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| Name | Class |
|---|---|
| Duchenne Alliance | OTHER |
| Milo Therapeutics | INDUSTRY |
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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| 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 |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| rAAV1.CMV.huFollistin344 | Biological | Six DMD patients will receive rAAV1.CMV.huFollistatin344 to both limbs by multiple injections to gluteal muscles, quadriceps and tibialis anterior muscles. |
| Measure | Description | Time Frame |
|---|---|---|
| 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:
| 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. |
| Measure | Description | Time Frame |
|---|---|---|
| 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. | 2 years |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Jerry R Mendell, MD | Director, Center for Gene Therapy, Nationwide Children's Hospital | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Nationwide Children's Hospital | Columbus | Ohio | 43205 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 25322757 | Background | 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. | |
| 20368179 |
| Label | URL |
|---|---|
| Click here for Center for Gene Therapy, The Research Institute at Nationwide Children's Hospital | View source |
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| ID | Title | Description |
|---|---|---|
| FG000 | 2.4E12 vg/kg CMV.huFollistatin344 | Participants enrolled will receive a single dose of 2.4E12 vg/kg (1.2E12vg/kg/limb) of rAAV1.CMV.huFollistatin344 delivered to the lower limbs |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
The Safety Population included all subjects who received one dose of 2.4E12 vg/kg (1.2E12vg/kg/limb) of rAAV1.CMV.huFollistatin344. The Safety Population is the primary analysis population for safety assessments
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| ID | Title | Description |
|---|---|---|
| BG000 | Dose Group 1 | Participants enrolled will receive a single dose of 2.4E12 vg/kg (1.2E12vg/kg/limb) of rAAV1.CMV.huFollistatin344 delivered to the lower limbs |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | 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:
| Safety Population: All subjects who receive a single total dose of 2.4E12 vg/kg (1.2E12vg/kg/limb) of rAAV1.CMV.huFollistatin344. | Posted | Number | Number of Events | 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. |
Adverse events will be recorded from the date of informed consent and for up to 2 years after gene therapy administration, the subject's last study visit. Serious adverse events will be recorded from the date of informed consent and for up to 2 years after gene therapy administration, the subject's last study visit.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | 2.4E12 vg/kg (1.2E12vg/kg/Limb) of rAAV1.CMV.huFollistatin344 | Participants enrolled will receive a total dose of 2.4E12 vg/kg (1.2E12vg/kg/limb) of rAAV1.CMV.huFollistatin344 delivered to the lower limbs |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Head Injury From Fall | Injury, poisoning and procedural complications | Systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Pain | Injury, poisoning and procedural complications | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Jerry Mendell | Nationwide Children's Hospital | 1-614-722-4877 | Jerry.Mendell@nationwidechildrens.org |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Jan 16, 2015 | Oct 3, 2019 | Prot_SAP_000.pdf |
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| ID | Term |
|---|---|
| D020388 | Muscular Dystrophy, Duchenne |
| D009136 | Muscular Dystrophies |
| ID | Term |
|---|---|
| D020966 | Muscular Disorders, Atrophic |
| D009135 | Muscular Diseases |
| D009140 | Musculoskeletal Diseases |
| D009468 | Neuromuscular Diseases |
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| 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) | 180.days |
| 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. | 2 years |
| Background |
| 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. |
| 19208403 | Background | 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. |
| 17164329 | Background | 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. |
| 40152935 | Derived | 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. |
| Participants |
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| Sex: Female, Male | Count of Participants | Participants |
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| Ethnicity (NIH/OMB) | Count of Participants | Participants |
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| Race (NIH/OMB) | Count of Participants | Participants |
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| Region of Enrollment | Number | participants |
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| Secondary | 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. | Participants enrolled will receive a single dose of 2.4E12 vg/kg (1.2E12vg/kg/limb) of rAAV1.CMV.huFollistatin344 delivered to the lower limbs | Posted | Count of Participants | Participants | 2 years |
|
|
|
| Secondary | 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) | All muscle biopsies were canceled per PI discretion due to the disease progression of each participant. | Posted | 180.days |
|
|
| Secondary | 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. | Participants enrolled who receive a single dose of 2.4E12 vg/kg (1.2E12vg/kg/limb) of rAAV1.CMV.huFollistatin344. | Posted | Count of Participants | Participants | 2 years |
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| 0 |
| 3 |
| 1 |
| 3 |
| 3 |
| 3 |
| Pharyngitis | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
|
| Rhinorrhea | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
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| Abrasion | Skin and subcutaneous tissue disorders | Systematic Assessment |
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| Anxiety | Psychiatric disorders | Systematic Assessment |
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| Behavioral Changes/Agitation | Psychiatric disorders | Systematic Assessment |
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| Insomnia | Psychiatric disorders | Systematic Assessment |
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| Bruising | Skin and subcutaneous tissue disorders | Systematic Assessment |
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| GERD | Gastrointestinal disorders | Systematic Assessment |
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| Constipation | Gastrointestinal disorders | Systematic Assessment |
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| Stye | Eye disorders | Systematic Assessment |
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| Increased Muscle Weakness | Musculoskeletal and connective tissue disorders | Systematic Assessment |
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| Compression Fracture | Injury, poisoning and procedural complications | Systematic Assessment |
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| Nasal congestion | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
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| Influenza | Infections and infestations | Systematic Assessment |
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| D009422 | Nervous System Diseases |
| D040181 | Genetic Diseases, X-Linked |
| D030342 | Genetic Diseases, Inborn |
| D009358 | Congenital, Hereditary, and Neonatal Diseases and Abnormalities |