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

A Long-term Follow-up Study of Patients in the Clinical Trials for Spinal Muscular Atrophy Receiving AVXS-101

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.

Study Overview

• Status: Active, not recruiting
• Conditions: SMA; Spinal Muscular Atrophy Type II; Spinal Muscular Atrophy Type I; Spinal Muscular Atrophy Type III
• Intervention / Treatment: Biological: Onasemnogene Abeparvovec-xioi

• Study Type: Interventional
• Enrollment (Actual): 85
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Randwick, New South Wales, Australia, 2145
      • Sydney Children's Hospital
• Belgium
  • Gent, Belgium, 9000
    • Universitair Ziekenhuis Gent
  • Liège, Belgium, B-4000
    • Centre de Référence des Maladies Neuromusculaires
• Canada
  • Ontario
    • Ottawa, Ontario, Canada, K1H8L1
      • Children's Hospital of Eastern Ontario Research Institute
• France
  • Paris, France, 75012
    • Hôpital Armand Trousseau
• Italy
  • Genova, Italy, 16147
    • Instituto Gianninia Gaslini
  • Milan, Italy, 20122
    • Universita Degli Studi Di Milano
  • Milan, Italy, 20133
    • Istituto Neurologico di Ricerca
  • Roma, Italy, 00168
    • Fondazione Policlinico Universitario Agostino Gemelli
• Japan
  • Tokyo, Japan, 162-8666
    • Tokyo Women's Medical University Hospital
• Taiwan
  • Taipei, Taiwan, 10048
    • National Taiwan University Hospital
• United Kingdom
  • London, United Kingdom, WC1N 3JH
    • Great Ormond Street Hospital for Children NHS Foundation Trust
  • Newcastle Upon Tyne, United Kingdom, NE1 4LP
    • The Newcastle upon Tyne Hospitals NHS Foundation Trust
• United States
  • California
    • Palo Alto, California, United States, 94304
      • Stanford University Medical Center
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Children's Hospital Colorado
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Ann Robert H. Lurie Children's Hospital of Chicago
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • John Hopkins Hospital - David M. Rubenstein Child Health Building
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital
    • Boston, Massachusetts, United States, 02115
      • Boston Children's Hospital
  • Michigan
    • Grand Rapids, Michigan, United States, 49503
      • Spectrum Health Hospitals Helen DeVos Children's Hospital
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington Unviersity School of Medicine in Saint Louis
  • New York
    • New York, New York, United States, 10032
      • Columbia University Medical Center
  • North Carolina
    • Durham, North Carolina, United States, 27713
      • Duke University
  • Ohio
    • Columbus, Ohio, United States, 43205
      • Nationwide Children's Hospital
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Children's Hospital of Philadelphia
    • Strasburg, Pennsylvania, United States, 17579
      • Clinic for Special Children
  • Texas
    • Dallas, Texas, United States, 75235
      • Children's Health Specialty Center Dallas Campus
  • Utah
    • Salt Lake City, Utah, United States, 84112
      • University of Utah Health
  • Virginia
    • Norfolk, Virginia, United States, 23507
      • Children's Hospital of The King's Daughters
    • Richmond, Virginia, United States, 23298
      • Virginia Commonwealth University
  • Wisconsin
    • Madison, Wisconsin, United States, 53792
      • University of Wisconsin, Madison

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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

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

Other: 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.

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 Names: Zolgensma

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants Who Reach Developmental Milestones	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.	Up to 5 years
Change From Baseline in Hammersmith Functional Motor Scale - Expanded (HFMSE) Score	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.	Up to 5 years
Number of Participants Who Experience a Clinically Significant Change From Baseline in Pulmonary Assessment Results and Require Ventilatory Support	Participants will receive pulmonary assessments by a pulmonologist or appropriate clinician. Respiratory device data will be reviewed for participants receiving non-invasive ventilatory support.	Up to 15 years
Number of Participants Who Experience Swallowing Dysfunction and Require Nutritional Support	Assessed via the swallowing function questionnaire, formed of 4 yes/ no questions and 1 body weight question.	Up to 5 years
Number of Participants Who Experience a Clinically Significant Change from Baseline in Physical Examination Findings	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.	Up to 5 years
Number of Participants Who Experience a Clinically Significant Change From Baseline in Vital Signs Measurements	Vital sign measurements will include blood pressure, respiratory rate, pulse, axillary temperature, and pulse oximetry.	Up to 5 years
Change From Baseline in Height Measurements		Up to 5 years
Change From Baseline in Weight Measurements		Up to 5 years
Number of Participants Who Experience a Clinically Significant Change From Baseline in Clinical Laboratory Assessments	Blood samples will be collected for hematology (including complete blood cell count) and chemistry.	Up to 5 years
Number of Participants Who Experience a Clinically Significant Change From Baseline in Cardiac Assessments	Cardiac assessments will include a 12-lead electrocardiogram, transthoracic echocardiogram and Troponin-I.	Up to 5 years
Number of Participants Who Experience a Clinically Significant Change From Baseline in Observational Phase Questionnaire Results	The observational phase questionnaire includes 7 yes/no questions. Observation categories include: adverse events, hospitalizations, concomitant medications, ventilatory support and feeding support.	Year 6 to Year 15
Number of Participants Who Experience at Least One Serious Adverse Event (SAE)	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	Up to 15 years
Number of Participants Who Experience at Least One Adverse Event of Special Interest (AESI)	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	Up to 15 years
Change From Baseline in Bayley Scales of Infant and Toddler Development	Third Edition (Bayley-III) to be performed in all patients up to 42 months, 15 days of age.	Up to 42 months, 15 days of age
Change From Baseline in Revised Upper Limb Module (RULM) Score	RULM score is based on a scale from 0 to 37 where lower scores reflect poorer upper limb functional ability.	Up to 5 years
Change From Baseline in Cogstate Computerized Cognitive Battery Performed in Age 48 Months and Older	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)).	Up to 5 years
Change From Baseline in Clinical Evaluation of Language Fundamentals Fifth Edition (CELF-5) Performed in All Participants 5 to 21 Years of Age	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.	Up to 5 years
Change From Baseline in Assessment of Caregiver Experience With Neuromuscular Disease (ACEND)	ACEND score is based on a scale from 1 to 41 where higher scores represent a better caregiver experience	Up to 5 years
Number of Participants With Concomitant Medications Overall and by Type of Medications		Up to 5 years
Number of Participants With Other SMA Therapies Overall and by Type of Medications		Year 6 to Year 15

Collaborators and Investigators

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

Publications and helpful links

General 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.

Study record dates

Study Major Dates

• Study Start (Actual): February 10, 2020
• Primary Completion (Estimated): December 31, 2035
• Study Completion (Estimated): December 31, 2035

Study Registration Dates

• First Submitted: July 31, 2019
• First Submitted That Met QC Criteria: July 31, 2019
• First Posted (Actual): August 1, 2019

Study Record Updates

• Last Update Posted (Estimated): February 22, 2024
• Last Update Submitted That Met QC Criteria: February 21, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Keywords: Gene replacement
• Additional Relevant MeSH Terms: Central Nervous System Diseases; Nervous System Diseases; Neurologic Manifestations; Genetic Diseases, Inborn; Neuromuscular Diseases; Neurodegenerative Diseases; Neuromuscular Manifestations; Pathological Conditions, Anatomical; Spinal Cord Diseases; Heredodegenerative Disorders, Nervous System; Motor Neuron Disease; Muscular Atrophy; Atrophy; Muscular Atrophy, Spinal; Spinal Muscular Atrophies of Childhood
• Other Study ID Numbers: AVXS-101-LT-002; 2019-002611-26 (EudraCT Number); 205305 (Other Identifier: JapicCTI); COAV101A12103 (Other Identifier: Novartis Pharmaceuticals)

Plan for Individual participant data (IPD)

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

Drug and device information, study documents

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