Gene Transfer Clinical Trial to Deliver rAAVrh74.MCK.GALGT2 for Duchenne Muscular Dystrophy

• Sponsor: Kevin Flanigan (Other)
• Overall Status: Active, not recruiting
• CT.gov ID: NCT03333590
• Collaborator: (none)
• Enrollment: 2
• Location: 1
• Arms: 2
• Anticipated Duration (Months): 70.8
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

The proposed clinical trial study of rAAVrh74.MCK.GALGT2 for duchenne muscular dystrophy (DMD) patients. There will be a modified intravascular limb infusion (ILI) procedure that will be used to sequentially deliver vector to each whole lower limb of DMD subjects via a major lower limb artery.

Condition or Disease	Intervention/Treatment	Phase
Duchenne Muscular Dystrophy	Biological: rAAVrh74.MCK.GALGT2	Phase 1/Phase 2

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 Design

• Study Type: Interventional
• Actual Enrollment: 2 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Intervention Model Description: This is a dose escalation trial that will begin with the minimal efficacious dose as determined by preclinical studies and approved by the FDA. During the course of the trial, if safety is shown the dose will be escalated according to the clinical protocol.This is a dose escalation trial that will begin with the minimal efficacious dose as determined by preclinical studies and approved by the FDA. During the course of the trial, if safety is shown the dose will be escalated according to the clinical protocol.
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase I/IIa Gene Transfer Clinical Trial for Duchenne Muscular Dystrophy Using rAAVrh74.MCK.GALGT2
• Actual Study Start Date: Nov 6, 2017
• Actual Primary Completion Date: Nov 4, 2020
• Anticipated Study Completion Date: Oct 1, 2023

Arms and Interventions

Arm	Intervention/Treatment
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)]	Biological: rAAVrh74.MCK.GALGT2; 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)
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)]	Biological: rAAVrh74.MCK.GALGT2; 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)

Outcome Measures

Primary Outcome Measures

1. Number of Unanticipated Grade III or Higher Treatment-Related Toxicities [2 years]

Secondary Outcome Measures

1. 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). [Day 90 (Cohort 2) and Day 120 (Cohort 1)]

   Percentage of fibers expressing GALGT2 in each biopsy sample.

2. 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) [Day 90 (Cohort 2) and Day 120 (Cohort 1)]

Other Outcome Measures

1. Number of Meters Walked During the 6 Minute Walk Test [Day 90 (Cohort 2) and Day 120 (Cohort 1) and Day 180 for both cohorts]

2. Strength of the Bilateral Knee Flexors and Extensors During the Maximal Voluntary Isometric Strength Test. [Days 90 (Cohort 2), 120 (Cohort 1) and both Cohorts at Day 180, Months 12, 18 and 24]

3. Time Taken to Walk 100 Meters During the 100 Meter Walk Test. [Days 90 (Cohort 2), 120 (Cohort 1); both Cohorts at Day 180, Months 12, 18 and Cohort 2 at Month 24]

4. Score of Muscle Function Using the The North Star Ambulatory Assessment (NSAA). [Days 90 (Cohort 2), 120 (Cohort 1) and both Cohorts at Day 180, Months 12, 18 and 24]

   The NSAA provides a score between 0 and 34 where higher numbers represent greater muscle function.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 4 Years and Older
• Sexes Eligible for Study: Male
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

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

Sponsors and Collaborators

• Kevin Flanigan

Investigators

• Principal Investigator: Kevin Flanigan, MD, Nationwide Children's Hospital

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Mar 27, 2019

More Information

Publications

• 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.
• 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.
• 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.
• 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. Epub 2006 Mar 20.
• 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.
• 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.
• 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.
• 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.
• 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 α2 surrogates. Mol Ther. 2014 Apr;22(4):713-24. doi: 10.1038/mt.2013.246. Epub 2013 Oct 22.
• 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.
• 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.
• Finkel RS, Flanigan KM, Wong B, Bönnemann 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.
• 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.
• 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. Epub 2003 Mar 11.
• 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. Epub 2004 Jul 25.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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, 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.
• 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.
• 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.
• 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, 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.
• 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. Review.
• 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.
• 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.
• 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.
• 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.
• 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.

• Responsible Party: Kevin Flanigan, Professor of Pediatrics, Nationwide Children's Hospital
• ClinicalTrials.gov Identifier: NCT03333590
• Other Study ID Numbers: GALGT2 Gene Therapy for DMD
• First Posted: Nov 7, 2017
• Last Update Posted: Jul 29, 2022
• Last Verified: Jul 1, 2022

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Kevin Flanigan, Professor of Pediatrics, Nationwide Children's Hospital: DMD; Duchenne Muscular Dystrophy
• Additional relevant MeSH terms: Muscular Dystrophies; Muscular Dystrophy, Duchenne

Study Results

Participant Flow

Arm/Group Title	Cohort 1 (Minimal Efficacious Dose) rAAVrh74.MCK.GALGT2	Cohort 2 (Minimal Efficacious Dose) rAAVrh74.MCK.GALGT2
Arm/Group Description	N = 3 [2.5 x E13 vg/kg per leg, delivered bilaterally (total 5.0 x E13 vg/kg)] rAAVrh74.MCK.GALGT2: 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)	N = 3 [5 x E13 vg/kg per leg, delivered bilaterally (total 1.0 x E14 vg/kg)] rAAVrh74.MCK.GALGT2: 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)
Period Title: Overall Study
STARTED	1	1
COMPLETED	1	1
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Cohort 1 (Minimal Efficacious Dose) rAAVrh74.MCK.GALGT2	Cohort 2 (Dose Escalation) rAAVrh74.MCK.GALGT2	Total
Arm/Group Description	N = 3 [2.5 x E13 vg/kg per leg, delivered bilaterally (total 5.0 x E13 vg/kg)] rAAVrh74.MCK.GALGT2: 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)	N=3 [5 x E13 vg/kg per leg, delivered bilaterally (total 1.0 x E14 vg/kg)] rAAVrh74.MCK.GALGT2: 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)	Total of all reporting groups
Overall Participants	1	1	2
Age (years) [Mean (Full Range) ]
Mean (Full Range) [years]	9	7	8
Sex: Female, Male (Count of Participants)
Female	0 0%	0 0%	0 0%
Male	1 100%	1 100%	2 100%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%	0 0%	0 0%
Not Hispanic or Latino	1 100%	1 100%	2 100%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	1 100%	1 50%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	0 0%
White	1 100%	0 0%	1 50%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
United States	1 100%	1 100%	2 100%

Outcome Measures

1. Primary Outcome

Title	Number of Unanticipated Grade III or Higher Treatment-Related Toxicities
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Cohort 1 (Minimal Efficacious Dose)	Cohort 2
Arm/Group Description	N = 1 [2.5 x E13 vg/kg per leg, delivered bilaterally (total 5.0 x E13 vg/kg)] rAAVrh74.MCK.GALGT2: 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)	N = 1 [5 x E13 vg/kg per leg, delivered bilaterally (total 1.0 x E14 vg/kg)] rAAVrh74.MCK.GALGT2: 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)
Measure Participants	1	1
Number [events]	0	0

2. Secondary Outcome

Title	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).
Description	Percentage of fibers expressing GALGT2 in each biopsy sample.
Time Frame	Day 90 (Cohort 2) and Day 120 (Cohort 1)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Cohort 1 (Minimal Efficacious Dose)	Cohort 2
Arm/Group Description	N = 1 [2.5 x E13 vg/kg per leg, delivered bilaterally (total 5.0 x E13 vg/kg)] rAAVrh74.MCK.GALGT2: 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)	N = 1 [5 x E13 vg/kg per leg, delivered bilaterally (total 1.0 x E14 vg/kg)] rAAVrh74.MCK.GALGT2: 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)
Measure Participants	1	1
Measure Biopsies	1	1
Number [Percentage of Positive Fibers]	1.95	1.72

3. Secondary Outcome

Title	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)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Cohort 1 (Minimal Efficacious Dose)	Cohort 2
Arm/Group Description	N = 1 [2.5 x E13 vg/kg per leg, delivered bilaterally (total 5.0 x E13 vg/kg)] rAAVrh74.MCK.GALGT2: 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)	N = 1 [5 x E13 vg/kg per leg, delivered bilaterally (total 1.0 x E14 vg/kg)] rAAVrh74.MCK.GALGT2: 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)
Measure Participants	1	1
Measure Biopsies	1	1
Number [ng/mg total protein]	12	14.6

4. Other Pre-specified Outcome

Title	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Cohort 1 (Minimal Efficacious Dose)	Cohort 2 (Minimal Efficacious Dose)
Arm/Group Description	N = 1 [2.5 x E13 vg/kg per leg, delivered bilaterally (total 5.0 x E13 vg/kg)] rAAVrh74.MCK.GALGT2: 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)	N = 1 [5 x E13 vg/kg per leg, delivered bilaterally (total 1.0 x E14 vg/kg)] rAAVrh74.MCK.GALGT2: 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)
Measure Participants	1	1
Day 90 (Cohort 2) /Day 120 (Cohort 1)	320	405
Day 180	324	416

5. Other Pre-specified Outcome

Title	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Cohort 1 (Minimal Efficacious Dose)	Cohort 2
Arm/Group Description	N = 1 [2.5 x E13 vg/kg per leg, delivered bilaterally (total 5.0 x E13 vg/kg)] rAAVrh74.MCK.GALGT2: 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)	N = 1 [5 x E13 vg/kg per leg, delivered bilaterally (total 1.0 x E14 vg/kg)] rAAVrh74.MCK.GALGT2: 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)
Measure Participants	1	1
Day 90/Day 120-Right Knee Extension	7.42	7.04
Day 90/Day 120-Right Knee Flexion	6.06	8.12
Day 90/Day 120- Left Knee Extension	8.78	5.9
Day 90/Day 120-Left Knee Flexion	6.12	8.4
Day 180-Right Knee Extension	7.13	9.73
Day 180-Right Knee Flexion	6.1	4.24
Day 180-Left Knee Extension	8.66	8.19
Day 180-Left Knee Flexion	6.69	5.25
Month 12-Right Knee Extension	7.49	9.85
Month 12-Right Knee Flexion	5.67	5.85
Month 12-Left Knee Extension	7.5	8.02
Month 12-Left Knee Flexion	5.32	5.12
Month 18-Right Knee Extension	4.55	7.67
Month 18-Right Knee Flexion	6.11	6.89
Month 18-Left Knee Extension	4.96	7.34
Month 18-Left Knee Flexion	6.26	6.08
Month 24-Right Knee Extension	5.06	9.81
Month 24-Right Knee Flexion	4.41	5.04
Month 24-Left Knee Extension	6.93	5.21
Month 24-Left Knee Flexion	4.17	4.87

6. Other Pre-specified Outcome

Title	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

Outcome Measure Data

Analysis Population Description

There is no data for Cohort 1, Month 24 because single subject was unable to perform the test.

Arm/Group Title	Cohort 1 (Minimal Efficacious Dose)	Cohort 2
Arm/Group Description	N = 1 [2.5 x E13 vg/kg per leg, delivered bilaterally (total 5.0 x E13 vg/kg)] rAAVrh74.MCK.GALGT2: 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)	rAAVrh74.MCK.GALGT2: 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)
Measure Participants	1	1
Day 90/Day 120	98.2	56.1
Day 180	110.9	44.9
Month 12	144.5	44.7
Month 18	167.8	65.6
Month 24	48.4

7. Other Pre-specified Outcome

Title	Score of Muscle Function Using the The North Star Ambulatory Assessment (NSAA).
Description	The NSAA provides a score between 0 and 34 where higher numbers represent greater muscle function.
Time Frame	Days 90 (Cohort 2), 120 (Cohort 1) and both Cohorts at Day 180, Months 12, 18 and 24

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Cohort 1 (Minimal Efficacious Dose)	Cohort 2
Arm/Group Description	N = 1 [2.5 x E13 vg/kg per leg, delivered bilaterally (total 5.0 x E13 vg/kg)] rAAVrh74.MCK.GALGT2: 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)	N = 1 [5 x E13 vg/kg per leg, delivered bilaterally (total 1.0 x E14 vg/kg)] rAAVrh74.MCK.GALGT2: 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)
Measure Participants	1	1
Day 90/Day 120	16	21
Day 180	14	23
Month 12	10	23
Month 18	6	23
Month 24	2	23

Adverse Events

Time Frame	Adverse events started to be collected on Day 0 as defined by the day of Gene Transfer and continued through during the active 2-year period following gene transfer as described in the protocol.
Arm/Group Title	Cohort 1 (Minimal Efficacious Dose) rAAVrh74.MCK.GALGT2		Cohort 1 rAAVrh74.MCK.GALGT2
Arm/Group Description	N = 1 [2.5 x E13 vg/kg per leg, delivered bilaterally (total 5.0 x E13 vg/kg)] rAAVrh74.MCK.GALGT2: 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)		N = 1 [5 x E13 vg/kg per leg, delivered bilaterally (total 1.0 x E14 vg/kg)] rAAVrh74.MCK.GALGT2: 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)
All Cause Mortality
	Cohort 1 (Minimal Efficacious Dose) rAAVrh74.MCK.GALGT2		Cohort 1 rAAVrh74.MCK.GALGT2
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/1 (0%)		0/1 (0%)
Serious Adverse Events
	Cohort 1 (Minimal Efficacious Dose) rAAVrh74.MCK.GALGT2		Cohort 1 rAAVrh74.MCK.GALGT2
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/1 (0%)		0/1 (0%)
Other (Not Including Serious) Adverse Events
	Cohort 1 (Minimal Efficacious Dose) rAAVrh74.MCK.GALGT2		Cohort 1 rAAVrh74.MCK.GALGT2
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/1 (100%)		1/1 (100%)
Blood and lymphatic system disorders
Low Hemoglobin	0/1 (0%)	0	1/1 (100%)	1
Decreased Lymphocyte	1/1 (100%)	1	1/1 (100%)	2
Pharyngitis and Adenitis	1/1 (100%)	1	0/1 (0%)	0
Cardiac disorders
Decrease in ejection fraction	1/1 (100%)	1	0/1 (0%)	0
Tachycardia	1/1 (100%)	1	0/1 (0%)	0
Endocrine disorders
Cushingoid Face	1/1 (100%)	1	0/1 (0%)	0
Weight Gain	1/1 (100%)	1	0/1 (0%)	0
Gastrointestinal disorders
Vomiting	0/1 (0%)	0	1/1 (100%)	1
Vascular disorders
Bleeding at the femoral catheterization site	1/1 (100%)	1	0/1 (0%)	0
Bruising	1/1 (100%)	1	1/1 (100%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT 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.