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

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)

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.

Study Overview

• Status: Completed
• Conditions: Spinal Muscular Atrophy
• Intervention / Treatment: Genetic: OAV101

Detailed Description

This was an open-label, single arm, multi-center study designed to evaluate the safety, tolerability and efficacy of OAV101 in participants with SMA who weigh ≥ 8.5 kg and ≤ 21 kg. The study aimed to enroll approximately 24 to 30 participants, with approximately 6 to 10 participants across each of 3 weight brackets (8.5 to 13 kg, >13 to 17 kg, >17 to 21 kg).

Eligible participants received a single administration of OAV101 at the approved dose of 1.1e14 vg/kg on Day 1 (Treatment period), and were followed for a period of 12 months.

Participants were admitted to the hospital on Day -1 for pre-treatment baseline procedures. After receiving OAV101 on Day 1, participants underwent in-patient safety monitoring over the next 48 hours, after which the participant could be discharged, based on Investigator judgment.

After study completion, eligible participants could enroll into a Long Term follow-up study to collect additional safety and efficacy data. (COAV101A12308 (NCT05335876) https://classic.clinicaltrials.gov/ct2/show/NCT05335876?term=COAV101A12308&draw=2&rank=1))

• Study Type: Interventional
• Enrollment (Actual): 24
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Novartis Gene Therapies Medical Information (US, Asia-Pacific, Latin America, and Canada); Phone Number: +1-833-828-3947; Email: medinfo.gtx@novartis.com
• Study Contact Backup: Name: Novartis Gene Therapies EMEA Medical Information (Europe, Middle East and Africa); Phone Number: +353 (1) 566-2364; Email: medinfoemea.gtx@novartis.com

Study Locations

• Australia
  • New South Wales
    • Randwick, New South Wales, Australia, 2031
      • Novartis Investigative Site
• Belgium
  • Leuven, Belgium, 3000
    • Novartis Investigative Site
• Canada
  • Quebec
    • Montreal, Quebec, Canada, H4A 3J1
      • Novartis Investigative Site
• France
  • Garches, France, 92380
    • Novartis Investigative Site
  • Strasbourg, France, 67000
    • Novartis Investigative Site
• Italy
  • RM
    • Roma, RM, Italy, 00168
      • Novartis Investigative Site
• Portugal
  • Lisboa, Portugal, 1600190
    • Novartis Investigative Site
• Taiwan
  • Kaohsiung, Taiwan, 80756
    • Novartis Investigative Site
  • Taipei, Taiwan, 10002
    • Novartis Investigative Site
• United Kingdom
  • London, United Kingdom, WC1N 3JH
    • Novartis Investigative Site
  • Newcastle Upon Tyne, United Kingdom, NE1 4LP
    • Novartis Investigative Site
• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Novartis Investigative Site
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Novartis Investigative Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 17 years (Child)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: OAV101; Participants received a single IV dose administration of OAV101	Genetic: OAV101; Gene Therapy - 1.1e14 vector genome (vg)/kg as a one-time IV infusion was administered over approximately 60 minutes.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Treatment Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) by Weight Bracket	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.	Up to Month 12
Number of Participants With Important Identified and Important Potential Risks (Adverse Events of Special Interest (AESI)) by Risk Name and Weight Bracket	Important identified and important potential risks included the following AESIs: Hepatotoxicity, Thrombocytopenia, Cardiac adverse events, Dorsal root ganglia toxicity and Thrombotic microangiopathy. These were assessed by the investigator.	Up to Month 12
Summary of Participants Meeting Criteria for Potentially Clinically Significant Vital Sign Values by Weight Bracket - Systolic and Diastolic Blood Pressure	Change from baseline in vital signs measurements - systolic and diastolic blood pressure (mmHg). Systolic Blood Pressure-Low:<=5th percentile of the age(Any Age), High:>=90th percentile of the age, gender, and height group (<18 yrs). Diastolic Blood Pressure-High:>=90th percentile of the age, gender, and height group(<18 yrs).	12 months
Change From Baseline in Vital Signs Measurements - Systolic Blood Pressure (mmHg)		Baseline, Days 2 and 3, Weeks 1, 2, 3, 4, 6, 8, 10, 13, 26, 39 and 52
Change From Baseline in Vital Signs Measurements - Diastolic Blood Pressure (mmHg)		Baseline, Days 2 and 3, Weeks 1, 2, 3, 4, 6, 8, 10, 13, 26, 39 and 52
Change From Baseline in Vital Signs Measurements - Respiratory Rate (Breaths/Min)	Change from baseline in vital signs measurements - Respiratory Rate (breaths/min)	Baseline, Days 2 and 3, Weeks 1, 2, 3, 4, 6, 8, 10, 13, 26, 39 and 52
Change From Baseline in Vital Signs Measurements - Pulse Rate (Beats/Min)	Change from baseline in vital signs measurements - Pulse Rate (beats/min	Baseline, Days 2 and 3, Weeks 1, 2, 3, 4, 6, 8, 10, 13, 26, 39 and 52
Summary of Participants Meeting Criteria for Potentially Clinically Significant Vital Sign Values by Weight Bracket - Temperature	Change from baseline in vital signs measurements - temperature (degrees Celsius) Temperature-Low:<=35ºC(Any Age),High:>=38.4ºC(<18 yrs).	12 months
Change From Baseline in Vital Signs Measurements - Temperature (Degrees Celsius)		Baseline, Days 2 and 3, Weeks 1, 2, 3, 4, 6, 8, 10, 13, 26, 39 and 52
Change From Baseline in Vital Signs Measurements - Oxygen Saturation Level	Change from baseline in vital signs measurements - oxygen saturation level (%). Oxygen saturation is the fraction of oxygen-saturated hemoglobin relative to total hemoglobin (unsaturated+saturated) in the blood and then multiplied by 100.	Baseline, Days 2 and 3, Weeks 1, 2, 3, 4, 6, 8, 10, 13, 26, 39 and 52

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 was modified and combined into a single scale expressly for this study, to measure developmental motor milestones. These were 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.	Baseline, Week 26 and Week 52
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.	Baseline, Week 4, Week 13, Week 26, Week 39 and Week 52
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.	Baseline, Week 4, Week 13, Week 26, Week 39 and Week 52

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals
• Investigators: Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Publications and helpful links

Helpful Links

• If you have inquiries about possible participation in this clinical study, please go to this website, and select your region or country, to see if there is an investigator site near you.

Study record dates

Study Major Dates

• Study Start (Actual): September 8, 2021
• Primary Completion (Actual): June 13, 2023
• Study Completion (Actual): June 13, 2023

Study Registration Dates

• First Submitted: April 6, 2021
• First Submitted That Met QC Criteria: April 19, 2021
• First Posted (Actual): April 21, 2021

Study Record Updates

• Last Update Posted (Actual): January 5, 2024
• Last Update Submitted That Met QC Criteria: January 3, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Keywords: gene therapy; spinal and bulbar muscular atrophy; spinal muscular atrophy; Muscle atrophy; muscle wasting; muscle function; myopathy; SBMA; Zolgensma; OAV101; AVXS 101; bulbar muscular atrophy; atrophied muscle; loss of muscle strength
• Additional Relevant MeSH Terms: Central Nervous System Diseases; Nervous System Diseases; Neurologic Manifestations; Neuromuscular Diseases; Neurodegenerative Diseases; Neuromuscular Manifestations; Pathological Conditions, Anatomical; Spinal Cord Diseases; Motor Neuron Disease; Muscular Atrophy; Atrophy; Muscular Atrophy, Spinal
• Other Study ID Numbers: COAV101A12306; 2020-005995-37 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data availability is according to the criteria and process described on https://www.clinicalstudydatarequest.com/.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No