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

• ClinicalTrials.gov Identifier: NCT04851873
• Recruitment Status: Completed
• First Posted: April 21, 2021
• Results First Posted: January 5, 2024
• Last Update Posted: January 5, 2024
• Sponsor: Novartis Pharmaceuticals
• Information provided by (Responsible Party): Novartis ( Novartis Pharmaceuticals )

Tracking Information

• First Submitted Date: April 6, 2021
• First Posted Date: April 21, 2021
• Results First Submitted Date: November 27, 2023
• Results First Posted Date: January 5, 2024
• Last Update Posted Date: January 5, 2024
• Actual Study Start Date: September 8, 2021
• Actual Primary Completion Date: June 13, 2023 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: January 3, 2024)

• Number of Participants With Treatment Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) by Weight Bracket [ Time Frame: Up to Month 12 ]
  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.
• Number of Participants With Important Identified and Important Potential Risks (Adverse Events of Special Interest (AESI)) by Risk Name and Weight Bracket [ Time Frame: Up to Month 12 ]
  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.
• Summary of Participants Meeting Criteria for Potentially Clinically Significant Vital Sign Values by Weight Bracket - Systolic and Diastolic Blood Pressure [ Time Frame: 12 months ]
  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).
• Change From Baseline in Vital Signs Measurements - Systolic Blood Pressure (mmHg) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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 - Pulse Rate (Beats/Min) [ Time Frame: 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
• Summary of Participants Meeting Criteria for Potentially Clinically Significant Vital Sign Values by Weight Bracket - Temperature [ Time Frame: 12 months ]
  Change from baseline in vital signs measurements - temperature (degrees Celsius) Temperature-Low:<=35ºC(Any Age),High:>=38.4ºC(<18 yrs).
• Change From Baseline in Vital Signs Measurements - Temperature (Degrees Celsius) [ Time Frame: 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 [ Time Frame: 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 (%). Oxygen saturation is the fraction of oxygen-saturated hemoglobin relative to total hemoglobin (unsaturated+saturated) in the blood and then multiplied by 100.

Original Primary Outcome Measures (submitted: April 19, 2021)

• 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.
• 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.
• 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)
• 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)
• Change from baseline in vital signs measurements - pulse [ Time Frame: 12 months ]
  Change from baseline in vital signs measurements - pulse (beats per minute)
• Change from baseline in vital signs measurements - temperature [ Time Frame: 12 months ]
  Change from baseline in vital signs measurements - temperature (degrees Celsius)
• Change from baseline in vital signs measurements - oxygen saturation level [ Time Frame: 12 months ]
  Change from baseline in vital signs measurements - oxygen saturation level (%)

Current Secondary Outcome Measures (submitted: November 27, 2023)

• Achievement of Development Motor Milestones According to the Modified and Combined WHO-MGRS and Bayley Scale of Infant and Toddler Development. [ Time Frame: Baseline, Week 26 and Week 52 ]
  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.
• Change From Baseline in Hammersmith Functional Motor Scale - Expanded (HFMSE), as Appropriate According to Participant Age [ Time Frame: Baseline, Week 4, Week 13, Week 26, Week 39 and Week 52 ]
  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.
• Change From Baseline in Revised Upper Limb Module (RULM), as Appropriate According to Participant Age. [ Time Frame: Baseline, Week 4, Week 13, Week 26, Week 39 and Week 52 ]
  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.

Original Secondary Outcome Measures (submitted: April 19, 2021)

• Achievement of development motor milestones according to the Bayley Scale of Infant and Toddler Development. [ Time Frame: 12 months ]
  Developmental motor milestones are assessed via the developmental 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.
• 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.
• 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.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Safety and Efficacy of Intravenous OAV101 (AVXS-101) in Pediatric Patients With Spinal Muscular Atrophy (SMA)
• 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)
• 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.

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
• Study Phase: Phase 3

Study Design

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

• Condition: Spinal Muscular Atrophy

Intervention

Genetic: OAV101

Gene Therapy - 1.1e14 vector genome (vg)/kg as a one-time IV infusion was administered over approximately 60 minutes.

Study Arms

Experimental: OAV101

Participants received a single IV dose administration of OAV101

Intervention: Genetic: OAV101

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: April 19, 2021): 24
• Original Estimated Enrollment: Same as current
• Actual Study Completion Date: June 13, 2023
• Actual Primary Completion Date: June 13, 2023 (Final data collection date for primary outcome measure)

Eligibility 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 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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: up to 17 Years (Child)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Australia, Belgium, Canada, France, Italy, Portugal, Taiwan, United Kingdom, United States
• Removed Location Countries: Switzerland

Administrative Information

• NCT Number: NCT04851873
• Other Study ID Numbers: COAV101A12306; 2020-005995-37 ( EudraCT Number )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

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

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/.

• Current Responsible Party: Novartis ( Novartis Pharmaceuticals )
• Original Responsible Party: Same as current
• Current Study Sponsor: Novartis Pharmaceuticals
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Novartis Pharmaceuticals; Novartis Pharmaceuticals

• PRS Account: Novartis
• Verification Date: January 2024