ClinicalTrials.gov
ClinicalTrials.gov Menu

Re-administration of Intramuscular AAV9 in Patients With Late-Onset Pompe Disease (AAV9-GAA_IM)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT02240407
Recruitment Status : Recruiting
First Posted : September 15, 2014
Last Update Posted : May 21, 2018
Sponsor:
Collaborator:
Audentes Therapeutics
Information provided by (Responsible Party):
University of Florida

Brief Summary:
A recombinant AAV vector has been generated to carry the codon-optimized acid alpha-glucosidase (coGAA) gene expressed from a human desmin enhancer/promoter (DES). The proposed clinical trial is a within-participant, double-blind, randomized, phase I controlled study evaluating the toxicology, biodistribution and potential activity of re-administration of rAAV9-DES-hGAA injected intramuscularly into the TA. Nine participants (18 to 50-years old) who reside within the United States with Late-Onset Pompe Disease (LOPD) will be included. The goal of the immune modulation strategy is to ablate B-cells (Rituximab and Sirolimus) prior to the initial exposure to the study agent in one leg and the subsequent exposure of the same vector to the contralateral leg after four months. At each study agent dosing, the contralateral leg will receive excipient. Patients will act as their own controls. Repeated measures, at baseline and during the following 3 months after each injection, will assess the safety, biochemical and functional impact of the vector.

Condition or disease Intervention/treatment Phase
Pompe Disease Genetic: Recombinant Adeno-Associated Virus Acid Alpha-Glucosidase Drug: Rapamycin Other: saline Drug: Rituxan Drug: Diphenhydramine Drug: Acetaminophen Drug: Lidocaine Drug: LMX 4 Topical Cream Phase 1

  Show Detailed Description

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 7 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Evaluation of Re-administration of Recombinant Adeno-Associated Virus Acid Alpha-Glucosidase (rAAV9-DES-hGAA) in Patients With Late-Onset Pompe Disease (LOPD)
Actual Study Start Date : October 17, 2017
Estimated Primary Completion Date : March 2019
Estimated Study Completion Date : June 2019


Arm Intervention/treatment
Experimental: rAAV9-DES-hGAA vector
Each subject will receive Rituxan and Rapamycin prior to the initial exposure to the study agent in one leg and the subsequent exposure of the same vector to the contralateral leg after four months. Diphenhydramine and acetaminophen will be provided before each Rituxan dose. Immune Globulin will be administered to each subject every other month after first exposure to Rituxan and as clinical necessary. Lidocaine will be administered through percutaneous infiltration before injection of the study agent. Side of administration will be randomized at first Recombinant Adeno-Associated Virus Acid Alpha-Glucosidase injection.
Genetic: Recombinant Adeno-Associated Virus Acid Alpha-Glucosidase
The dose selected for this study is a fixed dose of 4.6 x 10^13 vg per TA muscle (range of 7.64 x 10^11 vg/gm to 4.6 x 10^11 vg/gm based on TA weight).
Other Name: rAAV9-DES-hGAA

Drug: Rapamycin
Patients will receive Rapamycin (dose 0.6-2 mg/m^2/day, adjusted to maintain a trough serum sirolimus level of 2-4 ng/mL.) every day starting from 7 days before first injection of AAV9 until one month after second injection.
Other Name: Sirolimus

Drug: Rituxan
Patients will receive Rituxan (dose: 750 mg/m^2 twice) 21 and 7 day prior first AAV9 injection, with a Rituxan dose 375 mg/m^2 on the day of the injection. Rituxan will be repeated 7 days prior to the 2nd injection of the vector. The maintenance dose of Rituxan will be 375 mg/m^2.
Other Name: Rituximab

Drug: Diphenhydramine
25-50mg will be provided before each Rituximab dose.
Other Name: Benadryl

Drug: Acetaminophen
We will provide 650 mg of tylenol before each dose of Rituximab.
Other Name: Tylenol

Drug: Lidocaine
Lidocaine will be used based on standard of care: Percutaneous infiltration, concentration 0.5-1%, 1-10 mL, 5-300mg total dose.

Drug: LMX 4 Topical Cream
Topical anesthesia cream will be used prior to gene therapy/saline injection.

Sham Comparator: Excipient
Each subject will receive Rituxan and Rapamycin prior to the initial exposure to the study agent in one leg and the subsequent exposure of the same vector to the contralateral leg after four months. Diphenhydramine and acetaminophen will be provided before each Rituxan dose. Immune Globulin will be administered to each subject every other month after first exposure to Rituxan and as clinical necessary. Lidocaine will be administered through percutaneous infiltration before injection of the study agent. Side of administration will be randomized at first saline injection.
Drug: Rapamycin
Patients will receive Rapamycin (dose 0.6-2 mg/m^2/day, adjusted to maintain a trough serum sirolimus level of 2-4 ng/mL.) every day starting from 7 days before first injection of AAV9 until one month after second injection.
Other Name: Sirolimus

Other: saline
Same volume as rAAV9-DES-hGAA injection will be used.
Other Name: Excipient

Drug: Rituxan
Patients will receive Rituxan (dose: 750 mg/m^2 twice) 21 and 7 day prior first AAV9 injection, with a Rituxan dose 375 mg/m^2 on the day of the injection. Rituxan will be repeated 7 days prior to the 2nd injection of the vector. The maintenance dose of Rituxan will be 375 mg/m^2.
Other Name: Rituximab

Drug: Diphenhydramine
25-50mg will be provided before each Rituximab dose.
Other Name: Benadryl

Drug: Acetaminophen
We will provide 650 mg of tylenol before each dose of Rituximab.
Other Name: Tylenol

Drug: Lidocaine
Lidocaine will be used based on standard of care: Percutaneous infiltration, concentration 0.5-1%, 1-10 mL, 5-300mg total dose.

Drug: LMX 4 Topical Cream
Topical anesthesia cream will be used prior to gene therapy/saline injection.




Primary Outcome Measures :
  1. Safety of rAAV9-DES-hGAA vector in LOPD by blood and urine test. [ Time Frame: 520 days ]
    Safety will be tested by clinical pathology tests, blood assay for vector genomes, antibodies against GAA and T-cell ELISPOT against GAA and AAV.


Secondary Outcome Measures :
  1. Neurophysiological tests will be performed for neuro function of rAAV9-DES-hGAA vector. [ Time Frame: 520 days ]
    Neurophysiological tests: Surface testing of the common fibular nerve and neuromuscular junction transmission.

  2. Muscle biopsy will be performed for muscular function of rAAV9-DES-hGAA vector. [ Time Frame: 520 days ]
    Muscle biopsy for biochemistry and immunochemistry tests.

  3. Clinical tests will be performed for function of rAAV9-DES-hGAA vector. [ Time Frame: 520 days ]
    Clinical tests: 10 meter walk test and muscle strength test.

  4. Magnetic Resonance Imaging will be performed for visualization of muscle with rAAV9-DES-hGAA vector. [ Time Frame: 520 days ]
    MRI will provide a non-invasive means of evaluating maximum cross-sectional area (CSAmax) - an index of muscle mass - and the MR proton traverse relaxation time (T2) - an index of muscle damage and edema.

  5. Spectroscopy will be performed for function of rAAV9-DES-hGAA vector. [ Time Frame: 520 days ]
    MRS will provide a non-invasive means of evaluating glycogen concentration in muscle.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   18 Years to 50 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Male or female subjects 18 to 50-years old
  • Have a diagnosis of Pompe disease, as defined by protein assay AND/OR DNA sequence of the acid alpha-glucosidase gene, AND clinical symptoms of the disease
  • Have residual ability to complete the 10 meter walk test
  • Willing to discontinue aspirin, aspirin-containing products and other drugs that may alter platelet function, 7 days prior to dosing, resuming 24 hours after the dose has been administered
  • Consistently taking enzyme replacement therapy (ERT) or remain off ERT from baseline until Day 520
  • United States residents only.

Exclusion Criteria:

  • Be pregnant or nursing, and if the subject is of child bearing potential they should use contraception until the end of the study
  • Have required oral or systemic corticosteroids within the last 15 days prior to baseline screening
  • Have a platelet count less than 75,000/mm^3
  • Have an INR greater than 1.3
  • Have transaminases and alkaline phosphatase more than ten times the upper limit of normal at screening or Day-1
  • Have bilirubin and gamma-glutamyl transpeptidase greater than 2 times the upper limit of normal at screening or Day -1
  • Have any chronic liver disease (aside from hepatic dysfunction related to Pompe disease) such as hepatitis B and C and cirrhosis
  • Be currently, or within the past 30 days, participating in any other research protocol involving investigational agents or therapies
  • Have history of platelet dysfunction, evidence of abnormal platelet function at screening, or history of recent use of drugs that may alter platelet function, which the subject is unable/unwilling to discontinue for study agent administration
  • Have received gene transfer agents within the past 6 months
  • Have any medical condition or circumstance for which an MRI evaluation is contraindicated
  • Have any other concurrent condition that, in the opinion of the investigator, would make the subject unsuitable for the study
  • Inconsistent with use of ERT.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02240407


Contacts
Contact: Samantha Norman, MPH, BS 352-273-8218 samantha.norman@peds.ufl.edu
Contact: Manuela Corti, PT, PhD 352-294-5779 m.corti@peds.ufl.edu

Locations
United States, Florida
Clinical and Translational Research Building (CTRB), University of Florida Recruiting
Gainesville, Florida, United States, 32610
Contact: Samantha Norman, MPH, BS    352-273-8218    samantha.norman@peds.ufl.edu   
Sponsors and Collaborators
University of Florida
Audentes Therapeutics
Investigators
Principal Investigator: Barry J Byrne, M.D., Ph.D. University of Florida
Principal Investigator: Manuela Corti, P.T., PhD. University of Florida

Publications:
McKusick V. 232300 Glycogen Storage Disease II. OMIM. 1996.

Responsible Party: University of Florida
ClinicalTrials.gov Identifier: NCT02240407     History of Changes
Other Study ID Numbers: IRB201400137
First Posted: September 15, 2014    Key Record Dates
Last Update Posted: May 21, 2018
Last Verified: May 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by University of Florida:
Pompe Disease
Gene Therapy
Repeated dosing
Immune modulation

Additional relevant MeSH terms:
Glycogen Storage Disease Type II
Lysosomal Storage Diseases, Nervous System
Brain Diseases, Metabolic, Inborn
Brain Diseases, Metabolic
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Metabolism, Inborn Errors
Genetic Diseases, Inborn
Glycogen Storage Disease
Carbohydrate Metabolism, Inborn Errors
Lysosomal Storage Diseases
Metabolic Diseases
Rituximab
Sirolimus
Everolimus
Lidocaine
Diphenhydramine
Acetaminophen
Promethazine
Antineoplastic Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Anesthetics, Local
Anesthetics
Central Nervous System Depressants
Sensory System Agents
Peripheral Nervous System Agents
Anti-Arrhythmia Agents