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

Primary Purpose

Duchenne Muscular Dystrophy

Status

Withdrawn

Phase

Phase 1

Locations

United States

Study Type

Interventional

Intervention

rAAVrh74.MCK.GALGT2

PLACEBO (Saline)

About this trial

This is an interventional treatment trial for Duchenne Muscular Dystrophy focused on measuring DMD, Duchenne Muscular Dystrophy

Eligibility Criteria

9 Years - undefined (Child, Adult, Older Adult)MaleDoes not accept healthy volunteers

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

Sites / Locations

Nationwide Children's Hospital

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Arm Label

GALGT2 Viral Vector

Saline

Arm Description

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.

Outcomes

Primary Outcome Measures

Treatment related toxicities

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

Secondary Outcome Measures

Expression of GALGT2 demonstrated with anti-CT epitope antibodies.

GALGT2 protein expression quantified by western blot and assessed by densitometry

Transduction efficiency measured by qPCR of the GALGT transgene from muscle, and expressed as vector genomes normalized to a genomic single-copy control.

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

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

Utrophin expression

Leukocyte markers including CD45, CD3, CD4, CD8, and MAC 387

Muscle will be examined for histological appearance

Antibodies to rAAVrh74 along with PBMC ELISpots to both rAAVrh74 capsid and GALGT protein will be evaluated at different time points during the study

Full Information

NCT ID

NCT02704325

First Posted

December 23, 2015

Last Updated

February 2, 2018

Sponsor

Kevin Flanigan

1. Study Identification

Unique Protocol Identification Number

NCT02704325

Brief Title

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

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

February 2018

Overall Recruitment Status

Withdrawn

Study Start Date

April 2016 (Anticipated)

Primary Completion Date

July 2018 (Anticipated)

Study Completion Date

February 2020 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor-Investigator

Name of the Sponsor

Kevin Flanigan

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Duchenne Muscular Dystrophy

Keywords

DMD, Duchenne Muscular Dystrophy

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1, Phase 2

Interventional Study Model

Single Group Assignment

Model Description

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.

Masking

None (Open Label)

Allocation

Non-Randomized

Enrollment

0 (Actual)

8. Arms, Groups, and Interventions

Arm Title

GALGT2 Viral Vector

Arm Type

Experimental

Arm Description

Arm Title

Saline

Arm Type

Experimental

Arm Description

Intervention Type

Biological

Intervention Name(s)

rAAVrh74.MCK.GALGT2

Intervention Description

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.

Intervention Type

Other

Intervention Name(s)

PLACEBO (Saline)

Intervention Description

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.

Primary Outcome Measure Information:

Title

Treatment related toxicities

Description

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

Time Frame

2 years

Secondary Outcome Measure Information:

Title

Expression of GALGT2 demonstrated with anti-CT epitope antibodies.

Time Frame

6 or 12 weeks

Title

GALGT2 protein expression quantified by western blot and assessed by densitometry

Time Frame

6 or 12 weeks

Title

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

Title

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

Time Frame

6 or 12 weeks

Title

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

Time Frame

6 or 12 weeks

Title

Utrophin expression

Time Frame

6 or 12 weeks

Title

Leukocyte markers including CD45, CD3, CD4, CD8, and MAC 387

Time Frame

6 or 12 weeks

Title

Muscle will be examined for histological appearance

Time Frame

6 or 12 weeks

Title

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

10. Eligibility

Sex

Male

Minimum Age & Unit of Time

9 Years

Accepts Healthy Volunteers

Eligibility Criteria

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

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Kevin Flanigan, MD

Organizational Affiliation

Nationwide Children's Hospital

Official's Role

Principal Investigator

Facility Information:

Facility Name

Nationwide Children's Hospital

City

Columbus

State/Province

Ohio

ZIP/Postal Code

43205

Country

United States

12. IPD Sharing Statement

Citations:

PubMed Identifier

24145553

Citation

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.

Results Reference

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PubMed Identifier

19109526

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.

Results Reference

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

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