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

• Register: ClinicalTrials.gov
• Last refreshed on: 1 May 2023
• Main ID: NCT03381729
• Date of registration: 13/12/2017
• Prospective Registration: Yes
• Primary sponsor: Novartis Gene Therapies
• Public title: Study of Intrathecal Administration of Onasemnogene Abeparvovec-xioi for Spinal Muscular Atrophy STRONG
• Scientific title: Phase I, Open-Label, Dose Comparison Study of AVXS-101 for Sitting But Non-ambulatory Patients With Spinal Muscular Atrophy
• Date of first enrolment: December 14, 2017
• Target sample size: 32
• Recruitment status: Terminated
• URL: https://clinicaltrials.gov/show/NCT03381729
• Study type: Interventional
• Study design: Allocation: Non-Randomized. Intervention model: Parallel Assignment. Primary purpose: Treatment. Masking: None (Open Label).
• Phase: Phase 1

Countries of recruitment

United States

Key inclusion & exclusion 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



Age minimum: 6 Months
Age maximum: 60 Months
Gender: All

Health Condition(s) or Problem(s) studied

Spinal Muscular Atrophy

Intervention(s)

Biological: Onasemnogene Abeparvovec-xioi

Primary Outcome(s)

Number of Participants Who Experienced a Treatment-emergent Adverse Event (TEAE) [Time Frame: Adverse events were collected from the single dose of study treatment until the end of study visit (12 months for Cohort 1 and 2 and 15 months for Cohort 3)]

Age 24 to <60 Months Only: Change From Baseline in Hammersmith Functional Motor Scale-Expanded (HFMSE) Score at Month 12 [Time Frame: Baseline and Month 12]

Age 6 to <24 Months Only: Number of Participants Who Achieved the Ability to Stand Alone [Time Frame: From Day 1 up to Month 12]

Secondary Outcome(s)

Average Number of Hours Per Day of Non-invasive Ventilatory Support [Time Frame: Months 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12]

Number of Participants Who Achieved the Ability to Walk Alone [Time Frame: From Day 1 up to Month 12]

Secondary ID(s)

COAV101A12102

2020-003678-28

AVXS-101-CL-102

Source(s) of Monetary Support

Please refer to primary and secondary sponsors

Results

• Results available: Yes
• Date Posted: 16/02/2023
• URL: https://clinicaltrials.gov/ct2/show/results/NCT03381729