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

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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 13, 2019
Sponsor:
Information provided by (Responsible Party):
AveXis, Inc.

Tracking Information
First Submitted Date  ICMJE December 13, 2017
First Posted Date  ICMJE December 22, 2017
Last Update Posted Date November 13, 2019
Actual Study Start Date  ICMJE December 14, 2017
Estimated Primary Completion Date June 1, 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: August 13, 2019)
  • 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.
  • 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.
  • 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).
  • 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.
Original Primary Outcome Measures  ICMJE
 (submitted: December 18, 2017)
  • 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
  • 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
  • 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
  • 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
Change History Complete list of historical versions of study NCT03381729 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: July 15, 2019)
  • 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).
  • 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).
  • 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.
Original Secondary Outcome Measures  ICMJE
 (submitted: December 18, 2017)
  • 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)
  • 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)
Current Other Pre-specified Outcome Measures
 (submitted: July 15, 2019)
  • 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.
  • 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.
Original Other Pre-specified Outcome Measures
 (submitted: December 18, 2017)
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.
 
Descriptive Information
Brief Title  ICMJE Study of Intrathecal Administration of Onasemnogene Abeparvovec-xioi for Spinal Muscular Atrophy
Official Title  ICMJE Phase I, Open-Label, Dose Comparison Study of AVXS-101 for Sitting But Non-ambulatory Patients With Spinal Muscular Atrophy
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.
Detailed Description

This is a Phase 1, single-dose administration study of infants and children with a genetic diagnosis consistent with spinal muscular atrophy (SMA), bi-allelic deletion of survival motor neuron 1 gene (SMN1) and 3 copies of survival motor neuron 2 gene (SMN2) without the genetic modifier who are able to sit but cannot stand or walk at the time of study entry. Patients will receive onasemnogene abeparvovec-xioi in a dose comparison safety study of two (or three) potential therapeutic doses. Patients will be stratified in two groups, those ≥6 months and < 24 months of age at time of dosing and those ≥ 24 months and < 60 months of age at time of dosing. At least 15 patients ≥ 6 months and < 24 months, and at least 12 patients ≥ 24 < 60 months will be enrolled.

The first cohort will enroll three patients (Cohort 1) ≥ 6 months and < 24 months of age who will receive administration of 6.0 × 1013 vg of onasemnogene abeparvovec-xioi (Dose A). There will be at least a four week interval between the dosing of each patient within the cohort. AveXis, Inc. (AveXis) will confer with the Data Safety Monitoring Board (DSMB) on all Grade III or higher AEs within approximately 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 patients < 60 months of age will be enrolled (Cohort 2) and will receive administration of 1.2 × 1014 vg of onasemnogene abeparvovec-xioi (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 will decide and document during quarterly meetings whether further four-week intervals between patients dosing is necessary. AveXis 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. AveXis will confer with the DSMB on all Grade III or higher AEs within approximately 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 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 12 patients > 6 months and < 24 months and 12 patients ≥ 24 and < 60 months that have all received Dose B.

Based upon an ongoing assessment of safety and efficacy data from patients treated with the 1.2 × 1014 vg dose, an option for testing of a third dose (Dose C), will be considered. If, based on all available data, this is judged to be safe and necessary, three patients < 60 months of age will receive Dose C, 2.4 × 1014 vg administered IT. A meeting of the DSMB will be called to obtain a recommendation on the safety of escalating to a higher dose prior to proceeding. If a decision is made to proceed to testing a higher dose, there will again be a four-week interval between dosing of the first three patients receiving Dose C, as in Cohorts 1 and 2. Safety data will be reviewed by the DSMB during quarterly meetings. Following enrollment of the first three Dose C patients and based upon available safety data, the DSMB will be consulted and a decision will be made whether to: a) stop dosing Dose C due to safety concerns, or b) continue to enroll an additional 21 patients until there are a total of 12 patients > 6 months and < 24 months and 12 patients ≥ 24 and < 60 months that have received Dose C.

Patients from Cohort 3 will be followed for a total of 15 months post-dose. The primary analyses for efficacy will be assessed when all patients reach 12 months post-dose and the primary analyses for safety will be assessed when the last patient of Cohort 3 reaches 15 months post-dose (and database lock will be performed after the last patient reaches 15 months post-dose).

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Spinal Muscular Atrophy
Intervention  ICMJE Biological: Onasemnogene Abeparvovec-xioi
Self-complementary AAV9 carrying the SMN gene under the control of a hybrid CMV enhancer/chicken-β-actin promoter
Study Arms  ICMJE
  • Experimental: Dose A
    Intrathecal administration 6.0 X 10^13 vg of onasemnogene abeparvovec-xioi
    Intervention: Biological: Onasemnogene Abeparvovec-xioi
  • Experimental: Dose B
    Intrathecal administration 1.2 X 10^14 vg of onasemnogene abeparvovec-xioi
    Intervention: Biological: Onasemnogene Abeparvovec-xioi
  • Experimental: Dose C
    Intrathecal administration 2.4 X 10^14 vg of onasemnogene abeparvovec-xioi
    Intervention: Biological: Onasemnogene Abeparvovec-xioi
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Suspended
Estimated Enrollment  ICMJE
 (submitted: July 15, 2019)
51
Original Estimated Enrollment  ICMJE
 (submitted: December 18, 2017)
27
Estimated Study Completion Date  ICMJE June 1, 2021
Estimated Primary Completion Date June 1, 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 6 Months to 60 Months   (Child)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03381729
Other Study ID Numbers  ICMJE AVXS-101-CL-102
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party AveXis, Inc.
Study Sponsor  ICMJE AveXis, Inc.
Collaborators  ICMJE Not Provided
Investigators  ICMJE Not Provided
PRS Account AveXis, Inc.
Verification Date November 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP