Long-term Follow-up Study of Patients Receiving Onasemnogene Abeparvovec-xioi

• ClinicalTrials.gov Identifier: NCT04042025
• Recruitment Status: Active, not recruiting
• First Posted: August 1, 2019
• Last Update Posted: February 22, 2024
• Sponsor: Novartis Gene Therapies
• Information provided by (Responsible Party): Novartis ( Novartis Gene Therapies )

Tracking Information

• First Submitted Date: July 31, 2019
• First Posted Date: August 1, 2019
• Last Update Posted Date: February 22, 2024
• Actual Study Start Date: February 10, 2020
• Estimated Primary Completion Date: December 31, 2035 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: September 21, 2022)

• Number of Participants Who Reach Developmental Milestones [ Time Frame: Up to 5 years ]
  Assessed via the developmental milestone checklist, formed of 10 yes/no questions. 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.
• Change From Baseline in Hammersmith Functional Motor Scale - Expanded (HFMSE) Score [ Time Frame: Up to 5 years ]
  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 on the total scale of 0-66 indicates higher levels of motor ability.
• Number of Participants Who Experience a Clinically Significant Change From Baseline in Pulmonary Assessment Results and Require Ventilatory Support [ Time Frame: Up to 15 years ]
  Participants will receive pulmonary assessments by a pulmonologist or appropriate clinician. Respiratory device data will be reviewed for participants receiving non-invasive ventilatory support.
• Number of Participants Who Experience Swallowing Dysfunction and Require Nutritional Support [ Time Frame: Up to 5 years ]
  Assessed via the swallowing function questionnaire, formed of 4 yes/ no questions and 1 body weight question.
• Number of Participants Who Experience a Clinically Significant Change from Baseline in Physical Examination Findings [ Time Frame: Up to 5 years ]
  The physical examination includes review of the following systems: head, ears, eyes, nose and throat, lungs/thorax, cardiovascular, abdomen, musculoskeletal, neurologic, dermatologic, lymphatic, and genitourinary. In addition, visual inspection of the spine, back, shoulders, and hips looking for spinal curvature and asymmetry will be carried out. Joints will be assessed for loss of mobility and contractures.
• Number of Participants Who Experience a Clinically Significant Change From Baseline in Vital Signs Measurements [ Time Frame: Up to 5 years ]
  Vital sign measurements will include blood pressure, respiratory rate, pulse, axillary temperature, and pulse oximetry.
• Change From Baseline in Height Measurements [ Time Frame: Up to 5 years ]
• Change From Baseline in Weight Measurements [ Time Frame: Up to 5 years ]
• Number of Participants Who Experience a Clinically Significant Change From Baseline in Clinical Laboratory Assessments [ Time Frame: Up to 5 years ]
  Blood samples will be collected for hematology (including complete blood cell count) and chemistry.
• Number of Participants Who Experience a Clinically Significant Change From Baseline in Cardiac Assessments [ Time Frame: Up to 5 years ]
  Cardiac assessments will include a 12-lead electrocardiogram, transthoracic echocardiogram and Troponin-I.
• Number of Participants Who Experience a Clinically Significant Change From Baseline in Observational Phase Questionnaire Results [ Time Frame: Year 6 to Year 15 ]
  The observational phase questionnaire includes 7 yes/no questions. Observation categories include: adverse events, hospitalizations, concomitant medications, ventilatory support and feeding support.
• Number of Participants Who Experience at Least One Serious Adverse Event (SAE) [ Time Frame: Up to 15 years ]
  An SAE is defined as any adverse event (appearance of [or worsening of any pre existing]) undesirable sign(s), symptom(s), or medical conditions(s) which meets any one of the following criteria:

  • Fatal
  • Life-threatening
  • Results in persistent or significant disability/incapacity
  • Constitutes a congenital abnormality or birth defect
  • Requires in-patient hospitalization or prolongation of existing hospitalization
  • Is medically significant e.g. defined as an event that jeopardizes the participant or may require medical or surgical intervention to prevent one of the outcomes listed above
• Number of Participants Who Experience at Least One Adverse Event of Special Interest (AESI) [ Time Frame: Up to 15 years ]
  An AESI is defined as an AE occurring during any study phase that fulfills one of the following criteria:

  • Hepatotoxicity
  • Thrombotic microangiopathy
  • Cardiac adverse events
  • Dorsal root ganglia toxicity
  • New malignancies
  • New incidence of a neurologic disorder
  • New incidence of an autoimmune disorder
  • New incidence of hematologic disorder
• Change From Baseline in Bayley Scales of Infant and Toddler Development [ Time Frame: Up to 42 months, 15 days of age ]
  Third Edition (Bayley-III) to be performed in all patients up to 42 months, 15 days of age.
• Change From Baseline in Revised Upper Limb Module (RULM) Score [ Time Frame: Up to 5 years ]
  RULM score is based on a scale from 0 to 37 where lower scores reflect poorer upper limb functional ability.
• Change From Baseline in Cogstate Computerized Cognitive Battery Performed in Age 48 Months and Older [ Time Frame: Up to 5 years ]
  The Cogstate Computerized Cognitive Battery consists of the Identification Test (scored 0 (best) to 1.5708 (worst)), the International Shopping List Test (scored 0 (worst) to 999 (best)), the International Shopping List Test-Delayed Recall (scored 0 (worst) to 999 (best)), the One Card Learning Test (scored 0 (worst) to 1.5708 (best)), and the One Back Test (scored 0 (worst) to 1.5708 (best)).
• Change From Baseline in Clinical Evaluation of Language Fundamentals Fifth Edition (CELF-5) Performed in All Participants 5 to 21 Years of Age [ Time Frame: Up to 5 years ]
  The CELF-5 Following Directions and Sentence Repetition subtests use scoring that varies based on age, but will be administered to participants 5-21 years of age. The Following Directions subtest will be scored from 0-33 with higher score being more advanced and the Recalling Sentences subtest will be scored from 0-78 with higher score being more advanced.
• Change From Baseline in Assessment of Caregiver Experience With Neuromuscular Disease (ACEND) [ Time Frame: Up to 5 years ]
  ACEND score is based on a scale from 1 to 41 where higher scores represent a better caregiver experience
• Number of Participants With Concomitant Medications Overall and by Type of Medications [ Time Frame: Up to 5 years ]
• Number of Participants With Other SMA Therapies Overall and by Type of Medications [ Time Frame: Year 6 to Year 15 ]

Original Primary Outcome Measures (submitted: July 31, 2019)

• Number of participants who reach developmental milestones [ Time Frame: Up to 5 years ]
  Assessed via the developmental milestone checklist, formed of 10 yes/no questions. 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.
• Change from baseline in Hammersmith Functional Motor Scale - Expanded (HFMSE) score [ Time Frame: Up to 2 years ]
  The HFMSE was devised for use in children with SMA Type 2 and Type 3, 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.
• Number of participants who experience a clinically significant change from baseline in pulmonary assessment results [ Time Frame: Up to 15 years ]
  Participants will receive pulmonary assessments by a pulmonologist or appropriate clinician. Respiratory device data will be reviewed for participants receiving non-invasive ventilatory support.
• Number of participants who experience swallowing dysfunction [ Time Frame: Up to 5 years ]
  Assessed via the swallowing function questionnaire, formed of 4 yes/ no questions and 1 body weight question.
• Number of participants who experience a clinically significant change from baseline in physical examination findings [ Time Frame: Up to 5 years ]
  The physical examination includes review of the following systems: head, ears, eyes, nose and throat, lungs/thorax, cardiovascular, abdomen, musculoskeletal, neurologic, dermatologic, lymphatic, and genitourinary. In addition, visual inspection of the spine, back, shoulders, and hips looking for spinal curvature and asymmetry will be carried out. Joints will be assessed for loss of mobility and contractures.
• Number of participants who experience a clinically significant change from baseline in vital signs measurements [ Time Frame: Up to 5 years ]
  Vital sign measurements will include blood pressure, respiratory rate, pulse, axillary temperature, and pulse oximetry.
• Change from baseline in height measurements [ Time Frame: Up to 5 years ]
• Change from baseline in weight measurements [ Time Frame: Up to 5 years ]
• Number of participants who experience a clinically significant change from baseline in clinical laboratory assessments [ Time Frame: Up to 5 years ]
  Blood samples will be collected for hematology (including complete blood cell count) and chemistry.
• Number of participants who experience a clinically significant change from baseline in cardiac assessments [ Time Frame: Up to 5 years ]
  Cardiac assessments will include a 12-lead electrocardiogram, transthoracic echocardiogram and 24-hour Holter monitor.
• Number of participants who experience a clinically significant change from baseline in observational phase questionnaire results [ Time Frame: Year 6 to Year 15 ]
  The observational phase questionnaire includes 7 yes/no questions. Observation categories include: adverse events, hospitalizations, concomitant medications, ventilatory support and feeding support.
• Number of participants who experience at least one serious adverse event (SAE) [ Time Frame: Up to 15 years ]
  An adverse event (AE) is defined as the development of an undesirable medical condition or the deterioration of a pre-existing medical condition following or during exposure to a pharmaceutical product, whether or not considered casually related to the product. An SAE is defined as an AE occurring during any study phase that fulfills one or more of the following criteria:

  • Results in death
  • Is immediately life-threatening
  • Requires in-patient hospitalization or prolongation of existing hospitalization
  • Results in persistent or significant disability or incapacity
  • Results in a congenital abnormality or birth defect
  • Is an important medical event that may jeopardize the patient/subject or may require medical intervention to prevent one of the outcomes listed above.
• Number of participants who experience at least one adverse event of special interest (AESI) [ Time Frame: Up to 15 years ]
  An AESI is defined as an AE occurring during any study phase that fulfills one of the following criteria:

  • Liver function enzyme elevations 2 × the upper limit of normal
  • New neoplasms or malignancies
  • New incidence or exacerbation of a pre-existing neurologic disorder
  • New incidence or exacerbation of a prior rheumatologic or other autoimmune disorder
  • New incidence of hematologic disorder.

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

Descriptive Information

• Brief Title: Long-term Follow-up Study of Patients Receiving Onasemnogene Abeparvovec-xioi
• Official Title: A Long-term Follow-up Study of Patients in the Clinical Trials for Spinal Muscular Atrophy Receiving AVXS-101
• Brief Summary: This is a long-term follow-up safety and efficacy study of participants in clinical trials for spinal muscular atrophy (SMA) who were treated with onasemnogene abeparvovec-xioi. Participants will roll over from their respective previous (parent) study into this long-term study for continuous monitoring of safety as well as monitoring of continued efficacy and durability of response to onasemnogene abeparvovec-xioi treatment.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Spinal Muscular Atrophy Type I
• Spinal Muscular Atrophy Type II
• Spinal Muscular Atrophy Type III
• SMA

Intervention

Biological: Onasemnogene Abeparvovec-xioi

Onasemnogene abeparvovec-xioi is a non-replicating recombinant adeno-associated virus serotype 9 containing the human survival motor neuron gene under the control of the cytomegalovirus enhancer/chicken β-actin-hybrid promoter. Onasemnogene abeparvovec-xioi administered as a one-time intravenous (IV) infusion or intrathecal (IT) injection. Dosage determined by participant weight.

Other Name: Zolgensma

Study Arms

Intravenous (IV) & Intrathecal (IT) Onasemnogene Abeparvovec-xioi

Participants received treatment with IV onasemnogene abeparvovec-xioi in an onasemnogene abeparvovec-xioi or received treatment with IT onasemnogene abeparvovec-xioi in an onasemnogene.

Intervention: Biological: Onasemnogene Abeparvovec-xioi

• Publications *: Day JW, Mendell JR, Mercuri E, Finkel RS, Strauss KA, Kleyn A, Tauscher-Wisniewski S, Tukov FF, Reyna SP, Chand DH. Clinical Trial and Postmarketing Safety of Onasemnogene Abeparvovec Therapy. Drug Saf. 2021 Oct;44(10):1109-1119. doi: 10.1007/s40264-021-01107-6. Epub 2021 Aug 12. Erratum In: Drug Saf. 2022 Feb;45(2):191-192.

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: December 1, 2022): 85
• Original Estimated Enrollment (submitted: July 31, 2019): 308
• Estimated Study Completion Date: December 31, 2035
• Estimated Primary Completion Date: December 31, 2035 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Any participant with SMA who received onasemnogene abeparvovec-xioi gene replacement therapy in a Novartis Gene Therapies-sponsored clinical study
• Participant/parent/legal guardian willing and able to complete the informed consent process and comply with study procedures and visit schedule

Exclusion Criteria:

• Parent/legal guardian unable or unwilling to participate in the long-term follow-up safety study

Sex/Gender

• Sexes Eligible for Study: All

• Ages: Child, Adult, Older Adult
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: France, Australia, Belgium, Canada, Italy, Japan, Taiwan, United Kingdom, United States
• Removed Location Countries: Korea, Republic of, Spain

Administrative Information

• NCT Number: NCT04042025
• Other Study ID Numbers: AVXS-101-LT-002; 2019-002611-26 ( EudraCT Number ); 205305 ( Other Identifier: JapicCTI ); COAV101A12103 ( Other Identifier: Novartis Pharmaceuticals )
• 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

• Current Responsible Party: Novartis ( Novartis Gene Therapies )
• Original Responsible Party: AveXis, Inc.
• Current Study Sponsor: Novartis Gene Therapies
• Original Study Sponsor: AveXis, Inc.
• Collaborators: Not Provided

Investigators

• Study Chair: Sitra Tauscher-Wisniewski, MD; Novartis Gene Therapies, Inc.

• PRS Account: Novartis
• Verification Date: February 2024