Gene Transfer Clinical Trial for LGMD2D (Alpha-sarcoglycan Deficiency) Using scAAVrh74.tMCK.hSGCA

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
Jerry R. Mendell, Nationwide Children's Hospital
ClinicalTrials.gov Identifier:
NCT01976091
First received: July 24, 2013
Last updated: October 29, 2013
Last verified: October 2013
  Purpose

Dose escalation study of self-complementary scAAVrh74.tMCK.hSGCA to LGMD2D (alpha-SG deficient) subjects delivered bilaterally via a major lower limb artery to the whole lower limb of LGMD2D (alpha-SG deficient) subjects.


Condition Intervention Phase
Limb Girdle Muscular Dystrophy Type 2D (LGMD2D)
Drug: scAAVrh74.tMCK.hSGCA
Phase 1
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Phase I/IIa Gene Transfer Clinical Trial for LGMD2D (Alpha-sarcoglycan Deficiency) Using scAAVrh74.tMCK.hSGCA

Resource links provided by NLM:


Further study details as provided by Nationwide Children's Hospital:

Primary Outcome Measures:
  • Safety with fewer than 2 grade 3 adverse events [ Time Frame: 1 year from start ] [ Designated as safety issue: Yes ]
    Safety with fewer than 2 grade 3 adverse events


Secondary Outcome Measures:
  • Efficacy outcome measure 6MWT [ Time Frame: 2 years ] [ Designated as safety issue: No ]
    6 minute walk test (6MWT)-(primary variable to measure efficacy) Efficacy would be a significant improvement in distance walked in the 6 minute walk test.


Estimated Enrollment: 6
Study Start Date: October 2013
Estimated Study Completion Date: March 2016
Estimated Primary Completion Date: December 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: scAAVrh74.tMCK.hSGCA
Dose escalation study of self-complementary scAAVrh74.tMCK.hSGCA to LGMD2D (alpha-SG deficient) subjects delivered bilaterally via a major lower limb artery to the whole lower limb of LGMD2D (alpha-SG deficient) subjects.
Drug: scAAVrh74.tMCK.hSGCA

Detailed Description:

The proposed clinical trial is a dose escalation study of self-complementary scAAVrh74.tMCK.hSGCA to LGMD2D (alpha-SG deficient) subjects delivered via a major lower limb artery of each leg sequentially by modified isolated limb perfusion and isolated limb infusion (ILP/ILI);1 henceforth designated as isolated limb recirculation for gene therapy (ILR-GT). 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 2 x 1012 vg/kg split between the 2 lower extremities (1 x 1012 vg/kg per limb). The vector will be infused into an indwelling catheter in the femoral artery. This will be a one-time vector infusion that will recirculate over a period of 30 minutes in a closed circuit that includes: arterial delivery to an isolated limb (proximal tourniquet), return via the femoral vein and redelivered to the artery via extracorporeal pump. The second cohort will receive 6 x 1012 vg/kg total dose - split between the 2 lower extremities (3 x 1012 vg/kg per limb) delivered to the whole limb according to the same protocol. The total vector genome dose for each subject will be adjusted by rounding down to the closest 10 kg.

The primary objective of this study is the assessment of the safety of intravascular administration of scAAVrh.74.tMCK.hSGCA delivered via the femoral artery to both lower extremities LGMD2D (alpha-SG deficient) subjects. Safety monitoring during recirculation will include: activated clotting times, limb gases, real time monitoring of arterial and venous access pressures, and perfusate temperature. Safety endpoints will be assessed by changes in hematology, serum chemistry, urinalysis, immunologic response to rAAVrh74 and hSGCA, and reported history and observations of symptoms. The six minute walk test will be used as secondary outcome for these disorders. Other exploratory measure will include direct muscle testing for strength (MVICT) of lower limb muscles. These quantitative measures will be done at baseline, day 30, 60, 90, 180, and at the end of 1st and 2nd years. Subjects will be evaluated at baseline, infusion visit (days 0-2), and return for follow up visits on days 7, 14, 30, 60, 90, and 180. On Day 180, subjects will undergo a muscle biopsy on the injected muscles in one leg to compare with the pre-treatment biopsy done at baseline screening in the opposite leg to establish the size of muscle fibers and any potential toxicity from gene transfer.

  Eligibility

Ages Eligible for Study:   7 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria

  • Ambulant subjects, age 7 or older
  • Proven alpha-sarcoglycan deficiency by muscle biopsy or DNA testing.
  • Impaired muscle function based on clinical evidence of muscle weakness assessed by PI and staff.
  • Males and females 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), during the first six months after gene therapy (females) or until two negative sperm samples are obtained post gene transfer (males).

Exclusion Criteria

  • Active viral infection based on clinical observations.
  • The presence of SGCA mutations 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
  • Concomitant illness or requirement for chronic drug treatment that in the opinion of the PI creates unnecessary risks for gene transfer
  • Pregnancy
  • Subjects with AAVrh74 binding antibody titers ≥ 1:800 as determined by ELISA immunoassay
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01976091

Locations
United States, Ohio
Nationwide Children's Hospital
Columbus, Ohio, United States, 43205
Sponsors and Collaborators
Jerry R. Mendell
  More Information

Publications:
Responsible Party: Jerry R. Mendell, Director, Center for Gene Therapy, Nationwide Children's Hospital
ClinicalTrials.gov Identifier: NCT01976091     History of Changes
Other Study ID Numbers: 5U01AR060911
Study First Received: July 24, 2013
Last Updated: October 29, 2013
Health Authority: United States: Food and Drug Administration
NIH/Office of Biotechnology Activities (OBA): Recombinant DNA Advisory Committee (RAC)
United States: Data and Safety Monitoring Board
United States: Institutional Review Board

Keywords provided by Nationwide Children's Hospital:
limb girdle muscular dystrophy
LGMD2D
alpha-sarcoglycan
gene transfer
adeno-associated virus

Additional relevant MeSH terms:
Muscular Dystrophies
Muscular Dystrophies, Limb-Girdle
Muscular Disorders, Atrophic
Muscular Diseases
Musculoskeletal Diseases
Neuromuscular Diseases
Nervous System Diseases
Genetic Diseases, Inborn

ClinicalTrials.gov processed this record on September 18, 2014