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Pre-Symptomatic Study of Intravenous AVXS-101 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. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT03505099
Recruitment Status : Recruiting
First Posted : April 23, 2018
Last Update Posted : May 23, 2019
PRA Health Sciences
Information provided by (Responsible Party):
AveXis, Inc.

Brief Summary:
To evaluate the safety and efficacy of intravenous AVXS-101 in pre-symptomatic patients with SMA and 2 or 3 copies SMN2

Condition or disease Intervention/treatment Phase
Spinal Muscular Atrophy Biological: AVXS-101 Phase 3

Detailed Description:

Phase 3, open-label, single-arm study of a single, one-time dose of AVXS-101 (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 AVXS-101, 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)
Estimated Enrollment : 27 participants
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 : October 2020
Estimated Study Completion Date : June 2023

Arm Intervention/treatment
Experimental: AVXS-101
One-time intravenous infusion of AVXS-101 at 1.1 X 10^14 vg/kg
Biological: AVXS-101
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

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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

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Contact: AveXis MedInfo 833-828-3947

  Hide Study Locations
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United States, California
David Geffen School of Medicine at UCLA Recruiting
Los Angeles, California, United States, 90095
Contact: Clara Sam    310-825-3264   
Principal Investigator: Perry Shieh, MD         
Stanford University Not yet recruiting
Stanford, California, United States, 94305
Contact: Shirley Paulose    650-724-3792   
Contact: Carolyn McLaughlin Savage   
Principal Investigator: John Day, MD         
United States, Colorado
Children's Hospital Colorado Recruiting
Aurora, Colorado, United States, 80045
Contact: Hannah Johnson    720-777-6895   
Contact: Kyle Kusmik    720-777-8599   
Principal Investigator: Julie Parsons         
United States, Florida
Nemours Children's Hospital Recruiting
Orlando, Florida, United States, 32827
Contact: Kristine Moore    407-650-7967   
Contact: Virginia Rizzo    (407) 650-7403   
Principal Investigator: Richard Finkel, MD         
United States, Georgia
Center for Rare Neurological Diseases Recruiting
Norcross, Georgia, United States, 30093
Contact: Lisa Hardy    770-713-3653   
Principal Investigator: Daniel Tarquinio, MD         
United States, Massachusetts
Massachusetts General Hospital Recruiting
Boston, Massachusetts, United States, 02114
Contact: Kendall Trautman    617-724-2523   
Principal Investigator: Kathryn Swoboda, MD         
United States, Michigan
Helen DeVos Children's Hospital Recruiting
Grand Rapids, Michigan, United States, 49503
Contact: Christopher Russell    616-391-5093   
Principal Investigator: Jena Krueger, MD         
United States, Missouri
Washington Unviersity School of Medicine Not yet recruiting
Saint Louis, Missouri, United States, 63110
Contact: Pallavi Anand    314-362-2490   
Principal Investigator: Craig Zaidman, MD         
United States, New York
Columbia University Recruiting
New York, New York, United States, 10032
Contact: Kimberly Berry    212-342-3038   
Principal Investigator: Claudia Chiriboga, MD         
United States, Ohio
Nationwide Children's Hospital Recruiting
Columbus, Ohio, United States, 43205
Contact: Thelma Asare    614-355-2606   
Principal Investigator: Jerry R Mendell, M.D.         
United States, Pennsylvania
Clinic for Special Children Recruiting
Strasburg, Pennsylvania, United States, 17579
Contact: Karlla Brigatti    717-687-9407   
Principal Investigator: Kevin Strauss, MD         
United States, Texas
University of Texas Southwestern Medical Center Recruiting
Dallas, Texas, United States, 75235
Contact: Tammy Ramm    214-456-4426   
Principal Investigator: Susan Iannaccone, MD         
United States, Utah
University of Utah Recruiting
Salt Lake City, Utah, United States, 84112
Contact: Teresa Janecki    801-581-3724   
Principal Investigator: Nicholas Butterfield, MD         
United States, Virginia
Health Research of Hampton Roads - Norfolk, Inc. Recruiting
Norfolk, Virginia, United States, 23510
Contact: Terrie Conklin    757-668-9356   
Principal Investigator: Crystal Proud         
Virginia Commonwealth University Recruiting
Richmond, Virginia, United States, 23298
Contact: Sarah Valkovci    804-905-8361   
Principal Investigator: Nicholas Johnson         
United States, Wisconsin
University of Wisconsin (Madison) Recruiting
Madison, Wisconsin, United States, 53792
Contact: Constance Trantow    608-265-7814   
Principal Investigator: Jennifer Kwon, MD         
Australia, New South Wales
Sydney Children's Hospitals Network and Recruiting
Randwick, New South Wales, Australia, 2031
Contact: Aimee Williams    (02) 9382 5505   
Principal Investigator: Michelle Farrar         
Centre Hospitalier Régional Hôpital La Citadelle Recruiting
Liège, Belgium, 4000
Principal Investigator: Laurent Servais         
Neuropédiatrie - Centre de Référence des Maladies Neuromusculaires Not yet recruiting
Liège, Belgium
Contact: Anne-Catherine Defeldre   
Canada, Ontario
Canada Childrens Hospital of Eastern Ontario Recruiting
Ottawa, Ontario, Canada, K1H8L1
Contact: Rosa Ramos    (613) 737-7600 ext 6058   
Principal Investigator: Hugh McMillan, MD         
Dr. Von Haunersches Kinderspital Not yet recruiting
München, Germany, 80337
Schneider Children's Medical Center of Israel Not yet recruiting
Tel Aviv, Israel
Principal Investigator: Sharon Aharoni         
Ospedale Pediatrico Bambino Gesù Recruiting
Roma, Italy, 00165
Principal Investigator: Enrico Bertini         
Fondazione Policlinico Universitario Agostino Gemelli Recruiting
Roma, Italy, 00168
Principal Investigator: Eugenio Maria Mercuri         
Tokyo Women's Medical University Recruiting
Tokyo, Japan
Principal Investigator: Kayoko Saito         
Korea, Republic of
Pusan National University Children's Hospital Not yet recruiting
Yangsan, Gyeungsangnamdo, Korea, Republic of
Principal Investigator: Jin-Hong Shin         
Area Genetica Clínica y Molecular Not yet recruiting
Barcelona, Spain
Contact: Scherezade Sarri   
National Taiwan University Hospital Recruiting
Taipei, Taiwan
Principal Investigator: Yin-Hsiu Chien         
United Kingdom
Great Ormond Street Hospital for Children Recruiting
London, United Kingdom
Principal Investigator: Francesco Muntoni         
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     History of Changes
Other Study ID Numbers: AVXS-101-CL-304
2017-004087-35 ( EudraCT Number )
First Posted: April 23, 2018    Key Record Dates
Last Update Posted: May 23, 2019
Last Verified: May 2019
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
Signs and Symptoms
Spinal Cord Diseases
Central Nervous System Diseases
Motor Neuron Disease
Neurodegenerative Diseases
Neuromuscular Diseases