Phase IIIb, Open-label, Multi-center Study to Evaluate Safety, Tolerability and Efficacy of OAV101 Administered Intrathecally to Participants With SMA Who Discontinued Treatment With Nusinersen or Risdiplam

Study Overview
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Brief Summary
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This is an open-label, single arm, multi-center study. Approximately 28 participants aged 2 to <18 years will be enrolled stratified as 2 to 5 years and 6 to < 18 years. The study is comprised of 3 periods, Screening (up to 45 days), Treatment (1 day), and Follow-up (52 weeks).

Detailed Description
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During the Screening period and on Day -1 (Baseline), eligibility will be assessed, including confirmation that nusinersen (Spinraza®) or risdiplam (Evrysdi®) have not been used for the defined period (4 month and 15 days prior to Day -1 respectively). On Day - 1 (Baseline) participants will be admitted to the hospital for pre-treatment baseline procedures. Prednisolone (or equivalent) will be given and continued as per the study protocol. Participants who meet eligibility criteria at Screening and Baseline will receive a single dose of OAV101 (1.2 x 10^14 vector genomes) by lumbar intrathecal injection on Day 1 (Treatment) and will then undergo in-patient safety monitoring atleast the next 48 hours, after which the participant may be discharged according to Investigator judgement. During Follow-up, safety monitoring will continue as per the visits defined in the Assessment Schedule. Safety for participants enrolled will be evaluated by the study team together with the Data Monitoring Committee (DMC). Final analysis will be performed after all participants have completed Week 52 or discontinued prior to Week 52. At the end of study, participants will be invited to enroll in a Novartis-sponsored long-term follow-up study to monitor long-term safety and efficacy.

Official Title
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Phase IIIb, Open-label, Single-arm, Multi-center Study to Evaluate the Safety, Tolerability and Efficacy of OAV101 Administered Intrathecally (1.2 x 10^14 Vector Genomes) to Participants 2 to < 18 Years of Age With Spinal Muscular Atrophy (SMA) Who Have Discontinued Treatment With Nusinersen (Spinraza®) or Risdiplam (Evrysdi®)

Conditions
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Spinal Muscular Atrophy

Intervention / Treatment
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* Genetic: OAV101


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria SMA diagnosis Aged 2 to < 18 years Have had at least four loading doses of nusinersen (Spinraza®) or at least 3 months of treatment with risdiplam (Evrysdi®) at Screening Must have symptoms of SMA as defined in the protocol Exclusion Criteria: Anti Adeno Associated Virus Serotype 9 (AAV9) antibody titer using an immunoassay is reported as elevated Clinically significant abnormalities in test results during screening Contraindications for lumbar puncture procedure At Baseline, participants are excluded if they received: nusinersen (Spinraza®) or risdiplam (Evrysdi®) within a defined timeframe Vaccinations 2 weeks prior to administration of OAV101 Hospitalization for a pulmonary event, or for nutritional support within 2 months prior to Screening or inpatient major surgery planned. Presence of an infection or febrile illness up to 30 days prior to administration of OAV101 Requiring invasive ventilation

Ages Eligible for Study
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Minimum Age: 2 Years
Maximum Age: 17 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: OAV-101<br>Intrathecal administration of OAV101 at a dose of 1.2 x 10^14 vector genomes, one time dose | Genetic: OAV101<br>* Intrathecal administration of OAV101 at a dose of 1.2 x 10^14 vector genomes, one time dose<br>* Other names: Zolgensma;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number and percentage of participants reporting AEs, related AEs, SAEs, and AESIs | An adverse event (AE) is any untoward medical occurrence (e.g. any unfavorable and unintended sign [including abnormal laboratory findings], symptom or disease) in a clinical investigation participant after providing written informed consent for participation in the study. The occurrence of AEs must be sought by non-directive questioning of the participant at each visit during the study. Adverse events also may be detected when they are volunteered by the participant during or between visits or through physical examination findings, laboratory test findings, or other assessments. An AESI is primarily defined by using standard Medical Dictionary for Regulatory Activities (MedDRA) queries, and identified as follows: Hepatotoxicity, Thrombocytopenia, Thrombotic microangiopathy, Cardiac adverse events, and Dorsal root ganglia toxicity | 52 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline to Week 52 visit in the HFMSE total score | The Hammersmith Functional Motor Scale Expanded (HFMSE) is a SMA-specific 33-item assessment that is administered by clinical evaluators in a short period of time, requires minimal equipment, and is designed to factor in patient fatigue. Each motor skill item is scored on a 3-point Likert scale from 0 (no response) to 2 (full response), with a total score range of 0 to 66. A higher score indicates a higher ability level. | 52 weeks | 
| Change from baseline to Week 52 visit in the RULM total Score | The Revised Upper Limb Model (RULM) is a validated, SMA-specific assessment that measures motor performance in the upper limbs from childhood through adulthood in ambulatory and never ambulatory individuals with SMA. The revised version of the test consists of 19 scorable items: 18 items scored on a 0 (unable) to 2 (full achievement) scale, and one item that is scored from 0 (unable) to 1 (able). These item scores are summed to give a total score ranging from 0 to 37 points with lower scores reflecting poorer ability. | 52 weeks | 
| Change from baseline to Week 52 visit in Assessment of Caregiver Experience in ACEND instrument score | The Assessment of Caregiver Experience in Neuromuscular Disease (ACEND) instrument quantifies the caregiver impact experienced by parents/caregivers of children affected with severe neuromuscular diseases, including children with SMA The total score is on a scale of 0 to 100 with a higher score indicating a greater impact on the caregiver. | 52 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Zolgensma, Muscle atrophy, SBMA, SMA, OAV101, AVXS 101, gene therapy, spinal and bulbar muscular atrophy, spinal muscular atrophy, bulbar muscular atrophy, muscle function, myopathy, muscle wasting, atrophied muscle, loss of muscle strength