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

Study Status: Completed
Recruit Status: Completed
Study Type: Interventional

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 Mu

Brief Summary:

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.


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

Current Primary Outcome: 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.


Original Primary Outcome: The number of participants with adverse events [ Time Frame: Patricipants will be followed for the duration of the study; an expected 36 weeks ]

Current Secondary Outcome:

  • 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.


Original Secondary Outcome: 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)


Information By: Biogen

Dates:
Date Received: October 8, 2012
Date Started: October 2012
Date Completion:
Last Updated: January 20, 2017
Last Verified: January 2017