Study of Intrathecal Administration of Onasemnogene Abeparvovec-xioi for Spinal Muscular Atrophy

Phase 1

Terminated

• Conditions: Spinal Muscular Atrophy
• Interventions: Biological: Onasemnogene Abeparvovec-xioi

• Registration Number: NCT03381729
• Lead Sponsor: Novartis Gene Therapies

Brief Summary

The purpose of this trial is to evaluate the safety and tolerability of intrathecal administration of onasemnogene abeparvovec-xioi in infants and children with Spinal Muscular Atrophy with 3 copies of SMN2 and deletion of SMN1.

Detailed Description

This is a Phase 1, single-dose administration study of infants and children with a genetic diagnosis consistent with spinal muscular atrophy (SMA), bi-allelic deletion of survival motor neuron 1 gene (SMN1) and 3 copies of survival motor neuron 2 gene (SMN2) without the genetic modifier who are able to sit but cannot stand or walk at the time of study entry. Patients will receive onasemnogene abeparvovec-xioi in a dose comparison safety study of two (or three) potential therapeutic doses. Patients will be stratified in two groups, those ≥6 months and \< 24 months of age at time of dosing and those ≥ 24 months and \< 60 months of age at time of dosing. At least 15 patients ≥ 6 months and \< 24 months, and at least 12 patients ≥ 24 \< 60 months will be enrolled.

The first cohort will enroll three patients (Cohort 1) ≥ 6 months and \< 24 months of age who will receive administration of 6.0 × 1013 vg of onasemnogene abeparvovec-xioi (Dose A). There will be at least a four week interval between the dosing of each patient within the cohort. Novartis Gene Therapies, Inc. will confer with the Data Safety Monitoring Board (DSMB) on all Grade III or higher AEs within approximately 48 hours of awareness that are possibly, probably or definitely related to the study agent before continuing enrollment. Safety data will be reviewed by the DSMB during quarterly meetings; following enrollment of the three patients and based upon the available safety data a decision will be made whether to: a) stop due to toxicity, or b) proceed to Cohort 2 using Dose B.

Should the determination be made to advance to Dose B, three patients \< 60 months of age will be enrolled (Cohort 2) and will receive administration of 1.2 × 1014 vg of onasemnogene abeparvovec-xioi (Dose B). Again, there will be at least a four-week interval between dosing of the three patients within the cohort. Based on the available safety data from the three Cohort 2 patients and all of the Cohort 1 patients, the DSMB will decide and document during quarterly meetings whether further four-week intervals between patients dosing is necessary. Novartis Gene Therapies, Inc. will take this recommendation into consideration and will make the final determination whether to persist with four-week intervals between patients dosing going forward; the decision will be communicated to sites and Institutional Review Boards (IRBs) in a formal sponsor letter. Novartis Gene Therapies, Inc. will confer with the DSMB on all Grade III or higher AEs within approximately 48 hours of awareness that are possibly, probably or definitely related to the study agent before continuing enrollment. Safety data will be reviewed by the DSMB during quarterly meetings; following enrollment of the first six patients and based upon available safety data, a decision will be made whether to: a) stop due to toxicity, or b) continue to enroll an additional 21 patients until there are a total of 12 patients \> 6 months and \< 24 months and 12 patients ≥ 24 and \< 60 months that have all received Dose B.

Based upon an ongoing assessment of safety and efficacy data from patients treated with the 1.2 × 1014 vg dose, an option for testing of a third dose (Dose C), will be considered. If, based on all available data, this is judged to be safe and necessary, three patients \< 60 months of age will receive Dose C, 2.4 × 1014 vg administered IT. A meeting of the DSMB will be called to obtain a recommendation on the safety of escalating to a higher dose prior to proceeding. If a decision is made to proceed to testing a higher dose, there will again be a four-week interval between dosing of the first three patients receiving Dose C, as in Cohorts 1 and 2. Safety data will be reviewed by the DSMB during quarterly meetings. Following enrollment of the first three Dose C patients and based upon available safety data, the DSMB will be consulted and a decision will be made whether to: a) stop dosing Dose C due to safety concerns, or b) continue to enroll an additional 21 patients until there are a total of 12 patients \> 6 months and \< 24 months and 12 patients ≥ 24 and \< 60 months that have received Dose C.

Patients from Cohort 3 will be followed for a total of 15 months post-dose. The primary analyses for efficacy will be assessed when all patients reach 12 months post-dose and the primary analyses for safety will be assessed when the last patient of Cohort 3 reaches 15 months post-dose (and database lock will be performed after the last patient reaches 15 months post-dose).

Basic Information
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Recruitment & Eligibility
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Study & Design
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Trial Locations
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Related News

Study Timeline

• Study First Submitted: 2017-12-13
• Study Start: 2017-12-14
• Study First Submitted QC: 2017-12-18
• Study First Posted: 2017-12-22
• Primary Completion: 2021-11-18
• Study Completion: 2021-11-18
• Results First Submitted: 2022-05-18
• Results First Submitted QC: 2022-05-18
• Results First Posted: 2023-02-16
• Status Verified: 2023-04
• Last Update Submitted: 2023-04-20
• Last Update Posted: 2023-04-24

Recruitment & Eligibility

• Status: TERMINATED
• Sex: All
• Target Recruitment: 32

Inclusion Criteria

Not provided

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Exclusion Criteria

Not provided

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Dose B	Onasemnogene Abeparvovec-xioi	Intrathecal administration 1.2 X 10\^14 vg of onasemnogene abeparvovec-xioi
Dose C	Onasemnogene Abeparvovec-xioi	Intrathecal administration 2.4 X 10\^14 vg of onasemnogene abeparvovec-xioi
Dose A	Onasemnogene Abeparvovec-xioi	Intrathecal administration 6.0 X 10\^13 vg of onasemnogene abeparvovec-xioi

Primary Outcome Measures

Name	Time	Method
Age 6 to <24 Months Only: Number of Participants Who Achieved the Ability to Stand Alone	From Day 1 up to Month 12	Defined by the Bayley Scales of Infant and Toddler Development (BSID) Gross Motor (GM) subtest performance criteria number 40, confirmed by video recording, as a participant who stands alone for at least 3 seconds unsupported.
Age 24 to <60 Months Only: Change From Baseline in Hammersmith Functional Motor Scale-Expanded (HFMSE) Score at Month 12	Baseline and Month 12	The HFMSE contained 33 items which were scored on a scale of 0-2 with a total achievable score ranging from 0, if all activities are failed, to 66, if all the activities are achieved. A positive change from baseline indicates a better outcome.
Number of Participants Who Experienced a Treatment-emergent Adverse Event (TEAE)	Adverse events were collected from the single dose of study treatment until the end of study visit (12 months for Cohort 1 and 2 and 15 months for Cohort 3)	A TEAE was defined as any event that began or worsened in severity on or after the administration of AVXS-101 through the last study visit.; Evaluation of TEAEs included the number of participants with at least one: * TEAE; * Serious TEAE; * TEAE related to AVXS-101; * TEAE with Common Terminology Criteria for Adverse Events (CTCAE) grade ≥ 3 (grade 3 = severe or medically significant to grade 5 = death related to TEAE)

Secondary Outcome Measures

Name	Time	Method
Number of Participants Who Achieved the Ability to Walk Alone	From Day 1 up to Month 12	Defined by the BSID GM subtest performance criteria number 43, confirmed by video recording, as a participant who takes 5 coordinated independent steps.
Average Number of Hours Per Day of Non-invasive Ventilatory Support	Months 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12	Participants were assessed by a pulmonologist and may have been fitted with a non-invasive positive pressure ventilatory (e.g., Bilevel Positive Airway Pressure BiPAP) at the discretion of the pulmonologist and/or investigator. The number of hours per day of non-invasive ventilatory support was captured continuously by the device.

Trial Locations

Locations (11)

UCLA; 🇺🇸 Los Angeles, California, United States

Johns Hopkins; 🇺🇸 Baltimore, Maryland, United States

Boston Children's Hospital; 🇺🇸 Boston, Massachusetts, United States

Nemours Children's Hospital; 🇺🇸 Orlando, Florida, United States

Ann & Robert H. Lurie Children's Hospital; 🇺🇸 Chicago, Illinois, United States

Washington University; 🇺🇸 Saint Louis, Missouri, United States

Nationwide Children's Hospital; 🇺🇸 Columbus, Ohio, United States

Children's Hospital of Philadelphia; 🇺🇸 Philadelphia, Pennsylvania, United States

University of Utah; 🇺🇸 Salt Lake City, Utah, United States

UT Southwestern; 🇺🇸 Dallas, Texas, United States

Stanford University; 🇺🇸 Stanford, California, United States