A Phase 2 interventional study of Nusinersen in Spinal Muscular Atrophy, sponsored by Biogen. Completed at 21 sites in 7 countries. Open to participants aged 0 Weeks to 6 Weeks. Per ClinicalTrials.gov, last updated 2025-10-20.
Sponsored by Biogen · Phase 2, Interventional, and Prevention
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.
284 studies on the registry are indexed under Muscular Atrophy, Spinal; 76 are open to participants now.
This study's enrollment of 25 is close to the median of 27 across 161 interventional studies indexed under Muscular Atrophy, Spinal.
Browse Muscular Atrophy, Spinal studies →Biogen is the lead sponsor of 494 studies on the registry; 22 are open to participants now.
Of its 98 completed or terminated interventional studies of FDA-regulated products, 49 (50%) have results posted.
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Key Inclusion Criteria:
Key Exclusion Criteria:
Note: Other protocol defined Inclusion/Exclusion criteria may apply.
Nusinersen administered as an intrathecal injection
Drug: Nusinersen
Solution for intrathecal injection
Also known as: ISIS 396443, BIIB058, ISIS SMNRx, Spinraza
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
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
Percentage of Participants Alive
Time frame: Up to 8 years of age
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
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
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
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
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
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
Change From Baseline in Head Circumference
Time frame: Baseline, Day 2891
Change From Baseline in Chest Circumference
Time frame: Baseline, Day 2891
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
Change From Baseline in Arm Circumference
Time frame: Baseline, Day 2891
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)
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
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
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
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
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
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
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
Change From Baseline in Vital Signs (Temperature)
Negative change from baseline indicates reduction in temperature.
Time frame: Baseline, Day 2891
Change From Baseline in Vital Signs (Blood Pressure)
Time frame: Baseline, Day 2891
Change From Baseline in Vital Signs (Heart Rate)
Negative change from baseline indicates reduction in heart rate.
Time frame: Baseline, Day 2891
Change From Baseline in Vital Signs (Respiratory Rate)
Negative change from baseline indicates reduction in respiratory rate.
Time frame: Baseline, Day 2891
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)
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
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
Participants took part in the multiple investigative sites from 18 May 2015 to 17 Dec 2024.
| Milestone | ISIS 396443 2 SMN2 Copies | ISIS 396443 3 SMN2 Copies |
|---|---|---|
| Started | 15 | 10 |
| Completed | 13 | 9 |
| Not completed | 2 | 1 |
| Withdrew: Reason not specified | 1 | 1 |
| Withdrew: Withdrawal by parent/guardian | 1 | 0 |
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.
| months | ISIS 396443 2 SMN2 Copies | ISIS 396443 3 SMN2 Copies |
|---|---|---|
| Time to Death or Respiratory Intervention | NA (19.1 to NA) | — |
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
| proportion of participants | ISIS 396443 2 SMN2 Copies | ISIS 396443 3 SMN2 Copies |
|---|---|---|
| 13 months of age | 0.67 (0.39 to 0.87) | 0.20 (0.04 to 0.56) |
| 24 months of age | 0.47 (0.22 to 0.73) | 0 (0.00 to 0.34) |
| percentage of participants | ISIS 396443 2 SMN2 Copies | ISIS 396443 3 SMN2 Copies |
|---|---|---|
| Percentage of Participants Alive | 100 | 100 |
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 | ISIS 396443 2 SMN2 Copies | ISIS 396443 3 SMN2 Copies |
|---|---|---|
| First achievement of sitting milestone - Stable sit or Pivots (Rotates) | 100 | 100 |
| First achievement of standing with support milestone - Stands with support or Stands unaided | 93 | 100 |
| First achievement of standing unaided milestone - Stands unaided | 73 | 100 |
| First achievement of walking cruising milestone - Cruising (walks holding on)/Walking independently | 87 | 100 |
| First achievement of walking milestone - Walking independently | 67 | 100 |
| First achievement of head control - All the time maintained upright | 100 | 100 |
| First achievement of voluntary grasp - Pincer grasp | 100 | 100 |
| First achievement of ability to kick - Touches toes | 100 | 100 |
| First achievement of rolling - Prone to supine or Supine to prone | 100 | 100 |
| First achievement of crawling - Crawling on hands and knees | 73 | 100 |
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.
| percentage of participants | ISIS 396443 2 SMN2 Copies | ISIS 396443 3 SMN2 Copies |
|---|---|---|
| First sitting without support milestone achieved using caregiver or site reported dates | 100 | 100 |
| First hands-and-knees crawling milestone achieved using caregiver or site reported dates | 93 | 100 |
| First standing with assistance milestone achieved using caregiver or site reported dates | 100 | 100 |
| First walking with assistance milestone achieved using caregiver or site reported dates | 93 | 100 |
| First standing alone milestone achieved using caregiver or site reported dates | 93 | 100 |
| First walking alone milestone achieved using caregiver or site reported dates | 87 | 100 |
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.
| score on a scale | ISIS 396443 2 SMN2 Copies | ISIS 396443 3 SMN2 Copies |
|---|---|---|
| Baseline | 47.0 ± 10.04 | 51.9 ± 6.10 |
| Change at Day 2891 | 29.0 ± 11.31 | — |
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.
| score on a scale | ISIS 396443 2 SMN2 Copies | ISIS 396443 3 SMN2 Copies |
|---|---|---|
| Baseline | 34.5 ± 12.15 | 46.4 ± 7.44 |
| Change at Day 2160 | 23.5 ± 5.34 | 22.5 ± 5.68 |
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.
| percentile | ISIS 396443 2 SMN2 Copies | ISIS 396443 3 SMN2 Copies |
|---|---|---|
| Baseline | 44.04 ± 31.197 | 34.76 ± 16.054 |
| Change at Day 2891 | -1.46 ± 48.041 | 24.49 ± 40.263 |
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.
| percentile | ISIS 396443 2 SMN2 Copies | ISIS 396443 3 SMN2 Copies |
|---|---|---|
| Baseline | 21.63 ± 22.806 | 45.26 ± 28.039 |
| Change at Day 1849 | 38.94 ± NA | — |
| centimeter (cm) | ISIS 396443 2 SMN2 Copies | ISIS 396443 3 SMN2 Copies |
|---|---|---|
| Baseline | 35.59 ± 2.285 | 36.11 ± 2.198 |
| Change at Day 2891 | — | 19.00 ± NA |
| cm | ISIS 396443 2 SMN2 Copies | ISIS 396443 3 SMN2 Copies |
|---|---|---|
| Baseline | 34.43 ± 2.724 | 35.25 ± 2.551 |
| Change at Day 2891 | — | 28.20 ± NA |
Negative change from baseline indicates reduction in head-to-chest circumference ratio.
| ratio | ISIS 396443 2 SMN2 Copies | ISIS 396443 3 SMN2 Copies |
|---|---|---|
| Baseline | 1.036 ± 0.0537 | 1.027 ± 0.0595 |
| Change at Day 2891 | — | -0.186 ± NA |
| cm | ISIS 396443 2 SMN2 Copies | ISIS 396443 3 SMN2 Copies |
|---|---|---|
| Baseline | 10.85 ± 1.251 | 10.77 ± 1.656 |
| Change at Day 2891 | — | 9.40 ± NA |
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.
| Participants | ISIS 396443 2 SMN2 Copies | ISIS 396443 3 SMN2 Copies |
|---|---|---|
| AEs | 15 | 10 |
| SAEs | 10 | 4 |
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.
| Participants | ISIS 396443 2 SMN2 Copies | ISIS 396443 3 SMN2 Copies |
|---|---|---|
| Hemoglobin Shift to Low | 10 | 5 |
| Hemoglobin Shift to High | 3 | 4 |
| Hematocrit Shift to Low | 7 | 7 |
| Hematocrit Shift to High | 4 | 4 |
| Erythrocytes Shift to Low | 3 | 5 |
| Erythrocytes Shift to High | 9 | 3 |
| Leukocytes Shift to Low | 5 | 6 |
| Leukocytes Shift to High | 11 | 4 |
| Neutrophils/Leukocytes Shift to Low | 4 | 2 |
| Neutrophils/Leukocytes Shift to High | 4 | 0 |
| Eosinophils/Leukocytes Shift to Low | 0 | 0 |
| Eosinophils/Leukocytes Shift to High | 7 | 8 |
| Basophils/Leukocytes Shift to Low | 0 | 0 |
| Basophils/Leukocytes Shift to High | 10 | 9 |
| Lymphocytes/Leukocytes Shift to Low | 4 | 1 |
| Lymphocytes/Leukocytes Shift to High | 6 | 4 |
| Monocytes/Leukocytes Shift to Low | 11 | 7 |
| Monocytes/Leukocytes Shift to High | 4 | 1 |
| Neutrophils Shift to Low | 2 | 1 |
| Neutrophils Shift to High | 3 | 0 |
| Neutrophils, Segmented Shift to Low | 6 | 4 |
| Neutrophils, Segmented Shift to High | 9 | 1 |
| Eosinophils Shift to Low | 0 | 0 |
| Eosinophils Shift to High | 11 | 8 |
| Basophils Shift to Low | 0 | 0 |
| Basophils Shift to High | 4 | 2 |
| Lymphocytes Shift to Low | 2 | 1 |
| Lymphocytes Shift to High | 11 | 8 |
| Monocytes Shift to Low | 14 | 10 |
| Monocytes Shift to High | 4 | 0 |
| Platelets Shift to Low | 3 | 5 |
| Platelets Shift to High | 9 | 7 |
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.
| Participants | ISIS 396443 2 SMN2 Copies | ISIS 396443 3 SMN2 Copies |
|---|---|---|
| Bilirubin Shift to Low | 14 | 10 |
| Bilirubin Shift to High | 2 | 1 |
| Indirect Bilirubin Shift to Low | 0 | 0 |
| Indirect Bilirubin Shift to High | 1 | 1 |
| Direct Bilirubin Shift to Low | 14 | 10 |
| Direct Bilirubin Shift to High | 0 | 1 |
| Alkaline Phosphatase Shift to Low | 3 | 0 |
| Alkaline Phosphatase Shift to High | 2 | 5 |
| Alanine Aminotransferase Shift to Low | 0 | 0 |
| Alanine Aminotransferase Shift to High | 7 | 2 |
| Aspartate Aminotransferase Shift to Low | 0 | 0 |
| Aspartate Aminotransferase Shift to High | 6 | 2 |
| Gamma Glutamyl Transferase Shift to Low | 1 | 0 |
| Gamma Glutamyl Transferase Shift to High | 1 | 0 |
| Urea Nitrogen Shift to Low | 6 | 0 |
| Urea Nitrogen Shift to High | 0 | 2 |
| Creatinine Shift to Low | 5 | 2 |
| Creatinine Shift to High | 1 | 4 |
| Sodium Shift to Low | 2 | 0 |
| Sodium Shift to High | 0 | 1 |
| Potassium Shift to Low | 0 | 1 |
| Potassium Shift to High | 8 | 3 |
| Chloride Shift to Low | 0 | 1 |
| Chloride Shift to High | 0 | 2 |
| Protein Shift to Low | 2 | 5 |
| Protein Shift to High | 13 | 6 |
| Albumin Shift to Low | 0 | 0 |
| Albumin Shift to High | 10 | 8 |
| Bicarbonate Shift to Low | 8 | 7 |
| Bicarbonate Shift to High | 1 | 0 |
| Calcium Shift to Low | 3 | 3 |
| Calcium Shift to High | 6 | 8 |
| Phosphate Shift to Low | 0 | 0 |
| Phosphate Shift to High | 9 | 4 |
| Glucose Shift to Low | 7 | 6 |
| Glucose Shift to High | 11 | 7 |
| Cystatin C Shift to Low | 6 | 4 |
| Cystatin C Shift to High | 2 | 0 |
| Creatine Kinase Shift to Low | 0 | 0 |
| Creatine Kinase Shift to High | 8 | 6 |
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.
| Participants | ISIS 396443 2 SMN2 Copies | ISIS 396443 3 SMN2 Copies |
|---|---|---|
| Specific Gravity Shift to Low | 3 | 1 |
| Specific Gravity Shift to High | 6 | 5 |
| pH Shift to Low | 0 | 1 |
| pH Shift to High | 3 | 3 |
| Protein Shift to High/positive | 13 | 8 |
| Glucose Shift to High/positive | 1 | 0 |
| Ketones Shift to High/positive | 9 | 6 |
| Bilirubin Shift to High/positive | 0 | 0 |
| Occult Blood Shift to High/positive | 4 | 2 |
| Erythrocytes Shift to High/positive | 7 | 1 |
| Leukocytes Shift to High/positive | 5 | 4 |
| Epithelial Cells Shift to High/positive | 5 | 0 |
| Bacteria Shift to High/positive | 7 | 6 |
| Casts Shift to High/positive | 1 | 2 |
| Crystals Shift to High/positive | 1 | 2 |
aPTT was evaluated to assess safety. Shift to high measured change in normal, low and unknown values at baseline to high values postbaseline.
| Participants | ISIS 396443 2 SMN2 Copies | ISIS 396443 3 SMN2 Copies |
|---|---|---|
| Number of Participants With Shifts From Baseline in Coagulation Parameters [Activated Partial Thromboplastin Time (aPTT)] | 4 | 2 |
PT was evaluated to assess safety. Shift to high measured change in normal, low and unknown values at baseline to high values postbaseline.
| Participants | ISIS 396443 2 SMN2 Copies | ISIS 396443 3 SMN2 Copies |
|---|---|---|
| Number of Participants With Shifts From Baseline in Coagulation Parameters [Prothrombin Time (PT)] | 7 | 5 |
INR was evaluated to assess safety. Shift to high measured change in normal, low and unknown values at baseline to high values postbaseline.
| Participants | ISIS 396443 2 SMN2 Copies | ISIS 396443 3 SMN2 Copies |
|---|---|---|
| Number of Participants With Shifts From Baseline in Coagulation Parameters [International Normalized Ratio (INR)] | 4 | 4 |
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.
| percentage of participants | ISIS 396443 2 SMN2 Copies | ISIS 396443 3 SMN2 Copies |
|---|---|---|
| Percentage of Participants With Clinically Significant Shifts in Electrocardiograms (ECG) Abnormalities | 0 | 0 |
Negative change from baseline indicates reduction in temperature.
| degree Celsius | ISIS 396443 2 SMN2 Copies | ISIS 396443 3 SMN2 Copies |
|---|---|---|
| Baseline | 36.7 ± 0.39 | 36.8 ± 0.44 |
| Change at Day 2891 | 0.0 ± 0.54 | -0.1 ± 0.52 |
| millimeters of mercury (mmHg) | ISIS 396443 2 SMN2 Copies | ISIS 396443 3 SMN2 Copies |
|---|---|---|
| Baseline-Systolic Blood Pressure | 83.4 ± 16.40 | 88.1 ± 17.84 |
| Change at Day 2891-Systolic Blood Pressure | 22.9 ± 15.29 | 13.6 ± 15.24 |
| Baseline-Diastolic Blood Pressure | 51.1 ± 17.46 | 50.8 ± 12.30 |
| Change at Day 2891-Diastolic Blood Pressure | 12.8 ± 17.16 | 11.0 ± 13.07 |
Negative change from baseline indicates reduction in heart rate.
| beats per minute (beats/min) | ISIS 396443 2 SMN2 Copies | ISIS 396443 3 SMN2 Copies |
|---|---|---|
| Baseline | 141.5 ± 14.71 | 154.2 ± 16.55 |
| Change at Day 2891 | -47.2 ± 20.86 | -62.4 ± 25.16 |
Negative change from baseline indicates reduction in respiratory rate.
| breaths per minute (breaths/min) | ISIS 396443 2 SMN2 Copies | ISIS 396443 3 SMN2 Copies |
|---|---|---|
| Baseline | 42.1 ± 12.17 | 39.8 ± 13.87 |
| Change at Day 2891 | -21.0 ± 12.39 | -20.6 ± 14.43 |
Participants with abnormalities in neurological examinations recorded as AEs were reported.
| Participants | ISIS 396443 2 SMN2 Copies | ISIS 396443 3 SMN2 Copies |
|---|---|---|
| Muscle contractions involuntary | 8 | 1 |
| Dysarthria | 7 | 1 |
| Tremor | 8 | 0 |
| Hypotonia | 4 | 0 |
| Areflexia | 2 | 1 |
| Facial paresis | 2 | 0 |
| Hyperreflexia | 1 | 1 |
| Myoclonus | 2 | 0 |
| Clonus | 1 | 0 |
| Extensor plantar response | 1 | 0 |
| Peripheral sensory neuropathy | 1 | 0 |
| Unresponsive to stimuli | 1 | 0 |
| Muscular weakness | 9 | 1 |
| Torticollis | 1 | 1 |
| Muscle spasms | 0 | 1 |
| Muscle twitching | 0 | 1 |
| Trismus | 1 | 0 |
| Winged scapula | 1 | 0 |
| Anisocoria | 0 | 1 |
| Heterophoria | 1 | 0 |
| Strabismus | 0 | 1 |
| Vision blurred | 0 | 1 |
| Automatism | 1 | 0 |
| nanograms per milliliter (ng/mL) | ISIS 396443 2 SMN2 Copies | ISIS 396443 3 SMN2 Copies |
|---|---|---|
| Day 1, Pre-dose | 0.03 ± 0.00 | 0.03 ± 0.00 |
| Day 15, Pre-dose | 7.52 ± 189.00 | 10.22 ± 285.47 |
| Day 29, Pre-dose | 23.41 ± 72.04 | 24.56 ± 85.78 |
| Day 64, Pre-dose | 14.95 ± 58.06 | 21.33 ± 63.00 |
| Day 183, Pre-dose | 11.66 ± 69.60 | 13.85 ± 54.32 |
| Day 302, Pre-dose | 11.34 ± 54.67 | 10.06 ± 27.29 |
| Day 421, Pre-dose | 12.20 ± 66.72 | 10.53 ± 67.48 |
| Day 540, Pre-dose | 10.23 ± 38.84 | 9.42 ± 51.04 |
| Day 659, Pre-dose | 11.91 ± 42.32 | 10.30 ± 38.34 |
| Day 778, Pre-dose | 10.87 ± 54.28 | 11.77 ± 61.01 |
| Day 897, Pre-dose | 11.03 ± 43.91 | 10.72 ± 35.90 |
| Day 1016, Pre-dose | 12.06 ± 58.41 | 10.65 ± 39.34 |
| Day 1135, Pre-dose | 10.49 ± 46.05 | 10.87 ± 36.62 |
| Day 1254, Pre-dose | 12.88 ± 47.06 | 11.29 ± 33.29 |
| Day 1373, Pre-dose | 11.94 ± 61.51 | 10.19 ± 52.12 |
| Day 1492, Pre-dose | 15.04 ± 51.20 | 12.71 ± 92.23 |
| Day 1611, Pre-dose | 13.46 ± 40.19 | 13.90 ± 36.31 |
| Day 1730, Pre-dose | 13.63 ± 57.76 | 15.14 ± 42.12 |
| Day 1849, Pre-dose | 15.14 ± 63.15 | 14.19 ± 42.87 |
| Day 1968, Pre-dose | 16.52 ± 67.05 | 17.46 ± 48.67 |
| Day 2087, Pre-dose | 15.57 ± 47.34 | 17.07 ± 58.91 |
| Day 2206, Pre-dose | 16.95 ± 45.86 | 17.16 ± 46.34 |
| Day 2325, Pre-dose | 18.27 ± 59.23 | 20.02 ± 37.41 |
| Day 2444, Pre-dose | 16.92 ± 49.19 | 17.01 ± 40.87 |
| Day 2563, Pre-dose | 16.74 ± 53.14 | 13.37 ± 85.72 |
| Day 2682, Pre-dose | 17.42 ± 44.34 | 16.05 ± 41.83 |
| Day 2801, Pre-dose | 17.44 ± 45.60 | 17.85 ± 36.35 |
| ng/ml | ISIS 396443 2 SMN2 Copies | ISIS 396443 3 SMN2 Copies |
|---|---|---|
| Day 1, 4 hours post-dose | 391.66 ± 113.16 | 406.69 ± 82.92 |
| Day 64, Pre-dose | 1.60 ± 34.52 | 1.56 ± 46.54 |
| Day 183, Pre-dose | 0.73 ± 27.03 | 0.81 ± 19.82 |
| Day 302, Pre-dose | 0.82 ± 54.28 | 0.81 ± 21.12 |
| Day 421, Pre-dose | 0.78 ± 39.94 | 0.82 ± 29.31 |
| Day 540, Pre-dose | 0.72 ± 29.72 | 0.72 ± 19.16 |
| Day 659, Pre-dose | 0.74 ± 26.78 | 0.78 ± 32.51 |
| Day 778, Pre-dose | 0.68 ± 48.37 | 0.81 ± 23.52 |
| Day 897, Pre-dose | 0.71 ± 34.77 | 0.63 ± 40.31 |
| Day 1016, Pre-dose | 0.69 ± 38.47 | 0.74 ± 21.97 |
| Day 1135, Pre-dose | 0.67 ± 33.70 | 0.58 ± 33.78 |
| Day 1254, Pre-dose | 0.63 ± 27.16 | 0.60 ± 24.10 |
| Day 1373, Pre-dose | 0.60 ± 39.79 | 0.59 ± 17.98 |
| Day 1492, Pre-dose | 0.69 ± 40.55 | 0.68 ± 43.50 |
| Day 1611, Pre-dose | 0.62 ± 38.14 | 0.53 ± 43.12 |
| Day 1730, Pre-dose | 0.54 ± 16.13 | 0.53 ± 30.84 |
| Day 1849, Pre-dose | 0.47 ± 52.05 | 0.49 ± 36.37 |
| Day 1968, Pre-dose | 0.53 ± 25.66 | 0.43 ± 22.96 |
| Day 2087, Pre-dose | 0.55 ± 40.43 | 0.47 ± 31.50 |
| Day 2206, Pre-dose | 0.43 ± 43.01 | 0.40 ± 32.58 |
| Day 2325, Pre-dose | 0.46 ± 56.98 | 0.45 ± 35.19 |
| Day 2444, Pre-dose | 0.43 ± 35.15 | 0.51 ± 17.26 |
| Day 2563, Pre-dose | 0.38 ± 61.73 | 0.42 ± 31.10 |
| Day 2682, Pre-dose | 0.36 ± 55.66 | 0.40 ± 24.48 |
| Day 2801, Pre-dose | 0.39 ± 36.16 | 0.35 ± 65.12 |
Collected over From the signing of the ICF up to the end of the study (up to Day 2891). Non-serious events are listed at a 5% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| ISIS 396443 2 SMN2 Copies | 0/15 (0%) | 10/15 (66.7%) | 15/15 (100%) |
| ISIS 396443 3 SMN2 Copies | 0/10 (0%) | 4/10 (40%) | 10/10 (100%) |
| Event | ISIS 396443 2 SMN2 Copies | ISIS 396443 3 SMN2 Copies |
|---|---|---|
| PneumoniaInfections and infestations | 5/15 | 0/10 |
| ChokingRespiratory, thoracic and mediastinal disorders | 3/15 | 0/10 |
| PyrexiaGeneral disorders | 2/15 | 0/10 |
| Respiratory syncytial virus bronchiolitisInfections and infestations | 2/15 | 0/10 |
| Respiratory syncytial virus infectionInfections and infestations | 2/15 | 1/10 |
| DehydrationMetabolism and nutrition disorders | 2/15 | 0/10 |
| Respiratory distressRespiratory, thoracic and mediastinal disorders | 2/15 | 0/10 |
| Respiratory failureRespiratory, thoracic and mediastinal disorders | 2/15 | 0/10 |
| TonsillectomySurgical and medical procedures | 2/15 | 0/10 |
| DiarrhoeaGastrointestinal disorders | 0/15 | 1/10 |
| Event | ISIS 396443 2 SMN2 Copies | ISIS 396443 3 SMN2 Copies |
|---|---|---|
| PyrexiaGeneral disorders | 14/15 | 8/10 |
| NasopharyngitisInfections and infestations | 11/15 | 7/10 |
| Upper respiratory tract infectionInfections and infestations | 11/15 | 7/10 |
| CoughRespiratory, thoracic and mediastinal disorders | 11/15 | 7/10 |
| VomitingGastrointestinal disorders | 10/15 | 5/10 |
| DiarrhoeaGastrointestinal disorders | 4/15 | 6/10 |
| FallInjury, poisoning and procedural complications | 8/15 | 6/10 |
| Muscular weaknessMusculoskeletal and connective tissue disorders | 9/15 | 1/10 |
| Muscle contractions involuntaryNervous system disorders | 8/15 | 1/10 |
| TremorNervous system disorders | 8/15 | 0/10 |
The Intent-to-treat (ITT) set included all participants who received at least 1 dose of ISIS 396443.
| Age, Continuous(days) | ISIS 396443 2 SMN2 Copies | ISIS 396443 3 SMN2 Copies | Total |
|---|---|---|---|
| Mean | 19.5 ± 9.29 | 22.3 ± 12.45 | 20.6 ± 10.51 |
| Sex: Female, Male(Participants) | ISIS 396443 2 SMN2 Copies | ISIS 396443 3 SMN2 Copies | Total |
|---|---|---|---|
| Female | 7 | 6 | 13 |
| Male | 8 | 4 | 12 |
| Ethnicity (NIH/OMB)(Participants) | ISIS 396443 2 SMN2 Copies | ISIS 396443 3 SMN2 Copies | Total |
|---|---|---|---|
| Hispanic or Latino | 2 | 0 | 2 |
| Not Hispanic or Latino | 10 | 9 | 19 |
| Unknown or Not Reported | 3 | 1 | 4 |
| Race/Ethnicity, Customized(Participants) | ISIS 396443 2 SMN2 Copies | ISIS 396443 3 SMN2 Copies | Total |
|---|---|---|---|
| Race — American Indian or Alaska Native | 1 | 0 | 1 |
| Race — Asian | 1 | 2 | 3 |
| Race — White | 8 | 6 | 14 |
| Race — Other | 2 | 1 | 3 |
| Race — Not Reported Due to Confidentiality Regulations | 3 | 1 | 4 |
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