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Trial record 28 of 29 for:    lgmd

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 : May 13, 2019
Sponsor:
Information provided by (Responsible Party):
Jerry R. Mendell, Nationwide Children's Hospital

Tracking Information
First Submitted Date  ICMJE February 11, 2016
First Posted Date  ICMJE March 16, 2016
Last Update Posted Date May 13, 2019
Study Start Date  ICMJE March 2016
Estimated Primary Completion Date July 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: March 11, 2016)
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
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT02710500 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: March 11, 2016)
  • 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
  • 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
  • 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
  • Number of inflammatory cells in muscle [ Time Frame: 2 Years ]
    Number of inflammatory cells per mm2 area
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE rAAVrh74.MHCK7.DYSF.DV for Treatment of Dysferlinopathies
Official Title  ICMJE Phase I Intramuscular Gene Transfer Clinical Trial for Dysferlin Deficiency Delivering the Dysferlin Gene by AAVrh74
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.
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 Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE Dysferlinopathy
Intervention  ICMJE 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.
Study Arms  ICMJE
  • 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

    Intervention: Drug: rAAVrh74.MHCK7.DYSF.DV
  • 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

    Intervention: Drug: rAAVrh74.MHCK7.DYSF.DV
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: November 21, 2017)
2
Original Estimated Enrollment  ICMJE
 (submitted: March 11, 2016)
6
Estimated Study Completion Date  ICMJE July 2019
Estimated Primary Completion Date July 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02710500
Other Study ID Numbers  ICMJE IRB15-00669
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Jerry R. Mendell, Nationwide Children's Hospital
Study Sponsor  ICMJE Nationwide Children's Hospital
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Jerry R Mendell, MD Director, Center for Gene Therapy
PRS Account Nationwide Children's Hospital
Verification Date May 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP