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Follistatin Gene Transfer to Patients With Becker Muscular Dystrophy and Sporadic Inclusion Body Myositis

Primary Purpose

Becker Muscular Dystrophy, Sporadic Inclusion Body Myositis

Status

Completed

Phase

Phase 1

Locations

United States

Study Type

Interventional

Intervention

rAAV1.CMV.huFollistatin344

About this trial

This is an interventional other trial for Becker Muscular Dystrophy focused on measuring Becker muscular dystrophy, BMD, muscular dystrophy, inclusion body myositis, IBM, Follistatin

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

All subjects [sIBM and BMD must be ambulatory and have identifiable atrophy of the quadriceps muscle with muscle weakness ≥2 standard deviations below predicted using quantitative muscle testing (maximum voluntary isometric strength testing), and difficulty getting out of chairs, climbing stairs, and getting up from the floor.
sIBM patients include males and post-menopause females of any ethnic or racial group. Diagnosis of sIBM is based on previously published criteria that include distribution of weakness (knee extensor weakness, finger flexor weakness) and histological presence of inflammation and vacuolar myopathy. Patients with inflammation, vacuolar changes and intracellular amyloid deposits or 15/18nm filaments fulfill criteria irrespective of clinical features.
BMD patients include adult males (>18yo) of any ethnic or racial group with proven mutation of dystrophin gene and continued ambulation after age 15 years old.
Ability to cooperate for muscle testing
Deficit in muscle strength greater than 2 standard deviation below age expectations
Willingness of sexually active subjects with reproductive capacity (only male population) to practice reliable method of contraception until two negative sperm samples are obtained post gene transfer

Exclusion Criteria:

Active viral infection
History or evidence of active infection with hepatitis C, hepatitis A or B, or HIV
Patients with any other cause of muscle weakness based on medical history and screening physical exam including: myopathy (other dystrophies, polymyositis, and dermatomyositis), neuropathy (from any cause), myasthenia gravis, and weakness related to degenerative joint disease of the spine.
Ongoing immunosuppressive therapy or immunosuppressive therapy within 3 months of starting the trial (e.g. corticosteroids, cyclosporine, tacrolimus, methotrexate, cyclophosphamide, intravenous immunoglobulin, rituximab)
Concomitant illness or requirement for chronic drug treatment that in the opinion of the PI creates unnecessary risks for gene transfer. Patients taking any of the following drugs will be excluded: drugs for treatment of myopathy or neuropathy or agents used to treat diabetes mellitus
Knee or ankle contractures preventing proper muscle strength testing
Patients with AAV1 neutralizing antibody titers ≥ 1:1600 as determined by ELISA immunoassay
Patients with history of angina and patients with past history of myocardial infarction in the past 6 months

Sites / Locations

Nationwide Children's Hospital

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Arm Label

Cohort 1

Cohort 2

Cohort 3

Arm Description

Low Dose: 2E11 vg/kg of rAAV1.CMV.huFollistatin344 administered via intramuscular injection unilaterally to single quadriceps muscle (n=3, sIBM only)

Mid Dose: 3E11 vg/kg per quadriceps of rAAV1.CMV.huFollistatin344 administered via intramuscular injection bilaterally to both quadriceps muscles (n=6; 3 sIBM and 3 BMD)

Low Dose: 6E11 vg/kg per quadriceps of rAAV1.CMV.huFollistatin344 administered via intramuscular injection bilaterally to both quadriceps muscles (n=6; 3 sIBM and 3 BMD)

Outcomes

Primary Outcome Measures

Safety

Safety trial based on development of unacceptable toxicity defined as the occurrence of any Grade III or higher treatment-related toxicities.

Secondary Outcome Measures

Muscle Function and Strength Testing

Muscle function and strength: MRI of quadriceps muscles (bilateral) Muscle biopsies on quadriceps muscles (a muscle biopsy on one leg at baseline screening visit - except for cohort 1 - and the post gene transfer biopsy on the opposite leg at day 180) Thigh circumference measurement at baseline and post-gene transfer follow up visits up to day 180 (prior to second biopsy)

Full Information

NCT ID

NCT01519349

First Posted

January 23, 2012

Last Updated

September 29, 2023

Sponsor

Nationwide Children's Hospital

Collaborators

Parent Project Muscular Dystrophy

1. Study Identification

Unique Protocol Identification Number

NCT01519349

Brief Title

Follistatin Gene Transfer to Patients With Becker Muscular Dystrophy and Sporadic Inclusion Body Myositis

Official Title

Phase I Clinical Intramuscular Gene Transfer of rAAV1.CMV.huFollistatin344 Trial to Patients With Becker Muscular Dystrophy and Sporadic Inclusion Body Myositis.

Study Type

Interventional

2. Study Status

Record Verification Date

September 2023

Overall Recruitment Status

Completed

Study Start Date

January 2012 (undefined)

Primary Completion Date

October 2017 (Actual)

Study Completion Date

October 2017 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

Nationwide Children's Hospital

Collaborators

Parent Project Muscular Dystrophy

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

The investigators are performing a gene therapy clinical trial in Becker muscular dystrophy (BMD) and sporadic inclusion body myositis (sIBM) patients. Both of these conditions have an important common feature: loss of ability to walk because of weakness of the thigh muscles. The investigators plan to do a gene therapy trial to deliver a gene to muscle called follistatin (FS344) that can build muscle size and strength. If successful, the investigators can increase the size of the thigh muscle and potentially prolong a patient's ability to walk. The gene will be carried into the muscle by a virus called adeno-associated virus (AAV). This virus occurs naturally in muscle and does not cause any human disease, setting the stage for its safe use in a clinical trial. Presently there is no treatment that can reverse Becker muscular dystrophy or sporadic inclusion body myositis. Only supportive care is currently possible. In this study, subjects with either of these diseases will have shots of the follistatin gene injected directly into thigh muscle on one (first cohort) or both legs (2nd and 3rd cohort). One hundred and eighty days following the gene delivery, the muscle will undergo biopsy to look closely at the muscle to see if the muscle fibers are bigger. Between the time of the gene transfer and the muscle biopsy, patients will be carefully monitored for any side effects of the treatment. This will include an MRI of the thigh muscle before treatment and at day 180 following treatment. Blood and urine tests, as well as physical examination will be done on the subjects during the screening visit and on days 0, 1, 2, 7, 14, 30, 60, 90, and 180 to make sure that there are no side effects from the gene injections. Sutures will be removed 2 weeks post-biopsy. Additional blood samples will be collected at 9, 12, 18, and 24 months. Patients will be seen at the end of 1st and 2nd years for a physical exam, assessment of muscle strength and appropriate blood tests.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Becker Muscular Dystrophy, Sporadic Inclusion Body Myositis

Keywords

Becker muscular dystrophy, BMD, muscular dystrophy, inclusion body myositis, IBM, Follistatin

7. Study Design

Primary Purpose

Other

Study Phase

Phase 1

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

Non-Randomized

Enrollment

15 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Cohort 1

Arm Type

Experimental

Arm Description

Low Dose: 2E11 vg/kg of rAAV1.CMV.huFollistatin344 administered via intramuscular injection unilaterally to single quadriceps muscle (n=3, sIBM only)

Arm Title

Cohort 2

Arm Type

Experimental

Arm Description

Mid Dose: 3E11 vg/kg per quadriceps of rAAV1.CMV.huFollistatin344 administered via intramuscular injection bilaterally to both quadriceps muscles (n=6; 3 sIBM and 3 BMD)

Arm Title

Cohort 3

Arm Type

Experimental

Arm Description

Low Dose: 6E11 vg/kg per quadriceps of rAAV1.CMV.huFollistatin344 administered via intramuscular injection bilaterally to both quadriceps muscles (n=6; 3 sIBM and 3 BMD)

Intervention Type

Biological

Intervention Name(s)

rAAV1.CMV.huFollistatin344

Intervention Description

First cohort - Low Dose: 2E11 vg/kg with single leg injection (n=3 sIBM) Second cohort: 3E11 vg/kg per quad (n=3 sIBM; 3 BMD) Third cohort: 6E11 vg/kg per quad (n=3 sIBM; 3 BMD)

Primary Outcome Measure Information:

Title

Safety

Description

Safety trial based on development of unacceptable toxicity defined as the occurrence of any Grade III or higher treatment-related toxicities.

Time Frame

2 years

Secondary Outcome Measure Information:

Title

Muscle Function and Strength Testing

Description

Time Frame

2 years

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: All subjects [sIBM and BMD must be ambulatory and have identifiable atrophy of the quadriceps muscle with muscle weakness ≥2 standard deviations below predicted using quantitative muscle testing (maximum voluntary isometric strength testing), and difficulty getting out of chairs, climbing stairs, and getting up from the floor. sIBM patients include males and post-menopause females of any ethnic or racial group. Diagnosis of sIBM is based on previously published criteria that include distribution of weakness (knee extensor weakness, finger flexor weakness) and histological presence of inflammation and vacuolar myopathy. Patients with inflammation, vacuolar changes and intracellular amyloid deposits or 15/18nm filaments fulfill criteria irrespective of clinical features. BMD patients include adult males (>18yo) of any ethnic or racial group with proven mutation of dystrophin gene and continued ambulation after age 15 years old. Ability to cooperate for muscle testing Deficit in muscle strength greater than 2 standard deviation below age expectations Willingness of sexually active subjects with reproductive capacity (only male population) to practice reliable method of contraception until two negative sperm samples are obtained post gene transfer Exclusion Criteria: Active viral infection History or evidence of active infection with hepatitis C, hepatitis A or B, or HIV Patients with any other cause of muscle weakness based on medical history and screening physical exam including: myopathy (other dystrophies, polymyositis, and dermatomyositis), neuropathy (from any cause), myasthenia gravis, and weakness related to degenerative joint disease of the spine. Ongoing immunosuppressive therapy or immunosuppressive therapy within 3 months of starting the trial (e.g. corticosteroids, cyclosporine, tacrolimus, methotrexate, cyclophosphamide, intravenous immunoglobulin, rituximab) Concomitant illness or requirement for chronic drug treatment that in the opinion of the PI creates unnecessary risks for gene transfer. Patients taking any of the following drugs will be excluded: drugs for treatment of myopathy or neuropathy or agents used to treat diabetes mellitus Knee or ankle contractures preventing proper muscle strength testing Patients with AAV1 neutralizing antibody titers ≥ 1:1600 as determined by ELISA immunoassay Patients with history of angina and patients with past history of myocardial infarction in the past 6 months

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Jerry R Mendell, M.D.

Organizational Affiliation

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

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

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

result

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

URL

http://www.parentprojectmd.org

Description

Click here for Parent Project Muscular Dystrophy

URL

http://www.myositis.org/

Description

Click here for The Myositis Association

Learn more about this trial

Follistatin Gene Transfer to Patients With Becker Muscular Dystrophy and Sporadic Inclusion Body Myositis

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