Clinical trial NCT01703988: An Open-label Safety, Tolerability and Dose-Range Finding Study of Multiple Doses of Nusinersen (ISIS 396443) in Participants With Spinal Muscular Atrophy
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Spinal Muscular Atrophy
Keywords: Spinal Muscular Atrophy
SMA
SMN
SMNRx
ISIS-SMNRx
ISIS 396443
Lead sponsor: Biogen
Sponsor class: INDUSTRY
First posted: 2012-10-11
Enrollment: 34
Sex: ALL
Minimum age (years): 2
Maximum age (years): 15
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Number of Participants With Adverse Events (AEs), Serious AEs (SAEs), Discontinuations Due to AEs, and Highest Severity of AEs
timeFrame: Participants were followed for the duration of the study; mean (SD) duration of treatment was 82.9 (15.4) days
Secondary outcomes:
measure: Plasma Pharmacokinetics: Maximal Observed Plasma Drug Concentration (Cmax)
timeFrame: Day 1 and Day 85
measure: Plasma Pharmacokinetics: Time to Reach Cmax in Plasma
timeFrame: Day 1 and Day 85
measure: 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)
timeFrame: Day 1 and Day 85
measure: Cerebrospinal Fluid (CSF) Pharmacokinetics: Predose CSF Drug Concentrations
timeFrame: Day 1, Day 29, and Day 85
measure: Urine Pharmacokinetics: Renal Clearance, Cohort 4
timeFrame: Day 1 and Day 85
Other outcomes:
Locations:
city: Boston
country: United States
facility: Boston Children's Hospital
state: Massachusetts
city: New York
country: United States
facility: Columbia University Medical Center
state: New York
city: Dallas
country: United States
facility: UT Southwestern Medical Center - Children's Medical Center Dallas
state: Texas
city: Salt Lake City
country: United States
facility: University of Utah School of Medicine
state: Utah
Study officials:
affiliation: Biogen
name: Medical Director
role: STUDY_DIRECTOR
References:
citation: 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.