An Open-label Safety and Tolerability Study of Nusinersen (ISIS 396443) in Participants With Spinal Muscular Atrophy (SMA) Who Previously Participated in ISIS 396443-CS2 (NCT01703988) or ISIS 396443-CS10 (NCT01780246)

Study Overview
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Brief Summary
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The primary objective of this study is to examine the safety and tolerability of nusinersen (ISIS 396443) administered intrathecally to participants with Spinal Muscular Atrophy (SMA) who previously participated in ISIS 396443-CS2 (NCT01703988) or ISIS 396443-CS10 (NCT01780246). The secondary objective is to examine the plasma and cerebrospinal fluid (CSF) pharmacokinetic(s) (PK) of nusinersen administered intrathecally to participants with SMA who previously participated in ISIS 396443-CS2 or ISIS 396443-CS10.

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 Study to Assess the Safety and Tolerability of ISIS 396443 in Patients With Spinal Muscular Atrophy Who Previously Participated in 396443-CS2 or 396443-CS10

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: Clinical signs attributable to Spinal Muscular Atrophy Satisfactory completion of dosing and all study visits in ISIS 396443-CS2 (NCT01703988) or ISIS 396443 CS10 (NCT01780246) with an acceptable safety profile, per Investigator judgement. 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 Key Exclusion Criteria: Have any new or worsening of existing condition which in the opinion of the Investigator would make the subject unsuitable for enrollment, or could interfere with the participant participating in or completing the study. Dosing in ISIS 396443-CS2 (NCT01703988) or ISIS 396443-CS10 (NCT01780246) within 180 days (6 months) of screening, or longer ago than 396 days (13 months) from screening Hospitalization for surgery (i.e. 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 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. NOTE: Other protocol defined Inclusion/Exclusion criteria may apply.
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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: nusinersen<br> | Drug: nusinersen<br>* Administered by intrathecal (IT) injection<br>* Other names: ISIS SMNRx;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants that experience Adverse Events (AEs) and Serious Adverse Events |  | Up to 24 Months | 
| Number of participants with clinically significant neurological examination abnormalities |  | Up to 24 Months | 
| Number of participants with clinically significant vital sign abnormalities |  | Up to 24 Months | 
| Number of participants with clinically significant physical examination abnormalities |  | Up to 24 Months | 
| Number of participants with clinically significant weight abnormalities |  | Up to 24 Months | 
| Number of participants with clinically significant laboratory parameters |  | Up to 24 Months | 
| Number or participants with clinically significant cerbrospinal fluid (CSF) laboratory parameters |  | Up to Day 176 | 
| Number of participants with clinically significant electrocardiograms (ECGs) abnormalities |  | Up to 24 Months | 
| Change from Baseline in concomitant medications |  | Up to 24 Months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PK parameters of nusinersen (ISIS 396443) in CSF levels: Maximum observed plasma drug concentration (Cmax) |  | Pre-dose Day 176, Day 358 and Day 540 | 
| PK parameters of nusinersen in CSF levels: Time to reach maximum observed concentration (Tmax) |  | Pre-Dose Day 176, Day 358 and Day 540 | 
| PK parameters of nusinersen in CSF levels: Area under the plasma concentrations time curve from the time of the intrathecal (IT) dose to the last collected sample (AUCinf) |  | Pre-Dose Day 176, Day 358 and Day 540 | 

 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, IONIS-SMNRx, IONIS-SMN Rx, Spinraza