NCT00494195

Brief Summary

Limb girdle muscular dystrophy type 2D (LGMD2D) is a genetic disease that affects skeletal muscle. Insufficient levels of the protein alpha-sarcoglycan result in muscle weakness that worsens over time. The purpose of this study is to evaluate the safety and effectiveness of gene therapy in treating children and adults with LGMD2D.

Trial Health

87
On Track

Trial Health Score

Automated assessment based on enrollment pace, timeline, and geographic reach

Enrollment
6

participants targeted

Target at below P25 for phase_1

Timeline
Completed

Started Mar 2008

Typical duration for phase_1

Geographic Reach
1 country

1 active site

Status
completed

Health score is calculated from publicly available data and should be used for screening purposes only.

Trial Relationships

Click on a node to explore related trials.

Study Timeline

Key milestones and dates

First Submitted

Initial submission to the registry

June 27, 2007

Completed
2 days until next milestone

First Posted

Study publicly available on registry

June 29, 2007

Completed
8 months until next milestone

Study Start

First participant enrolled

March 1, 2008

Completed
3.3 years until next milestone

Primary Completion

Last participant's last visit for primary outcome

June 1, 2011

Completed
2 months until next milestone

Study Completion

Last participant's last visit for all outcomes

August 1, 2011

Completed
Last Updated

February 5, 2013

Status Verified

February 1, 2013

Enrollment Period

3.3 years

First QC Date

June 27, 2007

Last Update Submit

February 4, 2013

Conditions

Muscular Dystrophies

Keywords

limb girdle muscular dystrophy type 2Dalpha-sarcoglycanopathyLGMDLGMD2Dgene therapygene transfermuscular dystrophySGCAsarcoglycanlimb girdleadeno-associated virusAAVAAV1

Outcome Measures

Primary Outcomes (1)

  • Safety of AAV1.tMCK.human-alpha-sarcoglycan gene transfer via intramuscular injection to the EDB muscle

    Measured throughout the study

Secondary Outcomes (2)

  • Human-alpha-sarcoglycan gene expression at the site of gene transfer via muscle biopsy

    First cohort: Measured 45 days for two patients and at 90 days after gene transfer for one patient; Second cohort: Measured at 6 months after gene transfer for the three patients

  • Muscle strength of the gene transferred muscle via maximal volume isometric contraction testing (MVICT) if selected muscle is suitable for strenght testing

    Measured 45 or 90 days after gene transfer in the first cohort, or 6 months post-gene transfer in second cohort depending on muscle biopsy date

Study Arms (2)

1

EXPERIMENTAL

The first cohort will receive a total of 1.5 ml volume of study agent in two to six separate injections into the selected muscle (extensor digitorum brevis) or other muscle if more appropriate upon considering the individual patient. The dose will be 3.25 X 10 to the 11 vg in 1.5 ml. The anatomical midline point of the muscle will be identified on the skin and two to six vector injections will be distributed in the direction of an X. In each cohort, only one extremity will receive vector with transgene while the opposite extremity will be injected with placebo.

Genetic: rAAV1.tMCK.human-alpha-sarcoglycan- First cohort

2

EXPERIMENTAL

The second cohort will receive the same dose of 3.25 X 10 to the 11 vg in 1.5 ml delivered to muscle according to the same paradigm. In each cohort, only one extremity will receive vector with transgene while the opposite extremity will be injected with placebo.

Genetic: Genetic: rAAV1.tMCK.human-alpha-sarcoglycan- Second cohort

Interventions

rAAV1.tMCK.human-alpha-sarcoglycan- First cohortGENETIC

The first cohort of subjects with LGMD2D (alpha-sarcoglycan deficiency) and proven mutations will undergo gene transfer with a minimum of three subjects enrolled into this cohort and will receive a total of 1.5 ml volume of study agent in two to six separate injections into the selected muscle (extensor digitorum brevis) or other muscle if more appropriate upon considering the individual patient. The dose will be 3.25 X 10 to the 11 vg in 1.5 ml. In each cohort, only one extremity will receive vector with transgene while the opposite extremity will be injected with placebo.

Also known as: LGMD2D Gene therapy-First cohort
1
Genetic: rAAV1.tMCK.human-alpha-sarcoglycan- Second cohortGENETIC

The second cohort will receive the same dosis of 3.25 X 10 to the 11 vg in 1.5 ml delivered to muscle according to the same paradigm. In each cohort, only one extremity will receive vector with transgene while the opposite extremity will be injected with placebo.

Also known as: LGMD2D Gene therapy- Second cohort
2

Eligibility Criteria

Age5 Years+
Sexall
Healthy VolunteersNo
Age GroupsChild (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

  • Six LGMD2D subjects ages 5 and older based on the clinical degree of involvement (impaired muscle function/weakness, sufficient muscle preservation)
  • Preservation of EDB muscle or another muscle if judged more favorable because of adequate muscle mass for gene transfer
  • Males and females of any ethnic group
  • Established mutations of an -SG gene on both alleles
  • Ability to cooperate for testing
  • Sexually active patients must be willing to practice a reliable method of contraception during the study

You may not qualify if:

  • Active viral infection (symptoms listed in section 9.0 of the protocol)
  • LGMD2D subjects without weakness or functional loss
  • Cardiomyopathy based on clinical exam and ECHO with ejection fraction less than 40%
  • HIV infected
  • Hepatitis A, B, or C infected
  • Autoimmune diseases and immunosuppressive drugs (other than pulse methylprednisolone at time of gene transfer)
  • Persistent leucopenia or leucocytosis (WBC less than or equal to 3.5 K/cu mm or at least 20.0 K/ cu mm) or neutrophils less than 1.5 K/ cu mm
  • Concomitant illness or requirement for chronic drug treatment that in the opinion of the Principal Investigator creates unnecessary risks for gene transfer
  • Pregnancy
  • Abnormal laboratory values considered clinically significant
  • Alcoholism (CAGE questionnaire), and laboratory tests such as GGT and MCV

Contact the study team to confirm eligibility.

Sponsors & Collaborators

Study Sites (1)

The Research Institute at Nationwide Children's Hospital

Columbus, Ohio, 43205, United States

Location

Related Publications (6)

  • Allamand V, Donahue KM, Straub V, Davisson RL, Davidson BL, Campbell KP. Early adenovirus-mediated gene transfer effectively prevents muscular dystrophy in alpha-sarcoglycan-deficient mice. Gene Ther. 2000 Aug;7(16):1385-91. doi: 10.1038/sj.gt.3301247.

    PMID: 10981665BACKGROUND

  • Buning H, Nicklin SA, Perabo L, Hallek M, Baker AH. AAV-based gene transfer. Curr Opin Mol Ther. 2003 Aug;5(4):367-75.

    PMID: 14513679BACKGROUND

  • Bueno MR, Moreira ES, Vainzof M, Chamberlain J, Marie SK, Pereira L, Akiyama J, Roberds SL, Campbell KP, Zatz M. A common missense mutation in the adhalin gene in three unrelated Brazilian families with a relatively mild form of autosomal recessive limb-girdle muscular dystrophy. Hum Mol Genet. 1995 Jul;4(7):1163-7. doi: 10.1093/hmg/4.7.1163.

    PMID: 8528203BACKGROUND

  • Rodino-Klapac LR, Lee JS, Mulligan RC, Clark KR, Mendell JR. Lack of toxicity of alpha-sarcoglycan overexpression supports clinical gene transfer trial in LGMD2D. Neurology. 2008 Jul 22;71(4):240-7. doi: 10.1212/01.wnl.0000306309.85301.e2. Epub 2008 Jun 4.

    PMID: 18525034BACKGROUND

  • Mendell JR, Rodino-Klapac LR, Rosales XQ, Coley BD, Galloway G, Lewis S, Malik V, Shilling C, Byrne BJ, Conlon T, Campbell KJ, Bremer WG, Taylor LE, Flanigan KM, Gastier-Foster JM, Astbury C, Kota J, Sahenk Z, Walker CM, Clark KR. Sustained alpha-sarcoglycan gene expression after gene transfer in limb-girdle muscular dystrophy, type 2D. Ann Neurol. 2010 Nov;68(5):629-38. doi: 10.1002/ana.22251.

    PMID: 21031578RESULT

  • Mendell JR, Rodino-Klapac LR, Rosales-Quintero X, Kota J, Coley BD, Galloway G, Craenen JM, Lewis S, Malik V, Shilling C, Byrne BJ, Conlon T, Campbell KJ, Bremer WG, Viollet L, Walker CM, Sahenk Z, Clark KR. Limb-girdle muscular dystrophy type 2D gene therapy restores alpha-sarcoglycan and associated proteins. Ann Neurol. 2009 Sep;66(3):290-7. doi: 10.1002/ana.21732.

    PMID: 19798725RESULT

Related Links

MeSH Terms

Conditions

Muscular DystrophiesSarcoglycanopathies

Condition Hierarchy (Ancestors)

Muscular Disorders, AtrophicMuscular DiseasesMusculoskeletal DiseasesNeuromuscular DiseasesNervous System DiseasesGenetic Diseases, InbornCongenital, Hereditary, and Neonatal Diseases and AbnormalitiesMuscular Dystrophies, Limb-GirdleRespiration DisordersRespiratory Tract DiseasesCardiomyopathiesHeart DiseasesCardiovascular Diseases

Study Officials

  • Jerry R. Mendell, MD

    The Research Institute at Nationwide Children's Hospital

    PRINCIPAL INVESTIGATOR

Study Design

Study Type
interventional
Phase
phase 1
Allocation
RANDOMIZED
Masking
QUADRUPLE
Who Masked
PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
Purpose
TREATMENT
Intervention Model
PARALLEL
Sponsor Type
OTHER
Responsible Party
PRINCIPAL INVESTIGATOR
PI Title
Director, Center for Gene Therapy

Study Record Dates

First Submitted

June 27, 2007

First Posted

June 29, 2007

Study Start

March 1, 2008

Primary Completion

June 1, 2011

Study Completion

August 1, 2011

Last Updated

February 5, 2013

Record last verified: 2013-02

Locations

US(1)