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

Study Overview
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Brief Summary
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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).

Official Title
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Escalating Dose and Randomized, Controlled Study of Nusinersen (BIIB058) in Participants With Spinal Muscular Atrophy

Conditions
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Muscular Atrophy, Spinal

Intervention / Treatment
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* Drug: Nusinersen


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 7 Days

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 28/28 Milligram (mg) Safety Group<br>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. | Drug: Nusinersen<br>* Administered as specified in the treatment arm<br>* Other names: BIIB058;|
| Active Comparator: 12/12 mg Randomized Control Group<br>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. | Drug: Nusinersen<br>* Administered as specified in the treatment arm<br>* Other names: BIIB058;|
| Experimental: 50/28 mg Randomized Treatment Group<br>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. | Drug: Nusinersen<br>* Administered as specified in the treatment arm<br>* Other names: BIIB058;|
| Experimental: 12/50/28 mg Titration Group<br>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. | Drug: Nusinersen<br>* Administered as specified in the treatment arm<br>* Other names: BIIB058;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part B Infantile-onset SMA: Change from Baseline in CHOP-INTEND Total Score | The CHOP-INTEND test is designed to evaluate the motor skills of infants with significant motor weakness. It includes 16 items (capturing neck, trunk, and proximal and distal limb strength) structured to move from easiest to hardest with the grading including gravity eliminated (lower scores) to antigravity movements (higher scores). All item scores range from 0-4. | Baseline up to Day 183 | 
| Part A and C: Number of Participants with Adverse Events (AEs) and Serious Adverse Events (SAEs) | An AE is any untoward medical occurrence in a participant administered a pharmaceutical product and that does not necessarily have a causal relationship with this treatment. An AE can therefore be 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 is any untoward medical occurrence that at any dose results in death, in the view of the Investigator, places the participant at immediate risk of death, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, results in a birth defect. | Screening up to Day 389 | 
| Part A and C: Number of Participants with Clinically Significant Shifts from Baseline in Clinical Laboratory Parameters |  | Screening up to Day 302 | 
| Part A and C: Number of Participants with Clinically Significant Shifts from Baseline in Electrocardiograms (ECGs) |  | Screening up to Day 302 | 
| Part A and C: Number of Participants with Clinically Significant Shifts from Baseline in Vital Signs |  | Screening up to Day 302 | 
| Part A and C: Change from Baseline in Body Length/Height |  | Baseline up to Day 302 | 
| Part C Infantile-onset SMA: Change from Baseline in Head Circumference |  | Baseline up to Day 302 | 
| Part C Infantile-onset SMA: Change from Baseline in Chest Circumference |  | Baseline up to Day 302 | 
| Part C Infantile-onset SMA: Change from Baseline in Arm Circumference |  | Baseline up to Day 302 | 
| Part A and C Later-onset SMA: Change from Baseline in Ulnar Length |  | Baseline up to Day 302 | 
| Part A and C: Ratio of Weight for Age |  | Baseline up to Day 302 | 
| Part A and C: Ratio of Weight for Length |  | Baseline up to Day 302 | 
| Part C: Ratio of Head-to-chest Circumference |  | Baseline up to Day 302 | 
| Part A and C: Change from Baseline in Activated Partial Thromboplastin Time (aPTT) |  | Baseline up to Day 269 | 
| Part A and C: Change from Baseline in Prothrombin Time (PT) |  | Baseline up to Day 269 | 
| Part A and C: Change from Baseline in International Normalized Ratio (INR) |  | Baseline up to Day 269 | 
| Part A and C: Change in Urine Total Protein |  | Baseline up to Day 302 | 
| Part A and C: Change from Baseline in Neurological Examination Outcomes |  | Baseline up to Day 302 | 
| Part A and C: Percentage of Participants with a Postbaseline Platelet Count Below the Lower Limit of Normal on at least 2 Consecutive Measurements |  | Baseline up to Day 302 | 
| Part 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 |  | Baseline up to Day 302 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part B Infantile-onset SMA: Percentage of Hammersmith Infant Neurological Examination (HINE) Section 2 Motor Milestone Responders | Section 2 of the HINE is used to assess motor milestones of the participants It is composed of 8 motor milestone categories: voluntary grasp, ability to kick in supine position, head control, rolling, sitting, crawling, standing, and walking. | Day 302 | 
| Part B Infantile-onset SMA: Change from Baseline in HINE Section 2 Motor Milestones Total Score | Section 2 of the HINE is used to assess motor milestones of the participants. It is composed of 8 motor milestone categories: voluntary grasp, ability to kick in supine position, head control, rolling, sitting, crawling, standing, and walking. | Baseline up to Day 302 | 
| Part B Infantile-onset SMA: Time to Death or Permanent Ventilation | Permanent ventilation is defined as tracheostomy or ≥ 16 hours of ventilation/day continuously for > 21 days in the absence of an acute reversible event. | Screening up to Day 302 | 
| Part B Infantile-onset SMA: Time to Death (Overall Survival) |  | Screening up to Day 399 | 
| Part A and B Later-onset SMA: Change from Baseline in Hammersmith Functional Motor Scale Expanded (HFMSE) Score | HFMSE scale is a tool 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. | Baseline up to Day 302 | 
| Part A and B Later-onset SMA: Change from Baseline in Revised Upper Limb Module (RULM) Score | The RULM is developed to assess upper limb functional abilities participants with SMA. This test consists of upper limb performance items that are reflective of activities of daily living. | Baseline up to Day 302 | 
| Part A and B Later-onset SMA: Total Number of New WHO Motor Milestones |  | Baseline up to Day 302 | 
| Part A and B Later-onset SMA: Change from Baseline in Assessment of Caregiver Experience with Neuromuscular Disease (ACEND) | ACEND is designed to quantify the caregiver impact experienced by parents/caregivers of children affected with severe neuromuscular diseases. It includes domains assessing physical impact (including feeding/grooming/dressing, sitting/play, transfers, and mobility) and general caregiver impact (including time, emotion, and finance). | Baseline up to Day 302 | 
| Part A and B Later-onset SMA: Change from Baseline in Pediatric Quality of Life Inventory™ (PedsQL) | PedsQL is used to measure health related quality of life (HRQOL) in children and adolescents. The PedsQL Measurement 4.0 Generic Core Scales include assessment of physical functioning, emotional functioning, social functioning, and school functioning and the PedsQL 3.0 Neuromuscular Module measures HRQOL. | Baseline up to Day 302 | 
| Part B: Number of Participants with AEs and SAEs | An AE is any untoward medical occurrence in a participant administered a pharmaceutical product and that does not necessarily have a causal relationship with this treatment. An AE can therefore be 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 is any untoward medical occurrence that at any dose results in death, in the view of the Investigator, places the participant at immediate risk of death, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, results in a birth defect. | Screening up to Day 399 | 
| Part B: Number of Participants with Clinically Significant Shifts from Baseline in Clinical Laboratory Parameters |  | Screening up to Day 302 | 
| Part B: Number of Participants with Clinically Significant Shifts from Baseline in ECGs |  | Day 1 up to Day 302 | 
| Part B: Number of Participants with Clinically Significant Shifts from Baseline in Vital Signs |  | Screening up to Day 302 | 
| Part B: Change from Baseline in Body Length/Height |  | Baseline up to Day 302 | 
| Part B Infantile-onset SMA: Change from Baseline in Head Circumference |  | Baseline up to Day 302 | 
| Part B Infantile-onset SMA: Change from Baseline in Chest Circumference |  | Baseline up to Day 302 | 
| Part B Infantile-onset SMA: Change from Baseline in Arm Circumference |  | Baseline up to Day 302 | 
| Part B Later-onset SMA: Change from Baseline in Ulnar Length |  | Baseline up to Day 302 | 
| Part B: Ratio of Weight for Age |  | Baseline up to Day 302 | 
| Part B: Ratio of Weight for Length |  | Baseline up to Day 302 | 
| Part B: Ratio of Head-to-chest Circumference |  | Baseline up to Day 302 | 
| Part B: Change from Baseline in aPTT |  | Baseline up to Day 279 | 
| Part B: Change from Baseline in PT |  | Baseline up to Day 279 | 
| Part B: Change from Baseline in INR |  | Baseline up to Day 279 | 
| Part B: Change in Urine Total Protein |  | Baseline up to Day 302 | 
| Part B: Change from Baseline in Neurological Examination Outcomes |  | Baseline up to Day 302 | 
| Part B: Percentage of Participants with a Postbaseline Platelet Count Below the Lower Limit of Normal on at least 2 Consecutive Measurements |  | Baseline up to Day 302 | 
| 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 |  | Baseline up to Day 302 | 
| Part A, B and C: Number of Hospitalizations |  | Day 1 to Day 302 | 
| Part A, B and C: Duration of Hospitalizations |  | Day 1 to Day 302 | 
| Part A, B and C: Clinical Global Impression of Change (CGIC) | The CGIC scale is a 7 point scale that requires the clinician to assess how much the participant's illness has 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 will indicate worsening of the condition. | Day 302 | 
| Part A, B and C: Number of Participants with Serious Respiratory Events |  | Screening up to Day 399 | 
| Part B Infantile-onset SMA: Percentage of Time on Ventilation |  | Screening up to Day 302 | 
| Parts A, B and C: Ventilator Use |  | Screening up to Day 302 | 
| Parts A and B: Change from Baseline in the Parent Assessment of Swallowing Ability (PASA) Scale | PASA questionnaire is developed to assess the signs and symptoms of dysphagia. It includes 33 items across 4 domains. General feeding, drinking liquids and eating solid foods will be assessed with 5 levels of response (Never, Rarely, Sometimes, Often, and Always), and 2 items will be assessed with 'Yes'/'No'. The assessment of swallowing concerns has 4 levels of response: Strongly Agree, Agree, Disagree, and Strongly Disagree. For Part A, it will be assessed in participants with later-onset SMA and in Part B, it will be assessed in participants with infantile- and later-onset SMA. | Baseline up to Day 302 | 
| Part C: Change from Baseline in HFMSE Score | HFMSE scale is a tool 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. | Baseline up to Day 302 | 
| Part C: Change from Baseline in RULM Score | The RULM is developed to assess upper limb functional abilities participants with SMA. This test consists of upper limb performance items that are reflective of activities of daily living. | Baseline up to Day 302 | 
| Part C: Total Number of New WHO Motor Milestones |  | Baseline up to Day 302 | 
| Part C: Change from Baseline in ACEND | ACEND is designed to quantify the caregiver impact experienced by parents/caregivers of children affected with severe neuromuscular diseases. It includes domains assessing physical impact (including feeding/grooming/dressing, sitting/play, transfers, and mobility) and general caregiver impact (including time, emotion, and finance). | Baseline up to Day 302 | 
| Part C: Change from Baseline in PedsQL™ | PedsQL is used to measure healthrelated quality of life (HRQOL) in children and adolescents. The PedsQL Measurement 4.0 Generic Core Scales include assessment of physical functioning, emotional functioning, social functioning, and school functioning and the PedsQL 3.0 Neuromuscular Module measures HRQOL. | Baseline up to Day 302 | 
| Part C: Change from Baseline in CHOP-INTEND Total Score | The CHOP-INTEND test is designed to evaluate the motor skills of infants with significant motor weakness. It includes 16 items (capturing neck, trunk, and proximal and distal limb strength) structured to move from easiest to hardest with the grading including gravity eliminated (lower scores) to antigravity movements (higher scores). All item scores range from 0-4. | Baseline to up Day 302 | 
| Part C: Change from Baseline in HINE Section 2 Motor Milestones Total Score | Section 2 of the HINE is used to assess motor milestones of the participants. It is composed of 8 motor milestone categories: voluntary grasp, ability to kick in supine position, head control, rolling, sitting, crawling, standing, and walking. | Baseline up to Day 302 |