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

Phase 1

Withdrawn

• Conditions: Duchenne Muscular Dystrophy
• Interventions: Biological: rAAVrh74.MCK.GALGT2; Other: PLACEBO (Saline)

• Registration Number: NCT02704325
• Lead Sponsor: Kevin Flanigan

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).

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 Timeline

• Study First Submitted: 2015-12-23
• Study First Submitted QC: 2016-03-04
• Study First Posted: 2016-03-10
• Study Start: 2016-04
• Status Verified: 2018-02
• Last Update Submitted: 2018-02-02
• Last Update Posted: 2018-02-06
• Primary Completion: 2018-07
• Study Completion: 2020-02

Recruitment & Eligibility

• Status: WITHDRAWN
• Sex: Male
• Target Recruitment: Not specified

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 & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
GALGT2 Viral Vector	rAAVrh74.MCK.GALGT2	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.
Saline	PLACEBO (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.

Primary Outcome Measures

Name	Time	Method
Treatment related toxicities	2 years	Based on the development of unacceptable toxicity defined as the occurrence of any one Grade III or higher treatment-related toxicities.

Secondary Outcome Measures

Name	Time	Method
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
Utrophin expression	6 or 12 weeks
Leukocyte markers including CD45, CD3, CD4, CD8, and MAC 387	6 or 12 weeks
Muscle will be examined for histological appearance	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	6 or 12 weeks

Trial Locations

Locations (1)

Nationwide Children's Hospital; 🇺🇸 Columbus, Ohio, United States