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

Duchenne Muscular Dystrophy Clinical Trial

Official title:

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

Clinical Trial Details — Status: Withdrawn

Administrative data

• NCT number: NCT02704325
• Other study ID #: GALGT2 for DMD
• Status: Withdrawn
• Phase: Phase 1/Phase 2
• First received: December 23, 2015
• Last updated: February 2, 2018
• Start date: April 2016
• Est. completion date: February 2020

Study information

• Verified date: February 2018
• Source: Nationwide Children's Hospital
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

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.

Recruitment information / eligibility

• Status: Withdrawn
• Enrollment: 0
• Est. completion date: February 2020
• Est. primary completion date: July 2018
• Accepts healthy volunteers: No
• Gender: Male
• Age group: 9 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Duchenne Muscular Dystrophy
• Muscular Dystrophies
• Muscular Dystrophy, Duchenne

Intervention

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.

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.

Locations

Country	Name	City	State
United States	Nationwide Children's Hospital	Columbus	Ohio

Sponsors (1)

Lead Sponsor	Collaborator
Kevin Flanigan

Country where clinical trial is conducted

United States, 

References & 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 a2 surrogates. Mol Ther. 2014 Apr;22(4):713-24. doi: 10.1038/mt.2013.246. Epub 2013 Oct 22. — View Citation

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	Expression of GALGT2 demonstrated with anti-CT epitope antibodies.		6 or 12 weeks
Secondary	GALGT2 protein expression quantified by western blot and assessed by densitometry		6 or 12 weeks
Secondary	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
Secondary	Number of fibers containing central nuclei compared between muscles by paired t-tests		6 or 12 weeks
Secondary	Dystrophin expression demonstrated with antibodies to N-terminal, C-terminal, and rod domains		6 or 12 weeks
Secondary	Utrophin expression		6 or 12 weeks
Secondary	Leukocyte markers including CD45, CD3, CD4, CD8, and MAC 387		6 or 12 weeks
Secondary	Muscle will be examined for histological appearance		6 or 12 weeks
Secondary	Antibodies to rAAVrh74 along with PBMC ELISpots to both rAAVrh74 capsid and GALGT protein will be evaluated at different time points during the study		6 or 12 weeks