- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT03333590
Gene Transfer Clinical Trial to Deliver rAAVrh74.MCK.GALGT2 for Duchenne Muscular Dystrophy
Phase I/IIa Gene Transfer Clinical Trial for Duchenne Muscular Dystrophy Using rAAVrh74.MCK.GALGT2
Study Overview
Status
Conditions
Intervention / Treatment
Detailed Description
This is an open-label, dose escalation trial where the vector will be delivered via the femoral artery to the muscles of both legs of DMD subjects.
The primary objective of this study is the assessment of the safety of intravascular administration of rAAVrh74.MCK.GALGT2 to DMD patients. Safety endpoints will be assessed by changes in hematology, serum chemistry, urinalysis, immunologic response to rAAVrh74 and GALGT2, and reported history and observations of symptoms. Efficacy measures will be used as secondary outcome for this disorder including a combination of functional 6 minute walk test (6MWT) and direct muscle testing for strength (MVICT) of lower limb muscles.
Subjects will be evaluated at baseline, infusion visit (days 0-2), and return for follow up visits on days 7, 14, 30, 60, 90, and 180 and months 12, 18 and 24
Study Type
Enrollment (Actual)
Phase
- Phase 2
- Phase 1
Contacts and Locations
Study Locations
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Ohio
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Columbus, Ohio, United States, 43205
- Nationwide Children's Hospital
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Description
Inclusion Criteria
- Ambulant patients age 4 years or older
- Confirmed mutations in the DMD gene using a clinical accepted technique that completely defines the mutation 1,2
• Measurably impaired muscle function (defined as less than 80% of the predicted value for 100 MWT), but with sufficient muscle preservation to ensure assessment of muscle transfection based on clinical evaluation by the PI and expert colleagues. This degree of preservation will include:
- Ability to extend the knee fully against gravity
- Preserved ambulation with ability to walk ≥ 350 meters during the 6MWT
- A magnetic resonance image of the quadriceps showing preservation of sufficient muscle mass to permit transfection
- Males of any ethnic group will be eligible
- Ability to cooperate with muscle testing
- Stable daily dose of corticosteroid therapy (including either prednisone, prednisolone, deflazacort or their generic forms) for 12 weeks prior to gene transfer
Exclusion Criteria
- Active viral infection based on clinical observations
- The presence of a DMD mutation without weakness or loss of function
- Subject is amenable to or is currently being treated with eteplirsen
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 B or C infection
- Diagnosis of (or ongoing treatment for) an autoimmune disease
- Persistent leukopenia or leukocytosis (WBC ≤ 3.5 K/µL or ≥ 20.0 K/µL) or an absolute neutrophil count < 1.5K/µL
- Concomitant illness or requirement for chronic drug treatment that in the opinion of the PI creates unnecessary risks for gene transfer
- Subjects with rAAVrh74 binding antibody titers ≥ 1:50 as determined by ELISA immunoassay
- Presence of circulating anti-Sda antibodies as determined by study approved laboratory
- Abnormal laboratory values in the clinically significant range, based upon normal values in the Nationwide Children's Hospital Laboratory
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Non-Randomized
- Interventional Model: Single Group Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
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Experimental: Cohort 1 (Minimal Efficacious Dose) rAAVrh74.MCK.GALGT2
N = 3 [2.5 x E13 vg/kg per leg, delivered bilaterally (total 5.0 x E13 vg/kg)]
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Adeno-associated virus serotype rh74 carrying the GALGT2 gene under the control of a MCK promoter (rAAVrh74.MCK.GALGT2) will be delivered one time to each of the lower limbs through the femoral artery using an intravascular limb infusion technique (ILI)
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Experimental: Cohort 2 (Dose Escalation) rAAVrh74.MCK.GALGT2
N=3 [5 x E13 vg/kg per leg, delivered bilaterally (total 1.0 x E14 vg/kg)]
|
Adeno-associated virus serotype rh74 carrying the GALGT2 gene under the control of a MCK promoter (rAAVrh74.MCK.GALGT2) will be delivered one time to each of the lower limbs through the femoral artery using an intravascular limb infusion technique (ILI)
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Time Frame |
---|---|
Number of Unanticipated Grade III or Higher Treatment-Related Toxicities
Time Frame: 2 years
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2 years
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Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Expression of GALGT2 as Demonstrated by Immunofluorescent Staining With Anti-CT Epitope Antibodies or WFA Lectin in Muscle Biopsy Sections at 120 Days Post Injection (Cohort 1) and 90 Days Post-injection (Cohort 2).
Time Frame: Day 90 (Cohort 2) and Day 120 (Cohort 1)
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Percentage of fibers expressing GALGT2 in each biopsy sample.
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Day 90 (Cohort 2) and Day 120 (Cohort 1)
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GALGT2 Protein Expression Quantified by Western Blot and Assessed by Densitometry in Muscle Biopsy Tissue at 120 Days Post-injection (Cohort 1) and 90 Days Post-injection (Cohort 2)
Time Frame: Day 90 (Cohort 2) and Day 120 (Cohort 1)
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Day 90 (Cohort 2) and Day 120 (Cohort 1)
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Other Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Number of Meters Walked During the 6 Minute Walk Test
Time Frame: Day 90 (Cohort 2) and Day 120 (Cohort 1) and Day 180 for both cohorts
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Day 90 (Cohort 2) and Day 120 (Cohort 1) and Day 180 for both cohorts
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Strength of the Bilateral Knee Flexors and Extensors During the Maximal Voluntary Isometric Strength Test.
Time Frame: Days 90 (Cohort 2), 120 (Cohort 1) and both Cohorts at Day 180, Months 12, 18 and 24
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Days 90 (Cohort 2), 120 (Cohort 1) and both Cohorts at Day 180, Months 12, 18 and 24
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Time Taken to Walk 100 Meters During the 100 Meter Walk Test.
Time Frame: Days 90 (Cohort 2), 120 (Cohort 1); both Cohorts at Day 180, Months 12, 18 and Cohort 2 at Month 24
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Days 90 (Cohort 2), 120 (Cohort 1); both Cohorts at Day 180, Months 12, 18 and Cohort 2 at Month 24
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Score of Muscle Function Using the The North Star Ambulatory Assessment (NSAA).
Time Frame: Days 90 (Cohort 2), 120 (Cohort 1) and both Cohorts at Day 180, Months 12, 18 and 24
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The NSAA provides a score between 0 and 34 where higher numbers represent greater muscle function.
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Days 90 (Cohort 2), 120 (Cohort 1) and both Cohorts at Day 180, Months 12, 18 and 24
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Collaborators and Investigators
Sponsor
Investigators
- Principal Investigator: Kevin Flanigan, MD, Nationwide Children's Hospital
Publications and helpful links
General Publications
- Mendell JR, Rodino-Klapac LR, Rosales XQ, Coley BD, Galloway G, Lewis S, Malik V, Shilling C, Byrne BJ, Conlon T, Campbell KJ, Bremer WG, Taylor LE, Flanigan KM, Gastier-Foster JM, Astbury C, Kota J, Sahenk Z, Walker CM, Clark KR. Sustained alpha-sarcoglycan gene expression after gene transfer in limb-girdle muscular dystrophy, type 2D. Ann Neurol. 2010 Nov;68(5):629-38. doi: 10.1002/ana.22251.
- Mendell JR, Rodino-Klapac LR, Sahenk Z, Roush K, Bird L, Lowes LP, Alfano L, Gomez AM, Lewis S, Kota J, Malik V, Shontz K, Walker CM, Flanigan KM, Corridore M, Kean JR, Allen HD, Shilling C, Melia KR, Sazani P, Saoud JB, Kaye EM; Eteplirsen Study Group. Eteplirsen for the treatment of Duchenne muscular dystrophy. Ann Neurol. 2013 Nov;74(5):637-47. doi: 10.1002/ana.23982. Epub 2013 Sep 10.
- Mendell JR, Goemans N, Lowes LP, Alfano LN, Berry K, Shao J, Kaye EM, Mercuri E; Eteplirsen Study Group and Telethon Foundation DMD Italian Network. Longitudinal effect of eteplirsen versus historical control on ambulation in Duchenne muscular dystrophy. Ann Neurol. 2016 Feb;79(2):257-71. doi: 10.1002/ana.24555. Epub 2016 Jan 8.
- Mendell JR, Moxley RT, Griggs RC, Brooke MH, Fenichel GM, Miller JP, King W, Signore L, Pandya S, Florence J, et al. Randomized, double-blind six-month trial of prednisone in Duchenne's muscular dystrophy. N Engl J Med. 1989 Jun 15;320(24):1592-7. doi: 10.1056/NEJM198906153202405.
- Chicoine LG, Rodino-Klapac LR, Shao G, Xu R, Bremer WG, Camboni M, Golden B, Montgomery CL, Shontz K, Heller KN, Griffin DA, Lewis S, Coley BD, Walker CM, Clark KR, Sahenk Z, Mendell JR, Martin PT. Vascular delivery of rAAVrh74.MCK.GALGT2 to the gastrocnemius muscle of the rhesus macaque stimulates the expression of dystrophin and laminin alpha2 surrogates. Mol Ther. 2014 Apr;22(4):713-24. doi: 10.1038/mt.2013.246. Epub 2013 Oct 22.
- Biggar WD, Harris VA, Eliasoph L, Alman B. Long-term benefits of deflazacort treatment for boys with Duchenne muscular dystrophy in their second decade. Neuromuscul Disord. 2006 Apr;16(4):249-55. doi: 10.1016/j.nmd.2006.01.010. Epub 2006 Mar 20.
- Brooke MH, Fenichel GM, Griggs RC, Mendell JR, Moxley R, Miller JP, Province MA. Clinical investigation in Duchenne dystrophy: 2. Determination of the "power" of therapeutic trials based on the natural history. Muscle Nerve. 1983 Feb;6(2):91-103. doi: 10.1002/mus.880060204.
- Eagle M, Baudouin SV, Chandler C, Giddings DR, Bullock R, Bushby K. Survival in Duchenne muscular dystrophy: improvements in life expectancy since 1967 and the impact of home nocturnal ventilation. Neuromuscul Disord. 2002 Dec;12(10):926-9. doi: 10.1016/s0960-8966(02)00140-2.
- Griggs RC, Moxley RT 3rd, Mendell JR, Fenichel GM, Brooke MH, Pestronk A, Miller JP. Prednisone in Duchenne dystrophy. A randomized, controlled trial defining the time course and dose response. Clinical Investigation of Duchenne Dystrophy Group. Arch Neurol. 1991 Apr;48(4):383-8. doi: 10.1001/archneur.1991.00530160047012.
- Rodino-Klapac LR, Montgomery CL, Mendell JR, Chicoine LG. AAV-mediated gene therapy to the isolated limb in rhesus macaques. Methods Mol Biol. 2011;709:287-98. doi: 10.1007/978-1-61737-982-6_19.
- Rodino-Klapac LR, Montgomery CL, Bremer WG, Shontz KM, Malik V, Davis N, Sprinkle S, Campbell KJ, Sahenk Z, Clark KR, Walker CM, Mendell JR, Chicoine LG. Persistent expression of FLAG-tagged micro dystrophin in nonhuman primates following intramuscular and vascular delivery. Mol Ther. 2010 Jan;18(1):109-17. doi: 10.1038/mt.2009.254. Epub 2009 Nov 10.
- Rodino-Klapac LR, Janssen PM, Montgomery CL, Coley BD, Chicoine LG, Clark KR, Mendell JR. A translational approach for limb vascular delivery of the micro-dystrophin gene without high volume or high pressure for treatment of Duchenne muscular dystrophy. J Transl Med. 2007 Sep 24;5:45. doi: 10.1186/1479-5876-5-45.
- Flanigan KM, von Niederhausern A, Dunn DM, Alder J, Mendell JR, Weiss RB. Rapid direct sequence analysis of the dystrophin gene. Am J Hum Genet. 2003 Apr;72(4):931-9. doi: 10.1086/374176. Epub 2003 Mar 11.
- Seinen JM, Hoekstra HJ. Isolated limb perfusion of soft tissue sarcomas: a comprehensive review of literature. Cancer Treat Rev. 2013 Oct;39(6):569-77. doi: 10.1016/j.ctrv.2012.10.005. Epub 2012 Dec 8.
- Mendell JR, Shilling C, Leslie ND, Flanigan KM, al-Dahhak R, Gastier-Foster J, Kneile K, Dunn DM, Duval B, Aoyagi A, Hamil C, Mahmoud M, Roush K, Bird L, Rankin C, Lilly H, Street N, Chandrasekar R, Weiss RB. Evidence-based path to newborn screening for Duchenne muscular dystrophy. Ann Neurol. 2012 Mar;71(3):304-13. doi: 10.1002/ana.23528.
- Koenig M, Hoffman EP, Bertelson CJ, Monaco AP, Feener C, Kunkel LM. Complete cloning of the Duchenne muscular dystrophy (DMD) cDNA and preliminary genomic organization of the DMD gene in normal and affected individuals. Cell. 1987 Jul 31;50(3):509-17. doi: 10.1016/0092-8674(87)90504-6.
- Bonilla E, Samitt CE, Miranda AF, Hays AP, Salviati G, DiMauro S, Kunkel LM, Hoffman EP, Rowland LP. Duchenne muscular dystrophy: deficiency of dystrophin at the muscle cell surface. Cell. 1988 Aug 12;54(4):447-52. doi: 10.1016/0092-8674(88)90065-7.
- Oudet C, Hanauer A, Clemens P, Caskey T, Mandel JL. Two hot spots of recombination in the DMD gene correlate with the deletion prone regions. Hum Mol Genet. 1992 Nov;1(8):599-603. doi: 10.1093/hmg/1.8.599.
- Beggs AH, Koenig M, Boyce FM, Kunkel LM. Detection of 98% of DMD/BMD gene deletions by polymerase chain reaction. Hum Genet. 1990 Nov;86(1):45-8. doi: 10.1007/BF00205170.
- Chamberlain JS, Gibbs RA, Ranier JE, Nguyen PN, Caskey CT. Deletion screening of the Duchenne muscular dystrophy locus via multiplex DNA amplification. Nucleic Acids Res. 1988 Dec 9;16(23):11141-56. doi: 10.1093/nar/16.23.11141.
- Lalic T, Vossen RH, Coffa J, Schouten JP, Guc-Scekic M, Radivojevic D, Djurisic M, Breuning MH, White SJ, den Dunnen JT. Deletion and duplication screening in the DMD gene using MLPA. Eur J Hum Genet. 2005 Nov;13(11):1231-4. doi: 10.1038/sj.ejhg.5201465.
- Dent KM, Dunn DM, von Niederhausern AC, Aoyagi AT, Kerr L, Bromberg MB, Hart KJ, Tuohy T, White S, den Dunnen JT, Weiss RB, Flanigan KM. Improved molecular diagnosis of dystrophinopathies in an unselected clinical cohort. Am J Med Genet A. 2005 Apr 30;134(3):295-8. doi: 10.1002/ajmg.a.30617.
- Balaban B, Matthews DJ, Clayton GH, Carry T. Corticosteroid treatment and functional improvement in Duchenne muscular dystrophy: long-term effect. Am J Phys Med Rehabil. 2005 Nov;84(11):843-50. doi: 10.1097/01.phm.0000184156.98671.d0.
- Bushby K, Finkel R, Wong B, Barohn R, Campbell C, Comi GP, Connolly AM, Day JW, Flanigan KM, Goemans N, Jones KJ, Mercuri E, Quinlivan R, Renfroe JB, Russman B, Ryan MM, Tulinius M, Voit T, Moore SA, Lee Sweeney H, Abresch RT, Coleman KL, Eagle M, Florence J, Gappmaier E, Glanzman AM, Henricson E, Barth J, Elfring GL, Reha A, Spiegel RJ, O'donnell MW, Peltz SW, Mcdonald CM; PTC124-GD-007-DMD STUDY GROUP. Ataluren treatment of patients with nonsense mutation dystrophinopathy. Muscle Nerve. 2014 Oct;50(4):477-87. doi: 10.1002/mus.24332.
- Finkel RS, Flanigan KM, Wong B, Bonnemann C, Sampson J, Sweeney HL, Reha A, Northcutt VJ, Elfring G, Barth J, Peltz SW. Phase 2a study of ataluren-mediated dystrophin production in patients with nonsense mutation Duchenne muscular dystrophy. PLoS One. 2013 Dec 11;8(12):e81302. doi: 10.1371/journal.pone.0081302. eCollection 2013.
- Harper SQ, Hauser MA, DelloRusso C, Duan D, Crawford RW, Phelps SF, Harper HA, Robinson AS, Engelhardt JF, Brooks SV, Chamberlain JS. Modular flexibility of dystrophin: implications for gene therapy of Duchenne muscular dystrophy. Nat Med. 2002 Mar;8(3):253-61. doi: 10.1038/nm0302-253.
- Gregorevic P, Blankinship MJ, Allen JM, Crawford RW, Meuse L, Miller DG, Russell DW, Chamberlain JS. Systemic delivery of genes to striated muscles using adeno-associated viral vectors. Nat Med. 2004 Aug;10(8):828-34. doi: 10.1038/nm1085. Epub 2004 Jul 25.
- Xu R, DeVries S, Camboni M, Martin PT. Overexpression of Galgt2 reduces dystrophic pathology in the skeletal muscles of alpha sarcoglycan-deficient mice. Am J Pathol. 2009 Jul;175(1):235-47. doi: 10.2353/ajpath.2009.080967. Epub 2009 Jun 4.
- Xu R, Chandrasekharan K, Yoon JH, Camboni M, Martin PT. Overexpression of the cytotoxic T cell (CT) carbohydrate inhibits muscular dystrophy in the dyW mouse model of congenital muscular dystrophy 1A. Am J Pathol. 2007 Jul;171(1):181-99. doi: 10.2353/ajpath.2007.060927.
- Liu G, McNicol PL, Macall P, Bellomo R, Przybylowski G, Bowkett J, Connellan J, McInnes F, Thurlow PJ. The Effect of Preoperative Aspirin and/or Heparin Therapy on Coagulation and Postoperative Blood Loss after Coronary Artery Bypass Surgery. Crit Care Resusc. 1999 Jun;1(2):139.
- Veikutiene A, Sirvinskas E, Grybauskas P, Cimbolaityte J, Mongirdiene A, Veikutis V. [Influence of preoperative treatment with aspirin or heparin on platelet function and intensity of postoperative bleeding in early period after coronary artery bypass surgery]. Medicina (Kaunas). 2005;41(7):577-83. Lithuanian.
- Sun JC, Crowther MA, Warkentin TE, Lamy A, Teoh KH. Should aspirin be discontinued before coronary artery bypass surgery? Circulation. 2005 Aug 16;112(7):e85-90. doi: 10.1161/CIRCULATIONAHA.105.546697. No abstract available.
- Taylor LE, Kaminoh YJ, Rodesch CK, Flanigan KM. Quantification of dystrophin immunofluorescence in dystrophinopathy muscle specimens. Neuropathol Appl Neurobiol. 2012 Oct;38(6):591-601. doi: 10.1111/j.1365-2990.2012.01250.x.
- Anthony K, Arechavala-Gomeza V, Taylor LE, Vulin A, Kaminoh Y, Torelli S, Feng L, Janghra N, Bonne G, Beuvin M, Barresi R, Henderson M, Laval S, Lourbakos A, Campion G, Straub V, Voit T, Sewry CA, Morgan JE, Flanigan KM, Muntoni F. Dystrophin quantification: Biological and translational research implications. Neurology. 2014 Nov 25;83(22):2062-9. doi: 10.1212/WNL.0000000000001025. Epub 2014 Oct 29.
- Flanigan KM, Dunn DM, von Niederhausern A, Soltanzadeh P, Gappmaier E, Howard MT, Sampson JB, Mendell JR, Wall C, King WM, Pestronk A, Florence JM, Connolly AM, Mathews KD, Stephan CM, Laubenthal KS, Wong BL, Morehart PJ, Meyer A, Finkel RS, Bonnemann CG, Medne L, Day JW, Dalton JC, Margolis MK, Hinton VJ; United Dystrophinopathy Project Consortium; Weiss RB. Mutational spectrum of DMD mutations in dystrophinopathy patients: application of modern diagnostic techniques to a large cohort. Hum Mutat. 2009 Dec;30(12):1657-66. doi: 10.1002/humu.21114.
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Actual)
Study Completion (Estimated)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
Other Study ID Numbers
- GALGT2 Gene Therapy for DMD
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
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