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Trial details imported from ClinicalTrials.gov
For full trial details, please see the original record at
https://clinicaltrials.gov/study/NCT04089566
Registration number
NCT04089566
Ethics application status
Date submitted
11/09/2019
Date registered
13/09/2019
Date last updated
5/06/2025
Titles & IDs
Public title
Study of Nusinersen (BIIB058) in Participants With Spinal Muscular Atrophy
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Scientific title
Escalating Dose and Randomized, Controlled Study of Nusinersen (BIIB058) in Participants With Spinal Muscular Atrophy
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Secondary ID [1]
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2019-002663-10
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Secondary ID [2]
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232SM203
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Universal Trial Number (UTN)
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Trial acronym
DEVOTE
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Linked study record
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Health condition
Health condition(s) or problem(s) studied:
Muscular Atrophy, Spinal
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Condition category
Condition code
Musculoskeletal
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Other muscular and skeletal disorders
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Neurological
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Other neurological disorders
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Other
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Research that is not of generic health relevance and not applicable to specific health categories listed above
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Intervention/exposure
Study type
Interventional
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Description of intervention(s) / exposure
Treatment: Drugs - Nusinersen
Experimental: 28/28 Milligram (mg) Safety Group - Part A: Participants with later-onset SMA will receive loading doses of 28 mg of nusinersen intrathecally on Days 1, 15 and 29 followed by maintenance doses of 28 mg on Days 149 and 269.
Active comparator: 12/12 mg Active Control Group - Part B: Participants with infantile- or later-onset SMA will receive loading doses of 12 mg of nusinersen intrathecally on Days 1, 15, 29, and 64 followed by maintenance doses of 12 mg on Days 183 and 279. Sham procedure will be administered on Day 135.
Experimental: 50/28 mg Active Treatment Group - Part B: Participants with infantile- or later-onset SMA will receive loading doses of 50 mg of nusinersen intrathecally on Days 1 and 15 followed by maintenance doses of 28 mg on Days 135 and 279. Sham procedure will be administered on Days 29, 64 and 183.
Experimental: 12/50/28 mg Titration Group - Part C: Participants who have been receiving the approved dose of 12 mg for at least 1 year prior to entry, will receive a single bolus dose of 50 mg of nusinersen intrathecally on Day 1 (4 months after their most recent maintenance dose of 12 mg) followed by maintenance doses of 28 mg on Days 121 and 241.
Treatment: Drugs: Nusinersen
Administered as specified in the treatment arm
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Intervention code [1]
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Treatment: Drugs
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Comparator / control treatment
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Control group
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Outcomes
Primary outcome [1]
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Part B Infantile-onset SMA: Change From Baseline in CHOP-INTEND Total Score for 50/28mg Nusinersen Versus CS3B Matched Sham Control Group
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Assessment method [1]
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The CHOP-INTEND test was designed to evaluate the motor skills of infants with signi?cant motor weakness. It included 16 items (capturing neck, trunk, and proximal and distal limb strength), nine of which were scored 0, 1, 2, 3, or 4, ?ve 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). The change from baseline to Day 183 in the CHOP-INTEND total score was compared to CS3B study (NCT02193074) sham control group using the joint-rank methodology to account for mortality.
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Timepoint [1]
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Baseline, Day 183
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Primary outcome [2]
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Parts A and C: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (TESAEs)
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Assessment method [2]
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An adverse event (AE) was any unfavorable \& unintended sign (including an abnormal assessment such as an abnormal laboratory value), symptom, or disease temporally associated with use of an investigational product, whether or not related to investigational product. An SAE was any untoward medical occurrence that at any dose resulted in death, in the view of Investigator, placed 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. AE and SAEs were regarded as treatment-emergent if it was present prior to receiving first dose of nusinersen in this current study and subsequently worsened in severity or was not present prior to receiving first dose of nusinersen and subsequently appeared.
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Timepoint [2]
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Part A: From the first dose of the study drug up to Day 389, Part C: From the first dose of the study drug up to Day 361
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Primary outcome [3]
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Parts A and C: Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Blood Chemistry Parameters)
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Assessment method [3]
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Blood chemistry parameters included protein, albumin, creatinine, blood urea nitrogen, bilirubin (total and direct), alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transferase, glucose, calcium, phosphorus, bicarbonate, chloride, sodium, potassium, cystatin C, and 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, by the Investigator. Here, shift to low indicates 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 values postbaseline. The categories with at least one participant with shift from baseline in these parameters are reported.
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Timepoint [3]
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Parts A and C: Baseline up to Day 302
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Primary outcome [4]
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Parts A and C: Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Hematology Parameters)
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Assessment method [4]
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Hematology parameters included complete blood cell count, with di?erential and platelet count, and absolute neutrophil count. These parameters were flagged as low, normal, or high relative to parameter's normal range or as unknown if no result was available, by the Investigator. Here, shift to low indicates 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. The categories with at least one participant with shift from baseline in these parameters are reported.
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Timepoint [4]
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Parts A and C: Baseline up to Day 302
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Primary outcome [5]
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Parts A and C: Number of Participants With Shifts From Baseline in Urinalysis
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Assessment method [5]
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Urinalysis included assessments of urine total protein, specific gravity, pH, protein, glucose, ketones, bilirubin, blood, red blood cells (RBC), white blood cells (WBC), 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, by the Investigator. Here, shift to low indicates 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. The categories with at least one participant with shift from baseline in these parameters are reported.
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Timepoint [5]
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Parts A and C: Baseline up to Day 302
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Primary outcome [6]
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Parts A and C: Number of Participants With Shifts From Baseline in Cerebrospinal Fluid (CSF) Parameters
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Assessment method [6]
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CSF parameters included cell count, total protein, and glucose. These parameters were flagged as low, normal, or high relative to parameter's normal range or as unknown if no result was available, by the Investigator. Here, shift to low indicates 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 values postbaseline. The categories with at least one participant with shift from baseline in these parameters are reported.
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Timepoint [6]
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Part A: Baseline up to Day 269, Part C: Baseline up to Day 241
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Primary outcome [7]
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Parts A and C: Number of Participants With Shifts From Baseline in Electrocardiograms (ECGs)
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Assessment method [7]
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The ECGs were assessed by the investigator to be normal, abnormal and abnormal AE. The number of participants with ECG shifts from normal to each of the categorical values denoting an abnormal scan (abnormal not AE, abnormal AE) was assessed. Shift from baseline to worst post-baseline values were reported. The categories with at least one participant with shift from baseline in ECG are reported.
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Timepoint [7]
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Parts A and C: Baseline up to Day 302
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Primary outcome [8]
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Parts A and C: Number of Participants With Abnormalities in Vital Sign Parameters
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Assessment method [8]
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Vital sign assessment included temperature, pulse rate, systolic blood pressure, diastolic blood pressure, and respiratory rate. As pre-specified in protocol, the criteria for determining potentially clinically relevant abnormalities in vital signs included: temperature \< 36.0 and \> 38.0 degrees Celsius (C), pulse rate \< 60 and \> 100 beats per minute (bpm), systolic blood pressure \[\< 90, \> 140 and \> 160 millimeters of mercury (mmHg)\], diastolic blood pressure \< 50, \> 90 and \> 100 mmHg and respiratory rate \< 12 and \> 20 breaths per minute. The categories with at least one participant with clinically relevant vital sign abnormalities are reported.
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Timepoint [8]
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Parts A and C: Baseline up to Day 302
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Primary outcome [9]
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Parts A and C: Change From Baseline in Growth Parameters (Body Height)
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Assessment method [9]
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Timepoint [9]
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Parts A and C: Baseline, Day 302
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Primary outcome [10]
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Part C: Change From Baseline in Growth Parameters (Head Circumference)
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Assessment method [10]
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As pre-specified in the protocol, head circumference was measured for participants with infantile-onset SMA only.
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Timepoint [10]
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Baseline, Day 302
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Primary outcome [11]
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Part C: Change From Baseline in Growth Parameters (Chest Circumference)
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Assessment method [11]
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As pre-specified in protocol, chest circumference was measured for participants with infantile-onset SMA only.
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Timepoint [11]
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Baseline, Day 302
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Primary outcome [12]
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Part C: Change From Baseline in Growth Parameters (Arm Circumference)
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Assessment method [12]
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As pre-specified in the protocol, arm circumference was measured for participants with infantile-onset SMA. Here, negative change from baseline indicated reduction in arm circumference.
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Timepoint [12]
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Baseline, Day 302
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Primary outcome [13]
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Parts A and C: Change From Baseline in Growth Parameters (Ulnar Length)
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Assessment method [13]
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As pre-specified in the protocol, ulnar length was measured for participants with later-onset SMA.
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Timepoint [13]
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Parts A and C: Baseline, Day 302
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Primary outcome [14]
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Parts A and C: Change From Baseline in Growth Parameters (Weight for Age Percentile)
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Assessment method [14]
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World Health Organization (WHO) child growth standards (2006) was used to calculate the weight for age percentile in the infantile-onset participants while the 2000 Centers for Disease Control and Prevention (CDC) Growth Charts was used to calculate the weight for age percentile for later-onset participants. Negative change from baseline indicates low weight for age percentile.
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Timepoint [14]
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Parts A and C: Baseline, Day 302
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Primary outcome [15]
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Part C: Change From Baseline in Growth Parameters (Weight for Length Ratio)
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Assessment method [15]
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As pre-specified in the protocol, weight for length ratio was assessed only for the participants with infantile-onset SMA.
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Timepoint [15]
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Baseline, Day 302
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Primary outcome [16]
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Part C: Change From Baseline in Growth Parameters (Head-to-Chest Circumference Ratio)
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Assessment method [16]
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As pre-specified in the protocol, head to chest circumference ratio was assessed only for the participants with infantile-onset SMA.
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Timepoint [16]
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Baseline, Day 302
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Primary outcome [17]
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Parts A and C: Number of Participants With Shifts From Baseline in Coagulation Parameters (Activated Partial Thromboplastin Time (aPTT))
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Assessment method [17]
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Activated partial thromboplastin time was evaluated to assess safety. "Shift to low" measured change in normal, high and unknown values of aPTT at baseline to low values postbaseline. "Shift to high" measured change in normal, low and unknown values of aPTT at baseline to high values postbaseline.
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Timepoint [17]
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Parts A and C: Baseline up to Day 269
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Primary outcome [18]
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Parts A and C: Number of Participants With Shifts From Baseline in Coagulation Parameters (Prothrombin Time (PT))
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Assessment method [18]
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Prothrombin time was evaluated to assess safety. "Shift to low" measured change in normal, high and unknown values of PT at baseline to low values postbaseline. "Shift to high" measured change in normal, low and unknown values of PT at baseline to high values postbaseline.
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Timepoint [18]
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Parts A and C: Baseline up to Day 269
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Primary outcome [19]
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Parts A and C: Number of Participants With Shifts From Baseline in Coagulation Parameters (International Normalized Ratio (INR))
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Assessment method [19]
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INR was evaluated to assess safety. "Shift to low" measured change in normal, high and unknown values of INR at baseline to low values postbaseline. "Shift to high" measured change in normal, low and unknown values of INR at baseline to high values postbaseline. The category with at least one participant with shift from baseline in INR ratio is reported.
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Timepoint [19]
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Parts A and C: Baseline up to Day 269
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Primary outcome [20]
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Parts A and C: Change From Baseline in Urine Total Protein
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Assessment method [20]
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Timepoint [20]
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Parts A and C: Baseline, Day 302
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Primary outcome [21]
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Parts A and C: Number of Participants With Neurological Examination Abnormalities Reported as AEs
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Assessment method [21]
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Participants with abnormalities in neurological examinations recorded as AEs were reported.
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Timepoint [21]
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Parts A and C: Baseline up to Day 302
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Primary outcome [22]
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Parts A and C: Percentage of Participants With a Postbaseline Platelet Count Below the Lower Limit of Normal on at Least 2 Consecutive Measurements
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Assessment method [22]
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Timepoint [22]
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Parts A and C: Baseline up to Day 302
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Primary outcome [23]
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Parts A and C: Percentage of Participants With a Postbaseline Corrected QT Interval Using Fridericia's Formula (QTcF) of > 500 Millisecond (Msec) and an Increase From Baseline to Any Postbaseline Timepoint in QTcF of > 60 Msec
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Assessment method [23]
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Timepoint [23]
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Parts A and C: Baseline up to Day 302
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Secondary outcome [1]
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Part B Infantile-onset SMA: Percentage of Hammersmith Infant Neurological Examination (HINE) Section 2 Motor Milestone Responders for Nusinersen 50/28mg Treatment Group Versus CS3B Matched Sham Control Group
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Assessment method [1]
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Section 2 of HINE was used to assess motor milestones of participants. It's composed of 8 motor milestone categories: voluntary grasp, ability to kick in supine position, head control, rolling, sitting, crawling, standing, \& walking. Motor milestone responder: (i) a participant that demonstrated at least a 2-point increase in category of ability to kick or maximal score on that category or a 1-point increase in category of head control, rolling, sitting, crawling, standing, or walking, (ii) improvement in more categories than worsening, excluding category of voluntary grasp. For category of ability to kick, improvement, as defined in (i), worsening: at least a 2-point decrease or decrease to lowest possible score of no kicking. For other 6 categories, improvement: 1-point increase, worsening: at least 1-point decrease. Participants who died or withdrew from study were considered as non-responders. Difference in percentage of responders reported using Fisher's exact test.
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Timepoint [1]
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Baseline, Day 183
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Secondary outcome [2]
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Part B Infantile-onset SMA: Change From Baseline in HINE Section 2 Motor Milestones Total Score for Nusinersen 50/28mg Treatment Group Versus CS3B Matched Sham Control Group
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Assessment method [2]
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Section 2 of the HINE was used to assess motor milestones of the participants. It's composed of 8 motor milestone categories: voluntary grasp, ability to kick in supine position, head control, rolling, sitting, crawling, standing, and walking. Within each category, 3 to 5 levels can be achieved. The total HINE section 2 motor milestones score was calculated as sum of each level \& ranged from 0 to 26, higher score indicating improvement in motor milestones. A negative change from baseline indicates decline in motor milestones. Change from baseline in HINE section 2 motor milestones total score was compared to study CS3B (NCT02193074) matched sham control group, and was analysed using joint rank methodology.
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Timepoint [2]
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Baseline, Day 183
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Secondary outcome [3]
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Part B Infantile-onset SMA: Change From (Ratio to) Baseline in Plasma Concentration of Neurofilament Light Chain (NF-L) for 50/28mg Nusinersen Versus CS3B Matched Sham Control Group
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Assessment method [3]
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The change from baseline in the plasma concentration of NF-L was compared to the study CS3B (NCT02193074) matched sham control group. Joint rank methodology was used for the analysis to account for mortality. The change from baseline data was reported in terms of least square geometric mean ratio to baseline. Lower ratios to baseline represent greater reductions in concentrations of NF-L from baseline.
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Timepoint [3]
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Baseline, Day 183
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Secondary outcome [4]
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Part B Infantile-onset SMA: Change From Baseline in CHOP-INTEND Total Score for 50/28mg Nusinersen Versus 12/12mg Nusinersen
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Assessment method [4]
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The CHOP-INTEND test was designed to evaluate the motor skills of infants with signi?cant motor weakness. It included 16 items (capturing neck, trunk, and proximal and distal limb strength), nine of which were scored 0, 1, 2, 3, or 4, ?ve 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). The change from baseline to Day 302 in the total score was analyzed using the joint-rank methodology to account for mortality.
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Timepoint [4]
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Baseline, Day 302
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Secondary outcome [5]
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Part B Infantile-onset SMA: Change From Baseline in HINE Section 2 Motor Milestones Total Score for 50/28mg Nusinersen Versus 12/12mg Nusinersen
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Assessment method [5]
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Section 2 of the HINE was used to assess motor milestones of the participants. It's composed of 8 motor milestone categories: voluntary grasp, ability to kick in supine position, head control, rolling, sitting, crawling, standing, and walking. Within each of these categories, participants can progress from complete absence of a motor ability (the lowest level in each category) through multiple milestones (2 to 4 levels in each category) to the highest level within the category. The total motor milestones score for HINE section was calculated as the sum of each level and ranged from 0 to a maximum score of 26, higher score indicating improvement in motor milestones.
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Timepoint [5]
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Baseline, Day 302
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Secondary outcome [6]
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Part B Infantile-onset SMA: Change From (Ratio to) Baseline in Plasma Concentration of NF-L for 50/28mg Nusinersen Versus 12/12mg Nusinersen
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Assessment method [6]
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The change from baseline in plasma concentration of NF-L was analysed using the joint rank methodology to account for mortality. The change from baseline data was reported in terms of LS geometric mean ratio to baseline. Lower ratios to baseline represent greater reductions in concentrations of NF-L from baseline.
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Timepoint [6]
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Baseline, Day 64
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Secondary outcome [7]
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Part B Infantile-onset SMA: Time to Death or Permanent Ventilation for 50/28mg Nusinersen Versus CS3B Matched Sham Control Group
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Assessment method [7]
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Permanent ventilation was de?ned as tracheostomy or = 16 hours of ventilation/day continuously for \> 21 days in absence of an acute reversible event. An independent endpoint adjudication committee (EAC) determined date at which a participant was considered to have met protocol-specified criteria of an acute reversible event. Only events that were adjudicated by the EAC as meeting the criteria for permanent ventilation or death were included in analysis. Participants who did not meet the endpoint definition were censored on the last occasion the participant was seen (either in-person visit or by telephone contact), irrespective of whether the participant has completed the full course of treatment and whether the participant has completed the study or permanently withdrawn.
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Timepoint [7]
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Screening up to Day 399
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Secondary outcome [8]
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Part B Infantile-onset SMA: Time to Death (Overall Survival) for 50/28mg Nusinersen Versus CS3B Matched Sham Control Group
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Assessment method [8]
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Time to death was determined by an independent EAC. Time to death (overall survival) was compared to the study CS3B (NCT02193074) matched sham control group.
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Timepoint [8]
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Screening up to Day 399
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Secondary outcome [9]
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Part B Infantile-onset SMA: Time to Death or Permanent Ventilation for 50/28mg Nusinersen Versus 12/12mg Nusinersen
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Assessment method [9]
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Permanent ventilation was de?ned as tracheostomy or = 16 hours of ventilation/day continuously for \> 21 days in the absence of an acute reversible event. An independent EAC determined the date at which a participant was considered to have met the protocol-specified criteria of an acute reversible event. Only events that were adjudicated by the EAC as meeting the protocol defined criteria for permanent ventilation or death was included in the analysis. Participants who did not meet the endpoint definition were censored on the last occasion the participant was seen (either in-person visit or by telephone contact), irrespective of whether the participant has completed the full course of treatment and whether the participant has completed the study or permanently withdrawn.
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Timepoint [9]
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Screening up to Day 399
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Secondary outcome [10]
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Part B Infantile-onset SMA: Time to Death (Overall Survival) for 50/28mg Nusinersen Versus 12/12mg Nusinersen
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Assessment method [10]
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Time to death was determined by an independent EAC. Participants who did not die were censored on the last occasion the participant was seen (either in-person visit or by telephone contact), irrespective of whether the participant has completed the full course of treatment and whether the participant has completed the study or permanently withdrawn.
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Timepoint [10]
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Screening up to Day 399
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Secondary outcome [11]
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Part B Later-onset SMA: Change From Baseline in Hammersmith Functional Motor Scale Expanded (HFMSE) Score for 50/28mg Nusinersen Versus 12/12mg Nusinersen
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Assessment method [11]
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HFMSE scale was a tool used to assess motor function in children with later-onset SMA. The original 20 item Hammersmith Functional Motor Scale was expanded to include 13 additional adapted items from the Gross Motor Function Measure to improve sensitivity for the higher functioning ambulant population. Each item is scored 0 (unable), 1 (performs with modi?cation or adaptation) or 2 (able) and the total score was calculated by summing the 33 items and ranged from 0 to 66 with higher scores indicating greater motor function.
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Timepoint [11]
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Baseline, Day 302
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Secondary outcome [12]
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Part B Later-onset SMA: Change From Baseline in Revised Upper Limb Module (RULM) Score for 50/28mg Nusinersen Versus 12/12mg Nusinersen
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Assessment method [12]
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RULM test was developed to assess upper limb functional abilities. RULM test: total 20 items. First item was assessed on 7-point scale (0:No useful function to 6-Can abduct both arms simultaneously, elbows in extension in full circle until they touch above head). This first item did not contribute to total score. For remaining 19 items, 18 items were assessed on 3-point scale: 0-Unable to achieve independently; 1-Modified method but achieves goal independent of physical assistance from another person; 2-Normal -achieves goal without any assistance. One remaining item was assessed as either 0 or 1. For each item, score was collected on left \& right side. Derived total score=summing scores from these 19 individual items ranging from 0-if participant fails all activities to 37-if participant achieves all activities. If, for an individual item, response was recorded for both left \& right side, highest score was used in calculating total score. Higher scores=increased upper limb function.
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Timepoint [12]
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Baseline, Day 302
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Secondary outcome [13]
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Part B Later-onset SMA: Number of New World Health Organization (WHO) Motor Milestones Achieved Per Participant for 50/28mg Nusinersen Versus 12/12mg Nusinersen
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Assessment method [13]
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The WHO motor milestones were a set of six milestones in motor development: sitting without support, standing with assistance, hands and knees crawling, walking with assistance, standing alone and walking alone. The examiner recorded an overall rating of the participant's emotional state and then for each milestone one of the following four classi?cations: no (inability) - child tried but failed to perform the milestone, no (refusal) - child refused to perform despite being calm and alert, yes - child was able to perform the milestone, unable to test - could not be tested because of irritability, drowsiness or sickness. Mean of number of new milestones achieved per participant was calculated and reported in this outcome measure.
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Timepoint [13]
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Baseline, Day 302
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Secondary outcome [14]
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Part B Later-onset SMA: Change From Baseline in Assessment of Caregiver Experience With Neuromuscular Disease (ACEND) for 50/28mg Nusinersen Versus 12/12mg Nusinersen
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Assessment method [14]
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ACEND instrument was designed to quantify caregiver impact experienced by parents/caregivers of children affected with severe neuromuscular diseases, including children with SMA. The ACEND included 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 comprised several items. The total score for each domain was calculated on a scale of 0 to 100, with a higher score indicating a decreased caregiver burden. A negative change from baseline indicates an increased caregiver burden.
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Timepoint [14]
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Baseline, Day 302
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Secondary outcome [15]
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Part B Later-onset SMA: Change From Baseline in Pediatric Quality of Life Inventory™ (PedsQL) for 50/28mg Nusinersen Versus 12/12mg Nusinersen
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Assessment method [15]
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Participants were evaluated using PedsQL generic core scale \& neuromuscular module. PedsQL generic core scale was used to calculate PedsQL inventory total score (PQLI), that included parent \& participant's assessment on 4 dimensions: physical, emotional, social, \& school functioning \& psychosocial health. Each item was scored on 5-point ordinal scale (0=never to 4=almost always). PedsQL neuromuscular module (PQLN) measured HRQOL dimensions specific to with neuromuscular disorders, like SMA. Each item was scored on 5-point ordinal scale (0=never to 4=almost always). Dimensions were reversed scored \& were linearly transformed to 0-100 scale (0=100, 1=75, 2=50, 3=25, 4=0) for both PQLI and PQLN, higher scores indicative of better health related quality of life. Total scale scores were calculated as sum of all items over number of items answered on all scales. If more than 50% of items/more within a dimension were missing, scale score was not computed.
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Timepoint [15]
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Baseline, Day 302
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Secondary outcome [16]
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Part B Later-onset SMA: Change From (Ratio to) Baseline in CSF Concentration of NF-L for 50/28mg Nusinersen Versus 12/12mg Nusinersen
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Assessment method [16]
0
0
The change from baseline data was reported in terms of geometric mean ratio to baseline. Lower ratios to baseline represent greater reductions in concentrations of NF-L from baseline.
Query!
Timepoint [16]
0
0
Baseline, Day 279
Query!
Secondary outcome [17]
0
0
Part B Later-onset SMA: Change From (Ratio to) Baseline in Plasma Concentration of NF-L for 50/28mg Nusinersen Versus 12/12mg Nusinersen
Query!
Assessment method [17]
0
0
The change from baseline data was reported in terms of geometric mean ratio to baseline. Lower ratios to baseline represent greater reductions in concentrations of NF-L from baseline.
Query!
Timepoint [17]
0
0
Baseline, Day 302
Query!
Secondary outcome [18]
0
0
Part B: Number of Participants With TEAEs and TESAEs
Query!
Assessment method [18]
0
0
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. AE was regarded as treatment-emergent if it was present prior to receiving the first dose of nusinersen in the current study and subsequently worsened in severity or was not present prior to receiving the first dose of nusinersen and subsequently appeared.
Query!
Timepoint [18]
0
0
From the first dose of the study drug up to Day 399
Query!
Secondary outcome [19]
0
0
Part B: Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Hematology Parameters)
Query!
Assessment method [19]
0
0
Hematology parameters included complete blood cell count, with di?erential and platelet count, and absolute neutrophil count. These parameters were flagged as low, normal, or high relative to parameter's normal range or as unknown if no result was available, by the Investigator. Here, shift to low indicates 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 values postbaseline. The categories with at least one participant with shift from baseline in these parameters are reported.
Query!
Timepoint [19]
0
0
Baseline up to Day 302
Query!
Secondary outcome [20]
0
0
Part B: Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Blood Chemistry Parameters)
Query!
Assessment method [20]
0
0
Blood chemistry parameters included protein, albumin, creatinine, blood urea nitrogen, bilirubin (total and direct), alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transferase, glucose, calcium, phosphorus, bicarbonate, chloride, sodium, potassium, cystatin C, and creatine kinase. Parameters were flagged as low, normal, or high relative to parameter's normal range or as unknown if no result was available, by the Investigator. Here, shift to low indicates 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 values postbaseline. Categories with at least one participant with shift from baseline in these parameters are reported.
Query!
Timepoint [20]
0
0
Baseline up to Day 302
Query!
Secondary outcome [21]
0
0
Part B: Number of Participants With Shifts From Baseline in Urinalysis
Query!
Assessment method [21]
0
0
Urinalysis included assessments of urine total protein, specific gravity, pH, protein, glucose, ketones, bilirubin, blood, RBC , WBC, 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, by the Investigator. Here, shift to low indicates values that were normal, high, positive, abnormal or unknown at baseline and shifted to low values postbaseline. Shift to high indicates values that were normal, negative, absent, low or unknown at baseline and shifted to high values postbaseline. The categories with at least one participant with shift from baseline in these parameters are reported.
Query!
Timepoint [21]
0
0
Baseline up to Day 302
Query!
Secondary outcome [22]
0
0
Part B: Number of Participants With Shifts From Baseline in CSF Parameters
Query!
Assessment method [22]
0
0
CSF parameters included cell count, total protein, and glucose. These parameters were flagged as low, normal, or high relative to parameter's normal range or as unknown if no result was available, by the Investigator. Here, shift to low indicates 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 values postbaseline. The categories with at least one participant with shift from baseline in these parameters are reported.
Query!
Timepoint [22]
0
0
Baseline up to Day 302
Query!
Secondary outcome [23]
0
0
Part B: Number of Participants With Shift From Baseline in ECGs
Query!
Assessment method [23]
0
0
The ECGs were assessed by the investigator to be normal, abnormal and abnormal AE. The number of participants with ECG shifts from normal to each of the categorical values denoting an abnormal scan (abnormal not AE, abnormal AE) was assessed. Shift from baseline to worst post-baseline values were reported. The categories with at least one participant with shift from baseline in ECG are reported.
Query!
Timepoint [23]
0
0
Baseline up to Day 302
Query!
Secondary outcome [24]
0
0
Part B: Number of Participants With Abnormalities in Vital Sign Parameters
Query!
Assessment method [24]
0
0
Vital sign assessment included temperature, pulse rate systolic blood pressure, diastolic blood pressure, and respiratory rate. As pre-specified in protocol, the criteria for determining potentially clinically relevant abnormalities in vital signs included: temperature \< 36.0 and \> 38.0 degrees C, pulse rate \< 60 and \> 100 bpm, systolic blood pressure \< 90, \> 140 and \> 160 mmHg, diastolic blood pressure \< 50, \> 90 and \> 100 mmHg and respiratory rate \< 12 and \> 20 breaths per minute. The categories with at least one participant with clinically relevant vital sign abnormalities are reported.
Query!
Timepoint [24]
0
0
Baseline up to Day 302
Query!
Secondary outcome [25]
0
0
Part B: Change From Baseline in Growth Parameters (Body Height)
Query!
Assessment method [25]
0
0
Body height was measured for all participants (infantile-onset and later-onset SMA).
Query!
Timepoint [25]
0
0
Baseline, Day 302
Query!
Secondary outcome [26]
0
0
Part B Infantile-onset SMA: Change From Baseline in Growth Parameters (Head Circumference)
Query!
Assessment method [26]
0
0
Head circumference was measured in participants with infantile-onset SMA.
Query!
Timepoint [26]
0
0
Baseline, Day 302
Query!
Secondary outcome [27]
0
0
Part B Infantile-onset SMA: Change From Baseline in Growth Parameters (Chest Circumference)
Query!
Assessment method [27]
0
0
Chest circumference was measured in participants with infantile-onset SMA.
Query!
Timepoint [27]
0
0
Baseline, Day 302
Query!
Secondary outcome [28]
0
0
Part B Infantile-onset SMA: Change From Baseline in Growth Parameters (Arm Circumference)
Query!
Assessment method [28]
0
0
Arm circumference was measured in participants with infantile-onset SMA.
Query!
Timepoint [28]
0
0
Baseline, Day 302
Query!
Secondary outcome [29]
0
0
Part B: Change From Baseline in Growth Parameters (Ulnar Length)
Query!
Assessment method [29]
0
0
Ulnar length was measured in participants with later-onset SMA.
Query!
Timepoint [29]
0
0
Baseline, Day 302
Query!
Secondary outcome [30]
0
0
Part B: Change From Baseline in Growth Parameters (Weight for Age Percentile)
Query!
Assessment method [30]
0
0
WHO child growth standards (2006) was used to calculate the weight for age percentile in the infantile-onset participants. The 2000 CDC Growth Charts was used to calculate the weight for age percentile for later-onset participants. Negative change from baseline indicates reduction in weight for age percentile
Query!
Timepoint [30]
0
0
Baseline, Day 302
Query!
Secondary outcome [31]
0
0
Part B: Change From Baseline in Growth Parameters (Weight for Length Percentile)
Query!
Assessment method [31]
0
0
As pre-specified in the protocol, weight for length percentile was assessed only for the participants with infantile-onset SMA. Negative change from baseline indicates reduction in weight for length percentile.
Query!
Timepoint [31]
0
0
Baseline, Day 302
Query!
Secondary outcome [32]
0
0
Part B: Change From Baseline in Growth Parameters (Head-to-Chest Circumference Ratio)
Query!
Assessment method [32]
0
0
As pre-specified in the protocol, head to chest circumference ratio was assessed only for the participants with infantile-onset SMA. Negative change from baseline indicates reduction in head-to-chest circumference ratio.
Query!
Timepoint [32]
0
0
Baseline, Day 302
Query!
Secondary outcome [33]
0
0
Part B: Number of Participants With Shifts From Baseline in Coagulation Parameters (aPTT)
Query!
Assessment method [33]
0
0
aPTT was evaluated to assess safety. "Shift to low" measured change in normal, high and unknown values of aPTT at baseline to low values postbaseline. "Shift to high" measured change in normal, low and unknown values of aPTT at baseline to high values postbaseline.
Query!
Timepoint [33]
0
0
Baseline up to Day 279
Query!
Secondary outcome [34]
0
0
Part B: Number of Participants With Shifts From Baseline in Coagulation Parameters (PT)
Query!
Assessment method [34]
0
0
Prothrombin time was evaluated to assess safety. "Shift to low" measured change in normal, high and unknown values of PT at baseline to low values postbaseline. "Shift to high" measured change in normal, low and unknown values of PT at baseline to high values postbaseline.
Query!
Timepoint [34]
0
0
Baseline up to Day 279
Query!
Secondary outcome [35]
0
0
Part B: Number of Participants With Shifts From Baseline in Coagulation Parameters (INR)
Query!
Assessment method [35]
0
0
INR was evaluated to assess safety. "Shift to low" measured change in normal, high and unknown values of INR at baseline to low values postbaseline. "Shift to high" measured change in normal, low and unknown values of INR at baseline to high values postbaseline.
Query!
Timepoint [35]
0
0
Baseline up to Day 279
Query!
Secondary outcome [36]
0
0
Part B: Change From Baseline in Urine Total Protein
Query!
Assessment method [36]
0
0
Query!
Timepoint [36]
0
0
Baseline, Day 302
Query!
Secondary outcome [37]
0
0
Part B: Number of Participants With Neurological Examination Abnormalities Reported as AEs
Query!
Assessment method [37]
0
0
Participants with abnormalities in neurological examinations recorded as AEs were reported.
Query!
Timepoint [37]
0
0
Baseline up to Day 302
Query!
Secondary outcome [38]
0
0
Part B: Percentage of Participants With a Postbaseline Platelet Count Below the Lower Limit of Normal on at Least 2 Consecutive Measurements
Query!
Assessment method [38]
0
0
Query!
Timepoint [38]
0
0
Baseline up to Day 302
Query!
Secondary outcome [39]
0
0
Part B: Percentage of Participants With a Postbaseline QTcF of > 500 Msec and an Increase From Baseline to Any Postbaseline Timepoint in QTcF of > 60 Msec
Query!
Assessment method [39]
0
0
Query!
Timepoint [39]
0
0
Baseline up to Day 302
Query!
Secondary outcome [40]
0
0
Parts A, B and C: Number of Participants With Hospitalizations
Query!
Assessment method [40]
0
0
Query!
Timepoint [40]
0
0
Parts A, B, and C: Baseline up to Day 302
Query!
Secondary outcome [41]
0
0
Parts A, B and C: Percentage of Time of Hospitalization
Query!
Assessment method [41]
0
0
Query!
Timepoint [41]
0
0
Parts A, B, and C: Baseline up to Day 302
Query!
Secondary outcome [42]
0
0
Parts A, B and C: Number of Participants With Clinical Global Impression of Change (CGIC)
Query!
Assessment method [42]
0
0
The CGIC scale was a 7 point scale that required the clinician to assess how much the participant's illness had changed relative to a baseline state at the beginning of the intervention, where 1=very much improved, 2=much improved, 3=minimally improved, 4=no change, 5=minimally worse, 6=much worse, 7=very much worse. Higher rating indicates worsening of the condition. A separate CGIC assessment was performed by the Investigator (I) and caregiver (C). The categories with at least one participant having a CGIC score was reported.
Query!
Timepoint [42]
0
0
Parts A, B, and C: Day 302
Query!
Secondary outcome [43]
0
0
Parts A, B and C: Number of Serious Respiratory Events
Query!
Assessment method [43]
0
0
Query!
Timepoint [43]
0
0
Parts A, B, and C: Baseline up to Day 399
Query!
Secondary outcome [44]
0
0
Part B Infantile-onset SMA: Percentage of Time on Ventilation
Query!
Assessment method [44]
0
0
Query!
Timepoint [44]
0
0
Baseline up to Day 302
Query!
Secondary outcome [45]
0
0
Parts A, B and C: Number of Participants With Ventilator Use
Query!
Assessment method [45]
0
0
Query!
Timepoint [45]
0
0
Parts A, B, and C: Screening up to Day 302
Query!
Secondary outcome [46]
0
0
Part A: Change From Baseline in the Parent Assessment of Swallowing Ability (PASA) Scale
Query!
Assessment method [46]
0
0
PASA was assessed using a questionnaire. Caregivers were asked a series of questions regarding the mealtime behavior of the participant. The PASA questionnaire was developed to assess the signs and symptoms of dysphagia. It included 33 items across 4 domains: general feeding, drinking liquids, eating solid foods, \& assessment of swallowing concerns. Items in domains general feeding, drinking liquids, \& eating solid foods are assessed with 5 levels of response scored as 4-Never, 3-Rarely, 2-Sometimes, 1-Often, \& 0-Always. Domain for assessing swallowing concerns has 4 levels of responses scored as: 3-Strongly Disagree, 2-Disagree, 1-Agree, 0-Strongly Agree. Higher score= improvement. A negative change from baseline=decrease in swallowing ability. From domains 'drinking liquids' and 'eating solid foods', 2 items (attempted to drink liquids and eat solid foods) were assessed as "Yes"/"No", which are reported in another outcome measure.
Query!
Timepoint [46]
0
0
Baseline, Day 302
Query!
Secondary outcome [47]
0
0
Part A: Number of Participants With Shift From Baseline in PASA Scale Items - Attempted to Drink Liquids and Attempted to Eat Solid Foods
Query!
Assessment method [47]
0
0
PASA was assessed using a questionnaire. Caregivers were asked a series of questions regarding the mealtime behavior of the participant. The PASA questionnaire was developed to assess the signs and symptoms of dysphagia. It included 33 items across 4 domains that cover general feeding, drinking liquids, eating solid foods, and assessment of swallowing concerns. The 2 items of domains drinking liquids (attempted to drink liquids), eating solid foods (attempted to eat solid foods) were assessed as "Yes"/"No". Data for the 2 items were summarized in terms of the shift from baseline.
Query!
Timepoint [47]
0
0
Baseline, Day 302
Query!
Secondary outcome [48]
0
0
Part B: Change From Baseline in the PASA Scale
Query!
Assessment method [48]
0
0
PASA was assessed using a questionnaire. Caregivers were asked a series of questions regarding the mealtime behavior of the participant. The PASA questionnaire was developed to assess the signs and symptoms of dysphagia. It included 33 items across 4 domains that cover general feeding, drinking liquids, eating solid foods, and assessment of swallowing concerns. Items in domains of general feeding, drinking liquids, \& eating solid foods are assessed with 5 levels of response scored as 4-Never, 3-Rarely, 2-Sometimes, 1-Often, \& 0-Always. Domain for assessing swallowing concerns has 4 levels of responses scored as: 3-Strongly Disagree, 2-Disagree, 1-Agree, 0-Strongly Agree. Higher score= improvement. A negative change from baseline=decrease in swallowing ability. As planned, for part B of the study, the PASA scale was assessed for the domain general feeding only.
Query!
Timepoint [48]
0
0
Baseline, Day 302
Query!
Secondary outcome [49]
0
0
Part B: Infantile SMA-onset: Change From (Ratio to) Baseline in CSF Concentration of NF-L
Query!
Assessment method [49]
0
0
The change from baseline data was reported in terms of geometric mean ratio to baseline. Lower ratios to baseline represent greater reductions in concentrations of NF-L from baseline.
Query!
Timepoint [49]
0
0
Baseline, Day 279
Query!
Secondary outcome [50]
0
0
Parts A and C: Change From Baseline in HFMSE Total Score
Query!
Assessment method [50]
0
0
HFMSE scale was a tool used to assess motor function in children with SMA. The original 20 item Hammersmith Functional Motor Scale was expanded to include 13 additional adapted items from the Gross Motor Function Measure to improve sensitivity for the higher functioning ambulant population. Each item is scored 0 (unable), 1 (performs with modification or adaptation) or 2 (able) and the total score was calculated by summing the 33 items and ranged from 0 to 66 with higher scores indicating greater motor function. Negative change from baseline indicates decrease in motor function.
Query!
Timepoint [50]
0
0
Parts A and C: Baseline, Day 302
Query!
Secondary outcome [51]
0
0
Parts A and C: Change From Baseline in RULM Total Score
Query!
Assessment method [51]
0
0
RULM test was developed to assess upper limb functional abilities. RULM test: total 20 items. First item was assessed on 7-point scale (0:No useful function to 6-Can abduct both arms simultaneously, elbows in extension in full circle until they touch above head). This first item did not contribute to total score. For remaining 19 items, 18 items were assessed on 3-point scale: 0-Unable to achieve independently; 1-Modified method but achieves goal independent of physical assistance from another person; 2-Normal -achieves goal without any assistance. One remaining item was assessed as either 0 or 1. For each item, score was collected on left \& right side. Derived total score=summing scores from these 19 individual items ranging from 0-if participant fails all activities to 37-if participant achieves all activities. If, for an individual item, response was recorded for both left \& right side, highest score was used in calculating total score. Higher scores=increased upper limb function.
Query!
Timepoint [51]
0
0
Parts A and C: Baseline, Day 302
Query!
Secondary outcome [52]
0
0
Parts A and C: Number of Participants With WHO Motor Milestones Status
Query!
Assessment method [52]
0
0
The WHO motor milestones were a set of six milestones in motor development: sitting without support, standing with assistance, hands and knees crawling, walking with assistance, standing alone and walking alone. The examiner recorded an overall rating of the participant's emotional state and then for each milestone one of the following four classifications: no (inability) - child tried but failed to perform the milestone, no (refusal) - child refused to perform despite being calm and alert, yes - child was able to perform the milestone, unable to test - could not be tested because of irritability, drowsiness or sickness.
Query!
Timepoint [52]
0
0
Parts A and C: Baseline up to Day 302
Query!
Secondary outcome [53]
0
0
Parts A and C: Change From Baseline in ACEND Total Score
Query!
Assessment method [53]
0
0
ACEND instrument was designed to quantify caregiver impact experienced by parents/caregivers of children affected with severe neuromuscular diseases, including children with SMA. The ACEND included 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 comprised several items. The total score for each domain was calculated on a scale of 0 to 100, with a higher score indicating a decreased caregiver burden. A negative change from baseline indicates an increased caregiver burden.
Query!
Timepoint [53]
0
0
Parts A and C: Baseline, Day 302
Query!
Secondary outcome [54]
0
0
Parts A and C: Change From Baseline in PedsQL™ Total Score
Query!
Assessment method [54]
0
0
Participants were evaluated using PedsQL generic core scale \& neuromuscular module. PedsQL generic core scale was used to calculate PedsQL inventory total score (PQLI), that included parent \& participant's assessment on 4 dimensions: physical, emotional, social, \& school functioning \& psychosocial health. Each item was scored on 5-point ordinal scale (0=never to 4=almost always). PedsQL neuromuscular module (PQLN) measured HRQOL dimensions specific to with neuromuscular disorders, like SMA. Each item was scored on 5-point ordinal scale (0=never to 4=almost always). Dimensions were reversed scored \& were linearly transformed to 0-100 scale (0=100, 1=75, 2=50, 3=25, 4=0) for both PQLI and PQLN, higher scores indicative of better health related quality of life. Total scale scores were calculated as sum of all items over number of items answered on all scales. If more than 50% of items/more within a dimension were missing, scale score was not computed.
Query!
Timepoint [54]
0
0
Parts A and C: Baseline, Day 302
Query!
Secondary outcome [55]
0
0
Part C: Change From Baseline in CHOP-INTEND Total Score
Query!
Assessment method [55]
0
0
The CHOP-INTEND test was designed to evaluate the motor skills of infants with significant motor weakness. 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).
Query!
Timepoint [55]
0
0
Baseline, Day 302
Query!
Secondary outcome [56]
0
0
Part C: Change From Baseline in HINE Section 2 Motor Milestones Total Score
Query!
Assessment method [56]
0
0
Section 2 of the HINE was used to assess motor milestones of the infantile-onset SMA participants. It's composed of 8 motor milestone categories: voluntary grasp, ability to kick in supine position, head control, rolling, sitting, crawling, standing, and walking. Within each of these categories, participants can progress from complete absence of a motor ability (the lowest level in each category) through multiple milestones (2 to 4 levels in each category) to the highest level within the category. The 8 categories of HINE Section 2 can be summed to give a total score that ranges from 0 to 26.
Query!
Timepoint [56]
0
0
Baseline, Day 302
Query!
Eligibility
Key inclusion criteria
Key
Part A, B and C:
- Genetic documentation of 5q SMA (homozygous gene deletion, mutation, or compound heterozygote)
Part A:
* Onset of clinical signs and symptoms consistent with SMA at > 6 months (> 180 days) of age (i.e., later-onset SMA)
* Age 2 to = 15 years, inclusive, at the time of informed consent
Part B:
* Participants with SMA symptom onset = 6 months (= 180 days) of age (infantile onset) should have age > 1 week to = 7 months (= 210 days) at the time of informed consent
* Participants with SMA symptom onset > 6 months (> 180 days) of age (later onset):
* Age 2 to < 10 years at the time of informed consent
* Can sit independently but has never had the ability to walk independently
* HFMSE score = 10 and = 54 at Screening
Part C:
- Currently on nusinersen treatment at the time of Screening, with the first dose being at least 1 year prior to Screening
Part C Cohort 1:
- Participants of any age (individuals =18 years of age at Screening must be ambulatory)
Part C Cohort 2:
* Participants =18 years of age at Screening (can be ambulatory or nonambulatory)
* HFMSE total score =4 points at Screening
* RULM entry item A score =3 points at Screening
Key
Query!
Minimum age
7
Days
Query!
Query!
Maximum age
No limit
Query!
Query!
Sex
Both males and females
Query!
Can healthy volunteers participate?
No
Query!
Key exclusion criteria
Part A, B and C:
* Presence of an untreated or inadequately treated active infection requiring systemic antiviral or antimicrobial therapy at any time during the Screening period
* Presence of an implanted shunt for the drainage of cerebrospinal fluid (CSF) or of an implanted central nervous system (CNS) catheter
* Hospitalization for surgery, pulmonary event, or nutritional support within 2 months prior to Screening or planned within 12 months after the participant's first dose
Part A:
* Respiratory insufficiency, defined by the medical necessity for invasive or noninvasive ventilation for > 6 hours during a 24-hour period, at Screening
* Medical necessity for a gastric feeding tube
* Treatment with an investigational drug given for the treatment of SMA, biological agent, or device within 30 days or 5 half-lives of the agent, whichever is longer, prior to Screening or anytime during the study; any prior or current treatment with any survival motor neuron-2 gene (SMN2)-splicing modifier or gene therapy; or prior antisense oligonucleotide treatment, or cell transplantation
Part B:
* Treatment with an investigational drug including but not limited to the treatment of SMA, biological agent, or device within 30 days or 5 half-lives of the agent, whichever is longer, prior to Screening or anytime during the study; any prior or current treatment with any SMN2-splicing modifier or gene therapy; or prior antisense oligonucleotide treatment, or cell transplantation
* Participants with SMA symptom onset > 6 months (> 180 days) of age (later onset):
* Respiratory insufficiency, defined by the medical necessity for invasive or noninvasive ventilation for > 6 hours during a 24-hour period, at Screening
* Medical necessity for a gastric feeding tube
* Participants with SMA symptom onset = 6 months (= 180 days) of age (infantile onset): Signs or symptoms of SMA present at birth or within the first week after birth
Part C:
* Concurrent or previous participation and/or administration of nusinersen in another clinical study
* Concomitant or previous administration of any SMN2-splicing modifier (excluding nusinersen) or gene therapy, either in a clinical study or as part of medical care.
* Concurrent or previous participation in any interventional investigational study for any other drug or device within 30 days or 5 half-lives of the agent, whichever is longer, prior to Screening
NOTE: Other protocol defined Inclusion/Exclusion criteria may apply.
Query!
Study design
Purpose of the study
Treatment
Query!
Allocation to intervention
Randomised controlled trial
Query!
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Query!
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Query!
Masking / blinding
Blinded (masking used)
Query!
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
Query!
Query!
Query!
Query!
Intervention assignment
Other
Query!
Other design features
Query!
Phase
Phase 3
Query!
Type of endpoint/s
Query!
Statistical methods / analysis
Query!
Recruitment
Recruitment status
Completed
Query!
Data analysis
Query!
Reason for early stopping/withdrawal
Query!
Other reasons
Query!
Date of first participant enrolment
Anticipated
Query!
Actual
26/03/2020
Query!
Date of last participant enrolment
Anticipated
Query!
Actual
Query!
Date of last data collection
Anticipated
Query!
Actual
30/05/2024
Query!
Sample size
Target
Query!
Accrual to date
Query!
Final
145
Query!
Recruitment in Australia
Recruitment state(s)
Query!
Recruitment outside Australia
Country [1]
0
0
United States of America
Query!
State/province [1]
0
0
California
Query!
Country [2]
0
0
United States of America
Query!
State/province [2]
0
0
Colorado
Query!
Country [3]
0
0
United States of America
Query!
State/province [3]
0
0
Illinois
Query!
Country [4]
0
0
United States of America
Query!
State/province [4]
0
0
Maryland
Query!
Country [5]
0
0
United States of America
Query!
State/province [5]
0
0
Massachusetts
Query!
Country [6]
0
0
United States of America
Query!
State/province [6]
0
0
Tennessee
Query!
Country [7]
0
0
United States of America
Query!
State/province [7]
0
0
Texas
Query!
Country [8]
0
0
Brazil
Query!
State/province [8]
0
0
Minas Gerais
Query!
Country [9]
0
0
Brazil
Query!
State/province [9]
0
0
Rio Grande Do Sul
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Funding & Sponsors
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Biogen
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Summary
Brief summary
The primary objectives of this study are to examine the clinical efficacy of nusinersen administered intrathecally at higher doses to participants with spinal muscular atrophy (SMA), as measured by change in Children's Hospital of Philadelphia-Infant Test of Neuromuscular Disorders (CHOP-INTEND) total score (Part B); to examine the safety and tolerability of nusinersen administered intrathecally at higher doses to participants with SMA (Parts A and C). The secondary objectives of this study are to examine the clinical efficacy of nusinersen administered intrathecally at higher doses to participants with SMA (Parts A, B and C); to examine the effect of nusinersen administered intrathecally at higher doses to participants with SMA (Parts A and C); to examine the safety and tolerability of nusinersen administered intrathecally at higher doses to participants with SMA, to examine the effect of nusinersen administered intrathecally at higher doses compared to the currently approved dose in participants with SMA (Part B).
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Trial website
https://clinicaltrials.gov/study/NCT04089566
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Trial related presentations / publications
Finkel RS, Ryan MM, Pascual Pascual SI, Day JW, Mercuri E, De Vivo DC, Foster R, Montes J, Gurgel-Giannetti J, MacCannell D, Berger Z. Scientific rationale for a higher dose of nusinersen. Ann Clin Transl Neurol. 2022 Jun;9(6):819-829. doi: 10.1002/acn3.51562. Epub 2022 May 13.
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Public notes
This record is viewable in the ANZCTR as it had previously listed Australia and/or New Zealand as a recruitment site, however these sites have since been removed
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Biogen
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Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
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What data in particular will be shared?
In accordance with Biogen's Clinical Trial Transparency and Data Sharing Policy on https://www.biogentrialtransparency.com/
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When will data be available (start and end dates)?
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How or where can data be obtained?
IPD available at link: https://vivli.org/
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What supporting documents are/will be available?
No Supporting Document Provided
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Other Details
Attachment
Study protocol
https://cdn.clinicaltrials.gov/large-docs/66/NCT04089566/Prot_000.pdf
Statistical analysis plan
https://cdn.clinicaltrials.gov/large-docs/66/NCT04089566/SAP_001.pdf
Results publications and other study-related documents
No documents have been uploaded by study researchers.
Results are available at
https://clinicaltrials.gov/study/NCT04089566
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