An Open-label Safety and Tolerability Study of Nusinersen (ISIS 396443) in Participants With Spinal Muscular Atrophy Who Previously Participated in ISIS 396443-CS1 (NCT01494701)

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-CS1 (NCT02865109). The secondary objective was to examine the plasma pharmacokinetics of a single dose of ISIS 396443 administered intrathecally to participants with SMA who previously participated in ISIS 396443-CS1.

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 a Single Intrathecal Dose of ISIS 396443 in Patients With Spinal Muscular Atrophy Who Previously Participated in ISIS 396443-CS1

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-CS1 (NCT01494701) 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 participant unsuitable for enrollment, or could interfere with the participant participating in or completing the study. Dosing in ISIS 396443-CS1 (NCT01494701) within 270 days (9 months) of screening, or longer ago than 450 days (15 months) Dosing in ISIS 396443-CS2 (NCT01703988) 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 any time during the screening period Clinically significant abnormalities in hematology or clinical chemistry parameters 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 1 months of screening. Any history of gene therapy or cell transplantation 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
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: BIIB058;|

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 Weeks | 
| Number of participants with clinically significant neurological examination abnormalities |  | Up tp 24 Weeks | 
| Number of participants with clinically significant vital sign abnormalities |  | Up to 24 Weeks | 
| Number of participants with clinically significant physical examination abnormalities |  | Up to 24 Weeks | 
| Number of participants with clinically significant weight abnormalities |  | Up to 24 Weeks | 
| Number of participants with clinically significant laboratory parameters |  | Up to 24 Weeks | 
| Number of participants with clinically significant electrocardiograms (ECGs) abnormalities |  | Up to 24 Weeks | 
| Number of participants who use concomitant medications |  | Up to 24 Weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PK parameters of nusinersen (ISIS 396443): Maximum observed plasma drug concentration (Cmax) |  | Plasma at 1, 2, 4 and 6 hours after dosing | 
| PK parameters of nusinersen: Time to reach maximum observed concentration (Tmax) |  | Plasma at 1, 2, 4 and 6 hours after dosing | 
| 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) |  | Plasma at 1, 2, 4 and 6 hours after dosing | 
| PK parameters of nusinersen (ISIS 396443): Apparent terminal elimination half-life (t1/2), if possible |  | Plasma at 1, 2, 4 and 6 hours after dosing | 

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