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

September 12, 2023 updated by: Kevin Flanigan

Phase I/IIa Gene Transfer Clinical Trial for Duchenne Muscular Dystrophy Using rAAVrh74.MCK.GALGT2

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.

Study Overview

Status

Active, not recruiting

Intervention / Treatment

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 Type

Interventional

Enrollment (Actual)

2

Phase

  • Phase 2
  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

    • Ohio
      • Columbus, Ohio, United States, 43205
        • Nationwide Children's Hospital

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

4 years and older (Child, Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Non-Randomized
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / 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)]
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)]
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)

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
Number of Unanticipated Grade III or Higher Treatment-Related Toxicities
Time Frame: 2 years
2 years

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Expression of GALGT2 as Demonstrated by Immunofluorescent Staining With Anti-CT Epitope Antibodies or WFA Lectin in Muscle Biopsy Sections at 120 Days Post Injection (Cohort 1) and 90 Days Post-injection (Cohort 2).
Time Frame: Day 90 (Cohort 2) and Day 120 (Cohort 1)
Percentage of fibers expressing GALGT2 in each biopsy sample.
Day 90 (Cohort 2) and Day 120 (Cohort 1)
GALGT2 Protein Expression Quantified by Western Blot and Assessed by Densitometry in Muscle Biopsy Tissue at 120 Days Post-injection (Cohort 1) and 90 Days Post-injection (Cohort 2)
Time Frame: Day 90 (Cohort 2) and Day 120 (Cohort 1)
Day 90 (Cohort 2) and Day 120 (Cohort 1)

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
Number of Meters Walked During the 6 Minute Walk Test
Time Frame: Day 90 (Cohort 2) and Day 120 (Cohort 1) and Day 180 for both cohorts
Day 90 (Cohort 2) and Day 120 (Cohort 1) and Day 180 for both cohorts
Strength of the Bilateral Knee Flexors and Extensors During the Maximal Voluntary Isometric Strength Test.
Time Frame: Days 90 (Cohort 2), 120 (Cohort 1) and both Cohorts at Day 180, Months 12, 18 and 24
Days 90 (Cohort 2), 120 (Cohort 1) and both Cohorts at Day 180, Months 12, 18 and 24
Time Taken to Walk 100 Meters During the 100 Meter Walk Test.
Time Frame: Days 90 (Cohort 2), 120 (Cohort 1); both Cohorts at Day 180, Months 12, 18 and Cohort 2 at Month 24
Days 90 (Cohort 2), 120 (Cohort 1); both Cohorts at Day 180, Months 12, 18 and Cohort 2 at Month 24
Score of Muscle Function Using the The North Star Ambulatory Assessment (NSAA).
Time Frame: Days 90 (Cohort 2), 120 (Cohort 1) and both Cohorts at Day 180, Months 12, 18 and 24
The NSAA provides a score between 0 and 34 where higher numbers represent greater muscle function.
Days 90 (Cohort 2), 120 (Cohort 1) and both Cohorts at Day 180, Months 12, 18 and 24

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Investigators

  • Principal Investigator: Kevin Flanigan, MD, Nationwide Children's Hospital

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

November 6, 2017

Primary Completion (Actual)

November 4, 2020

Study Completion (Estimated)

October 1, 2023

Study Registration Dates

First Submitted

November 1, 2017

First Submitted That Met QC Criteria

November 3, 2017

First Posted (Actual)

November 7, 2017

Study Record Updates

Last Update Posted (Actual)

September 14, 2023

Last Update Submitted That Met QC Criteria

September 12, 2023

Last Verified

September 1, 2023

More Information

Terms related to this study

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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