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

NCT02704325 | Withdrawn Phase 1 DMC FDA Drug

• 1 other identifier: GALGT2 for DMD
• Study Type: interventional
• Target: N/A
• Locations: 1 country
• Sites: 1

Brief Summary

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).

Conditions

Duchenne Muscular Dystrophy

Keywords

DMD; Duchenne Muscular Dystrophy

Outcome Measures

Primary Outcomes (1)

• Treatment related toxicities

  Based on the development of unacceptable toxicity defined as the occurrence of any one Grade III or higher treatment-related toxicities.

  2 years

Secondary Outcomes (9)

• Expression of GALGT2 demonstrated with anti-CT epitope antibodies.

  6 or 12 weeks

• GALGT2 protein expression quantified by western blot and assessed by densitometry

  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.

  6 or 12 weeks

• Number of fibers containing central nuclei compared between muscles by paired t-tests

  6 or 12 weeks

• Dystrophin expression demonstrated with antibodies to N-terminal, C-terminal, and rod domains

  6 or 12 weeks

Study Arms (2)

GALGT2 Viral Vector

EXPERIMENTAL

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

Saline

EXPERIMENTAL

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)

Interventions

rAAVrh74.MCK.GALGT2 BIOLOGICAL

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.

GALGT2 Viral Vector

PLACEBO (Saline) OTHER

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.

Saline

Eligibility Criteria

• Age: 9 Years+
• Sex: male
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Kevin Flanigan: lead

Study Sites (1)

Nationwide Children's Hospital

Columbus, Ohio, 43205, United States

Location

Related Publications (2)

• Chicoine LG, Rodino-Klapac LR, Shao G, Xu R, Bremer WG, Camboni M, Golden B, Montgomery CL, Shontz K, Heller KN, Griffin DA, Lewis S, Coley BD, Walker CM, Clark KR, Sahenk Z, Mendell JR, Martin PT. Vascular delivery of rAAVrh74.MCK.GALGT2 to the gastrocnemius muscle of the rhesus macaque stimulates the expression of dystrophin and laminin alpha2 surrogates. Mol Ther. 2014 Apr;22(4):713-24. doi: 10.1038/mt.2013.246. Epub 2013 Oct 22.

  PMID: 24145553 BACKGROUND

• Martin PT, Xu R, Rodino-Klapac LR, Oglesbay E, Camboni M, Montgomery CL, Shontz K, Chicoine LG, Clark KR, Sahenk Z, Mendell JR, Janssen PM. Overexpression of Galgt2 in skeletal muscle prevents injury resulting from eccentric contractions in both mdx and wild-type mice. Am J Physiol Cell Physiol. 2009 Mar;296(3):C476-88. doi: 10.1152/ajpcell.00456.2008. Epub 2008 Dec 24.

  PMID: 19109526 BACKGROUND

MeSH Terms

Conditions

Muscular Dystrophy, Duchenne

Interventions

Sodium Chloride

Condition Hierarchy (Ancestors)

Muscular Dystrophies; Muscular Disorders, Atrophic; Muscular Diseases; Musculoskeletal Diseases; Neuromuscular Diseases; Nervous System Diseases; Genetic Diseases, X-Linked; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Intervention Hierarchy (Ancestors)

Chlorides; Hydrochloric Acid; Chlorine Compounds; Inorganic Chemicals; Sodium Compounds

Study Officials

• Kevin Flanigan, MD

  Nationwide Children's Hospital

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Professor of Pediatrics

Model Details: This is a dose escalation trial that will begin with the minimal efficacious dose as determined by preclinical studies and approved by the FDA. During the course of the trial, if safety is shown the dose will be escalated according to the clinical protocol.

Study Record Dates

• First Submitted: December 23, 2015
• First Posted: March 10, 2016
• Study Start: April 1, 2016
• Primary Completion: July 1, 2018
• Study Completion: February 1, 2020
• Last Updated: February 6, 2018

Record last verified: 2018-02

Locations

US (1)