AVXS-101 STRIVE

Principal Investigator: Russell Butterfield
Keywords: Spinal Musculas Atrpohy , SMA Type 1 , Gene Replacement Therapy , SMA , AVXS-101 Department: Pediatric Administration
IRB Number: 00099640 Co Investigator: Russell Butterfield
Specialty: Neurology, Neurology
Sub Specialties: Neuromuscular Diseases, Spinal Muscular Atrophy
Recruitment Status: Not yet recruiting

Contact Information

Nicholas Johnson
nicholas.johnson@hsc.utah.edu
801-581-3724

Brief Summary

Primary Objectives

The co-primary objectives are to:

  • Determine the efficacy of AVXS-101 by demonstrating achievement of developmental milestone of functional independent sitting for at least 30 seconds at the 18 months of age study visit.
  • Determine the efficacy of AVXS-101 based on survival at 14 months of age. Survival is defined by the avoidance of combined endpoint of either (a) death or (b) permanent ventilation, which is defined by tracheostomy or by the requirement of ≥ 16 hours of respiratory assistance per day (via non-invasive ventilatory support) for ≥ 14 consecutive days in the absence of an acute reversible illness, excluding perioperative ventilation. Permanent ventilation, so defined, is considered a surrogate for death.

Secondary Objective

The co-secondary objectives are to:

  • Determine the effect of AVXS-101 on the on the ability to thrive defined as achieving all of the following at 18 months of age
    • Does not receive nutrition through mechanical support (e.g., feeding tube)
    • Ability to tolerate thin liquids as demonstrated through a formal swallowing test
    • Maintains weight (> third percentile for age and gender)
  • Determine the effect of AVXS-101 on the ability to remain independent of ventilatory support, defined as requiring no daily ventilator support/usage at 18 months of age, excluding acute reversible illness and perioperative ventilation, as defined above through assessment of actual usage data captured from the device, for patients issued a Trilogy 100 BiPAP device

Exploratory Objectives

For the following exploratory efficacy endpoints, a Responder will be defined as a patient who demonstrates achievement of the endpoint at any post-procedure visit up to and including the 18 months of age study visit.

  • Determine the efficacy of AVXS-101 by demonstrating achievement of developmental milestone of ability to hold head erect without support
  • Determine the efficacy of AVXS-101 by demonstrating achievement of developmental milestone of ability to roll from back to both sides
  • Determine the efficacy of AVXS-101 by demonstrating achievement of developmental milestone of ability to sit with support
  • Determine the efficacy of AVXS-101 by demonstrating achievement of developmental milestone of ability to sit independently (> 10 seconds; WHO [22])
  • Determine the efficacy of AVXS-101 by demonstrating achievement of developmental milestone of ability to crawl
  • Determine the efficacy of AVXS-101 by demonstrating achievement of developmental milestone of ability to pull to stand
  • Determine the efficacy of AVXS-101 by demonstrating achievement of developmental milestone of ability to stand with assistance
  • Determine the efficacy of AVXS-101 by demonstrating achievement of developmental milestone of ability to stand alone
  • Determine the efficacy of AVXS-101 by demonstrating achievement of developmental milestone of ability to walk with assistance
  • Determine the efficacy of AVXS-101 by demonstrating achievement of developmental milestone of ability to walk alone
  • Determine the efficacy of AVXS-101 by demonstrating improvement of motor function as determined by improvement in the fine and gross motor domain components of the Bayley Scales of Infant and Toddler Development (Version 3)
  • Determine the efficacy of AVXS-101 by demonstrating improvement of gross motor function as determined by improvement in Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders [23,24] (CHOP-INTEND) score
  • Characterize physiological efficacy of AVXS-101 by demonstrating improvement in peroneal nerve compound motor action potential (CMAP) amplitude

Safety Objectives

The safety objectives are to:

  • Evaluate the safety of AVXS-101 in patients with SMA Type 1
  • Determine the safety of AVXS-101 based on the development of unacceptable toxicity defined as the occurrence of any Common Terminology Criteria for Adverse Events (CTCAE) [9] Grade 3 or higher, unanticipated, treatment-related toxicity.

Inclusion Criteria


1.    Patients with SMA Type 1 as determined by the following features:
a.    Diagnosis of SMA based on gene mutation analysis with bi-allelic SMN1 mutations (deletion or point mutations) and 1 or 2 copies of SMN2 (inclusive of the known SMN2 gene modifier mutation (c.859G>C))
2.    Patients must be < 6 months (< 180 days) of age at the time of AVXS-101 infusion
3.    Patients must have a swallowing evaluation test performed prior to administration of gene replacement therapy
4.    Up-to-date on childhood vaccinations. Seasonal vaccinations 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 (27)
5.    Parent(s)/legal guardian(s) willing and able to complete the informed consent process and comply with study procedures and visit schedule including parental blood draw from mothers 

6.Informed consent will be requested from the biological mother of the patient to screen the mother for circulating antibodies to AAV9 

Exclusion Criteria


1.    Previous, planned or expected scoliosis repair surgery/procedure during the study assessment period
2.    Pulse oximetry < 96% saturation at screening while the patient is awake or asleep without any supplemental oxygen or respiratory support, or for altitudes > 1000 m, oxygen saturation
< 92% awake or asleep without any supplemental oxygen or respiratory support
Pulse oximetry saturation may decrease to < 96% after screening provided that the saturation does not decrease by ≥ 4 percentage points
3.    Tracheostomy or current use or requirement of non-invasive ventilatory support averaging
≥ 6 hours/day over the 7 days prior to the screening visit; or ≥ 6 hours/day on average during the screening period or requiring ventilatory support while awake over the 7 days prior to screening or at any point during the screening period prior to dosing
4.    Patients with signs of aspiration/inability to tolerate non-thickened liquids based on a formal swallowing test performed as part of screening. Patients with a gastrostomy tube who pass the swallowing test will be allowed to enroll in the study
5.    Patients whose weight-for-age is below the third percentile based on World Health Organization (WHO) Child Growth Standards [26]
6.    Active viral infection (includes human immunodeficiency virus [HIV] or positive serology for hepatitis B or C, or Zika virus)
7.    Serious non- respiratory tract illness requiring systemic treatment and/or hospitalization within 2 weeks prior to screening
8.    Upper or lower respiratory infection requiring medical attention, medical intervention, or increase in supportive care of any manner within 4 weeks prior to screening
9.    Severe non-pulmonary/respiratory tract infection (e.g., pyelonephritis or meningitis) within
4 weeks before administration of gene replacement therapy or concomitant illness that, in the opinion of the Principal Investigator, creates unnecessary risks for gene replacement therapy such as:
a.    Major renal or hepatic impairment
b.    Known seizure disorder
c.    Diabetes mellitus
d.    Idiopathic hypocalcuria
e.    Symptomatic cardiomyopathy
10.  Known allergy or hypersensitivity to prednisolone or other glucocorticosteroids or their excipients
11.  Concomitant use of any of the following: drugs for the treatment of myopathy or neuropathy, agents used to treat diabetes mellitus, or ongoing immunosuppressive therapy, plasmapheresis, immunomodulators such as adalimumab, immunosuppressive therapy within 3 months prior to gene replacement therapy (e.g., corticosteroids, cyclosporine, tacrolimus, methotrexate, cyclophosphamide, IV immunoglobulin, rituximab)
12.    Anti-AAV9 antibody titer > 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
13.    Clinically significant abnormal laboratory values (international normalized ratio [INR] > 1.4; GGT, ALT, and AST > 3 × ULN; bilirubin ≥ 3.0 mg/dL; creatinine ≥ 1.0 mg/dL; hemoglobin
< 8 or > 18 g/dL; white blood cells [WBC] > 20,000/cmm) prior to gene replacement therapy
14.    Participation in recent SMA treatment clinical study (with the exception of observational cohort studies or non-interventional studies) or receipt of an investigational or commercial compound, product or therapy administered with the intent to treat SMA (e.g., nusinersen, valproic acid) at any time prior to screening for this study. Oral β-agonists must be discontinued at least 30 days prior to gene therapy 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
15.    Expectation of major surgical procedures during the study assessment period (e.g., spinal surgery or tracheostomy)
16.    Parent(s)/legal guardian(s) unable or unwilling to comply with study procedures or inability to travel for repeat visits
17.    Parent(s)/legal guardian(s) unwilling to keep study results/observations confidential or to refrain from posting confidential study results/observations on social media sites
18.    Parent(s)/legal guardian(s) refuses to sign consent form

19. Mother is unwilling to provide blood for antibody screening.