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

• ClinicalTrials.gov Identifier: NCT04851873
• Recruitment Status: Active, not recruiting
• First Posted: April 21, 2021
• Last Update Posted: May 17, 2023
• Sponsor: Novartis Pharmaceuticals
• Information provided by (Responsible Party): Novartis ( Novartis Pharmaceuticals )

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Spinal Muscular Atrophy	Genetic: OAV101	Phase 3

Detailed Description:

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 24 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Intervention Model Description: Participants will receive a single administration of OAV101
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 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)
• Actual Study Start Date: September 8, 2021
• Estimated Primary Completion Date: July 5, 2023
• Estimated Study Completion Date: July 5, 2023

Arms and Interventions

Arm	Intervention/treatment
Experimental: OAV101; Participants will receive a single IV dose administration of OAV101	Genetic: OAV101; Gene Therapy

Outcome Measures

Primary Outcome Measures :

1. Number of participants with treatment emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) [ Time Frame: 12 months ]
   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.
2. Number of participants with important identified and important potential risks (Adverse Events of Special Interest (AESI)) [ Time Frame: 12 months ]

   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.

3. Change from baseline in vital signs measurements - systolic and diastolic blood pressure [ Time Frame: 12 months ]
   Change from baseline in vital signs measurements - systolic and diastolic blood pressure (mmHg)
4. Change from baseline in vital signs measurements - respiratory rate [ Time Frame: 12 months ]
   Change from baseline in vital signs measurements - respiratory rate (breaths per minute)
5. Change from baseline in vital signs measurements - pulse [ Time Frame: 12 months ]
   Change from baseline in vital signs measurements - pulse (beats per minute)
6. Change from baseline in vital signs measurements - temperature [ Time Frame: 12 months ]
   Change from baseline in vital signs measurements - temperature (degrees Celsius)
7. Change from baseline in vital signs measurements - oxygen saturation level [ Time Frame: 12 months ]
   Change from baseline in vital signs measurements - oxygen saturation level (%)

Secondary Outcome Measures :

1. Achievement of development motor milestones according to the modified and combined WHO-MGRS and Bayley scale of Infant and Toddler Development. [ Time Frame: 12 months ]
   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.
2. Change from baseline in Hammersmith Functional Motor Scale - Expanded (HFMSE), as appropriate according to participant age [ Time Frame: 12 months ]
   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 rated from 0 (unable to perform functional task) to 2 (able to perform functional task unassisted). Higher scores indicated higher levels of motor ability.
3. Change from baseline in Revised Upper Limb Module (RULM), as appropriate according to participant age. [ Time Frame: 12 months ]
   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.

Eligibility Criteria

• Ages Eligible for Study: up to 17 Years (Child)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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 AAV9 gene therapy
• Body Mass Index (BMI) < 3rd percentile based on World Health Organization (WHO) Child Growth Standard
• Participant with history of aspiration pneumonia or signs of aspiration (eg, coughing or sputtering of food) within 4 weeks prior to screening
• Anti-Adeno-associated virus serotype 9 (AAV9) antibody titer > 1:50 as determined by ligand binding immunoassay at the time of screening
• History of gene therapy, hematopoietic transplantation, or solid organ transplantation

Contacts and Locations

Locations

United States, Massachusetts

Novartis Investigative Site

Boston, Massachusetts, United States, 02115

United States, Missouri

Novartis Investigative Site

Saint Louis, Missouri, United States, 63110

Australia, New South Wales

Novartis Investigative Site

Randwick, New South Wales, Australia, 2031

Belgium

Novartis Investigative Site

Leuven, Belgium, 3000

Canada, Quebec

Novartis Investigative Site

Montreal, Quebec, Canada, H4A 3J1

France

Novartis Investigative Site

Garches, France, 92380

Novartis Investigative Site

Strasbourg Cedex, France, F 67098

Italy

Novartis Investigative Site

Roma, RM, Italy, 00168

Portugal

Novartis Investigative Site

Lisboa, Portugal, 1600190

Taiwan

Novartis Investigative Site

Kaohsiung, Taiwan, 80756

Novartis Investigative Site

Taipei, Taiwan, 10002

United Kingdom

Novartis Investigative Site

London, United Kingdom, WC1N 3JH

Novartis Investigative Site

Newcastle Upon Tyne, United Kingdom, NE1 4LP

Sponsors and Collaborators

Novartis Pharmaceuticals

Investigators

• Study Director: Novartis Pharmaceuticals; Novartis Pharmaceuticals

More Information

Additional Information:

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. 

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT04851873
• Other Study ID Numbers: COAV101A12306
• First Posted: April 21, 2021
• Last Update Posted: May 17, 2023
• Last Verified: May 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes

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/.

• URL: https://www.clinicalstudydatarequest.com/.

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Novartis ( Novartis Pharmaceuticals ):

Zolgensma; AVXS 101; spinal muscular atrophy; OAV101; gene therapy; Muscle atrophy; SBMA; spinal and bulbar muscular atrophy; bulbar muscular atrophy; muscle function; myopathy; muscle wasting; atrophied muscle; loss of muscle strength

Additional relevant MeSH terms:

Muscular Atrophy; Muscular Atrophy, Spinal; Atrophy; Pathological Conditions, Anatomical; Neuromuscular Manifestations; Neurologic Manifestations; Nervous System Diseases; Spinal Cord Diseases; Central Nervous System Diseases; Motor Neuron Disease; Neurodegenerative Diseases; Neuromuscular Diseases