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

This study has been completed.
Information provided by (Responsible Party):
Biogen Identifier:
First received: October 8, 2012
Last updated: January 20, 2017
Last verified: January 2017

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.

Condition Intervention Phase
Spinal Muscular Atrophy Drug: Nusinersen Phase 1 Phase 2

Access to an investigational treatment associated with this study is available outside the clinical trial.   More info ...

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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

Resource links provided by NLM:

Further study details as provided by Biogen:

Primary Outcome Measures:
  • Number of Participants With Adverse Events (AEs), Serious AEs (SAEs), Discontinuations Due to AEs, and Highest Severity of AEs [ Time Frame: Participants were followed for the duration of the study; mean (SD) duration of treatment was 82.9 (15.4) days ]
    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.

Secondary Outcome Measures:
  • Plasma Pharmacokinetics: Maximal Observed Plasma Drug Concentration (Cmax) [ Time Frame: Day 1 and Day 85 ]
  • Plasma Pharmacokinetics: Time to Reach Cmax in Plasma [ Time Frame: 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) [ Time Frame: Day 1 and Day 85 ]
  • Cerebrospinal Fluid (CSF) Pharmacokinetics: Predose CSF Drug Concentrations [ Time Frame: Day 1, Day 29, and Day 85 ]
  • Urine Pharmacokinetics: Renal Clearance, Cohort 4 [ Time Frame: Day 1 and Day 85 ]
    Renal clearance of nusinersen for participants was assessed in the 12 mg reporting group only, per protocol.

Enrollment: 34
Study Start Date: October 2012
Study Completion Date: January 2015
Primary Completion Date: January 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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
  • BIIB058
  • Spinraza
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
  • BIIB058
  • Spinraza
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
  • BIIB058
  • Spinraza
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
  • BIIB058
  • Spinraza

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.

Ages Eligible for Study:   2 Years to 15 Years   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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.

  Contacts and Locations
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Please refer to this study by its identifier: NCT01703988

United States, Massachusetts
Boston Children's Hospital
Boston, Massachusetts, United States, 02115
United States, New York
Columbia University Medical Center
New York, New York, United States, 10032
United States, Texas
UT Southwestern Medical Center - Children's Medical Center Dallas
Dallas, Texas, United States, 75207
United States, Utah
University of Utah School of Medicine
Salt Lake City, Utah, United States, 84132
Sponsors and Collaborators
Study Director: Medical Director Biogen
  More Information

Responsible Party: Biogen Identifier: NCT01703988     History of Changes
Other Study ID Numbers: ISIS 396443 - CS2
2017-000327-27 ( EudraCT Number )
Study First Received: October 8, 2012
Results First Received: January 20, 2017
Last Updated: January 20, 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes

Keywords provided by Biogen:
Spinal Muscular Atrophy
ISIS 396443

Additional relevant MeSH terms:
Muscular Atrophy
Muscular Atrophy, Spinal
Pathological Conditions, Anatomical
Neuromuscular Manifestations
Neurologic Manifestations
Nervous System Diseases
Signs and Symptoms
Spinal Cord Diseases
Central Nervous System Diseases
Motor Neuron Disease
Neurodegenerative Diseases
Neuromuscular Diseases processed this record on September 19, 2017