The primary objective is to evaluate long-term safety and tolerability of nusinersen (ISIS 396443) administered by intrathecal (IT) injection to participants with Spinal Muscular Atrophy (SMA) who previously participated in investigational studies of nusinersen. The secondary objective is to examine the long-term efficacy of nusinersen administered by IT injection to participants with SMA who previously participated in investigational studies of nusinersen.
This study was initiated and the protocol was registered by Ionis Pharmaceuticals, Inc. In August 2016, Biogen assumed responsibility for this study.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
292
Administered by intrathecal (IT) injection
Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)
AE:unfavorable and unintended sign, symptom, or disease temporally associated with study/use of an investigational drug, whether or not it's considered related to investigational drug. SAE:AE that in view of either Investigator/Sponsor, meets any of the following criteria: results in death;is life-threatening:i.e.poses risk of death, hospitalization/it's prolongation;results in a persistent or significant incapacity or substantial disruption of normal life functions;results in congenital anomaly or birth defect in offspring;is an important event in the opinion of Investigator/Sponsor. TEAE: if it was present prior to first dose of nusinersen or first sham procedure in index study and subsequently worsened in severity/was not present prior to first dose of nusinersen or first sham procedure in index study but subsequently appeared.
Time frame: From Day 1 up to the end of the study (up to 2848 days)
Number of Participants With Vital Sign Abnormalities Reported as AEs
The vital sign assessments included blood pressure, temperature, pulse rate, and respiratory rate. Participants with abnormalities in these assessments recorded as AEs were reported.
Time frame: From Day 1 up to the end of the study (up to 2848 days)
Number of Participants With Weight Abnormalities Reported as AEs
Weight decrease was characterized by a decrease of \>=7% from baseline and weight increase was characterized by an increase of \>=7% from baseline. Participants with these abnormalities recorded as AEs were reported.
Time frame: From Day 1 up to the end of the study (up to 2848 days)
Number of Participants With Neurological Abnormalities Reported as AEs
Participants with abnormalities in neurological examinations recorded as AEs were reported.
Time frame: From Day 1 up to the end of the study (up to 2848 days)
Number of Participants With Laboratory Abnormalities Reported as AEs
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David Geffen School of Medicine at UCLA
Los Angeles, California, United States
Stanford University School of Medicine
Palo Alto, California, United States
Children's Hospital Colorado
Aurora, Colorado, United States
Connecticut Children's Medical Center
Hartford, Connecticut, United States
Nemours Children's Clinic
Orlando, Florida, United States
Ann & Robert H. Lurie Children's Hospital of Chicago
New York, Illinois, United States
The Johns Hopkins Hospital
Baltimore, Maryland, United States
Boston Children's Hospital
Boston, Massachusetts, United States
Gillette Children's Specialty Healthcare
Saint Paul, Minnesota, United States
Washington University School of Medicine
St Louis, Missouri, United States
...and 37 more locations
Laboratory investigations included hematology, coagulation, serum chemistry and urinalysis parameters. Participants with abnormalities in these laboratory investigations recorded as AEs were reported.
Time frame: From Day 1 up to the end of the study (up to 2848 days)
Number of Participants With Coagulation Parameters Reported as AEs
Coagulation parameters included activated partial thromboplastin time (aPTT) and international normalized ratio (INR). Participants with abnormalities in these coagulation parameters recorded as AEs were reported.
Time frame: From Day 1 up to the end of the study (up to 2848 days)
Number of Participants With Clinically Significant Shifts in12 Lead Electrocardiogram (ECG) Results
Clinical significance of abnormalities in 12 lead ECG was determined based on the investigator's discretion.
Time frame: From Day 1 up to the end of the study (up to 2848 days)
Number of Participants Taking Any Concomitant Medication
A concomitant therapy is any non-protocol-specified drug or substance (including over-the-counter medications, herbal medications, and vitamin supplements) administered between the beginning of screening and the last telephone contact or study visit.
Time frame: From Day 1 up to the end of the study (up to 2848 days)
Mean Number of New Motor Milestones Achieved 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. Mean of number of new milestones achieved was calculated and reported in this outcome measure.
Time frame: MMDR Period: At Day 1800
Percentage of Participants With <2 Years of Age Who Attained Motor Milestones as Assessed by Section 2 of 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: At Day 309
Number of Participants Who Died or Met Permanent Ventilation
Permanent ventilation was defined as tracheostomy or \>=16 hours of ventilator support per day continuously for \>21 days in the absence of an acute reversible event.
Time frame: MMDR Period: Up to Day 1800
Number of Participants Not Requiring Permanent Ventilation
Permanent ventilation was defined as tracheostomy or \>=16 hours of ventilator support per day continuously for \>21 days in the absence of an acute reversible event.
Time frame: MMDR Period: Up to Day 1800
Change From Baseline in Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) Motor Function Scale
The CHOP INTEND test is designed to evaluate the motor skills of infants with significant motor weakness, including infants with SMA. Participants who are ≥2 years will be continued to be assessed until a CHOP INTEND maximum score of 64 is achieved. It includes 16 items structured to move from easiest to hardest with the grading including gravity eliminated (lower scores) to antigravity movements (higher scores). All item scores range from 0 (worst) to 4 (best). Total scores range from 0 to 64, with higher scores indicating better movement functioning.
Time frame: Baseline, Day 2198
Change From Baseline in Hammersmith Functional Motor Scale Expanded (HFMSE) Total Score
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 with a maximum achievable score of 66. Higher scores indicate increased motor function.
Time frame: MMDR Period: Baseline, MMDR Day 1800
Change From Baseline in Revised Upper Limb Module (RULM) Total Score
RULM Test is used in participants with SMA to assess upper limb functional ability items and has total of 20 items with an entry item that serves as functional class identification and does not contribute to total score. Remaining 19 scorable items reflect different functional domains and graded on 3-point system with score of 0 (unable), 1 (able, with modification), and 2 (able, no difficulty). There is only 1 item that is scored as a can/cannot score, with 1 as the highest score. Scorable items are summed for total score (0-37), higher scores indicating increased upper limb function. Positive change from baseline indicates improvement.
Time frame: MMDR Period: Baseline, MMDR Day 1800
Change From Baseline in Total Distance Walked Over Time as Assessed by 6-Minute Walk Test (6MWT)
The 6MWT measures the distance an individual can walk over a total of six minutes on a hard, flat surface. The goal is for the individual to walk as far as possible in six minutes.
Time frame: Baseline, Day 2670
Number of Participants Who Experienced Contracture Assesment
Contracture assessment is performed to assess the motor performance in SMA. The number of participants who experienced at least one contracture at any location and severe contractures in any of the five locations (hip flexors, knee flexors, ankle planter flexors, elbow flexors, forearm flexors) are reported in this outcome measure.
Time frame: MMDR Period: At MMDR Day 1800
Change From Baseline in Compound Muscular Action Potential (CMAP)
CMAP is an electrophysiological technique that can be used to determine the approximate number of motor neurons in a muscle or group of muscles. Peroneal amplitude (PA) and ulnar amplitude (UA) data is reported in this OM. Score \<0 indicated worse response and \>0 indicated better response than the normal matched population. Score change \<0 indicated worsening and \>0 indicated improvement as compared to baseline.
Time frame: MMDR Period: Baseline, MMDR Day 1800
Change From Baseline in Body Length
Participants were analyzed for change in growth parameter of body length to evaluate clinical efficacy. The body length was calculated using either WHO or Centers for Disease Control and Prevention (CDC) scales. The CDC scale allows to calculate the body length up to 20 years, while the WHO scale allows to calculate it only up to 10 years.
Time frame: MMDR Period: up to Day 1800
Change From Baseline in Weight
Participants were analyzed for change in growth parameter of weight to evaluate clinical efficacy. The weight was calculated using either WHO or CDC scales. The CDC scale allows to calculate the weight up to 20 years, while the WHO scale allows to calculate it only up to 10 years.
Time frame: MMDR Period: up to Day 1800
Change From Baseline in Weight for Age Percentile
Participants who were below the age of 36 months were analyzed for change in growth parameter of weight for age to evaluate clinical efficacy. The weight for age percentile was calculated using either WHO or CDC scales. The CDC scale allows to calculate the weight for age percentile up to 20 years, while the WHO scale allows to calculate it only up to 10 years.
Time frame: MMDR Period: up to Day 1800
Percentage of 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 responder if they had a peroneal amplitude ≥1 mV at last visit (including the amplitude ≥1 mV at baseline and also demonstrated as such at last visit).
Time frame: MMDR Period: At Day 1800
Number of Participants Who Achieved Motor Milestones
Motor milestones were measured based on 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 (SWS), standing with assistance (SWA), hands and knees crawling (HKC), and walking alone (WA).
Time frame: MMDR Period: up to Day 1800
Number of Participants Who Achieved Standing Alone and Walking With Assistance
Motor milestones were measured based on 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: SWS, SWA, HKC, WWA, WA and standing alone (SA). SA and WWA were assessed in this outcome measure.
Time frame: MMDR Period: up to Day 1800
Total Number of Hospitalizations Due to Serious Respiratory Events
Total number of hospitalizations is total number of serious events that occurred during study for all participants under each group. For a participant with multiple SAEs which started at the same date and led to hospitalization, it is counted as one hospitalization.
Time frame: Up to day 2520
Total Number of Hospitalizations Due to Serious Adverse Events
Total number of hospitalizations is total number of serious events that occurred during study for all participants under each group. For a participant with multiple SAEs which started at the same date and led to hospitalization, it is counted as one hospitalization.
Time frame: Up to day 2520
Percent of Time in Hospitalization
Time frame: Upto day 2160
Change From Baseline in Cobb-Angle on X-Ray of the Thoracolumbar Spine by Visit
Cobb angle is a measurement of the degree of side-to-side spinal curvature used to define scoliosis.
Time frame: MMDR Period: Baseline, MMDR Day 1800
Pediatric Quality of Life Inventory (PedsQL) Questionnaires Total Score by Domain
Items on the PedsQL generic core scale are reverse scored and transformed to a 0-100 scale. The PedsQL parent (P) and self (S) reported questionnaire was collected for participants from 2 to 25 years of age. Four dimensions were collected: Physical, Emotional, Social and School functioning and each item was scored on a 5 point ordinal scale. 0 (never) =100, 1 (almost never) = 75, 2 (sometimes)= 50, 3 (often) = 25, 4 (almost always) = 0. A total score was calculated as the sum of all the items over the number of items answered on all the scales. If more than 50% of items or more were missing, the scale score was not computed. Higher scores indicated better health related quality of life.
Time frame: MMDR Period: At Day 1800
Change From Baseline in Assessment of Caregiver Experience With Neuromuscular Disease (ACEND) Questionnaire Total Score
The ACEND is a questionnaire that includes a total of seven domains assessing physical impact (including feeding/grooming/dressing, sitting/play, transfers, and mobility) and general caregiver impact (including time, emotion, and finance) and each domain comprises several items. The total score (TS) for each domain will be calculated on a scale of 0 to 100. Higher scores indicate a greater impact on the caregiver.
Time frame: MMDR Period: up to Day 1800
Number of Participants With Disease-related Hospitalizations and AEs
Time frame: MMDR Period: up to Day 1800
Survival Rate
Survival rate was defined as the percentage of participants alive during the study and was estimated from the Kaplan Meier (KM) curve for time to death.
Time frame: MMDR Period: up to Day 1800