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 : November 21, 2018
Information provided by (Responsible Party):
AveXis, Inc.

Brief Summary:
A global study of intravenous AVXS-101 in pre-symptomatic patients with SMA with 2, 3, and 4 copies of 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 (SMA) who meet enrollment criteria and are genetically defined by bi-allelic deletion of SMN1 with 2, 3, or 4 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 will enroll at least fifteen (15) patients with 2 copies of SMN2 that meet the Intent To Treat (ITT) criteria, at least twelve (12) patients with 3 copies of SMN2 that meet the ITT criteria and at least seventeen (17) patients with 4 copies of SMN2 that meet the ITT criteria. Patients in all three cohorts must be ≤6 weeks of age at the time of gene replacement therapy (Day 1).

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, 24 or 36 months 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), 24 months of age (SMN2 = 3) or 36 months of age (SMN2 = 4). After the End of Study visit, eligible patients will be asked to rollover into a long-term follow up study.

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 44 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 : April 2023

Arm Intervention/treatment
Experimental: AVXS-101
One-time intravenous infusion of AVXS-101 at 1.1 X 1014 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. 2 copies SMN2 gene: functional independent sitting [ Time Frame: 18 months of age ]
    Proportion of patients demonstrating functional independent sitting for at least 30 seconds

  2. 3 copies of SMN2 gene: standing without support [ Time Frame: 24 months of age ]
    Proportion of patients achieving the ability to stand without support for at least three seconds

  3. 4 copies of SMN2 gene: demonstrating motor improvements inconsistent with SMA natural history [ Time Frame: 36 months of age ]
    Proportion of patients demonstrating the ability to achieve a scaled score on Bayley V.3 Gross and Fine Motor Subtests within 1.5 standard deviations of chronological development reference standard

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 2 copies of SMN2 (n ≥15)

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

      − 2 copies of SMN2 Patients with 3 copies of SMN2 (n ≥12)

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

      − 3 copies of SMN2 Patients with 4 copies of SMN2 (n ≥17)

    • Patients with pre-symptomatic SMA Type 3 as determined by the following features:

      • 4 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 (e.g., tongue fasciculation, hypotonia, areflexia)
  • 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 [25]

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

Contact: AveXis MedInfo 833-828-3947

  Show 23 Study Locations
Sponsors and Collaborators
AveXis, Inc.
Study Chair: Doug Feltner, MD AveXis, Inc.

Responsible Party: AveXis, Inc. Identifier: NCT03505099     History of Changes
Other Study ID Numbers: AVXS-101-CL-304
First Posted: April 23, 2018    Key Record Dates
Last Update Posted: November 21, 2018
Last Verified: November 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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:
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