Safety and Efficacy of Intravenous OAV101 (AVXS-101) in Pediatric Patients With Spinal Muscular Atrophy (SMA)

Study Overview
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Brief Summary
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To evaluate the safety, tolerability and efficacy of intravenous administration of OAV101 (AVXS-101) in patients with spinal muscular atrophy (SMA) with bi-allelic mutations in the survival motor neuron 1 (SMN1) gene weighing ≥ 8.5 kg and ≤ 21 kg, over a 12 month period.

Detailed Description
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This is an open-label, single arm, multi-center study to evaluate the safety, tolerability and efficacy of IV OAV101 in SMA participants. The study will enroll participants that weigh ≥ 8.5 kg and ≤ 21 kg. An even weight distribution across the desired range will be achieved by aiming to enroll approximately 6-10 participants across 3 weight brackets (≥ 8.5-13 kg, > 13-17 kg, > 17-21 kg). Participants will receive a single administration of IV OAV101. Participants who meet eligibility criteria at screening and baseline visits will receive a single-dose of IV OAV101 on Day 1 (Treatment period) and will be followed for a period of 12 months. The study will include a standard screening period that can last up to 45 days, during which eligibility will be assessed and baseline assessments will be performed prior to treatment. For the study duration, participants will complete visits as defined in the Schedule of Assessments. Prednisolone treatment will be given per study protocol. On Day -1, participants will be admitted to the hospital for pre-treatment baseline procedures. On Day 1, participants will receive a 1-time IV infusion of OAV101 and will undergo in-patient safety monitoring over the next 48 hours, after which the participant may be discharged, based on Investigator judgment. Safety monitoring will be performed as per study schedule and protocol requirement. Safety for the participants enrolled in the study will be evaluated by the study team together with Data Monitoring Committee (DMC) as described in the charter. An interim analysis for safety and efficacy maybe performed once the last participant completes 6-months of follow-up, and will include all available data up until that data cut-off. Final analysis will be planned after the 12 months visits (End of Study (EOS)). After study completion eligible participants will be invited to enroll into Long Term follow-up study to collect additional safety and efficacy data.

Official Title
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A Phase IIIb, Open-label, Single-arm, Single-dose, Multicenter Study to Evaluate the Safety, Tolerability and Efficacy of Gene Replacement Therapy With Intravenous OAV101 (AVXS-101) in Pediatric Patients With Spinal Muscular Atrophy (SMA)

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 Symptomatic SMA diagnosis based on gene mutation analysis with bi-allelic survival motor neuron 1 (SMN1) mutations (deletion or point mutations) and any copy of the survival motor neuron 2 (SMN2) gene. Weight ≥ 8.5 kg and ≤ 21 kg at the time of Screening Visit 2 Naive to treatment or have discontinued an approved drug/therapy Exclusion: Previous OAV101 use or previous use of any adeno-associated virus serotype 9 (AAV9) gene therapy BMI < 3rd percentile Participant with history of aspiration pneumonia or signs of aspiration Elevated anti-AAV9 antibody History of gene therapy, hematopoietic transplantation, or solid organ transplantation Inability to take corticosteroids Concomitant use of immunosuppressive therapy Requiring invasive ventilation, tracheostomy or awake non-invasive ventilation 9. Administration of vaccines 2 weeks prior to infusion of OAV101 Awake hypoxemia or awake oxygen saturation level decrease Hepatic dysfunction Presence of a confirmed or suspected infection If previously treated with disease modifying therapy, specified washout times apply Documented any parental consanguinity. Additional criteria may apply.

Ages Eligible for Study
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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
Intervention Model: Single Group Assignment
Interventional Model Description: Participants will receive a single administration of OAV101
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: OAV101<br>Participants will receive a single IV dose administration of OAV101 | Genetic: OAV101<br>* Gene Therapy<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with treatment emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | An 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. | 12 months | 
| Number of participants with important identified and important potential risks (Adverse Events of Special Interest (AESI)) | The following are important identified and important potential risks (AESI) associated with OAV101: Hepatotoxicity, Thrombocytopenia, Cardiac adverse events, Sensory abnormalities suggestive of ganglionopathy, and Thrombotic microangiopathy. These will be assessed by the investigator. | 12 months | 
| Change from baseline in vital signs measurements - systolic and diastolic blood pressure | Change from baseline in vital signs measurements - systolic and diastolic blood pressure (mmHg) | 12 months | 
| Change from baseline in vital signs measurements - respiratory rate | Change from baseline in vital signs measurements - respiratory rate (breaths per minute) | 12 months | 
| Change from baseline in vital signs measurements - pulse | Change from baseline in vital signs measurements - pulse (beats per minute) | 12 months | 
| Change from baseline in vital signs measurements - temperature | Change from baseline in vital signs measurements - temperature (degrees Celsius) | 12 months | 
| Change from baseline in vital signs measurements - oxygen saturation level | Change from baseline in vital signs measurements - oxygen saturation level (%) | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Achievement of development motor milestones according to the modified and combined WHO-MGRS and Bayley scale of Infant and Toddler Development. | The World Health Organization-Multicentre Growth Reference Study (WHO-MGRS) and Bayley scale of Infant and Toddler Development will be modified and combined into a single scale expressly for this study, to measure developmental motor milestones. These will be assessed via the milestone checklist, formed of 10 yes/no questions with optional video documentation. The developmental milestones are: head control, sitting with support, sitting without support, sitting without support for 30 seconds, hands-and-knees crawling, pulls to stand, standing with assistance, walking with assistance, standing alone and walking alone. A yes response indicates that the patient reached a particular development milestone. | 12 months | 
| Change from baseline in Hammersmith Functional Motor Scale - Expanded (HFMSE), as appropriate according to participant age | The HFMSE was devised for use in children with SMA to give objective information on motor ability and clinical progression. The HFMSE is formed of 33 assessments. 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 level of ability. | 12 months | 
| Change from baseline in Revised Upper Limb Module (RULM), as appropriate according to participant age. | The RULM assesses motor performance in the upper limbs from childhood through adulthood in ambulatory and non-ambulatory individuals with SMA. 'The scale consists of an entry item to establish functional levels and 19 items covering distal to proximal movements. The entry item is a modified version of the Brooke scale, including activities ranging from no functional use of hands (score 0) to full bilateral shoulder abduction (score 6). The entry item does not contribute to the total score but serves as a functional classification of overall upper limb functional ability. Of the remaining 19 items, 18 are scored on a 3 point scoring system and 1 item is scored on a 2 point scoring system. The test is performed unilaterally using the limb preferred by the participant. The total score ranges from 0, if all the items cannot be performed, to 37, if all the activities are achieved fully without any compensation. ' Higher scores indicate higher levels of motor ability. | 12 months | 

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