Single-Dose Gene Replacement Therapy Clinical Trial for Participants With Spinal Muscular Atrophy Type 1

Study Overview
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Brief Summary
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Phase 3, open-label, single-arm, single-dose, trial of onasemnogene abeparvovec-xioi (gene replacement therapy) in patients with spinal muscular atrophy (SMA) Type 1 who meet enrollment criteria and are genetically defined by a biallelic pathogenic mutation of the survival motor neuron 1 gene (SMN1) with one or two copies of survival motor neuron 2 gene (SMN2). Up to 30 patients < 6 months (< 180 days) of age at the time of gene replacement therapy (Day 1) will be enrolled.

Detailed Description
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Phase 3, open-label, single-arm, single-dose, trial of onasemnogene abeparvovec-xioi (gene replacement therapy) in patients with spinal muscular atrophy (SMA) Type 1 who meet enrollment criteria and are genetically defined by a biallelic pathogenic mutation of the survival motor neuron 1 gene (SMN1) with one or two copies of survival motor neuron 2 gene (SMN2). 30 patients < 6 months (< 180 days) of age at the time of gene replacement therapy (Day 1) will be enrolled. The trial includes a screening period, a gene replacement therapy period, and a follow-up period. During the screening period (Days -30 to -2), patients whose parent(s)/legal guardian(s) provide informed consent will complete screening procedures to determine eligibility for trial enrollment. Patients who meet the entry criteria will enter the in-patient gene replacement therapy period (Day -1 to Day 3). On Day -1, patients will be admitted to the hospital for pre-treatment baseline procedures. On Day 1, patients will receive a one-time intravenous (IV) infusion of onasemnogene abeparvovec-xioi, and will undergo in-patient safety monitoring over the next 48 hours. Patients may be discharged 48 hours after the infusion, based on Investigator judgment. During the outpatient follow-up period (Days 4 to End of Trial at 18 months of age), patients will return at regularly scheduled intervals for efficacy and safety assessments until the End of Trial when the patient reaches 18 months of age. After the End of Trial visit, eligible patients will be asked to participate into the long-term follow up trial. All post-treatment visits will be relative to the date on which gene replacement therapy is administered, until the patient is 14 months of age, after which they will be relevant to the patient's date of birth.

Official Title
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Phase 3, Open-Label, Single-Arm, Single-Dose Gene Replacement Therapy Clinical Trial for Patients With Spinal Muscular Atrophy Type 1 With One or Two SMN2 Copies Delivering AVXS-101 by Intravenous Infusion

Conditions
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SMA

Intervention / Treatment
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* Biological: Onasemnogene Abeparvovec-xioi


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with SMA Type 1 as determined by diagnosis of SMA based on gene mutation analysis with biallelic SMN1 mutations (deletion or point mutations) and one or two copies of SMN2 [inclusive of the known SMN2 gene modifier mutation (c.859G>C)] Patients must be < 6 months (< 180 days) of age at the time of onasemnogene abeparvovec-xioi infusion Patients must have a swallowing evaluation test performed prior to administration of gene replacement therapy Exclusion Criteria: Previous, planned or expected scoliosis repair surgery/procedure prior to 18 months of age Use of invasive ventilatory support (tracheotomy with positive pressure) or pulse oximetry < 95% saturation at screening Use or requirement of non-invasive ventilatory support for 12 or more hours daily in the two weeks prior to dosing Patient with signs of aspiration based on a swallowing test or whose weight-for-age falls below the 3rd percentile based on World Health Organization (WHO) Child Growth Standards and unwilling to use an alternative method to oral feeding Participation in recent SMA treatment clinical trial (with the exception of observational cohort studies or non-interventional studies) or receipt of an investigational or commercial compound, product or therapy administered with the intent to treat SMA (eg, nusinersen, valproic acid,) at any time prior to screening for this trial.

Ages Eligible for Study
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Maximum Age: 6 Months

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
Interventional Model Description: Open-label, single-arm, single-dose, trial of onasemnogene abeparvovec-xioi
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Onasemnogene Abeparvovec-xioi<br>Onasemnogene abeparvovec-xioi is a non-replicating recombinant adeno-associated virus serotype 9 (AAV9) containing the human survival motor neuron (SMN) gene under the control of the cytomegalovirus (CMV) enhancer/chicken β-actin-hybrid promoter (CB). | Biological: Onasemnogene Abeparvovec-xioi<br>* Onasemnogene abeparvovec-xioi is a non-replicating recombinant adeno-associated virus serotype 9 (AAV9) containing the human survival motor neuron (SMN) gene under the control of the cytomegalovirus (CMV) enhancer/chicken β-actin-hybrid promoter (CB).<br>* Other names: Zolgensma;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Who Achieve Independent Sitting for at Least 10 Seconds | Independent sitting is defined by the World Health Organization Multicentre Growth Reference Study, confirmed by video recording, as a participant who sits up straight with head erect for at least 10 seconds; participant does not use arms or hands to balance body or support position. | From Day 1 up to 18 Months of Age Visit (Up to a Maximum of Approximately 17 Months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Event-free Survival at 14 Months of Age | Event-free survival at 14 months of age was defined as the number of participants who did not die, did not require permanent ventilation and did not withdraw from the study by 14 months of age. | Up to 14 months of age |