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Extension Study of Nusinersen (BIIB058) in Participants With Spinal Muscular Atrophy Who Previously Participated in a Study With Nusinersen (ONWARD)

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ClinicalTrials.gov Identifier: NCT04729907
Recruitment Status : Enrolling by invitation
First Posted : January 29, 2021
Last Update Posted : March 15, 2024
Sponsor:
Information provided by (Responsible Party):
Biogen

Brief Summary:

The primary objective of this study is to evaluate the long-term safety and tolerability of nusinersen administered intrathecally at higher doses to participants with spinal muscular atrophy (SMA) who previously participated in study 232SM203 (NCT04089566).

The secondary objective of this study is to evaluate the long-term efficacy of nusinersen administered intrathecally at higher doses to participants with SMA who previously participated in study 232SM203 (NCT04089566).


Condition or disease Intervention/treatment Phase
Muscular Atrophy, Spinal Drug: Nusinersen Phase 3

Expanded Access : An investigational treatment associated with this study is no longer available outside the clinical trial.   More info ...

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 145 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Long-Term Extension Study of Nusinersen (BIIB058) Administered at Higher Doses in Participants With Spinal Muscular Atrophy Who Previously Participated in an Investigational Study With Nusinersen
Actual Study Start Date : April 19, 2021
Estimated Primary Completion Date : July 31, 2026
Estimated Study Completion Date : July 31, 2026


Arm Intervention/treatment
Experimental: BIIB058 28 mg (Prior Maintenance Dose 28 mg)
Participants who received maintenance dose of 28 milligrams (mg) nusinersen in study 232SM203 (NCT04089566), will receive maintenance dose of 28 mg nusinersen, by intrathecal injection, on Day 1, followed by maintenance dose of 28 mg nusinersen, by intrathecal injection, every 4 months, up to Day 1921.
Drug: Nusinersen
Administered as specified in the treatment arm
Other Names:
  • BIIB058
  • Spinraza

Experimental: BIIB058 50/28 mg (Prior Maintenance Dose 12 mg)
Participants who received maintenance dose of 12 mg nusinersen in study 232SM203 (NCT04089566), will receive loading dose of 50 mg nusinersen, by intrathecal injection, on Day 1, followed by maintenance dose of 28 mg nusinersen, by intrathecal injection, every 4 months, up to Day 1921.
Drug: Nusinersen
Administered as specified in the treatment arm
Other Names:
  • BIIB058
  • Spinraza




Primary Outcome Measures :
  1. Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) [ Time Frame: Up to Day 1921 ]
    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, 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. Change from Baseline in Growth Parameters [ Time Frame: Up to Day 1921 ]
    Growth parameters will be assessed by measuring body length or height (if feasible and appropriate), ulnar length (all participants), and head circumference, chest circumference, and arm circumference (all participants 3 years of age and younger) in centimeters.

  3. Number of Participants With Shifts from Baseline in Clinical Laboratory Parameters [ Time Frame: Up to Day 1921 ]
  4. Number of Participants With Shifts from Baseline in Electrocardiogram (ECG) [ Time Frame: Up to Day 1921 ]
  5. Number of Participants With Shifts from Baseline in Vital Signs [ Time Frame: Up to Day 1921 ]
  6. Change from Baseline in Activated Partial Thromboplastin Time (aPTT) [ Time Frame: Up to Day 1921 ]
  7. Change from Baseline in Prothrombin Time (PT) [ Time Frame: Up to Day 1921 ]
  8. Change from Baseline in International Normalized Ratio (INR) [ Time Frame: Up to Day 1921 ]
  9. Change from Baseline in Urine Total Protein [ Time Frame: Up to Day 1921 ]
  10. Change from Baseline in Neurological Examination Outcomes for Participants ≤2 Years of Age [ Time Frame: Up to Day 1921 ]
    For participants 2 years of age and younger, the Hammersmith Infant Neurological Exam (HINE) Sections 1 and 3 will be conducted. This standard examination (developed by [Dubowitz and Dubowitz 1981]) is a quantitative scorable method for assessing the neurological development of infants between 2 and 24 months of age. The examination includes assessment of cranial nerve functions, posture, movements, tone, and reflexes. The HINE Section 1 form utilized in ONWARD contains 26 items and the Section 3 form utilized contains 3 items. For HINE Section 1 items, each item is scored 0-3. For HINE Section 3 items, scoring is variable (1-4, 1-5, or 1-6). Higher scores indicate better neurological function.

  11. Number of Participants with Change from Baseline in Neurological Examination Outcomes for Participants >2 Years of Age [ Time Frame: Up to Day 1921 ]
    For all participants >2 years of age, standard neurological examinations, which include assessments of mental status, level of consciousness, sensory function, motor function, cranial nerve function, and reflexes, will be conducted.

  12. Percentage of Participants With a Postbaseline Platelet Count Below the Lower Limit of Normal on at least 2 Consecutive Measurements [ Time Frame: Up to Day 1921 ]
  13. Percentage of Participants With a Postbaseline Corrected QT Interval Using Fridericia's Formula (QTcF) of >500 millisecond (msec) and an Increase from Baseline to Any Postbaseline Timepoint in QTcF of >60 msec [ Time Frame: Up toDay 1921 ]

Secondary Outcome Measures :
  1. Total Number of New World Health Organization (WHO) Motor Milestones [ Time Frame: Up to Day 1921 ]
  2. Number of Participants Who Used Respiratory Support, by Type [ Time Frame: Up to Day 1921 ]
  3. Number of Hours Per Day of Respiratory Support [ Time Frame: Up to Day 1921 ]
  4. Number of Days That Respiratory Support Is Used [ Time Frame: Up to Day 1921 ]
  5. Time to Death (Overall Survival) [ Time Frame: Up to Day 1921 ]
  6. Change from Baseline in Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) Total Score [ Time Frame: Up to Day 1921 ]
    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. This outcome measure will be assessed for participants who were evaluated with this measure in study 232SM203 (NCT04089566).

  7. Change from Baseline in Hammersmith Infant Neurological Examination (HINE) Section 2 Motor Milestones [ Time Frame: Up to Day 1921 ]
    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. This outcome measure will be assessed for participants who were evaluated with this measure in study 232SM203 (NCT04089566).

  8. Percentage of HINE Section 2 Motor Milestone Responders [ Time Frame: Up to Day 1921 ]
    Section 2 of HINE is used to assess motor milestones of 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 sum of points from each item and can range from 0 to 26, with higher scores depicting better level of ability. HINE section 2 motor milestone responder is participant who demonstrates at least 2-point increase in category of ability to kick or increase to maximal score on that category or 1-point increase in motor milestones category of head control, rolling, sitting, crawling, standing, or walking, and among 7 motor milestone categories (excluding voluntary grasp), participant demonstrates improvement in more categories than worsening. This outcome measure will be assessed for participants who were evaluated with this measure in study 232SM203 (NCT04089566).

  9. Percentage of Time Spent on Ventilation [ Time Frame: Up to Day 1921 ]
    This outcome measure will be assessed for participants who were evaluated with this measure in study 232SM203 (NCT04089566).

  10. Time to Death or Permanent Ventilation [ Time Frame: Up to Day 1921 ]
    Permanent ventilation is defined as tracheostomy or ≥16 hours of ventilation/day continuously for >21 days in the absence of an acute reversible event. This outcome measure will be assessed for participants who were evaluated with this measure in study 232SM203 (NCT04089566).

  11. Change from Baseline in Hammersmith Functional Motor Scale - Expanded (HFMSE) Score [ Time Frame: Up to Day 1921 ]
    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. Participants ≥ 2 years of age (at the time of the study visit) will be evaluated with HFMSE.

  12. Change from Baseline in Revised Upper Limb Module (RULM) Score [ Time Frame: Up to Day 1921 ]
    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. Participants ≥ 2 years of age (at the time of the study visit) will be evaluated with RULM.

  13. Change From Baseline in Plasma Levels of Neurofilament (NF) [ Time Frame: Up to Day 1921 ]


Information from the National Library of Medicine

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Ages Eligible for Study:   Child, Adult, Older Adult
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Key Inclusion Criteria:

  • Completed the Day 302 visit in study 232SM203 (NCT04089566) in accordance with the study protocol

Key Exclusion Criteria:

  • Treatment with another investigational therapy or enrollment in another interventional clinical study
  • Treatment with an approved therapy for SMA after the Day 302 Visit of Study 232SM203 (NCT04089566)

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 ClinicalTrials.gov identifier (NCT number): NCT04729907


Locations
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Sponsors and Collaborators
Biogen
Investigators
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Study Director: Medical Director Biogen
Additional Information:
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Responsible Party: Biogen
ClinicalTrials.gov Identifier: NCT04729907    
Other Study ID Numbers: 232SM302
2023-505637-27 ( Other Identifier: EU CTIS )
First Posted: January 29, 2021    Key Record Dates
Last Update Posted: March 15, 2024
Last Verified: March 2024
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 https://www.biogentrialtransparency.com/
URL: https://vivli.org/

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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
Atrophy
Pathological Conditions, Anatomical
Neuromuscular Manifestations
Neurologic Manifestations
Nervous System Diseases
Spinal Cord Diseases
Central Nervous System Diseases
Motor Neuron Disease
Neurodegenerative Diseases
Neuromuscular Diseases