Clinical trial NCT02354781: 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
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Duchenne Muscular Dystrophy
Keywords: DMD
muscular dystrophy
Follistatin
Lead sponsor: Nationwide Children's Hospital
Sponsor class: OTHER
Collaborators: name: Duchenne Alliance
name: Milo Therapeutics
First posted: 2015-02-03
Enrollment: 3
Sex: MALE
Minimum age (years): 7
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: OTHER

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.

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

Primary outcomes:
measure: Number of Dose Limiting Toxicity (DLT) Adverse Events as Assessed by 21 CFR 312.32.
timeFrame: 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 outcomes:
measure: Muscle Function Measured by Six-minute Walk Test (6MWT)
timeFrame: 2 years
measure: Expression of Viral DNA (qPCR), and Follistatin Transgene in Muscle Tissue
timeFrame: 180.days
measure: Improvement of Muscle Function as Measured by North Star Ambulatory Assessment (NSAA)
timeFrame: 2 years
Other outcomes:
Locations:
city: Columbus
country: United States
facility: Nationwide Children's Hospital
state: Ohio
Study officials:
affiliation: Director, Center for Gene Therapy, Nationwide Children's Hospital
name: Jerry R Mendell, MD
role: PRINCIPAL_INVESTIGATOR
References:
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.
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.
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.
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.