Gene Replacement Therapy Clinical Trial for Participants With Spinal Muscular Atrophy Type 1

Gene Therapy Clinical Trial

— STR1VE  

Official title:

Phase 3, Open-Label, Single-Arm, Single-Dose Gene Replacement Therapy Clinical Trial for Patients With Spinal Muscular Atrophy Type 1 With One or Two SMN2 Copies Delivering AVXS-101 by Intravenous Infusion

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03306277
• Other study ID #: AVXS-101-CL-303
• Secondary ID: 2020-000095-38CO
• Status: Completed
• Phase: Phase 3
• Start date: October 24, 2017
• Est. completion date: November 12, 2019

Study information

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

Clinical Trial Summary

Phase 3 pivotal US trial studying open-label intravenous administration of onasemnogene abeparvovec-xioi in spinal muscular atrophy (SMA) Type 1 participants.

Description:

Phase 3, open-label, single-arm, single-dose, study of onasemnogene abeparvovec-xioi (gene replacement therapy) in participants with spinal muscular atrophy (SMA) Type 1 who meet enrollment criteria and are genetically defined by nonfunctional survival motor neuron 1 gene (SMN1) with 1 or 2 copies of survival motor neuron 2 gene (SMN2). Fifteen (15) participants < 6 months (< 180 days) of age at the time of gene replacement therapy (Day 1) will be enrolled.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 22
• Est. completion date: November 12, 2019
• Est. primary completion date: November 12, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A to 180 Days

Eligibility

Inclusion Criteria:

• Participants with SMA Type 1 as determined by the following features: a. Diagnosis of SMA based on gene mutation analysis with bi-allelic SMN1 mutations (deletion or point mutations) and 1 or 2 copies of SMN2 (inclusive of the known SMN2 gene modifier mutation (c.859G>C))2

• The first 3 participants enrolled must meet the criteria for the Intent-To-Treat Population

• Participants must be < 6 months (< 180 days) of age at the time of onasemnogene abeparvovec-xioi infusion

• Participants must have a swallowing evaluation test performed prior to administration of gene replacement therapy

• Up-to-date on childhood vaccinations. Seasonal vaccinations that include palivizumab prophylaxis (also known as Synagis) to prevent respiratory syncytial virus (RSV) infections are also recommended in accordance with American Academy of Pediatrics

• Parent(s)/legal guardian(s) willing and able to complete the informed consent process and comply with study procedures and visit schedule

Exclusion Criteria:

• Previous, planned or expected scoliosis repair surgery/procedure during the study assessment period

• Pulse oximetry < 96% saturation at screening while the participant is awake or asleep without any supplemental oxygen or respiratory support, or for altitudes > 1000 m, oxygen saturation < 92% awake or asleep without any supplemental oxygen or respiratory support Pulse oximetry saturation may decrease to < 96% after screening provided that the saturation does not decrease by = 4 percentage points

• Tracheostomy or current use or requirement of non-invasive ventilatory support averaging = 6 hours daily over the 7 days prior to the screening visit; or = 6 hours/day on average during the screening period or requiring ventilatory support while awake over the 7 days prior to screening or at any point during the screening period prior to dosing

• Participants with signs of aspiration/inability to tolerate non-thickened- liquids based on a formal swallowing test performed as part of screening. Participants with a gastrostomy tube who pass the swallowing test will be allowed to enroll in the study

• Participants whose weight-for-age is below the third percentile based on World Health Organization (WHO) Child Growth Standards

• Active viral infection (includes human immunodeficiency virus [HIV] or positive serology for hepatitis B or C, or Zika virus)

• Serious non-respiratory 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 screening

• Severe non-pulmonary/respiratory tract infection within 4 weeks before administration of gene replacement therapy or concomitant illness that creates unnecessary risks for gene replacement therapy such as: a. Major renal or hepatic impairment b. Known seizure disorder c. Diabetes mellitus d. Idiopathic hypocalcuria e. Symptomatic cardiomyopathy

• Known allergy or hypersensitivity to prednisolone or other glucocorticosteroids or their excipients

• 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 3 months prior to gene replacement therapy

• Anti-adeno-associated virus serotype 9 (AAV9) antibody titer > 1:50 as determined by Enzyme-linked Immunosorbent Assay (ELISA) binding immunoassay. Should a potential participant demonstrate Anti-AAV9 antibody titer > 1:50, he or she may receive retesting within 30 days of the screening period and will be eligible to participate if the Anti-AAV9 antibody titer upon retesting is = 1:50

• Clinically significant abnormal laboratory values (gamma glutamyl- transpeptidase [GGT], ALT, and AST > 3 × ULN, bilirubin = 3.0 mg/dL, 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

• Participation in recent SMA treatment clinical study (with the exception of observational Cohort studies or non-interventional studies) or receipt of an investigational or commercial compound, product, or therapy administered with the intent to treat SMA at any time prior to screening for this study. Oral ß-agonists must be discontinued at least 30 days before gene therapy dosing. Inhaled albuterol specifically prescribed for the purposes of respiratory (bronchodilator) management is acceptable and not a contraindication at any time prior to screening for this study

• Expectation of major surgical procedures during the study assessment period

• Parent(s)/legal guardian(s) unable or unwilling to comply with study procedures or inability to travel for repeat visits

• Parent(s)/legal guardian(s) unwilling to keep study results/observations confidential or to refrain from posting confidential study results/observations on social media sites

• Parent(s)/legal guardian(s) refuses to sign consent form

• Gestational age at birth < 35 weeks (245 days)

Related Conditions & MeSH terms

• Atrophy
• Gene Therapy
• Muscular Atrophy
• Muscular Atrophy, Spinal
• SMA - Spinal Muscular Atrophy

Intervention

Biological:
• Onasemnogene Abeparvovec-xioi
Non-replicating recombinant adeno-associated virus serotype 9 (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
United States	Children's Hospital Colorado	Aurora	Colorado
United States	Johns Hopkins Pediatric Neurology	Baltimore	Maryland
United States	Boston Children's Hospital	Boston	Massachusetts
United States	Ann and Robert H Lurie Children's Hospital	Chicago	Illinois
United States	Nationwide Children's Hospital	Columbus	Ohio
United States	University of Texas Southwestern Medical Center	Dallas	Texas
United States	Duke University	Durham	North Carolina
United States	David Geffen School of Medicine at UCLA	Los Angeles	California
United States	University of Wisconsin (Madison)	Madison	Wisconsin
United States	Columbia University	New York	New York
United States	Nemours Children's Hospital	Orlando	Florida
United States	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania
United States	Oregon Health and Science University	Portland	Oregon
United States	Washington Unviersity School of Medicine	Saint Louis	Missouri
United States	University of Utah	Salt Lake City	Utah
United States	Stanford University	Stanford	California

Sponsors (1)

Lead Sponsor	Collaborator
Novartis Gene Therapies

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Achievement of Independent Sitting for at Least 30 Seconds	Independent sitting is defined as sitting up straight with head erect for at least 30 seconds.; This endpoint is a co-primary endpoint. The two co-primary efficacy endpoints were assessed in sequence: The endpoint of functional independent sitting was assessed first and, only when this assessment met statistical significance, was the endpoint of event-free survival assessed.	Up to 18 months
Primary	Event-free Survival	Survival is defined by the avoidance of combined endpoint of either death or permanent ventilation, which is defined by tracheostomy or by the requirement of = 16 hours of respiratory assistance per day for = 14 consecutive days in the absence of an acute reversible illness, excluding perioperative ventilation. Permanent ventilation is considered a surrogate for death. An acute reversible illness is defined as any condition other than SMA that results in increased medical intervention.; The endpoint is a co-primary endpoint. The two co-primary efficacy endpoints were assessed in sequence: The endpoint of functional independent sitting was assessed first and, only when this assessment met statistical significance was the survival endpoint assessed.	14 months
Secondary	Ability to Thrive	Ability to thrive is defined as achieving all of the following at 18 months of age: does not receive nutrition through mechanical support or other non-oral method; ability to tolerate thin liquids as demonstrated through a formal swallowing test; maintains weight; This is a co-secondary endpoint. The two co-secondary endpoints were assessed in sequence: The endpoint of ability to thrive was assessed first and, only when this assessment met statistical significance was the endpoint of ventilatory support independence assessed.	18 months
Secondary	Ventilatory Support Independence	Ventilatory support independence is defined as requiring no daily ventilator support/usage at 18 months of age, excluding acute reversible illness and perioperative ventilation, through assessment of actual usage data captured from the device (Phillips Trilogy BiPAP device). This endpoint is derived solely from the Phillips Trilogy BiPAP device.; This is a co-secondary endpoint. The two co-secondary endpoints were assessed in sequence: The endpoint of ability to thrive was assessed first and, only when this assessment met statistical significance was the endpoint of ventilatory support independence assessed.	Up to 18 months

External Links

•   Novartis Results Record
•   Recruitment Website
•   sponsor company website