Spinal Muscular Atrophy
Conditions
Keywords
Spinal muscular atrophy, SMA, onasemnogene abeparvovec-brve, intrathecal gene therapy, ITVISMA®, real-world evidence, sponsor-funded, real-world pragmatic trial;, motor function, safety.
Brief summary
The primary purpose is to address critical evidence in the treatment landscape for Spinal Muscular Atrophy (SMA), specifically focusing on the intrathecal formulation of onasemnogene abeparvovec-brve (ITVISMA®). U.S. Pragmatic Multicenter Study (STREAM).
Detailed description
STREAM is a prospective, multicentre cohort study that will follow U.S. participants with genetically confirmed SMA who receive a single, intrathecal dose of onasemnogene abeparvovec-brve. All eligible participants are enrolled prior to therapeutic injection. No randomisation, blinding, or placebo control is employed; instead, each participant acts as his or her own baseline comparator. This study will use an exploratory external cohort of patients matched by age, clinical characteristics, treatment history and availability of at least 1 year of pre-treatment medical history. This patient cohort will be based on a database of retrospectively collected electronic medical records data and will be used descriptively to contextualize study outcomes. Bias is minimised through pre-specified endpoints, uniform rater training on motor-function scales, and a detailed statistical analysis plan that stipulates handling of missing data and intercurrent events in advance.
Interventions
DRUGOnasemnogene Abeparvovec-brve
administered once via lumbar puncture with systemic corticosteroid prophylaxis per label.
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
2 Years to 100 Years
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: A participant will be enrolled in STREAM only if all the following conditions are met: * The participant has a genetically confirmed diagnosis of SMA (biallelic SMN1 deletion or mutation). * He or she is ≥ 2 years of age on the day of the intrathecal injection. * The treating Investigator intends to administer within the current episode of care, a single dose of ITVISMA® (1.2 × 10¹⁴ vg) in routine U.S. practice after written informed consent obtained. * One of the following functional categories applies at screening: 1. independently ambulatory child/adolescent 2 - \<18 years; or 2. independently ambulatory adult (≥ 18 years). 3. non-ambulatory (includes walkers with assistance) adult \> 18 years with entry level RULM at baseline * At least 1 year of pre-treatment medical history, including motor-function documentation, can be retrieved from the site electronic record. Key
Exclusion criteria
A participant will be excluded if any of the following conditions apply: * Contraindication for lumbar puncture as determined by the investigator (e.g., spinal anatomy that precludes safe lumbar puncture) * An uncontrolled acute illness, active infection, febrile illness or acute medical condition, within 30 days prior to dosing * Inability to tolerate corticosteroids administered by mouth or gastrostomy tube * Current participation in another interventional clinical trial that would interfere with the objectives or endpoints of STREAM. Note: participation in observational cohort studies or non-interventional studies in which the participant does not receive treatment or undergo procedures which may compromise this study data integrity may be allowed following Sponsor approval * Planned relocation or any circumstance that is likely to prevent completion of the minimum 12-month follow-up. Other protocol inclusion,
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change from baseline in HFMSE for independently ambulatory participants | Baseline, 6, 12, 18 and 24 months | The HFMSE is a validated SMA specific assessment devised for use in children with SMA to give objective information on motor ability and clinical progression. The HFMSE contains 33 items rated from 0 (unable to perform) to 2 (performs without modification/adaptation/compensation). Total scores range from 0-66. Higher scores indicate higher levels of motor ability. |
| Change from baseline in RULM for non-ambulatory (including walkers with assistance) participants | Baseline, 6, 12, 18 and 24 months | The RULM is a validated SMA specific assessment of motor performance in the upper limbs from childhood through adulthood in independent ambulatory and non-ambulatory (including walkers with assistance) individuals with SMA. The scale consists of 19 scorable items: 18 items scored on 0 (unable) to 2 (full achievement) scale, and one item that is scored from 0 (unable) to 1 (able). Total scores range from 0-37 points. Higher scores reflect higher level of motor ability. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of Adverse Events (AEs) and Serious Adverse Events (SAEs) | up to 5 years | Incidence of AEs and SAEs, including changes in laboratory tests and procedure-related events qualifying and reported as AEs. |
| Modified SMA Functional Rating Scale (SMA-FRS) for independently ambulatory participants (≥ 18 years of age) and non-ambulatory particpants | Baseline, 6, 12, 18 and 24 months and Years 3, 4, and 5 | Modified Spinal Muscular Atrophy Functional Rating Scale (SMAFRS): Ten items address questions related to eating, upper extremity dressing, lower extremity dressing, grooming, bathing, toileting, turning in bed and adjusting bed clothes, transfers, walking, and climbing stairs. This outcome measure includes effectiveness assessment across predefined participant groups based on relevant clinical and demographic factors, as specified in the protocol. |
| Assessment of Caregiver Experience with Neuromuscular Disease (ACEND) for independently ambulatory participants (<18 years of age) | Baseline, Months 6, 12, 18, 24, and Years 3, 4, and 5 | The Assessment of Caregiver Experience with Neuromuscular Disease (ACEND): quantifies caregivers' perceptions of function and quality of life pertaining to time, finance and emotion. The ACEND was developed and validated to specifically assess caregiver impact experienced by raising children severely affected by neuromuscular diseases. While specifically developed for application to caregivers of patients undergoing orthopedic surgery, it has application to those with SMA. This outcome measure includes effectiveness assessment across predefined participant groups based on relevant clinical and demographic factors, as specified in the protocol. |
| Subgroup outcomes: Hammersmith Functional Motor Scale Expanded (HFMSE) | Baseline, 6, 12, 18 and 24 months | Effectiveness assessment across predefined participant groups based on relevant clinical and demographic factors, as specified in the protocol. The HFMSE is a validated SMA specific assessment to give objective information on motor ability and clinical progression. Total scores range from 0-66. Higher scores indicate higher levels of motor ability. |
| Subgroup outcomes: Revised Upper Limb Module (RULM) | Baseline, 6, 12, 18 and 24 months | Effectiveness assessment across predefined participant groups based on relevant clinical and demographic factors, as specified in the protocol. The RULM is a validated SMA specific assessment of motor performance in the upper limbs from childhood through adulthood in independent ambulatory and non-independent ambulatory individuals with SMA. Total scores range from 0-37 points. Higher scores reflect higher level of motor ability. |
| Frequency of hospitalizations emergency department visits, outpatient visits, respiratory interventions and nutritional support interventions | Baseline, Months 6, 12, 18, 24, and Years 3, 4, and 5 | Assessment of SMA-related healthcare-resource utilisation. |
| Duration of hospitalizations emergency department visits, outpatient visits, respiratory interventions and nutritional support interventions | Baseline, Months 6, 12, 18, 24, and Years 3, 4, and 5 | Assessment of SMA-related healthcare-resource utilisation. |
| Cobb angle | Baseline, up to 24 months | Assessment of scoliosis progression as a disease-progression marker. |
| Daily hours of respiratory support (none, non-invasive ventilation, invasive ventilation) | Baseline, up to 24 months | Assessment of respiratory function as a disease-progression marker. |
| Joint-range limitation measured by goniometer | Baseline, up to 24 months | Assessment of evolution of joint contractures as a disease-progression marker. |
| Nutritional-support category (oral, gastrostomy feeds, total parenteral nutrition) | Baseline, up to 24 months | Assessment of nutrition status as a disease-progression marker. |
| 6-Minute Walk Test (6MWT) for ambulatory patients | Baseline, Months 6, 12, 18, and 24 | To assess disease-progression markers. 6MWT: distance in metres; greater distance indicates better ambulatory capacity. |
Contacts
CONTACTNovartis Pharmaceuticals
Outcome results
None listed