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) (NCT05067790) — USA Trial Details

Condition(s) studied

Spinal Muscular Atrophy

Investigational drug(s) / intervention(s)

Nusinersen

Nusinersen: Administered as specified in the treatment arm

Study summary

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.

Eligibility

Sex

ALL

Min age

15 Years

Max age

50 Years

Healthy volunteers

No

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.

Primary outcome measure(s)

Change in Total Revised Upper Limb Module (RULM) Score — Up to Day 855
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.

Trial sites (22)

Facility	City	Region
Barrow Neurological Institute	Phoenix	Arizona
Stanford Neuroscience Health Center	Palo Alto	California
Rare Disease Research, LLC	Atlanta	Georgia
Boston Children's Hospital	Boston	Massachusetts
Memorial Healthcare	Owosso	Michigan
Columbia University	New York	New York
Wake Forest University - School of Medicine - Central	Winston-Salem	North Carolina
University of Pennsylvania	Philadelphia	Pennsylvania
Neurology Rare Disease Center	Denton	Texas
The University of Texas Health Science Center at Houston	Houston	Texas
University of Washington Medical Center	Seattle	Washington
Universitaetsklinikum Heidelberg	Heidelberg	Baden-Wurttemberg
Universitaetsklinikum Ulm	Ulm	Baden-Wurttemberg
Klinikum rechts der Isar der TU Muenchen	Munich	Bavaria
Universitaetsklinikum Essen	Essen	North Rhine-Westphalia
Semmelweis Egyetem	Budapest	Hungary
Fondazione IRCCS Istituto Neurologico Carlo Besta	Milan	Italy
Fondazione Serena Onlus - Centro Clinico Nemo	Milan	Italy
Fondazione Policlinico Universitario Agostino Gemelli IRCCS	Roma	Italy
Ospedale S G Battista Molinette	Torino	Italy
Yokohama City University Hospital	Yokohama	Kanagawa
NHO Osaka Toneyama Medical Center	Toyonaka-shi	Osaka

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