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

• ClinicalTrials.gov Identifier: NCT04089566
• Recruitment Status: Active, not recruiting
• First Posted: September 13, 2019
• Last Update Posted: April 18, 2024
• Sponsor: Biogen
• Information provided by (Responsible Party): Biogen

Tracking Information

• First Submitted Date: September 11, 2019
• First Posted Date: September 13, 2019
• Last Update Posted Date: April 18, 2024
• Actual Study Start Date: March 26, 2020
• Actual Primary Completion Date: February 21, 2024 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: June 23, 2022)

• Part B Infantile-onset SMA: Change from Baseline in CHOP-INTEND Total Score [ Time Frame: Baseline up to Day 183 ]
  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.
• Part A and C: Number of Participants with Adverse Events (AEs) and Serious Adverse Events (SAEs) [ Time Frame: Screening up to Day 389 ]
  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.
• Part A and C: Number of Participants with Clinically Significant Shifts from Baseline in Clinical Laboratory Parameters [ Time Frame: Screening up to Day 302 ]
• Part A and C: Number of Participants with Clinically Significant Shifts from Baseline in Electrocardiograms (ECGs) [ Time Frame: Screening up to Day 302 ]
• Part A and C: Number of Participants with Clinically Significant Shifts from Baseline in Vital Signs [ Time Frame: Screening up to Day 302 ]
• Part A and C: Change from Baseline in Body Length/Height [ Time Frame: Baseline up to Day 302 ]
• Part C Infantile-onset SMA: Change from Baseline in Head Circumference [ Time Frame: Baseline up to Day 302 ]
• Part C Infantile-onset SMA: Change from Baseline in Chest Circumference [ Time Frame: Baseline up to Day 302 ]
• Part C Infantile-onset SMA: Change from Baseline in Arm Circumference [ Time Frame: Baseline up to Day 302 ]
• Part A and C Later-onset SMA: Change from Baseline in Ulnar Length [ Time Frame: Baseline up to Day 302 ]
• Part A and C: Ratio of Weight for Age [ Time Frame: Baseline up to Day 302 ]
• Part A and C: Ratio of Weight for Length [ Time Frame: Baseline up to Day 302 ]
• Part C: Ratio of Head-to-chest Circumference [ Time Frame: Baseline up to Day 302 ]
• Part A and C: Change from Baseline in Activated Partial Thromboplastin Time (aPTT) [ Time Frame: Baseline up to Day 269 ]
• Part A and C: Change from Baseline in Prothrombin Time (PT) [ Time Frame: Baseline up to Day 269 ]
• Part A and C: Change from Baseline in International Normalized Ratio (INR) [ Time Frame: Baseline up to Day 269 ]
• Part A and C: Change in Urine Total Protein [ Time Frame: Baseline up to Day 302 ]
• Part A and C: Change from Baseline in Neurological Examination Outcomes [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: Baseline up to Day 302 ]

Original Primary Outcome Measures (submitted: September 12, 2019)

• Part B Infantile-onset SMA: Change from Baseline in Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) Total Score [ Time Frame: Baseline up to Day 183 ]
  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.
• Part B Infantile-onset SMA: Percentage of Hammersmith Infant Neurological Examination (HINE) Section 2 Motor Milestone Responders [ Time Frame: Day 302 ]
  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.
• Part B Infantile-onset SMA: Change from Baseline in HINE Section 2 Motor Milestones Total Score [ Time Frame: Baseline up to Day 302 ]
  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.
• Part B Infantile-onset SMA: Time to Permanent Ventilation [ Time Frame: Screening up to Day 302 ]
  Permanent ventilation is defined as tracheostomy or ≥ 16 hours of ventilation/day continuously for > 21 days in the absence of an acute reversible event.
• Part B Infantile-onset SMA: Time to Death (Overall Survival) [ Time Frame: Screening up to Day 302 ]
• Part A, B and C Later-onset SMA: Change from Baseline in Hammersmith Functional Motor Scale - Expanded (HFMSE) Score [ Time Frame: Baseline up to Day 302 ]
  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.
• Part A, B and C Later-onset SMA: Change from Baseline in Revised Upper Limb Module (RULM) Score [ Time Frame: Baseline up to Day 302 ]
  The RULM is developed to assess upper limib functional abilities participants with SMA. This test consists of upper limb performance items that are reflective of activities of daily living.
• Part A, B and C Later-onset SMA: Number of New WHO Motor Milestones Responders [ Time Frame: Baseline up to Day 302 ]
• Part A, B and C Later-onset SMA: Change from Baseline in Assessment of Caregiver Experience with Neuromuscular Disease (ACEND) [ Time Frame: Baseline up to Day 302 ]
  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).
• Part A, B and C Later-onset SMA: Change from Baseline in Pediatric Quality of Life Inventory™ (PedsQL) [ Time Frame: Baseline up to Day 302 ]
  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.
• Part C Infantile-onset SMA: Change from Baseline in CHOP INTEND Total Score [ Time Frame: Baseline to up Day 302 ]
  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.
• Part C Infantile-onset SMA: Change from Baseline in HINE Section 2 Motor Milestones Total Score [ Time Frame: Baseline up to Day 302 ]
  Section 2 of the HINE is composed of 8 motor milestone categories: voluntary grasp, ability to kick in supine position, head control, rolling, sitting, crawling, standing, and walking. The score scale ranges from 0 to 4, where increase in number indicates improvement.
• Part C Later-onset SMA: Change from Baseline in 6-Minute Walk Test (6MWT) Distance [ Time Frame: Baseline up to Day 302 ]
  6MWT measures the distance a participant can walk quickly in 6 minutes.
• Part C Later-onset SMA: Change from Baseline in 10-Meter Walk/Run Test (10MWR) [ Time Frame: Baseline up to Day 302 ]
  10MWR is a measure of the time required to walk/run 10 meters.
• Part C Later-onset SMA: Change from Baseline in Spinal Muscular Atrophy-Health Index (SMA-HI) [ Time Frame: Baseline up to Day 302 ]
  SMA-HI questionnaire measures a participant's perception of total disease burden

Current Secondary Outcome Measures (submitted: June 23, 2022)

• Part B Infantile-onset SMA: Percentage of Hammersmith Infant Neurological Examination (HINE) Section 2 Motor Milestone Responders [ Time Frame: Day 302 ]
  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.
• Part B Infantile-onset SMA: Change from Baseline in HINE Section 2 Motor Milestones Total Score [ Time Frame: Baseline up to Day 302 ]
  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.
• Part B Infantile-onset SMA: Time to Death or Permanent Ventilation [ Time Frame: Screening up to Day 302 ]
  Permanent ventilation is defined as tracheostomy or ≥ 16 hours of ventilation/day continuously for > 21 days in the absence of an acute reversible event.
• Part B Infantile-onset SMA: Time to Death (Overall Survival) [ Time Frame: Screening up to Day 399 ]
• Part A and B Later-onset SMA: Change from Baseline in Hammersmith Functional Motor Scale Expanded (HFMSE) Score [ Time Frame: Baseline up to Day 302 ]
  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.
• Part A and B Later-onset SMA: Change from Baseline in Revised Upper Limb Module (RULM) Score [ Time Frame: Baseline up to Day 302 ]
  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.
• Part A and B Later-onset SMA: Total Number of New WHO Motor Milestones [ Time Frame: Baseline up to Day 302 ]
• Part A and B Later-onset SMA: Change from Baseline in Assessment of Caregiver Experience with Neuromuscular Disease (ACEND) [ Time Frame: Baseline up to Day 302 ]
  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).
• Part A and B Later-onset SMA: Change from Baseline in Pediatric Quality of Life Inventory™ (PedsQL) [ Time Frame: Baseline up to Day 302 ]
  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.
• Part B: Number of Participants with AEs and SAEs [ Time Frame: Screening up to Day 399 ]
  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.
• Part B: Number of Participants with Clinically Significant Shifts from Baseline in Clinical Laboratory Parameters [ Time Frame: Screening up to Day 302 ]
• Part B: Number of Participants with Clinically Significant Shifts from Baseline in ECGs [ Time Frame: Day 1 up to Day 302 ]
• Part B: Number of Participants with Clinically Significant Shifts from Baseline in Vital Signs [ Time Frame: Screening up to Day 302 ]
• Part B: Change from Baseline in Body Length/Height [ Time Frame: Baseline up to Day 302 ]
• Part B Infantile-onset SMA: Change from Baseline in Head Circumference [ Time Frame: Baseline up to Day 302 ]
• Part B Infantile-onset SMA: Change from Baseline in Chest Circumference [ Time Frame: Baseline up to Day 302 ]
• Part B Infantile-onset SMA: Change from Baseline in Arm Circumference [ Time Frame: Baseline up to Day 302 ]
• Part B Later-onset SMA: Change from Baseline in Ulnar Length [ Time Frame: Baseline up to Day 302 ]
• Part B: Ratio of Weight for Age [ Time Frame: Baseline up to Day 302 ]
• Part B: Ratio of Weight for Length [ Time Frame: Baseline up to Day 302 ]
• Part B: Ratio of Head-to-chest Circumference [ Time Frame: Baseline up to Day 302 ]
• Part B: Change from Baseline in aPTT [ Time Frame: Baseline up to Day 279 ]
• Part B: Change from Baseline in PT [ Time Frame: Baseline up to Day 279 ]
• Part B: Change from Baseline in INR [ Time Frame: Baseline up to Day 279 ]
• Part B: Change in Urine Total Protein [ Time Frame: Baseline up to Day 302 ]
• Part B: Change from Baseline in Neurological Examination Outcomes [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: Baseline up to Day 302 ]
• Part A, B and C: Number of Hospitalizations [ Time Frame: Day 1 to Day 302 ]
• Part A, B and C: Duration of Hospitalizations [ Time Frame: Day 1 to Day 302 ]
• Part A, B and C: Clinical Global Impression of Change (CGIC) [ Time Frame: Day 302 ]
  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.
• Part A, B and C: Number of Participants with Serious Respiratory Events [ Time Frame: Screening up to Day 399 ]
• Part B Infantile-onset SMA: Percentage of Time on Ventilation [ Time Frame: Screening up to Day 302 ]
• Parts A, B and C: Ventilator Use [ Time Frame: Screening up to Day 302 ]
• Parts A and B: Change from Baseline in the Parent Assessment of Swallowing Ability (PASA) Scale [ Time Frame: Baseline up to Day 302 ]
  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.
• Part C: Change from Baseline in HFMSE Score [ Time Frame: Baseline up to Day 302 ]
  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.
• Part C: Change from Baseline in RULM Score [ Time Frame: Baseline up to Day 302 ]
  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.
• Part C: Total Number of New WHO Motor Milestones [ Time Frame: Baseline up to Day 302 ]
• Part C: Change from Baseline in ACEND [ Time Frame: Baseline up to Day 302 ]
  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).
• Part C: Change from Baseline in PedsQL™ [ Time Frame: Baseline up to Day 302 ]
  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.
• Part C: Change from Baseline in CHOP-INTEND Total Score [ Time Frame: Baseline to up Day 302 ]
  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.
• Part C: Change from Baseline in HINE Section 2 Motor Milestones Total Score [ Time Frame: Baseline up to Day 302 ]
  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.

Original Secondary Outcome Measures (submitted: September 12, 2019)

• Part A, B and C: Number of Participants with Adverse Events (AEs) and Serious Adverse Events (SAEs) [ Time Frame: Screening up to Day 302 ]
  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.
• Part A, B and C: Number of Participants with Clinically Significant Shifts from Baseline in Clinical Laboratory Parameters [ Time Frame: Screening up to Day 302 ]
• Part A, B and C: Number of Participants with Clinically Significant Shifts from Baseline in Electrocardiograms (ECGs) [ Time Frame: Screening up to Day 302 ]
• Part A, B and C: Number of Participants with Clinically Significant Shifts from Baseline in Vital Signs [ Time Frame: Screening up to Day 302 ]
• Part A, B and C: Change from Baseline in Body Length/Height [ Time Frame: Baseline up to Day 302 ]
• Part B Infantile-onset SMA: Change from Baseline in Head Circumference [ Time Frame: Baseline up to Day 302 ]
• Part B Infantile-onset SMA: Change from Baseline in Chest Circumference [ Time Frame: Baseline up to Day 302 ]
• Part B Infantile-onset SMA: Change from Baseline in Arm Circumference [ Time Frame: Baseline up to Day 302 ]
• Part A, B and C Later-onset SMA: Change from Baseline in Ulnar Length [ Time Frame: Baseline up to Day 302 ]
• Part A, B and C: Ratio of Weight for Age [ Time Frame: Baseline up to Day 302 ]
• Part A, B and C: Ratio of Weight for Length [ Time Frame: Baseline up to Day 302 ]
• Part A, B and C: Ratio of Head-to-chest Circumference [ Time Frame: Baseline up to Day 302 ]
• Part A, B and C: Change from Baseline in Activated Partial Thromboplastin Time [ Time Frame: Baseline up to Day 279 ]
• Part A, B and C: Change from Baseline in Prothrombin Time [ Time Frame: Baseline up to Day 279 ]
• Part A, B and C: Change from Baseline in International Normalized Ratio [ Time Frame: Baseline up to Day 279 ]
• Part A, B and C: Change in Urine Total Protein [ Time Frame: Baseline up to Day 279 ]
• Part A, B and C: Change from Baseline in Neurological Examination Outcomes [ Time Frame: Baseline up to Day 302 ]
• Part A, B and C: Percentage of Participants with a Postbaseline Platelet Count Below the Lower Limit of Normal on at least 2 Consecutive Measurements [ Time Frame: Baseline up to Day 302 ]
• Part A, B 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: Baseline up to Day 302 ]
• Part A, B and C: Number of Hospitalizations [ Time Frame: Day 1 to Day 279 ]
• Part A, B and C: Duration of Hospitalizations [ Time Frame: Day 1 to Day 279 ]
• Part A, B and C: Clinical Global Impression of Change (CGIC) [ Time Frame: Baseline up to Day 302 ]
  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.
• Part A, B and C: Number of Participants with Serious Respiratory Events [ Time Frame: Screening up to Day 302 ]
• Part A and B: Change from Baseline in the Parent Assessment of Swallowing Ability (PASA) Scale [ Time Frame: Baseline up to Day 302 ]
  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.
• Part A, B and C: Cerebrospinal Fluid (CSF) Levels of Nusinersen [ Time Frame: Baseline up to Day 279 ]
• Part A, B and C: Plasma Levels of Nusinersen [ Time Frame: Baseline up to Day 302 ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

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

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).

• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Sequential Assignment; Masking: Double (Participant, Care Provider); Primary Purpose: Treatment
• Condition: Muscular Atrophy, Spinal

Intervention

Drug: Nusinersen

Administered as specified in the treatment arm

Other Name: BIIB058

Study Arms

• 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.
  Intervention: Drug: Nusinersen
• Active Comparator: 12/12 mg Randomized 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.
  Intervention: Drug: Nusinersen
• Experimental: 50/28 mg Randomized 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.
  Intervention: Drug: Nusinersen
• 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.
  Intervention: Drug: Nusinersen

• 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.

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: June 23, 2022): 145
• Original Estimated Enrollment (submitted: September 12, 2019): 125
• Estimated Study Completion Date: June 4, 2024
• Actual Primary Completion Date: February 21, 2024 (Final data collection date for primary outcome measure)

Eligibility Criteria

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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 7 Days and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Australia, Brazil, Canada, Chile, China, Colombia, Estonia, France, Germany, Greece, Hungary, Ireland, Israel, Italy, Japan, Korea, Republic of, Latvia, Lebanon, Mexico, Netherlands, Poland, Russian Federation, Saudi Arabia, Spain, Taiwan, Turkey, United Kingdom, United States

Administrative Information

• NCT Number: NCT04089566
• Other Study ID Numbers: 232SM203; 2019-002663-10 ( EudraCT Number )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Yes
• Plan Description: In accordance with Biogen's Clinical Trial Transparency and Data Sharing Policy on https://www.biogentrialtransparency.com/
• URL: https://vivli.org/

• Current Responsible Party: Biogen
• Original Responsible Party: Same as current
• Current Study Sponsor: Biogen
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Medical Director; Biogen

• PRS Account: Biogen
• Verification Date: April 2024