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

This study is enrolling participants by invitation only.
Sponsor:
Information provided by (Responsible Party):
Jerry R. Mendell, Nationwide Children's Hospital
ClinicalTrials.gov Identifier:
NCT01976091
First received: July 24, 2013
Last updated: February 26, 2015
Last verified: February 2015
  Purpose

Dose escalation study of self-complementary (sc) AAVrh74.tMCK.hSGCA delivered to single leg (low dose n=2) and bilaterally (n=6) via a major lower limb artery to the whole lower limb of limb girdle muscular dystrophy type 2D (LGMD2D; alpha-sarcoglycan deficient) patients.


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

Study Type: Interventional
Study Design: Allocation: Non-Randomized
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 one grade 3 adverse events or fewer than two grade 2 adverse events [ Time Frame: 2 years ] [ Designated as safety issue: Yes ]
    Safety will be measured based on fewer than one grade 3 adverse event or fewer than two grade 2 adverse events


Secondary Outcome Measures:
  • Change in Six-Minute-Walk-Test (6MWT) distance from baseline over two years [ Time Frame: 2 years ] [ Designated as safety issue: No ]
    Efficacy would be a significant improvement in distance walked in the 6 minute walk test.


Estimated Enrollment: 8
Study Start Date: February 2015
Estimated Study Completion Date: February 2017
Estimated Primary Completion Date: February 2017 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Cohort 1A
Two (n=2) adult LGMD2D wheelchair-dependent subjects will receive self-complementary scAAVrh74.tMCK.hSGCA via single-limb perfusion at the low dose. Subjects will receive a dose of 1 x 10 12th vg/kg in a single limb with delivery to the whole limb.
Drug: scAAVrh74.tMCK.hSGCA
Experimental: Cohort 1B
Three (n=3) LGMD2D subjects will receive self-complementary scAAVrh74.tMCK.hSGCA via bilateral whole limb perfusion at low dose of 1 x 10 12th vg/kg.
Drug: scAAVrh74.tMCK.hSGCA
Experimental: Cohort 2
Three (n=3) LGMD2D subjects will receive self-complementary scAAVrh74.tMCK.hSGCA bilateral whole limb perfusion at high dose.Subjects will receive a total dose of 3 x 10 12th vg/kg per limb delivered to both extremities
Drug: scAAVrh74.tMCK.hSGCA

Detailed Description:

The proposed clinical trial is a dose escalation study of self-complementary scAAVrh74.tMCK.hSGCA to LGMD2D (alpha-sarcoglycan deficient) subjects delivered via a major lower limb artery of each leg sequentially by isolated limb perfusion (ILP). Three cohorts (Cohorts 1A, 1B, and 2) will undergo gene transfer in a dose escalation scheme to establish maximum tolerated dose (MTD) using toxicity. Two (n=2) adult wheelchair-dependent patients will be enrolled in Cohort 1A and three (n =3) ambulatory subjects will be enrolled in Cohort 1B. Three (n =3) ambulatory subjects will be enrolled in Cohort 2. The first cohort (1A) will receive a dose of 1E12 vg/kg in a single limb with delivery to the whole limb. This same dose will be delivered to both limbs in Cohort 1B. Cohort 2 will receive a total dose escalation of 3E12vg/kg per limb delivered to both extremities. The vector will be infused into an indwelling catheter in the femoral artery. This will be a one-time vector infusion to an isolated limb with a 10-minute dwell time. The total vector genome dose for each subject will be adjusted by rounding down to the closest 10 kg.

Safety monitoring during infusion 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. Efficacy will be measured by the six minute walk test as well as 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

  • Subjects age 7 or older; cohort 1A must be adult and wheelchair-dependent
  • Proven alpha-sarcoglycan deficiency by muscle biopsy or DNA testing.
  • Onset of weakness by 5 years age based on history of difficulty running, jumping and climbing stairs.
  • Subject enrolled in Cohort 1A must be adult and wheelchair dependent
  • Subjects enrolled in Cohorts 1B or 2 must be able to walk independently, but must exhibit signs of lower extremity weakness (i.e. a Gowers' sign, use a handrail for climbing stairs) and walk ≤ 80% of predicted distance on the 6MWT based on normative data.
  • 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
  • Abnormal laboratory values considered clinically significant (GGT > 3XULN, bilirubin ≥ 3.0 mg/dL , creatinine ≥ 1.8 mg/dL, Hgb < 8 or > 18 g/Dl; WBC > 15,000 per cmm)
  • 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 or AAV8 binding antibody titers ≥ 1:50 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

Additional 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: February 26, 2015
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
Genetic Diseases, Inborn
Muscular Diseases
Muscular Disorders, Atrophic
Musculoskeletal Diseases
Nervous System Diseases
Neuromuscular Diseases

ClinicalTrials.gov processed this record on April 26, 2015