A Study for Participants With Spinal Muscular Atrophy (SMA) Who Previously Participated in Nusinersen (ISIS 396443) Investigational Studies

Study Overview
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Brief Summary
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The primary objective is to evaluate the long-term safety and tolerability of nusinersen (ISIS 396443) administered by intrathecal (IT) injection to participants with Spinal Muscular Atrophy (SMA) who previously participated in investigational studies of nusinersen. The secondary objective is to examine the long-term efficacy of nusinersen administered by IT injection to participants with SMA who previously participated in investigational studies of nusinersen.

Detailed Description
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This study was initiated and the protocol was registered by Ionis Pharmaceuticals, Inc. In August 2016, Biogen assumed responsibility for this study.

Official Title
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An Open-Label Extension Study for Patients With Spinal Muscular Atrophy Who Previously Participated in Investigational Studies of ISIS 396443

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: Signed informed consent of parent or guardian and signed informed assent of participant, if indicated per participant's age and institutional guidelines. Completion of the index study in accordance with the study protocol or as a result of Sponsor decision (e.g., early termination of the index study) within the preceding 16 weeks Key Exclusion Criteria: Have any condition or worsening 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 Clinically significant abnormalities in hematology or clinical chemistry parameters or electrocardiogram (ECG), as assessed by the Site Investigator, at the Screening visit that would render the participant unsuitable for participation in the study Participant's parent or legal guardian is not willing or able to meet standard of care guidelines (including vaccinations and respiratory syncytial virus prophylaxis if available), nor provide nutritional and respiratory support throughout the study Treatment with another investigational agent, biological agent, or device within one month of Screening, or 5 half-lives of study agent, whichever is longer 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
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group 1<br>Participants transitioned from ISIS 396443-CS3B (NCT02193074) | Drug: nusinersen<br>* Administered by intrathecal (IT) injection<br>* Other names: ISIS SMNRx;|
| Experimental: Group 2<br>Participants transitioned from ISIS 396443-CS4 (NCT02292537) | Drug: nusinersen<br>* Administered by intrathecal (IT) injection<br>* Other names: ISIS SMNRx;|
| Experimental: Group 3<br>Participants transitioned from ISIS 396443-CS12 (NCT02052791) | Drug: nusinersen<br>* Administered by intrathecal (IT) injection<br>* Other names: ISIS SMNRx;|
| Experimental: Group 4<br>Participants transitioned from ISIS 396443-CS3A (NCT01839656) | Drug: nusinersen<br>* Administered by intrathecal (IT) injection<br>* Other names: ISIS SMNRx;|
| Experimental: Group 5<br>Participants transitioned from 232SM202 (NCT02462759) | 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 experiencing Adverse events (AEs) and/or Serious Adverse Events (SAEs) |  | Up to Day 1814 | 
| Number of participants with clinically significant vital sign abnormalities |  | Up to Day 1814 | 
| Number of participants with clinically significant weight abnormalities |  | Up to Day 1814 | 
| Number of participants with clinically significant neurological examination abnormalities |  | Up to Day 1814 | 
| Number of participants with clinically significant laboratory assessment abnormalities |  | Up to Day 1814 | 
| Number of participants with clinically significant coagulation parameter abnormalities |  | Up to Day 1814 | 
| Number of participants with clinically significant 12-lead electrocardiograms (ECGs) abnormalities |  | Up to Day 1814 | 
| Change from Baseline in concomitant medications |  | Up to Day 1814 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of participants who attained motor milestones as assessed by World Health Organization (WHO) criteria |  | Up to Day 1814 | 
| Percentage of participants who attained motor milestones as assessed by Section 2 of Hammersmith Infant Neurological Examination (HINE) |  | Up to Day 1814 | 
| Time to death or permanent ventilation |  | Up to Day 1814 | 
| Percentage of participants not requiring permanent ventilation |  | Up to Day 1814 | 
| Change from Baseline in the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) motor function scale | CHOP-INTEND tests includes 16 items structured to move from easiest to hardest with the grading including gravity eliminated (lower scores) to antigravity movements (higher scores). All item scores range from 0-4. | Up to Day 1814 | 
| Change from Baseline in Hammersmith Functional Motor Scale | The HFMSE tests motor function of participants with SMA. The original 20 item Hammersmith Functional Motor Scale was expanded to include 13 additional adapted items from the Gross Motor Function Measure to improve sensitivity for the higher functioning ambulant population. | Up to Day 1814 | 
| Change from Baseline in Revised Upper Limb Module (RULM) |  | Up to Day 1814 | 
| Change from Baseline in 6-Minute Walk Test (6MWT) | 6MWT: walking up and down a 25 meter track without aids or orthotics as fast as possible for 6 minutes. Lap splits, minute splits and total distance are recorded, in addition to any rests and falls. | Up to Day 1814 | 
| Change from Baseline in Compound Muscular Action Potential (CMAP) | CMAP is an electrophysiological technique that can be used to determine the approximate number of motor neurons in a muscle or group of muscles. | Up to Day 1814 | 
| Change from Baseline in body length and/or height (for all participants) |  | Up to Day 1814 | 
| Change from Baseline in head circumference (for participants up to 36 months of age) |  | Up to Day 1814 | 
| Change from Baseline in chest circumference (for participants up to 36 months of age) |  | Up to Day 1814 | 
| Change from Baseline in arm circumference (for participants up to 36 months of age) |  | Up to Day 1814 | 
| Proportion of CMAP responders |  | Up to Day 1814 | 
| Number of participants with motor milestones achieved |  | Up to Day 1814 | 
| Proportion of participants who achieved standing alone |  | Up to Day 1814 | 
| Proportion of participants who achieved walking with assistance |  | Up to Day 1814 | 
| Number of participants with serious respiratory events |  | Up to Day 1814 | 
| Number of participants hospitalized |  | Up to Day 1814 | 
| Duration of hospitalizations |  | Up to Day 1814 | 
| Change from Baseline in Cobb-Angle on X-Ray of the thoracolumbar spine |  | Up to Day 1814 | 
| Change from Baseline in Quality of Life (QOL) Questionnaires |  | Up to Day 1814 | 
| Number of Disease-related hospitalizations and AEs |  | Up to Day 1814 | 
| Overall survival rate |  | Up to Day 1814 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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IONIS-SMN Rx, SMA, SMN, SMNRx, ISIS-SMNRx, ISIS 396443, SHINE, IONIS-SMNRx, Spinraza, nusinersen