chemistry Parameters) | Phosphate Shift to High | 9 Participants |
| ISIS 396443 2 SMN2 Copies | Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Blood Chemistry Parameters) | Glucose Shift to Low | 7 Participants |
| ISIS 396443 2 SMN2 Copies | Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Blood Chemistry Parameters) | Glucose Shift to High | 11 Participants |
| ISIS 396443 2 SMN2 Copies | Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Blood Chemistry Parameters) | Cystatin C Shift to Low | 6 Participants |
| ISIS 396443 2 SMN2 Copies | Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Blood Chemistry Parameters) | Cystatin C Shift to High | 2 Participants |
| ISIS 396443 2 SMN2 Copies | Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Blood Chemistry Parameters) | Creatine Kinase Shift to Low | 0 Participants |
| ISIS 396443 2 SMN2 Copies | Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Blood Chemistry Parameters) | Creatine Kinase Shift to High | 8 Participants |
| ISIS 396443 3 SMN2 Copies | Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Blood Chemistry Parameters) | Cystatin C Shift to High | 0 Participants |
| ISIS 396443 3 SMN2 Copies | Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Blood Chemistry Parameters) | Bilirubin Shift to Low | 10 Participants |
| ISIS 396443 3 SMN2 Copies | Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Blood Chemistry Parameters) | Potassium Shift to Low | 1 Participants |
| ISIS 396443 3 SMN2 Copies | Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Blood Chemistry Parameters) | Bilirubin Shift to High | 1 Participants |
| ISIS 396443 3 SMN2 Copies | Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Blood Chemistry Parameters) | Calcium Shift to Low | 3 Participants |
| ISIS 396443 3 SMN2 Copies | Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Blood Chemistry Parameters) | Indirect Bilirubin Shift to Low | 0 Participants |
| ISIS 396443 3 SMN2 Copies | Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Blood Chemistry Parameters) | Potassium Shift to High | 3 Participants |
| ISIS 396443 3 SMN2 Copies | Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Blood Chemistry Parameters) | Indirect Bilirubin Shift to High | 1 Participants |
| ISIS 396443 3 SMN2 Copies | Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Blood Chemistry Parameters) | Glucose Shift to High | 7 Participants |
| ISIS 396443 3 SMN2 Copies | Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Blood Chemistry Parameters) | Direct Bilirubin Shift to Low | 10 Participants |
| ISIS 396443 3 SMN2 Copies | Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Blood Chemistry Parameters) | Chloride Shift to Low | 1 Participants |
| ISIS 396443 3 SMN2 Copies | Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Blood Chemistry Parameters) | Direct Bilirubin Shift to High | 1 Participants |
| ISIS 396443 3 SMN2 Copies | Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Blood Chemistry Parameters) | Calcium Shift to High | 8 Participants |
| ISIS 396443 3 SMN2 Copies | Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Blood Chemistry Parameters) | Alkaline Phosphatase Shift to Low | 0 Participants |
| ISIS 396443 3 SMN2 Copies | Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Blood Chemistry Parameters) | Chloride Shift to High | 2 Participants |
| ISIS 396443 3 SMN2 Copies | Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Blood Chemistry Parameters) | Alkaline Phosphatase Shift to High | 5 Participants |
| ISIS 396443 3 SMN2 Copies | Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Blood Chemistry Parameters) | Creatine Kinase Shift to High | 6 Participants |
| ISIS 396443 3 SMN2 Copies | Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Blood Chemistry Parameters) | Alanine Aminotransferase Shift to Low | 0 Participants |
| ISIS 396443 3 SMN2 Copies | Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Blood Chemistry Parameters) | Protein Shift to Low | 5 Participants |
| ISIS 396443 3 SMN2 Copies | Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Blood Chemistry Parameters) | Alanine Aminotransferase Shift to High | 2 Participants |
| ISIS 396443 3 SMN2 Copies | Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Blood Chemistry Parameters) | Phosphate Shift to Low | 0 Participants |
| ISIS 396443 3 SMN2 Copies | Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Blood Chemistry Parameters) | Aspartate Aminotransferase Shift to Low | 0 Participants |
| ISIS 396443 3 SMN2 Copies | Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Blood Chemistry Parameters) | Protein Shift to High | 6 Participants |
| ISIS 396443 3 SMN2 Copies | Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Blood Chemistry Parameters) | Aspartate Aminotransferase Shift to High | 2 Participants |
| ISIS 396443 3 SMN2 Copies | Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Blood Chemistry Parameters) | Cystatin C Shift to Low | 4 Participants |
| ISIS 396443 3 SMN2 Copies | Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Blood Chemistry Parameters) | Gamma Glutamyl Transferase Shift to Low | 0 Participants |
| ISIS 396443 3 SMN2 Copies | Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Blood Chemistry Parameters) | Albumin Shift to Low | 0 Participants |
| ISIS 396443 3 SMN2 Copies | Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Blood Chemistry Parameters) | Gamma Glutamyl Transferase Shift to High | 0 Participants |
| ISIS 396443 3 SMN2 Copies | Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Blood Chemistry Parameters) | Phosphate Shift to High | 4 Participants |
| ISIS 396443 3 SMN2 Copies | Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Blood Chemistry Parameters) | Urea Nitrogen Shift to Low | 0 Participants |
| ISIS 396443 3 SMN2 Copies | Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Blood Chemistry Parameters) | Albumin Shift to High | 8 Participants |
| ISIS 396443 3 SMN2 Copies | Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Blood Chemistry Parameters) | Urea Nitrogen Shift to High | 2 Participants |
| ISIS 396443 3 SMN2 Copies | Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Blood Chemistry Parameters) | Creatine Kinase Shift to Low | 0 Participants |
| ISIS 396443 3 SMN2 Copies | Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Blood Chemistry Parameters) | Creatinine Shift to Low | 2 Participants |
| ISIS 396443 3 SMN2 Copies | Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Blood Chemistry Parameters) | Bicarbonate Shift to Low | 7 Participants |
| ISIS 396443 3 SMN2 Copies | Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Blood Chemistry Parameters) | Creatinine Shift to High | 4 Participants |
| ISIS 396443 3 SMN2 Copies | Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Blood Chemistry Parameters) | Glucose Shift to Low | 6 Participants |
| ISIS 396443 3 SMN2 Copies | Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Blood Chemistry Parameters) | Sodium Shift to Low | 0 Participants |
| ISIS 396443 3 SMN2 Copies | Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Blood Chemistry Parameters) | Bicarbonate Shift to High | 0 Participants |
| ISIS 396443 3 SMN2 Copies | Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Blood Chemistry Parameters) | Sodium Shift to High | 1 Participants |
Secondary
Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Hematology Parameters)
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.
Time frame: Baseline up to 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 of the specified hematology parameter.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| ISIS 396443 2 SMN2 Copies | Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Hematology Parameters) | Neutrophils/Leukocytes Shift to Low | 4 Participants |
| ISIS 396443 2 SMN2 Copies | Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Hematology Parameters) | Hemoglobin Shift to High | 3 Participants |
| ISIS 396443 2 SMN2 Copies | Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Hematology Parameters) | Hematocrit Shift to Low | 7 Participants |
| ISIS 396443 2 SMN2 Copies | Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Hematology Parameters) | Hematocrit Shift to High | 4 Participants |
| ISIS 396443 2 SMN2 Copies | Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Hematology Parameters) | Erythrocytes Shift to Low | 3 Participants |
| ISIS 396443 2 SMN2 Copies | Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Hematology Parameters) | Erythrocytes Shift to High | 9 Participants |
| ISIS 396443 2 SMN2 Copies | Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Hematology Parameters) | Leukocytes Shift to Low | 5 Participants |
| ISIS 396443 2 SMN2 Copies | Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Hematology Parameters) | Leukocytes Shift to High | 11 Participants |
| ISIS 396443 2 SMN2 Copies | Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Hematology Parameters) | Hemoglobin Shift to Low | 10 Participants |
| ISIS 396443 2 SMN2 Copies | Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Hematology Parameters) | Neutrophils/Leukocytes Shift to High | 4 Participants |
| ISIS 396443 2 SMN2 Copies | Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Hematology Parameters) | Eosinophils/Leukocytes Shift to Low | 0 Participants |
| ISIS 396443 2 SMN2 Copies | Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Hematology Parameters) | Eosinophils/Leukocytes Shift to High | 7 Participants |
| ISIS 396443 2 SMN2 Copies | Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Hematology Parameters) | Basophils/Leukocytes Shift to Low | 0 Participants |
| ISIS 396443 2 SMN2 Copies | Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Hematology Parameters) | Basophils/Leukocytes Shift to High | 10 Participants |
| ISIS 396443 2 SMN2 Copies | Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Hematology Parameters) | Lymphocytes/Leukocytes Shift to Low | 4 Participants |
| ISIS 396443 2 SMN2 Copies | Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Hematology Parameters) | Lymphocytes/Leukocytes Shift to High | 6 Participants |
| ISIS 396443 2 SMN2 Copies | Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Hematology Parameters) | Monocytes/Leukocytes Shift to Low | 11 Participants |
| ISIS 396443 2 SMN2 Copies | Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Hematology Parameters) | Monocytes/Leukocytes Shift to High | 4 Participants |
| ISIS 396443 2 SMN2 Copies | Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Hematology Parameters) | Neutrophils Shift to Low | 2 Participants |
| ISIS 396443 2 SMN2 Copies | Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Hematology Parameters) | Neutrophils Shift to High | 3 Participants |
| ISIS 396443 2 SMN2 Copies | Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Hematology Parameters) | Neutrophils, Segmented Shift to Low | 6 Participants |
| ISIS 396443 2 SMN2 Copies | Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Hematology Parameters) | Neutrophils, Segmented Shift to High | 9 Participants |
| ISIS 396443 2 SMN2 Copies | Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Hematology Parameters) | Eosinophils Shift to Low | 0 Participants |
| ISIS 396443 2 SMN2 Copies | Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Hematology Parameters) | Eosinophils Shift to High | 11 Participants |
| ISIS 396443 2 SMN2 Copies | Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Hematology Parameters) | Basophils Shift to Low | 0 Participants |
| ISIS 396443 2 SMN2 Copies | Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Hematology Parameters) | Basophils Shift to High | 4 Participants |
| ISIS 396443 2 SMN2 Copies | Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Hematology Parameters) | Lymphocytes Shift to Low | 2 Participants |
| ISIS 396443 2 SMN2 Copies | Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Hematology Parameters) | Lymphocytes Shift to High | 11 Participants |
| ISIS 396443 2 SMN2 Copies | Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Hematology Parameters) | Monocytes Shift to Low | 14 Participants |
| ISIS 396443 2 SMN2 Copies | Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Hematology Parameters) | Monocytes Shift to High | 4 Participants |
| ISIS 396443 2 SMN2 Copies | Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Hematology Parameters) | Platelets Shift to Low | 3 Participants |
| ISIS 396443 2 SMN2 Copies | Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Hematology Parameters) | Platelets Shift to High | 9 Participants |
| ISIS 396443 3 SMN2 Copies | Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Hematology Parameters) | Platelets Shift to High | 7 Participants |
| ISIS 396443 3 SMN2 Copies | Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Hematology Parameters) | Hemoglobin Shift to Low | 5 Participants |
| ISIS 396443 3 SMN2 Copies | Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Hematology Parameters) | Monocytes/Leukocytes Shift to Low | 7 Participants |
| ISIS 396443 3 SMN2 Copies | Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Hematology Parameters) | Hemoglobin Shift to High | 4 Participants |
| ISIS 396443 3 SMN2 Copies | Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Hematology Parameters) | Basophils Shift to Low | 0 Participants |
| ISIS 396443 3 SMN2 Copies | Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Hematology Parameters) | Hematocrit Shift to Low | 7 Participants |
| ISIS 396443 3 SMN2 Copies | Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Hematology Parameters) | Monocytes/Leukocytes Shift to High | 1 Participants |
| ISIS 396443 3 SMN2 Copies | Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Hematology Parameters) | Hematocrit Shift to High | 4 Participants |
| ISIS 396443 3 SMN2 Copies | Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Hematology Parameters) | Monocytes Shift to Low | 10 Participants |
| ISIS 396443 3 SMN2 Copies | Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Hematology Parameters) | Erythrocytes Shift to Low | 5 Participants |
| ISIS 396443 3 SMN2 Copies | Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Hematology Parameters) | Neutrophils Shift to Low | 1 Participants |
| ISIS 396443 3 SMN2 Copies | Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Hematology Parameters) | Erythrocytes Shift to High | 3 Participants |
| ISIS 396443 3 SMN2 Copies | Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Hematology Parameters) | Basophils Shift to High | 2 Participants |
| ISIS 396443 3 SMN2 Copies | Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Hematology Parameters) | Leukocytes Shift to Low | 6 Participants |
| ISIS 396443 3 SMN2 Copies | Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Hematology Parameters) | Neutrophils Shift to High | 0 Participants |
| ISIS 396443 3 SMN2 Copies | Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Hematology Parameters) | Leukocytes Shift to High | 4 Participants |
| ISIS 396443 3 SMN2 Copies | Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Hematology Parameters) | Platelets Shift to Low | 5 Participants |
| ISIS 396443 3 SMN2 Copies | Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Hematology Parameters) | Neutrophils/Leukocytes Shift to Low | 2 Participants |
| ISIS 396443 3 SMN2 Copies | Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Hematology Parameters) | Neutrophils, Segmented Shift to Low | 4 Participants |
| ISIS 396443 3 SMN2 Copies | Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Hematology Parameters) | Neutrophils/Leukocytes Shift to High | 0 Participants |
| ISIS 396443 3 SMN2 Copies | Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Hematology Parameters) | Lymphocytes Shift to Low | 1 Participants |
| ISIS 396443 3 SMN2 Copies | Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Hematology Parameters) | Eosinophils/Leukocytes Shift to Low | 0 Participants |
| ISIS 396443 3 SMN2 Copies | Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Hematology Parameters) | Neutrophils, Segmented Shift to High | 1 Participants |
| ISIS 396443 3 SMN2 Copies | Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Hematology Parameters) | Eosinophils/Leukocytes Shift to High | 8 Participants |
| ISIS 396443 3 SMN2 Copies | Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Hematology Parameters) | Monocytes Shift to High | 0 Participants |
| ISIS 396443 3 SMN2 Copies | Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Hematology Parameters) | Basophils/Leukocytes Shift to Low | 0 Participants |
| ISIS 396443 3 SMN2 Copies | Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Hematology Parameters) | Eosinophils Shift to Low | 0 Participants |
| ISIS 396443 3 SMN2 Copies | Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Hematology Parameters) | Basophils/Leukocytes Shift to High | 9 Participants |
| ISIS 396443 3 SMN2 Copies | Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Hematology Parameters) | Lymphocytes Shift to High | 8 Participants |
| ISIS 396443 3 SMN2 Copies | Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Hematology Parameters) | Lymphocytes/Leukocytes Shift to Low | 1 Participants |
| ISIS 396443 3 SMN2 Copies | Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Hematology Parameters) | Eosinophils Shift to High | 8 Participants |
| ISIS 396443 3 SMN2 Copies | Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Hematology Parameters) | Lymphocytes/Leukocytes Shift to High | 4 Participants |
Secondary
Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Urinalysis Parameters)
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.
Time frame: Baseline up to 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 of the specified urinalysis parameter.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| ISIS 396443 2 SMN2 Copies | Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Urinalysis Parameters) | Protein Shift to High/positive | 13 Participants |
| ISIS 396443 2 SMN2 Copies | Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Urinalysis Parameters) | Occult Blood Shift to High/positive | 4 Participants |
| ISIS 396443 2 SMN2 Copies | Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Urinalysis Parameters) | Specific Gravity Shift to High | 6 Participants |
| ISIS 396443 2 SMN2 Copies | Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Urinalysis Parameters) | Erythrocytes Shift to High/positive | 7 Participants |
| ISIS 396443 2 SMN2 Copies | Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Urinalysis Parameters) | Glucose Shift to High/positive | 1 Participants |
| ISIS 396443 2 SMN2 Copies | Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Urinalysis Parameters) | Leukocytes Shift to High/positive | 5 Participants |
| ISIS 396443 2 SMN2 Copies | Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Urinalysis Parameters) | pH Shift to High | 3 Participants |
| ISIS 396443 2 SMN2 Copies | Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Urinalysis Parameters) | Epithelial Cells Shift to High/positive | 5 Participants |
| ISIS 396443 2 SMN2 Copies | Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Urinalysis Parameters) | Ketones Shift to High/positive | 9 Participants |
| ISIS 396443 2 SMN2 Copies | Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Urinalysis Parameters) | Bacteria Shift to High/positive | 7 Participants |
| ISIS 396443 2 SMN2 Copies | Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Urinalysis Parameters) | pH Shift to Low | 0 Participants |
| ISIS 396443 2 SMN2 Copies | Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Urinalysis Parameters) | Casts Shift to High/positive | 1 Participants |
| ISIS 396443 2 SMN2 Copies | Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Urinalysis Parameters) | Bilirubin Shift to High/positive | 0 Participants |
| ISIS 396443 2 SMN2 Copies | Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Urinalysis Parameters) | Crystals Shift to High/positive | 1 Participants |
| ISIS 396443 2 SMN2 Copies | Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Urinalysis Parameters) | Specific Gravity Shift to Low | 3 Participants |
| ISIS 396443 3 SMN2 Copies | Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Urinalysis Parameters) | Crystals Shift to High/positive | 2 Participants |
| ISIS 396443 3 SMN2 Copies | Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Urinalysis Parameters) | Specific Gravity Shift to Low | 1 Participants |
| ISIS 396443 3 SMN2 Copies | Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Urinalysis Parameters) | Specific Gravity Shift to High | 5 Participants |
| ISIS 396443 3 SMN2 Copies | Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Urinalysis Parameters) | pH Shift to Low | 1 Participants |
| ISIS 396443 3 SMN2 Copies | Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Urinalysis Parameters) | pH Shift to High | 3 Participants |
| ISIS 396443 3 SMN2 Copies | Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Urinalysis Parameters) | Protein Shift to High/positive | 8 Participants |
| ISIS 396443 3 SMN2 Copies | Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Urinalysis Parameters) | Glucose Shift to High/positive | 0 Participants |
| ISIS 396443 3 SMN2 Copies | Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Urinalysis Parameters) | Ketones Shift to High/positive | 6 Participants |
| ISIS 396443 3 SMN2 Copies | Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Urinalysis Parameters) | Bilirubin Shift to High/positive | 0 Participants |
| ISIS 396443 3 SMN2 Copies | Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Urinalysis Parameters) | Occult Blood Shift to High/positive | 2 Participants |
| ISIS 396443 3 SMN2 Copies | Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Urinalysis Parameters) | Erythrocytes Shift to High/positive | 1 Participants |
| ISIS 396443 3 SMN2 Copies | Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Urinalysis Parameters) | Leukocytes Shift to High/positive | 4 Participants |
| ISIS 396443 3 SMN2 Copies | Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Urinalysis Parameters) | Epithelial Cells Shift to High/positive | 0 Participants |
| ISIS 396443 3 SMN2 Copies | Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Urinalysis Parameters) | Bacteria Shift to High/positive | 6 Participants |
| ISIS 396443 3 SMN2 Copies | Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Urinalysis Parameters) | Casts Shift to High/positive | 2 Participants |
Secondary
Number of Participants With Shifts From Baseline in Coagulation Parameters [Activated Partial Thromboplastin Time (aPTT)]
aPTT was evaluated to assess safety. Shift to high measured change in normal, low and unknown values at baseline to high values postbaseline.
Time frame: Baseline up to Day 2891
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.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| ISIS 396443 2 SMN2 Copies | Number of Participants With Shifts From Baseline in Coagulation Parameters [Activated Partial Thromboplastin Time (aPTT)] | 4 Participants |
| ISIS 396443 3 SMN2 Copies | Number of Participants With Shifts From Baseline in Coagulation Parameters [Activated Partial Thromboplastin Time (aPTT)] | 2 Participants |
Secondary
Number of Participants With Shifts From Baseline in Coagulation Parameters [International Normalized Ratio (INR)]
INR was evaluated to assess safety. Shift to high measured change in normal, low and unknown values at baseline to high values postbaseline.
Time frame: Baseline up to Day 2891
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.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| ISIS 396443 2 SMN2 Copies | Number of Participants With Shifts From Baseline in Coagulation Parameters [International Normalized Ratio (INR)] | 4 Participants |
| ISIS 396443 3 SMN2 Copies | Number of Participants With Shifts From Baseline in Coagulation Parameters [International Normalized Ratio (INR)] | 4 Participants |
Secondary
Number of Participants With Shifts From Baseline in Coagulation Parameters [Prothrombin Time (PT)]
PT was evaluated to assess safety. Shift to high measured change in normal, low and unknown values at baseline to high values postbaseline.
Time frame: Baseline up to Day 2891
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.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| ISIS 396443 2 SMN2 Copies | Number of Participants With Shifts From Baseline in Coagulation Parameters [Prothrombin Time (PT)] | 7 Participants |
| ISIS 396443 3 SMN2 Copies | Number of Participants With Shifts From Baseline in Coagulation Parameters [Prothrombin Time (PT)] | 5 Participants |
Secondary
Percentage of Participants Alive
Time frame: Up to 8 years of age
Population: The ITT set included all participants who received at least 1 dose of ISIS 396443.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| ISIS 396443 2 SMN2 Copies | Percentage of Participants Alive | 100 percentage of participants |
| ISIS 396443 3 SMN2 Copies | Percentage of Participants Alive | 100 percentage of participants |
Secondary
Percentage of Participants Who Attained Motor Milestones as Assessed by World Health Organization (WHO) Criteria
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.
Time frame: Baseline up to Day 2891
Population: The ITT set included all participants who received at least 1 dose of ISIS 396443.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| ISIS 396443 2 SMN2 Copies | 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 |
| ISIS 396443 2 SMN2 Copies | 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 |
| ISIS 396443 2 SMN2 Copies | 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 |
| ISIS 396443 2 SMN2 Copies | 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 |
| ISIS 396443 2 SMN2 Copies | 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 |
| ISIS 396443 2 SMN2 Copies | 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 |
| ISIS 396443 3 SMN2 Copies | 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 | 100 percentage of participants |
| ISIS 396443 3 SMN2 Copies | 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 |
| ISIS 396443 3 SMN2 Copies | 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 | 100 percentage of participants |
| ISIS 396443 3 SMN2 Copies | 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 | 100 percentage of participants |
| ISIS 396443 3 SMN2 Copies | 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 | 100 percentage of participants |
| ISIS 396443 3 SMN2 Copies | 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 |
Secondary
Percentage of Participants Who Attained Motor Milestones Assessed as Part of the Hammersmith Infant Neurological Examination (HINE)
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.
Time frame: Day 700
Population: The ITT set included all participants who received at least 1 dose of ISIS 396443.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| ISIS 396443 2 SMN2 Copies | 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 |
| ISIS 396443 2 SMN2 Copies | 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 |
| ISIS 396443 2 SMN2 Copies | 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 |
| ISIS 396443 2 SMN2 Copies | 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 |
| ISIS 396443 2 SMN2 Copies | 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 |
| ISIS 396443 2 SMN2 Copies | 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 |
| ISIS 396443 2 SMN2 Copies | 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 |
| ISIS 396443 2 SMN2 Copies | 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 |
| ISIS 396443 2 SMN2 Copies | 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 |
| ISIS 396443 2 SMN2 Copies | 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 |
| ISIS 396443 3 SMN2 Copies | 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 |
| ISIS 396443 3 SMN2 Copies | 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 |
| ISIS 396443 3 SMN2 Copies | 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 |
| ISIS 396443 3 SMN2 Copies | 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 | 100 percentage of participants |
| ISIS 396443 3 SMN2 Copies | 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 | 100 percentage of participants |
| ISIS 396443 3 SMN2 Copies | 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 | 100 percentage of participants |
| ISIS 396443 3 SMN2 Copies | 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 |
| ISIS 396443 3 SMN2 Copies | 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 | 100 percentage of participants |
| ISIS 396443 3 SMN2 Copies | 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 |
| ISIS 396443 3 SMN2 Copies | Percentage of Participants Who Attained Motor Milestones Assessed as Part of the Hammersmith Infant Neurological Examination (HINE) | First achievement of walking milestone - Walking independently | 100 percentage of participants |
Secondary
Percentage of Participants With Clinically Significant Shifts in Electrocardiograms (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.
Time frame: 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.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| ISIS 396443 2 SMN2 Copies | Percentage of Participants With Clinically Significant Shifts in Electrocardiograms (ECG) Abnormalities | 0 percentage of participants |
| ISIS 396443 3 SMN2 Copies | Percentage of Participants With Clinically Significant Shifts in Electrocardiograms (ECG) Abnormalities | 0 percentage of participants |
Secondary
Plasma Concentration of Nusinersen
Time frame: 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
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.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| ISIS 396443 2 SMN2 Copies | Plasma Concentration of Nusinersen | Day 659, Pre-dose | 0.74 ng/ml | Geometric Coefficient of Variation 26.78 |
| ISIS 396443 2 SMN2 Copies | Plasma Concentration of Nusinersen | Day 1373, Pre-dose | 0.60 ng/ml | Geometric Coefficient of Variation 39.79 |
| ISIS 396443 2 SMN2 Copies | Plasma Concentration of Nusinersen | Day 302, Pre-dose | 0.82 ng/ml | Geometric Coefficient of Variation 54.28 |
| ISIS 396443 2 SMN2 Copies | Plasma Concentration of Nusinersen | Day 1492, Pre-dose | 0.69 ng/ml | Geometric Coefficient of Variation 40.55 |
| ISIS 396443 2 SMN2 Copies | Plasma Concentration of Nusinersen | Day 778, Pre-dose | 0.68 ng/ml | Geometric Coefficient of Variation 48.37 |
| ISIS 396443 2 SMN2 Copies | Plasma Concentration of Nusinersen | Day 1611, Pre-dose | 0.62 ng/ml | Geometric Coefficient of Variation 38.14 |
| ISIS 396443 2 SMN2 Copies | Plasma Concentration of Nusinersen | Day 1, 4 hours post-dose | 391.66 ng/ml | Geometric Coefficient of Variation 113.16 |
| ISIS 396443 2 SMN2 Copies | Plasma Concentration of Nusinersen | Day 1730, Pre-dose | 0.54 ng/ml | Geometric Coefficient of Variation 16.13 |
| ISIS 396443 2 SMN2 Copies | Plasma Concentration of Nusinersen | Day 897, Pre-dose | 0.71 ng/ml | Geometric Coefficient of Variation 34.77 |
| ISIS 396443 2 SMN2 Copies | Plasma Concentration of Nusinersen | Day 1849, Pre-dose | 0.47 ng/ml | Geometric Coefficient of Variation 52.05 |
| ISIS 396443 2 SMN2 Copies | Plasma Concentration of Nusinersen | Day 421, Pre-dose | 0.78 ng/ml | Geometric Coefficient of Variation 39.94 |
| ISIS 396443 2 SMN2 Copies | Plasma Concentration of Nusinersen | Day 1968, Pre-dose | 0.53 ng/ml | Geometric Coefficient of Variation 25.66 |
| ISIS 396443 2 SMN2 Copies | Plasma Concentration of Nusinersen | Day 183, Pre-dose | 0.73 ng/ml | Geometric Coefficient of Variation 27.03 |
| ISIS 396443 2 SMN2 Copies | Plasma Concentration of Nusinersen | Day 2087, Pre-dose | 0.55 ng/ml | Geometric Coefficient of Variation 40.43 |
| ISIS 396443 2 SMN2 Copies | Plasma Concentration of Nusinersen | Day 1016, Pre-dose | 0.69 ng/ml | Geometric Coefficient of Variation 38.47 |
| ISIS 396443 2 SMN2 Copies | Plasma Concentration of Nusinersen | Day 2206, Pre-dose | 0.43 ng/ml | Geometric Coefficient of Variation 43.01 |
| ISIS 396443 2 SMN2 Copies | Plasma Concentration of Nusinersen | Day 540, Pre-dose | 0.72 ng/ml | Geometric Coefficient of Variation 29.72 |
| ISIS 396443 2 SMN2 Copies | Plasma Concentration of Nusinersen | Day 2325, Pre-dose | 0.46 ng/ml | Geometric Coefficient of Variation 56.98 |
| ISIS 396443 2 SMN2 Copies | Plasma Concentration of Nusinersen | Day 1135, Pre-dose | 0.67 ng/ml | Geometric Coefficient of Variation 33.7 |
| ISIS 396443 2 SMN2 Copies | Plasma Concentration of Nusinersen | Day 2444, Pre-dose | 0.43 ng/ml | Geometric Coefficient of Variation 35.15 |
| ISIS 396443 2 SMN2 Copies | Plasma Concentration of Nusinersen | Day 64, Pre-dose | 1.60 ng/ml | Geometric Coefficient of Variation 34.52 |
| ISIS 396443 2 SMN2 Copies | Plasma Concentration of Nusinersen | Day 2563, Pre-dose | 0.38 ng/ml | Geometric Coefficient of Variation 61.73 |
| ISIS 396443 2 SMN2 Copies | Plasma Concentration of Nusinersen | Day 1254, Pre-dose | 0.63 ng/ml | Geometric Coefficient of Variation 27.16 |
| ISIS 396443 2 SMN2 Copies | Plasma Concentration of Nusinersen | Day 2801, Pre-dose | 0.39 ng/ml | Geometric Coefficient of Variation 36.16 |
| ISIS 396443 2 SMN2 Copies | Plasma Concentration of Nusinersen | Day 2682, Pre-dose | 0.36 ng/ml | Geometric Coefficient of Variation 55.66 |
| ISIS 396443 3 SMN2 Copies | Plasma Concentration of Nusinersen | Day 2801, Pre-dose | 0.35 ng/ml | Geometric Coefficient of Variation 65.12 |
| ISIS 396443 3 SMN2 Copies | Plasma Concentration of Nusinersen | Day 1, 4 hours post-dose | 406.69 ng/ml | Geometric Coefficient of Variation 82.92 |
| ISIS 396443 3 SMN2 Copies | Plasma Concentration of Nusinersen | Day 64, Pre-dose | 1.56 ng/ml | Geometric Coefficient of Variation 46.54 |
| ISIS 396443 3 SMN2 Copies | Plasma Concentration of Nusinersen | Day 183, Pre-dose | 0.81 ng/ml | Geometric Coefficient of Variation 19.82 |
| ISIS 396443 3 SMN2 Copies | Plasma Concentration of Nusinersen | Day 302, Pre-dose | 0.81 ng/ml | Geometric Coefficient of Variation 21.12 |
| ISIS 396443 3 SMN2 Copies | Plasma Concentration of Nusinersen | Day 421, Pre-dose | 0.82 ng/ml | Geometric Coefficient of Variation 29.31 |
| ISIS 396443 3 SMN2 Copies | Plasma Concentration of Nusinersen | Day 540, Pre-dose | 0.72 ng/ml | Geometric Coefficient of Variation 19.16 |
| ISIS 396443 3 SMN2 Copies | Plasma Concentration of Nusinersen | Day 659, Pre-dose | 0.78 ng/ml | Geometric Coefficient of Variation 32.51 |
| ISIS 396443 3 SMN2 Copies | Plasma Concentration of Nusinersen | Day 778, Pre-dose | 0.81 ng/ml | Geometric Coefficient of Variation 23.52 |
| ISIS 396443 3 SMN2 Copies | Plasma Concentration of Nusinersen | Day 2682, Pre-dose | 0.40 ng/ml | Geometric Coefficient of Variation 24.48 |
| ISIS 396443 3 SMN2 Copies | Plasma Concentration of Nusinersen | Day 897, Pre-dose | 0.63 ng/ml | Geometric Coefficient of Variation 40.31 |
| ISIS 396443 3 SMN2 Copies | Plasma Concentration of Nusinersen | Day 1016, Pre-dose | 0.74 ng/ml | Geometric Coefficient of Variation 21.97 |
| ISIS 396443 3 SMN2 Copies | Plasma Concentration of Nusinersen | Day 1135, Pre-dose | 0.58 ng/ml | Geometric Coefficient of Variation 33.78 |
| ISIS 396443 3 SMN2 Copies | Plasma Concentration of Nusinersen | Day 1254, Pre-dose | 0.60 ng/ml | Geometric Coefficient of Variation 24.1 |
| ISIS 396443 3 SMN2 Copies | Plasma Concentration of Nusinersen | Day 1373, Pre-dose | 0.59 ng/ml | Geometric Coefficient of Variation 17.98 |
| ISIS 396443 3 SMN2 Copies | Plasma Concentration of Nusinersen | Day 1492, Pre-dose | 0.68 ng/ml | Geometric Coefficient of Variation 43.5 |
| ISIS 396443 3 SMN2 Copies | Plasma Concentration of Nusinersen | Day 1611, Pre-dose | 0.53 ng/ml | Geometric Coefficient of Variation 43.12 |
| ISIS 396443 3 SMN2 Copies | Plasma Concentration of Nusinersen | Day 1730, Pre-dose | 0.53 ng/ml | Geometric Coefficient of Variation 30.84 |
| ISIS 396443 3 SMN2 Copies | Plasma Concentration of Nusinersen | Day 1849, Pre-dose | 0.49 ng/ml | Geometric Coefficient of Variation 36.37 |
| ISIS 396443 3 SMN2 Copies | Plasma Concentration of Nusinersen | Day 1968, Pre-dose | 0.43 ng/ml | Geometric Coefficient of Variation 22.96 |
| ISIS 396443 3 SMN2 Copies | Plasma Concentration of Nusinersen | Day 2087, Pre-dose | 0.47 ng/ml | Geometric Coefficient of Variation 31.5 |
| ISIS 396443 3 SMN2 Copies | Plasma Concentration of Nusinersen | Day 2206, Pre-dose | 0.40 ng/ml | Geometric Coefficient of Variation 32.58 |
| ISIS 396443 3 SMN2 Copies | Plasma Concentration of Nusinersen | Day 2325, Pre-dose | 0.45 ng/ml | Geometric Coefficient of Variation 35.19 |
| ISIS 396443 3 SMN2 Copies | Plasma Concentration of Nusinersen | Day 2444, Pre-dose | 0.51 ng/ml | Geometric Coefficient of Variation 17.26 |
| ISIS 396443 3 SMN2 Copies | Plasma Concentration of Nusinersen | Day 2563, Pre-dose | 0.42 ng/ml | Geometric Coefficient of Variation 31.1 |
Secondary
Proportion of Participants Developing Clinically Manifested Spinal Muscular Atrophy (SMA)
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
Time frame: At 13 and 24 months of age
Population: The ITT set included all participants who received at least 1 dose of ISIS 396443.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| ISIS 396443 2 SMN2 Copies | Proportion of Participants Developing Clinically Manifested Spinal Muscular Atrophy (SMA) | 13 months of age | 0.67 proportion of participants |
| ISIS 396443 2 SMN2 Copies | Proportion of Participants Developing Clinically Manifested Spinal Muscular Atrophy (SMA) | 24 months of age | 0.47 proportion of participants |
| ISIS 396443 3 SMN2 Copies | Proportion of Participants Developing Clinically Manifested Spinal Muscular Atrophy (SMA) | 13 months of age | 0.20 proportion of participants |
| ISIS 396443 3 SMN2 Copies | Proportion of Participants Developing Clinically Manifested Spinal Muscular Atrophy (SMA) | 24 months of age | 0 proportion of participants |