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Pre-Symptomatic Study of Intravenous Onasemnogene Abeparvovec-xioi in Spinal Muscular Atrophy (SMA) for Patients With Multiple Copies of SMN2 (SPR1NT)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT03505099
Recruitment Status : Active, not recruiting
First Posted : April 23, 2018
Last Update Posted : May 18, 2020
PRA Health Sciences
Information provided by (Responsible Party):
AveXis, Inc.

Brief Summary:
To evaluate the safety and efficacy of intravenous onasemnogene abeparvovec-xioi in pre-symptomatic patients with SMA and 2 or 3 copies SMN2

Condition or disease Intervention/treatment Phase
Spinal Muscular Atrophy Biological: onasemnogene abeparvovec-xioi Phase 3

Detailed Description:

Phase 3, open-label, single-arm study of a single, one-time dose of onasemnogene abeparvovec-xioi (gene replacement therapy) in patients with spinal muscular atrophy who meet enrollment criteria and are genetically defined by bi-allelic deletion of survival motor neuron 1 gene (SMN1) with 2 or 3 copies of survival motor neuron 2 gene (SMN2). Patients with SMN1 point mutations or the SMN2 gene modifier mutation (c.859G>C) may enroll but will not be included in the efficacy analysis sets.

The study 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 undergo screening procedures to determine eligibility for study enrollment. Patients who meet the entry criteria will enter the in-patient gene replacement therapy period (Day -1 to Day 2). On Day -1, patients will be admitted to the hospital for pre-treatment baseline procedures. On Day 1, patients will receive a single, one-time intravenous (IV) infusion of onasemnogene abeparvovec-xioi, and will undergo in-patient safety monitoring for a minimum of 24 hours post infusion. Patients may be discharged 24 hours after the infusion, based on Investigator judgment. During the outpatient follow-up period (Days 3 to End of Study at 18 or 24 of age, dependent upon respective SMN2 copy number), patients will return at regularly scheduled intervals for efficacy and safety assessments until the End of Study when the patient reaches 18 months of age (SMN2 = 2) or 24 months of age (SMN2 = 3). After the End of Study visit, eligible patients will be asked to rollover into a long-term follow up study.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 30 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Intervention Model Description: Open-label, single arm
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Global Study of a Single, One-Time Dose of AVXS-101 Delivered to Infants With Genetically Diagnosed and Pre-symptomatic Spinal Muscular Atrophy With Multiple Copies of SMN2
Actual Study Start Date : April 10, 2018
Estimated Primary Completion Date : June 24, 2021
Estimated Study Completion Date : July 26, 2021

Arm Intervention/treatment
Experimental: onasemnogene abeparvovec-xioi
One-time intravenous infusion of onasemnogene abeparvovec-xioi at 1.1 X 10^14 vg/kg
Biological: onasemnogene abeparvovec-xioi
A non-replicating recombinant 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.

Primary Outcome Measures :
  1. Percentage of participants achieving functional independent sitting for at least 30 seconds at any visit [ Time Frame: 18 months ]
    Participants with bi-allelic SMN1 deletions and 2 copies of SMN2

  2. Percentage of participants achieving the ability to stand without support for at least 3 seconds at any visit [ Time Frame: 24 months ]
    Participants with bi-allelic SMN1 deletions and 3 copies of SMN2

Secondary Outcome Measures :
  1. Percentage of participants surviving without permanent ventilation in the absence of acute illness and perioperatively [ Time Frame: 14 months ]
    Participants with bi-allelic SMN1 deletions and 2 copies of SMN2

  2. Percentage of participants achieving the ability to maintain weight at or above the 3rd percentile without non-oral/mechanical feeding support at any visit [ Time Frame: 18 months ]
    Participants with bi-allelic SMN1 deletions and 2 copies of SMN2

  3. Percentage of participants demonstrating the ability to walk alone at any visit [ Time Frame: 24 months ]
    Participants with bi-allelic SMN1 deletions and 3 copies of SMN2. Ability to walk alone is defined as the ability to take at least 5 steps independently displaying coordination and balance.

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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Ages Eligible for Study:   up to 42 Days   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • Age ≤6 weeks (≤42 days) at time of dose
  • Ability to tolerate thin liquids as demonstrated through a formal bedside swallowing test
  • Compound muscle action potential (CMAP) ≥2mV at Baseline; centralized review of CMAP data will be conducted
  • Gestational age of 35 to 42 weeks

    • Patients with pre-symptomatic SMA Type 1 as determined by the following features:

  • 2 copies of SMN2 Patients with 2 copies of SMN2 (n ≥12)

    • Patients with pre-symptomatic SMA Type 2 as determined by the following features:

  • 3 copies of SMN2

Exclusion Criteria:

  • Weight at screening visit <2 kg
  • Hypoxemia (oxygen saturation <96% awake or asleep without any supplemental oxygen or respiratory support) at the screening visit or for altitudes >1000 m, oxygen saturation <92% awake or asleep without any supplemental oxygen or respiratory support at the screening visit
  • Any clinical signs or symptoms at screening or immediately prior to dosing that are, in the opinion of the Investigator, strongly suggestive of SMA
  • Tracheostomy or current prophylactic use or requirement of noninvasive ventilatory support at any time and for any duration prior to screening or during the screening period
  • Patients with signs of aspiration/inability to tolerate nonthickened liquids based on a formal swallowing test performed as part of screening or patients receiving any non-oral feeding method
  • Clinically significant abnormalities in hematology or clinical chemistry parameters as determined by investigator or medical monitor
  • Treatment with an investigational or commercial product, including nusinersen, given for the treatment of SMA. This includes any history of gene therapy, prior antisense oligonucleotide treatment, or cell transplantation.
  • Patients whose weight-for-age is below the third percentile based on World Health Organization (WHO) Child Growth Standards
  • Biological mother with active viral infection as determined by screening laboratory samples (includes human immunodeficiency virus [HIV] or positive serology for hepatitis B or C)

    • Biological mothers with clinical suspicion of Zika virus that meet Centers for Disease Control and Prevention (CDC) Zika virus epidemiological criteria including history of residence in or travel to a geographic region with active Zika transmission at the time of travel will be tested for Zika virus RNA. Positive results warrant confirmed negative Zika virus RNA testing in the patient prior to enrollment.

  • Serious nonrespiratory 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 dosing
  • Severe nonpulmonary/respiratory tract infection within 4 Weeks before administration of gene replacement therapy or concomitant illness that, in the opinion of the Investigator or Sponsor medical monitor, creates unnecessary risks for gene replacement therapy such as:

    • Major renal or hepatic impairment
    • Known seizure disorder
    • Diabetes mellitus
    • Idiopathic hypocalciuria
    • Symptomatic cardiomyopathy
  • Known allergy or hypersensitivity to prednisolone or other glucocorticosteroids or their excipients
  • Previous, planned or expected major surgical procedure including scoliosis repair surgery/procedure during the study assessment period
  • 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 4 Weeks prior to gene replacement therapy
  • AntiAAV9 antibody titer >1:50 as determined by Enzyme-linked Immunosorbent Assay (ELISA) binding immunoassay

    • Should a potential patient demonstrate AntiAAV9 antibody titer >1:50, he or she may receive retesting inside the 30-Day screening period and will be eligible to participate if the AntiAAV9 antibody titer upon retesting is ≤1:50, provided the <6 Week age requirement at the time of dosing is still met

  • Biological mother involved with the care of the child refuses anti-AAV9 antibody testing prior to dosing

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 identifier (NCT number): NCT03505099

Hide Hide 29 study locations
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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, Georgia
Center for Rare Neurological Diseases
Norcross, Georgia, United States, 30093
United States, Massachusetts
Massachusetts General Hospital
Boston, Massachusetts, United States, 02114
United States, Michigan
Helen DeVos Children's Hospital
Grand Rapids, Michigan, United States, 49503
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, Ohio
Nationwide Children's Hospital
Columbus, Ohio, United States, 43205
United States, Pennsylvania
Clinic for Special Children
Strasburg, Pennsylvania, United States, 17579
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, Virginia
Health Research of Hampton Roads - Norfolk, Inc.
Norfolk, Virginia, United States, 23510
Virginia Commonwealth University
Richmond, Virginia, United States, 23298
United States, Wisconsin
University of Wisconsin (Madison)
Madison, Wisconsin, United States, 53792
Australia, New South Wales
Sydney Children's Hospitals Network and
Randwick, New South Wales, Australia, 2031
Centre Hospitalier Régional Hôpital La Citadelle
Liège, Belgium, 4000
Neuropédiatrie - Centre de Référence des Maladies Neuromusculaires
Liège, Belgium
Canada, Ontario
Canada Childrens Hospital of Eastern Ontario
Ottawa, Ontario, Canada, K1H8L1
Dr. Von Haunersches Kinderspital
München, Germany, 80337
Schneider Children's Medical Center of Israel
Tel Aviv, Israel
Ospedale Pediatrico Bambino Gesù
Roma, Italy, 00165
Fondazione Policlinico Universitario Agostino Gemelli
Roma, Italy, 00168
Tokyo Women's Medical University
Tokyo, Japan
Korea, Republic of
Pusan National University Children's Hospital
Yangsan, Gyeungsangnamdo, Korea, Republic of
Area Genetica Clínica y Molecular
Barcelona, Spain
National Taiwan University Hospital
Taipei, Taiwan
United Kingdom
Great Ormond Street Hospital for Children
London, United Kingdom
Sponsors and Collaborators
AveXis, Inc.
PRA Health Sciences
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Study Chair: Doug Feltner, MD AveXis, Inc.
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Responsible Party: AveXis, Inc. Identifier: NCT03505099    
Other Study ID Numbers: AVXS-101-CL-304
2017-004087-35 ( EudraCT Number )
JapicCTI-184203 ( Registry Identifier: JapicCTI )
First Posted: April 23, 2018    Key Record Dates
Last Update Posted: May 18, 2020
Last Verified: May 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by AveXis, Inc.:
gene therapy
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