An Open-label Safety, Tolerability and Dose-Range Finding Study of Multiple Doses of Nusinersen (ISIS 396443) in Participants With Spinal Muscular Atrophy

An Open-Label, Dose Escalation Study to Assess the Safety, Tolerability and Dose-Range Finding of Multiple Doses of ISIS 396443 Delivered Intrathecally to Patients With Spinal Muscular Atrophy

This study will test the safety, tolerability, and pharmacokinetics of escalating doses of nusinersen (ISIS 396443) administered into the spinal fluid either two or three times over the duration of the trial, in participants with spinal muscular atrophy (SMA).

Four dose levels will be evaluated sequentially. Each dose level will be studied in a cohort of approximately 8 participants, where all participants will receive active drug.

Study Overview

• Status: Completed
• Conditions: Spinal Muscular Atrophy
• Intervention / Treatment: Drug: Nusinersen

Detailed Description

This study was conducted and the protocol was registered by Ionis Pharmaceuticals, Inc. In August 2016, sponsorship of the trial was transferred to Biogen.

• Study Type: Interventional
• Enrollment (Actual): 34
• Phase: Phase 2; Phase 1

Expanded Access

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

Contacts and Locations

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Boston Children's Hospital
  • New York
    • New York, New York, United States, 10032
      • Columbia University Medical Center
  • Texas
    • Dallas, Texas, United States, 75207
      • UT Southwestern Medical Center - Children's Medical Center Dallas
  • Utah
    • Salt Lake City, Utah, United States, 84132
      • University of Utah School of Medicine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 year to 11 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Key Inclusion Criteria:

• Genetic documentation of 5q SMA (homozygous gene deletion or mutation)
• Clinical signs attributable to SMA
• Able to complete all study procedures, measurements, and visits and parent/patient has adequately supportive psychosocial circumstances, in the opinion of the Investigator
• Estimated life expectancy > 2 years from Screening
• Meets age-appropriate institutional criteria for use of anesthesia/sedation, if use is planned for study procedure

Key Exclusion Criteria:

• Respiratory insufficiency defined by the medical necessity for invasive or non-invasive ventilation during a 24-hour period
• Medical necessity for a gastric feeding tube, where the majority of feeds are given by this route, as assessed by the Investigator
• Previous scoliosis surgery that would interfere with the lumbar puncture injection procedure
• Hospitalization for surgery (e.g. scoliosis surgery) or pulmonary event within 2 months of screening or planned during the duration of the study
• Presence of an untreated or inadequately treated active infection requiring systemic antiviral or antimicrobial therapy at any time during the screening period
• History of brain or spinal cord disease that would interfere with lumbar puncture procedures or cerebrospinal fluid (CSF) circulation
• Presence of an implanted shunt for the drainage of CSF or an implanted central nervous system catheter
• History of bacterial meningitis
• Dosing with ISIS 396443 in clinical study ISIS 396443-CS1 Cohorts 2, 3, or 4
• Dosing with ISIS 396443 in clinical study ISIS 396443-CS10
• Clinically significant abnormalities in hematology or clinical chemistry parameters or electrocardiogram (ECG) at the Screening visit, as assessed by the Site Investigator that would render the subject unsuitable for inclusion
• Treatment with investigational drug, biological agent, or device within 1-month of Screening or 5 half-lives of study agent, whichever is longer. Treatment with valproate or hydroxyurea within 3-months of screening. Any history of gene therapy or cell transplantation
• Ongoing medical condition that would interfere with the conduct and assessments of the study. Examples are medical disability (e.g. wasting or cachexia, severe anemia) that would interfere with the assessment of safety or would compromise the ability of the patient to undergo study procedures.

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: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Nusinersen 3 mg; 3 mg nusinersen on Days 1, 29, 85, intrathecal (IT) injection	Drug: Nusinersen; Single IT injection for each dose; Other Names: ISIS 396443; Spinraza; BIIB058; ISIS-SMNRx
Experimental: Nusinersen 6 mg; 6 mg nusinersen on Days 1, 29, 85, IT injection	Drug: Nusinersen; Single IT injection for each dose; Other Names: ISIS 396443; Spinraza; BIIB058; ISIS-SMNRx
Experimental: Nusinersen 9 mg; 9 mg nusinersen on Days 1 and 85, IT injection	Drug: Nusinersen; Single IT injection for each dose; Other Names: ISIS 396443; Spinraza; BIIB058; ISIS-SMNRx
Experimental: Nusinersen 12 mg; 12 mg nusinersen on Days 1, 29, 85, IT injection	Drug: Nusinersen; Single IT injection for each dose; Other Names: ISIS 396443; Spinraza; BIIB058; ISIS-SMNRx

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Adverse Events (AEs), Serious AEs (SAEs), Discontinuations Due to AEs, and Highest Severity of AEs	An AE is any unfavorable and unintended sign, symptom, or disease temporally associated with the study or use of the investigational drug product, whether or not the AE is considered related to the investigational drug product. An SAE is any AE that, in the view of either the Investigator or Sponsor, meets any of the following criteria: results in death; is life threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in a persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions; results in congenital anomaly or birth defect; and is an important medical event in the judgment of the investigator. Drug-related is an event related or possibly related to study drug. Severity of AEs was assessed as mild, moderate, or severe.	Participants were followed for the duration of the study; mean (SD) duration of treatment was 82.9 (15.4) days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Plasma Pharmacokinetics: Maximal Observed Plasma Drug Concentration (Cmax)		Day 1 and Day 85
Plasma Pharmacokinetics: Time to Reach Cmax in Plasma		Day 1 and Day 85
Plasma Pharmacokinetics: Plasma Pharmacokinetics: Area Under the Plasma Concentration Time Curve From the Time of the IT Dose to 6 Hours After Dosing (AUC0-6hr)		Day 1 and Day 85
Cerebrospinal Fluid (CSF) Pharmacokinetics: Predose CSF Drug Concentrations		Day 1, Day 29, and Day 85
Urine Pharmacokinetics: Renal Clearance, Cohort 4	Renal clearance of nusinersen for participants was assessed in the 12 mg reporting group only, per protocol.	Day 1 and Day 85

Collaborators and Investigators

• Sponsor: Biogen

Publications and helpful links

General Publications

• Darras BT, Farrar MA, Mercuri E, Finkel RS, Foster R, Hughes SG, Bhan I, Farwell W, Gheuens S. An Integrated Safety Analysis of Infants and Children with Symptomatic Spinal Muscular Atrophy (SMA) Treated with Nusinersen in Seven Clinical Trials. CNS Drugs. 2019 Sep;33(9):919-932. doi: 10.1007/s40263-019-00656-w.

Helpful Links

• Clinical Study Report (CSR) Synopsis - a results summary

Study record dates

Study Major Dates

• Study Start (Actual): October 31, 2012
• Primary Completion (Actual): January 31, 2015
• Study Completion (Actual): January 31, 2015

Study Registration Dates

• First Submitted: October 8, 2012
• First Submitted That Met QC Criteria: October 8, 2012
• First Posted (Estimate): October 11, 2012

Study Record Updates

• Last Update Posted (Actual): April 13, 2021
• Last Update Submitted That Met QC Criteria: March 22, 2021
• Last Verified: March 1, 2021

More Information

Terms related to this study

• Keywords: Spinal Muscular Atrophy; SMA; SMN; SMNRx; ISIS-SMNRx; ISIS 396443
• 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: ISIS 396443 - CS2; 2017-000327-27 (EudraCT Number)

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 http://clinicalresearch.biogen.com/