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

Duchenne Muscular Dystrophy Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02376816
• Other study ID #: 14-00718
• Status: Completed
• Phase: Phase 1
• First received: February 26, 2015
• Last updated: November 21, 2017
• Start date: March 2015
• Est. completion date: September 2017

Study information

• Verified date: November 2017
• Source: Nationwide Children's Hospital
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 2
• Est. completion date: September 2017
• Est. primary completion date: September 2017
• Accepts healthy volunteers: No
• Gender: Male
• Age group: 7 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Duchenne Muscular Dystrophy
• Muscular Dystrophies
• Muscular Dystrophy, Duchenne

Intervention

Biological:
• rAAVrh74.MCK.micro-Dystrophin
Recombinant adeno-associated virus carrying a truncated "micro" dystrophin transgene under control of a muscle specific MCK promoter.

Locations

Country	Name	City	State
United States	Nationwide Children's Hospital	Columbus	Ohio

Sponsors (2)

Lead Sponsor	Collaborator
Jerry R. Mendell	Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

Country where clinical trial is conducted

United States, 

References & Publications (3)

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. — View 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. — View 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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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

External Links

•   Center for Gene Therapy, The Research Institute at Nationwide Children's Hospital
•   Gene Therapy Clinical Studies at Nationwide Children's Hospital
•   Senator Paul D. Wellstone Muscular Dystrophy Cooperative Research Center at Nationwide Children's Hospital