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

• Sponsor: Jerry R. Mendell (Other)
• Overall Status: Completed
• CT.gov ID: NCT02354781
• Collaborator: Duchenne Alliance (Other), Milo Therapeutics (Other)
• Enrollment: 3
• Location: 1
• Arm: 1
• Duration (Months): 34
• Patients Per Site Per Month: 0.1

Study Details

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.

Condition or Disease	Intervention/Treatment	Phase
Duchenne Muscular Dystrophy	Biological: rAAV1.CMV.huFollistin344	Phase 1/Phase 2

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 3 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Other
• Official Title: Phase I/II Clinical Intramuscular Gene Transfer of rAAV1.CMV.huFollistatin344 Trial to Patients With Duchenne Muscular Dystrophy
• Study Start Date: Jan 1, 2015
• Actual Primary Completion Date: Nov 1, 2017
• Actual Study Completion Date: Nov 1, 2017

Arms and Interventions

Arm	Intervention/Treatment
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	Biological: 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.

Outcome Measures

Primary Outcome Measures

1. Number of Dose Limiting Toxicity (DLT) Adverse Events as Assessed by 21 CFR 312.32. [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.]

   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

1. Muscle Function Measured by Six-minute Walk Test (6MWT) [2 years]

   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. Expression of Viral DNA (qPCR), and Follistatin Transgene in Muscle Tissue [180.days]

   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)

3. Muscle Function Measured by North Star Ambulatory Assessment (NSAA) [2 years]

   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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 7 Years and Older
• Sexes Eligible for Study: Male
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Nationwide Children's Hospital	Columbus	Ohio	United States	43205

Sponsors and Collaborators

• Jerry R. Mendell
• Duchenne Alliance
• Milo Therapeutics

Investigators

• Principal Investigator: Jerry R Mendell, MD, Director, Center for Gene Therapy, Nationwide Children's Hospital

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Jan 16, 2015

More Information

Additional Information:

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

Publications

• 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.
• 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.
• 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.
• 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.

• Responsible Party: Jerry R. Mendell, Center Director for Gene Therapy, Nationwide Children's Hospital
• ClinicalTrials.gov Identifier: NCT02354781
• Other Study ID Numbers: 14-00630
• First Posted: Feb 3, 2015
• Last Update Posted: Apr 15, 2020
• Last Verified: Apr 1, 2020

• Keywords provided by Jerry R. Mendell, Center Director for Gene Therapy, Nationwide Children's Hospital: DMD; muscular dystrophy; Follistatin
• Additional relevant MeSH terms: Muscular Dystrophies; Muscular Dystrophy, Duchenne

Study Results

Participant Flow

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 Participants	3
Age (Count of Participants)
<=18 years	3 100%
Between 18 and 65 years	0 0%
>=65 years	0 0%
Sex: Female, Male (Count of Participants)
Female	0 0%
Male	3 100%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%
Not Hispanic or Latino	3 100%
Unknown or Not Reported	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	0 0%
White	3 100%
More than one race	0 0%
Unknown or Not Reported	0 0%
Region of Enrollment (participants) [Number]
United States	3 100%

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.
Measure Participants	3
Number [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
Measure Participants	3
Count of Participants [Participants]	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.
Measure Participants	3
Count of Participants [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.
Measure Participants	3
Count of Participants [Participants]	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.
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 (%)	# Events
Total	0/3 (0%)
Serious Adverse Events
	2.4E12 vg/kg (1.2E12vg/kg/Limb) of rAAV1.CMV.huFollistatin344
	Affected / at Risk (%)	# Events
Total	1/3 (33.3%)
Injury, poisoning and procedural complications
Head Injury From Fall	1/3 (33.3%)	1
Other (Not Including Serious) Adverse Events
	2.4E12 vg/kg (1.2E12vg/kg/Limb) of rAAV1.CMV.huFollistatin344
	Affected / at Risk (%)	# Events
Total	3/3 (100%)
Eye disorders
Stye	1/3 (33.3%)	1
Gastrointestinal disorders
GERD	1/3 (33.3%)	1
Constipation	1/3 (33.3%)	1
Infections and infestations
Influenza	1/3 (33.3%)	1
Injury, poisoning and procedural complications
Pain	3/3 (100%)	5
Compression Fracture	1/3 (33.3%)	1
Musculoskeletal and connective tissue disorders
Increased Muscle Weakness	1/3 (33.3%)	1
Psychiatric disorders
Anxiety	1/3 (33.3%)	2
Behavioral Changes/Agitation	1/3 (33.3%)	1
Insomnia	1/3 (33.3%)	1
Respiratory, thoracic and mediastinal disorders
Pharyngitis	1/3 (33.3%)	1
Rhinorrhea	1/3 (33.3%)	1
Nasal congestion	1/3 (33.3%)	1
Skin and subcutaneous tissue disorders
Abrasion	1/3 (33.3%)	2
Bruising	2/3 (66.7%)	3

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.