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

Study Overview
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Brief Summary
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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.

Official Title
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An Open-Label Study to Assess the Efficacy, Safety, Tolerability, and Pharmacokinetics of Multiple Doses of ISIS 396443 Delivered Intrathecally to Subjects With Genetically Diagnosed and Presymptomatic Spinal Muscular Atrophy

Conditions
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Spinal Muscular Atrophy

Intervention / Treatment
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* Drug: Nusinersen


Participation Criteria
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Eligibility Criteria
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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/Exclusion criteria may apply.

Ages Eligible for Study
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Maximum Age: 6 Weeks

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Nusinersen<br>Nusinersen administered as an intrathecal injection | Drug: Nusinersen<br>* Solution for intrathecal injection<br>* Other names: Spinraza;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to death or respiratory intervention | The time will be the age of the participant at the first occurrence of either a respiratory intervention or death. Respiratory intervention is defined as invasive or noninvasive ventilation for ≥6 hours/day continuously for 7 or more days OR tracheostomy. | Up to Day 2891 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of participants developing clinically manifested spinal muscular atrophy (SMA) |  | At 13 and 24 months of age | 
| Percentage of participants alive |  | At 13 months, and 2, 3, 4, 5, 6, 7 and 8 years of age | 
| Percentage of participants who attained motor milestones assessed as part of the Hammersmith Infant Neurological Examination (HINE) |  | At 13 and 24 months of age | 
| Percentage of participants who attained motor milestones as assessed by World Health Organization (WHO) criteria |  | Up to Day 2891 | 
| Change from Baseline in the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) motor function scale |  | Up to Day 2891 | 
| Change from Baseline in Hammersmith Functional Motor Scale - Expanded (HFMSE) |  | Up to Day 2891 | 
| Change from Baseline in weight for age/length |  | Up to Day 2891 | 
| Change from Baseline in head circumference |  | Up to Day 2891 | 
| Change from Baseline in chest circumference ratio |  | Up to Day 2891 | 
| Change from Baseline in head to chest circumference ratio |  | Up to Day 2891 | 
| Change from Baseline in arm circumference ratio |  | Up to Day 2891 | 
| Incidence of adverse events (AEs) and/or serious adverse events (SAEs) |  | Up to Day 2891 | 
| Change from Baseline in clinical laboratory parameters | Assessed by the following laboratory tests: Hematology: red blood cells, hemoglobin, hematocrit, platelets, white blood cells, white blood cell differential, Blood chemistry: total protein, albumin, creatinine, cystatin C, creatine phosphokinase, blood urea nitrogen, total bilirubin (direct and indirect), alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, glucose, calcium, phosphorous, chloride, sodium, potassium. Urinalysis: specific gravity, pH, protein, glucose, ketones, bilirubin, red blood cells, white blood cells, epithelial cells, bacteria, casts, crystals | Up to Day 2891 | 
| Change from Baseline in electrocardiograms (ECGs) |  | Up to Day 2891 | 
| Change from Baseline in vital signs | Vital sign will be assessed by: temperature, pulse rate, resting systolic and diastolic blood pressure, and respiratory rate. | Up to Day 2891 | 
| Change from Baseline in neurological examinations |  | Up to Day 2891 | 
| Cerebrospinal fluid (CSF) and plasma Nusinersen concentrations |  | Up to Day 2801 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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NURTURE