Gene Transfer Clinical Trial for Spinal Muscular Atrophy Type 1

August 30, 2022 updated by: Novartis Gene Therapies

Phase I Gene Transfer Clinical Trial for Spinal Muscular Atrophy Type 1 Delivering AVXS-101

The purpose of this trial is to evaluate safety and efficacy of intravenous delivery of AVXS-101 as a treatment of spinal muscular atrophy Type 1 (SMN1).

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

The study will evaluate safety and efficacy of gene therapy 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 effective treatment for SMA and current drug therapy has been unsuccessful in stabilizing or reversing this disease. Only supportive care is currently possible.

Open-label, dose-escalation clinical trial of AVXS-101 injected intravenously through a peripheral limb vein. Short-term safety will be evaluated over a two year period. Patients will be tested at baseline and return for follow up visits on days 7, 14, 21, 30, followed by once every month through 12 months post dose, and then every three months through two (2) years post infusion. Unscheduled visits may occur if the PI determines that they are necessary.

The primary analysis for efficacy will be assessed when all patients reach 13.6 months of age (a database lock will be performed at the time point at which all patients reach 13.6 months of age). A follow-up safety analysis will be completed at the time point at which the last patient reaches 24 months post-dose.

Upon completion of the 2-year study period, patients will be monitored annually as per standard of care for up to 15 years.

Study Type

Interventional

Enrollment (Actual)

15

Phase

  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Ohio
      • Columbus, Ohio, United States, 43205
        • Nationwide Children's Hospital

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

No older than 6 months (Child)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • Six or nine months of age and younger (depending on cohort) on day of vector infusion with Type 1 SMA as defined by the following features:

    • Diagnosis of SMA based on gene mutation analysis with bi-allelic SMN1 mutations (deletion or point mutations) and 2 copies of SMN2.
    • Onset of disease at birth up to 6 months of age.
    • 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.
  • Patients with a single base substitution in SMN2 (c.859G>C in exon 7) will be excluded based on predicted mild phenotype.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Non-Randomized
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Cohort 1
6.7 X 10^13 vg/kg of AVXS-101 delivered one-time through a venous catheter inserted into a peripheral vein (n=3)
Biological: AVXS-101
Self-complementary AAV9 carrying the SMN gene under the control of a hybrid CMV enhancer/chicken-β-actin promoter
Other Names:
  • Zolgensma
Experimental: Cohort 2
2.0 X 10^14 vg/kg of AVXS-101 delivered one-time through a venous catheter inserted into a peripheral vein (n=12)
Biological: AVXS-101
Self-complementary AAV9 carrying the SMN gene under the control of a hybrid CMV enhancer/chicken-β-actin promoter
Other Names:
  • Zolgensma

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
Number of Participants That Experienced One Grade III or Higher Unanticipated, Treatment-related Toxicity That Presents With Clinical Symptoms and Requires Medical Treatment
Time Frame: 2 years
2 years

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Number of Participants Who Experienced Permanent Ventilation or Death
Time Frame: Up to 13.6 months of age
Permanent ventilation was defined as the requirement of ≥ 16-hour respiratory assistance, including non-invasive ventilatory support, per day continuously for ≥ 2 weeks in the absence of an acute reversible illness, excluding perioperative ventilation.
Up to 13.6 months of age
Percent Change From Baseline in Mean Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND) Score
Time Frame: Baseline to 24 months post-dose
Score ranges from 0 to 64, where 64 is the maximum possible score. A higher score is indicative of higher/better motor function. CHOP-INTEND assessments were discontinued once patients achieved higher functioning status, so the number of available data points decreased over time.
Baseline to 24 months post-dose
Number of Participants With Assessed Improvement in Motor Function
Time Frame: 24 months post-dose
Improvement in motor function was determined by achievement of developmental milestones, specifically achievement of ability to sit unassisted for at least 30 seconds, determined by physical therapist and confirmed by an independent central video reviewer. Achievement of functional independent sitting was defined as the ability to maintain a sitting position independently for at least 30 seconds as confirmed per video evaluation by an expert central reviewer based on videos taken either at scheduled visits or provided by the parent/legal guardian.
24 months post-dose

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Novartis Gene Therapies

Investigators

  • Principal Investigator: Jerry R Mendell, MD, The Research Institute at Nationwide Children's Hospital

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

May 5, 2014

Primary Completion (Actual)

December 15, 2017

Study Completion (Actual)

December 15, 2017

Study Registration Dates

First Submitted

April 23, 2014

First Submitted That Met QC Criteria

April 23, 2014

First Posted (Estimate)

April 25, 2014

Study Record Updates

Last Update Posted (Actual)

September 15, 2022

Last Update Submitted That Met QC Criteria

August 30, 2022

Last Verified

August 1, 2022

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • AVXS-101-CL-101
  • COAV101A12101 (Other Identifier: Novartis Pharmaceuticals)

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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