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

Primary Purpose

Duchenne Muscular Dystrophy

Status
Completed
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
rAAV1.CMV.huFollistin344
Sponsored by
Jerry R. Mendell
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional other trial for Duchenne Muscular Dystrophy focused on measuring DMD, muscular dystrophy, Follistatin

Eligibility Criteria

7 Years - undefined (Child, Adult, Older Adult)MaleDoes not accept healthy volunteers

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

Sites / Locations

  • Nationwide Children's Hospital

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Experimental

Arm Description

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

Outcomes

Primary Outcome Measures

Number of Dose Limiting Toxicity (DLT) Adverse Events as Assessed by 21 CFR 312.32.
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: Mild adverse event; did not require treatment Moderate adverse event; resolved with treatment Severe adverse event; inability to carry on normal activities; required professional medical attention Life-threatening or permanently disabling adverse event Fatal adverse event In this grading system, "severe" is not equivalent to seriousness.

Secondary Outcome Measures

Muscle Function Measured by Six-minute Walk Test (6MWT)
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.
Expression of Viral DNA (qPCR), and Follistatin Transgene in Muscle Tissue
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)
Improvement of Muscle Function as Measured by North Star Ambulatory Assessment (NSAA)
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.

Full Information

First Posted
January 26, 2015
Last Updated
September 29, 2023
Sponsor
Jerry R. Mendell
Collaborators
Duchenne Alliance, Milo Therapeutics
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1. Study Identification

Unique Protocol Identification Number
NCT02354781
Brief Title
Clinical Intramuscular Gene Transfer of rAAV1.CMV.huFollistatin344 Trial to Patients With Duchenne Muscular Dystrophy
Official Title
Phase I/II Clinical Intramuscular Gene Transfer of rAAV1.CMV.huFollistatin344 Trial to Patients With Duchenne Muscular Dystrophy
Study Type
Interventional

2. Study Status

Record Verification Date
September 2023
Overall Recruitment Status
Completed
Study Start Date
January 2015 (undefined)
Primary Completion Date
November 2017 (Actual)
Study Completion Date
November 2017 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
Jerry R. Mendell
Collaborators
Duchenne Alliance, Milo Therapeutics

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
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
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Duchenne Muscular Dystrophy
Keywords
DMD, muscular dystrophy, Follistatin

7. Study Design

Primary Purpose
Other
Study Phase
Phase 1, Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
3 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Experimental
Arm Type
Experimental
Arm Description
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
Intervention Type
Biological
Intervention Name(s)
rAAV1.CMV.huFollistin344
Intervention Description
Six DMD patients will receive rAAV1.CMV.huFollistatin344 to both limbs by multiple injections to gluteal muscles, quadriceps and tibialis anterior muscles.
Primary Outcome Measure Information:
Title
Number of Dose Limiting Toxicity (DLT) Adverse Events as Assessed by 21 CFR 312.32.
Description
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: Mild adverse event; did not require treatment Moderate adverse event; resolved with treatment Severe adverse event; inability to carry on normal activities; required professional medical attention Life-threatening or permanently disabling adverse event Fatal adverse event In this grading system, "severe" is not equivalent to seriousness.
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.
Secondary Outcome Measure Information:
Title
Muscle Function Measured by Six-minute Walk Test (6MWT)
Description
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.
Time Frame
2 years
Title
Expression of Viral DNA (qPCR), and Follistatin Transgene in Muscle Tissue
Description
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)
Time Frame
180.days
Title
Improvement of Muscle Function as Measured by North Star Ambulatory Assessment (NSAA)
Description
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.
Time Frame
2 years

10. Eligibility

Sex
Male
Minimum Age & Unit of Time
7 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Jerry R Mendell, MD
Organizational Affiliation
Director, Center for Gene Therapy, Nationwide Children's Hospital
Official's Role
Principal Investigator
Facility Information:
Facility Name
Nationwide Children's Hospital
City
Columbus
State/Province
Ohio
ZIP/Postal Code
43205
Country
United States

12. IPD Sharing Statement

Citations:
PubMed Identifier
25322757
Citation
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.
Results Reference
background
PubMed Identifier
20368179
Citation
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.
Results Reference
background
PubMed Identifier
19208403
Citation
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.
Results Reference
background
PubMed Identifier
17164329
Citation
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.
Results Reference
background
Links:
URL
http://www.nationwidechildrens.org/center-for-gene-therapy
Description
Click here for Center for Gene Therapy, The Research Institute at Nationwide Children's Hospital

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

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