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

• ClinicalTrials.gov Identifier: NCT02354781
• Recruitment Status: Completed
• First Posted: February 3, 2015
• Results First Posted: April 15, 2020
• Last Update Posted: April 15, 2020
• Sponsor: Jerry R. Mendell
• Collaborators: Duchenne Alliance; Milo Therapeutics
• Information provided by (Responsible Party): Jerry R. Mendell, Nationwide Children's Hospital

• Study Type: Interventional
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Other
• Condition: Duchenne Muscular Dystrophy
• Intervention: Biological: rAAV1.CMV.huFollistin344
• Enrollment: 3

Participant Flow

Recruitment Details
Pre-assignment Details

Arm/Group Title	2.4E12 vg/kg CMV.huFollistatin344
Arm/Group Description	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
Period Title: Overall Study
Started	3
Completed	3
Not Completed	0

Baseline Characteristics

Arm/Group Title		Dose Group 1
Arm/Group Description		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
Overall Number of Baseline Participants		3
Baseline Analysis Population Description		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
Age, Categorical; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	3 participants
	<=18 years	3 100.0%
	Between 18 and 65 years	0 0.0%
	>=65 years	0 0.0%
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	3 participants
	Female	0 0.0%
	Male	3 100.0%
Ethnicity (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	3 participants
	Hispanic or Latino	0 0.0%
	Not Hispanic or Latino	3 100.0%
	Unknown or Not Reported	0 0.0%
Race (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	3 participants
	American Indian or Alaska Native	0 0.0%
	Asian	0 0.0%
	Native Hawaiian or Other Pacific Islander	0 0.0%
	Black or African American	0 0.0%
	White	3 100.0%
	More than one race	0 0.0%
	Unknown or Not Reported	0 0.0%
Region of Enrollment; Measure Type: Number; Unit of measure: Participants
United States	Number Analyzed	3 participants
		3

Outcome Measures

1. Primary Outcome

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.

Outcome Measure Data

Analysis Population Description

Safety Population: All subjects who receive a single total dose of 2.4E12 vg/kg (1.2E12vg/kg/limb) of rAAV1.CMV.huFollistatin344.

Arm/Group Title	2.4E12 vg/kg CMV.huFollistatin344
Arm/Group Description:	Participants enrolled who receive a total dose of 2.4E12 vg/kg (1.2E12vg/kg/limb) of rAAV1.CMV.huFollistatin344.
Overall Number of Participants Analyzed	3
Measure Type: Number; Unit of Measure: Number of Events
	0

2. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	2.4E12 vg/kg CMV.huFollistatin344
Arm/Group Description:	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
Overall Number of Participants Analyzed	3
Measure Type: Count of Participants; Unit of Measure: Participants
	0 0.0%

3. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	2.4E12 vg/kg CMV.huFollistatin344
Arm/Group Description:	Participants enrolled who receive a total dose of 2.4E12 vg/kg (1.2E12vg/kg/limb) of rAAV1.CMV.huFollistatin344.
Overall Number of Participants Analyzed	3
Measure Type: Count of Participants; Unit of Measure: Participants
	1 33.3%

4. Secondary Outcome

Title	Muscle Function 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

Outcome Measure Data

Analysis Population Description

Participants enrolled who receive a single dose of 2.4E12 vg/kg (1.2E12vg/kg/limb) of rAAV1.CMV.huFollistatin344.

Arm/Group Title	2.4E12 vg/kg CMV.huFollistatin344
Arm/Group Description:	Participants enrolled who receive a total dose of 2.4E12 vg/kg (1.2E12vg/kg/limb) of rAAV1.CMV.huFollistatin344.
Overall Number of Participants Analyzed	3
Measure Type: Count of Participants; Unit of Measure: Participants
	0 0.0%

Adverse Events

Time Frame	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.
Adverse Event Reporting Description	[Not Specified]
Arm/Group Title	2.4E12 vg/kg (1.2E12vg/kg/Limb) of rAAV1.CMV.huFollistatin344
Arm/Group Description	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
All-Cause Mortality
	2.4E12 vg/kg (1.2E12vg/kg/Limb) of rAAV1.CMV.huFollistatin344
	Affected / at Risk (%)
Total	0/3 (0.00%)
Serious Adverse Events
	2.4E12 vg/kg (1.2E12vg/kg/Limb) of rAAV1.CMV.huFollistatin344
	Affected / at Risk (%)	# Events
Total	1/3 (33.33%)
Injury, poisoning and procedural complications
Head Injury From Fall †	1/3 (33.33%)	1
† Indicates events were collected by systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	0%
	2.4E12 vg/kg (1.2E12vg/kg/Limb) of rAAV1.CMV.huFollistatin344
	Affected / at Risk (%)	# Events
Total	3/3 (100.00%)
Eye disorders
Stye †	1/3 (33.33%)	1
Gastrointestinal disorders
GERD †	1/3 (33.33%)	1
Constipation †	1/3 (33.33%)	1
Infections and infestations
Influenza †	1/3 (33.33%)	1
Injury, poisoning and procedural complications
Pain †	3/3 (100.00%)	5
Compression Fracture †	1/3 (33.33%)	1
Musculoskeletal and connective tissue disorders
Increased Muscle Weakness †	1/3 (33.33%)	1
Psychiatric disorders
Anxiety †	1/3 (33.33%)	2
Behavioral Changes/Agitation †	1/3 (33.33%)	1
Insomnia †	1/3 (33.33%)	1
Respiratory, thoracic and mediastinal disorders
Pharyngitis †	1/3 (33.33%)	1
Rhinorrhea †	1/3 (33.33%)	1
Nasal congestion †	1/3 (33.33%)	1
Skin and subcutaneous tissue disorders
Abrasion †	1/3 (33.33%)	2
Bruising †	2/3 (66.67%)	3
† Indicates events were collected by systematic assessment

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

Results Point of Contact

• Name/Title: Dr. Jerry Mendell
• Organization: Nationwide Children's Hospital
• Phone: 1-614-722-4877
• EMail: Jerry.Mendell@nationwidechildrens.org

Publications:

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.

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.

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. Review.

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. Epub 2006 Dec 12.

• Responsible Party: Jerry R. Mendell, Nationwide Children's Hospital
• ClinicalTrials.gov Identifier: NCT02354781
• Other Study ID Numbers: 14-00630
• First Submitted: January 26, 2015
• First Posted: February 3, 2015
• Results First Submitted: January 24, 2020
• Results First Posted: April 15, 2020
• Last Update Posted: April 15, 2020