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Study of Intrathecal Administration of AVXS-101 for Spinal Muscular Atrophy (STRONG)

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ClinicalTrials.gov Identifier: NCT03381729
Recruitment Status : Recruiting
First Posted : December 22, 2017
Last Update Posted : February 7, 2019
Sponsor:
Information provided by (Responsible Party):
AveXis, Inc.

Brief Summary:
The purpose of this trial is to evaluate the safety and tolerability of intrathecal administration of AVXS-101 in patients with Spinal Muscular Atrophy with 3 copies of SMN2

Condition or disease Intervention/treatment Phase
Spinal Muscular Atrophy Biological: AVXS-101 Phase 1

Detailed Description:

This is a Phase 1, single-dose administration study of infants and children with a genetic diagnosis consistent with SMA, bi-allelic deletion of SMN1 and 3 copies of SMN2 without the genetic modifier who are able to sit but cannot stand or walk at the time of study entry. Patients will receive AVXS-101 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 fifteen (15) patients ≥6 months and < 24 months, and at least twelve (12) patients ≥ 24 < 60 months will be enrolled.

The first cohort will enroll three (3) patients (Cohort 1) ≥6 months and < 24 months of age who will receive administration of 6.0 × 1013 vg of AVXS-101 (Dose A). There will be at least a four (4) week interval between the dosing of each patient within the cohort. The investigators will confer with the Data Safety Monitoring Board (DSMB) on all Grade III or higher AEs within 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 (3) patients < 60 months of age will be enrolled (Cohort 2) and will receive administration of 1.2 × 1014 vg of AVXS-101 (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. AveXis, 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. The investigators will confer with the DSMB on all Grade III or higher AEs within 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 (6) 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 twelve (12) patients > 6 months and < 24 months and twelve (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 (3) patients < 60 months of age will receive Dose C which will be no greater than 2.4 × 1014 vg administered intrathecally. 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 (3) 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 twelve (12) patients > 6 months and < 24 months and twelve (12) patients ≥ 24 and < 60 months that have received Dose C.

All patients in the study will be followed for a total of 12 months. The primary analyses for efficacy will be assessed when all patients reach 12 months post-dose.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 27 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase I, Open-Label, Dose Comparison Study of AVXS-101 for Sitting But Non-ambulatory Patients With Spinal Muscular Atrophy
Actual Study Start Date : December 14, 2017
Estimated Primary Completion Date : September 1, 2020
Estimated Study Completion Date : September 1, 2020


Arm Intervention/treatment
Experimental: Dose A
Intrathecal administration 6.0 X 10^13 vg of AVXS-101
Biological: AVXS-101
Self-complementary AAV9 carrying the SMN gene under the control of a hybrid CMV enhancer/chicken-β-actin promoter

Experimental: Dose B
Intrathecal administration 1.2 X 10^14 vg of AVXS-101
Biological: AVXS-101
Self-complementary AAV9 carrying the SMN gene under the control of a hybrid CMV enhancer/chicken-β-actin promoter

Experimental: Dose C
Intrathecal administration 2.4 X 10^14 vg of AVXS-101
Biological: AVXS-101
Self-complementary AAV9 carrying the SMN gene under the control of a hybrid CMV enhancer/chicken-β-actin promoter




Primary Outcome Measures :
  1. Incidence of Adverse Events [ Time Frame: 12 months ]
    To assess the safety and tolerability of intrathecal administration of AVXS-101 by the incidence and severity of adverse events

  2. Determine Optimal Dose [ Time Frame: 12 months ]
    To determine the optimal dose of AVXS-101 that demonstrates acceptable safety with maximum preliminary efficacy administered by intrathecal injection

  3. Patients < 24 months patients: Standing Milestone [ Time Frame: 12 months ]
    Proportion of patients ≥ 6 months and < 24 months months at time of dosing achieving the ability to stand without support for at least three seconds

  4. Patients ≥ 24 months and < 60 months patients: Change in HFMSE [ Time Frame: 12 months ]
    Change in Hammersmith Functional Motor Scale-Expanded from baseline among patients ≥ 24 months at time of dosing


Secondary Outcome Measures :
  1. Patients < 24 months patients: Walking Milestone [ Time Frame: 12 months ]
    Proportion of patients that achieve ability to walk without assistance defined as taking at least five steps independently displaying coordination and balance (Bayley Scales of Infant and Toddler Development - Gross Motor Subset #43)

  2. Patients ≥ 24 months and < 60 months patients: Walking Milestone [ Time Frame: 12 months ]
    Proportion of patients that achieve ability to walk without assistance defined as taking at least five steps independently displaying coordination and balance (Bayley Scales of Infant Development -Gross Motor Subset #43)


Other Outcome Measures:
  1. Change from baseline in Bayley Scales [ Time Frame: 12 months ]
    Change from baseline in fine and gross motor components of the Bayley Scales of Infant and Toddler Development, v 3.0- a standardized, norm-referenced infant assessment of developmental functioning across 5 domains. The motor subtests will be used in this study.



Information from the National Library of Medicine

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Ages Eligible for Study:   6 Months to 60 Months   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Key Inclusion Criteria

  • Patients ≥6 months and up to 60 months (1800 days) of age at time of dosing following diagnostic confirmation during screening period by genotype who demonstrate the ability to sit unassisted for 10 or more seconds but cannot stand or walk
  • Diagnostic confirmation by genotype includes lab documentation of homozygous absence of SMN1 exon 7; with exactly three copies of SMN2
  • Negative gene testing for SMN2 gene modifier mutation (c.859G>C)
  • Onset of clinical signs and symptoms consistent with spinal muscular atrophy (SMA) at < 12 months of age
  • Able to sit independently and not standing or walking independently. Definition of sitting independently is defined by the World Health Organization Multicentre Growth Reference Study (WHO-MGRS) criteria of being able to sit up unsupported with head erect for at least 10 seconds. Child should not use arms or hands to balance body or support position (Wijnhoven 2004)
  • Be up-to-date on childhood vaccines. 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 (AAP 2009)

Key Exclusion Criteria

  • Current or historical ability to stand or walk independently
  • Contraindications for spinal tap procedure or administration of intrathecal therapy or presence of an implanted shunt for the drainage of CSF or an implanted central venous (CNS) catheter
  • Severe contractures as determined by designated Physical Therapist(s) at screening that interfere with either the ability to attain/demonstrate functional measures or interferes with ability to receive intrathecal (IT) dosing
  • Severe scoliosis (defined as ≥ 50° curvature of spine) evident on X-ray examination
  • Previous, planned or expected scoliosis repair surgery/procedure within 1 year of dose administration
  • Use of invasive ventilatory support (tracheotomy with positive pressure) or pulse oximetry < 95% saturation at screening while the patient is awake, or for high altitudes > 1000 m, oxygen saturation < 92% while the patient is awake
  • Pulse oximetry saturation must not decrease ≥ four (4) percentage points between screening and highest value on day of dosing
  • Use or requirement of non-invasive ventilatory support for 12 or more hours daily over the two (2) weeks prior to dosing
  • Medical necessity for a gastric feeding tube, where the majority of feedings are given by non-oral methods (i.e., nasogastric tube or nasojejunal tube) or patients whose weight-for-age falls below the 3rd percentile based on WHO Child Growth Standards (Onis 2006). Placement of a permanent gastrostomy prior to screening is not an exclusion
  • Use or requirement of non-invasive ventilatory support for 12 or more hours daily over the two (2) weeks prior to dosing
  • Medical necessity for a gastric feeding tube, where the majority of feedings are given by non-oral methods or patients whose weight-for-age falls below the 3rd percentile based on WHO Child Growth Standards (Onis 2006). Placement of a permanent gastrostomy prior to screening is not an exclusion
  • Active viral infection (includes human immunodeficiency virus (HIV) or serology positive for hepatitis B or C, or Zika virus)
  • Serious non-respiratory tract illness requiring systemic treatment and/or hospitalization within two (2) weeks prior to study entry
  • Respiratory infection requiring medical attention, medical intervention or increase in supportive care of any manner within four (4) weeks prior to study entry
  • Severe non-pulmonary/respiratory tract infection within four (4) weeks before study dosing or concomitant illness that in the opinion of the Principal Investigator (PI) creates unnecessary risks for gene transfer such as:

    • Major renal or hepatic impairment
    • Known seizure disorder
    • Diabetes mellitus
    • Idiopathic hypocalciuria
    • Symptomatic cardiomyopathy
  • History of bacterial meningitis or brain or spinal cord disease, including tumors, or abnormalities by magnetic resonance imaging (MRI) or computerized tomography (CT) that would interfere with the lumbar puncture (LP) procedures or CSF circulation
  • Known allergy or hypersensitivity to prednisolone or other glucocorticosteroids or their excipients
  • Known allergy or hypersensitivity to iodine or iodine-containing products
  • 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, or immunosuppressive therapy within 3 months of study dosing
  • Inability to withhold use of laxatives or diuretics in the 24 hours prior to dose administration
  • Anti-AAV9 antibody titers >1:50 as determined by Enzyme-linked Immunosorbent Assay (ELISA) binding immunoassay

    • Should a potential patient 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
  • Abnormal laboratory values considered to be clinically significant (INR >1.4), GGT >3XULN, Bilirubin ≥3.0 mg/dL, Creatinine ≥1.0 mg/dL, Hgb <8 or >18 g/Dl; WBC >20,000 per cmm) prior to study dosing
  • Participation in recent SMA treatment clinical trial or receipt of an investigational or approved compound product or therapy received with the intent to treat SMA at any time prior to screening for this study

    • Oral beta agonists must be discontinued 30 days prior to 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 1-year study assessment period

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03381729


Contacts
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Contact: AveXis MedInfo 833-828-3947 medinfo@avexis.com

Locations
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United States, California
UCLA Recruiting
Los Angeles, California, United States, 90095
Contact: Clara Sam    310-825-3264    chsam@mednet.ucla.edu   
Principal Investigator: Perry Shieh, MD/PhD         
Stanford University Recruiting
Stanford, California, United States, 94305
Contact: Shirley Paulose    650-724-3792    spaulose@stanford.edu   
Principal Investigator: John Day, MD         
United States, Florida
Nemours Children's Hospital Recruiting
Orlando, Florida, United States, 32827
Contact: Debbie Berry    407-650-7523    debbie.berry@nemours.org   
Principal Investigator: Richard Finkel, MD         
United States, Illinois
Ann & Robert H. Lurie Children's Hospital Recruiting
Chicago, Illinois, United States, 60611
Contact: Hannah Munson    312-227-2201    hmunson@luriechildrens.org   
Principal Investigator: Nancy Kuntz, MD         
United States, Maryland
Johns Hopkins Recruiting
Baltimore, Maryland, United States, 21287
Contact: Agnes Rennie    443-287-6294    aking2@jhmi.edu   
Principal Investigator: Tom Crawford, MD         
United States, Massachusetts
Boston Children's Hospital Recruiting
Boston, Massachusetts, United States, 02115
Contact: Grace Ordonez    617-355-7384    grace.ordonez@childrens.harvard.edu   
Principal Investigator: Basil Darras, MD         
United States, Missouri
Washington University Recruiting
Saint Louis, Missouri, United States, 63130
Contact: Pallavi Anand    314-362-2490    anandp@neuro.wustl.edu   
Principal Investigator: Anne Connolly, MD         
United States, Ohio
Nationwide Children's Hospital Recruiting
Columbus, Ohio, United States, 43205
Contact: Markus McColly    614-355-2825    Markus.McColly@nationwidechildrens.org   
Principal Investigator: Jerry Mendell, MD         
United States, Pennsylvania
Children's Hospital of Philadelphia Recruiting
Philadelphia, Pennsylvania, United States, 19104
Contact: Diane Barcoski    267-425-0158    barcoskid@email.chop.edu   
Contact: Josh Zigmont    267-426-7161    zigmontj@email.chop.edu   
Principal Investigator: Gihan Tennekoon, MD         
United States, Texas
UT Southwestern Recruiting
Dallas, Texas, United States, 75390
Contact: Tammy Ramm    214-456-4426    Tammy.Ramm@UTSouthwestern.edu   
Principal Investigator: Susan Iannaccone, MD         
United States, Utah
University of Utah Recruiting
Salt Lake City, Utah, United States, 84112
Contact: Teresa Janecki    801-581-3724    Teresa.Janecki@hsc.utah.edu   
Principal Investigator: Russell Butterfield, MD         
Sponsors and Collaborators
AveXis, Inc.

Publications:
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Responsible Party: AveXis, Inc.
ClinicalTrials.gov Identifier: NCT03381729     History of Changes
Other Study ID Numbers: AVXS-101-CL-102
First Posted: December 22, 2017    Key Record Dates
Last Update Posted: February 7, 2019
Last Verified: February 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by AveXis, Inc.:
Gene Transfer
Gene Therapy
Adeno-associated virus
Survival Motor Neuron
SMN
AAV9

Additional relevant MeSH terms:
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Atrophy
Muscular Atrophy
Muscular Atrophy, Spinal
Pathological Conditions, Anatomical
Neuromuscular Manifestations
Neurologic Manifestations
Nervous System Diseases
Signs and Symptoms
Spinal Cord Diseases
Central Nervous System Diseases
Motor Neuron Disease
Neurodegenerative Diseases
Neuromuscular Diseases