A Phase 4 Study of Nusinersen (BIIB058) Among Patients With Spinal Muscular Atrophy Who Received Onasemnogene Abeparvovec
Trial Snapshot
- Phase
- Phase 4
- Status
- Completed
- Sponsor
- Biogen
- Enrollment
- 46
- Locations
- 15
- Primary Endpoint
- Total Hammersmith Infant Neurological Examination (HINE) Section 2 Motor Milestones Score
Study Overview
Brief Summary
In this study, researchers will learn more about the use of nusinersen (BIIB058) in participants with spinal muscular atrophy (SMA). This study will focus on children under the age of 3 who were previously treated with the gene therapy onasemnogene abeparvovec but are still facing health challenges related to their disease.
The main goal of the study is to learn about the effect nusinersen has on muscle and movement ability (motor function). The main question researchers want to answer is:
- What score do participants have on the HINE Section 2 Motor Milestones test after treatment?
The Hammersmith Infant Neurological Examination (HINE) Section 2 Motor Milestones is an assessment that tests movements in different positions. This includes grasping, kicking, head control, rolling, sitting, crawling, standing, and walking.
Researchers will use a group of tests to study body movements, reflexes, balance, and coordination. They will also record if participants need help with breathing.
Researchers will also learn more about the safety of nusinersen. They will check participants for adverse events and changes in vital signs, heart tests, and laboratory tests including blood and urine tests.
The study will be done as follows:
- Participants will be screened to check if they can join the study.
- Each participant will receive 4 initial doses of 12 mg of nusinersen on Days 1, 15, 29, and 64 of the Treatment Period. Then, they will receive 12 mg doses once every 4 months.
- The total number of doses of nusinersen will be 9.
- Nusinersen will be given through a lumbar puncture, which involves injecting the drug into the fluid around the spinal cord in the lower back.
- The treatment period will last for up to 95 weeks (close to 2 years).
- There will be a follow-up safety period that lasts about 4 months.
- In total, participants will have up to 14 study visits. Participants will stay in the study for up to 115 weeks.
Detailed Description
The primary objective of this study is to evaluate the clinical outcomes following treatment with nusinersen in participants with spinal muscular atrophy (SMA) who previously received onasemnogene abeparvovec.
The secondary objectives of this study are to evaluate the safety and tolerability; clinical outcomes and pharmacodynamics (PD) of nusinersen treatment in participants with SMA who previously received onasemnogene abeparvovec.
Study Design
- Study Type
- Interventional
- Allocation
- Na
- Intervention Model
- Single Group
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 2 Months to 36 Months (Child)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •For all participants:
- •Genetic documentation of 5q SMA homozygous gene survival motor neuron 1 (SMN1) deletion or mutation, or compound heterozygous mutation
- •SMN2 copy number of ≥1
- •≤36 months of age at the time of first Nusinersen dose
- •Must have previously received onasemnogene abeparvovec per the approved label or local/regional regulations ≥2 months prior to first Nusinersen dose
- •Must have suboptimal clinical status per the Investigator
- •Additional Criteria for Subgroups A and B:
- •<300 days of age at the time of first Nusinersen dose
- •SMN2 copy number of 2
- •Additional Criteria for Subgroup A:
- •SMA symptom onset ≤4 months (120 days) of age
- •Must have received intravenous (IV) onasemnogene abeparvovec at >6 weeks to ≤6 months (43 days to 180 days) of age
- •Must have received IV onasemnogene abeparvovec after SMA symptom onset
- •Additional Criteria for Subgroup B:
- •Must have received IV onasemnogene abeparvovec at ≤6 weeks (42 days) of age
Exclusion Criteria
- •For all participants:
- •Prior exposure to Nusinersen
- •Ongoing severe or serious AEs related to onasemnogene abeparvovec
- •Treatment with an investigational drug, biological agent, or device within 30 days or 5 half-lives of the agent, whichever is longer, prior to study; any prior or current treatment with any survival motor neuron 2 (SMN2)-directed splicing modifier; prior antisense oligonucleotide treatment or cell transplantation; gene therapy for the treatment of SMA other than onasemnogene abeparvovec. Note: treatment with onasemnogene abeparvovec as part of an investigational study is allowed
- •Additional Criteria for Subgroups A and B:
- •Weight-for-age is below the third percentile, based on WHO Child Growth Standards at the time of receiving onasemnogene abeparvovec. Adjustments for the gestational weight of premature babies enrolled in Subgroups A and B are allowed provided IV onasemnogene abeparvovec was dosed per the approved label or per local/regional regulations.
- •Note: Other protocol defined Inclusion/Exclusion criteria may apply.
Arms & Interventions
Nusinersen 12 mg
Participants will receive Nusinersen 12 milligrams (mg) via intrathecal (IT) injection as loading doses on Days 1, 15, 29, and 64 followed by maintenance doses, every 4 months, on Days 183, 302, 421, 540 and 659.
Intervention: Nusinersen (Drug)
Outcomes
Primary Outcomes
Total Hammersmith Infant Neurological Examination (HINE) Section 2 Motor Milestones Score
Time Frame: Up to Day 778
Section 2 of the HINE is used to assess motor milestones of the participants. It is composed of 8 motor milestone categories: voluntary grasp (0 to 3), ability to kick in supine position (0 to 4), head control (0 to 2), rolling (0 to 3), sitting (0 to 4), crawling (0 to 4), standing (0 to 3), and walking (0 to 3). Total HINE score is the sum of points from each item and can range from 0 to 26, with higher scores depicting better level of ability.
Secondary Outcomes
- Number of Participants with Change from Baseline in Clinical Laboratory Parameters(Up to Day 778)
- Number of Participants with Adverse Events (AEs) and Serious Adverse Events (SAEs)(Up to Day 778)
- Number of Participants who Achieved Motor Milestones as Assessed by World Health Organization (WHO) Criteria(Up to Day 778)
- Number of Participants with Change from Baseline in Electrocardiograms (ECGs)(Up to Day 778)
- Number of Participants with Change from Baseline in Vital Signs(Up to Day 778)
- Change from Baseline in Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) Score(Up to Day 778)
- Time to Death or Permanent Ventilation(Up to Day 778)
- Change From Baseline in Cerebrospinal Fluid (CSF) Levels of Neurofilament Light Subunit (NF-L)(Up to Day 659)
- Change from Baseline in Hammersmith Functional Motor Scale - Expanded (HFMSE) Score(Up to Day 778)
- Change from Baseline in Revised Upper Limb Module (RULM) Score(Up to Day 778)
- Change From Baseline in Plasma Levels of NF-L(Up to Day 778)