Clinical Intramuscular Gene Transfer of rAAV1.CMV.huFollistatin344 Trial to Patients With Duchenne Muscular Dystrophy

September 29, 2023 updated by: Jerry R. Mendell

Phase I/II Clinical Intramuscular Gene Transfer of rAAV1.CMV.huFollistatin344 Trial to Patients With Duchenne Muscular Dystrophy

The proposed clinical trial is an outgrowth of the safety record and functional improvement seen in the BMD follistatin gene therapy trial. In this study the investigators propose to inject AAV1.CMV.huFS344 at a total dose of 2.4E12 vg/kg to six DMD patients. This dose will be divided between gluteal muscles, quadriceps and tibialis anterior. This is a wider distribution of vector than given to BMD patients, who overall improved the distance walked on the 6MWT without adverse events related to viral transduction into a single muscle.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

The primary objective of this study is safety and endpoints will include hematology, serum chemistry, urinalysis, immunologic response to rAAV1 and follistatin, and reported history and observations of symptoms. Efficacy measures will be used as secondary outcomes and include the distance walked on the 6MWT, functional tests by PT, life quality questionnaire, MRI, EIM, and muscle biopsy. Subject will have follow up visits on days 7, 14, 30, 45, 60, 90, 180 and 9,12, 18 and 24 months post-gene transfer.

Study Type

Interventional

Enrollment (Actual)

3

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

  • United States
    • 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

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

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  • Age 7 or older
  • Confirmed DMD gene mutations
  • Impaired muscle function based on clinical evidence including difficulty climbing stairs, getting from the floor (Gowers' sign), and weakness of individual muscles of extremities
  • Males of any ethnic group will be eligible
  • Ability to cooperate with study procedures including muscle testing.
  • Willingness of sexually active subjects with reproductive capacity to practice reliable method of contraception
  • Subjects must be on stable dose of prednisone for three months at time of enrollment or be started on oral dose of daily prednisone regimen for 30 days prior to gene transfer. Study participants will continue prednisone post gene transfer unless there is adverse event that warrants prednisone taper or withdrawal.

Exclusion Criteria:

  • Active viral infection based on clinical observations.
  • The presence of a DMD gene mutation 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%
  • Serological evidence of HIV infection, or Hepatitis A, B or C infection
  • Diagnosis of (or ongoing treatment for) an autoimmune disease
  • Concomitant illness or requirement for chronic drug treatment that in the opinion of the PI creates unnecessary risks for gene transfer
  • Subjects with rAAV1 binding antibody titers > 1:50 as determined by ELISA immunoassay
  • Abnormal laboratory values for liver, kidney, CBC, 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: Other
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Experimental
The vector will be delivered to both limbs via multiple, direct intramuscular injections of rAAV1.CMV.huFollistin344; the number of injections per muscle will depend on the size of the patient. A total dose of 2.4E12 vg/kg (1.2E12vg/kg/limb) will be delivered to the lower limbs of 6 DMD subjects
Biological: rAAV1.CMV.huFollistin344
Six DMD patients will receive rAAV1.CMV.huFollistatin344 to both limbs by multiple injections to gluteal muscles, quadriceps and tibialis anterior muscles.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Number of Dose Limiting Toxicity (DLT) Adverse Events as Assessed by 21 CFR 312.32.
Time Frame: DLT Adverse events will be recorded from the date of dosing and through the time of the subject's last study visit. Serious adverse events will be recorded from the date of dosing and for up to 2 years after gene therapy administration.

Dose limiting toxicity (DLT) is defined as any adverse event that is possibly, probably, or definitely related to the study agent. This would include any grade 3 according to the classification given above. Study enrollment will be halted by the investigators when any subject experiences a Grade 3, or higher adverse event toxicity that is possibly, probably, or definitely related to the study drug. Only those adverse events requiring treatment will qualify as DLT.

The classification for adverse events to be used is the following:

  1. Mild adverse event; did not require treatment
  2. Moderate adverse event; resolved with treatment
  3. Severe adverse event; inability to carry on normal activities; required professional medical attention
  4. Life-threatening or permanently disabling adverse event
  5. Fatal adverse event In this grading system, "severe" is not equivalent to seriousness.
DLT Adverse events will be recorded from the date of dosing and through the time of the subject's last study visit. Serious adverse events will be recorded from the date of dosing and for up to 2 years after gene therapy administration.

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Expression of Viral DNA (qPCR), and Follistatin Transgene in Muscle Tissue
Time Frame: 180.days

Muscle biopsies on quadriceps muscles a muscle biopsy on one leg at baseline screening visit and the post gene transfer biopsy on the opposite leg at day 180. Muscle tissue obtained at biopsy will also be assessed for viral DNA (qPCR), and follistatin transgene expression.

Measured in CMV.FS344 Gene Copy Number in Genomic DNA (Copies/ug DNA)
180.days
Muscle Function Measured by Six-minute Walk Test (6MWT)
Time Frame: 2 years
Number of subjects with increased distance walked in meters on the Six Minute Walk Test. The participant was asked to walk a set course of 25 meters for 6 minutes (timed) and the distance walked in meters was recorded. Increases from baseline in 6MWT distance are indicative of improvement and decreases from baseline indicate worsening.
2 years
Improvement of Muscle Function as Measured by North Star Ambulatory Assessment (NSAA)
Time Frame: 2 years

Overall Improvement in North Star Ambulatory Assessment

The activities are graded as follows:

2 - "Normal" - no obvious modification of activity

1 - Modified method but achieves goal independent of physical assistance from another 0 - Unable to achieve independently This scale is ordinal with 34 as the maximum score indicating fully-independent function.
2 years

Collaborators and Investigators

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

Sponsor

Jerry R. Mendell

Collaborators

Duchenne Alliance
Milo Therapeutics

Investigators

  • Principal Investigator: Jerry R Mendell, MD, Director, Center for Gene Therapy, 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

Helpful Links

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

January 1, 2015

Primary Completion (Actual)

November 1, 2017

Study Completion (Actual)

November 1, 2017

Study Registration Dates

First Submitted

January 26, 2015

First Submitted That Met QC Criteria

February 2, 2015

First Posted (Estimated)

February 3, 2015

Study Record Updates

Last Update Posted (Actual)

October 11, 2023

Last Update Submitted That Met QC Criteria

September 29, 2023

Last Verified

September 1, 2023

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 14-00630

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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