A Study to Learn About the Effect of Higher Doses of Nusinersen (BIIB058) Given as Injections to Participants With Spinal Muscular Atrophy (SMA) Who Were Previously Treated With Risdiplam (ASCEND) (ASCEND)

A Phase 3b Study to Evaluate Higher Dose Nusinersen (BIIB058) in Patients With Spinal Muscular Atrophy Previously Treated With Risdiplam

In this study, researchers will learn more about the use of a higher dose of nusinersen (BIIB058) in participants with spinal muscular atrophy (SMA). This study will focus on teenagers and adults who are unable to walk on their own and who have previously taken another drug for SMA called risdiplam.

The main goal of this study is to learn about the effect of high dose (HD) nusinersen on muscle and movement ability (motor function) in SMA. The main question that researchers want to answer is:

- How do the scores of a movement test called the Revised Upper Limb Module change from the start of treatment?

The Revised Upper Limb Module is a test used to measure a participant's ability to do specific tasks that involve their shoulders, arms, wrist, elbows, and hands. It measures the changes in their abilities over time.

Researchers will also learn more about the safety of HD nusinersen. They will check participants for adverse events and changes in vital signs, heart tests, and laboratory tests including blood and urine tests.

The study will be done as follows:

• Participants will be screened to check if they can join the study.
• After screening, participants will enter the Core Treatment period.
• At the start of the Core Treatment period, they will receive 2 "loading" doses of nusinersen. These are 50 mg doses of nusinersen given 2 weeks apart.
• Afterwards, they will continue to receive "maintenance" doses of nusinersen once every 4 months. These doses will be 28 mg.
• The Core Treatment period will last about 2 years, with a follow-up visit 4 months after the last dose.
• Participants who complete the Core Treatment period will have the option to continue receiving 28 mg of nusinersen in the Long-Term Extension (LTE) period for about 2 years. There will also be a follow-up visit 4 months after the last dose.
• Nusinersen will be given through a lumbar puncture, which involves injecting the drug into the fluid around the spinal cord in the lower back.
• In total, participants will have up to 18 study visits. They will also be called by researchers after each dose of nusinersen.
• Participants will stay in the study for about 4.5 years if they complete both the Core Treatment and LTE periods.

Study Overview

• Status: Active, not recruiting
• Conditions: Spinal Muscular Atrophy
• Intervention / Treatment: Drug: Nusinersen

Detailed Description

The primary objective of this study is to evaluate motor function following treatment with HD nusinersen in participants with spinal muscular atrophy (SMA) previously treated with risdiplam.

The secondary objective of this study is to evaluate the safety and tolerability of HD nusinersen in participants with SMA previously treated with risdiplam.

• Study Type: Interventional
• Enrollment (Actual): 45
• Phase: Phase 3

Contacts and Locations

Study Locations

• Germany
  • Baden-Wurttemberg
    • Heidelberg, Baden-Wurttemberg, Germany, 69120
      • Universitaetsklinikum Heidelberg
    • Ulm, Baden-Wurttemberg, Germany, 89081
      • Universitaetsklinikum Ulm
  • Bavaria
    • Munich, Bavaria, Germany, 81675
      • Klinikum rechts der Isar der TU Muenchen
  • North Rhine-Westphalia
    • Essen, North Rhine-Westphalia, Germany, 45122
      • Universitaetsklinikum Essen
• Hungary
  • Budapest, Hungary, 1085
    • Semmelweis Egyetem
• Italy
  • Milan, Italy, 20133
    • Fondazione IRCCS Istituto Neurologico Carlo Besta
  • Milan, Italy, 20162
    • Fondazione Serena Onlus - Centro Clinico Nemo
  • Roma, Italy, 168
    • Fondazione Policlinico Universitario Agostino Gemelli IRCCS
  • Torino, Italy, 10126
    • Ospedale S G Battista Molinette
• Japan
  • Kanagawa
    • Yokohama, Kanagawa, Japan, 236-0004
      • Yokohama City University Hospital
  • Osaka
    • Toyonaka-shi, Osaka, Japan, 560-8552
      • NHO Osaka Toneyama Medical Center
• United States
  • Arizona
    • Phoenix, Arizona, United States, 85013
      • Barrow Neurological Institute
  • California
    • Palo Alto, California, United States, 94304
      • Stanford Neuroscience Health Center
  • Georgia
    • Atlanta, Georgia, United States, 30329
      • Rare Disease Research, LLC
  • Massachusetts
    • Boston, Massachusetts, United States, 02115-5724
      • Boston Children's Hospital
  • Michigan
    • Owosso, Michigan, United States, 48867
      • Memorial Healthcare
  • New York
    • New York, New York, United States, 10032
      • Columbia University
  • North Carolina
    • Winston-Salem, North Carolina, United States, 27157
      • Wake Forest University - School of Medicine - Central
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • University of Pennsylvania
  • Texas
    • Denton, Texas, United States, 76208
      • Neurology Rare Disease Center
    • Houston, Texas, United States, 77030
      • The University of Texas Health Science Center at Houston
  • Washington
    • Seattle, Washington, United States, 98195
      • University of Washington Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 15 years to 50 years (Child, Adult)
• Accepts Healthy Volunteers: No

Description

Key Inclusion Criteria:

• Genetic documentation of 5q SMA homozygous survival motor neuron-1 (SMN1) gene deletion or mutation or compound heterozygous mutation.
• Diagnosis of later-onset SMA with symptom onset at age >6 months.
• Aged ≥15 to ≤50 years at the time of informed consent
• Body weight >20 kg.

• Received oral risdiplam per the approved label or per the managed access program as follows

  1. Nusinersen-naive participants must have had prior treatment with risdiplam for ≥6 months before enrollment.
  2. Nusinersen-experienced participants must have stopped nusinersen for ≥16 months and must have been on risdiplam for ≥12 months before enrollment.
• Able to perform the age-appropriate functional assessments in the study.
• RULM entry item A score ≥3.
• RULM total score ≥5 and ≤30 at Screening.
• Nonambulatory, defined as not able to walk 15 feet (4.57 meters) independently without support.
• Willing to stop risdiplam treatment.
• Willing and able to start treatment with HD nusinersen.

Key Exclusion Criteria:

• Any major illness within 1 month before the screening examination or within 1 week prior to Screening and up to first dose administration.
• Presence of an untreated or inadequately treated active infection requiring systemic antiviral or antimicrobial therapy at any time during the Screening Period.
• Presence of an implanted shunt for the drainage of CSF or of an implanted central nervous system catheter.
• Permanent tracheostomy or permanent ventilation at Screening.
• The medical necessity, as defined by the Investigator, for noninvasive ventilation such as bilevel positive airway pressure or continuous positive airway pressure outside of regular sleep hours for any reason other than proactive SMA management, at Screening.
• History of bacterial meningitis, viral encephalitis, or hydrocephalus.
• Ongoing medical condition that according to the Investigator would interfere with the conduct and assessments of the study. An example is a medical disability (e.g., wasting or cachexia, severe anemia, and respiratory parameters) that would interfere with the assessment of safety or would compromise the ability of the participant to undergo study procedures.
• Participants who are pregnant or currently breastfeeding and those intending to become pregnant during the study.
• Treatment with an investigational drug, biological agent, or device within 30 days or 5 half-lives of the agent, whichever is longer, prior to Screening or anytime during the study; any prior or current treatment with gene therapy for the treatment of SMA.

NOTE: Other protocol defined Inclusion/Exclusion criteria may apply.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Higher Dose Nusinersen; All participants in the core study period, previously treated with risdiplam (nusinersen-naive participants and nusinersen-experienced participants), will receive HD nusinersen, administered as 2 loading doses of 50 milligrams (mg) each, approximately 2 weeks apart, followed by maintenance doses of 28 mg approximately every 4 months. Following the core study period, participants may be given the opportunity to receive maintenance doses of 28 mg nusinersen administered approximately every 4 months up to 2 years during the optional long-term extension (LTE) period.

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
Change in Total Revised Upper Limb Module (RULM) Score	The RULM is being utilized to assess upper limb functional abilities of 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 855

Secondary 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 that does not necessarily have a causal relationship with the 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 or 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 1695
Number of Participants With Change in Clinical Laboratory Parameters, Electrocardiogram (ECG), Vital Signs and Pulse Oximetry from Baseline		Up to Day 1695

Collaborators and Investigators

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

Publications and helpful links

Helpful Links

• Disclaimer: Residents in the United States may click here to find out more about participation in this trial.

Study record dates

Study Major Dates

• Study Start (Actual): January 21, 2022
• Primary Completion (Estimated): September 24, 2027
• Study Completion (Estimated): September 24, 2027

Study Registration Dates

• First Submitted: September 24, 2021
• First Submitted That Met QC Criteria: September 24, 2021
• First Posted (Actual): October 5, 2021

Study Record Updates

• Last Update Posted (Actual): May 22, 2026
• Last Update Submitted That Met QC Criteria: May 20, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Central Nervous System Diseases; Nervous System Diseases; Neuromuscular Diseases; Neurodegenerative Diseases; Spinal Cord Diseases; Motor Neuron Disease; Muscular Atrophy, Spinal; nusinersen
• Other Study ID Numbers: 232SM303; 2021-001294-23 (EudraCT Number); 2023-505639-11 (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