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

Study Overview
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Brief Summary
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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
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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.

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

Conditions
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Duchenne Muscular Dystrophy

Intervention / Treatment
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* Biological: rAAVrh74.MCK.micro-Dystrophin


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 7 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1: Low Dose<br>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<br>* Recombinant adeno-associated virus carrying a truncated micro dystrophin transgene under control of a muscle specific MCK promoter.<br>|
| Experimental: Cohort 2: High Dose<br>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<br>* Recombinant adeno-associated virus carrying a truncated micro dystrophin transgene under control of a muscle specific MCK promoter.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety based on number of participants with adverse events | 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 | Biologic activity of the vector will be measured by immunohistochemistry detection of dystrophin on muscle biopsies as compared to placebo treated controls. | 180 Days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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DMD, muscular dystrophy, dystrophin