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

NCT ID: NCT02354781

Last Updated: 2023-10-11

Study Results

Results available

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Basic Information

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Recruitment Status

COMPLETED

Clinical Phase

PHASE1/PHASE2

Total Enrollment

3 participants

Study Classification

INTERVENTIONAL

Study Start Date

2015-01-31

Study Completion Date

2017-11-30

Brief Summary

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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.

Detailed Description

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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.

Conditions

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Duchenne Muscular Dystrophy

Study Design

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Allocation Method

NA

Intervention Model

SINGLE_GROUP

Primary Study Purpose

OTHER

Blinding Strategy

NONE

Study Groups

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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

Group Type EXPERIMENTAL

rAAV1.CMV.huFollistin344

Intervention Type BIOLOGICAL

Six DMD patients will receive rAAV1.CMV.huFollistatin344 to both limbs by multiple injections to gluteal muscles, quadriceps and tibialis anterior muscles.

Interventions

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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.

Intervention Type BIOLOGICAL

Eligibility Criteria

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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
Minimum Eligible Age

7 Years

Eligible Sex

MALE

Accepts Healthy Volunteers

No

Sponsors

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Duchenne Alliance

OTHER

Sponsor Role collaborator

Milo Therapeutics

INDUSTRY

Sponsor Role collaborator

Jerry R. Mendell

OTHER

Sponsor Role lead

Responsible Party

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Jerry R. Mendell

Center Director for Gene Therapy

Responsibility Role SPONSOR_INVESTIGATOR

Principal Investigators

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Jerry R Mendell, MD

Role: PRINCIPAL_INVESTIGATOR

Director, Center for Gene Therapy, Nationwide Children's Hospital

Locations

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Nationwide Children's Hospital

Columbus, Ohio, United States

Site Status

Countries

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United States

References

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Mendell JR, Sahenk Z, Malik V, Gomez AM, Flanigan KM, Lowes LP, Alfano LN, Berry K, Meadows E, Lewis S, Braun L, Shontz K, Rouhana M, Clark KR, Rosales XQ, Al-Zaidy S, Govoni A, Rodino-Klapac LR, Hogan MJ, Kaspar BK. A phase 1/2a follistatin gene therapy trial for becker muscular dystrophy. Mol Ther. 2015 Jan;23(1):192-201. doi: 10.1038/mt.2014.200. Epub 2014 Oct 17.

Reference Type BACKGROUND
PMID: 25322757 (View on PubMed)

Kota J, Handy CR, Haidet AM, Montgomery CL, Eagle A, Rodino-Klapac LR, Tucker D, Shilling CJ, Therlfall WR, Walker CM, Weisbrode SE, Janssen PM, Clark KR, Sahenk Z, Mendell JR, Kaspar BK. Follistatin gene delivery enhances muscle growth and strength in nonhuman primates. Sci Transl Med. 2009 Nov 11;1(6):6ra15. doi: 10.1126/scitranslmed.3000112.

Reference Type BACKGROUND
PMID: 20368179 (View on PubMed)

Rodino-Klapac LR, Haidet AM, Kota J, Handy C, Kaspar BK, Mendell JR. Inhibition of myostatin with emphasis on follistatin as a therapy for muscle disease. Muscle Nerve. 2009 Mar;39(3):283-96. doi: 10.1002/mus.21244.

Reference Type BACKGROUND
PMID: 19208403 (View on PubMed)

Miller TM, Kim SH, Yamanaka K, Hester M, Umapathi P, Arnson H, Rizo L, Mendell JR, Gage FH, Cleveland DW, Kaspar BK. Gene transfer demonstrates that muscle is not a primary target for non-cell-autonomous toxicity in familial amyotrophic lateral sclerosis. Proc Natl Acad Sci U S A. 2006 Dec 19;103(51):19546-51. doi: 10.1073/pnas.0609411103. Epub 2006 Dec 12.

Reference Type BACKGROUND
PMID: 17164329 (View on PubMed)

Bian X, Snow ZK, Zinn CJ, Gowan CC, Conley SM, Bratulin AL, Elhusseiny KM, Miller J, Tchkonia T, Kirkland JL, Lerman LO, Hickson LJ. Activin A Antagonism with Follistatin Reduces Kidney Fibrosis, Injury, and Cellular Senescence-Associated Inflammation in Murine Diabetic Kidney Disease. Kidney360. 2025 Mar 28;6(8):1278-1291. doi: 10.34067/KID.0000000776.

Reference Type DERIVED
PMID: 40152935 (View on PubMed)

Provided Documents

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Document Type: Study Protocol and Statistical Analysis Plan

View Document

Related Links

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http://www.nationwidechildrens.org/center-for-gene-therapy

Click here for Center for Gene Therapy, The Research Institute at Nationwide Children's Hospital

Other Identifiers

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14-00630

Identifier Type: -

Identifier Source: org_study_id

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