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

Muscular Atrophy, Spinal Clinical Trial

— RESPOND  

Official title:

A Phase 4 Study of Nusinersen (BIIB058) Among Patients With Spinal Muscular Atrophy Who Received Onasemnogene Abeparvovec

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT04488133
• Other study ID #: 232SM404
• Secondary ID: 2020-003492-1820
• Status: Active, not recruiting
• Phase: Phase 4
• Start date: January 4, 2021
• Est. completion date: October 7, 2025

Study information

• Verified date: December 2023
• Source: Biogen
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 46
• Est. completion date: October 7, 2025
• Est. primary completion date: October 7, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 2 Months to 36 Months

Eligibility

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.

Related Conditions & MeSH terms

• Atrophy
• Muscular Atrophy
• Muscular Atrophy, Spinal

Intervention

Drug:
• Nusinersen
Administered as specified in the treatment arm.

Locations

Country	Name	City	State
Germany	Universitaetsklinikum Hamburg-Eppendorf	Hamburg
Israel	Schneider Children's Medical Center	Petah Tikva
Italy	Fondazione IRCCS Istituto Neurologico Carlo Besta	Milano	Milan
Italy	Fondazione Policlinico Universitario Agostino Gemelli IRCCS	Roma
Spain	Hospital Sant Joan de Déu	Esplugues Del Llobregat	Barcelona
Spain	Hospital Universitario La paz	Madrid
United States	Children's Hospital Colorado	Aurora	Colorado
United States	Massachusetts General Hospital	Boston	Massachusetts
United States	Ann & Robert H. Lurie Children's Hospital of Chicago	Chicago	Illinois
United States	Arkansas Children's Hospital Research Institute	Little Rock	Arkansas
United States	Children's Hospital of The King's Daughters	Norfolk	Virginia
United States	Stanford Neuromuscular Research	Palo Alto	California
United States	Children's Hospital Philadelphia - Neurology	Philadelphia	Pennsylvania
United States	Oregon Health and Science University (OHSU)	Portland	Oregon
United States	University of Utah	Salt Lake City	Utah

Sponsors (1)

Lead Sponsor	Collaborator
Biogen

Countries where clinical trial is conducted

United States,  Germany,  Israel,  Italy,  Spain, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Total Hammersmith Infant Neurological Examination (HINE) Section 2 Motor Milestones 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 (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.	Up to Day 778
Secondary	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 or is a medically important event.	Up to Day 778
Secondary	Number of Participants with Change from Baseline in Clinical Laboratory Parameters		Up to Day 778
Secondary	Number of Participants with Change from Baseline in Electrocardiograms (ECGs)		Up to Day 778
Secondary	Number of Participants with Change from Baseline in Vital Signs		Up to Day 778
Secondary	Number of Participants who Achieved Motor Milestones as Assessed by World Health Organization (WHO) Criteria	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.	Up to Day 778
Secondary	Change from Baseline in Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) 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. The total score ranges from 0-64, with higher scores depicting better response.	Up to Day 778
Secondary	Change from Baseline in Hammersmith Functional Motor Scale - Expanded (HFMSE) Score	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.	Up to Day 778
Secondary	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. The RULM is scored from 0 to 37 points, with higher scores indicating better function.	Up to Day 778
Secondary	Time to Death or Permanent Ventilation	Permanent ventilation is defined as tracheostomy or =16 hours ventilation/day continuously for >21 days in the absence of an acute reversible event.	Up to Day 778
Secondary	Change From Baseline in Cerebrospinal Fluid (CSF) Levels of Neurofilament Light Subunit (NF-L)		Up to Day 659
Secondary	Change From Baseline in Plasma Levels of NF-L		Up to Day 778

External Links

•   Biogen Trial Link
•   Child Neurology Foundation
•   CureSMA
•   Muscular Dystrophy Association
•   SMA Europe