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

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

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).

Study Overview

• Status: Enrolling by invitation
• Conditions: Muscular Atrophy, Spinal
• Intervention / Treatment: Drug: Nusinersen

• Study Type: Interventional
• Enrollment (Estimated): 145
• Phase: Phase 3

Expanded Access

No longer available outside the clinical trial. See expanded access record.

Contacts and Locations

Study Locations

• Brazil
  • Porto Alegre, Brazil, 90035-903
    • Hospital de Clinicas de Porto Alegre
  • São Paulo, Brazil, 5403900
    • Hospital das Clinicas - FMUSP
• Canada
  • Ontario
    • London, Ontario, Canada, N6A 5W9
      • London Health Sciences Centre (LHSC) - Children's Hospital
• Chile
  • Santiago, Chile, 7500539
    • Hospital Luis Calvo Mackenna
  • Santiago, Chile, 7550000
    • Clinica Las Condes
  • Santiago, Chile, 7691236
    • Clinica MEDS La Dehesa
• China
  • Guangdong
    • Guangzhou, Guangdong, China, 510623
      • Guangzhou Woman and Children's Medical Center
  • Zhejiang
    • Hangzhou, Zhejiang, China, 310052
      • The Children's Hospital of Zhejiang University School of Medicine
• Colombia
  • Bogota, Colombia, 110231
    • Hospital Universitario San Ignacio
• Estonia
  • Tallinn, Estonia, 13419
    • Tallinn Children's Hospital
• Germany
  • Baden Wuerttemberg
    • Freiburg, Baden Wuerttemberg, Germany, 79106
      • Universitaetsklinikum Freiburg
  • Hessen
    • Giessen, Hessen, Germany, 35392
      • Universitaetsklinikum Giessen und Marburg GmbH
• Italy
  • Milano, Italy, 20162
    • Fondazione Serena Onlus - Centro Clinico Nemo
  • Roma, Italy, 168
    • Fondazione Policlinico Universitario Agostino Gemelli IRCCS
• Japan
  • Fukuoka-Ken
    • Kurume-shi, Fukuoka-Ken, Japan, 830-0011
      • Kurume University Hospital
  • Hyogo-Ken
    • Nishinomiya-shi, Hyogo-Ken, Japan, 663-8501
      • Hyogo Medical University Hospital
  • Tokyo-To
    • Shinjuku-ku, Tokyo-To, Japan, 162-8666
      • Tokyo Women's Medical University Hospital
• Lebanon
  • Beirut, Lebanon, 11 00 2807
    • Saint George University Hospital Medical Center
• Mexico
  • Guadalajara, Mexico, 44280
    • Antiguo Hospital Civil de Guadalajara Fray Antonio Alcalde
  • Distrito Federal
    • Mexico, Distrito Federal, Mexico, 4530
      • Instituto Nacional de Pediatria
    • Mexico, Distrito Federal, Mexico, 6720
      • Hospital Infantil de Mexico Federico Gomez
• Poland
  • Warszawa, Poland, 04-730
    • Instytut 'Pomnik - Centrum Zdrowia Dziecka'
• Russian Federation
  • Ekaterinburg, Russian Federation, 620149
    • Regional Pediatric Clinical Hospital #1
  • Moskva, Russian Federation, 125412
    • Russian Children Neuromuscular Center of Veltischev
• Saudi Arabia
  • Dammam, Saudi Arabia, 31444
    • King Fahad Specialist Hospital
  • Jeddah, Saudi Arabia, 21423
    • National Guard Health Affairs: King Abdulaziz Medical City
  • Riyadh, Saudi Arabia, 11211
    • King Faisal Specialist Hospital & Research Center
• Spain
  • Madrid, Spain, 28046
    • Hospital Universitario La Paz
  • Valencia, Spain, 46026
    • Hospital Universitari i Politecnic La Fe
• Taiwan
  • Kaohsiung, Taiwan, 807
    • Kaohsiung Medical University Chung-Ho Memorial Hospital
  • Taipei, Taiwan, 100
    • National Taiwan University Hospital
• United States
  • California
    • Sacramento, California, United States, 94304
      • Stanford University Medical Center
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Children's Hospital Colorado
  • Illinois
    • Chicago, Illinois, United States, 60611-260
      • Ann & Robert H. Lurie Children's Hospital of Chicago
  • Maryland
    • Baltimore, Maryland, United States, 21205
      • The Johns Hopkins Hospital
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Boston Children's Hospital
  • Tennessee
    • Memphis, Tennessee, United States, 38105
      • St. Jude Children's Research Hospital
  • Texas
    • Plano, Texas, United States, 75024
      • Children's Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / 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: Spinraza; BIIB058
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: Spinraza; BIIB058

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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, 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 1921
Change from Baseline in Growth Parameters	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.	Up to Day 1921
Number of Participants With Shifts from Baseline in Clinical Laboratory Parameters		Up to Day 1921
Number of Participants With Shifts from Baseline in Electrocardiogram (ECG)		Up to Day 1921
Number of Participants With Shifts from Baseline in Vital Signs		Up to Day 1921
Change from Baseline in Activated Partial Thromboplastin Time (aPTT)		Up to Day 1921
Change from Baseline in Prothrombin Time (PT)		Up to Day 1921
Change from Baseline in International Normalized Ratio (INR)		Up to Day 1921
Change from Baseline in Urine Total Protein		Up to Day 1921
Change from Baseline in Neurological Examination Outcomes for Participants ≤2 Years of Age	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.	Up to Day 1921
Number of Participants with Change from Baseline in Neurological Examination Outcomes for Participants >2 Years of Age	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.	Up to Day 1921
Percentage of Participants With a Postbaseline Platelet Count Below the Lower Limit of Normal on at least 2 Consecutive Measurements		Up to Day 1921
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		Up toDay 1921

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Total Number of New World Health Organization (WHO) Motor Milestones		Up to Day 1921
Number of Participants Who Used Respiratory Support, by Type		Up to Day 1921
Number of Hours Per Day of Respiratory Support		Up to Day 1921
Number of Days That Respiratory Support Is Used		Up to Day 1921
Time to Death (Overall Survival)		Up to Day 1921
Change from Baseline in Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) Total 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. This outcome measure will be assessed for participants who were evaluated with this measure in study 232SM203 (NCT04089566).	Up to Day 1921
Change from Baseline in Hammersmith Infant Neurological Examination (HINE) Section 2 Motor Milestones	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).	Up to Day 1921
Percentage of HINE Section 2 Motor Milestone Responders	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).	Up to Day 1921
Percentage of Time Spent on Ventilation	This outcome measure will be assessed for participants who were evaluated with this measure in study 232SM203 (NCT04089566).	Up to Day 1921
Time to Death or Permanent Ventilation	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).	Up to Day 1921
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. Participants ≥ 2 years of age (at the time of the study visit) will be evaluated with HFMSE.	Up to Day 1921
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. Participants ≥ 2 years of age (at the time of the study visit) will be evaluated with RULM.	Up to Day 1921
Change From Baseline in Plasma Levels of Neurofilament (NF)		Up to Day 1921

Collaborators and Investigators

• Sponsor: Biogen
• Investigators: Study Director: Medical Director, Biogen

Publications and helpful links

Helpful Links

• SMA Europe
• CureSMA
• Muscular Dystrophy Association

Study record dates

Study Major Dates

• Study Start (Actual): April 19, 2021
• Primary Completion (Estimated): July 31, 2026
• Study Completion (Estimated): July 31, 2026

Study Registration Dates

• First Submitted: December 11, 2020
• First Submitted That Met QC Criteria: January 27, 2021
• First Posted (Actual): January 29, 2021

Study Record Updates

• Last Update Posted (Actual): March 15, 2024
• Last Update Submitted That Met QC Criteria: March 13, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Central Nervous System Diseases; Nervous System Diseases; Neurologic Manifestations; Neuromuscular Diseases; Neurodegenerative Diseases; Neuromuscular Manifestations; Pathological Conditions, Anatomical; Spinal Cord Diseases; Motor Neuron Disease; Muscular Atrophy; Atrophy; Muscular Atrophy, Spinal
• Other Study ID Numbers: 232SM302; 2023-505637-27 (Other Identifier: EU CTIS)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: In accordance with Biogen's Clinical Trial Transparency and Data Sharing Policy on https://www.biogentrialtransparency.com/

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No