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Study of Intrathecal Administration of AVXS-101 for Spinal Muscular Atrophy (STRONG)

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ClinicalTrials.gov Identifier: NCT03381729
Recruitment Status : Recruiting
First Posted : December 22, 2017
Last Update Posted : February 12, 2018
Sponsor:
Information provided by (Responsible Party):
AveXis, Inc.

Brief Summary:
The purpose of this trial is to evaluate the safety and tolerability of intrathecal administration of AVXS-101 in patients with Spinal Muscular Atrophy with 3 copies of SMN2

Condition or disease Intervention/treatment Phase
Spinal Muscular Atrophy Biological: AVXS-101 Phase 1

Detailed Description:

This is a Phase I, single-dose administration study of infants and children with a genetic diagnosis consistent with SMA, bi-allelic deletion of SMN1 and 3 copies of SMN2 without the genetic modifier who are able to sit but cannot stand or walk at the time of study entry. Patients will receive AVXS-101 in a dose comparison safety study of two potential therapeutic doses (3 patients at each dose). Patients will be stratified in two groups, those < 24 months of age at time of dosing and those ≥ 24 months and < 60 months of age at time of dosing. Fifteen (15) patients < 24 months will be enrolled and twelve (12) patients ≥ 24 < 60 months will be enrolled.

The first cohort will enroll three (3) patients (Cohort 1) < 24 months of age who will receive administration of 6.0e13 vg of AVXS-101 (Dose A). There will be at least a four (4) week interval between the dosing of each patient within the cohort. The investigators will confer with the Data Safety Monitoring Board (DSMB) on all Grade III or higher AEs within 48 hours of awareness that are possibly, probably, or definitely related to the study agent before continuing enrollment. Safety data will be reviewed by the DSMB during quarterly meetings; following enrollment of the three patients and based upon the available safety data a decision will be made whether to: a) stop due to toxicity, or b) proceed to Cohort 2 using Dose B.

Should the determination be made to advance to Dose B, three (3) patients < 60 months of age will be enrolled (Cohort 2) and will receive administration of 1.2e14 vg of AVXS-101 (Dose B). Again, there will be at least a four-week interval between dosing of the three patients within the cohort. Based on the available safety data from the three Cohort 2 patients and all of the Cohort 1 patients, the DSMB may decide and document during quarterly meetings that further four-week intervals between patients dosing is unnecessary. AveXis, Inc. will take this recommendation into consideration and will make the final determination whether to persist with four-week intervals between patients dosing going forward; the decision will be communicated to sites and Institutional Review Boards (IRBs) in a formal sponsor letter. The investigators will confer with the DSMB on all Grade III or higher AEs within 48 hours of awareness that are possibly, probably, or definitely related to the study agent before continuing enrollment. Safety data will be reviewed by the DSMB during quarterly meetings; following enrollment of the first six (6) patients and based upon available safety data, a decision will be made whether to: a) stop due to toxicity, or b) continue to enroll an additional 21 patients until there are a total of twelve (12) patients < 24 months and twelve (12) patients ≥ 24 and < 60 months that have received Dose B.

All patients in the study will be followed for a total of 12 months. The primary analyses for efficacy will be assessed when all patients reach 12 months post-dose.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 27 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase I, Open-Label, Dose Comparison Study of AVXS-101 for Sitting But Non-ambulatory Patients With Spinal Muscular Atrophy
Actual Study Start Date : December 14, 2017
Estimated Primary Completion Date : August 30, 2019
Estimated Study Completion Date : August 30, 2019


Arm Intervention/treatment
Experimental: Dose A
Intrathecal administration 6.0 X 10^13 vg of AVXS-101
Biological: AVXS-101
Self-complementary AAV9 carrying the SMN gene under the control of a hybrid CMV enhancer/chicken-β-actin promoter

Experimental: Dose B
Intrathecal administration 1.2 X 10^14 vg of AVXS-101
Biological: AVXS-101
Self-complementary AAV9 carrying the SMN gene under the control of a hybrid CMV enhancer/chicken-β-actin promoter




Primary Outcome Measures :
  1. Incidence of Adverse Events [ Time Frame: 12 months ]
    To assess the safety and tolerability of intrathecal administration of AVXS-101 by the incidence and severity of adverse events

  2. Determine Optimal Dose [ Time Frame: 12 months ]
    To determine the optimal dose of AVXS-101 that demonstrates acceptable safety with maximum preliminary efficacy administered by intrathecal injection

  3. Patients < 24 months patients: Standing Milestone [ Time Frame: 12 months ]
    Proportion of patients < 24 months at time of dosing achieving the ability to stand without support for at least three seconds

  4. Patients ≥ 24 months and < 60 months patients: Change in HFMSE [ Time Frame: 12 months ]
    Change in Hammersmith Functional Motor Scale-Expanded from baseline among patients ≥ 24 months at time of dosing


Secondary Outcome Measures :
  1. Patients < 24 months patients: Walking Milestone [ Time Frame: 12 months ]
    Proportion of patients that achieve ability to walk without assistance defined as taking at least five steps independently displaying coordination and balance (Bayley Scales of Infant and Toddler Development - Gross Motor Subset #43)

  2. Patients ≥ 24 months and < 60 months patients: Walking Milestone [ Time Frame: 12 months ]
    Proportion of patients that achieve ability to walk without assistance defined as taking at least five steps independently displaying coordination and balance (Bayley Scales of Infant Development -Gross Motor Subset #43)


Other Outcome Measures:
  1. Change from baseline in Bayley Scales [ Time Frame: 12 months ]
    Change from baseline in fine and gross motor components of the Bayley Scales of Infant and Toddler Development, v 3.0- a standardized, norm-referenced infant assessment of developmental functioning across 5 domains. The motor subtests will be used in this study.



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Ages Eligible for Study:   up to 60 Months   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Key Inclusion Criteria

  • Patients up to 60 months (1800 days) of age at time of dosing following diagnostic confirmation during screening period by genotype who demonstrate the ability to sit unassisted for 10 or more seconds but cannot stand or walk
  • Diagnostic confirmation by genotype includes lab documentation of homozygous absence of SMN1 exon 7; with exactly three copies of SMN2
  • Negative gene testing for SMN2 gene modifier mutation (c.859G>C)
  • Onset of clinical signs and symptoms consistent with spinal muscular atrophy (SMA) at < 12 months of age
  • Able to sit independently and not standing or walking independently. Definition of sitting independently is defined by the World Health Organization Multicentre Growth Reference Study (WHO-MGRS) criteria of being able to sit up unsupported with head erect for at least 10 seconds.

Key Exclusion Criteria

  • Current or historical ability to stand or walk independently
  • Contraindications for spinal tap procedure or administration of intrathecal therapy (e.g., spina bifida, meningitis, impairment, or clotting abnormalities, or obstructive spinal hardware preventing effective access to cerebrospinal fluid (CSF) space) or presence of an implanted shunt for the drainage of CSF or an implanted central venous (CNS) catheter
  • Severe contractures as determined by designated Physical Therapist(s) at screening that interfere with either the ability to attain/demonstrate functional measures (e.g., standing, walking) or interferes with ability to receive intrathecal (IT) dosing
  • Severe scoliosis (defined as ≥ 50° curvature of spine) evident on X-ray examination
  • Previous, planned or expected scoliosis repair surgery/procedure within 1 year of dose administration
  • Use of invasive ventilatory support (tracheotomy with positive pressure) or pulse oximetry < 95% saturation at screening while the patient is awake
  • Use or requirement of non-invasive ventilatory support for 12 or more hours daily over the two (2) weeks prior to dosing
  • Medical necessity for a gastric feeding tube, where the majority of feedings are given by non-oral methods (i.e., nasogastric tube or nasojejunal tube) or patients whose weight-for-age falls below the 3rd percentile based on WHO Child Growth Standards (Onis 2006). Placement of a permanent gastrostomy prior to screening is not an exclusion

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): NCT03381729


Contacts
Contact: AveXis MedInfo 833-828-3947 medinfo@avexis.com

Locations
United States, California
UCLA Recruiting
Los Angeles, California, United States, 90095
Contact: Clara Sam    310-825-3264    chsam@mednet.ucla.edu   
Principal Investigator: Perry Shieh, MD/PhD         
Stanford University Recruiting
Stanford, California, United States, 94305
Contact: Shirley Paulose    650-724-3792    spaulose@stanford.edu   
Principal Investigator: John Day, MD         
United States, Florida
Nemours Children's Hospital Recruiting
Orlando, Florida, United States, 32827
Contact: Debbie Berry    407-650-7523    debbie.berry@nemours.org   
Principal Investigator: Richard Finkel, MD         
United States, Illinois
Ann & Robert H. Lurie Children's Hospital Recruiting
Chicago, Illinois, United States, 60611
Contact: Hannah Munson    312-227-2201    hmunson@luriechildrens.org   
Principal Investigator: Nancy Kuntz, MD         
United States, Maryland
Johns Hopkins Recruiting
Baltimore, Maryland, United States, 21287
Contact: Agnes Rennie    443-287-6294    aking2@jhmi.edu   
Principal Investigator: Tom Crawford, MD         
United States, Massachusetts
Boston Children's Hospital Recruiting
Boston, Massachusetts, United States, 02115
Contact: Grace Ordonez    617-355-7384    grace.ordonez@childrens.harvard.edu   
Principal Investigator: Basil Darras, MD         
United States, Missouri
Washington University Recruiting
Saint Louis, Missouri, United States, 63130
Principal Investigator: Anne Connolly, MD         
United States, Ohio
Nationwide Children's Hospital Recruiting
Columbus, Ohio, United States, 43205
Contact: Markus McColly    614-355-2825    Markus.McColly@nationwidechildrens.org   
Principal Investigator: Jerry Mendell, MD         
United States, Pennsylvania
Children's Hospital of Philadelphia Recruiting
Philadelphia, Pennsylvania, United States, 19104
Contact: Diane Barcoski    267-425-0158    barcoskid@email.chop.edu   
Contact: Josh Zigmont    267-426-7161    zigmontj@email.chop.edu   
Principal Investigator: Gihan Tennekoon, MD         
United States, Texas
UT Southwestern Not yet recruiting
Dallas, Texas, United States, 75390
Principal Investigator: Susan Iannaccone, MD         
United States, Utah
University of Utah Recruiting
Salt Lake City, Utah, United States, 84112
Contact: Bryant Gordon    801-585-5052    Bryant.Gordon@hsc.utah.edu   
Principal Investigator: Nicholas Johnson, MD         
Sponsors and Collaborators
AveXis, Inc.

Publications:
Responsible Party: AveXis, Inc.
ClinicalTrials.gov Identifier: NCT03381729     History of Changes
Other Study ID Numbers: AVXS-101-CL-102
First Posted: December 22, 2017    Key Record Dates
Last Update Posted: February 12, 2018
Last Verified: February 2018

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by AveXis, Inc.:
Gene Transfer
Gene Therapy
Adeno-associated virus
Survival Motor Neuron
SMN
AAV9

Additional relevant MeSH terms:
Atrophy
Muscular Atrophy
Muscular Atrophy, Spinal
Spinal Cord Diseases
Pathological Conditions, Anatomical
Neuromuscular Manifestations
Neurologic Manifestations
Nervous System Diseases
Signs and Symptoms
Central Nervous System Diseases
Motor Neuron Disease
Neurodegenerative Diseases
Neuromuscular Diseases