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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.
Sponsor:
Information provided by (Responsible Party):
Biogen
ClinicalTrials.gov Identifier:
NCT01703988
First received: October 8, 2012
Last updated: January 20, 2017
Last verified: January 2017
October 8, 2012
January 20, 2017
October 2012
January 2015   (Final data collection date for primary outcome measure)
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.
The number of participants with adverse events [ Time Frame: Patricipants will be followed for the duration of the study; an expected 36 weeks ]
Complete list of historical versions of study NCT01703988 on ClinicalTrials.gov Archive Site
  • 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.
Plasma Pharmacokinetics (See clarification.) [ Time Frame: Plasma at 1, 2, 4, 6 and 20 hours after dosing ]
  • the maximal observed plasma drug concentration (Cmax)
  • the time to reach Cmax in plasma (Tmax)
  • the area under the plasma concentrations time curve from the time of the intrathecal dose to the last collected sample (20 hours after dosing)
Not Provided
CSF Pharmacokinetics (See clarification.) [ Time Frame: CSF at Day 1, Day 29, and Day 85 ]
- The observed CSF drug concentration
 
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.

This study was conducted and the protocol was registered by Ionis Pharmaceuticals, Inc. In August 2016, sponsorship of the trial was transferred to Biogen.
Interventional
Phase 1
Phase 2
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Spinal Muscular Atrophy
Drug: Nusinersen
Single IT injection for each dose
Other Names:
  • ISIS-SMNRx
  • ISIS 396443
  • BIIB058
  • Spinraza
  • Experimental: Nusinersen 3 mg
    3 mg nusinersen on Days 1, 29, 85, intrathecal (IT) injection
    Intervention: Drug: Nusinersen
  • Experimental: Nusinersen 6 mg
    6 mg nusinersen on Days 1, 29, 85, IT injection
    Intervention: Drug: Nusinersen
  • Experimental: Nusinersen 9 mg
    9 mg nusinersen on Days 1 and 85, IT injection
    Intervention: Drug: Nusinersen
  • Experimental: Nusinersen 12 mg
    12 mg nusinersen on Days 1, 29, 85, IT injection
    Intervention: Drug: Nusinersen
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Completed
34
January 2015
January 2015   (Final data collection date for primary outcome measure)

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.

Sexes Eligible for Study: All
2 Years to 15 Years   (Child)
No
Contact information is only displayed when the study is recruiting subjects
United States
 
 
NCT01703988
ISIS 396443 - CS2
2017-000327-27 ( EudraCT Number )
Yes
Not Provided
Plan to Share IPD: Yes
Biogen
Biogen
Not Provided
Study Director: Medical Director Biogen
Biogen
January 2017

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP