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

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

Official Title
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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

Conditions
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Spinal Muscular Atrophy

Intervention / Treatment
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* Drug: Nusinersen


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 2 Years
Maximum Age: 15 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Nusinersen 3 mg<br>3 mg nusinersen on Days 1, 29, 85, intrathecal (IT) injection | Drug: Nusinersen<br>* Single IT injection for each dose<br>* Other names: Spinraza;|
| Experimental: Nusinersen 6 mg<br>6 mg nusinersen on Days 1, 29, 85, IT injection | Drug: Nusinersen<br>* Single IT injection for each dose<br>* Other names: Spinraza;|
| Experimental: Nusinersen 9 mg<br>9 mg nusinersen on Days 1 and 85, IT injection | Drug: Nusinersen<br>* Single IT injection for each dose<br>* Other names: Spinraza;|
| Experimental: Nusinersen 12 mg<br>12 mg nusinersen on Days 1, 29, 85, IT injection | Drug: Nusinersen<br>* Single IT injection for each dose<br>* Other names: Spinraza;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Adverse Events (AEs), Serious AEs (SAEs), Discontinuations Due to AEs, and Highest Severity of AEs | 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. | Participants were followed for the duration of the study; mean (SD) duration of treatment was 82.9 (15.4) days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Plasma Pharmacokinetics: Maximal Observed Plasma Drug Concentration (Cmax) |  | Day 1 and Day 85 | 
| Plasma Pharmacokinetics: Time to Reach Cmax in Plasma |  | 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) |  | Day 1 and Day 85 | 
| Cerebrospinal Fluid (CSF) Pharmacokinetics: Predose CSF Drug Concentrations |  | Day 1, Day 29, and Day 85 | 
| Urine Pharmacokinetics: Renal Clearance, Cohort 4 | Renal clearance of nusinersen for participants was assessed in the 12 mg reporting group only, per protocol. | Day 1 and Day 85 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Spinal Muscular Atrophy, SMA, SMN, SMNRx, ISIS-SMNRx, ISIS 396443