A Study of Nusinersen Among Participants With Spinal Muscular Atrophy Who Received Onasemnogene Abeparvovec (RESPOND)

• ClinicalTrials.gov Identifier: NCT04488133
• Recruitment Status: Active, not recruiting
• First Posted: July 27, 2020
• Last Update Posted: December 20, 2023
• Sponsor: Biogen
• Information provided by (Responsible Party): Biogen

Tracking Information

• First Submitted Date: July 20, 2020
• First Posted Date: July 27, 2020
• Last Update Posted Date: December 20, 2023
• Actual Study Start Date: January 4, 2021
• Estimated Primary Completion Date: October 7, 2025 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: July 24, 2020)

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.

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: December 14, 2023)

• Number of Participants with Adverse Events (AEs) and Serious Adverse Events (SAEs) [ Time Frame: Up to Day 778 ]
  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 or is a medically important event.
• Number of Participants with Change from Baseline in Clinical Laboratory Parameters [ Time Frame: Up to Day 778 ]
• Number of Participants with Change from Baseline in Electrocardiograms (ECGs) [ Time Frame: Up to Day 778 ]
• Number of Participants with Change from Baseline in Vital Signs [ Time Frame: Up to Day 778 ]
• Number of Participants who Achieved Motor Milestones as Assessed by World Health Organization (WHO) Criteria [ Time Frame: Up to Day 778 ]
  The motor milestones as defined by WHO criteria includes the following six test items: sitting without support, hands-and-knees crawling, standing with assistance, walking with assistance, standing alone, and walking alone.
• Change from Baseline in Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) Score [ Time Frame: Up to Day 778 ]
  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. The total score ranges from 0-64, with higher scores depicting better response.
• Change from Baseline in Hammersmith Functional Motor Scale - Expanded (HFMSE) Score [ Time Frame: Up to Day 778 ]
  The HFMSE is a tool used to assess motor function in children with SMA. The original 20 item Hammersmith Functional Motor Scale (HFMS) was expanded to include 13 additional items to improve sensitivity for the higher functioning ambulant population. Participants will be asked to complete a specific movement and are then graded on the quality and execution of that movement. Higher scores indicate higher levels of motor ability. The overall score is the sum of the scores for all activities, with a maximum score of 66 with higher scores depicting better ability to perform activities.
• Change from Baseline in Revised Upper Limb Module (RULM) Score [ Time Frame: Up to Day 778 ]
  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. The RULM is scored from 0 to 37 points, with higher scores indicating better function.
• Time to Death or Permanent Ventilation [ Time Frame: Up to Day 778 ]
  Permanent ventilation is defined as tracheostomy or ≥16 hours ventilation/day continuously for >21 days in the absence of an acute reversible event.
• Change From Baseline in Cerebrospinal Fluid (CSF) Levels of Neurofilament Light Subunit (NF-L) [ Time Frame: Up to Day 659 ]
• Change From Baseline in Plasma Levels of NF-L [ Time Frame: Up to Day 778 ]

Original Secondary Outcome Measures (submitted: July 24, 2020)

• Number of Participants with Adverse Events (AEs) and Serious Adverse Events (SAEs) [ Time Frame: Up to Day 778 ]
  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.
• Number of Participants with Change from Baseline in Clinical Laboratory Parameters [ Time Frame: Up to Day 778 ]
• Number of Participants with Change from Baseline in Electrocardiograms (ECGs) [ Time Frame: Up to Day 778 ]
• Number of Participants with Change from Baseline in Vital Signs [ Time Frame: Up to Day 778 ]
• Number of Participants who Achieved Motor Milestones as Assessed by World Health Organization (WHO) Criteria [ Time Frame: Up to Day 778 ]
  The motor milestones as defined by WHO criteria includes the following six test items: sitting without support, hands-and-knees crawling, standing with assistance, walking with assistance, standing alone, and walking alone.
• Change from Baseline in Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) Score [ Time Frame: Up to Day 778 ]
  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. The total score ranges from 0-64, with higher scores depicting better response.
• Change from Baseline in Hammersmith Functional Motor Scale - Expanded (HFMSE) Score [ Time Frame: Up to Day 778 ]
  The HFMSE is a tool used to assess motor function in children with SMA. The original 20 item Hammersmith Functional Motor Scale (HFMS) was expanded to include 13 additional items to improve sensitivity for the higher functioning ambulant population. Participants will be asked to complete a specific movement and are then graded on the quality and execution of that movement. Higher scores indicate higher levels of motor ability. The overall score is the sum of the scores for all activities, with a maximum score of 66 with higher scores depicting better ability to perform activities.
• Change from Baseline in Revised Upper Limb Module (RULM) Score [ Time Frame: Up to Day 778 ]
  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. The RULM is scored from 0 to 37 points, with higher scores indicating better function.
• Time to Death or Permanent Ventilation [ Time Frame: Up to Day 778 ]
  Permanent ventilation is defined as tracheostomy or ≥16 hours ventilation/day continuously for >21 days in the absence of an acute reversible event.

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

Descriptive Information

• Brief Title: A Study of Nusinersen Among Participants With Spinal Muscular Atrophy Who Received Onasemnogene Abeparvovec
• Official Title: A Phase 4 Study of Nusinersen (BIIB058) Among Patients With Spinal Muscular Atrophy Who Received Onasemnogene Abeparvovec

Brief Summary

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.

• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 4
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Muscular Atrophy, Spinal

Intervention

Drug: Nusinersen

Administered as specified in the treatment arm.

Other Names:

• ISIS 396443
• BIIB058
• Spinraza

Study Arms

Experimental: 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: Drug: Nusinersen

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: September 15, 2023): 46
• Original Estimated Enrollment (submitted: July 24, 2020): 60
• Estimated Study Completion Date: October 7, 2025
• Estimated Primary Completion Date: October 7, 2025 (Final data collection date for primary outcome measure)

Eligibility Criteria

Key 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

Key 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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 2 Months to 36 Months (Child)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Germany, Israel, Italy, Spain, United States
• Removed Location Countries: Japan

Administrative Information

• NCT Number: NCT04488133
• Other Study ID Numbers: 232SM404; 2020-003492-18 ( EudraCT Number ); 2023-505640-18 ( Other Identifier: EU Trial 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 http://clinicalresearch.biogen.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: December 2023