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

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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:
Collaborators:
Duchenne Alliance
Milo Therapeutics
Information provided by (Responsible Party):
Jerry R. Mendell, Nationwide Children's Hospital

Tracking Information
First Submitted Date  ICMJE January 26, 2015
First Posted Date  ICMJE February 3, 2015
Results First Submitted Date  ICMJE January 24, 2020
Results First Posted Date  ICMJE April 15, 2020
Last Update Posted Date April 15, 2020
Study Start Date  ICMJE January 2015
Actual Primary Completion Date November 2017   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: April 1, 2020)
Number of Dose Limiting Toxicity (DLT) Adverse Events as Assessed by 21 CFR 312.32. [ 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. ]
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:
  1. Mild adverse event; did not require treatment
  2. Moderate adverse event; resolved with treatment
  3. Severe adverse event; inability to carry on normal activities; required professional medical attention
  4. Life-threatening or permanently disabling adverse event
  5. Fatal adverse event In this grading system, "severe" is not equivalent to seriousness.
Original Primary Outcome Measures  ICMJE
 (submitted: February 2, 2015)
Organ system toxicity based on blood chemistries and immune studies [ Time Frame: 2 years ]
The blood chemistries and immune studies to monitor organs system abnormalities and T cell response measured by ELISpots.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: April 1, 2020)
  • Muscle Function Measured by Six-minute Walk Test (6MWT) [ Time Frame: 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.
  • Expression of Viral DNA (qPCR), and Follistatin Transgene in Muscle Tissue [ Time Frame: 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)
  • Muscle Function Measured by North Star Ambulatory Assessment (NSAA) [ Time Frame: 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.
Original Secondary Outcome Measures  ICMJE
 (submitted: February 2, 2015)
  • Muscle Function [ Time Frame: 2 years ]
    The distance walked on the 6MWT is the major functional outcome to be evaluated.
  • Size of muscle fibers with lack of toxicity of follistatin following gene transfer [ Time Frame: 2 years ]
    • 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.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Clinical Intramuscular Gene Transfer of rAAV1.CMV.huFollistatin344 Trial to Patients With Duchenne Muscular Dystrophy
Official Title  ICMJE Phase I/II Clinical Intramuscular Gene Transfer of rAAV1.CMV.huFollistatin344 Trial to Patients With Duchenne Muscular Dystrophy
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.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Other
Condition  ICMJE Duchenne Muscular Dystrophy
Intervention  ICMJE 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.
Study Arms  ICMJE 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
Intervention: Biological: rAAV1.CMV.huFollistin344
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: November 29, 2017)
3
Original Estimated Enrollment  ICMJE
 (submitted: February 2, 2015)
6
Actual Study Completion Date  ICMJE November 2017
Actual Primary Completion Date November 2017   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: Male
Ages  ICMJE 7 Years and older   (Child, Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02354781
Other Study ID Numbers  ICMJE 14-00630
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Jerry R. Mendell, Nationwide Children's Hospital
Study Sponsor  ICMJE Jerry R. Mendell
Collaborators  ICMJE
  • Duchenne Alliance
  • Milo Therapeutics
Investigators  ICMJE
Principal Investigator: Jerry R Mendell, MD Director, Center for Gene Therapy, Nationwide Children's Hospital
PRS Account Nationwide Children's Hospital
Verification Date April 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP