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

November 21, 2017 updated by: Jerry R. Mendell

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

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

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.

Study Type

Interventional

Enrollment (Actual)

2

Phase

  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Ohio
      • Columbus, Ohio, United States, 43205
        • Nationwide Children's Hospital

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

7 years and older (Child, Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

Male

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Single Group Assignment
  • Masking: Quadruple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Cohort 1: Low Dose
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.
Biological: rAAVrh74.MCK.micro-Dystrophin
Recombinant adeno-associated virus carrying a truncated "micro" dystrophin transgene under control of a muscle specific MCK promoter.
Experimental: Cohort 2: High Dose
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.
Biological: rAAVrh74.MCK.micro-Dystrophin
Recombinant adeno-associated virus carrying a truncated "micro" dystrophin transgene under control of a muscle specific MCK promoter.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Safety based on number of participants with adverse events
Time Frame: 2 years
AEs will be monitored and scored for severity and relatedness to the study article.
2 years

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Transgene Expression
Time Frame: 180 Days
Biologic activity of the vector will be measured by immunohistochemistry detection of dystrophin on muscle biopsies as compared to placebo treated controls.
180 Days

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Jerry R. Mendell

Collaborators

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

Investigators

  • Principal Investigator: Jerry R Mendell, MD, Nationwide Children's Hospital

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

March 1, 2015

Primary Completion (Actual)

September 1, 2017

Study Completion (Actual)

September 1, 2017

Study Registration Dates

First Submitted

February 26, 2015

First Submitted That Met QC Criteria

February 26, 2015

First Posted (Estimate)

March 3, 2015

Study Record Updates

Last Update Posted (Actual)

November 24, 2017

Last Update Submitted That Met QC Criteria

November 21, 2017

Last Verified

November 1, 2017

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 14-00718

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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