Pompe DiseasePhase 1AAV9-GAA_IMNCT02240407
Re-administration of Intramuscular AAV9 in Patients With Late-Onset Pompe Disease
A Phase 1 study testing Recombinant Adeno-Associated Virus Acid Alpha-Glucosidase, Rapamycin and saline in people with Pompe Disease, run by University of Florida at 1 site in United States.
Trial 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… Read more about this study
- Who is it for?
- Ages 18 to 50 years
- Conditions the study is for
- Pompe Disease
- What is being tested?
- Recombinant Adeno-Associated Virus Acid Alpha-Glucosidase, Rapamycin and saline
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 2 participants
- Where
- 1 siteUnited States
- Study dates
- 17 Oct 2017to 26 Aug 2021
- Phase
- Phase 1
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 50 years
- All sexes
- No healthy volunteers
- Adult
Who may be able to join
- 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.
Who cannot join
- 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 seronegative to AAV9 capsid protein (neutralizing Ab titers <1:5 and total binding Ab titer <50 U/ml)
- Have transaminases and alkaline phosphatase more than ten times the upper limit of normal at screening or Day-1
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- 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.
Trial locations and contacts
1 site in 1 country.
United States1 site
Clinical and Translational Research Building (CTRB), University of Florida
Gainesville, Florida, 32610
About this study
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)
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.
Read the detailed description
Enrolling in this study will entail participating in 18 months of study-related visits. Patients will be asked to come to the Clinical and Translational Research Building at the University of Florida for a series of onsite study visits.
All the visits will be performed as outpatient procedures at the Clinical Research Center (CRC) and at other facilities at the University of Florida. Overnight observation will not be needed, however, patients will be asked to stay overnight in a hotel near the University of Florida. During the first 4 months after each injection, patients will be asked to perform outpatient laboratory work at a laboratory facility convenient for them.
In addition, during this study patients will be asked to take medications that will modulate the ability of their immune system to react against foreign agents including the gene transfer agent. The purpose of these medications is to improve the activity of the GAA within the body. Patients will receive a Rituximab injection 21 days prior to the first injection of the study agent and 7 days before each injection of the study agent and the day of the first injection. Rituximab will be delivered by infusion that may last 2-6 hours. Patients will need to take another medication (Sirolimus) every day starting 7 days before the first injection of the study agent until four months after the second injection of the study agent.
The following discusses what will occur at each visit:
Baseline Baseline Evaluation and first Rituximab infusion - Day -22/-21/-20
- Medical history: Patients will be asked to complete a questionnaire about his/her medical history.
- Physical exam: The study doctor will perform a general physical exam to evaluate patients physical health.
- Blood and urine tests: These tests will be used for evaluating the safety of the gene transfer agent.
- Electrocardiogram (ECG): This test will measure the electrical activity of patient's heart to see if it is working properly.
- Quantitative Muscle Testing (QMT): This test finds out how strong the patient's leg muscles are.
- 10 Meter Walk Test: Patients will be instructed to walk a set distance (10 meters); time will be measured while patient walks the set distance and the distance covered will be divided by the time it took to walk that distance.
- Gait analysis: Gait will be tested with Gait Mat II, which will record the spatial and temporal parameters of his/her walk such as cadence, speed and distance between your feet.
- Magnetic Resonance Imaging (MRI) and Spectroscopy (MRS): MRI and MRS testing will be done inside a large magnet that lets the study doctors measure the size and health of the patient's muscles. These tests are done at the same time. MRI and MRS testing will require the patient to stay very still for up to an hour.
- Magnetic stimulation of the common fibular nerve: The common fibular nerve, which is the nerve that controls the injected muscle, will be stimulated with a magnetic field to test the impact of the gene transfer agent to the nervous system.
- The patient will receive the first Rituximab infusion. It might last between 2 and 6 hours.
Rituximab infusion - Day -6
- The patient will receive the 2nd Rituximab infusion 7 days before the gene transfer agent. It might last between 2 and 6 hours.
- Patient will begin Rapamycin. 1st Injection - Day 0/1
- The patient will receive the 3rd Rituximab infusion the day before the gene transfer agent. It might last between 2 and 6 hours.
- Patient will receive the gene transfer agent in 1 injection (a total of about 1 teaspoon) into the tibialis anterior (TA) muscle of one leg. The other leg will receive a pharmacologically inactive solution. An ultrasound will be used to detect the proper location of injection. A photograph of the injection at the injection site may be taken. If the patient agrees to this, he/she will be asked to sign a consent form for this procedure.
On day 1, blood tests will be done.
Outpatient lab work - Day 3/7/15/30/60
- Blood and urine tests
Onsite visit - Day 89/90
- Medical history
- Physical Exam
- Blood and urine tests
- Quantitative Muscle Testing (QMT)
- 10 Meter Walk Test
- Gait analysis
- Magnetic Resonance Imaging (MRI) and Spectroscopy (MRS)
- Muscle Biopsy: Tissue samples obtained will be used for evaluation of muscle glycogen and GAA activity in the injected muscle.
- Magnetic stimulation of the common fibular nerve
Rituximab infusion - Day 114
- The patient will receive the 4th Rituximab infusion, it might last between 2-6 hours. 2nd Injection - Day 121/122
- The patient will receive the second gene transfer agent injection in the leg that previously received the inactive solution. The leg that previously received the study agent will receive the inactive solution. The injection procedure and the amount of study agent injected will be the same as the first injection.
On day 122, blood tests will be done.
Outpatient lab work - Day 124/128/135/150/180
- Blood and urine tests
Onsite visit - Day 209/210
- Medical History
- Physical Exam
- Blood and urine tests
- Quantitative Muscle Testing (QMT)
- 10 Meter Walk Test
- Gait analysis
- Magnetic Resonance Imaging (MRI) and Spectroscopy (MRS)
- Muscle Biopsy
- Magnetic stimulation of the common fibular nerve
Onsite visit - Day 365
- Medical history
- Physical exam
- Quantitative Muscle Testing (QMT)
- 10 Meter Walk Test
- Blood and urine tests
Onsite visit - Day 520
- Medical history
- Physical exam
- Quantitative Muscle Testing (QMT)
- 10 Meter Walk Test
- Blood and urine tests
- Conditions
- Pompe Disease
- Being tested
- Recombinant Adeno-Associated Virus Acid Alpha-Glucosidase, Rapamycin, saline, Rituxan, Diphenhydramine
- Keywords
- Pompe Disease, Gene Therapy, Repeated dosing, Immune modulation
- Medical subject headings
- Glycogen Storage Disease Type II
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Recombinant Adeno-Associated Virus Acid Alpha-GlucosidaseGenetic
Also called rAAV9-DES-hGAA
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).
RapamycinDrug
Also called Sirolimus
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 four months after second injection.
salineOther
Also called Excipient
Same volume as rAAV9-DES-hGAA injection will be used.
RituxanDrug
Also called Rituximab
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.
DiphenhydramineDrug
Also called Benadryl
25-50mg will be provided before each Rituximab dose.
AcetaminophenDrug
Also called Tylenol
We will provide 650 mg of tylenol before each dose of Rituximab.
LidocaineDrug
Also called Xylocaine
Lidocaine will be used based on standard of care: Percutaneous infiltration, concentration 0.5-1%, 1-10 mL, 5-300mg total dose.
LMX 4 Topical CreamDrug
Also called Lidocaine 4%
Topical anesthesia cream will be used prior to gene therapy/saline injection.
| Study group | Role | What they receive |
|---|---|---|
| rAAV9-DES-hGAA vector | Experimental | 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. Receives: Genetic: Recombinant Adeno-Associated Virus Acid Alpha-Glucosidase; Drug: Rapamycin; Drug: Rituxan; Drug: Diphenhydramine; Drug: Acetaminophen; Drug: Lidocaine; Drug: LMX 4 Topical Cream |
| Excipient | Sham comparator | 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. Receives: Drug: Rapamycin; Other: saline; Drug: Rituxan; Drug: Diphenhydramine; Drug: Acetaminophen; Drug: Lidocaine; Drug: LMX 4 Topical Cream |
What is being measured
The primary outcome is the main question the study is designed to answer.
Safety of rAAV9-DES-hGAA vector in LOPD by blood and urine test.
Safety will be tested by clinical pathology tests, blood assay for vector genomes, antibodies against GAA and T-cell ELISPOT against GAA and AAV.
Measured: 520 days
Secondary outcomes (5)
Neurophysiological tests will be performed for neuro function of rAAV9-DES-hGAA vector.
Neurophysiological tests: Surface testing of the common fibular nerve and neuromuscular junction transmission.
Measured: 520 days
Muscle biopsy will be performed for muscular function of rAAV9-DES-hGAA vector.
Muscle biopsy for biochemistry and immunochemistry tests.
Measured: 520 days
Clinical tests will be performed for function of rAAV9-DES-hGAA vector.
Clinical tests: 10 meter walk test and muscle strength test.
Measured: 520 days
Magnetic Resonance Imaging will be performed for visualization of muscle with rAAV9-DES-hGAA vector.
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.
Measured: 520 days
Spectroscopy will be performed for function of rAAV9-DES-hGAA vector.
MRS will provide a non-invasive means of evaluating glycogen concentration in muscle.
Measured: 520 days
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted15 Sep 2014 (estimated)
- Study start17 Oct 2017
- Primary completion26 Aug 2021
- Study completion26 Aug 2021
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (29)Papers the sponsor has linked to this study.
- Other trials for Pompe DiseaseStudies of the same condition, open and under way.
- More trials run by University of FloridaThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind
- Who is masked
- Participant, Investigator, Outcomes assessor
- Enrolment
- 2 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of Florida
- Sponsor type
- University, hospital or other
- Collaborators
- Lacerta Therapeutics
- Responsible party
- Sponsor
- Investigators
- Manuela Corti, P.T., PhD., Principal investigator, University of Florida
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02240407
- Sponsor's protocol ID
- IRB201400137
- Other IDs
- 20182574
- Acronym
- AAV9-GAA_IM
- Status last verified
- Mar 2022
- First submitted
- 11 Sep 2014
- Last updated
- 5 Apr 2022
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- Undecided
Publications
Corti M, Smith BK, Falk DJ, Lawson LA, Fuller DD, Subramony SH, Byrne BJ, Christou EA. Altered activation of the tibialis anterior in individuals with Pompe disease: Implications for motor unit dysfunction. Muscle Nerve. 2015 Jun;51(6):877-83. doi: 10.1002/mus.24444. Epub 2015 Apr 24.
PubMed 25186912McKusick V. 232300 Glycogen Storage Disease II. OMIM. 1996.
Moufarrej NA, Bertorini TE. Respiratory insufficiency in adult-type acid maltase deficiency. South Med J. 1993 May;86(5):560-7. doi: 10.1097/00007611-199305000-00015.
PubMed 8488406Wokke JH, Escolar DM, Pestronk A, Jaffe KM, Carter GT, van den Berg LH, Florence JM, Mayhew J, Skrinar A, Corzo D, Laforet P. Clinical features of late-onset Pompe disease: a prospective cohort study. Muscle Nerve. 2008 Oct;38(4):1236-45. doi: 10.1002/mus.21025.
PubMed 18816591Byrne BJ, Falk DJ, Pacak CA, Nayak S, Herzog RW, Elder ME, Collins SW, Conlon TJ, Clement N, Cleaver BD, Cloutier DA, Porvasnik SL, Islam S, Elmallah MK, Martin A, Smith BK, Fuller DD, Lawson LA, Mah CS. Pompe disease gene therapy. Hum Mol Genet. 2011 Apr 15;20(R1):R61-8. doi: 10.1093/hmg/ddr174. Epub 2011 Apr 25.
PubMed 21518733Byrne BJ, Kishnani PS, Case LE, Merlini L, Muller-Felber W, Prasad S, van der Ploeg A. Pompe disease: design, methodology, and early findings from the Pompe Registry. Mol Genet Metab. 2011 May;103(1):1-11. doi: 10.1016/j.ymgme.2011.02.004. Epub 2011 Feb 11.
PubMed 21439876Lee KZ, Qiu K, Sandhu MS, Elmallah MK, Falk DJ, Lane MA, Reier PJ, Byrne BJ, Fuller DD. Hypoglossal neuropathology and respiratory activity in pompe mice. Front Physiol. 2011 Jun 30;2:31. doi: 10.3389/fphys.2011.00031. eCollection 2011.
PubMed 21747768Benowitz LI, Routtenberg A. GAP-43: an intrinsic determinant of neuronal development and plasticity. Trends Neurosci. 1997 Feb;20(2):84-91. doi: 10.1016/s0166-2236(96)10072-2.
PubMed 9023877Kanazir S, Ruzdijic S, Vukosavic S, Ivkovic S, Milosevic A, Zecevic N, Rakic L. GAP-43 mRNA expression in early development of human nervous system. Brain Res Mol Brain Res. 1996 May;38(1):145-55. doi: 10.1016/0169-328x(96)00008-3.
PubMed 8737678Vilchez D, Ros S, Cifuentes D, Pujadas L, Valles J, Garcia-Fojeda B, Criado-Garcia O, Fernandez-Sanchez E, Medrano-Fernandez I, Dominguez J, Garcia-Rocha M, Soriano E, Rodriguez de Cordoba S, Guinovart JJ. Mechanism suppressing glycogen synthesis in neurons and its demise in progressive myoclonus epilepsy. Nat Neurosci. 2007 Nov;10(11):1407-13. doi: 10.1038/nn1998. Epub 2007 Oct 21.
PubMed 17952067DeRuisseau LR, Fuller DD, Qiu K, DeRuisseau KC, Donnelly WH Jr, Mah C, Reier PJ, Byrne BJ. Neural deficits contribute to respiratory insufficiency in Pompe disease. Proc Natl Acad Sci U S A. 2009 Jun 9;106(23):9419-24. doi: 10.1073/pnas.0902534106. Epub 2009 May 27.
PubMed 19474295Foust KD, Nurre E, Montgomery CL, Hernandez A, Chan CM, Kaspar BK. Intravascular AAV9 preferentially targets neonatal neurons and adult astrocytes. Nat Biotechnol. 2009 Jan;27(1):59-65. doi: 10.1038/nbt.1515. Epub 2008 Dec 21.
PubMed 19098898Weinstein DA, Correia CE, Conlon T, Specht A, Verstegen J, Onclin-Verstegen K, Campbell-Thompson M, Dhaliwal G, Mirian L, Cossette H, Falk DJ, Germain S, Clement N, Porvasnik S, Fiske L, Struck M, Ramirez HE, Jordan J, Andrutis K, Chou JY, Byrne BJ, Mah CS. Adeno-associated virus-mediated correction of a canine model of glycogen storage disease type Ia. Hum Gene Ther. 2010 Jul;21(7):903-10. doi: 10.1089/hum.2009.157.
PubMed 20163245Mah C, Pacak CA, Cresawn KO, Deruisseau LR, Germain S, Lewis MA, Cloutier DA, Fuller DD, Byrne BJ. Physiological correction of Pompe disease by systemic delivery of adeno-associated virus serotype 1 vectors. Mol Ther. 2007 Mar;15(3):501-7. doi: 10.1038/sj.mt.6300100. Epub 2007 Jan 23.
PubMed 17245350Pacak CA, Conlon T, Mah CS, Byrne BJ. Relative persistence of AAV serotype 1 vector genomes in dystrophic muscle. Genet Vaccines Ther. 2008 Oct 15;6:14. doi: 10.1186/1479-0556-6-14.
PubMed 18854054
Study at a glance
From the registry record, last updated by the sponsor on 5 Apr 2022. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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)
- ClinicalTrials.gov ID
- NCT02240407
- Acronym / sponsor ID
- AAV9-GAA_IM / IRB201400137
- Conditions
- Pompe Disease
- Keywords
- Pompe Disease, Gene Therapy, Repeated dosing, Immune modulation
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 2 participants (actual)
- Lead sponsor
- University of FloridaUniversity, hospital or other
- Collaborators
- Lacerta Therapeutics
- Study start
- 17 Oct 2017 (actual)
- Primary completion
- 26 Aug 2021 (actual)
- Study completion
- 26 Aug 2021 (actual)
- First posted
- 15 Sep 2014 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Detailed description
Enrolling in this study will entail participating in 18 months of study-related visits. Patients will be asked to come to the Clinical and Translational Research Building at the University of Florida for a series of onsite study visits.
All the visits will be performed as outpatient procedures at the Clinical Research Center (CRC) and at other facilities at the University of Florida. Overnight observation will not be needed, however, patients will be asked to stay overnight in a hotel near the University of Florida. During the first 4 months after each injection, patients will be asked to perform outpatient laboratory work at a laboratory facility convenient for them.
In addition, during this study patients will be asked to take medications that will modulate the ability of their immune system to react against foreign agents including the gene transfer agent. The purpose of these medications is to improve the activity of the GAA within the body. Patients will receive a Rituximab injection 21 days prior to the first injection of the study agent and 7 days before each injection of the study agent and the day of the first injection. Rituximab will be delivered by infusion that may last 2-6 hours. Patients will need to take another medication (Sirolimus) every day starting 7 days before the first injection of the study agent until four months after the second injection of the study agent.
The following discusses what will occur at each visit:
Baseline Baseline Evaluation and first Rituximab infusion - Day -22/-21/-20
- Medical history: Patients will be asked to complete a questionnaire about his/her medical history.
- Physical exam: The study doctor will perform a general physical exam to evaluate patients physical health.
- Blood and urine tests: These tests will be used for evaluating the safety of the gene transfer agent.
- Electrocardiogram (ECG): This test will measure the electrical activity of patient's heart to see if it is working properly.
- Quantitative Muscle Testing (QMT): This test finds out how strong the patient's leg muscles are.
- 10 Meter Walk Test: Patients will be instructed to walk a set distance (10 meters); time will be measured while patient walks the set distance and the distance covered will be divided by the time it took to walk that distance.
- Gait analysis: Gait will be tested with Gait Mat II, which will record the spatial and temporal parameters of his/her walk such as cadence, speed and distance between your feet.
- Magnetic Resonance Imaging (MRI) and Spectroscopy (MRS): MRI and MRS testing will be done inside a large magnet that lets the study doctors measure the size and health of the patient's muscles. These tests are done at the same time. MRI and MRS testing will require the patient to stay very still for up to an hour.
- Magnetic stimulation of the common fibular nerve: The common fibular nerve, which is the nerve that controls the injected muscle, will be stimulated with a magnetic field to test the impact of the gene transfer agent to the nervous system.
- The patient will receive the first Rituximab infusion. It might last between 2 and 6 hours.
Rituximab infusion - Day -6
- The patient will receive the 2nd Rituximab infusion 7 days before the gene transfer agent. It might last between 2 and 6 hours.
- Patient will begin Rapamycin. 1st Injection - Day 0/1
- The patient will receive the 3rd Rituximab infusion the day before the gene transfer agent. It might last between 2 and 6 hours.
- Patient will receive the gene transfer agent in 1 injection (a total of about 1 teaspoon) into the tibialis anterior (TA) muscle of one leg. The other leg will receive a pharmacologically inactive solution. An ultrasound will be used to detect the proper location of injection. A photograph of the injection at the injection site may be taken. If the patient agrees to this, he/she will be asked to sign a consent form for this procedure.
On day 1, blood tests will be done.
Outpatient lab work - Day 3/7/15/30/60
- Blood and urine tests
Onsite visit - Day 89/90
- Medical history
- Physical Exam
- Blood and urine tests
- Quantitative Muscle Testing (QMT)
- 10 Meter Walk Test
- Gait analysis
- Magnetic Resonance Imaging (MRI) and Spectroscopy (MRS)
- Muscle Biopsy: Tissue samples obtained will be used for evaluation of muscle glycogen and GAA activity in the injected muscle.
- Magnetic stimulation of the common fibular nerve
Rituximab infusion - Day 114
- The patient will receive the 4th Rituximab infusion, it might last between 2-6 hours. 2nd Injection - Day 121/122
- The patient will receive the second gene transfer agent injection in the leg that previously received the inactive solution. The leg that previously received the study agent will receive the inactive solution. The injection procedure and the amount of study agent injected will be the same as the first injection.
On day 122, blood tests will be done.
Outpatient lab work - Day 124/128/135/150/180
- Blood and urine tests
Onsite visit - Day 209/210
- Medical History
- Physical Exam
- Blood and urine tests
- Quantitative Muscle Testing (QMT)
- 10 Meter Walk Test
- Gait analysis
- Magnetic Resonance Imaging (MRI) and Spectroscopy (MRS)
- Muscle Biopsy
- Magnetic stimulation of the common fibular nerve
Onsite visit - Day 365
- Medical history
- Physical exam
- Quantitative Muscle Testing (QMT)
- 10 Meter Walk Test
- Blood and urine tests
Onsite visit - Day 520
- Medical history
- Physical exam
- Quantitative Muscle Testing (QMT)
- 10 Meter Walk Test
- Blood and urine tests
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind (participant, investigator, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| rAAV9-DES-hGAA vector | Experimental | Genetic: Recombinant Adeno-Associated Virus Acid Alpha-Glucosidase, Drug: Rapamycin, Drug: Rituxan, Drug: Diphenhydramine, Drug: Acetaminophen, Drug: Lidocaine, Drug: LMX 4 Topical CreamEach 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. |
| Excipient | Sham comparator | Drug: Rapamycin, Other: saline, Drug: Rituxan, Drug: Diphenhydramine, Drug: Acetaminophen, Drug: Lidocaine, Drug: LMX 4 Topical CreamEach 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. |
Who may qualify
- Ages
- 18 to 50 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult
Key inclusion criteria (6 listed)
- 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
Key exclusion criteria (14 listed)
- 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 seronegative to AAV9 capsid protein (neutralizing Ab titers <1:5 and total binding Ab titer <50 U/ml)
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Recombinant Adeno-Associated Virus Acid Alpha-GlucosidaseAlso: rAAV9-DES-hGAAThe 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). | Genetic | rAAV9-DES-hGAA vector |
| RapamycinAlso: SirolimusPatients 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 four months after second injection. | Drug | Excipient, rAAV9-DES-hGAA vector |
| salineAlso: ExcipientSame volume as rAAV9-DES-hGAA injection will be used. | Other | Excipient |
| RituxanAlso: RituximabPatients 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. | Drug | Excipient, rAAV9-DES-hGAA vector |
| DiphenhydramineAlso: Benadryl25-50mg will be provided before each Rituximab dose. | Drug | Excipient, rAAV9-DES-hGAA vector |
| AcetaminophenAlso: TylenolWe will provide 650 mg of tylenol before each dose of Rituximab. | Drug | Excipient, rAAV9-DES-hGAA vector |
| LidocaineAlso: XylocaineLidocaine will be used based on standard of care: Percutaneous infiltration, concentration 0.5-1%, 1-10 mL, 5-300mg total dose. | Drug | Excipient, rAAV9-DES-hGAA vector |
| LMX 4 Topical CreamAlso: Lidocaine 4%Topical anesthesia cream will be used prior to gene therapy/saline injection. | Drug | Excipient, rAAV9-DES-hGAA vector |
Primary outcome
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.
5 secondary outcomes
Neurophysiological tests will be performed for neuro function of rAAV9-DES-hGAA vector.
Time frame: 520 days
Muscle biopsy will be performed for muscular function of rAAV9-DES-hGAA vector.
Time frame: 520 days
Clinical tests will be performed for function of rAAV9-DES-hGAA vector.
Time frame: 520 days
Magnetic Resonance Imaging will be performed for visualization of muscle with rAAV9-DES-hGAA vector.
Time frame: 520 days
Spectroscopy will be performed for function of rAAV9-DES-hGAA vector.
Time frame: 520 days
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 5 Apr 2022.
- Background: PubMed 25186912Corti M, Smith BK, Falk DJ, Lawson LA, Fuller DD, Subramony SH, Byrne BJ, Christou EA. Altered activation of the tibialis anterior in individuals with Pompe disease: Implications for motor unit dysfunction. Muscle Nerve. 2015 Jun;51(6):877-83. doi: 10.1002/mus.24444. Epub 2015 Apr 24.
- BackgroundMcKusick V. 232300 Glycogen Storage Disease II. OMIM. 1996.
- Background: PubMed 8488406Moufarrej NA, Bertorini TE. Respiratory insufficiency in adult-type acid maltase deficiency. South Med J. 1993 May;86(5):560-7. doi: 10.1097/00007611-199305000-00015.
- Background: PubMed 18816591Wokke JH, Escolar DM, Pestronk A, Jaffe KM, Carter GT, van den Berg LH, Florence JM, Mayhew J, Skrinar A, Corzo D, Laforet P. Clinical features of late-onset Pompe disease: a prospective cohort study. Muscle Nerve. 2008 Oct;38(4):1236-45. doi: 10.1002/mus.21025.
- Background: PubMed 21518733Byrne BJ, Falk DJ, Pacak CA, Nayak S, Herzog RW, Elder ME, Collins SW, Conlon TJ, Clement N, Cleaver BD, Cloutier DA, Porvasnik SL, Islam S, Elmallah MK, Martin A, Smith BK, Fuller DD, Lawson LA, Mah CS. Pompe disease gene therapy. Hum Mol Genet. 2011 Apr 15;20(R1):R61-8. doi: 10.1093/hmg/ddr174. Epub 2011 Apr 25.
- Background: PubMed 21439876Byrne BJ, Kishnani PS, Case LE, Merlini L, Muller-Felber W, Prasad S, van der Ploeg A. Pompe disease: design, methodology, and early findings from the Pompe Registry. Mol Genet Metab. 2011 May;103(1):1-11. doi: 10.1016/j.ymgme.2011.02.004. Epub 2011 Feb 11.
- Background: PubMed 21747768Lee KZ, Qiu K, Sandhu MS, Elmallah MK, Falk DJ, Lane MA, Reier PJ, Byrne BJ, Fuller DD. Hypoglossal neuropathology and respiratory activity in pompe mice. Front Physiol. 2011 Jun 30;2:31. doi: 10.3389/fphys.2011.00031. eCollection 2011.
- Background: PubMed 9023877Benowitz LI, Routtenberg A. GAP-43: an intrinsic determinant of neuronal development and plasticity. Trends Neurosci. 1997 Feb;20(2):84-91. doi: 10.1016/s0166-2236(96)10072-2.
- Background: PubMed 8737678Kanazir S, Ruzdijic S, Vukosavic S, Ivkovic S, Milosevic A, Zecevic N, Rakic L. GAP-43 mRNA expression in early development of human nervous system. Brain Res Mol Brain Res. 1996 May;38(1):145-55. doi: 10.1016/0169-328x(96)00008-3.
- Background: PubMed 17952067Vilchez D, Ros S, Cifuentes D, Pujadas L, Valles J, Garcia-Fojeda B, Criado-Garcia O, Fernandez-Sanchez E, Medrano-Fernandez I, Dominguez J, Garcia-Rocha M, Soriano E, Rodriguez de Cordoba S, Guinovart JJ. Mechanism suppressing glycogen synthesis in neurons and its demise in progressive myoclonus epilepsy. Nat Neurosci. 2007 Nov;10(11):1407-13. doi: 10.1038/nn1998. Epub 2007 Oct 21.
- Background: PubMed 19474295DeRuisseau LR, Fuller DD, Qiu K, DeRuisseau KC, Donnelly WH Jr, Mah C, Reier PJ, Byrne BJ. Neural deficits contribute to respiratory insufficiency in Pompe disease. Proc Natl Acad Sci U S A. 2009 Jun 9;106(23):9419-24. doi: 10.1073/pnas.0902534106. Epub 2009 May 27.
- Background: PubMed 19098898Foust KD, Nurre E, Montgomery CL, Hernandez A, Chan CM, Kaspar BK. Intravascular AAV9 preferentially targets neonatal neurons and adult astrocytes. Nat Biotechnol. 2009 Jan;27(1):59-65. doi: 10.1038/nbt.1515. Epub 2008 Dec 21.
- Individual participant dataSharing planned: Undecided
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Manuela Corti, P.T., PhD. principal investigator
University of Florida
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing Recombinant Adeno-Associated Virus Acid Alpha-Glucosidase, Rapamycin and saline in people with Pompe Disease, run by University of Florida at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 6 inclusion and 14 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 5 Apr 2022. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Safety of rAAV9-DES-hGAA vector in LOPD by blood and urine test. (time frame: 520 days). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02240407, which also lists 29 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 5 Apr 2022.