A Study to Assess the Efficacy and Safety of Nusinersen (ISIS 396443) in Infants With Spinal Muscular Atrophy

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.

Time frame: assessed at the later of the Day 183, Day 302, or Day 394 study visits

Population: Intent-to-treat population: all randomized participants who received ≥ 1 dose of study drug/sham procedure with Day 183, Day 302, or Day 394 data; the last available assessment was used. (Participants who died or withdrew from the study were counted as non-responders and were included in the denominator for the calculation of the percentages.)

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.

Time frame: Day 91, Day 182, Day 273, Day 364, Day 394

Population: Intent-to-treat population: all randomized participants who received ≥ 1 dose of study drug/sham procedure and who died or required permanent ventilation.

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.

Time frame: Screening through Day 394 (± 7 days) or early termination

Population: Safety Population: all subjects who received ≥ 1 dose of study drug/sham procedure.

Time frame: up to Day 394 (± 7 days) or early termination

Population: Safety Population: all subjects who received ≥ 1 dose of study drug/sham procedure and had an assessment.

Time frame: up to Day 394 (± 7 days) or early termination

Population: Safety Population: all subjects who received ≥ 1 dose of study drug/sham procedure.

Time frame: up to Day 394 (± 7 days) or early termination

Population: Safety Population: all subjects who received ≥ 1 dose of study drug/sham procedure.

Time frame: up to Day 394 (± 7 days) or early termination

Population: Safety Population: all subjects who received ≥ 1 dose of study drug/sham procedure.

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.

Time frame: assessed at Baseline and the later of the Day 183, Day 302, or Day 394 study visits

Population: Intent-to-treat population: all randomized participants who received ≥ 1 dose of study drug/sham procedure with Day 183, Day 302, or Day 394 data; the last available assessment was used. (Participants who died or withdrew from the study were counted as non-responders and were included in the denominator for the calculation of the percentages.)

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.

Time frame: assessed at the later of the Day 183, Day 302, or Day 394 study visits

Population: Intent-to-treat population: all randomized participants who received ≥ 1 dose of study drug/sham procedure with Day 183, Day 302, or Day 394 data; the last available assessment was used. (Participants who died or withdrew from the study were counted as non-responders and were included in the denominator for the calculation of the percentages.)

Time frame: Up to Day 394

Population: Intent-to-treat population: all randomized participants who received ≥ 1 dose of study drug/sham procedure.

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'.

Time frame: up to Day 394 (± 7 days) or early termination

Population: Safety Population: all subjects who received ≥ 1 dose of study drug/sham procedure and whose baseline value was not abnormal and who had at least one post-baseline value.

Estimated proportion of participants who died by given duration thresholds, based on the Kaplan-Meier product-limit method.

Time frame: Day 91, Day 182, Day 273, Day 364, Day 394

Population: Intent-to-treat population: all randomized participants who received ≥ 1 dose of study drug/sham procedure and who died. Results are based on all available data.

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.

Time frame: Day 91, Day 182, Day 273, Day 364, Day 394

Population: Intent-to-treat population: all randomized participants who received ≥ 1 dose of study drug/sham procedure and were above 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.

Time frame: Day 91, Day 182, Day 273, Day 364, Day 394

Population: Intent-to-treat population: all randomized participants who received ≥ 1 dose of study drug/sham procedure and were below the study median disease duration.