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

Primary Purpose

Muscular Atrophy, Spinal

Status
Active
Phase
Phase 4
Locations
International
Study Type
Interventional
Intervention
Nusinersen
Sponsored by
Biogen
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Muscular Atrophy, Spinal

Eligibility Criteria

2 Months - 36 Months (Child)All SexesDoes not accept healthy volunteers

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:

  • ≤9 months of age (270 days) 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.

Sites / Locations

  • Arkansas Children's Hospital Research Institute
  • Stanford Neuromuscular Research
  • Children's Hospital Colorado
  • Ann & Robert H. Lurie Children's Hospital of Chicago
  • Massachusetts General Hospital
  • Oregon Health and Science University (OHSU)
  • Children's Hospital Philadelphia - Neurology
  • University of Utah
  • Children's Hospital of The King's Daughters
  • Universitaetsklinikum Hamburg-Eppendorf
  • Schneider Children's Medical Center
  • Fondazione IRCCS Istituto Neurologico Carlo Besta
  • Fondazione Policlinico Universitario Agostino Gemelli IRCCS
  • Hospital Sant Joan de Déu
  • Hospital Universitario La paz

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Nusinersen 12 mg

Arm Description

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.

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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.
Number of Participants with Change from Baseline in Clinical Laboratory Parameters
Number of Participants with Change from Baseline in Electrocardiograms (ECGs)
Number of Participants with Change from Baseline in Vital Signs
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.
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.
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.
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.
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.

Full Information

First Posted
July 20, 2020
Last Updated
October 16, 2023
Sponsor
Biogen
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1. Study Identification

Unique Protocol Identification Number
NCT04488133
Brief Title
A Study of Nusinersen Among Participants With Spinal Muscular Atrophy Who Received Onasemnogene Abeparvovec
Acronym
RESPOND
Official Title
A Phase 4 Study of Nusinersen (BIIB058) Among Patients With Spinal Muscular Atrophy Who Received Onasemnogene Abeparvovec
Study Type
Interventional

2. Study Status

Record Verification Date
October 2023
Overall Recruitment Status
Active, not recruiting
Study Start Date
January 4, 2021 (Actual)
Primary Completion Date
October 7, 2025 (Anticipated)
Study Completion Date
October 7, 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Biogen

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

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; and clinical outcomes following treatment with Nusinersen in participants with SMA who previously received onasemnogene abeparvovec.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Muscular Atrophy, Spinal

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 4
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
46 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Nusinersen 12 mg
Arm Type
Experimental
Arm Description
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 Type
Drug
Intervention Name(s)
Nusinersen
Other Intervention Name(s)
ISIS 396443, BIIB058, Spinraza
Intervention Description
Administered as specified in the treatment arm.
Primary Outcome Measure Information:
Title
Total Hammersmith Infant Neurological Examination (HINE) Section 2 Motor Milestones Score
Description
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.
Time Frame
Up to Day 778
Secondary Outcome Measure Information:
Title
Number of Participants with Adverse Events (AEs) and Serious Adverse Events (SAEs)
Description
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.
Time Frame
Up to Day 778
Title
Number of Participants with Change from Baseline in Clinical Laboratory Parameters
Time Frame
Up to Day 778
Title
Number of Participants with Change from Baseline in Electrocardiograms (ECGs)
Time Frame
Up to Day 778
Title
Number of Participants with Change from Baseline in Vital Signs
Time Frame
Up to Day 778
Title
Number of Participants who Achieved Motor Milestones as Assessed by World Health Organization (WHO) Criteria
Description
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.
Time Frame
Up to Day 778
Title
Change from Baseline in Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) Score
Description
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.
Time Frame
Up to Day 778
Title
Change from Baseline in Hammersmith Functional Motor Scale - Expanded (HFMSE) Score
Description
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.
Time Frame
Up to Day 778
Title
Change from Baseline in Revised Upper Limb Module (RULM) Score
Description
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 Frame
Up to Day 778
Title
Time to Death or Permanent Ventilation
Description
Permanent ventilation is defined as tracheostomy or ≥16 hours ventilation/day continuously for >21 days in the absence of an acute reversible event.
Time Frame
Up to Day 778

10. Eligibility

Sex
All
Minimum Age & Unit of Time
2 Months
Maximum Age & Unit of Time
36 Months
Accepts Healthy Volunteers
No
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: ≤9 months of age (270 days) 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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Medical Director
Organizational Affiliation
Biogen
Official's Role
Study Director
Facility Information:
Facility Name
Arkansas Children's Hospital Research Institute
City
Little Rock
State/Province
Arkansas
ZIP/Postal Code
72202
Country
United States
Facility Name
Stanford Neuromuscular Research
City
Palo Alto
State/Province
California
ZIP/Postal Code
94304
Country
United States
Facility Name
Children's Hospital Colorado
City
Aurora
State/Province
Colorado
ZIP/Postal Code
80045
Country
United States
Facility Name
Ann & Robert H. Lurie Children's Hospital of Chicago
City
Chicago
State/Province
Illinois
ZIP/Postal Code
60611
Country
United States
Facility Name
Massachusetts General Hospital
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02114
Country
United States
Facility Name
Oregon Health and Science University (OHSU)
City
Portland
State/Province
Oregon
ZIP/Postal Code
97239
Country
United States
Facility Name
Children's Hospital Philadelphia - Neurology
City
Philadelphia
State/Province
Pennsylvania
ZIP/Postal Code
19104
Country
United States
Facility Name
University of Utah
City
Salt Lake City
State/Province
Utah
ZIP/Postal Code
84112
Country
United States
Facility Name
Children's Hospital of The King's Daughters
City
Norfolk
State/Province
Virginia
ZIP/Postal Code
23510
Country
United States
Facility Name
Universitaetsklinikum Hamburg-Eppendorf
City
Hamburg
ZIP/Postal Code
20246
Country
Germany
Facility Name
Schneider Children's Medical Center
City
Petah Tikva
ZIP/Postal Code
4920235
Country
Israel
Facility Name
Fondazione IRCCS Istituto Neurologico Carlo Besta
City
Milano
State/Province
Milan
ZIP/Postal Code
20133
Country
Italy
Facility Name
Fondazione Policlinico Universitario Agostino Gemelli IRCCS
City
Roma
ZIP/Postal Code
00168
Country
Italy
Facility Name
Hospital Sant Joan de Déu
City
Esplugues Del Llobregat
State/Province
Barcelona
ZIP/Postal Code
08950
Country
Spain
Facility Name
Hospital Universitario La paz
City
Madrid
ZIP/Postal Code
28046
Country
Spain

12. IPD Sharing Statement

Plan to Share IPD
Yes
IPD Sharing Plan Description
In accordance with Biogen's Clinical Trial Transparency and Data Sharing Policy on http://clinicalresearch.biogen.com/
IPD Sharing URL
https://vivli.org/
Links:
URL
https://www.sma-europe.eu/
Description
SMA Europe
URL
https://www.curesma.org/
Description
CureSMA
URL
https://www.mda.org/disease/spinal-muscular-atrophy
Description
Muscular Dystrophy Association
URL
https://www.childneurologyfoundation.org/
Description
Child Neurology Foundation
URL
https://www.biogentriallink.com/en-us/home.html
Description
Biogen Trial Link

Learn more about this trial

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

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