Pre-Symptomatic Study of Intravenous Onasemnogene Abeparvovec-xioi in Spinal Muscular Atrophy (SMA) for Patients With Multiple Copies of SMN2

Spinal Muscular Atrophy Clinical Trial

— SPR1NT  

Official title:

A Global Study of a Single, One-Time Dose of AVXS-101 Delivered to Infants With Genetically Diagnosed and Pre-symptomatic Spinal Muscular Atrophy With Multiple Copies of SMN2

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03505099
• Other study ID #: AVXS-101-CL-304
• Secondary ID: 2017-004087-35Ja
• Status: Completed
• Phase: Phase 3
• Start date: April 2, 2018
• Est. completion date: June 15, 2021

Study information

• Verified date: August 2022
• Source: Novartis
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

To evaluate the safety and efficacy of intravenous onasemnogene abeparvovec-xioi in pre-symptomatic patients with SMA and 2 or 3 copies SMN2

Description:

Phase 3, open-label, single-arm study of a single, one-time dose of onasemnogene abeparvovec-xioi (gene replacement therapy) in patients with spinal muscular atrophy who meet enrollment criteria and are genetically defined by bi-allelic deletion of survival motor neuron 1 gene (SMN1) with 2 or 3 copies of survival motor neuron 2 gene (SMN2). Patients with SMN1 point mutations or the SMN2 gene modifier mutation (c.859G>C) may enroll but will not be included in the efficacy analysis sets. The study includes a screening period, a gene replacement therapy period, and a follow-up period. During the screening period (Days -30 to -2), patients whose parent(s)/legal guardian(s) provide informed consent will undergo screening procedures to determine eligibility for study enrollment. Patients who meet the entry criteria will enter the in-patient gene replacement therapy period (Day -1 to Day 2). On Day -1, patients will be admitted to the hospital for pre-treatment baseline procedures. On Day 1, patients will receive a single, one-time intravenous (IV) infusion of onasemnogene abeparvovec-xioi, and will undergo in-patient safety monitoring for a minimum of 24 hours post infusion. Patients may be discharged 24 hours (48 hours in Japan) after the infusion, based on Investigator judgment. During the outpatient follow-up period (Days 3 to End of Study at 18 or 24 of age, dependent upon respective SMN2 copy number), patients will return at regularly scheduled intervals for efficacy and safety assessments until the End of Study when the patient reaches 18 months of age (SMN2 = 2) or 24 months of age (SMN2 = 3). After the End of Study visit, eligible patients will be invited to rollover into a long-term follow up study.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 30
• Est. completion date: June 15, 2021
• Est. primary completion date: June 15, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A to 42 Days

Eligibility

Inclusion Criteria:

• Age =6 weeks (=42 days) at time of dose
• Ability to tolerate thin liquids as demonstrated through a formal bedside swallowing test
• Compound muscle action potential (CMAP) =2mV at Baseline; centralized review of CMAP data will be conducted
• Gestational age of 35 to 42 weeks
• Parent(s)/legal guardian(s) willing and able to complete the informed consent process and comply with study procedures and visit schedule
• Patients with pre-symptomatic SMA Type 1 as determined by the following features:

a. 2 copies of SMN2 (n =14)

• Patients with pre-symptomatic SMA Type 2 as determined by the following features:

1. 3 copies of SMN2 (n =12)

Exclusion Criteria:

• Weight at screening visit <2 kg
• Hypoxemia (oxygen saturation <96% awake or asleep without any supplemental oxygen or respiratory support) at the screening visit or for altitudes >1000 m, oxygen saturation <92% awake or asleep without any supplemental oxygen or respiratory support at the screening visit
• Any clinical signs or symptoms at screening or immediately prior to dosing that are, in the opinion of the Investigator, strongly suggestive of SMA
• Tracheostomy or current prophylactic use or requirement of noninvasive ventilatory support at any time and for any duration prior to screening or during the screening period
• Patients with signs of aspiration/inability to tolerate nonthickened liquids based on a formal swallowing test performed as part of screening or patients receiving any non-oral feeding method
• Clinically significant abnormal laboratory values (gamma-glutamyl transferase [GGT], Alanine transaminase [ALT], and aspartate aminotransferase [AST], or total bilirubin > 2 × the upper limit of normal [ULN], creatinine = 1.0 mg/dL, hemoglobin [Hgb] < 8 or > 18 g/dL; white blood cell [WBC] > 20,000 per cmm) prior to gene replacement therapy. Patients with an elevated bilirubin level that is unequivocally the result of neonatal jaundice shall not be excluded
• Treatment with an investigational or commercial product, including nusinersen, given for the treatment of SMA. This includes any history of gene therapy, prior antisense oligonucleotide treatment, or cell transplantation.
• Patients whose weight-for-age is below the third percentile based on World Health Organization (WHO) Child Growth Standards
• Biological mother with active viral infection as determined by screening laboratory samples (includes human immunodeficiency virus [HIV] or positive serology for hepatitis B or C)
• Biological mothers with clinical suspicion of Zika virus that meet Centers for Disease Control and Prevention (CDC) Zika virus epidemiological criteria including history of residence in or travel to a geographic region with active Zika transmission at the time of travel will be tested for Zika virus RNA. Positive results warrant confirmed negative Zika virus RNA testing in the patient prior to enrollment.
• Serious nonrespiratory tract illness requiring systemic treatment and/or hospitalization within 2 Weeks prior to screening
• Upper or lower respiratory infection requiring medical attention, medical intervention, or increase in supportive care of any manner within 4 Weeks prior to dosing
• Severe nonpulmonary/respiratory tract infection within 4 Weeks before administration of gene replacement therapy or concomitant illness that, in the opinion of the Investigator or Sponsor medical monitor, creates unnecessary risks for gene

replacement therapy such as:

• Major renal or hepatic impairment
• Known seizure disorder
• Diabetes mellitus
• Idiopathic hypocalciuria
• Symptomatic cardiomyopathy
• Known allergy or hypersensitivity to prednisolone or other glucocorticosteroids or their excipients
• Previous, planned or expected major surgical procedure including scoliosis repair surgery/procedure during the study assessment period
• Concomitant use of any of the following: drugs for treatment of myopathy or neuropathy, agents used to treat diabetes mellitus, or ongoing immunosuppressive therapy, plasmapheresis, immunomodulators such as adalimumab, immunosuppressive therapy within 4 Weeks prior to gene replacement therapy
• AntiAAV9 antibody titer >1:50 as determined by Enzyme-linked Immunosorbent Assay (ELISA) binding immunoassay
• Should a potential patient demonstrate AntiAAV9 antibody titer >1:50, he or she may receive retesting inside the 30-Day screening period and will be eligible to participate if the AntiAAV9 antibody titer upon retesting is =1:50, provided the <6 Week age requirement at the time of dosing is still met
• Biological mother involved with the care of the child refuses anti-AAV9 antibody testing prior to dosing

Related Conditions & MeSH terms

• Atrophy
• Muscular Atrophy
• Muscular Atrophy, Spinal
• Spinal Muscular Atrophy

Intervention

Biological:
• onasemnogene abeparvovec-xioi
A non-replicating recombinant AAV9 containing the complimentary deoxyribonucleic acid (cDNA) of the human SMN gene under the control of the cytomegalovirus (CMV) enhancer/chicken-ß-actin-hybrid promoter (CB). The AAV inverted terminal repeat (ITR) has been modified to promote intramolecular annealing of the transgene, thus forming a double-stranded transgene ready for transcription.

Locations

Country	Name	City	State
Australia	Sydney Children's Hospital	Randwick	New South Wales
Belgium	Centre Hospitalier Régional Hôpital La Citadelle	Liège
Canada	Canada Childrens Hospital of Eastern Ontario	Ottawa	Ontario
Japan	Tokyo Women's Medical	Tokyo
United Kingdom	Great Ormond Street Hospital for Children NHS Foundation Trust	London
United States	Children's Hospital Colorado	Aurora	Colorado
United States	Massachusetts General Hospital	Boston	Massachusetts
United States	Nationwide Children's Hospital	Columbus	Ohio
United States	Children's Medical Center Dallas	Dallas	Texas
United States	Helen DeVos Children's Hospital	Grand Rapids	Michigan
United States	David Geffen School of Medicine at UCLA	Los Angeles	California
United States	University Hospital and UW Health Clinics	Madison	Wisconsin
United States	Columbia University Medical Center	New York	New York
United States	Nemours Children's Hospital	Orlando	Florida
United States	St. Louis Children's Hospital	Saint Louis	Missouri
United States	Clinic for Special Children	Strasburg	Pennsylvania

Sponsors (2)

Lead Sponsor	Collaborator
Novartis Gene Therapies	PRA Health Sciences

Countries where clinical trial is conducted

United States,  Australia,  Belgium,  Canada,  Japan,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Cohort 1: Number of Participants Who Achieved Sitting Alone for at Least 30 Seconds	Defined by the Bayley Scales of Infant and Toddler Development (BSID) Gross Motor (GM) subtest performance criteria number 26, confirmed by video recording, as a participant who sits for at least 30 seconds without assistance from another person or object. The participant was allowed to use their upper extremities.	From Day 1 up to 18 months of age visit
Primary	Cohort 2: Number of Participants Who Achieved Standing Alone for at Least 3 Seconds	Defined by the BSID GM subtest performance criteria number 40, confirmed by video recording, as a participant who stands alone for at least 3 seconds unsupported.	From Day 1 up to 24 months of age visit
Secondary	Cohort 1: Event-free Survival at 14 Months of Age	Event-free survival at 14 months of age was defined as the number of participants who did not die, did not require permanent ventilation and did not withdraw from the study by 14 months of age.	From Day 1 up to 14 months of age
Secondary	Cohort 1: Number of Participants Who Achieved the Ability to Maintain Weight at or Above the Third Percentile Without the Need for Non-Oral or Mechanical Feeding Support	The ability to maintain weight at or above the third percentile without the need for non-oral or mechanical feeding support was defined by meeting the following criteria at each visit up to 18 months of age: Did not receive nutrition through mechanical support (i.e., feeding tube); Maintained weight (= third percentile for age and sex as defined by World Health Organization [WHO] guidelines) consistent with the participant's age at the assessment.	From Day 1 up to 18 months of age
Secondary	Cohort 2: Number of Participants Who Achieved the Ability to Walk Alone	Defined by the BSID GM subtest performance criteria number 43, confirmed by video recording, as a participant who takes 5 coordinated independent steps.	From Day 1 up to 24 months of age visit

External Links

•   Novartis Clinical Trial Results