SPRINT - 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
Study ID: STU 022018-080
This is a Phase 3, open-label, single-arm study of a single, one-time dose of aVXS-101 (gene replacement therapy) in patients with SMa who meet enrollment criteria and are genetically defined by bi-allelic deletion of SMn1 with 2, 3, or 4 copies of survival motor neuron 2 gene (SMn2). The study includes a screening period, a gene replacement therapy period, and a follow-up period. Patients will receive a single, one-time intravenous (iV) infusion of aVXS-101. During the outpatient follow-up period, patients will return at regularly scheduled intervals until the end of Study. after the end of Study visit, eligible patients will be asked to rollover into a long-term follow up study. at least fifteen (15) patients with bi-allelic deletion of SMn1 and 2 copies of SMn2, at least twelve (12) patients with bi-allelic deletion of SMn1 and 3 copies of SMn2 and at least seventeen (17) patients with bi-allelic deletion of SMn1 and 4 copies of SMn2 that are [LessThanorequalTo]6 weeks of age at the time of gene replacement therapy (Day 1) will be enrolled. The study includes a screening period, a gene replacement therapy period, and a follow-up period. During the screening period (Days x30 to x2) and after obtaining informed consent, patients will undergo screening procedures to determine eligibility. eligible patients will enter the in-patient gene replacement therapy period (Day x1 to Day 2) and will receive a single, one-time intravenous (iV) infusion of aVXS-101 on Day -1, with inpatient safety monitoring over the next 24 hours. Patients may be discharged 24 hours after the infusion. During the outpatient follow-up period (Days 3 to end of Study at 18, 24 or 36 months of age, dependent upon respective SMn2 copy number), patients will return at regularly scheduled intervals until the end of Study. after the end of Study visit, eligible patients will be asked to rollover into a long-term follow up study. Follow-up visits will occur every week for the first four weeks followed by Month 2 and 3, then every 3 months, based on patient age, The eoS visit for patients with 2, 3, and 4 copies of SMn2 will be the 18, 24, and 36 months old visits, respectively. all patients will receive prophylactic prednisolone at approximately 1 mg/kg/day beginning 24 hours prior to aVXS-101 infusion until at least 30 days post-infusion. The primary and secondary endpoints and will be referred to as the intent-To-Treat (iTT) population. Patients with SMn1 point mutations and patients with the SMn2 gene modifier mutation (c.859G[Greater Than]C) will be evaluated separately as part of additional subgroup analyses.
Age <=6 weeks (<=42 days) at time of dose 2. Ability to tolerate thin liquids as demonstrated through a formal bedside swallowing test 3. Compound muscle action potential (CMAP) >=2mV at Baseline; centralized review of CMAP data will be conducted 4. Gestational age of 35 to 42 weeks 5. 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. 6. Able and willing to follow the Consensus Statement for Standard of Care in Spinal Muscular Atrophy 7. Parent(s)/legal guardian(s) willing and able to complete the informed consent process and comply with study procedures and visit schedule 8. 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: [?] 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 Patients with 4 copies of SMN2 (n >=17) * Patients with pre-symptomatic SMA Type 3 as determined by the following features: [?] 4 copies of SMN2
- Cancer Related
- Healthy Volunteers
- UT Southwestern Principal Investigator
- SUSAN THERESA IANNACCONE
evaluate the safety of aVXS-101 through incidence of adverse events (aes) and or serious adverse events. evaluate the safety of aVXS-101 based on the change from baseline in clinical laboratory parameters. efficacy to assess survival and maintaining weight, achievement of motor milestones, respiratory intervention, and tracheostomy events between the 3 cohorts. Patients with pre-symptomatic genetically diagnosed Spinal Muscular atrophy(SMa) have been chosen as the target population for this gene therapy study based on studies of the natural history of this disease. The classification of SMa in which SMa Types 0 to 4 are described. Spinal muscular atrophy is conventionally classified into 4 phenotypes on the basis of age at onset and highest motor function achieved, with an additional phenotype (Type 0) to describe the severe forms of antenatal-onset SMa. Clinical Studies, a robust clinical response was seen amongst symptomatic patients with 2 copies of SMn2 and early symptom onset consistent with SMa Type 1, with 9 of 12 patients treated at the proposed therapeutic dose achieving the ability to sit independently, and 11 of 12 surpassing a CHoP-inTenD score of 40 points, a threshold not achieved by any untreated type 1 patients older than 6 months of age. There appears to be a relationship between baseline age and function and motor function achievement. one patient treated at almost 8 months of age with poor baseline function showed modest response to treatment; in contrast two patients treated within the first 2 months of life with relatively modest symptoms have showed a dramatic clinical response and are both walking independently. This suggests that there is a critical window to treat before significant motor neuron loss has occurred to achieve the optimal response to intervention with aVXS-101. under this paradigm, treating patients in a pre-symptomatic setting represents the idealized approach to therapeutic intervention in this disease.