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Gene Replacement Therapy Clinical Trial for Participants With Spinal Muscular Atrophy Type 1 (STR1VE)

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ClinicalTrials.gov Identifier: NCT03306277
Recruitment Status : Completed
First Posted : October 11, 2017
Results First Posted : July 16, 2020
Last Update Posted : June 14, 2021
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Gene Therapies )

Tracking Information
First Submitted Date  ICMJE October 2, 2017
First Posted Date  ICMJE October 11, 2017
Results First Submitted Date  ICMJE June 25, 2020
Results First Posted Date  ICMJE July 16, 2020
Last Update Posted Date June 14, 2021
Actual Study Start Date  ICMJE October 24, 2017
Actual Primary Completion Date November 12, 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: June 25, 2020)
  • Achievement of Independent Sitting for at Least 30 Seconds [ Time Frame: Up to 18 months ]
    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.
  • Event-free Survival [ Time Frame: 14 months ]
    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.
Original Primary Outcome Measures  ICMJE
 (submitted: October 4, 2017)
  • Achievement of independent sitting [ Time Frame: 18 months of age visit ]
    Achievement of developmental milestone of independent sitting at 18 months of age
  • Event-free Survival [ Time Frame: 14 months of age visit ]
    Event-free survival at 14 months of age.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: June 25, 2020)
  • Ability to Thrive [ Time Frame: 18 months ]
    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.
  • Ventilatory Support Independence [ Time Frame: Up to 18 months ]
    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.
Original Secondary Outcome Measures  ICMJE
 (submitted: October 4, 2017)
  • Ability to thrive [ Time Frame: Through 18 months of age ]
    Determine effect of AVXS-101 on the ability to thrive.
  • Ventilatory support independence [ Time Frame: Through 18 months of age ]
    Determine the effect of AVXS-101 on the ability to remain independent of ventilatory support
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Gene Replacement Therapy Clinical Trial for Participants With Spinal Muscular Atrophy Type 1
Official Title  ICMJE 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
Brief Summary Phase 3 pivotal US trial studying open-label intravenous administration of onasemnogene abeparvovec-xioi in spinal muscular atrophy (SMA) Type 1 participants.
Detailed 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.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Intervention Model Description:
One-time intravenous administration of onasemnogene abeparvovec-xioi.
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • SMA - Spinal Muscular Atrophy
  • Gene Therapy
Intervention  ICMJE 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-β-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.
Other Name: Zolgensma
Study Arms  ICMJE Experimental: Onasemnogene Abeparvovec-xioi
One-time Intravenous administration of onasemnogene abeparvovec-xioi at the therapeutic dose.
Intervention: Biological: Onasemnogene Abeparvovec-xioi
Publications * Day JW, Finkel RS, Chiriboga CA, Connolly AM, Crawford TO, Darras BT, Iannaccone ST, Kuntz NL, Peña LDM, Shieh PB, Smith EC, Kwon JM, Zaidman CM, Schultz M, Feltner DE, Tauscher-Wisniewski S, Ouyang H, Chand DH, Sproule DM, Macek TA, Mendell JR. Onasemnogene abeparvovec gene therapy for symptomatic infantile-onset spinal muscular atrophy in patients with two copies of SMN2 (STR1VE): an open-label, single-arm, multicentre, phase 3 trial. Lancet Neurol. 2021 Apr;20(4):284-293. doi: 10.1016/S1474-4422(21)00001-6. Epub 2021 Mar 17.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: November 27, 2019)
22
Original Estimated Enrollment  ICMJE
 (submitted: October 4, 2017)
15
Actual Study Completion Date  ICMJE November 12, 2019
Actual Primary Completion Date November 12, 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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 β-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)
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE up to 180 Days   (Child)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03306277
Other Study ID Numbers  ICMJE AVXS-101-CL-303
2020-000095-38 ( EudraCT Number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Novartis ( Novartis Gene Therapies )
Study Sponsor  ICMJE Novartis Gene Therapies
Collaborators  ICMJE Not Provided
Investigators  ICMJE Not Provided
PRS Account Novartis
Verification Date June 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP