A Global Study of a Single, One-Time Dose of AVXS-101 Delivered to Infants with Genetically Diagnosed and Pre-Symptomatic Spinal Muscular Atrophy with Multiple Copies of SMN2
- Conditions
- SMASpinal Muscular Atrophy10029317
- Registration Number
- NL-OMON46178
- Lead Sponsor
- A
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- Withdrawn
- Sex
- Not specified
- Target Recruitment
- 3
All patients
* Age *6 Weeks (*42 days) at time of dose
* Ability to tolerate thin liquids as demonstrated through a formal bedside swallowing test
* Compound muscle action potential (CMAP) *2 mV at Baseline; centralized review of CMAP data will be conducted
* Gestational age of 35 to 42 weeks
* 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 the guidance of local health authorities.
* Able and willing to follow the Consensus Statement for Standard of Care in Spinal Muscular Atrophy.
* Parent(s)/legal guardian(s) willing and able to complete the informed consent process and comply with study procedures and visit schedule
* Genetic diagnosis as described below, obtained from an acceptable newborn or pre-natal screening test method
Patients with 2 copies of SMN2 (n *15)
* Patients with pre-symptomatic SMA Type 1 as determined by the following features:
* 2 copies of SMN2
Patients with 3 copies of SMN2 (n *12)
* Patients with pre-symptomatic SMA Type 2 as determined by the following features:
* 3 copies of SMN2
* Weight at screening visit <2 kg
* Hypoxemia (oxygen saturation <96% awake or asleep without any supplemental oxygen or respiratory support) at the screening visit or for altitudes >1000 m, oxygen saturation <92% awake or asleep without any supplemental oxygen or respiratory support at the screening visit
* Any clinical signs or symptoms at screening or immediately prior to dosing that are, in the opinion of the Investigator, strongly suggestive of SMA (e.g., tongue fasciculation, hypotonia, areflexia)
* Tracheostomy or current prophylactic use or requirement of non invasive ventilatory support at any time and for any duration prior to screening or during the screening period
* Patients with signs of aspiration/inability to tolerate non thickened liquids based on a formal swallowing test performed as part of screening or patients receiving any non-oral feeding method
* Clinically significant abnormalities in hematology or clinical chemistry parameters as determined by the investigator or medical monitor
* Treatment with an investigational or commercial product, including nusinersen, given for the treatment of SMA. This includes any history of gene therapy, prior antisense oligonucleotide treatment, or cell transplantation.
* Patients whose weight-for-age is below the third percentile based on World Health Organization (WHO) Child Growth Standards [33]
* Biological mother with active viral infection as determined by screening laboratory samples (includes human immunodeficiency virus [HIV] or positive serology for hepatitis B or C)
* Biological mothers with clinical suspicion of Zika virus that meet Centers for Disease Control and Prevention (CDC) Zika virus epidemiological criteria including history of residence in or travel to a geographic region with active Zika transmission at the time of travel will be tested for Zika virus RNA; positive results warrant confirmed negative Zika virus ribonucleic acid (RNA) testing in the patient prior to enrollment
* Serious non respiratory tract illness requiring systemic treatment and/or hospitalization within 2 Weeks prior to screening
* Upper or lower respiratory infection requiring medical attention, medical intervention, or increase in supportive care of any manner within 4 Weeks prior to dosing
* 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 Investigator or Sponsor medical monitor, creates unnecessary risks for gene replacement therapy such as:
* Major renal or hepatic impairment
* Known seizure disorder
* Diabetes mellitus
* Idiopathic hypocalciuria
* Symptomatic cardiomyopathy
* Known allergy or hypersensitivity to prednisolone or other glucocorticosteroids or their excipients
* Previous, planned or expected major surgical procedure including scoliosis repair surgery/procedure during the study assessment period
* 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, immunosuppressive therapy within 4 Weeks prior to gene replacement therapy (e.g., corticosteroids, cyclosporine, tacrolimus, methotrexate, cyclophosphamide, IV immunoglobulin, rituximab)
* Anti AAV9 antibody titer >1:50 as deter
Study & Design
- Study Type
- Interventional
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method <p>Criteria for Evaluation:<br /><br>Safety:<br /><br>Primary:<br /><br>*Incidence of adverse events (AEs) and/or serious adverse events (SAEs)<br /><br>*Change from baseline in clinical laboratory parameters<br /><br>Efficacy objectives will be assessed independently for each cohort.<br /><br><br /><br>Efficacy for patients with bi-allelic SMN1 deletions and 2 copies of SMN2:<br /><br>Primary:<br /><br>*Proportion of patients achieving the development milestone of functional<br /><br>independent sitting at any visit up to 18 months of age<br /><br><br /><br>Efficacy for patients with bi-allelic SMN1 deletions and 3 copies of SMN2:<br /><br>Primary:<br /><br>*Proportion of patients achieving the ability to stand without support for at<br /><br>least three seconds at any visit up to 24 months of age</p><br>
- Secondary Outcome Measures
Name Time Method <p>Patients with 2 copies of SMN2:<br /><br>* Proportion of patients that have survived and have not required permanent<br /><br>ventilation in the absence of acute illness or perioperatively<br /><br>assessed at 14 months of age<br /><br>* Proportion of patients that have achieved the ability to maintain weight at<br /><br>or above the third percentile without need for nonoral/mechanical feeding<br /><br>support at any visit up to 18 months of age<br /><br>Patients with 3 copies of SMN2:<br /><br>* Proportion of patients demonstrating the ability to walk alone definedas the<br /><br>ability to take at least five steps independently displaying<br /><br>coordination and balance at any visit up to 24 months of age</p><br>