A Study to Assess the Efficacy and Safety of Nusinersen (ISIS 396443) in Infants With 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 clinical efficacy of nusinersen (ISIS 396443) administered intrathecally (IT) to participants with infantile-onset with infantile-onset spinal muscular atrophy (SMA). The secondary objective of the study is to examine the safety and tolerability of nusinersen administered intrathecally to participants with infantile-onset SMA.

Detailed Description
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This study was conducted and the protocol was registered by Ionis Pharmaceuticals, Inc.. In August 2016, sponsorship of the trial was transferred to Biogen.

Official Title
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A Phase 3, Randomized, Double-Blind, Sham-Procedure Controlled Study to Assess the Clinical Efficacy and Safety of ISIS 396443 Administered Intrathecally in Patients With Infantile-onset Spinal Muscular Atrophy

Conditions
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Spinal Muscular Atrophy

Intervention / Treatment
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* Drug: nusinersen
* Procedure: Sham procedure


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Be born (gestational age) between 37 and 42 weeks Be medically diagnosed with spinal muscular atrophy (SMA) Have Survival Motor Neuron2 (SMN2) Copy number = 2 Body weight equal to or greater than 3rd percentile for age using appropriate country-specific guidelines Be able to follow all study procedures Reside within approximately 9 hours ground-travel distance from a participating study center, for the duration of the study Key Exclusion Criteria: Hypoxemia (oxygen [O2] saturation awake less than 96% or O2 saturation asleep less than 96%, without ventilation support) during screening evaluation Clinically significant abnormalities in hematology or clinical chemistry parameters or Electrocardiogram (ECG), as assessed by the Site Investigator, at the Screening visit that would render the participant unsuitable for participation in the study Participant's parent or legal guardian is not willing to meet standard of care guidelines (including vaccinations and respiratory syncytial virus prophylaxis if available), nor provide nutritional and respiratory support throughout the study NOTE: Other protocol defined Inclusion/Exclusion criteria may apply.

Ages Eligible for Study
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Maximum Age: 210 Days

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: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: nusinersen<br> | Drug: nusinersen<br>* Administered by intrathecal (IT) injection as specified in the treatment arm.<br>* Other names: ISIS SMNRx;|
| Sham Comparator: Sham procedure<br> | Procedure: Sham procedure<br>* Small needle prick on the lower back at the location where the IT injection is normally made<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Motor Milestones Responders | The definition of a motor milestones responder was based on improvement in the motor milestones categories in Section 2 of the Hammersmith Infant Neurological Examination (HINE), with the exclusion of voluntary grasp, as follows: (i) subject demonstrates ≥ 2-point increase in the motor milestones category of ability to kick or achievement of maximal score on that category (touching toes), or a 1-point increase in the motor milestones category of head control, rolling, sitting, crawling, standing, or walking, and (ii) among the motor milestone categories, with the exclusion of voluntary grasp, there are more categories where there is improvement as defined in (i) than worsening. (For the category of ability to kick, worsening is defined as ≥ 2-point decrease or decrease to the lowest possible score of no kicking. For the other categories, worsening is defined as ≥ 1-point decrease.) The lowest possible score for the HINE is 0 (zero), and the highest possible score for the HINE is 28. | assessed at the later of the Day 183, Day 302, or Day 394 study visits | 
| Time to Death or Permanent Ventilation | Estimated proportion of participants who died or required permanent ventilation by a given study day, based on the Kaplan-Meier product-limit method. Time to death or permanent ventilation was defined as either tracheostomy or ≥ 16 hours ventilation/day continuously for > 21 days in the absence of an acute reversible event. This endpoint was adjudicated by a blinded, independent group of experienced clinicians, the Event Adjudication Committee (EAC), based on review of clinical study data and supporting information. Results are based on all available data. | Day 91, Day 182, Day 273, Day 364, Day 394 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND) Responders | A participants was considered a CHOP-INTEND responder if the change from baseline in CHOP-INTEND total score is ≥ 4 points based on assessment at the later of the Day 183, Day 302, or Day 394 study visits. CHOP-INTEND tests includes 16 items structured to move from easiest to hardest with the grading including gravity eliminated (lower scores) to antigravity movements (higher scores). Total scores range from 0 to 64, with higher scores indicating better movement functioning. Results are based on all available data. | assessed at Baseline and the later of the Day 183, Day 302, or Day 394 study visits | 
| Summary of Time to Death | Estimated proportion of participants who died by given duration thresholds, based on the Kaplan-Meier product-limit method. | Day 91, Day 182, Day 273, Day 364, Day 394 | 
| Percentage of Participants Not Requiring Permanent Ventilation |  | Up to Day 394 | 
| Percentage of Compound Muscular Action Potential (CMAP) Responders | CMAP is an electrophysiological technique that can be used to determine the approximate number of motor neurons in a muscle or group of muscles. A participant was defined as a CMAP responder if the CMAP amplitude at the peroneal nerve was increasing to or maintained at ≥ 1 mV (comparing to the baseline) based on assessment at the later of the Day 183, Day 302, or Day 394 study visits. Results are based on all available data. | assessed at the later of the Day 183, Day 302, or Day 394 study visits | 
| Time to Death or Permanent Ventilation in the Subgroup of Participants Below the Study Median Disease Duration | Estimated proportion of participants who died or required permanent ventilation (EAC-adjudicated events) among participants below the study median disease duration (13.1 weeks), by given duration thresholds, based on the Kaplan-Meier product-limit method. | Day 91, Day 182, Day 273, Day 364, Day 394 | 
| Time to Death or Permanent Ventilation in the Subgroup of Participants Above the Study Median Disease Duration | Estimated proportion of participants who died or required permanent ventilation (EAC-adjudicated events) among participants above the study median disease duration (13.1 weeks), by given duration thresholds, based on the Kaplan-Meier product-limit method. | Day 91, Day 182, Day 273, Day 364, Day 394 | 
| Number of Participants Experiencing Adverse Events (AEs), Serious AEs (SAEs) and Discontinuations Due to AEs | AE: any unfavorable and unintended sign, symptom, or disease temporally associated with the study or use of investigational drug product, whether or not the AE is considered related to the investigational drug product. SAE: any AE that in the view of either the Investigator or Sponsor, meets any of the following criteria: results in death; is life threatening: that is, poses an immediate risk of death at the time of the event; requires in-patient hospitalization or prolongation of existing hospitalization; results in a persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions; results in congenital anomaly or birth defect in the offspring of the participant (whether male or female); is an important medical event in the opinion of the Investigator or Sponsor. | Screening through Day 394 (± 7 days) or early termination | 
| Number of Participants With AEs Corresponding to Changes in Hematology Values |  | up to Day 394 (± 7 days) or early termination | 
| Number of Participants With AEs Corresponding to Changes in Blood Chemistry Values |  | up to Day 394 (± 7 days) or early termination | 
| Number of Participants Meeting Selected Vital Sign Criteria Post-Baseline |  | up to Day 394 (± 7 days) or early termination | 
| Summary of Shifts in 12-lead Electrocardiogram (ECG) Results | Shift to 'abnormal, not clinically significant' includes 'unknown' or 'normal' to 'abnormal, not clinically significant'. Shift to 'abnormal, clinically significant' includes 'unknown' or 'normal' to 'abnormal, clinically significant'. | up to Day 394 (± 7 days) or early termination | 
| Number of Participants With Clinically Significant Changes From Baseline in Urinalysis Values |  | up to Day 394 (± 7 days) or early termination | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Spinal Muscular Atrophy, SMA, SMN, SMNRx, ISIS-SMNRx, ISIS-SMN Rx, ISIS 396443, IONIS-SMNRx, IONIS-SMN Rx, Spinraza, ENDEAR