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

Primary Purpose

Spinal Muscular Atrophy Type I, Spinal Muscular Atrophy Type II, Spinal Muscular Atrophy Type III

Status
Active
Phase
Phase 3
Locations
International
Study Type
Interventional
Intervention
Onasemnogene Abeparvovec-xioi
Sponsored by
Novartis Gene Therapies
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Spinal Muscular Atrophy Type I focused on measuring Gene replacement

Eligibility Criteria

undefined - undefined (Child, Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Stanford University Medical Center
  • Children's Hospital Colorado
  • Ann Robert H. Lurie Children's Hospital of Chicago
  • John Hopkins Hospital - David M. Rubenstein Child Health Building
  • Massachusetts General Hospital
  • Boston Children's Hospital
  • Spectrum Health Hospitals Helen DeVos Children's Hospital
  • Washington Unviersity School of Medicine in Saint Louis
  • Columbia University Medical Center
  • Duke University
  • Nationwide Children's Hospital
  • Children's Hospital of Philadelphia
  • Clinic for Special Children
  • Children's Health Specialty Center Dallas Campus
  • University of Utah Health
  • Children's Hospital of The King's Daughters
  • Virginia Commonwealth University
  • University of Wisconsin, Madison
  • Sydney Children's Hospital
  • Universitair Ziekenhuis Gent
  • Centre de Référence des Maladies Neuromusculaires
  • Children's Hospital of Eastern Ontario Research Institute
  • Hôpital Armand Trousseau
  • Instituto Gianninia Gaslini
  • Universita Degli Studi Di Milano
  • Istituto Neurologico di Ricerca
  • Fondazione Policlinico Universitario Agostino Gemelli
  • Tokyo Women's Medical University Hospital
  • National Taiwan University Hospital
  • Great Ormond Street Hospital for Children NHS Foundation Trust
  • The Newcastle Upon Tyne Hospitals NHS Foundation Trust

Arms of the Study

Arm 1

Arm Type

Other

Arm Label

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

Arm Description

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

Outcomes

Primary Outcome Measures

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.
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.
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.
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.
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.
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.
Change From Baseline in Height Measurements
Change From Baseline in Weight Measurements
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.
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.
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.
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
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
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.
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.
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)).
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.
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
Number of Participants With Concomitant Medications Overall and by Type of Medications
Number of Participants With Other SMA Therapies Overall and by Type of Medications

Secondary Outcome Measures

Full Information

First Posted
July 31, 2019
Last Updated
July 10, 2023
Sponsor
Novartis Gene Therapies
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1. Study Identification

Unique Protocol Identification Number
NCT04042025
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
Study Type
Interventional

2. Study Status

Record Verification Date
July 2023
Overall Recruitment Status
Active, not recruiting
Study Start Date
February 10, 2020 (Actual)
Primary Completion Date
December 29, 2035 (Anticipated)
Study Completion Date
December 29, 2035 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Novartis Gene Therapies

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Spinal Muscular Atrophy Type I, Spinal Muscular Atrophy Type II, Spinal Muscular Atrophy Type III, SMA
Keywords
Gene replacement

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
85 (Actual)

8. Arms, Groups, and Interventions

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

10. Eligibility

Sex
All
Accepts Healthy Volunteers
No
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Sitra Tauscher-Wisniewski, MD
Organizational Affiliation
Novartis Gene Therapies, Inc.
Official's Role
Study Chair
Facility Information:
Facility Name
Stanford University Medical Center
City
Palo Alto
State/Province
California
ZIP/Postal Code
94304
Country
United States
Facility Name
Children's Hospital Colorado
City
Aurora
State/Province
Colorado
ZIP/Postal Code
80045
Country
United States
Facility Name
Ann Robert H. Lurie Children's Hospital of Chicago
City
Chicago
State/Province
Illinois
ZIP/Postal Code
60611
Country
United States
Facility Name
John Hopkins Hospital - David M. Rubenstein Child Health Building
City
Baltimore
State/Province
Maryland
ZIP/Postal Code
21287
Country
United States
Facility Name
Massachusetts General Hospital
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02114
Country
United States
Facility Name
Boston Children's Hospital
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02115
Country
United States
Facility Name
Spectrum Health Hospitals Helen DeVos Children's Hospital
City
Grand Rapids
State/Province
Michigan
ZIP/Postal Code
49503
Country
United States
Facility Name
Washington Unviersity School of Medicine in Saint Louis
City
Saint Louis
State/Province
Missouri
ZIP/Postal Code
63110
Country
United States
Facility Name
Columbia University Medical Center
City
New York
State/Province
New York
ZIP/Postal Code
10032
Country
United States
Facility Name
Duke University
City
Durham
State/Province
North Carolina
ZIP/Postal Code
27713
Country
United States
Facility Name
Nationwide Children's Hospital
City
Columbus
State/Province
Ohio
ZIP/Postal Code
43205
Country
United States
Facility Name
Children's Hospital of Philadelphia
City
Philadelphia
State/Province
Pennsylvania
ZIP/Postal Code
19104
Country
United States
Facility Name
Clinic for Special Children
City
Strasburg
State/Province
Pennsylvania
ZIP/Postal Code
17579
Country
United States
Facility Name
Children's Health Specialty Center Dallas Campus
City
Dallas
State/Province
Texas
ZIP/Postal Code
75235
Country
United States
Facility Name
University of Utah Health
City
Salt Lake City
State/Province
Utah
ZIP/Postal Code
84112
Country
United States
Facility Name
Children's Hospital of The King's Daughters
City
Norfolk
State/Province
Virginia
ZIP/Postal Code
23507
Country
United States
Facility Name
Virginia Commonwealth University
City
Richmond
State/Province
Virginia
ZIP/Postal Code
23298
Country
United States
Facility Name
University of Wisconsin, Madison
City
Madison
State/Province
Wisconsin
ZIP/Postal Code
53792
Country
United States
Facility Name
Sydney Children's Hospital
City
Randwick
State/Province
New South Wales
ZIP/Postal Code
2145
Country
Australia
Facility Name
Universitair Ziekenhuis Gent
City
Gent
ZIP/Postal Code
9000
Country
Belgium
Facility Name
Centre de Référence des Maladies Neuromusculaires
City
Liège
ZIP/Postal Code
B-4000
Country
Belgium
Facility Name
Children's Hospital of Eastern Ontario Research Institute
City
Ottawa
State/Province
Ontario
ZIP/Postal Code
K1H8L1
Country
Canada
Facility Name
Hôpital Armand Trousseau
City
Paris
ZIP/Postal Code
75012
Country
France
Facility Name
Instituto Gianninia Gaslini
City
Genova
ZIP/Postal Code
16147
Country
Italy
Facility Name
Universita Degli Studi Di Milano
City
Milan
ZIP/Postal Code
20122
Country
Italy
Facility Name
Istituto Neurologico di Ricerca
City
Milan
ZIP/Postal Code
20133
Country
Italy
Facility Name
Fondazione Policlinico Universitario Agostino Gemelli
City
Roma
ZIP/Postal Code
00168
Country
Italy
Facility Name
Tokyo Women's Medical University Hospital
City
Tokyo
ZIP/Postal Code
162-8666
Country
Japan
Facility Name
National Taiwan University Hospital
City
Taipei
ZIP/Postal Code
10048
Country
Taiwan
Facility Name
Great Ormond Street Hospital for Children NHS Foundation Trust
City
London
ZIP/Postal Code
WC1N 3JH
Country
United Kingdom
Facility Name
The Newcastle Upon Tyne Hospitals NHS Foundation Trust
City
Newcastle Upon Tyne
ZIP/Postal Code
NE1 4LP
Country
United Kingdom

12. IPD Sharing Statement

Plan to Share IPD
Yes
Citations:
PubMed Identifier
34383289
Citation
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.
Results Reference
derived

Learn more about this trial

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

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