An Open-label, Escalating Dose Study to Assess the Safety, Tolerability and Dose-range Finding of a Single Intrathecal Dose of ISIS 396443 in Patients With Spinal Muscular Atrophy
Overview
- Phase
- Phase 1
- Intervention
- nusinersen
- Conditions
- Spinal Muscular Atrophy
- Sponsor
- Biogen
- Enrollment
- 28
- Locations
- 4
- Primary Endpoint
- Number of participants that experience Adverse Events (AEs) and Serious Adverse Events
- Status
- Completed
- Last Updated
- 5 years ago
Overview
Brief Summary
This objectives of this study are to evaluate the safety, tolerability, and pharmacokinetics of a single dose of nusinersen (ISIS 396443) administered intrathecally to participants with Spinal Muscular Atrophy (SMA).
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.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Documented Survival Motor Neuron1 (SMN1) homozygous gene deletion
- •Clinical signs attributable to Spinal Muscular Atrophy (SMA)
- •Able to complete all study procedures, measurements and visits and parent/participant 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
Exclusion Criteria
- •Respiratory insufficiency defined by the need for invasive or non-invasive ventilation during a 24 hour period
- •Presence of a gastric feeding tube
- •Previous scoliosis surgery or scoliosis surgery planned during the duration of the study that would interfere with the lumbar puncture (LP) injection procedure
- •Hospitalization for surgery or pulmonary event within the last 2 months or planned during the study
- •Presence of an untreated or inadequately treated active infection requiring systemic antiviral or antimicrobial therapy
- •History of brain or spinal cord disease that would interfere with LP procedures or cerebrospinal fluid (CSF) circulation
- •Presence of an implanted shunt for the draining of CSF or an implanted Central Nervous System (CNS) catheter
- •History of bacterial meningitis
- •Clinically significant abnormalities in hematology or clinical chemistry parameters
- •Treatment with another investigational drug, biological agent, or device within 1-month of Screening or 5 half-lives of study agent whichever is longer. Any history of gene therapy or cell transplantation
Arms & Interventions
Cohort 1 (n=6)
Intervention: nusinersen
Cohort 2 (n=6)
Intervention: nusinersen
Cohort 3 (n=6)
Intervention: nusinersen
Cohort 4 (n=10)
Intervention: nusinersen
Outcomes
Primary Outcomes
Number of participants that experience Adverse Events (AEs) and Serious Adverse Events
Time Frame: Up to 88 Days
Number or participants with clinically significant cerbrospinal fluid (CSF) laboratory parameters
Time Frame: Up to 88 Days
PK parameters of nusinersen (ISIS 396443): Apparent terminal elimination half-life (t1/2), if possible
Time Frame: Plasma at 1, 2, 4 and 20 hours after dosing
Number of participants with clinically significant physical examination abnormalities
Time Frame: Up to 88 Days
Number of participants with clinically significant laboratory parameters
Time Frame: Up to 88 Days
Number of participants with clinically significant vital sign abnormalities
Time Frame: Up to 88 Days
Number of participants with clinically significant weight abnormalities
Time Frame: Up to 88 Days
Number of participants with clinically significant electrocardiograms (ECGs) abnormalities
Time Frame: Up to 88 Days
PK parameters of nusinersen (ISIS 396443): Maximum observed plasma drug concentration (Cmax)
Time Frame: Plasma at 1, 2, 4 and 20 hours after dosing
PK parameters of nusinersen: Time to reach maximum observed concentration (Tmax)
Time Frame: Plasma at 1, 2, 4 and 20 hours after dosing
Number of participants with clinically significant neurological examination abnormalities
Time Frame: Up to 88 Days
Number of participants who use concomitant medications
Time Frame: Up to 88 Days
PK parameters of nusinersen: Area under the plasma concentrations time curve from the time of the intrathecal (IT) dose to the last collected sample (AUCinf)
Time Frame: Plasma at 1, 2, 4 and 20 hours after dosing