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Clinical Study of AAV1-gamma-sarcoglycan Gene Therapy for Limb Girdle Muscular Dystrophy Type 2C

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ClinicalTrials.gov Identifier: NCT01344798
Recruitment Status : Completed
First Posted : April 29, 2011
Last Update Posted : April 29, 2011
Sponsor:
Information provided by:
Genethon

Study Description
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Brief Summary:
The purpose of this trial is to study the evaluation of clinical safety and feasibility of gene therapy in patients with limb girdle muscular dystrophy type 2C (gamma-sarcoglycanopathy).

Condition or disease Intervention/treatment Phase
Limb Girdle Muscular Dystrophy Type 2C Gamma-sarcoglycanopathy Biological: AAV1-gamma-sarcoglycan vector injection Phase 1

Study Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 9 participants
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase I Clinical Study of AAV1-gamma-sarcoglycan Gene Therapy for Limb Girdle Muscular Dystrophy Type 2C
Study Start Date : November 2006
Actual Primary Completion Date : June 2010
Actual Study Completion Date : June 2010

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Arms and Interventions
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Arm Intervention/treatment
Experimental: Dose level 1
AAV1-gamma-sarcoglycan vector dose level: 3x10e9 vg/100µl
 Biological: AAV1-gamma-sarcoglycan vector injection
single intramuscular injection into carpi radialis muscle under open procedure
Other Name: in vivo gene therapy - Intramuscular route
Experimental: Dose level 2
AAV1-gamma-sarcoglycan vector dose level: 1.5x10e10 vg/100µl
 Biological: AAV1-gamma-sarcoglycan vector injection
single intramuscular injection into carpi radialis muscle under open procedure
Other Name: in vivo gene therapy - Intramuscular route
Experimental: Dose level 3
AAV1-gamma-sarcoglycan vector dose level: 4.5x10e10 vg/300µl
 Biological: AAV1-gamma-sarcoglycan vector injection
single intramuscular injection into carpi radialis muscle under open procedure
Other Name: in vivo gene therapy - Intramuscular route


Outcome Measures
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Primary Outcome Measures :
  1. Number of patients with adverse events or general or local signs as a measure of clinical safety [ Time Frame: 6 months ]
    Standard general and local clinical examination as well as vital signs assessement, including pain, local inflammation, stiffness and fatigability.


Secondary Outcome Measures :
  1. Number of patients with modified biological values (blood count, standard biochemistry, viral serology) [ Time Frame: 6 months ]

    Assessment of biological tolerance:

    • blood count
    • standard biochemistry
    • CPK viral serology (hepatitis B & C)

  2. number of patients with changed or increased humoral immunity to AAV [ Time Frame: 6 months ]
    assessment of anti-AAV antibodies titers

  3. Number of patients with changed/increased humoral immunity to transgene [ Time Frame: 6 months ]
    assessment of anti-gamma-sarcoglycan antibodies titers

  4. Number of patients with changed/increased cellular immunity to AAV [ Time Frame: 6 months ]
    assessment cellular immunity against AAV (ELispot assay)

  5. Number of patients with changed/increased cellular immunity to transgene [ Time Frame: 6 months ]
    assessment cellular immunity against gamma-sarcoglycan (ELispot assay)

  6. number of patients with positively stained muscular fibers to gamma-sarcoglycan protein [ Time Frame: 30 days ]
    Muscular biopsy immunohistaining for the detection of gamma-sarcoglycan

  7. Number of patients with modified/decreased muscular force [ Time Frame: 6 months ]
    functional testing of treated muscle through a specially designed ergometer


Eligibility Criteria
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Ages Eligible for Study:   15 Years and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Confirmed diagnosis of LGMD 2C including:

    • Molecular analysis proving del525T mutation on γ-sarcoglycan gene (chromosome 13) at homozygous state
    • Muscle biopsy with immunohistochemical and/or Western blot analyses showing marked decrease or absence of γ-sarcoglycan staining in muscle, as well as a fibrosis assessment should be available. If not, an initial muscular biopsy may be performed during the pre-enrollment period
  2. Lower age limit of 15 years
  3. Males and females may be equally enrolled

  4. Adequate carpi radialis muscle bulk for muscle biopsy as assessed by examination. Subjects should be able to communicate with the investigation staff. They should be able to understand, to comply with and to perform all needed evaluations during the trial period, including muscle strength tests. Forearm muscle strength should be of at least 3+ as assessed through the British Medical Research Council (MRC) Manual Muscle Testing (MMT) scale.

    Subjects should also have already lost ambulation

  5. Subjects should be able and willing to return for follow up
  6. Subjects should be able and willing to give signed informed consent. For minor subjects, a signed informed consent will be given by legally authorized representative
  7. Eligible subjects belonging to a multiplex family should not be enrolled in the same cohort.

Exclusion Criteria:

  1. Severity of disease and presence of ill-prognosis complications:

    • Severe respiratory dysfunction such as subjects with tracheostomy or forced vital capacity (FVC) < 1000 ml and/or < 30%;
    • Uncompensated heart failure;
    • An ejection fraction (EF) < 30% as measured on either echocardiography or scintigraphy;
    • Severe rhythm disturbances and/or high degree conduction defect in the absence of a pacemaker insertion.

  2. Underlying conditions, diseases or active viral infections likely to increase risk of complications or to interfere with the investigational treatment:

    • contraindications for injections and muscle biopsies
    • Platelet count < 100,000 / mm3
    • Total bilirubin > 10 mg/l (> 17 µmol/l)
    • Serum creatinin > 110 µmol/l
    • Lymphocytes CD4+ < 250/mm3 (< 15%)
    • History of diabetes mellitus
    • Current infectious diseases, including known positive HIV serology, hepatitis B and C
    • Abnormal profile on protein immunoelectrophoresis
    • Immunizations of any kind within the past month
    • receipt of another investigational agent within 4 weeks of study enrollment
    • History of or current steroid medication for indications other than muscular dystrophy, chemotherapy, radiotherapy or other immunosuppressive therapy. Steroid medication, if any, should be discontinued at least 3 months before entering the protocol and not received during the study
    • Pregnant or lactating women. Females or males of childbearing age must be willing to employ adequate contraception, that is to use condoms during the 3 months following the administration of the product
    • Pre-injection neutralizing anti-AAV1 antibodies titer (on pre-enrollment / D-30 visit) superior or equal to 1/800.
Contacts and Locations
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To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01344798


Locations
France
Hôpital Pitié-Salpêtrière
Paris, France, 75013
Sponsors and Collaborators
Genethon
Investigators
Principal Investigator: Serge Herson, Prof Assistance Publique - Hôpitaux de Paris
More Information
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Responsible Party: Frederic Revah, CEO, Genethon
ClinicalTrials.gov Identifier: NCT01344798     History of Changes
Other Study ID Numbers: GTG001.06
First Posted: April 29, 2011    Key Record Dates
Last Update Posted: April 29, 2011
Last Verified: April 2011

Keywords provided by Genethon:
limb girdle muscular dystrophy type 2C
gamma-sarcoglycanopathy
gene therapy
 AAV vector
neuromuscular disease
orphan disease

Additional relevant MeSH terms:
Muscular Dystrophies
Muscular Dystrophies, Limb-Girdle
Sarcoglycanopathies
Muscular Disorders, Atrophic
Muscular Diseases
Musculoskeletal Diseases
Neuromuscular Diseases
 Nervous System Diseases
Genetic Diseases, Inborn
Respiration Disorders
Respiratory Tract Diseases
Cardiomyopathies
Heart Diseases
Cardiovascular Diseases