Phase 2
N=34
An Open-label Safety, Tolerability and Dose-Range Finding Study of Multiple Doses of Nusinersen (ISIS 396443) in Participants With Spinal Muscular Atrophy
Spinal Muscular Atrophy
Bottom Line
View on ClinicalTrials.gov: NCT01703988 ↗Enrolled (actual)
34
Serious AEs
8.8%
Results posted
Mar 2017
Primary outcome: Primary: Number of Participants With Adverse Events (AEs), Serious AEs (SAEs), Discontinuations Due to AEs, and Highest Severity of AEs — 8; 6; 9; 9 Participants
Study Design & Population
- Study type
- Interventional
- Phase
- Phase 2
- Interventions
- Nusinersen (Drug)
- Age
- Pediatric · 2+ yrs
- Sex
- All
- Sponsor
- Biogen
- Primary completion
- Jan 2015
Outcome Measures
| Outcome | Result | p-value |
|---|---|---|
| PRIMARY Number of Participants With Adverse Events (AEs), Serious AEs (SAEs), Discontinuations Due to AEs, and Highest Severity of AEs |
8; 6; 9; 9; 0; 0 | — |
| SECONDARY Plasma Pharmacokinetics: Maximal Observed Plasma Drug Concentration (Cmax) |
51.5; 79.8; 141.0; 208.0; 32.5; 52.8 | — |
| SECONDARY Plasma Pharmacokinetics: Time to Reach Cmax in Plasma |
5.09; 5.93; 3.92; 4.05; 6.08; 6.04 | — |
| SECONDARY 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) |
181; 306; 601; 823; 110; 179 | — |
| SECONDARY Cerebrospinal Fluid (CSF) Pharmacokinetics: Predose CSF Drug Concentrations |
0.0651; 0.0560; NA; NA; 1.41; 2.65 | — |
| SECONDARY Urine Pharmacokinetics: Renal Clearance, Cohort 4 |
0.674; 77.5 | — |
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.
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.
Data sourced from ClinicalTrials.gov (NCT01703988). Outcome figures and adverse-event rates are extracted automatically from the registry's posted results and are provided for clinician reference, not as a substitute for the primary publication.