Expired Study
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Columbus, Ohio 43205


Purpose:

Dose escalation study of self-complementary (sc) AAVrh74.tMCK.hSGCA delivered to single leg (low dose n=2) and bilaterally (n=6) via a major lower limb artery to the whole lower limb of limb girdle muscular dystrophy type 2D (LGMD2D; alpha-sarcoglycan deficient) patients.


Study summary:

The proposed clinical trial is a dose escalation study of self-complementary scAAVrh74.tMCK.hSGCA to LGMD2D (alpha-sarcoglycan deficient) subjects delivered via a major lower limb artery of each leg sequentially by isolated limb perfusion (ILP). Three cohorts (Cohorts 1A, 1B, and 2) will undergo gene transfer in a dose escalation scheme to establish maximum tolerated dose (MTD) using toxicity. Two (n=2) adult wheelchair-dependent patients will be enrolled in Cohort 1A and three (n =3) ambulatory subjects will be enrolled in Cohort 1B. Three (n =3) ambulatory subjects will be enrolled in Cohort 2. The first cohort (1A) will receive a dose of 1E12 vg/kg in a single limb with delivery to the whole limb. This same dose will be delivered to both limbs in Cohort 1B. Cohort 2 will receive a total dose escalation of 3E12vg/kg per limb delivered to both extremities. The vector will be infused into an indwelling catheter in the femoral artery. This will be a one-time vector infusion to an isolated limb with a 10-minute dwell time. The total vector genome dose for each subject will be adjusted by rounding down to the closest 10 kg. Safety monitoring during infusion will include: activated clotting times, limb gases, real time monitoring of arterial and venous access pressures, and perfusate temperature. Safety endpoints will be assessed by changes in hematology, serum chemistry, urinalysis, immunologic response to rAAVrh74 and hSGCA, and reported history and observations of symptoms. Efficacy will be measured by the six minute walk test as well as direct muscle testing for strength (MVICT) of lower limb muscles. These quantitative measures will be done at baseline, day 30, 60, 90, 180, and at the end of 1st and 2nd years. 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. On Day 180, subjects will undergo a muscle biopsy on the injected muscles in one leg to compare with the pre-treatment biopsy done at baseline screening in the opposite leg to establish the size of muscle fibers and any potential toxicity from gene transfer.


Criteria:

Inclusion Criteria - Subjects age 7 or older; cohort 1A must be adult and wheelchair-dependent - Proven alpha-sarcoglycan deficiency by muscle biopsy or DNA testing. - Onset of weakness by 5 years age based on history of difficulty running, jumping and climbing stairs. - Subject enrolled in Cohort 1A must be adult and wheelchair dependent - Subjects enrolled in Cohorts 1B or 2 must be able to walk independently, but must exhibit signs of lower extremity weakness (i.e. a Gowers' sign, use a handrail for climbing stairs) and walk ≤ 80% of predicted distance on the 6MWT based on normative data. - Males and females of any ethnic group will be eligible - Ability to cooperate with muscle testing. - Willingness of sexually active subjects with reproductive capacity to practice reliable method of contraception (If appropriate), during the first six months after gene therapy (females) or until two negative sperm samples are obtained post gene transfer (males). Exclusion Criteria - Active viral infection based on clinical observations. - The presence of SGCA mutations 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 - Abnormal laboratory values considered clinically significant (GGT > 3XULN, bilirubin ≥ 3.0 mg/dL , creatinine ≥ 1.8 mg/dL, Hgb < 8 or > 18 g/Dl; WBC > 15,000 per cmm) - Concomitant illness or requirement for chronic drug treatment that in the opinion of the PI creates unnecessary risks for gene transfer - Pregnancy - Subjects with AAVrh74 or AAV8 binding antibody titers ≥ 1:50 as determined by ELISA immunoassay


Study is Available At:


Original ID:

5U01AR060911


NCT ID:

NCT01976091


Secondary ID:


Study Acronym:


Brief Title:

Gene Transfer Clinical Trial for LGMD2D (Alpha-sarcoglycan Deficiency) Using scAAVrh74.tMCK.hSGCA


Official Title:

Phase I/IIa Gene Transfer Clinical Trial for LGMD2D (Alpha-sarcoglycan Deficiency) Using scAAVrh74.tMCK.hSGCA


Overall Status:

Completed


Study Phase:

Phase 1/Phase 2


Genders:

N/A


Minimum Age:

7 Years


Maximum Age:

N/A


Quick Facts

Healthy Volunteers
Oversight Has DMC
Study Is FDA Regulated
Study Is Section 801
Has Expanded Access

Study Source:

Nationwide Children's Hospital


Oversight Authority:

  • United States: Food and Drug Administration
  • NIH/Office of Biotechnology Activities (OBA): Recombinant DNA Advisory Committee (RAC)
  • United States: Data and Safety Monitoring Board
  • United States: Institutional Review Board


Reasons Why Stopped:


Study Type:

Interventional


Study Design:


Number of Arms:

3


Number of Groups:

0


Total Enrollment:

6


Enrollment Type:

Actual


Study Dates

Start Date:February 2015
Completion Date:March 14, 2019
Completion Type:Actual
Primary Completion Date:March 14, 2019
Primary Completion Type:Actual
Verification Date:July 2019
Last Changed Date:July 22, 2019
First Received Date:July 24, 2013

Study Outcomes

Outcome Type:Secondary Outcome
Measure:Change in Six-Minute-Walk-Test (6MWT) distance from baseline over two years
Time Frame:2 years
Safety Issues:False
Description:Efficacy would be a significant improvement in distance walked in the 6 minute walk test.
Outcome Type:Primary Outcome
Measure:Safety with fewer than one grade 3 adverse events or fewer than two grade 2 adverse events
Time Frame:2 years
Safety Issues:False
Description:Safety will be measured based on fewer than one grade 3 adverse event or fewer than two grade 2 adverse events

Study Interventions

Intervention Type:Drug
Name:scAAVrh74.tMCK.hSGCA
Arm Name:Cohort 1A
Other Name:SGCA gene therapy

Study Arms

Study Arm Type:Experimental
Arm Name:Cohort 2
Description:Three (n=3) LGMD2D subjects will receive self-complementary scAAVrh74.tMCK.hSGCA bilateral whole limb perfusion at high dose.Subjects will receive a total dose of 3 x 10 12th vg/kg per limb delivered to both extremities
Study Arm Type:Experimental
Arm Name:Cohort 1B
Description:Three (n=3) LGMD2D subjects will receive self-complementary scAAVrh74.tMCK.hSGCA via bilateral whole limb perfusion at low dose of 1 x 10 12th vg/kg.
Study Arm Type:Experimental
Arm Name:Cohort 1A
Description:Two (n=2) adult LGMD2D wheelchair-dependent subjects will receive self-complementary scAAVrh74.tMCK.hSGCA via single-limb perfusion at the low dose. Subjects will receive a dose of 1 x 10 12th vg/kg in a single limb with delivery to the whole limb.

Study Agencies

Agency Class:Other
Agency Type:Lead Sponsor
Agency Name:Jerry R. Mendell

Sample and Retention Information

There are no available Sample and Retention Information

Study References

Reference Type:Reference
Citation:Mendell JR, Rodino-Klapac LR, Rosales-Quintero X, Kota J, Coley BD, Galloway G, Craenen JM, Lewis S, Malik V, Shilling C, Byrne BJ, Conlon T, Campbell KJ, Bremer WG, Viollet L, Walker CM, Sahenk Z, Clark KR. Limb-girdle muscular dystrophy type 2D gene therapy restores alpha-sarcoglycan and associated proteins. Ann Neurol. 2009 Sep;66(3):290-7. doi: 10.1002/ana.21732.
PMID:19798725
Reference Type:Reference
Citation: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.
PMID:21031578

Data Source: ClinicalTrials.gov

Date Processed: January 21, 2020

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