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Gene Replacement Therapy Clinical Trial for Participants With Spinal Muscular Atrophy Type 1 (STR1VE)

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ClinicalTrials.gov Identifier: NCT03306277
Recruitment Status : Completed
First Posted : October 11, 2017
Results First Posted : July 16, 2020
Last Update Posted : August 16, 2022
Information provided by (Responsible Party):
Novartis ( Novartis Gene Therapies )

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

Condition or disease Intervention/treatment Phase
SMA - Spinal Muscular Atrophy Gene Therapy Biological: Onasemnogene Abeparvovec-xioi Phase 3

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 22 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Intervention Model Description: One-time intravenous administration of onasemnogene abeparvovec-xioi.
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : October 24, 2017
Actual Primary Completion Date : November 12, 2019
Actual Study Completion Date : November 12, 2019

Arm Intervention/treatment
Experimental: Onasemnogene Abeparvovec-xioi
One-time Intravenous administration of onasemnogene abeparvovec-xioi at the therapeutic dose.
Biological: 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.
Other Name: Zolgensma

Primary Outcome Measures :
  1. Achievement of Independent Sitting for at Least 30 Seconds [ Time Frame: Up to 18 months ]

    Independent sitting is defined as sitting up straight with head erect for at least 30 seconds.

    This endpoint is a co-primary endpoint. The two co-primary efficacy endpoints were assessed in sequence: The endpoint of functional independent sitting was assessed first and, only when this assessment met statistical significance, was the endpoint of event-free survival assessed.

  2. Event-free Survival [ Time Frame: 14 months ]

    Survival is defined by the avoidance of combined endpoint of either death or permanent ventilation, which is defined by tracheostomy or by the requirement of ≥ 16 hours of respiratory assistance per day for ≥ 14 consecutive days in the absence of an acute reversible illness, excluding perioperative ventilation. Permanent ventilation is considered a surrogate for death. An acute reversible illness is defined as any condition other than SMA that results in increased medical intervention.

    The endpoint is a co-primary endpoint. The two co-primary efficacy endpoints were assessed in sequence: The endpoint of functional independent sitting was assessed first and, only when this assessment met statistical significance was the survival endpoint assessed.

Secondary Outcome Measures :
  1. Ability to Thrive [ Time Frame: 18 months ]

    Ability to thrive is defined as achieving all of the following at 18 months of age:

    • does not receive nutrition through mechanical support or other non-oral method
    • ability to tolerate thin liquids as demonstrated through a formal swallowing test
    • maintains weight

    This is a co-secondary endpoint. The two co-secondary endpoints were assessed in sequence: The endpoint of ability to thrive was assessed first and, only when this assessment met statistical significance was the endpoint of ventilatory support independence assessed.

  2. Ventilatory Support Independence [ Time Frame: Up to 18 months ]

    Ventilatory support independence is defined as requiring no daily ventilator support/usage at 18 months of age, excluding acute reversible illness and perioperative ventilation, through assessment of actual usage data captured from the device (Phillips Trilogy BiPAP device). This endpoint is derived solely from the Phillips Trilogy BiPAP device.

    This is a co-secondary endpoint. The two co-secondary endpoints were assessed in sequence: The endpoint of ability to thrive was assessed first and, only when this assessment met statistical significance was the endpoint of ventilatory support independence assessed.

Information from the National Library of Medicine

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Ages Eligible for Study:   up to 180 Days   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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)

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03306277

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United States, California
David Geffen School of Medicine at UCLA
Los Angeles, California, United States, 90095
Stanford University
Stanford, California, United States, 94305
United States, Colorado
Children's Hospital Colorado
Aurora, Colorado, United States, 80045
United States, Florida
Nemours Children's Hospital
Orlando, Florida, United States, 32827
United States, Illinois
Ann and Robert H Lurie Children's Hospital
Chicago, Illinois, United States, 60611
United States, Maryland
Johns Hopkins Pediatric Neurology
Baltimore, Maryland, United States, 21287
United States, Massachusetts
Boston Children's Hospital
Boston, Massachusetts, United States, 02115
United States, Missouri
Washington Unviersity School of Medicine
Saint Louis, Missouri, United States, 63110
United States, New York
Columbia University
New York, New York, United States, 10032
United States, North Carolina
Duke University
Durham, North Carolina, United States, 27713
United States, Ohio
Nationwide Children's Hospital
Columbus, Ohio, United States, 43205
United States, Oregon
Oregon Health and Science University
Portland, Oregon, United States, 97239
United States, Pennsylvania
Children's Hospital of Philadelphia
Philadelphia, Pennsylvania, United States, 19104
United States, Texas
University of Texas Southwestern Medical Center
Dallas, Texas, United States, 75235
United States, Utah
University of Utah
Salt Lake City, Utah, United States, 84112
United States, Wisconsin
University of Wisconsin (Madison)
Madison, Wisconsin, United States, 53792
Sponsors and Collaborators
Novartis Gene Therapies
  Study Documents (Full-Text)

Documents provided by Novartis ( Novartis Gene Therapies ):
Study Protocol  [PDF] October 4, 2018
Statistical Analysis Plan  [PDF] December 11, 2019

Additional Information:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Novartis Gene Therapies
ClinicalTrials.gov Identifier: NCT03306277    
Other Study ID Numbers: AVXS-101-CL-303
2020-000095-38 ( EudraCT Number )
COAV101A12302 ( Other Identifier: Novartis Pharmaceuticals )
First Posted: October 11, 2017    Key Record Dates
Results First Posted: July 16, 2020
Last Update Posted: August 16, 2022
Last Verified: August 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
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/.

URL: https://www.clinicalstudydatarequest.com/.

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Muscular Atrophy
Muscular Atrophy, Spinal
Pathological Conditions, Anatomical
Neuromuscular Manifestations
Neurologic Manifestations
Nervous System Diseases
Spinal Cord Diseases
Central Nervous System Diseases
Motor Neuron Disease
Neurodegenerative Diseases
Neuromuscular Diseases