Clinical trial NCT05067790: 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)
Official title: A Phase 3b Study to Evaluate Higher Dose Nusinersen (BIIB058) in Patients With Spinal Muscular Atrophy Previously Treated With Risdiplam
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: Spinal Muscular Atrophy
Lead sponsor: Biogen
Sponsor class: INDUSTRY
First posted: 2021-10-05
Enrollment: 45
Sex: ALL
Minimum age (years): 15
Maximum age (years): 50
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief 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.

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.

Eligibility criteria: 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 outcomes:
measure: Change in Total Revised Upper Limb Module (RULM) Score
timeFrame: Up to Day 855
Secondary outcomes:
measure: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
timeFrame: Up to Day 1695
measure: Number of Participants With Change in Clinical Laboratory Parameters, Electrocardiogram (ECG), Vital Signs and Pulse Oximetry from Baseline
timeFrame: Up to Day 1695
Other outcomes:
Locations:
city: Phoenix
country: United States
facility: Barrow Neurological Institute
state: Arizona
city: Little Rock
country: United States
facility: Arkansas Children's Hospital
state: Arkansas
city: Loma Linda
country: United States
facility: Loma Linda University Children's Hospital
state: California
city: Palo Alto
country: United States
facility: Stanford Neuroscience Health Center
state: California
city: Washington
country: United States
facility: Georgetown University
state: District of Columbia
city: Atlanta
country: United States
facility: Rare Disease Research, LLC
state: Georgia
city: Chicago
country: United States
facility: Ann & Robert H. Lurie Children's Hospital of Chicago
state: Illinois
city: Iowa City
country: United States
facility: University of Iowa Stead Family Children's Hospital
state: Iowa
city: Boston
country: United States
facility: Boston Children's Hospital
state: Massachusetts
city: Owosso
country: United States
facility: Memorial Healthcare
state: Michigan
city: New York
country: United States
facility: Columbia University
state: New York
city: Winston-Salem
country: United States
facility: Wake Forest University - School of Medicine - Central
state: North Carolina
city: Columbus
country: United States
facility: The Ohio State
state: Ohio
city: Philadelphia
country: United States
facility: University of Pennsylvania
state: Pennsylvania
city: Denton
country: United States
facility: Neurology Rare Disease Center
state: Texas
city: Houston
country: United States
facility: The University of Texas Health Science Center at Houston
state: Texas
city: Norfolk
country: United States
facility: Children's Hospital of The King's Daughters
state: Virginia
city: Seattle
country: United States
facility: University of Washington Medical Center
state: Washington
city: Madison
country: United States
facility: University of Wisconsin
state: Wisconsin
city: Gent
country: Belgium
facility: UZ Gent
city: Leuven
country: Belgium
facility: UZ Leuven
city: Porto Alegre
country: Brazil
facility: Hospital de Clínicas de Porto Alegre
state: Rio Grande Do Sul
city: Sao Paulo
country: Brazil
facility: Hospital das Clinicas - FMUSP
city: Heidelberg
country: Germany
facility: Universitaetsklinikum Heidelberg
state: Baden Wuerttemberg
city: Ulm
country: Germany
facility: Universitaetsklinikum Ulm
state: Baden Wuerttemberg
city: Muenchen
country: Germany
facility: Klinikum rechts der Isar der TU Muenchen
state: Bayern
city: Giessen
country: Germany
facility: Universitaetsklinikum Giessen und Marburg GmbH
state: Hessen
city: Essen
country: Germany
facility: Universitaetsklinikum Essen
state: Nordrhein Westfalen
city: Essen
country: Germany
facility: Universitaetsklinikum Essen
state: Nordrhein Westfalen
city: Berlin
country: Germany
facility: Charité - Campus Virchow-Klinikum
city: Budapest
country: Hungary
facility: Semmelweis Egyetem
city: Rome
country: Italy
facility: Ospedale Pediatrico Bambino Gesù
state: Roma
city: Milano
country: Italy
facility: Fondazione IRCCS Istituto Neurologico Carlo Besta
city: Milano
country: Italy
facility: Fondazione Serena Onlus - Centro Clinico Nemo
city: Roma
country: Italy
facility: Fondazione Policlinico Universitario Agostino Gemelli IRCCS
city: Torino
country: Italy
facility: Ospedale S G Battista Molinette
city: Yokohama-shi
country: Japan
facility: Yokohama City University Hospital
state: Kanagawa-Ken
city: Toyonaka-shi
country: Japan
facility: NHO Osaka Toneyama Medical Center
state: Osaka-Fu
city: Krakow
country: Poland
facility: Szpital Specjalistyczny im. L.Rydygiera w Krakowie
city: Lodz
country: Poland
facility: Instytut Centrum Zdrowia Matki Polki
city: Warszawa
country: Poland
facility: Samodzielny Publiczny Centralny Szpital Kliniczny
city: Wroclaw
country: Poland
facility: Uniwersytecki Szpital Kliniczny im. Jana Mikulicza Radeckiego we Wroclawiu
city: Esplugues de Llobregat
country: Spain
facility: Hospital Sant Joan de Deu
state: Barcelona
city: Valencia
country: Spain
facility: Hospital Universitari i Politecnic La Fe
Study officials:
affiliation: Biogen
name: Medical Director
role: STUDY_DIRECTOR
References: