Gene Transfer Clinical Trial for Duchenne Muscular Dystrophy Using rAAVrh74.MCK.GALGT2

February 2, 2018 updated by: Kevin Flanigan

Phase I Gene Transfer Clinical Trial for Duchenne Muscular Dystrophy Using rAAVrh74.MCK.GALGT2

The proposed clinical trial study of rAAVrh74.MCK.GALGT2 for duchenne muscular dystrophy (DMD) patients that will involve direct intramuscular injection to the extensor digitorum brevis muscle (EDB).

Study Overview

Status

Withdrawn

Conditions

Intervention / Treatment

Detailed Description

This is a phase I safety and tolerability study. Three DMD subjects will receive bilateral injections into the EDB muscle, with one EDB receiving the GALGT2 vector (rAAVrh74.MCK.GALGT2) and the other side receiving saline alone (assigned in a randomized fashion). Three subjects will receive a single gene transfer dose of 1E12 vector genomes, and patients and investigators will be blinded as to which muscle is injected with vector. Muscle biopsies will be performed at three months (12 weeks) in two subjects and at 1.5 months (6 weeks) in one subject and evaluated blindly for the expression of the GALGT2 transgene.

Study Type

Interventional

Phase

  • Phase 2
  • 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

7 years and older (Child, Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

Male

Description

Inclusion Criteria:

  • Nonambulant subjects, age 9 or older
  • Confirmed mutation in the DMD gene using a clinically accepted technique that completely defines the mutation
  • A magnetic resonance image of the EDB showing preservation of sufficient muscle mass to permit transfection
  • Males of any ethnic group will be eligible
  • Ability to cooperate with all study procedures
  • Willingness of sexually active subjects with reproductive capacity to practice reliable method of contraception (If appropriate).
  • Stable dose of corticosteroid therapy (including either prednisone or deflazacort and their generic forms) for 12 weeks prior to gene transfer

Exclusion Criteria:

  • Active viral infection based on clinical observations.
  • The presence of a DMD mutation without weakness or loss of function
  • Symptoms or signs of cardiomyopathy, including:
  • Dyspnea on exertion, pedal edema, shortness of breath upon lying flat, or rales at the base of the lungs
  • Echocardiogram with ejection fraction below 40%
  • Serological evidence of HIV infection, or Hepatitis A, B or C infection
  • Diagnosis of (or ongoing treatment for) an autoimmune disease
  • Persistent leukopenia or leukocytosis (WBC ≤ 3.5 K/µL or ≥ 20.0 K/µL) or an absolute neutrophil count < 1.5K/µL
  • Concomitant illness or requirement for chronic drug treatment that in the opinion of the PI creates unnecessary risks for gene transfer
  • Subjects with rAAVrh74 binding antibody titers ≥ 1:400 as determined by ELISA immunoassay
  • Presence of circulating anti-Sda antibodies as determined by study approved laboratory.
  • Abnormal laboratory values in the clinically significant range, based upon normal values in the Nationwide Children's Hospital Laboratory

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: GALGT2 Viral Vector
Dose: 1E12 vg (total dose) (n=3) of rAAVrh74.MCK.GALGT2 vs Placebo (Saline). All participants will receive rAAVrh74.MCK.GALGT2 in the right or the left EDB muscle and receive Saline in the opposite EDB muscles. The investigator will not know which side will receive rAAVrh74.MCK.GALGT2 vs Saline until after the trial is over. At the end of the trial the investigator will be unblinded.
Biological: rAAVrh74.MCK.GALGT2
Direct intramuscular injection of rAAVrh74.MCK.GALGT2 transferred to the extensor digitorum brevis muscle (EDB) of one foot and the other side receiving saline alone.
Experimental: Saline
Dose: 1E12 vg (total dose) (n=3) of rAAVrh74.MCK.GALGT2 vs Placebo (Saline). All participants will receive rAAVrh74.MCK.GALGT2 in the right or the left EDB muscle and receive Saline in the opposite EDB muscles. The investigator will not know which side will receive rAAVrh74.MCK.GALGT2 vs Saline until after the trial is over. At the end of the trial the investigator will be unblinded.
Other: PLACEBO (Saline)
Direct intramuscular injection of rAAVrh74.MCK.GALGT2 transferred to the extensor digitorum brevis muscle (EDB) of one foot and the OTHER side receiving saline alone.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Treatment related toxicities
Time Frame: 2 years
Based on the development of unacceptable toxicity defined as the occurrence of any one Grade III or higher treatment-related toxicities.
2 years

Secondary Outcome Measures

Outcome Measure
Time Frame
Expression of GALGT2 demonstrated with anti-CT epitope antibodies.
Time Frame: 6 or 12 weeks
6 or 12 weeks
GALGT2 protein expression quantified by western blot and assessed by densitometry
Time Frame: 6 or 12 weeks
6 or 12 weeks
Transduction efficiency measured by qPCR of the GALGT transgene from muscle, and expressed as vector genomes normalized to a genomic single-copy control.
Time Frame: 6 or 12 weeks
6 or 12 weeks
Number of fibers containing central nuclei compared between muscles by paired t-tests
Time Frame: 6 or 12 weeks
6 or 12 weeks
Dystrophin expression demonstrated with antibodies to N-terminal, C-terminal, and rod domains
Time Frame: 6 or 12 weeks
6 or 12 weeks
Utrophin expression
Time Frame: 6 or 12 weeks
6 or 12 weeks
Leukocyte markers including CD45, CD3, CD4, CD8, and MAC 387
Time Frame: 6 or 12 weeks
6 or 12 weeks
Muscle will be examined for histological appearance
Time Frame: 6 or 12 weeks
6 or 12 weeks
Antibodies to rAAVrh74 along with PBMC ELISpots to both rAAVrh74 capsid and GALGT protein will be evaluated at different time points during the study
Time Frame: 6 or 12 weeks
6 or 12 weeks

Collaborators and Investigators

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

Sponsor

Kevin Flanigan

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

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 (Anticipated)

April 1, 2016

Primary Completion (Anticipated)

July 1, 2018

Study Completion (Anticipated)

February 1, 2020

Study Registration Dates

First Submitted

December 23, 2015

First Submitted That Met QC Criteria

March 4, 2016

First Posted (Estimate)

March 10, 2016

Study Record Updates

Last Update Posted (Actual)

February 6, 2018

Last Update Submitted That Met QC Criteria

February 2, 2018

Last Verified

February 1, 2018

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • GALGT2 for DMD

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

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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