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

NCT ID: NCT03306277

Last Updated: 2026-01-26

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 22 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2017-10-24
• Study Completion Date: 2019-11-12

Brief Summary

Phase 3 pivotal US trial studying open-label intravenous administration of onasemnogene abeparvovec-xioi in spinal muscular atrophy (SMA) Type 1 participants.

Detailed Description

Phase 3, open-label, single-arm, single-dose, study of onasemnogene abeparvovec-xioi (gene replacement therapy) in participants with spinal muscular atrophy (SMA) Type 1 who meet enrollment criteria and are genetically defined by nonfunctional survival motor neuron 1 gene (SMN1) with 1 or 2 copies of survival motor neuron 2 gene (SMN2). Fifteen (15) participants < 6 months (< 180 days) of age at the time of gene replacement therapy (Day 1) will be enrolled.

Conditions

SMA - Spinal Muscular Atrophy; Gene Therapy

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Onasemnogene Abeparvovec-xioi

One-time Intravenous administration of onasemnogene abeparvovec-xioi at the therapeutic dose.

Group Type: EXPERIMENTAL

Onasemnogene Abeparvovec-xioi

Intervention Type: BIOLOGICAL

Non-replicating recombinant adeno-associated virus serotype 9 (AAV9) containing the complimentary deoxyribonucleic acid (cDNA) of the human SMN gene under the control of the cytomegalovirus (CMV) enhancer/chicken-β-actin-hybrid promoter (CB). The AAV inverted terminal repeat (ITR) has been modified to promote intramolecular annealing of the transgene, thus forming a double-stranded transgene ready for transcription.

Interventions

Onasemnogene Abeparvovec-xioi

Non-replicating recombinant adeno-associated virus serotype 9 (AAV9) containing the complimentary deoxyribonucleic acid (cDNA) of the human SMN gene under the control of the cytomegalovirus (CMV) enhancer/chicken-β-actin-hybrid promoter (CB). The AAV inverted terminal repeat (ITR) has been modified to promote intramolecular annealing of the transgene, thus forming a double-stranded transgene ready for transcription.

Intervention Type: BIOLOGICAL

Other Intervention Names

Zolgensma

Eligibility Criteria

Inclusion Criteria

• Participants with SMA Type 1 as determined by the following features: a. Diagnosis of SMA based on gene mutation analysis with bi-allelic SMN1 mutations (deletion or point mutations) and 1 or 2 copies of SMN2 (inclusive of the known SMN2 gene modifier mutation (c.859G>C))2
• The first 3 participants enrolled must meet the criteria for the Intent-To-Treat Population
• Participants must be < 6 months (< 180 days) of age at the time of onasemnogene abeparvovec-xioi infusion
• Participants must have a swallowing evaluation test performed prior to administration of gene replacement therapy
• Up-to-date on childhood vaccinations. Seasonal vaccinations that include palivizumab prophylaxis (also known as Synagis) to prevent respiratory syncytial virus (RSV) infections are also recommended in accordance with American Academy of Pediatrics
• Parent(s)/legal guardian(s) willing and able to complete the informed consent process and comply with study procedures and visit schedule

Exclusion Criteria

• Previous, planned or expected scoliosis repair surgery/procedure during the study assessment period
• Pulse oximetry < 96% saturation at screening while the participant is awake or asleep without any supplemental oxygen or respiratory support, or for altitudes > 1000 m, oxygen saturation < 92% awake or asleep without any supplemental oxygen or respiratory support Pulse oximetry saturation may decrease to < 96% after screening provided that the saturation does not decrease by ≥ 4 percentage points
• Tracheostomy or current use or requirement of non-invasive ventilatory support averaging ≥ 6 hours daily over the 7 days prior to the screening visit; or ≥ 6 hours/day on average during the screening period or requiring ventilatory support while awake over the 7 days prior to screening or at any point during the screening period prior to dosing
• Participants with signs of aspiration/inability to tolerate non-thickened- liquids based on a formal swallowing test performed as part of screening. Participants with a gastrostomy tube who pass the swallowing test will be allowed to enroll in the study
• Participants whose weight-for-age is below the third percentile based on World Health Organization (WHO) Child Growth Standards
• Active viral infection (includes human immunodeficiency virus [HIV] or positive serology for hepatitis B or C, or Zika virus)
• Serious non-respiratory tract illness requiring systemic treatment and/or hospitalization within 2 weeks prior to screening
• Upper or lower respiratory infection requiring medical attention, medical intervention, or increase in supportive care of any manner within 4 weeks prior to screening
• Severe non-pulmonary/respiratory tract infection within 4 weeks before administration of gene replacement therapy or concomitant illness that creates unnecessary risks for gene replacement therapy such as: a. Major renal or hepatic impairment b. Known seizure disorder c. Diabetes mellitus d. Idiopathic hypocalcuria e. Symptomatic cardiomyopathy
• Known allergy or hypersensitivity to prednisolone or other glucocorticosteroids or their excipients
• Concomitant use of any of the following: drugs for treatment of myopathy or neuropathy, agents used to treat diabetes mellitus, or ongoing immunosuppressive therapy, plasmapheresis, immunomodulators such as adalimumab, immunosuppressive therapy within 3 months prior to gene replacement therapy
• Anti-adeno-associated virus serotype 9 (AAV9) antibody titer > 1:50 as determined by Enzyme-linked Immunosorbent Assay (ELISA) binding immunoassay. Should a potential participant demonstrate Anti-AAV9 antibody titer > 1:50, he or she may receive retesting within 30 days of the screening period and will be eligible to participate if the Anti-AAV9 antibody titer upon retesting is ≤ 1:50
• Clinically significant abnormal laboratory values (gamma glutamyl- transpeptidase [GGT], ALT, and AST > 3 × ULN, bilirubin ≥ 3.0 mg/dL, creatinine ≥ 1.0 mg/dL, hemoglobin [Hgb] < 8 or > 18 g/dL; white blood cell [WBC] > 20,000 per cmm) prior to gene replacement therapy
• Participation in recent SMA treatment clinical study (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 at any time prior to screening for this study. Oral β-agonists must be discontinued at least 30 days before gene therapy dosing. Inhaled albuterol specifically prescribed for the purposes of respiratory (bronchodilator) management is acceptable and not a contraindication at any time prior to screening for this study
• Expectation of major surgical procedures during the study assessment period
• Parent(s)/legal guardian(s) unable or unwilling to comply with study procedures or inability to travel for repeat visits
• Parent(s)/legal guardian(s) unwilling to keep study results/observations confidential or to refrain from posting confidential study results/observations on social media sites
• Parent(s)/legal guardian(s) refuses to sign consent form
• Gestational age at birth < 35 weeks (245 days)

• Maximum Eligible Age: 180 Days
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Novartis Gene Therapies

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Locations

David Geffen School of Medicine at UCLA

Los Angeles, California, United States

Stanford University

Stanford, California, United States

Children's Hospital Colorado

Aurora, Colorado, United States

Nemours Children's Hospital

Orlando, Florida, United States

Ann and Robert H Lurie Children's Hospital

Chicago, Illinois, United States

Johns Hopkins Pediatric Neurology

Baltimore, Maryland, United States

Boston Children's Hospital

Boston, Massachusetts, United States

Washington Unviersity School of Medicine

St Louis, Missouri, United States

Columbia University

New York, New York, United States

Duke University

Durham, North Carolina, United States

Nationwide Children's Hospital

Columbus, Ohio, United States

Oregon Health and Science University

Portland, Oregon, United States

Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, United States

University of Texas Southwestern Medical Center

Dallas, Texas, United States

University of Utah

Salt Lake City, Utah, United States

University of Wisconsin (Madison)

Madison, Wisconsin, United States

Countries

United States

References

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.

Reference Type: DERIVED

PMID: 34383289 (View on PubMed)

Day JW, Finkel RS, Chiriboga CA, Connolly AM, Crawford TO, Darras BT, Iannaccone ST, Kuntz NL, Pena LDM, Shieh PB, Smith EC, Kwon JM, Zaidman CM, Schultz M, Feltner DE, Tauscher-Wisniewski S, Ouyang H, Chand DH, Sproule DM, Macek TA, Mendell JR. Onasemnogene abeparvovec gene therapy for symptomatic infantile-onset spinal muscular atrophy in patients with two copies of SMN2 (STR1VE): an open-label, single-arm, multicentre, phase 3 trial. Lancet Neurol. 2021 Apr;20(4):284-293. doi: 10.1016/S1474-4422(21)00001-6. Epub 2021 Mar 17.

Reference Type: DERIVED

PMID: 33743238 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Related Links

http://AveXis.com

sponsor company website

https://www.novctrd.com/ctrdweb/trialresult/trialresults/pdf?trialResultId=17657

Novartis Results Record

https://www.novctrd.com/ctrdweb/patientsummary/patientsummaries?patientSummaryId=1219

A Plain Language Trial Summary is available on www.novctrd.com

Other Identifiers

2020-000095-38

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

COAV101A12302

Identifier Type: OTHER

Identifier Source: secondary_id

AVXS-101-CL-303

Identifier Type: -

Identifier Source: org_study_id