SMA
Conditions
Brief summary
Phase 3, open-label, single-arm, single-dose, trial of onasemnogene abeparvovec-xioi (gene replacement therapy) in patients with spinal muscular atrophy (SMA) Type 1 who meet enrollment criteria and are genetically defined by a biallelic pathogenic mutation of the survival motor neuron 1 gene (SMN1) with one or two copies of survival motor neuron 2 gene (SMN2). Up to 30 patients \< 6 months (\< 180 days) of age at the time of gene replacement therapy (Day 1) will be enrolled.
Detailed description
Phase 3, open-label, single-arm, single-dose, trial of onasemnogene abeparvovec-xioi (gene replacement therapy) in patients with spinal muscular atrophy (SMA) Type 1 who meet enrollment criteria and are genetically defined by a biallelic pathogenic mutation of the survival motor neuron 1 gene (SMN1) with one or two copies of survival motor neuron 2 gene (SMN2). 30 patients \< 6 months (\< 180 days) of age at the time of gene replacement therapy (Day 1) will be enrolled. The trial includes a screening period, a gene replacement therapy period, and a follow-up period. During the screening period (Days -30 to -2), patients whose parent(s)/legal guardian(s) provide informed consent will complete screening procedures to determine eligibility for trial enrollment. Patients who meet the entry criteria will enter the in-patient gene replacement therapy period (Day -1 to Day 3). On Day -1, patients will be admitted to the hospital for pre-treatment baseline procedures. On Day 1, patients will receive a one-time intravenous (IV) infusion of onasemnogene abeparvovec-xioi, and will undergo in-patient safety monitoring over the next 48 hours. Patients may be discharged 48 hours after the infusion, based on Investigator judgment. During the outpatient follow-up period (Days 4 to End of Trial at 18 months of age), patients will return at regularly scheduled intervals for efficacy and safety assessments until the End of Trial when the patient reaches 18 months of age. After the End of Trial visit, eligible patients will be asked to participate into the long-term follow up trial. All post-treatment visits will be relative to the date on which gene replacement therapy is administered, until the patient is 14 months of age, after which they will be relevant to the patient's date of birth.
Interventions
BIOLOGICALOnasemnogene Abeparvovec-xioi
Onasemnogene abeparvovec-xioi is a non-replicating recombinant adeno-associated virus serotype 9 (AAV9) containing the human survival motor neuron (SMN) gene under the control of the cytomegalovirus (CMV) enhancer/chicken β-actin-hybrid promoter (CB).
Sponsors
Novartis Gene Therapies
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Open-label, single-arm, single-dose, trial of onasemnogene abeparvovec-xioi
Eligibility
Sex/Gender
ALL
Age
No minimum to 6 Months
Healthy volunteers
No
Inclusion criteria
* Patients with SMA Type 1 as determined by diagnosis of SMA based on gene mutation analysis with biallelic SMN1 mutations (deletion or point mutations) and one or two copies of SMN2 \[inclusive of the known SMN2 gene modifier mutation (c.859G\>C)\] * Patients must be \< 6 months (\< 180 days) of age at the time of onasemnogene abeparvovec-xioi infusion * Patients must have a swallowing evaluation test performed prior to administration of gene replacement therapy
Exclusion criteria
* Previous, planned or expected scoliosis repair surgery/procedure prior to 18 months of age * Use of invasive ventilatory support (tracheotomy with positive pressure) or pulse oximetry \< 95% saturation at screening * Use or requirement of non-invasive ventilatory support for 12 or more hours daily in the two weeks prior to dosing * Patient with signs of aspiration based on a swallowing test or whose weight-for-age falls below the 3rd percentile based on World Health Organization (WHO) Child Growth Standards and unwilling to use an alternative method to oral feeding * Participation in recent SMA treatment clinical trial (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 (eg, nusinersen, valproic acid,) at any time prior to screening for this trial.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Who Achieve Independent Sitting for at Least 10 Seconds | From Day 1 up to 18 Months of Age Visit (Up to a Maximum of Approximately 17 Months) | Independent sitting is defined by the World Health Organization Multicentre Growth Reference Study, confirmed by video recording, as a participant who sits up straight with head erect for at least 10 seconds; participant does not use arms or hands to balance body or support position. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Event-free Survival at 14 Months of Age | Up to 14 months of age | Event-free survival at 14 months of age was defined as the number of participants who did not die, did not require permanent ventilation and did not withdraw from the study by 14 months of age. |
Countries
Belgium, France, Italy, United Kingdom
Contacts
STUDY_CHAIRAveXis Medinfo
Sponsor GmbH
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Onasemnogene Abeparvovec-xioi Participants received a single dose of onasemnogene abeparvovec-xioi administered as an intravenous (IV) infusion over 60 minutes at a dose of 1.1 × 10\^14 vg/kg (vector genome per kilogram) on Day 1 of the overall study. | 33 |
| Total | 33 |
Baseline characteristics
| Characteristic | Onasemnogene Abeparvovec-xioi |
|---|---|
| Age, Categorical <=18 years | 33 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants |
| Age, Continuous | 4.055 months STANDARD_DEVIATION 1.2799 |
| Region of Enrollment Belgium | 4 participants |
| Region of Enrollment France | 2 participants |
| Region of Enrollment Italy | 23 participants |
| Region of Enrollment United Kingdom | 4 participants |
| Sex: Female, Male Female | 19 Participants |
| Sex: Female, Male Male | 14 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 1 / 33 |
| other Total, other adverse events | 32 / 33 |
| serious Total, serious adverse events | 19 / 33 |
Outcome results
Primary
Number of Participants Who Achieve Independent Sitting for at Least 10 Seconds
Independent sitting is defined by the World Health Organization Multicentre Growth Reference Study, confirmed by video recording, as a participant who sits up straight with head erect for at least 10 seconds; participant does not use arms or hands to balance body or support position.
Time frame: From Day 1 up to 18 Months of Age Visit (Up to a Maximum of Approximately 17 Months)
Population: The analysis population was the Intent-to-Treat (ITT) population which consisted of symptomatic participants with bi-allelic deletion of SMN1 (exon 7/8 common homozygous deletions) and 2 copies of SMN2 without the known gene modifier mutation (c.859G\>C) who received an IV infusion of onasemnogene abeparvovec-xioi at less than 180 days of age.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Onasemnogene Abeparvovec-xioi | Number of Participants Who Achieve Independent Sitting for at Least 10 Seconds | 14 Participants |
Secondary
Event-free Survival at 14 Months of Age
Event-free survival at 14 months of age was defined as the number of participants who did not die, did not require permanent ventilation and did not withdraw from the study by 14 months of age.
Time frame: Up to 14 months of age
Population: The analysis population was the ITT population which consisted of symptomatic participants with bi-allelic deletion of SMN1 (exon 7/8 common homozygous deletions) and 2 copies of SMN2 without the known gene modifier mutation (c.859G\>C) who received an IV infusion of onasemnogene abeparvovec-xioi at less than 180 days of age.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Onasemnogene Abeparvovec-xioi | Event-free Survival at 14 Months of Age | 31 Participants |
p-value: <0.000195% CI: [0.48, 0.87]Fisher Exact