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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT04488133
Recruitment Status : Active, not recruiting
First Posted : July 27, 2020
Last Update Posted : December 20, 2023
Information provided by (Responsible Party):

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.

Condition or disease Intervention/treatment Phase
Muscular Atrophy, Spinal Drug: Nusinersen Phase 4

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 46 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 4 Study of Nusinersen (BIIB058) Among Patients With Spinal Muscular Atrophy Who Received Onasemnogene Abeparvovec
Actual Study Start Date : January 4, 2021
Estimated Primary Completion Date : October 7, 2025
Estimated Study Completion Date : October 7, 2025

Arm Intervention/treatment
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.
Drug: Nusinersen
Administered as specified in the treatment arm.
Other Names:
  • ISIS 396443
  • BIIB058
  • Spinraza

Primary Outcome Measures :
  1. 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 Outcome Measures :
  1. 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.

  2. Number of Participants with Change from Baseline in Clinical Laboratory Parameters [ Time Frame: Up to Day 778 ]
  3. Number of Participants with Change from Baseline in Electrocardiograms (ECGs) [ Time Frame: Up to Day 778 ]
  4. Number of Participants with Change from Baseline in Vital Signs [ Time Frame: Up to Day 778 ]
  5. 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.

  6. 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.

  7. 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.

  8. 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.

  9. 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.

  10. Change From Baseline in Cerebrospinal Fluid (CSF) Levels of Neurofilament Light Subunit (NF-L) [ Time Frame: Up to Day 659 ]
  11. Change From Baseline in Plasma Levels of NF-L [ Time Frame: Up to Day 778 ]

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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Ages Eligible for Study:   2 Months to 36 Months   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT04488133

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United States, Arkansas
Arkansas Children's Hospital Research Institute
Little Rock, Arkansas, United States, 72202
United States, California
Stanford Neuromuscular Research
Palo Alto, California, United States, 94304
United States, Colorado
Children's Hospital Colorado
Aurora, Colorado, United States, 80045
United States, Illinois
Ann & Robert H. Lurie Children's Hospital of Chicago
Chicago, Illinois, United States, 60611
United States, Massachusetts
Massachusetts General Hospital
Boston, Massachusetts, United States, 02114
United States, Oregon
Oregon Health and Science University (OHSU)
Portland, Oregon, United States, 97239
United States, Pennsylvania
Children's Hospital Philadelphia - Neurology
Philadelphia, Pennsylvania, United States, 19104
United States, Utah
University of Utah
Salt Lake City, Utah, United States, 84112
United States, Virginia
Children's Hospital of The King's Daughters
Norfolk, Virginia, United States, 23510
Universitaetsklinikum Hamburg-Eppendorf
Hamburg, Germany, 20246
Schneider Children's Medical Center
Petah Tikva, Israel, 4920235
Fondazione IRCCS Istituto Neurologico Carlo Besta
Milano, Milan, Italy, 20133
Fondazione Policlinico Universitario Agostino Gemelli IRCCS
Roma, Italy, 00168
Hospital Sant Joan de Déu
Esplugues Del Llobregat, Barcelona, Spain, 08950
Hospital Universitario La paz
Madrid, Spain, 28046
Sponsors and Collaborators
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Study Director: Medical Director Biogen
Additional Information:
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Responsible Party: Biogen Identifier: NCT04488133    
Other Study ID Numbers: 232SM404
2020-003492-18 ( EudraCT Number )
2023-505640-18 ( Other Identifier: EU Trial Number )
First Posted: July 27, 2020    Key Record Dates
Last Update Posted: December 20, 2023
Last Verified: December 2023
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: In accordance with Biogen's Clinical Trial Transparency and Data Sharing Policy on

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Muscular Atrophy
Muscular Atrophy, Spinal
Pathological Conditions, Anatomical
Neuromuscular Manifestations
Neurologic Manifestations
Nervous System Diseases
Spinal Cord Diseases
Central Nervous System Diseases
Motor Neuron Disease
Neurodegenerative Diseases
Neuromuscular Diseases