Clinical trial NCT03461289: Single-Dose Gene Replacement Therapy Clinical Trial for Participants With Spinal Muscular Atrophy Type 1
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: SMA
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2018-03-12
Enrollment: 33
Sex: ALL
Maximum age (years): 6
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: Open-label, single-arm, single-dose, trial of onasemnogene abeparvovec-xioi
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Number of Participants Who Achieve Independent Sitting for at Least 10 Seconds
timeFrame: From Day 1 up to 18 Months of Age Visit (Up to a Maximum of Approximately 17 Months)
Secondary outcomes:
measure: Event-free Survival at 14 Months of Age
timeFrame: Up to 14 months of age
Other outcomes:
Locations:
city: Ghent
country: Belgium
facility: University Hospital Ghent Neuromuscular reference center
city: Liège
country: Belgium
facility: Neuropédiatrie - Centre de Référence des Maladies Neuromusculaires
city: Paris
country: France
facility: Hôpital Armand Trousseau
city: Genova
country: Italy
facility: Istituto Gianninia Gaslini
city: Messina
country: Italy
facility: Policlinico "G. Martino"
city: Milan
country: Italy
facility: Carlo Besta Neurological Research Institute
city: Milan
country: Italy
facility: University of Milan
city: Rome
country: Italy
facility: Policlinico Gemelli
city: London
country: United Kingdom
facility: Great Ormond Street Hospital for Children
city: Newcastle Upon Tyne
country: United Kingdom
facility: The John Walton Muscular Dystrophy Research Centre MRC Centre for Neuromuscular Diseases at Newcastle
Study officials:
affiliation: Sponsor GmbH
name: AveXis Medinfo
role: STUDY_CHAIR
References:
citation: Mercuri E, Muntoni F, Baranello G, Masson R, Boespflug-Tanguy O, Bruno C, Corti S, Daron A, Deconinck N, Servais L, Straub V, Ouyang H, Chand D, Tauscher-Wisniewski S, Mendonca N, Lavrov A; STR1VE-EU study group. Onasemnogene abeparvovec gene therapy for symptomatic infantile-onset spinal muscular atrophy type 1 (STR1VE-EU): an open-label, single-arm, multicentre, phase 3 trial. Lancet Neurol. 2021 Oct;20(10):832-841. doi: 10.1016/S1474-4422(21)00251-9.
citation: Day JW, Mendell JR, Mercuri E, Finkel RS, Strauss KA, Kleyn A, Tauscher-Wisniewski S, Tukov FF, Reyna SP, Chand DH. Clinical Trial and Postmarketing Safety of Onasemnogene Abeparvovec Therapy. Drug Saf. 2021 Oct;44(10):1109-1119. doi: 10.1007/s40264-021-01107-6. Epub 2021 Aug 12.