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rAAVrh74.MHCK7.DYSF.DV for Treatment of Dysferlinopathies

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ClinicalTrials.gov Identifier: NCT02710500
Recruitment Status : Active, not recruiting
First Posted : March 16, 2016
Last Update Posted : November 24, 2017
Sponsor:
Information provided by (Responsible Party):

Study Description
Brief Summary:
The proposed clinical trial is a double-blind, randomized controlled study with direct intramuscular injection of rAAVrh.74.MHCK7.DYSF.DV gene vector to the extensor digitorum brevis muscle (EDB). Two cohorts of subjects with dysferlin deficiency, each with proven mutations will undergo gene transfer. A minimum of three subjects will be enrolled into each cohort.

Condition or disease Intervention/treatment Phase
Dysferlinopathy Drug: rAAVrh74.MHCK7.DYSF.DV Phase 1

Detailed Description:
This is a phase I safety and tolerability study with a direct intramuscular injection of rAAVrh.74.MHCK7.DYSF.DV transferred to the extensor digitorum brevis muscle (EDB). The study is designed as a randomized, controlled, dose escalation trial with one EDB receiving the rAAVrh.74.MHCK7.DYSF.DV and the other side receiving saline alone. It will follow the previously safe and effective IM gene transfer to EDB for LGMD2D.2, 3 The first cohort, inclusive of three Dysferlinopathy subjects, will receive a gene transfer total dose of 2 x 10^12 vector genomes. Muscle biopsies will be performed at Day 45 (two subjects) and Day 90 (one subject). If there are no safety concerns, three additional subjects will be enrolled and receive an escalated dose at 6 X 10^12 vg (total dose). Muscle biopsies in the second cohort will be performed at Day 90 (one subject) and Day 180 (two subjects). This protocol design gives us a maximum period of observation ranging from 6 weeks to 6 months to capture both transient and delayed gene expression, and to recognize sustained expression.

Study Design

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 2 participants
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Phase I Intramuscular Gene Transfer Clinical Trial for Dysferlin Deficiency Delivering the Dysferlin Gene by AAVrh74
Study Start Date : March 2016
Estimated Primary Completion Date : March 2018
Estimated Study Completion Date : March 2018


Arms and Interventions

Arm Intervention/treatment
Experimental: Cohort 1 (Low Dose)

Three (n=3) dysferlin deficiency subjects will receive bilateral injections with one extensor digitorum brevis muscle (EDB) receiving the rAAVrh74.MHCK7.DYSF.DV and the other side receiving saline alone.Subjects will receive a total dose of 2 x 10^12 in one muscle.

Intervention Drug: rAAVrh.MHCK7.DYSF.DV

Drug: rAAVrh74.MHCK7.DYSF.DV
Biological/Vaccine: rAAVrh74.MHCK7.DYSF.DV Recombinant adeno-associated virus carrying a dysferlin transgene under control of a muscle specific MHCK7 promoter.
Experimental: Cohort 2 (High Dose)

Three (n=3) dysferlin deficiency subjects will receive bilateral injections with one extensor digitorum brevis muscle (EDB) receiving the rAAVrh74.MHCK7.DYSF.DV and the other side receiving saline alone.Subjects will receive a total dose of 6 x 10^12 vg in one muscle.

Intervention Drug: rAAVrh74.MHCK7.DYSF.DV

Drug: rAAVrh74.MHCK7.DYSF.DV
Biological/Vaccine: rAAVrh74.MHCK7.DYSF.DV Recombinant adeno-associated virus carrying a dysferlin transgene under control of a muscle specific MHCK7 promoter.


Outcome Measures

Primary Outcome Measures :
  1. Determination of safety based on the development of unacceptable toxicity [ Time Frame: 2 Years ]
    Defined as the occurrence of any one Grade III or higher, unanticipated, treatment-related toxicity


Secondary Outcome Measures :
  1. Number of participants showing dysferlin protein expression in muscle tissue [ Time Frame: 2 Years ]

    More than 3 fold increase in dysferlin protein expression in muscle compared to control side by western blot or more than 30% increase in dysferlin-expressing fibers

    Dysferlin protein expression as demonstrated with N -terminal anti-dysferlin antibodies will be quantified using BioQuant


  2. Leukocyte marker counts including CD45, CD3, CD4, CD8, and MAC 387. [ Time Frame: 2 Years ]
    Number of CD4+ cells/ mm2 area; Number of CD8+ cells/ mm2 area; Number of muscle fibers expressing MHCI staining / mm2 area; Number of muscle fibers expressing MHCII staining / mm2 area

  3. Binding antibodies counts and ELISpot counts to both rAAVrh74 capsid and dysferlin protein. [ Time Frame: 2 Years ]
    AAVrh74 or AAV8 binding antibody titers > 1:50 as determined by ELISA immunoassay

  4. Number of inflammatory cells in muscle [ Time Frame: 2 Years ]
    Number of inflammatory cells per mm2 area


Eligibility Criteria

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Must be Non-ambulant (cannot walk 10 meters in ≤ 30 sec) and age 18 years or older
  • Established mutations of the dysferlin gene on both alleles
  • Impaired muscle function but with sufficient muscle preservation to ensure muscle transfection based on magnetic resonance image of the EDB showing sufficient muscle preservation to permit transfection
  • Willingness of sexually active subjects with reproductive capacity to practice reliable method of contraception (If appropriate), during the first six months after gene transfer (females) or until two negative sperm samples are obtained post gene transfer (males).

Exclusion Criteria:

  • Active viral infection based on clinical observations or serological evidence of HIV, or Hepatitis A, B or C infection
  • The presence of a Dysferlin 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%
  • Diagnosis of (or ongoing treatment for) an autoimmune disease
  • Persistent leukopenia or leukocytosis (WBC ≤ 3.5 K/µL or ≥ 20.0 K/µL) or an absolute neutrophil count < 1.5K/µL
  • Concomitant illness or requirement for chronic drug treatment that in the opinion of the PI creates unnecessary risks for gene transfer
  • Pregnancy
  • AAVrh74 or AAV8 binding antibody titers > 1:50 as determined by ELISA immunoassay
  • Abnormal laboratory values in the clinically significant range in the table below, based upon normal values in the Nationwide Children's Hospital Laboratory: GGT, Total Bilirubin, Cystatine, Hemoglobin, White Blood Cells
Contacts and Locations

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): NCT02710500


Locations
United States, Ohio
Nationwide Children's Hosptial
Columbus, Ohio, United States, 43205
Sponsors and Collaborators
Nationwide Children's Hospital
Investigators
Principal Investigator: Jerry R Mendell, MD Director, Center for Gene Therapy
More Information

Additional Information:
Publications:
Responsible Party: Jerry R. Mendell, Director, Center for Gene Therapy, Nationwide Children's Hospital
ClinicalTrials.gov Identifier: NCT02710500     History of Changes
Other Study ID Numbers: IRB15-00669
First Posted: March 16, 2016    Key Record Dates
Last Update Posted: November 24, 2017
Last Verified: November 2017

Keywords provided by Jerry R. Mendell, Nationwide Children's Hospital:
LGMD2B
Limb Girdle Muscular Dystrophy
Miyoshi
Gene Transfer
Dysferlin

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