A Phase 1/2 Study of Intravenous Gene Transfer With an AAV9 Vector Expressing Human Beta-galactosidase in Type I and Type II GM1 Gangliosidosis
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 入组人数
- 54
- 试验地点
- 2
- 主要终点
- Safety
研究概览
简要总结
Background:
GM1 gangliosidosis is a disorder that destroys nerve cells. It is fatal. There is no treatment. People with GM1 are deficient in a certain enzyme. A gene therapy may help the body make this enzyme. This could improve GM1 symptoms.
Objective:
To test if a gene therapy helps Type I and Type II GM1 gangliosidosis symptoms.
Eligibility:
Type I subjects will be male and female >= 6 months <= 12 months of age at the time of full ICF signing.
Type II subjects will be male and female > 12 months old and < 12 years old at the time of full ICF signing.
Design:
Participants will be screened with their medical history and a phone survey.
Participants will stay at NIH for 8-10 weeks.
Participants will have baseline tests:
Blood, urine, and heart tests
Hearing tests
Ultrasound of abdomen
EEG: Sticky patches on the participant s head will measure brain function.
Lumbar puncture: A needle will be stuck into the participant s spine to remove fluid.
MRI scans, bone x-rays, and bone scans: Participants will lie in a machine that takes pictures of the body
IQ tests
Neurology exams
Central line placement
Skin biopsy: A small piece of the participant s skin will be removed.
Speech tests
Participants will have an x-ray while swallowing food.
Participants will take drugs by mouth and IV. This will get their immune system ready for therapy.
Participants will get the gene therapy by IV. They may stay at NIH for a week to watch for side effects.
Participants will have visits 3 and 6 months after treatment. Then visits will be every 6 months for 2 years. Then they will have a visit at 3 years. Visits will take 4-5 days.
Participants will return to NIH once a year for 2 years for tests in an extension study....
详细描述
This is a non-randomized, Phase 1/2 clinical trial to study the safety and efficacy of a single dose gene transfer vector AAV9/GLB1 (AAV9-GLB1) by intravenous infusion to subjects with Type I and Type II GM1 gangliosidosis.
Type I subjects in this study will be male and female, >= 6 months old and <=12 months of age at the time of full ICF signing, with a diagnosis of Type I GM1 gangliosidosis. Type II subjects in this study will be male and female, > 6 months old and < 12 years old at the time of full ICF signing, with a diagnosis of Type II GM1 gangliosidosis. The subjects must have biallelic mutations in GLB1, a deficiency of Beta-galactosidase enzyme documented by testing in a CLIA-certified clinical laboratory, and serum AAV9 antibodies titers <= 1:50). Other inclusion/exclusion criteria apply. In Stage 1, up to 6 Type II subjects will receive 1.5E13 vg/kg of the gene transfer agent, and up to 6 Type II subjects will receive 4.5E13 vg/kg, and up to 6 Type II subjects will recieve 7.5E13 vg/kg of the gene transfer agent. In Stage 1, up to 3 Type I subjects will receive 1.5E13 of the gene transfer agent (Cohort 1) and up to 3 will then receive 4.5E13 of the gene transfer agent (Cohort 2). Dosing will be staggered to ensure subject safety.
Following the last Stage 1 subject s 6 months visit, data will be reviewed, and Stage 2 dosing will be determined. Up to 12 Type II and 6 Type I subjects are planned to be treated in Stage 2 of the study. If Stage 2 dosing is to proceed, it will be reflected in a protocol amendment.
The primary objective of Stage 1 of the study is to assess the safety of the AAV9-GLB1 vector following intravenous infusion. Stage 1 secondary and exploratory objectives include assessment of gene therapy on disease biomarkers, neurologic development and motor function, brain volume and myelination, and immune tolerance to the gene transfer vector.
Stage 2 of the study will assess the safety and efficacy of AAV9-GLB1 vector following intravenous infusion of the dose selected based on data from both Type I and II subjects.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 6 Months 至 12 Years（Child）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •INCLUSION CRITERIA:
- •Type I subjects
- •Male or female subjects >= 6 months old and <= 12 months old at time of full ICF signing
- •Biallelic mutations in GLB1
- •Documented deficiency of Beta-galactosidase enzyme by clinical laboratory testing
- •Phenotype consistent with a diagnosis of Type I GM1 gangliosidosis
- •Symptomatic subjects: as determined by the opinion of the Principal Investigator and based on the criteria set forth by Brunetti-Pierri et al:
- •Age of symptom onset <= 6 months of age
- •Rapidly progressive with developmental delay and hypotonia
- •Pre- symptomatic subjects: must have mutations confirmed to be associated with the Type I subtype
- •AAV9 antibody titers <=1:50
- •Agree to reside within 50 miles of the study site for at least 1 month following treatment
- •Type II subjects
- •Vineland-3 Adaptive Behavior composite standard score greater than or equal to 40
- •Male or female subjects > 6 months old and < 12 years old at time of full ICF signing
- •Biallelic mutations in GLB1
- •Documented deficiency of beta-galactosidase enzyme by clinical laboratory testing
- •Phenotype consistent with a diagnosis of Type II GM1 gangliosidosis, with symptom onset after the first year of life
- •AAV9 antibody titers <=1:50
- •Agree to reside within 50 miles of the study site for at least 1 month following treatment
排除标准
- •AAV9 antibody titers >1:50
- •Contraindications to concomitant medications
- •Serious illness that would not allow travel to the study site
- •Unwilling to undergo study interventions as outlined in the Schedule of Events
- •Subjects receiving other unapproved, off-label or experimental therapies for GM1 gangliosidosis (i.e. miglustat, Tanganil) within the last 60 days
- •Any prior participation in a study in which a gene therapy vector or stem cell transplantation was administered
- •Pregnant or lactating subjects
- •Immunizations of any kind in the month prior to screening
- •Evidence of cardiomyopathy on history, exam, or additional testing (echocardiogram or electrocardiogram) or other cardiac disease that in the opinion of the investigator would deem the subject unsafe to participate in the trial
- •Indwelling ferromagnetic devices that would preclude MRI/fMRI/MRS imaging
- •Ongoing medical condition that is deemed by the Principal Investigator to interfere with the conduct or assessments of the study
- •History of infection with human immunodeficiency virus (HIV), hepatitis A, B, or C, or tuberculosis.
- •History of or current chemotherapy, radiotherapy or other immunosuppressive therapy within the past 30 days. Corticosteroid treatment may be permitted at the discretion of the PI
- •Abnormal laboratory values considered clinically significant per the investigator
- •Failure to thrive, defined as:
- •-- Falling 20 percentiles (20/100) in body weight in the 3 months preceding Screening/Baseline
- •Underlying defect in immune function
- •History of multiple and severe life-threatening infections
研究组 & 干预措施
1
In Stage 1, up to 6 Type II subjects will receive 1.5E13 vg/kg of the gene transfer agent, up to 6 Type II subjects will receive 4.5E13 vg/kg, and up to 6 Type II subjects will receive 7.5E13 vg/kg of the gene transfer agent. In Stage 1, up to 3 Type I subjects will receive 1.5E13 of the gene transfer agent (Cohort 1) and up to 3 will then receive 4.5E13 of the gene transfer agent (Cohort 2).
干预措施: Rituximab (Drug)
1
In Stage 1, up to 6 Type II subjects will receive 1.5E13 vg/kg of the gene transfer agent, up to 6 Type II subjects will receive 4.5E13 vg/kg, and up to 6 Type II subjects will receive 7.5E13 vg/kg of the gene transfer agent. In Stage 1, up to 3 Type I subjects will receive 1.5E13 of the gene transfer agent (Cohort 1) and up to 3 will then receive 4.5E13 of the gene transfer agent (Cohort 2).
干预措施: Neurology exam (Other)
2
Following the last Stage 1 subject s 6 months visit, data will be reviewed, and Stage 2 dosing and assessments will be determined. If Stage 2 dosing is to proceed, it will be reflected in a protocol amendment.
干预措施: AAV9-GLB1 (Biological)
2
Following the last Stage 1 subject s 6 months visit, data will be reviewed, and Stage 2 dosing and assessments will be determined. If Stage 2 dosing is to proceed, it will be reflected in a protocol amendment.
干预措施: Sirolimus (Drug)
2
Following the last Stage 1 subject s 6 months visit, data will be reviewed, and Stage 2 dosing and assessments will be determined. If Stage 2 dosing is to proceed, it will be reflected in a protocol amendment.
干预措施: Electrocardiogram (EKG) (Diagnostic Test)
1
In Stage 1, up to 6 Type II subjects will receive 1.5E13 vg/kg of the gene transfer agent, up to 6 Type II subjects will receive 4.5E13 vg/kg, and up to 6 Type II subjects will receive 7.5E13 vg/kg of the gene transfer agent. In Stage 1, up to 3 Type I subjects will receive 1.5E13 of the gene transfer agent (Cohort 1) and up to 3 will then receive 4.5E13 of the gene transfer agent (Cohort 2).
干预措施: Echocardiogram (Diagnostic Test)
1
In Stage 1, up to 6 Type II subjects will receive 1.5E13 vg/kg of the gene transfer agent, up to 6 Type II subjects will receive 4.5E13 vg/kg, and up to 6 Type II subjects will receive 7.5E13 vg/kg of the gene transfer agent. In Stage 1, up to 3 Type I subjects will receive 1.5E13 of the gene transfer agent (Cohort 1) and up to 3 will then receive 4.5E13 of the gene transfer agent (Cohort 2).
干预措施: PICC or other Central line placement (Behavioral)
1
In Stage 1, up to 6 Type II subjects will receive 1.5E13 vg/kg of the gene transfer agent, up to 6 Type II subjects will receive 4.5E13 vg/kg, and up to 6 Type II subjects will receive 7.5E13 vg/kg of the gene transfer agent. In Stage 1, up to 3 Type I subjects will receive 1.5E13 of the gene transfer agent (Cohort 1) and up to 3 will then receive 4.5E13 of the gene transfer agent (Cohort 2).
干预措施: Ophthalmology exam (Procedure)
2
Following the last Stage 1 subject s 6 months visit, data will be reviewed, and Stage 2 dosing and assessments will be determined. If Stage 2 dosing is to proceed, it will be reflected in a protocol amendment.
干预措施: Prednisone (Drug)
2
Following the last Stage 1 subject s 6 months visit, data will be reviewed, and Stage 2 dosing and assessments will be determined. If Stage 2 dosing is to proceed, it will be reflected in a protocol amendment.
干预措施: Echocardiogram (Diagnostic Test)
2
Following the last Stage 1 subject s 6 months visit, data will be reviewed, and Stage 2 dosing and assessments will be determined. If Stage 2 dosing is to proceed, it will be reflected in a protocol amendment.
干预措施: Neurology exam (Other)
2
Following the last Stage 1 subject s 6 months visit, data will be reviewed, and Stage 2 dosing and assessments will be determined. If Stage 2 dosing is to proceed, it will be reflected in a protocol amendment.
干预措施: Electroencephalogram (EEG) awake and extended overnight (Other)
1
In Stage 1, up to 6 Type II subjects will receive 1.5E13 vg/kg of the gene transfer agent, up to 6 Type II subjects will receive 4.5E13 vg/kg, and up to 6 Type II subjects will receive 7.5E13 vg/kg of the gene transfer agent. In Stage 1, up to 3 Type I subjects will receive 1.5E13 of the gene transfer agent (Cohort 1) and up to 3 will then receive 4.5E13 of the gene transfer agent (Cohort 2).
干预措施: AAV9-GLB1 (Biological)
1
In Stage 1, up to 6 Type II subjects will receive 1.5E13 vg/kg of the gene transfer agent, up to 6 Type II subjects will receive 4.5E13 vg/kg, and up to 6 Type II subjects will receive 7.5E13 vg/kg of the gene transfer agent. In Stage 1, up to 3 Type I subjects will receive 1.5E13 of the gene transfer agent (Cohort 1) and up to 3 will then receive 4.5E13 of the gene transfer agent (Cohort 2).
干预措施: Abdominal ultrasound (Procedure)
1
In Stage 1, up to 6 Type II subjects will receive 1.5E13 vg/kg of the gene transfer agent, up to 6 Type II subjects will receive 4.5E13 vg/kg, and up to 6 Type II subjects will receive 7.5E13 vg/kg of the gene transfer agent. In Stage 1, up to 3 Type I subjects will receive 1.5E13 of the gene transfer agent (Cohort 1) and up to 3 will then receive 4.5E13 of the gene transfer agent (Cohort 2).
干预措施: Sirolimus (Drug)
1
In Stage 1, up to 6 Type II subjects will receive 1.5E13 vg/kg of the gene transfer agent, up to 6 Type II subjects will receive 4.5E13 vg/kg, and up to 6 Type II subjects will receive 7.5E13 vg/kg of the gene transfer agent. In Stage 1, up to 3 Type I subjects will receive 1.5E13 of the gene transfer agent (Cohort 1) and up to 3 will then receive 4.5E13 of the gene transfer agent (Cohort 2).
干预措施: Methylprednisolone (Drug)
1
In Stage 1, up to 6 Type II subjects will receive 1.5E13 vg/kg of the gene transfer agent, up to 6 Type II subjects will receive 4.5E13 vg/kg, and up to 6 Type II subjects will receive 7.5E13 vg/kg of the gene transfer agent. In Stage 1, up to 3 Type I subjects will receive 1.5E13 of the gene transfer agent (Cohort 1) and up to 3 will then receive 4.5E13 of the gene transfer agent (Cohort 2).
干预措施: Prednisone (Drug)
1
In Stage 1, up to 6 Type II subjects will receive 1.5E13 vg/kg of the gene transfer agent, up to 6 Type II subjects will receive 4.5E13 vg/kg, and up to 6 Type II subjects will receive 7.5E13 vg/kg of the gene transfer agent. In Stage 1, up to 3 Type I subjects will receive 1.5E13 of the gene transfer agent (Cohort 1) and up to 3 will then receive 4.5E13 of the gene transfer agent (Cohort 2).
干预措施: Audiology assessment with ABR (Diagnostic Test)
1
In Stage 1, up to 6 Type II subjects will receive 1.5E13 vg/kg of the gene transfer agent, up to 6 Type II subjects will receive 4.5E13 vg/kg, and up to 6 Type II subjects will receive 7.5E13 vg/kg of the gene transfer agent. In Stage 1, up to 3 Type I subjects will receive 1.5E13 of the gene transfer agent (Cohort 1) and up to 3 will then receive 4.5E13 of the gene transfer agent (Cohort 2).
干预措施: Bone density scan (DEXA) (Diagnostic Test)
1
In Stage 1, up to 6 Type II subjects will receive 1.5E13 vg/kg of the gene transfer agent, up to 6 Type II subjects will receive 4.5E13 vg/kg, and up to 6 Type II subjects will receive 7.5E13 vg/kg of the gene transfer agent. In Stage 1, up to 3 Type I subjects will receive 1.5E13 of the gene transfer agent (Cohort 1) and up to 3 will then receive 4.5E13 of the gene transfer agent (Cohort 2).
干预措施: Electrocardiogram (EKG) (Diagnostic Test)
1
In Stage 1, up to 6 Type II subjects will receive 1.5E13 vg/kg of the gene transfer agent, up to 6 Type II subjects will receive 4.5E13 vg/kg, and up to 6 Type II subjects will receive 7.5E13 vg/kg of the gene transfer agent. In Stage 1, up to 3 Type I subjects will receive 1.5E13 of the gene transfer agent (Cohort 1) and up to 3 will then receive 4.5E13 of the gene transfer agent (Cohort 2).
干预措施: Electroencephalogram (EEG) awake and extended overnight (Other)
1
In Stage 1, up to 6 Type II subjects will receive 1.5E13 vg/kg of the gene transfer agent, up to 6 Type II subjects will receive 4.5E13 vg/kg, and up to 6 Type II subjects will receive 7.5E13 vg/kg of the gene transfer agent. In Stage 1, up to 3 Type I subjects will receive 1.5E13 of the gene transfer agent (Cohort 1) and up to 3 will then receive 4.5E13 of the gene transfer agent (Cohort 2).
干预措施: Laboratory tests (Diagnostic Test)
1
In Stage 1, up to 6 Type II subjects will receive 1.5E13 vg/kg of the gene transfer agent, up to 6 Type II subjects will receive 4.5E13 vg/kg, and up to 6 Type II subjects will receive 7.5E13 vg/kg of the gene transfer agent. In Stage 1, up to 3 Type I subjects will receive 1.5E13 of the gene transfer agent (Cohort 1) and up to 3 will then receive 4.5E13 of the gene transfer agent (Cohort 2).
干预措施: Lumbar puncture (Procedure)
1
In Stage 1, up to 6 Type II subjects will receive 1.5E13 vg/kg of the gene transfer agent, up to 6 Type II subjects will receive 4.5E13 vg/kg, and up to 6 Type II subjects will receive 7.5E13 vg/kg of the gene transfer agent. In Stage 1, up to 3 Type I subjects will receive 1.5E13 of the gene transfer agent (Cohort 1) and up to 3 will then receive 4.5E13 of the gene transfer agent (Cohort 2).
干预措施: Brain MRI/MRS/fMRI (Procedure)
1
In Stage 1, up to 6 Type II subjects will receive 1.5E13 vg/kg of the gene transfer agent, up to 6 Type II subjects will receive 4.5E13 vg/kg, and up to 6 Type II subjects will receive 7.5E13 vg/kg of the gene transfer agent. In Stage 1, up to 3 Type I subjects will receive 1.5E13 of the gene transfer agent (Cohort 1) and up to 3 will then receive 4.5E13 of the gene transfer agent (Cohort 2).
干预措施: Neurocognitive testing (Behavioral)
1
In Stage 1, up to 6 Type II subjects will receive 1.5E13 vg/kg of the gene transfer agent, up to 6 Type II subjects will receive 4.5E13 vg/kg, and up to 6 Type II subjects will receive 7.5E13 vg/kg of the gene transfer agent. In Stage 1, up to 3 Type I subjects will receive 1.5E13 of the gene transfer agent (Cohort 1) and up to 3 will then receive 4.5E13 of the gene transfer agent (Cohort 2).
干预措施: Skeletal survey (Procedure)
1
In Stage 1, up to 6 Type II subjects will receive 1.5E13 vg/kg of the gene transfer agent, up to 6 Type II subjects will receive 4.5E13 vg/kg, and up to 6 Type II subjects will receive 7.5E13 vg/kg of the gene transfer agent. In Stage 1, up to 3 Type I subjects will receive 1.5E13 of the gene transfer agent (Cohort 1) and up to 3 will then receive 4.5E13 of the gene transfer agent (Cohort 2).
干预措施: Skin biopsy (Procedure)
1
In Stage 1, up to 6 Type II subjects will receive 1.5E13 vg/kg of the gene transfer agent, up to 6 Type II subjects will receive 4.5E13 vg/kg, and up to 6 Type II subjects will receive 7.5E13 vg/kg of the gene transfer agent. In Stage 1, up to 3 Type I subjects will receive 1.5E13 of the gene transfer agent (Cohort 1) and up to 3 will then receive 4.5E13 of the gene transfer agent (Cohort 2).
干预措施: Speech and modified barium swallow study (Procedure)
2
Following the last Stage 1 subject s 6 months visit, data will be reviewed, and Stage 2 dosing and assessments will be determined. If Stage 2 dosing is to proceed, it will be reflected in a protocol amendment.
干预措施: Abdominal ultrasound (Procedure)
2
Following the last Stage 1 subject s 6 months visit, data will be reviewed, and Stage 2 dosing and assessments will be determined. If Stage 2 dosing is to proceed, it will be reflected in a protocol amendment.
干预措施: Rituximab (Drug)
2
Following the last Stage 1 subject s 6 months visit, data will be reviewed, and Stage 2 dosing and assessments will be determined. If Stage 2 dosing is to proceed, it will be reflected in a protocol amendment.
干预措施: Methylprednisolone (Drug)
2
Following the last Stage 1 subject s 6 months visit, data will be reviewed, and Stage 2 dosing and assessments will be determined. If Stage 2 dosing is to proceed, it will be reflected in a protocol amendment.
干预措施: Audiology assessment with ABR (Diagnostic Test)
2
Following the last Stage 1 subject s 6 months visit, data will be reviewed, and Stage 2 dosing and assessments will be determined. If Stage 2 dosing is to proceed, it will be reflected in a protocol amendment.
干预措施: Bone density scan (DEXA) (Diagnostic Test)
2
Following the last Stage 1 subject s 6 months visit, data will be reviewed, and Stage 2 dosing and assessments will be determined. If Stage 2 dosing is to proceed, it will be reflected in a protocol amendment.
干预措施: Laboratory tests (Diagnostic Test)
2
Following the last Stage 1 subject s 6 months visit, data will be reviewed, and Stage 2 dosing and assessments will be determined. If Stage 2 dosing is to proceed, it will be reflected in a protocol amendment.
干预措施: Lumbar puncture (Procedure)
2
Following the last Stage 1 subject s 6 months visit, data will be reviewed, and Stage 2 dosing and assessments will be determined. If Stage 2 dosing is to proceed, it will be reflected in a protocol amendment.
干预措施: Brain MRI/MRS/fMRI (Procedure)
2
Following the last Stage 1 subject s 6 months visit, data will be reviewed, and Stage 2 dosing and assessments will be determined. If Stage 2 dosing is to proceed, it will be reflected in a protocol amendment.
干预措施: Neurocognitive testing (Behavioral)
2
Following the last Stage 1 subject s 6 months visit, data will be reviewed, and Stage 2 dosing and assessments will be determined. If Stage 2 dosing is to proceed, it will be reflected in a protocol amendment.
干预措施: PICC or other Central line placement (Behavioral)
2
Following the last Stage 1 subject s 6 months visit, data will be reviewed, and Stage 2 dosing and assessments will be determined. If Stage 2 dosing is to proceed, it will be reflected in a protocol amendment.
干预措施: Skeletal survey (Procedure)
2
Following the last Stage 1 subject s 6 months visit, data will be reviewed, and Stage 2 dosing and assessments will be determined. If Stage 2 dosing is to proceed, it will be reflected in a protocol amendment.
干预措施: Skin biopsy (Procedure)
2
Following the last Stage 1 subject s 6 months visit, data will be reviewed, and Stage 2 dosing and assessments will be determined. If Stage 2 dosing is to proceed, it will be reflected in a protocol amendment.
干预措施: Speech and modified barium swallow study (Procedure)
2
Following the last Stage 1 subject s 6 months visit, data will be reviewed, and Stage 2 dosing and assessments will be determined. If Stage 2 dosing is to proceed, it will be reflected in a protocol amendment.
干预措施: Ophthalmology exam (Procedure)
结局指标
主要结局
Safety
时间窗: Several time points over 3 years
Assess the safety of the AAV9/GLB1 vector (AAV9-GLB1) following intravenous delivery.
次要结局
- Neurological function(Several timepoints over 3 years)
- Overall survival(Throughout study)
- CGI scale(Several timepoints over 3 years)
- Motor function(Varies between Type II and Type I subjects.)
- Brain MRI/MRS/fMRI(Varies between Type II and Type I subjects.)
- Developmental changes(Varies between Type II and Type I subjects.)
- Diffusion tensor imaging(Comparing timepoints throughout the study. Varies between Type II and Type I subjects.)