Study of Nusinersen (BIIB058) in Participants With Spinal Muscular Atrophy

Biogen145 enrolled

Overview

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).

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

DOUBLE

Enrollment

145

Conditions

Muscular Atrophy, Spinal

Interventions

Eligibility

Sex: ALLMin age: 7 Days

Medical Language ↔ Plain English

Key Inclusion Criteria: 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 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.

Locations (45)

Stanford Hospital and Clinics

Palo Alto, California, United States

Children's Hospital Colorado

Aurora, Colorado, United States

Ann & Robert H. Lurie Children's Hospital of Chicago

Chicago, Illinois, United States

The Johns Hopkins Hospital

Baltimore, Maryland, United States

Boston Children's Hospital

Boston, Massachusetts, United States

Outcomes

Primary Outcomes

Part B Infantile-onset SMA: Change From Baseline in CHOP-INTEND Total Score for 50/28mg Nusinersen Versus CS3B Matched Sham Control Group

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). 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.

Time frame: Baseline, Day 183

Parts A and C: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (TESAEs)

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.

Time frame: 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

Parts A and C: Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Blood Chemistry Parameters)

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.

Time frame: Parts A and C: Baseline up to Day 302

Parts A and C: Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Hematology Parameters)

Hematology parameters included complete blood cell count, with diﬀerential 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.

Time frame: Parts A and C: Baseline up to Day 302

Parts A and C: Number of Participants With Shifts From Baseline in Urinalysis

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.

Time frame: Parts A and C: Baseline up to Day 302

Parts A and C: Number of Participants With Shifts From Baseline in Cerebrospinal Fluid (CSF) Parameters

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.

Time frame: Part A: Baseline up to Day 269, Part C: Baseline up to Day 241

Parts A and C: Number of Participants With Shifts From Baseline in Electrocardiograms (ECGs)

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.

Time frame: Parts A and C: Baseline up to Day 302

Parts A and C: Number of Participants With Abnormalities in Vital Sign Parameters

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.

Time frame: Parts A and C: Baseline up to Day 302

Parts A and C: Change From Baseline in Growth Parameters (Body Height)

Time frame: Parts A and C: Baseline, Day 302

Part C: Change From Baseline in Growth Parameters (Head Circumference)

As pre-specified in the protocol, head circumference was measured for participants with infantile-onset SMA only.

Time frame: Baseline, Day 302

Part C: Change From Baseline in Growth Parameters (Chest Circumference)

As pre-specified in protocol, chest circumference was measured for participants with infantile-onset SMA only.

Time frame: Baseline, Day 302

Part C: Change From Baseline in Growth Parameters (Arm Circumference)

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.

Time frame: Baseline, Day 302

Parts A and C: Change From Baseline in Growth Parameters (Ulnar Length)

As pre-specified in the protocol, ulnar length was measured for participants with later-onset SMA.

Time frame: Parts A and C: Baseline, Day 302

Parts A and C: Change From Baseline in Growth Parameters (Weight for Age Percentile)

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.

Time frame: Parts A and C: Baseline, Day 302

Part C: Change From Baseline in Growth Parameters (Weight for Length Ratio)

As pre-specified in the protocol, weight for length ratio was assessed only for the participants with infantile-onset SMA.

Time frame: Baseline, Day 302

Part C: Change From Baseline in Growth Parameters (Head-to-Chest Circumference Ratio)

As pre-specified in the protocol, head to chest circumference ratio was assessed only for the participants with infantile-onset SMA.

Time frame: Baseline, Day 302

Parts A and C: Number of Participants With Shifts From Baseline in Coagulation Parameters (Activated Partial Thromboplastin Time (aPTT))

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.

Time frame: Parts A and C: Baseline up to Day 269

Parts A and C: Number of Participants With Shifts From Baseline in Coagulation Parameters (Prothrombin Time (PT))

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.

Time frame: Parts A and C: Baseline up to Day 269

Parts A and C: Number of Participants With Shifts From Baseline in Coagulation Parameters (International Normalized Ratio (INR))

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.

Time frame: Parts A and C: Baseline up to Day 269

Parts A and C: Change From Baseline in Urine Total Protein

Time frame: Parts A and C: Baseline, Day 302

Parts A and C: Number of Participants With Neurological Examination Abnormalities Reported as AEs

Participants with abnormalities in neurological examinations recorded as AEs were reported.

Time frame: Parts A and C: Baseline up to Day 302

Parts A and C: Percentage of Participants With a Postbaseline Platelet Count Below the Lower Limit of Normal on at Least 2 Consecutive Measurements

Time frame: Parts A and C: Baseline up to Day 302

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

Time frame: Parts A and C: Baseline up to Day 302

Secondary Outcomes

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

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.

Time frame: Baseline, Day 183

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

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.

Time frame: Baseline, Day 183

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

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.

Part B Infantile-onset SMA: Change From Baseline in CHOP-INTEND Total Score for 50/28mg Nusinersen Versus 12/12mg Nusinersen

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). The change from baseline to Day 302 in the total score was analyzed using the joint-rank methodology to account for mortality.

Time frame: Baseline, Day 302

Part B Infantile-onset SMA: Change From Baseline in HINE Section 2 Motor Milestones Total Score for 50/28mg Nusinersen Versus 12/12mg Nusinersen

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.

Time frame: Baseline, Day 302

Part B Infantile-onset SMA: Time to Death or Permanent Ventilation for 50/28mg Nusinersen Versus CS3B Matched Sham Control Group

Permanent ventilation was deﬁned 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.

Time frame: Screening up to Day 399

Part B Infantile-onset SMA: Time to Death or Permanent Ventilation for 50/28mg Nusinersen Versus 12/12mg Nusinersen

Permanent ventilation was deﬁned 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.

Time frame: Screening up to Day 399

Part B Later-onset SMA: Change From Baseline in Hammersmith Functional Motor Scale Expanded (HFMSE) Score for 50/28mg Nusinersen Versus 12/12mg Nusinersen

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 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.

Time frame: Baseline, Day 302

Part B Later-onset SMA: Change From Baseline in Revised Upper Limb Module (RULM) Score for 50/28mg Nusinersen Versus 12/12mg Nusinersen

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.

Time frame: Baseline, Day 302

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

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. Mean of number of new milestones achieved per participant was calculated and reported in this outcome measure.

Time frame: Baseline, Day 302

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

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.

Time frame: Baseline, Day 302

Part B Later-onset SMA: Change From Baseline in Pediatric Quality of Life Inventory™ (PedsQL) for 50/28mg Nusinersen Versus 12/12mg Nusinersen

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.

Time frame: Baseline, Day 302

Part B: Number of Participants With TEAEs and TESAEs

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.

Time frame: From the first dose of the study drug up to Day 399

Part B: Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Hematology Parameters)

Hematology parameters included complete blood cell count, with diﬀerential 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.

Time frame: Baseline up to Day 302

Part B: Number of Participants With Shifts From Baseline in Clinical Laboratory Parameters (Blood Chemistry Parameters)

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.

Time frame: Baseline up to Day 302

Part B: Number of Participants With Shifts From Baseline in Urinalysis

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.

Time frame: Baseline up to Day 302

Part B: Number of Participants With Shifts From Baseline in CSF Parameters

Time frame: Baseline up to Day 302

Part B: Number of Participants With Abnormalities in Vital Sign Parameters

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.

Time frame: Baseline up to Day 302

Parts A, B and C: Number of Participants With Clinical Global Impression of Change (CGIC)

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.

Time frame: Parts A, B, and C: Day 302

Part A: Change From Baseline in the Parent Assessment of Swallowing Ability (PASA) Scale

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.

Time frame: Baseline, Day 302

Part A: Number of Participants With Shift From Baseline in PASA Scale Items - Attempted to Drink Liquids and Attempted to Eat Solid Foods

Time frame: Baseline, Day 302

Part B: Change From Baseline in the PASA Scale

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.

Time frame: Baseline, Day 302

Parts A and C: Change From Baseline in HFMSE Total Score

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.

Time frame: Parts A and C: Baseline, Day 302

Parts A and C: Change From Baseline in RULM Total Score

Time frame: Parts A and C: Baseline, Day 302

Parts A and C: Number of Participants With WHO Motor Milestones Status

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.

Time frame: Parts A and C: Baseline up to Day 302

Parts A and C: Change From Baseline in ACEND Total Score

Time frame: Parts A and C: Baseline, Day 302

Parts A and C: Change From Baseline in PedsQL™ Total Score

Time frame: Parts A and C: Baseline, Day 302

Part C: Change From Baseline in CHOP-INTEND Total Score

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).

Time frame: Baseline, Day 302

Part C: Change From Baseline in HINE Section 2 Motor Milestones Total Score

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.

Time frame: Baseline, Day 302