Gene Transfer Clinical Trial for Spinal Muscular Atrophy Type 1

This study is currently recruiting participants. (see Contacts and Locations)
Verified April 2014 by Nationwide Children's Hospital
Sponsor:
Collaborators:
AveXis Inc
The Sophia's Cure Foundation
Information provided by (Responsible Party):
Jerry R. Mendell, Nationwide Children's Hospital
ClinicalTrials.gov Identifier:
NCT02122952
First received: April 23, 2014
Last updated: NA
Last verified: April 2014
History: No changes posted
  Purpose

The purpose of this trial is to evaluate safety and efficacy of intravenous delivery of self-complementary scAAV9.CB.SMN as a treatment of Spinal Muscular Atrophy type 1 (SMN1).


Condition Intervention Phase
Spinal Muscular Atrophy 1
Biological: scAAV9.CB.SMN
Phase 1

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Phase I Gene Transfer Clinical Trial for Spinal Muscular Atrophy Type 1 Delivering the Survival Motor Neuron Gene by Self-Complementary AAV9

Resource links provided by NLM:


Further study details as provided by Nationwide Children's Hospital:

Primary Outcome Measures:
  • Safety Outcome Measure [ Time Frame: 2 years ] [ Designated as safety issue: Yes ]
    Any one Grade III or higher treatment-related toxicity


Secondary Outcome Measures:
  • Mortality [ Time Frame: 2 years ] [ Designated as safety issue: No ]
    Time from birth to time of death

  • Time-to-Event Outcome Measure [ Time Frame: 2 years ] [ Designated as safety issue: No ]
    Time from birth to medically prescribed respiratory assistance required 16 hours per day or more.


Estimated Enrollment: 9
Study Start Date: April 2014
Estimated Study Completion Date: June 2017
Estimated Primary Completion Date: June 2017 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Cohort 1
Low dose: 6.7 X 10^13 vg/kg of scAAV9.CB.SMN delivered one-time through a venous catheter inserted into a peripheral vein (n=3)
Biological: scAAV9.CB.SMN
Self-complementary AAV9 carrying the SMN gene under the control of a hybrid CMV enhancer/chicken-β-actin promoter
Experimental: Cohort 2
High dose: 3.3 X 10^14 vg/kg of scAAV9.CB.SMN delivered one-time through a venous catheter inserted into a peripheral vein (n=6)
Biological: scAAV9.CB.SMN
Self-complementary AAV9 carrying the SMN gene under the control of a hybrid CMV enhancer/chicken-β-actin promoter

Detailed Description:

The study will evaluate safety and efficacy of gene transfer in Spinal Muscular Atrophy Type 1 (SMA1) patients. SMA is caused by low levels of the survival motor neuron (SMN) protein, and affects all muscles in the body. There is no other effective treatment for SMA and current drug therapy has been unsuccessful in stabilizing or reversing this disease. Only supportive care is currently possible.

The gene transfer trial will deliver SMN gene intravenously (i.v.) using the adeno-associated virus serotype 9 (AAV9). Two cohorts will undergo gene transfer in a standard three-six dose escalation scheme to establish maximum tolerated dose (MTD) using toxicity. The first cohort will consist of three participants, and the second cohort will consist of six participants to receive a 5-fold increase in dose.

The primary objective of this study is the assessment of the safety of scAAV9.CB.SMN delivered intravenously to SMA type 1 patients. Following gene transfer i.v. infusion, participants will be carefully monitored for any side effects at the outpatient follow-up visits weekly for 3 weeks followed by monthly visits over two years of active study period. Safety endpoints will be assessed by changes in hematology, serum chemistry, urinalysis, immunologic response to rAAV9 and SMN, and reported history and observations of symptoms. The time from birth to study pre-defined use of respiratory assistance devices or death will be used as a secondary outcome measure of efficacy. Exploratory outcome measures include nerve conduction and muscle assessment studies. The active phase of this study will last for two-years post-infusion, following which, participants will be asked to transfer into a monitoring program where medical progress will continue to be collected from annual standard care medical exams for the next 15 years.

  Eligibility

Ages Eligible for Study:   up to 9 Months
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Nine months of age and younger at day of vector infusion with Type 1 SMA as defined by the following features:

    1. Bi-allelic SMN1 gene mutations (deletion or point mutation) with two copies of SMN2 (no more and no fewer).
    2. Onset of disease at birth to 6 months of age.
    3. Hypotonia by clinical evaluation with delay in motor skills, poor head control, round shoulder posture and hypermobility of joints.

Exclusion Criteria:

  • Active viral infection (includes HIV or serology positive for hepatitis B or C)
  • Use of invasive ventilatory support (tracheotomy with positive pressure)* or pulse oximetry <95% saturation.

    * Patients may be put on non-invasive ventilator support (BiPAP) for less than 16 hours a day at the discretion of their physician or research staff.

  • Concomitant illness that in the opinion of the PI creates unnecessary risks for gene transfer
  • Concomitant use of any of the following drugs: drugs for treatment of myopathy or neuropathy, agents used to treat diabetes mellitus, or ongoing immunosuppressive therapy or immunosuppressive therapy within 3 months of starting the trial (e.g. corticosteroids, cyclosporine, tacrolimus, methotrexate, cyclophosphamide, intravenous immunoglobulin, rituximab)
  • Patients with Anti-AAV9 antibody titers >1:50 as determined by ELISA binding immunoassay.
  • Abnormal laboratory values considered clinically significant (GGT > 3XULN, bilirubin ≥ 3.0 mg/dL , creatinine ≥ 1.8 mg/dL, Hgb < 8 or > 18 g/Dl; WBC > 20,000 per cmm) Participation in a recent SMA treatment clinical trial that in the opinion of the PI creates unnecessary risks for gene transfer.
  • Family does not want to disclose patient's study participation with primary care physician and other medical providers.
  • Patient with signs of aspiration based on a swallowing test and unwilling to use an alternative method to oral feeding.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02122952

Contacts
Contact: Sohyun L McElroy, Ph.D. 614-355-2606 Sohyun.McElroy@nationwidechildrens.org

Locations
United States, Ohio
Nationwide Children's Hospital Recruiting
Columbus, Ohio, United States, 43205
Principal Investigator: Jerry R Mendell, M.D.         
Sponsors and Collaborators
Jerry R. Mendell
AveXis Inc
The Sophia's Cure Foundation
Investigators
Principal Investigator: Jerry R Mendell, MD The Research Institute at Nationwide Children's Hospital
  More Information

Additional Information:
Publications:
Responsible Party: Jerry R. Mendell, Director, Center for Gene Therapy, Nationwide Children's Hospital
ClinicalTrials.gov Identifier: NCT02122952     History of Changes
Other Study ID Numbers: IRB13-00627
Study First Received: April 23, 2014
Last Updated: April 23, 2014
Health Authority: United States: Food and Drug Administration
United States: Data and Safety Monitoring Board
United States: Institutional Review Board

Keywords provided by Nationwide Children's Hospital:
Gene Transfer
Gene Therapy
Adeno-associated virus
Survival Motor Neuron
SMN
AAV9

Additional relevant MeSH terms:
Spinal Muscular Atrophies of Childhood
Atrophy
Muscular Atrophy
Muscular Atrophy, Spinal
Central Nervous System Diseases
Genetic Diseases, Inborn
Heredodegenerative Disorders, Nervous System
Motor Neuron Disease
Nervous System Diseases
Neurodegenerative Diseases
Neurologic Manifestations
Neuromuscular Diseases
Neuromuscular Manifestations
Pathological Conditions, Anatomical
Signs and Symptoms
Spinal Cord Diseases

ClinicalTrials.gov processed this record on October 20, 2014