Single dose gene replacement therapy clinical trial for infants with genetically diagnosed and pre-symptomatic Spinal Muscular Atrophy

• Register: EUCTR
• Last refreshed on: 30 August 2021
• Main ID: EUCTR2017-004087-35-BE
• Date of registration: 16/05/2018
• Prospective Registration: Yes
• Primary sponsor: AveXis, Inc.
• Public title: Single dose gene replacement therapy clinical trial for infants with genetically diagnosed and pre-symptomatic Spinal Muscular Atrophy
• Scientific title: 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 - SPR1NT
• Date of first enrolment: 31/01/2019
• Target sample size: 29
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2017-004087-35
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: no Randomised: no Open: yes Single blind: no Double blind: no Parallel group: no Cross over: no Other: yes Other trial design description: Open-label, single-arm, single-dose If controlled, specify comparator, Other Medicinial Product: no Placebo: no Other: no
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): no Therapeutic confirmatory - (Phase III): yes Therapeutic use (Phase IV): no

Countries of recruitment

Australia, Belgium, Canada, Germany, Israel, Italy, Japan, Korea, Democratic People's Republic of, Netherlands, Spain, Taiwan, United Kingdom, United States

Contacts

• Name: Sr. Global Trial Operations Manager
• Affiliation: AveXis, Inc.

• Name: Sr. Global Trial Operations Manager
• Affiliation: AveXis, Inc.

Key inclusion & exclusion criteria

Inclusion criteria:
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
• Gestational age of 35 to 42 weeks
• Genetic diagnosis as described below, obtained from an acceptable newborn or pre-natal screening test method

Patients with 2 copies of SMN2
• Patients with pre-symptomatic SMA Type 1 as determined by the following features:
• Bi-allelic deletion of SMN1
• 2 copies of SMN2

Patients with 3 copies of SMN2
• Patients with pre-symptomatic SMA Type 2 as determined by the following features:
• Bi-allelic deletion of SMN1
• 3 copies of SMN2






Are the trial subjects under 18? yes
Number of subjects for this age range: 29
F.1.2 Adults (18-64 years) no
F.1.2.1 Number of subjects for this age range
F.1.3 Elderly (>=65 years) no
F.1.3.1 Number of subjects for this age range

Exclusion criteria:
• Weight at screening visit <2 kg
• Hypoxemia (oxygen saturation <96% 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 abnormal laboratory values (GGT, ALT, and AST , or total bilirubin > 2 × the 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.
• Patients with any other 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
• 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
• 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 determined by Enzyme linked Immunosorbent Assay (ELISA) binding immunoassay






Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Spinal Muscular Atrophy

Therapeutic area: Diseases [C] - Nervous System Diseases [C10]

Intervention(s)

Product Name: AVXS-101 (previously known as scAAV9.CB.SMN)
Product Code: AVXS-101
Pharmaceutical Form: Infusion
INN or Proposed INN: onasemnogene abeparvovec
CAS Number: 1922968-73-7
Current Sponsor code: AVXS-101
Concentration unit: vector genomes (vg)/mL
Concentration type: range
Concentration number: 20000000000000-60000000000000

Primary Outcome(s)

Secondary Objective: Efficacy for patients with 2 copies of SMN2:
• Determine the efficacy of AVXS-101 based on survival, defined as avoidance of death or the requirement of permanent ventilation in the absence of acute illness or perioperatively as assessed at 14 months of age
• Assess efficacy of AVXS-101 by demonstrating the ability to maintain weight at or above the third percentile without need for non-oral/mechanical feeding support at any visit up to 18 months of age

Efficacy for patients with 3 copies of SMN2:
• • Assess the efficacy of AVXS-101 by demonstrating the ability to walk alone defined as the ability to take at least five steps independently displaying coordination and balance at any visit up to 24 months of age

Primary end point(s): Criteria for Evaluation:
Safety:
Primary:
• Incidence of adverse events (AEs) and/or serious adverse events (SAEs)
• Change from baseline in clinical laboratory parameters

Efficacy objectives will be assessed independently for each cohort.

Efficacy for patients with 2 copies of SMN2:
Primary:
• Proportion of patients achieving the development milestone of functional independent sitting at any visit up to 18 months of age

Efficacy for patients with 3 copies of SMN2:
Primary:
• Proportion of patients achieving the ability to stand without support for at least three seconds at any visit up to 24 months of age

Main Objective: Safety
• Evaluate the safety of AVXS-101 through incidence of adverse events (AEs) and/or serious adverse events (SAEs)
• Evaluate the safety of AVXS-101 based on the change from baseline in clinical laboratory parameters

Efficacy objectives will be assessed independently for each cohort.
Efficacy for patients with bi-allelic SMN1 deletions and 2 copies of SMN2:
• Assess the efficacy of AVXS-101 by demonstrating functional independent sitting for at least 30 seconds up to 18 months of age
Efficacy for patients with 3 copies of SMN2:
• Assess the efficacy of AVXS-101 based on the proportion of patients achieving the ability to stand without support for at least three seconds up to 24 months of age
e

Timepoint(s) of evaluation of this end point: Patients with 2 copies of SMN2:
18 months of age
Patients with 3 copies of SMN2:
24 months of age

Secondary Outcome(s)

Secondary end point(s): Patients with 2 copies of SMN2:
• Proportion of patients that have survived and have not required permanent ventilation in the absence of acute illness or perioperatively assessed at 14 months of age
• Proportion of patients that have achieved the ability to maintain weight at or above the third percentile without need for non-oral/mechanical feeding support at any visit up to 18 months of age


Patients with 3 copies of SMN2:
• Proportion of patients demonstrating the ability to walk alone defined as the ability to take at least five steps independently displaying coordination and balance at any visit up to 24 months of age

Timepoint(s) of evaluation of this end point: Patients with 2 copies of SMN2:
• Proportion of patients that have survived and have not required permanent ventilation assessed at 14 months of age
• Proportion of patients that have achieved the ability to maintain weight at or above the third percentile without need for non-oral/mechanical feeding support at any visit up to 18 months of age

Patients with 3 copies of SMN2:
• 24 months of age

Secondary ID(s)

2017-004087-35-ES

AVXS-101-CL-304

Source(s) of Monetary Support

AveXis, Inc.

Ethics review

Status: Approved
Approval date: 21/06/2018
Contact: