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

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

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.

Study Overview

• Status: Completed
• Conditions: SMA
• Intervention / Treatment: Biological: Onasemnogene Abeparvovec-xioi

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.

• Study Type: Interventional
• Enrollment (Actual): 33
• Phase: Phase 3

Contacts and Locations

Study Locations

• Belgium
  • Ghent, Belgium
    • University Hospital Ghent Neuromuscular reference center
  • Liège, Belgium
    • Neuropédiatrie - Centre de Référence des Maladies Neuromusculaires
• France
  • Paris, France
    • Hôpital Armand Trousseau
• Italy
  • Genova, Italy
    • Istituto Gianninia Gaslini
  • Messina, Italy
    • Policlinico "G. Martino"
  • Milan, Italy
    • University of Milan
  • Milan, Italy
    • Carlo Besta Neurological Research Institute
  • Rome, Italy
    • Policlinico Gemelli
• United Kingdom
  • London, United Kingdom
    • Great Ormond Street Hospital for Children
  • Newcastle Upon Tyne, United Kingdom
    • The John Walton Muscular Dystrophy Research Centre MRC Centre for Neuromuscular Diseases at Newcastle

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 10 months (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Onasemnogene Abeparvovec-xioi; 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; 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).; Other Names: Zolgensma; AVXS-101; OAV101

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Novartis Gene Therapies
• Investigators: Study Chair: AveXis Medinfo, Sponsor GmbH

Publications and helpful links

General Publications

• 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. Erratum In: Drug Saf. 2022 Feb;45(2):191-192.
• 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.

Helpful Links

• patient recruitment website
• The Novartis Clinical Trial Results

Study record dates

Study Major Dates

• Study Start (Actual): August 16, 2018
• Primary Completion (Actual): September 11, 2020
• Study Completion (Actual): September 11, 2020

Study Registration Dates

• First Submitted: March 4, 2018
• First Submitted That Met QC Criteria: March 8, 2018
• First Posted (Actual): March 12, 2018

Study Record Updates

• Last Update Posted (Actual): August 16, 2022
• Last Update Submitted That Met QC Criteria: August 12, 2022
• Last Verified: August 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Central Nervous System Diseases; Nervous System Diseases; Neurologic Manifestations; Neuromuscular Diseases; Neurodegenerative Diseases; Neuromuscular Manifestations; Pathological Conditions, Anatomical; Spinal Cord Diseases; Motor Neuron Disease; Muscular Atrophy; Atrophy; Muscular Atrophy, Spinal
• Other Study ID Numbers: AVXS-101-CL-302; 2017-000266-29 (EudraCT Number); COAV101A12301 (Other Identifier: Novartis Pharmaceuticals)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes

IPD Plan Description

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data availability is according to the criteria and process described on https://www.clinicalstudydatarequest.com/.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes