Evaluation of Re-administration of Recombinant Adeno-Associated Virus Acid Alpha-Glucosidase (rAAV9-DES-hGAA) in Patients With Late-Onset Pompe Disease (LOPD)
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 2
- 试验地点
- 1
- 主要终点
- Safety of rAAV9-DES-hGAA vector in LOPD by blood and urine test.
研究概览
简要总结
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.
详细描述
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
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Triple (Participant, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 50 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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.
排除标准
- •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
- •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.
研究组 & 干预措施
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.
干预措施: Recombinant Adeno-Associated Virus Acid Alpha-Glucosidase (Genetic)
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.
干预措施: Rapamycin (Drug)
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.
干预措施: Rituxan (Drug)
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.
干预措施: Diphenhydramine (Drug)
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.
干预措施: Acetaminophen (Drug)
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.
干预措施: Lidocaine (Drug)
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.
干预措施: LMX 4 Topical Cream (Drug)
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.
干预措施: Rapamycin (Drug)
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.
干预措施: saline (Other)
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.
干预措施: Rituxan (Drug)
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.
干预措施: Diphenhydramine (Drug)
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.
干预措施: Acetaminophen (Drug)
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.
干预措施: Lidocaine (Drug)
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.
干预措施: LMX 4 Topical Cream (Drug)
结局指标
主要结局
Safety of rAAV9-DES-hGAA vector in LOPD by blood and urine test.
时间窗: 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.
次要结局
- Muscle biopsy will be performed for muscular function of rAAV9-DES-hGAA vector.(520 days)
- Magnetic Resonance Imaging will be performed for visualization of muscle with rAAV9-DES-hGAA vector.(520 days)
- Neurophysiological tests will be performed for neuro function of rAAV9-DES-hGAA vector.(520 days)
- Clinical tests will be performed for function of rAAV9-DES-hGAA vector.(520 days)
- Spectroscopy will be performed for function of rAAV9-DES-hGAA vector.(520 days)