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Clinical Intramuscular Gene Transfer Trial of rAAVrh74.MCK.Micro-Dystrophin to Patients With Duchenne Muscular Dystrophy

Primary Purpose

Duchenne Muscular Dystrophy

Status

Completed

Phase

Phase 1

Locations

United States

Study Type

Interventional

Intervention

rAAVrh74.MCK.micro-Dystrophin

About this trial

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

Eligibility Criteria

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

Inclusion Criteria:

Age 7 or older; must be wheelchair-dependent
Confirmed Dystrophin mutations based on mutation compatibility with micro-dys cDNA based on previously published methods.
Males of any ethnic group will be eligible.
Ability to cooperate with muscle testing.
Willingness of sexually active subjects with reproductive capacity to practice reliable method of contraception (If appropriate).

Exclusion Criteria:

Active viral infection based on clinical observations.
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
Concomitant illness or requirement for chronic drug treatment that in the opinion of the PI creates unnecessary risks for gene transfer.
Subjects with AAVrh74 binding antibody titers ≥ 1:50 as determined by ELISA immunoassay.
Abnormal laboratory values in the clinically significant range as defined in protocol or 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

Cohort 1: Low Dose

Cohort 2: High Dose

Arm Description

The rAAVrh74.MCK.micro-Dystrophin vector will be injected to the Extensor Digitorum Brevis (EDB) muscle of a single foot at a total dose of 3E11 vg. The contralateral EDB muscle will injected with normal saline placebo as a comparator. Both physician and study team will be blinded as to which muscle received vector vs placebo. A minimum of three (3) patients with DMD will be enrolled in this cohort.

The rAAVrh74.MCK.micro-Dystrophin vector will be injected to the Extensor Digitorum Brevis (EDB) muscle of a single foot at a total dose of 1E12 vg. The contralateral EDB muscle will injected with normal saline placebo as a comparator. Both physician and study team will be blinded as to which muscle received vector vs placebo. A minimum of three (3) patients with DMD will be enrolled in this cohort.

Outcomes

Primary Outcome Measures

Safety based on number of participants with adverse events

AEs will be monitored and scored for severity and relatedness to the study article.

Secondary Outcome Measures

Transgene Expression

Biologic activity of the vector will be measured by immunohistochemistry detection of dystrophin on muscle biopsies as compared to placebo treated controls.

Full Information

NCT ID

NCT02376816

First Posted

February 26, 2015

Last Updated

November 21, 2017

Sponsor

Jerry R. Mendell

Collaborators

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

1. Study Identification

Unique Protocol Identification Number

NCT02376816

Brief Title

Clinical Intramuscular Gene Transfer Trial of rAAVrh74.MCK.Micro-Dystrophin to Patients With Duchenne Muscular Dystrophy

Official Title

Phase I Gene Transfer Clinical Trial for Duchenne Muscular Dystrophy Using rAAVrh74.MCK.Micro-dystrophin

Study Type

Interventional

2. Study Status

Record Verification Date

November 2017

Overall Recruitment Status

Completed

Study Start Date

March 2015 (undefined)

Primary Completion Date

September 2017 (Actual)

Study Completion Date

September 2017 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor-Investigator

Name of the Sponsor

Jerry R. Mendell

Collaborators

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

The proposed phase I clinical trial is a pilot study to evaluate safety and biological activity of the rAAVrh74.MCK.micro-Dystrophin vector administered by an intramuscular route. This study will evaluated the micro-Dystrophin vector as a potential dystrophin replacement mechanism for Duchenne Muscular Dystrophy. Two cohorts will undergo gene transfer in a standard three-six dose escalation scheme to establish maximum tolerated dose (MTD) using toxicity. A minimum of three subjects will be enrolled into each cohort. The first cohort will receive a total dose of 3E11 vg. The second cohort will receive 1E12 vg total dose.

Detailed Description

The primary objective of this study is the assessment of the safety of an intramuscular administration of rAAVrh74.MCK.micro-Dystrophin to the Extensor Digitorum Brevis (EDB) muscle of patients with Duchenne Muscular Dystrophy (DMD). Safety will be assessed by changes in hematology, serum chemistry, urinalysis, immunologic response to rAAVrh74 and micro-Dystrophin protein, and reported history and observations of symptoms. Subjects will be evaluated at baseline, injection visit (days 0-2), and return for follow up visits on days 7, 14, 30,60, 90, and 180 and at the end of 1st and 2nd years. On Day 180, subjects will undergo a muscle biopsy on the injected muscles in one foot compared with placebo-treatment in the opposite foot to establish transgene expression and any potential toxicity from gene transfer.

6. Conditions and Keywords

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

Duchenne Muscular Dystrophy

Keywords

DMD, muscular dystrophy, dystrophin

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1

Interventional Study Model

Single Group Assignment

Masking

ParticipantCare ProviderInvestigatorOutcomes Assessor

Allocation

Randomized

Enrollment

2 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Cohort 1: Low Dose

Arm Type

Experimental

Arm Description

Arm Title

Cohort 2: High Dose

Arm Type

Experimental

Arm Description

Intervention Type

Biological

Intervention Name(s)

rAAVrh74.MCK.micro-Dystrophin

Intervention Description

Recombinant adeno-associated virus carrying a truncated "micro" dystrophin transgene under control of a muscle specific MCK promoter.

Primary Outcome Measure Information:

Title

Safety based on number of participants with adverse events

Description

AEs will be monitored and scored for severity and relatedness to the study article.

Time Frame

2 years

Secondary Outcome Measure Information:

Title

Transgene Expression

Description

Biologic activity of the vector will be measured by immunohistochemistry detection of dystrophin on muscle biopsies as compared to placebo treated controls.

Time Frame

180 Days

10. Eligibility

Sex

Male

Minimum Age & Unit of Time

7 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Age 7 or older; must be wheelchair-dependent Confirmed Dystrophin mutations based on mutation compatibility with micro-dys cDNA based on previously published methods. Males of any ethnic group will be eligible. Ability to cooperate with muscle testing. Willingness of sexually active subjects with reproductive capacity to practice reliable method of contraception (If appropriate). Exclusion Criteria: Active viral infection based on clinical observations. 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 Concomitant illness or requirement for chronic drug treatment that in the opinion of the PI creates unnecessary risks for gene transfer. Subjects with AAVrh74 binding antibody titers ≥ 1:50 as determined by ELISA immunoassay. Abnormal laboratory values in the clinically significant range as defined in protocol or based upon normal values in the Nationwide Children's Hospital Laboratory.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Jerry R Mendell, 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

21194036

Citation

Rodino-Klapac LR, Montgomery CL, Mendell JR, Chicoine LG. AAV-mediated gene therapy to the isolated limb in rhesus macaques. Methods Mol Biol. 2011;709:287-98. doi: 10.1007/978-1-61737-982-6_19.

Results Reference

background

PubMed Identifier

19904237

Citation

Rodino-Klapac LR, Montgomery CL, Bremer WG, Shontz KM, Malik V, Davis N, Sprinkle S, Campbell KJ, Sahenk Z, Clark KR, Walker CM, Mendell JR, Chicoine LG. Persistent expression of FLAG-tagged micro dystrophin in nonhuman primates following intramuscular and vascular delivery. Mol Ther. 2010 Jan;18(1):109-17. doi: 10.1038/mt.2009.254. Epub 2009 Nov 10.

Results Reference

background

PubMed Identifier

17892583

Citation

Rodino-Klapac LR, Janssen PM, Montgomery CL, Coley BD, Chicoine LG, Clark KR, Mendell JR. A translational approach for limb vascular delivery of the micro-dystrophin gene without high volume or high pressure for treatment of Duchenne muscular dystrophy. J Transl Med. 2007 Sep 24;5:45. doi: 10.1186/1479-5876-5-45.

Results Reference

background

Links:

URL

http://www.nationwidechildrens.org/center-for-gene-therapy

Description

Center for Gene Therapy, The Research Institute at Nationwide Children's Hospital

URL

http://www.nationwidechildrens.org/wellstone-center

Description

Senator Paul D. Wellstone Muscular Dystrophy Cooperative Research Center at Nationwide Children's Hospital

URL

http://www.nationwidechildrens.org/gene-therapy-clinical-studies--1

Description

Gene Therapy Clinical Studies at Nationwide Children's Hospital

Learn more about this trial

Clinical Intramuscular Gene Transfer Trial of rAAVrh74.MCK.Micro-Dystrophin to Patients With Duchenne Muscular Dystrophy

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