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Gene Transfer Clinical Trial for LGMD2E (Beta-sarcoglycan Deficiency) Using scAAVrh74.MHCK7.hSGCB

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ClinicalTrials.gov Identifier: NCT03652259
Recruitment Status : Recruiting
First Posted : August 29, 2018
Last Update Posted : October 31, 2018
Sponsor:
Collaborator:
Myonexus Therapeutics
Information provided by (Responsible Party):
Jerry R. Mendell, Nationwide Children's Hospital

Brief Summary:
The proposed clinical trial is the first-in-human, randomized, double-blinded, single dose study of self-complementary AAVrh.74 carrying the human β-sarcoglycan gene under the control of an MHCK7 promoter (scAAVrh74.MHCK7.hSGCB) delivered through a single systemic injection in a peripheral vein of LGMD2E. Nine total subjects (6 treated, 3 placebo) will be enrolled.

Condition or disease Intervention/treatment Phase
Limb-Girdle Muscular Dystrophy, Type 2E Drug: scAAVrh74.MHCK7.hSGCB Phase 1 Phase 2

Detailed Description:
The proposed clinical trial is the first-in-human, randomized, double-blinded, single dose study of self-complementary AAVrh.74 carrying the human β-sarcoglycan gene under the control of an MHCK7 promoter (scAAVrh74.MHCK7.hSGCB) delivered through a single systemic injection in a peripheral vein of LGMD2E patients. A minimum of nine patients will be enrolled. Cohort 1 will consist of 3 treated subjects. Based on data from Cohort 1, there is the potential to escalate dose for Cohort 2 which will include 6 subjects randomized resulting in 3 treated and 3 placebo subjects. Placebo subjects will be treated by completion of study.

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 9 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Phase I/IIa Gene Transfer Clinical Trial for LGMD2E (β-sarcoglycan Deficiency) Using scAAVrh74.MHCK7.hSGCB Administered by Systemic Perfusion
Actual Study Start Date : October 26, 2018
Estimated Primary Completion Date : December 31, 2020
Estimated Study Completion Date : December 31, 2020


Arm Intervention/treatment
Experimental: Cohort 1 low dose
N=3 (3 treated) LGMD2E subjects. Cohort 1 will receive a dose of 5 x 10^13 vg/kg of scAAVrh74.MHCK7.hSGCB or placebo.
Drug: scAAVrh74.MHCK7.hSGCB
Subjects with diagnosis of LGMD2E will receive scAAVrh74.MHCK7.hSGCB administered through a single systemic injection in a peripheral vein.
Other Name: LGMD2E vector

Experimental: Cohort 2 high dose
N=6 (3 treated, 3 placebo). There is the potential to escalate dose to 2 x 10^14vg/kg of scAAVrh74.MHCK7.hSGCB based on expression in Cohort 1.
Drug: scAAVrh74.MHCK7.hSGCB
Subjects with diagnosis of LGMD2E will receive scAAVrh74.MHCK7.hSGCB administered through a single systemic injection in a peripheral vein.
Other Name: LGMD2E vector




Primary Outcome Measures :
  1. Safety based on number of participants with adverse events. [ Time Frame: 3 years ]
    AEs will be monitored and scored for severity and relatedness to the study article.


Secondary Outcome Measures :
  1. Physical Therapy Assessments The 100 Meter Timed Test (100m) [ Time Frame: Screening, Day 30-3 Years ]
    Clinically significant improvement in 100 meter time ≥10% compared to baseline for each participant 3 years post gene transfer.

  2. Beta-SG gene expression quantification by immunofluorescence [ Time Frame: Day 60 and year 2 ]
    Demonstration of Beta-SG gene expression levels (≥ 20% above baseline) will be quantified by immunofluorescence and compared in pre and post muscle biopsies.

  3. Beta-SG gene expression quantification by western blot [ Time Frame: Day 60 and year 2 ]
    Beta-SG gene expression levels will be quantified by western blot and compared in pre and post muscle biopsies.

  4. CK levels following gene therapy [ Time Frame: 3 years ]
    Reduction in CK levels in circulating blood

  5. Skeletal muscle MRI [ Time Frame: Screening, Months 12, 24, 36 ]
    Change in muscle mass, fat, connective tissue and inflammation.

  6. Cardiac MRI [ Time Frame: Screening, Months 12, 24, 36 ]
    Stable or improved cardiac function

  7. Physical Therapy Assessments Workspace Volume [ Time Frame: Screening, Day 30-3 Years ]
    Quantitative measure of the space an individual can reach to perform activities of daily living.

  8. Physical Therapy Assessments Strength testing Hand Held Dynamometry (HHD) [ Time Frame: Screening, Day 30-3 Years ]
    Hand Held Dynamometry (HHD) for knee extensors and knee flexors, and elbow flexors and elbow extensors.

  9. Physical Therapy Assessments Ascend and Descend of 4 steps [ Time Frame: Screening, Day 30-3 Years ]
    Outcome will include ascend and descend of 4 steps.

  10. Physical Therapy Assessments North Star Assessment for Dysferlinopathy (NSAD) [ Time Frame: Screening, Day 30-3 Years ]
    The North Star Assessment for Dysferlinopathy (NSAD) will be an outcome. The NSAD measures the quality of ambulation.

  11. Physical Therapy Assessments PROMIS Upper Extremity and Mobility questionnaires [ Time Frame: Screening, Day 30-3 Years ]
    Outcome quantifying physical, mental, and social health; functioning and well being.

  12. Physical Therapy Assessments Pulmonary function testing (PFTs), including spirometry [ Time Frame: Screening, Day 30-3 Years ]
    Stable or improved FVC

  13. Physical Therapy Assessments Activity level as determined by a Fitbit or similar activity monitoring device [ Time Frame: Day 30-3 Years ]
    Measure daily activity (number of steps)

  14. Physical Therapy Assessments TImed up and Go [ Time Frame: Day 30-3 Years ]
    Measure time to rise from a chair



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Ages Eligible for Study:   4 Years to 15 Years   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

INCLUSION CRITERIA

  • Subjects ages 4 through age 15, inclusive
  • Males or females of any ethnic group
  • SGCB DNA gene mutations at both alleles.
  • Weakness demonstrated based on history of difficulty running, jumping and climbing stairs.
  • 100m timed test: ≥40% of predicted for age, height and weight matched healthy controls at the screening visit.
  • 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.

EXCLUSION CRITERIA

Individuals who meet the following exclusion criteria will not be eligible to participate in the study:

  • Active viral infection based on clinical observations.
  • Cardiac MRI determined ejection fraction <40%
  • Serological evidence of HIV infection, or Hepatitis 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 binding antibody titers > 1:400 as determined by ELISA immunoassay. If endpoint titer is positive at screening, testing may be repeated in 1 month.
  • Has a medical condition or circumstance that could compromise the protocol compliance or compromise safety
  • Severe infection (e.g. pneumonia, pyelonephritis, or meningitis) within 4 weeks before gene transfer visit (enrollment may be postponed).
  • Family does not want to disclose patient's study participation with primary care physician and other medical providers.

Information from the National Library of Medicine

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): NCT03652259


Contacts
Contact: Stephanie Diemer, MS 614-355-2679 Stephanie.Diemer@nationwidechildrens.org
Contact: Katie Church, MSW 614-722-6961 kathleen.church@gmail.com

Locations
United States, Ohio
Nationwide Children's Hospital Recruiting
Columbus, Ohio, United States, 43205
Contact: Stephanie Diemer, M.S.         
Principal Investigator: Jerry R Mendell, M.D.         
Sponsors and Collaborators
Jerry R. Mendell
Myonexus Therapeutics
Investigators
Principal Investigator: Jerry Mendell, MD Nationwide Children's Hospital

Responsible Party: Jerry R. Mendell, Principal Investigator, Center for Gene Therapy, Nationwide Children's Hospital
ClinicalTrials.gov Identifier: NCT03652259     History of Changes
Other Study ID Numbers: IRB17-00253
First Posted: August 29, 2018    Key Record Dates
Last Update Posted: October 31, 2018
Last Verified: October 2018

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Jerry R. Mendell, Nationwide Children's Hospital:
limb girdle muscular dystrophy
LGMD2E
beta-sarcoglycan
gene transfer
adeno-associated virus

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