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Gene Transfer Clinical Trial to Deliver rAAVrh74.MCK.GALGT2 for Duchenne Muscular Dystrophy

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ClinicalTrials.gov Identifier: NCT03333590
Recruitment Status : Recruiting
First Posted : November 7, 2017
Last Update Posted : May 2, 2018
Sponsor:
Information provided by (Responsible Party):
Kevin Flanigan, Nationwide Children's Hospital

Study Description
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Brief Summary:
The proposed clinical trial study of rAAVrh74.MCK.GALGT2 for duchenne muscular dystrophy (DMD) patients. There will be a modified intravascular limb infusion (ILI) procedure that will be used to sequentially deliver vector to each whole lower limb of DMD subjects via a major lower limb artery.

Condition or disease Intervention/treatment Phase
Duchenne Muscular Dystrophy Biological: rAAVrh74.MCK.GALGT2 Phase 1 Phase 2

Detailed Description:

This is an open-label, dose escalation trial where the vector will be delivered via the femoral artery to the muscles of both legs of DMD subjects.

The primary objective of this study is the assessment of the safety of intravascular administration of rAAVrh74.MCK.GALGT2 to DMD patients. Safety endpoints will be assessed by changes in hematology, serum chemistry, urinalysis, immunologic response to rAAVrh74 and GALGT2, and reported history and observations of symptoms. Efficacy measures will be used as secondary outcome for this disorder including a combination of functional 6 minute walk test (6MWT) and direct muscle testing for strength (MVICT) of lower limb muscles.

Subjects will be evaluated at baseline, infusion visit (days 0-2), and return for follow up visits on days 7, 14, 30, 60, 90, and 180 and months 12, 18 and 24


Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 6 participants
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Intervention Model Description: This is a dose escalation trial that will begin with the minimal efficacious dose as determined by preclinical studies and approved by the FDA. During the course of the trial, if safety is shown the dose will be escalated according to the clinical protocol.
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase I/IIa Gene Transfer Clinical Trial for Duchenne Muscular Dystrophy Using rAAVrh74.MCK.GALGT2
Actual Study Start Date : November 6, 2017
Estimated Primary Completion Date : November 2020
Estimated Study Completion Date : November 2020

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
Experimental: Cohort 1 (Minimal Efficacious Dose) rAAVrh74.MCK.GALGT2
N = 3 [2.5 x E13 vg/kg per leg, delivered bilaterally (total 5.0 x E13 vg/kg)]
 Biological: rAAVrh74.MCK.GALGT2
Adeno-associated virus serotype rh74 carrying the GALGT2 gene under the control of a MCK promoter (rAAVrh74.MCK.GALGT2) will be delivered one time to each of the lower limbs through the femoral artery using an intravascular limb infusion technique (ILI)
Experimental: Cohort 2 (Dose Escalation) rAAVrh74.MCK.GALGT2
N=3 [5 x E13 vg/kg per leg, delivered bilaterally (total 1.0 x E14 vg/kg)]
 Biological: rAAVrh74.MCK.GALGT2
Adeno-associated virus serotype rh74 carrying the GALGT2 gene under the control of a MCK promoter (rAAVrh74.MCK.GALGT2) will be delivered one time to each of the lower limbs through the femoral artery using an intravascular limb infusion technique (ILI)


Outcome Measures
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Primary Outcome Measures :
  1. The primary objective is assessment of safety based on the development of unacceptable toxicity. [ Time Frame: 2 years ]
    Unacceptable toxicity is defined as the occurrence of two or more unanticipated Grade III or higher treatment-related toxicities.


Secondary Outcome Measures :
  1. Expression of GALGT2 as demonstrated by immunofluorescent staining with anti-CT epitope antibodies or WFA lectin in muscle biopsy sections at 90 and 180 days post-injection [ Time Frame: 90 and 180 Days ]
  2. GALGT2 protein expression quantified by western blot and assessed by densitometry in muscle biopsy tissue at 90 and 180 days post-injection [ Time Frame: 90 and 180 Days ]

Other Outcome Measures:
  1. The 6 minute walk test (6MWT) will be an exploratory outcome measure. Either stabilization or a statistically significant change in distance walked on the 6MWT will be considered evidence of a positive result. [ Time Frame: 90 and 180 days ]
  2. The maximum voluntary isometric contraction testing (MVICT) will be an exploratory outcome measure. [ Time Frame: Days 90 and 180, Months 12, 18 and 24 ]
  3. The 100 meter walk time will be an exploratory outcome measure. [ Time Frame: Days 90 and 180, Months 12, 18 and 24 ]
  4. The North Star Ambulatory Assessment will be an exploratory outcome measure. [ Time Frame: Days 90 and 180, Months 12, 18 and 24 ]

Eligibility Criteria
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Ages Eligible for Study:   4 Years and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   Male
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria

  • Ambulant patients age 4 years or older
  • Confirmed mutations in the DMD gene using a clinical accepted technique that completely defines the mutation 1,2

  • • Measurably impaired muscle function (defined as less than 80% of the predicted value for 100 MWT), but with sufficient muscle preservation to ensure assessment of muscle transfection based on clinical evaluation by the PI and expert colleagues. This degree of preservation will include:

    • Ability to extend the knee fully against gravity
    • Preserved ambulation with ability to walk ≥ 350 meters during the 6MWT
    • A magnetic resonance image of the quadriceps showing preservation of sufficient muscle mass to permit transfection
  • Males of any ethnic group will be eligible
  • Ability to cooperate with muscle testing
  • Stable daily dose of corticosteroid therapy (including either prednisone, prednisolone, deflazacort or their generic forms) for 12 weeks prior to gene transfer

Exclusion Criteria

  • Active viral infection based on clinical observations
  • The presence of a DMD mutation without weakness or loss of function
  • Subject is amenable to or is currently being treated with eteplirsen

  • 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%
  • Serological evidence of HIV infection, or Hepatitis B or C infection
  • 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
  • Subjects with rAAVrh74 binding antibody titers ≥ 1:50 as determined by ELISA immunoassay
  • Presence of circulating anti-Sda antibodies as determined by study approved laboratory
  • Abnormal laboratory values in the clinically significant range, based upon normal values in the Nationwide Children's Hospital Laboratory
Contacts and Locations
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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): NCT03333590


Contacts
Contact: Federica Rinaldi 614-355-2897 federica.rinaldi@nationwidechildrens.org
Contact: Tabatha Simmons 614-722-6921 tabatha.simmons@nationwidechildrens.org

Locations
United States, Ohio
Nationwide Children's Hospital Recruiting
Columbus, Ohio, United States, 43205
Sponsors and Collaborators
Kevin Flanigan
Investigators
Principal Investigator: Kevin Flanigan, MD Nationwide Children's Hospital
More Information
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Publications:

Responsible Party: Kevin Flanigan, Professor of Pediatrics, Nationwide Children's Hospital
ClinicalTrials.gov Identifier: NCT03333590     History of Changes
Other Study ID Numbers: GALGT2 Gene Therapy for DMD
First Posted: November 7, 2017    Key Record Dates
Last Update Posted: May 2, 2018
Last Verified: May 2018

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

Keywords provided by Kevin Flanigan, Nationwide Children's Hospital:
DMD
Duchenne Muscular Dystrophy

Additional relevant MeSH terms:
Muscular Dystrophies
Muscular Dystrophy, Duchenne
Muscular Disorders, Atrophic
Muscular Diseases
Musculoskeletal Diseases
 Neuromuscular Diseases
Nervous System Diseases
Genetic Diseases, Inborn
Genetic Diseases, X-Linked