Working…
ClinicalTrials.gov
ClinicalTrials.gov Menu

Study of Intrathecal Administration of Onasemnogene Abeparvovec-xioi for Spinal Muscular Atrophy (STRONG)

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.
 
ClinicalTrials.gov Identifier: NCT03381729
Recruitment Status : Suspended (FDA placed AVXS-101 IT administration studies on clinical hold pending further discussions regarding pre-clinical findings.)
First Posted : December 22, 2017
Last Update Posted : November 25, 2019
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 onasemnogene abeparvovec-xioi in infants and children with Spinal Muscular Atrophy with 3 copies of SMN2 and deletion of SMN1.

Condition or disease Intervention/treatment Phase
Spinal Muscular Atrophy Biological: Onasemnogene Abeparvovec-xioi Phase 1

  Show Detailed Description

Layout table for study information
Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 51 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 : June 1, 2021
Estimated Study Completion Date : June 1, 2021


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

Experimental: Dose C
Intrathecal administration 2.4 X 10^14 vg of onasemnogene abeparvovec-xioi
Biological: Onasemnogene Abeparvovec-xioi
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: Baseline to 15 months ]
    To assess the safety and tolerability of intrathecal administration of onasemnogene abeparvovec-xioi by the incidence and severity of adverse events.

  2. Determine Optimal Dose [ Time Frame: Baseline to 15 months ]
    To determine the optimal dose of AVXonasemnogene abeparvovec-xioiS-101 that demonstrates acceptable safety with maximum preliminary efficacy administered by intrathecal injection.

  3. Patients ≥ 6 months and < 24 months: Standing Milestone [ Time Frame: Baseline to 12 months ]
    Percentage of patients that achieve ability to stand without support for at least three seconds (Bayley Scales of Infant Development - Gross Motor Subset #40).

  4. Patients ≥ 24 months and < 60 months: Change from Baseline in the Hammersmith Functional Motor Scale-Expanded (HFMSE) score [ Time Frame: Baseline, 12 months ]
    Assessed in patients ≥ 24 months and < 60 months at time of dosing.


Secondary Outcome Measures :
  1. Patients ≥ 6 months and < 24 months: Walking Milestone [ Time Frame: Baseline to 12 months ]
    Percentage 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: Walking Milestone [ Time Frame: Baseline to 12 months ]
    Percentage 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).

  3. Change from Baseline in Ventilation Support [ Time Frame: Baseline, 15 months ]
    Change from baseline in the number of hours of non-invasive ventilation support required per day.


Other Outcome Measures:
  1. Change from baseline in Bayley Scales [ Time Frame: Baseline, 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.

  2. Patients ≥ 6 months and < 24 months: Change from Baseline in the Hammersmith Functional Motor Scale-Expanded (HFMSE) score [ Time Frame: Baseline, 12 months ]
    Assessed in patients ≥ 6 months and < 24 months at time of dosing.



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.


Layout table for eligibility information
Ages Eligible for Study:   6 Months to 60 Months   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Key Inclusion Criteria

  • Patients ≥6 months and 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. Child should not use arms or hands to balance body or support position (Wijnhoven 2004)
  • Be up-to-date on childhood vaccines 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 (AAP 2009)

Key Exclusion Criteria

  • Current or historical ability to stand or walk independently
  • Contraindications for spinal tap procedure or administration of intrathecal therapy 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 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, or for high altitudes > 1000 m, oxygen saturation < 92% while the patient is awake
  • Pulse oximetry saturation must not decrease ≥ four (4) percentage points between screening and highest value on day of dosing
  • 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
  • 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 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
  • Active viral infection (includes human immunodeficiency virus (HIV) or serology positive for hepatitis B or C, or Zika virus)
  • Serious non-respiratory tract illness requiring systemic treatment and/or hospitalization within two (2) weeks prior to study entry
  • Respiratory infection requiring medical attention, medical intervention or increase in supportive care of any manner within four (4) weeks prior to study entry
  • Severe non-pulmonary/respiratory tract infection within four (4) weeks before study dosing or concomitant illness that in the opinion of the Principal Investigator (PI) creates unnecessary risks for gene transfer such as:

    • Major renal or hepatic impairment
    • Known seizure disorder
    • Diabetes mellitus
    • Idiopathic hypocalciuria
    • Symptomatic cardiomyopathy
  • History of bacterial meningitis or brain or spinal cord disease, including tumors, or abnormalities by magnetic resonance imaging (MRI) or computerized tomography (CT) that would interfere with the lumbar puncture (LP) procedures or CSF circulation
  • Known allergy or hypersensitivity to prednisolone or other glucocorticosteroids or their excipients
  • Known allergy or hypersensitivity to iodine or iodine-containing products
  • 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, or immunosuppressive therapy within 3 months of study dosing
  • Inability to withhold use of laxatives or diuretics in the 24 hours prior to dose administration
  • Anti-AAV9 antibody titers >1:50 as determined by Enzyme-linked Immunosorbent Assay (ELISA) binding immunoassay

    • Should a potential patient 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 (GGT, ALT, and AST, or total bilirubin > 2 × ULN, 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. Patients with an elevated bilirubin level that is unequivocally the result of neonatal jaundice shall not be excluded
  • Participation in recent SMA treatment clinical trial or receipt of an investigational or approved compound product or therapy received with the intent to treat SMA at any time prior to screening for this study

    • Oral beta agonists must be discontinued 30 days prior to 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 1-year study assessment period

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


Locations
Layout table for location information
United States, California
UCLA
Los Angeles, California, United States, 90095
Stanford University
Stanford, California, United States, 94305
United States, Florida
Nemours Children's Hospital
Orlando, Florida, United States, 32827
United States, Illinois
Ann & Robert H. Lurie Children's Hospital
Chicago, Illinois, United States, 60611
United States, Maryland
Johns Hopkins
Baltimore, Maryland, United States, 21287
United States, Massachusetts
Boston Children's Hospital
Boston, Massachusetts, United States, 02115
United States, Missouri
Washington University
Saint Louis, Missouri, United States, 63130
United States, Ohio
Nationwide Children's Hospital
Columbus, Ohio, United States, 43205
United States, Pennsylvania
Children's Hospital of Philadelphia
Philadelphia, Pennsylvania, United States, 19104
United States, Texas
UT Southwestern
Dallas, Texas, United States, 75390
United States, Utah
University of Utah
Salt Lake City, Utah, United States, 84112
Sponsors and Collaborators
AveXis, Inc.

Publications:
Layout table for additonal information
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: November 25, 2019
Last Verified: November 2019

Layout table for additional information
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:
Layout table for MeSH terms
Muscular Atrophy
Muscular Atrophy, Spinal
Atrophy
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